Enhanced Medial Collateral Ligament Healing using Mesenchymal Stem Cells: Dosage Effects on Cellular Response and Cytokine Profile

PubMed Central

Saether, Erin E.; Chamberlain, Connie S.; Leiferman, Ellen M.; Kondratko-Mittnacht, Jaclyn R.; Li, Wan Ju; Brickson, Stacey L.; Vanderby, Ray

2013-01-01

Mesenchymal stem cells (MSCs) have potential therapeutic applications for musculoskeletal injuries due to their ability to differentiate into several tissue cell types and modulate immune and inflammatory responses. These immune-modulatory properties were examined in vivo during early stage rat medial collateral ligament healing. Two different cell doses (low dose 1×106 or high dose 4×106 MSCs) were administered at the time of injury and compared with normal ligament healing at days 5 and 14 post-injury. At both times, the high dose MSC group demonstrated a significant decrease in M2 macrophages compared to controls. At day 14, fewer M1 macrophages were detected in the low dose group compared to the high dose group. These results, along with significant changes in procollagen I, proliferating cells, and endothelialization suggest that MSCs can alter the cellular response during healing in a dose-dependent manner. The higher dose ligaments also had increased expression of several pro-inflammatory cytokines at day 5 (IL-1β, IFNγ, IL-2) and increased expression of IL-12 at day 14. Mechanical testing at day 14 revealed increased failure strength and stiffness in low dose ligaments compared to controls. Based on these improved mechanical properties, MSCs enhanced functional healing when applied at a lower dose. Different doses of MSCs uniquely affected the cellular response and cytokine expression in healing ligaments. Interestingly, the lower dose of cells proved to be most effective in improving functional properties. PMID:24174129

Impact of Uncertainties in Exposure Assessment on Thyroid Cancer Risk among Persons in Belarus Exposed as Children or Adolescents Due to the Chernobyl Accident.

PubMed

Little, Mark P; Kwon, Deukwoo; Zablotska, Lydia B; Brenner, Alina V; Cahoon, Elizabeth K; Rozhko, Alexander V; Polyanskaya, Olga N; Minenko, Victor F; Golovanov, Ivan; Bouville, André; Drozdovitch, Vladimir

2015-01-01

The excess incidence of thyroid cancer in Ukraine and Belarus observed a few years after the Chernobyl accident is considered to be largely the result of 131I released from the reactor. Although the Belarus thyroid cancer prevalence data has been previously analyzed, no account was taken of dose measurement error. We examined dose-response patterns in a thyroid screening prevalence cohort of 11,732 persons aged under 18 at the time of the accident, diagnosed during 1996-2004, who had direct thyroid 131I activity measurement, and were resident in the most radio-actively contaminated regions of Belarus. Three methods of dose-error correction (regression calibration, Monte Carlo maximum likelihood, Bayesian Markov Chain Monte Carlo) were applied. There was a statistically significant (p<0.001) increasing dose-response for prevalent thyroid cancer, irrespective of regression-adjustment method used. Without adjustment for dose errors the excess odds ratio was 1.51 Gy- (95% CI 0.53, 3.86), which was reduced by 13% when regression-calibration adjustment was used, 1.31 Gy- (95% CI 0.47, 3.31). A Monte Carlo maximum likelihood method yielded an excess odds ratio of 1.48 Gy- (95% CI 0.53, 3.87), about 2% lower than the unadjusted analysis. The Bayesian method yielded a maximum posterior excess odds ratio of 1.16 Gy- (95% BCI 0.20, 4.32), 23% lower than the unadjusted analysis. There were borderline significant (p = 0.053-0.078) indications of downward curvature in the dose response, depending on the adjustment methods used. There were also borderline significant (p = 0.102) modifying effects of gender on the radiation dose trend, but no significant modifying effects of age at time of accident, or age at screening as modifiers of dose response (p>0.2). In summary, the relatively small contribution of unshared classical dose error in the current study results in comparatively modest effects on the regression parameters.

Ranitidine Can Potentiate The Prokinetic Effect Of Itopride At Low Doses- An In Vitro Study.

PubMed

Butt, Aroosa Ishtiaq; Khan, Bushra Tayyaba; Khan, Asma; Khan, Qamar-Uz-Zaman

2017-01-01

Gastroparesis and GERD occur concomitantly in 40 percent of the cases. Prokinetic drugs and acid blockers are employed as the main treatment modality. Ranitidine is an acid blocker with additional prokinetic activity and Itopride is a known prokinetic drug. This study was designed to observe the synergistic potentiating prokinetic effect of Ranitidine on itopride on isolated duodenum of rabbits. Ranitidine (10-5-10-3) and itopride (10-6-10-5) were added in increasing concentrations to isolated duodenum of rabbits and contractions were recorded on PowerLab Data acquisition unit AHK/214. Cumulative dose response curves were constructed. The potentiating prokinetic effect of Ranitidine on itopride was seen by using a fixed dose of ranitidine and cumulatively enhancing doses of itopride on iWorx. Ranitidine and itopride produced a dose dependent reversible contraction of the isolated tissue of rabbits with ranitidine showing a max response of 0.124mV and itopride showing a maximum response of 0.131mV. Ranitidine was able to potentiate the prokinetic effect of itopride at low doses but at high dose the effect began to wane off. Ranitidine and itopride produce a statistically significant synergistic potentiating prokinetic effect at low doses in vitro.

Probiotic Lactobacillus rhamnosus GG Enhanced Th1 Cellular Immunity but Did Not Affect Antibody Responses in a Human Gut Microbiota Transplanted Neonatal Gnotobiotic Pig Model

PubMed Central

Wen, Ke; Tin, Christine; Wang, Haifeng; Yang, Xingdong; Li, Guohua; Giri-Rachman, Ernawati; Kocher, Jacob; Bui, Tammy; Clark-Deener, Sherrie; Yuan, Lijuan

2014-01-01

This study aims to establish a human gut microbiota (HGM) transplanted gnotobiotic (Gn) pig model of human rotavirus (HRV) infection and diarrhea, and to verify the dose-effects of probiotics on HRV vaccine-induced immune responses. Our previous studies using the Gn pig model found that probiotics dose-dependently regulated both T cell and B cell immune responses induced by rotavirus vaccines. We generated the HGM transplanted neonatal Gn pigs through daily feeding of neonatal human fecal suspension to germ-free pigs for 3 days starting at 12 hours after birth. We found that attenuated HRV (AttHRV) vaccination conferred similar overall protection against rotavirus diarrhea and virus shedding in Gn pigs and HGM transplanted Gn pigs. HGM promoted the development of the neonatal immune system, as evidenced by the significantly enhanced IFN-γ producing T cell responses and reduction of regulatory T cells and their cytokine production in the AttHRV-vaccinated pigs. The higher dose Lactobacillus rhamnosus GG (LGG) feeding (14 doses, up to 109 colony-forming-unit [CFU]/dose) effectively increased the LGG counts in the HGM Gn pig intestinal contents and significantly enhanced HRV-specific IFN-γ producing T cell responses to the AttHRV vaccine. Lower dose LGG (9 doses, up to 106 CFU/dose) was ineffective. Neither doses of LGG significantly improved the protection rate, HRV-specific IgA and IgG antibody titers in serum, or IgA antibody titers in intestinal contents compared to the AttHRV vaccine alone, suggesting that an even higher dose of LGG is needed to overcome the influence of the microbiota to achieve the immunostimulatory effect in the HGM pigs. This study demonstrated that HGM Gn pig is an applicable animal model for studying immune responses to rotavirus vaccines and can be used for studying interventions (i.e., probiotics and prebiotics) that may enhance the immunogenicity and protective efficacy of vaccines through improving the gut microbiota. PMID:24722168

Dose-Response for Multiple Biomarkers of Exposure and Genotoxic Effect Following Repeated Treatment of Rats with the Alkylating Agents, MMS and MNU.

PubMed

Ji, Zhiying; LeBaron, Matthew J; Schisler, Melissa R; Zhang, Fagen; Bartels, Michael J; Gollapudi, B Bhaskar; Pottenger, Lynn H

2016-05-01

The nature of the dose-response relationship for various in vivo endpoints of exposure and effect were investigated using the alkylating agents, methyl methanesulfonate (MMS) and methylnitrosourea (MNU). Six male F344 rats/group were dosed orally with 0, 0.5, 1, 5, 25 or 50mg/kg bw/day (mkd) of MMS, or 0, 0.01, 0.1, 1, 5, 10, 25 or 50 mkd of MNU, for 4 consecutive days and sacrificed 24h after the last dose. The dose-responses for multiple biomarkers of exposure and genotoxic effect were investigated. In MMS-treated rats, the hemoglobin adduct level, a systemic exposure biomarker, increased linearly with dose (r (2) = 0.9990, P < 0.05), indicating the systemic availability of MMS; however, the N7MeG DNA adduct, a target exposure biomarker, exhibited a non-linear dose-response in blood and liver tissues. Blood reticulocyte micronuclei (MN), a genotoxic effect biomarker, exhibited a clear no-observed-genotoxic-effect-level (NOGEL) of 5 mkd as a point of departure (PoD) for MMS. Two separate dose-response models, the Lutz and Lutz model and the stepwise approach using PROC REG both supported a bilinear/threshold dose-response for MN induction. Liver gene expression, a mechanistic endpoint, also exhibited a bilinear dose-response. Similarly, in MNU-treated rats, hepatic DNA adducts, gene expression changes and MN all exhibited clear PoDs, with a NOGEL of 1 mkd for MN induction, although dose-response modeling of the MNU-induced MN data showed a better statistical fit for a linear dose-response. In summary, these results provide in vivo data that support the existence of clear non-linear dose-responses for a number of biologically significant events along the pathway for genotoxicity induced by DNA-reactive agents. © The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Investigation of J-shaped dose-responses induced by exposure to the alkylating agent N-methyl-N-nitrosourea.

PubMed

Chapman, Katherine E; Hoffmann, George R; Doak, Shareen H; Jenkins, Gareth J S

2017-07-01

Hormesis is defined as a biphasic dose-response where biological effects of low doses of a stressor demonstrate the opposite effect to high-dose effects of the same stressor. Hormetic, or J-shaped, dose-response relationships are relatively rarely observed in toxicology, resulting in a limited understanding and even some skepticism of the concept. Low dose-response studies for genotoxicity endpoints have been performed at Swansea University for over a decade. However, no statistically significant decreases below control genotoxicity levels have been detected until recently. A hormetic-style dose-response following a 24h exposure to the alkylating agent N-methyl-N-nitrosourea (MNU) was observed in a previous study for HPRT mutagenesis in the human lymphoblastoid cell line AHH-1. A second recent study demonstrated a J-shaped dose-response for the induction of micronuclei by MNU in a 24h treatment in a similar test system. Following mechanistic investigations, it was hypothesized that p53 may be responsible for the observed hormetic phenomenon. As genotoxic carcinogens are a major causative factor of many cancers, consideration of hormesis in carcinogenesis could be important in safety assessment. The data examined here offer possible insights into hormesis, including its estimated prevalence, underlying mechanisms and lack of generalizability. Copyright © 2017 Elsevier B.V. All rights reserved.

SU-E-J-274: Responses of Medulloblastoma Cells to Radiation Dosimetric Parameters in Intensity-Modulated Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Park, J; Molecular Imaging Program at Stanford, Stanford, CA; Bio-X Program, Stanford, CA

2015-06-15

Purpose: To evaluate radiation responses of the medulloblastoma cell line Daoy in intensity-modulated radiation therapy (IMRT), quantitative variations to variable radiation dosimetic parameters were tracked by bioluminescent images (BLIs). Methods: The luciferase and green fluorescent protein positive Daoy cells were cultured on dishes. The medulloblastoma cells irradiated to different dose rate, interval of fractionated doses, field margin and misalignment, and dose uniformity in IMRT were monitored using bioluminescent images. The cultured cells were placed into a dedicated acrylic phantom to deliver intensity-modulated fluences and calculate accurate predicted dose distribution. The radiation with dose rate from 0.5 Gy/min to 15 Gy/minmore » was irradiated by adjusting monitor unit per minute and source-to-surface distances. The intervals of fractionated dose delivery were changed considering the repair time of double strand breaks (DSB) revealed by straining of gamma-H2AX.The effect of non-uniform doses on the cells were visualized by registering dose distributions and BLIs. The viability according to dosimetric parameters was correlated with bioluminescent intensities for cross-check of radiation responses. Results: The DSB and cell responses due to the first fractionated dose delivery significantly affected final tumor control rather than other parameters. The missing tumor volumes due to the smaller field margin than the tumor periphery or field misalignment caused relapse of cell responses on BLIs. The dose rate and gradient had effect on initial responses but could not bring out the distinguishable killing effect on cancer cells. Conclusion: Visualized and quantified bioluminescent images were useful to correlate the dose distributions with spatial radiation effects on cells. This would derive the effective combination of dose delivery parameters and fractionation. Radiation responses in particular IMRT configuration could be reflected to image based-dose re-optimization.« less

Enhancement of phototropic response to a range of light doses in Triticum aestivum coleoptiles in clinostat-simulated microgravity

NASA Technical Reports Server (NTRS)

Heathcote, D. G.; Bircher, B. W.; Brown, A. H. (Principal Investigator)

1987-01-01

The phototropic dose-response relationship has been determined for Triticum aestivum cv. Broom coleoptiles growing on a purpose-built clinostat apparatus providing gravity compensation by rotation about a horizontal axis at 2 rev min-1. These data are compared with data sets obtained with the clinostat axis vertical and stationary, as a 1 g control, and rotating vertically to examine clinostat effects other than gravity compensation. Triticum at 1 g follows the well-established pattern of other cereal coleoptiles with a first positive curvature at low doses, followed by an indifferent response region, and a second positive response at progressively increasing doses. However, these response regions lie at higher dose levels than reported for Avena. There is no significant difference between the responses observed with the clinostat axis vertical in the rotating and stationary modes, but gravity compensation by horizontal rotation increases the magnitude of first and second positive curvatures some threefold at 100 min after stimulation. The indifferent response is replaced by a significant curvature towards the light source, but remains apparent as a reduced curvature response at these dose levels.

No adaptive response is induced by chronic low-dose radiation from Ra-226 in the CHSE/F fish embryonic cell line and the HaCaT human epithelial cell line

DOE Office of Scientific and Technical Information (OSTI.GOV)

Shi, Xiaopei, E-mail: shix22@mcmaster.ca; Mothersi

Purpose: To determine whether chronic low-dose α-particle radiation from Ra-226 over multiple cell generations can lead to an adaptive response in CHSE/F fish embryonic cells or HaCaT human epithelial cells receiving subsequent acute high-dose γ-ray radiation. Methods: CHSE/F and HaCaT cells were exposed to very low doses of Ra-226 in medium for multiple generations prior to being challenged by a higher dose γ-ray radiation. The clonogenic assay was used to test the clonogenic survival of cells with or without being pretreated by radiation from Ra-226. Results: In general, pretreatment with chronic radiation has no significant influence on the reaction ofmore » cells to the subsequent challenge radiation. Compared to unprimed cells, the change in clonogenic survival of primed cells after receiving challenge radiation is mainly due to the influence of the chronic exposure, and there's little adaptive response induced. However at several dose points, pretreatment of CHSE/F fish cells with chronic radiation resulted in a radiosensitive response to a challenge dose of γ-ray radiation, and pretreatment of HaCaT cells resulted in no effect except for a slightly radioresistant response to the challenge radiation which was not significant. Conclusion: The results suggest that chronic low-dose radiation is not effective enough to induce adaptive response. There was a difference between human and fish cells and it may be important to consider results from multiple species before making conclusions about effects of chronic or low doses of radiation in the environment. The term “radiosensitive” or “adaptive” make no judgment about whether such responses are ultimately beneficial or harmful. - Highlights: • No obvious adaptive response is induced by chronic low-dose radiation from Ra-226. • Priming radiation from Ra-226 sensitized CHSE/F cells to the challenge radiation. • Linear model is inconsistent with current work using chronic low-dose radiation.« less

A targeted and adjuvanted nanocarrier lowers the effective dose of liposomal amphotericin B and enhances adaptive immunity in murine cutaneous leishmaniasis.

PubMed

Daftarian, Pirouz M; Stone, Geoffrey W; Kovalski, Leticia; Kumar, Manoj; Vosoughi, Aram; Urbieta, Maitee; Blackwelder, Pat; Dikici, Emre; Serafini, Paolo; Duffort, Stephanie; Boodoo, Richard; Rodríguez-Cortés, Alhelí; Lemmon, Vance; Deo, Sapna; Alberola, Jordi; Perez, Victor L; Daunert, Sylvia; Ager, Arba L

2013-12-01

Amphotericin B (AmB), the most effective drug against leishmaniasis, has serious toxicity. As Leishmania species are obligate intracellular parasites of antigen presenting cells (APC), an immunopotentiating APC-specific AmB nanocarrier would be ideally suited to reduce the drug dosage and regimen requirements in leishmaniasis treatment. Here, we report a nanocarrier that results in effective treatment shortening of cutaneous leishmaniasis in a mouse model, while also enhancing L. major specific T-cell immune responses in the infected host. We used a Pan-DR-binding epitope (PADRE)-derivatized-dendrimer (PDD), complexed with liposomal amphotericin B (LAmB) in an L. major mouse model and analyzed the therapeutic efficacy of low-dose PDD/LAmB vs full dose LAmB. PDD was shown to escort LAmB to APCs in vivo, enhanced the drug efficacy by 83% and drug APC targeting by 10-fold and significantly reduced parasite burden and toxicity. Fortuitously, the PDD immunopotentiating effect significantly enhanced parasite-specific T-cell responses in immunocompetent infected mice. PDD reduced the effective dose and toxicity of LAmB and resulted in elicitation of strong parasite specific T-cell responses. A reduced effective therapeutic dose was achieved by selective LAmB delivery to APC, bypassing bystander cells, reducing toxicity and inducing antiparasite immunity.

Analysis of Dose Response for Circulatory Disease After Radiotherapy for Benign Disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Little, Mark P., E-mail: mark.little@nih.gov; Kleinerman, Ruth A.; Stovall, Marilyn

Purpose: To assess the shape of the dose-response for various circulatory disease endpoints, and modifiers by age and time since exposure. Methods and Materials: This was an analysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by circulatory disease endpoint (ischemic heart, cerebrovascular, other circulatory disease). Results: There were significant excess risks for all circulatory disease, with an excess relative risk Gy{sup -1} of 0.082 (95% CI 0.031-0.140), and ischemic heart disease, with an excess relative risk Gy{sup -1} of 0.102 (95% CI 0.039-0.174) (both p = 0.01), and indications of excess risk for stroke. Theremore » were no statistically significant (p > 0.2) differences between risks by endpoint, and few indications of curvature in the dose-response. There were significant (p < 0.001) modifications of relative risk by time since exposure, the magnitude of which did not vary between endpoints (p > 0.2). Risk modifications were similar if analysis was restricted to patients receiving radiation, although the relative risks were slightly larger and the risk of stroke failed to be significant. The slopes of the dose-response were generally consistent with those observed in the Japanese atomic bomb survivors and in occupationally and medically exposed groups. Conclusions: There were excess risks for a variety of circulatory diseases in this dataset, with significant modification of risk by time since exposure. The consistency of the dose-response slopes with those observed in radiotherapeutically treated groups at much higher dose, as well as in lower dose-exposed cohorts such as the Japanese atomic bomb survivors and nuclear workers, implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.« less

Dose-dependent inhibition of gastric injury by hydrogen in alkaline electrolyzed drinking water.

PubMed

Xue, Jinling; Shang, Guodong; Tanaka, Yoshinori; Saihara, Yasuhiro; Hou, Lingyan; Velasquez, Natalia; Liu, Wenjun; Lu, Yun

2014-03-03

Hydrogen has been reported to relieve damage in many disease models, and is a potential additive in drinking water to provide protective effects for patients as several clinical studies revealed. However, the absence of a dose-response relationship in the application of hydrogen is puzzling. We attempted to identify the dose-response relationship of hydrogen in alkaline electrolyzed drinking water through the aspirin induced gastric injury model. In this study, hydrogen-rich alkaline water was obtained by adding H2 to electrolyzed water at one atmosphere pressure. After 2 weeks of drinking, we detected the gastric mucosal damage together with MPO, MDA and 8-OHdG in rat aspirin induced gastric injury model. Hydrogen-dose dependent inhibition was observed in stomach mucosal. Under pH 8.5, 0.07, 0.22 and 0.84 ppm hydrogen exhibited a high correlation with inhibitory effects showed by erosion area, MPO activity and MDA content in the stomach. Gastric histology also demonstrated the inhibition of damage by hydrogen-rich alkaline water. However, 8-OHdG level in serum did not have significant hydrogen-dose dependent effect. pH 9.5 showed higher but not significant inhibitory response compared with pH 8.5. Hydrogen is effective in relieving the gastric injury induced by aspirin-HCl, and the inhibitory effect is dose-dependent. The reason behind this may be that hydrogen-rich water directly interacted with the target tissue, while the hydrogen concentration in blood was buffered by liver glycogen, evoking a suppressed dose-response effect. Drinking hydrogen-rich water may protect healthy individuals from gastric damage caused by oxidative stress.

Tissue responses to low protracted doses of high let radiations or photons: Early and late damage relevant to radio-protective countermeasures

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ainsworth, E.J.; Afzal, S.M.J.; Crouse, D.A.

1988-01-01

Early and late murine tissue responses to single or fractionated low doses of heavy charged particles, fission-spectrum neutrons or gamma rays are considered. Damage to the hematopoietic system is emphasized, but results on acute lethality, host response to challenge with transplanted leukemia cells and life-shortening are presented. Low dose rates per fraction were used in some neutron experiments. Split-dose lethality studies (LD 50/30) with fission neutrons indicated greater accumulation of injury during a 9 fraction course (over 17 days) than was the case for ..gamma..-radiation. When total doses of 96 or 247 cGy of neutrons or ..gamma.. rays were givenmore » as a single dose or in 9 fractions, a significant sparing effect on femur CFU-S depression was observed for both radiation qualities during the first 11 days, but there was not an earlier return to normal with dose fractionation. During the 9 fraction sequence, a significant sparing effect of low dose rate on CFU-S depression was observed in both neutron and ..gamma..-irradiated mice. CFU-S content at the end of the fractionation sequence did not correlate with measured LD 50/30. Sustained depression of femur and spleen CFU-S and a significant thrombocytopenia were observed when a total neutron dose of 240 cGy was given in 72 fractions over 24 weeks at low dose rates. The temporal aspects of CFU-S repopulation were different after a single versus fractionated neutron doses. The sustained reduction in the size of the CFU-S population was accompanied by an increase in the fraction in DNA synthesis. The proliferation characteristics and effects of age were different for radial CFU-S population closely associated with bone, compared with the axial population that can be readily aspirated from the femur. In aged irradiated animals, the CFU-S proliferation/redistribution response to typhoid vaccine showed both an age and radiation effect. 63 refs., 6 figs., 7 tabs.« less

Low-dose mitomycin C, etoposide, and cisplatin for invasive vulvar Paget's disease.

PubMed

Watanabe, Yoh; Hoshiai, H; Ueda, H; Nakai, H; Obata, K; Noda, K

2002-01-01

We report the effect of low-dose mitomycin C, etoposide, and cisplatin (low-dose MEP) therapy for three patients with invasive vulvar Paget's disease (invasive VPD) who declined radical vulvectomy and skin grafting. One patient achieved a complete response, while the other two showed partial responses (PR) without grade 3 or 4 adverse effects. The two patients with PR were undergone partial vulvectomy and inguinal lymph node dissection. All patients have no sign of recurrence for 10 months after chemotherapy. Our present results suggest that low-dose MEP is an effective and safe chemotherapy for invasive VPD and low-dose MEP may significantly improve postoperative quality of life in patients with invasive VPD by avoiding extensive vulvar resection and skin grafting.

Enkephalinase inhibitor potentiates substance P- and electrically induced contraction in ferret trachea.

PubMed

Sekizawa, K; Tamaoki, J; Nadel, J A; Borson, D B

1987-10-01

To determine the role of endogenous enkephalinase (EC 3.4.24.11) in regulating peptide-induced contraction of airway smooth muscle, we studied the effect of the enkephalinase inhibitor, leucine-thiorphan (Leu-thiorphan), on responses of isolated ferret tracheal smooth muscle segments to substance P (SP) and to electrical field stimulation (EFS). Leu-thiorphan shifted the dose-response curve to SP to lower concentrations. Atropine or the SP antagonist [D-Pro2,D-Trp7,9]SP significantly inhibited SP-induced contractions in the presence of Leu-thiorphan. Leu-thiorphan increased the contractile responses to EFS dose dependently, an effect that was significantly inhibited by the SP antagonist [D-Pro2,D-Trp7,9]SP. SP, in a concentration that did not cause contraction, increased the contractile responses to EFS. This effect was augmented by Leu-thiorphan dose dependently and was not inhibited by hexamethonium or by phentolamine but was inhibited by atropine. Because contractile responses to acetylcholine were not significantly affected by SP or by Leu-thiorphan, the potentiating effects of SP were probably on presynaptic-postganglionic cholinergic neurotransmission. Captopril, bestatin, or leupeptin did not augment contractions, suggesting that enkephalinase was responsible for the effects. These results suggest that endogenous tachykinins modulate smooth muscle contraction and endogenous enkephalinase modulates contractions produced by endogenous or exogenous tachykinins and tachykinin-induced facilitation of cholinergic neurotransmission.

Differential effects of low and high dose folic acid on endothelial dysfunction in a murine model of mild hyperhomocysteinaemia.

PubMed

Clarke, Zoe L; Moat, Stuart J; Miller, Alastair L; Randall, Michael D; Lewis, Malcolm J; Lang, Derek

2006-12-03

The exact mechanism(s) by which hyperhomocysteinaemia promotes vascular disease remains unclear. Moreover, recent evidence suggests that the beneficial effect of folic acid on endothelial function is independent of homocysteine-lowering. In the present study the effect of a low (400 microg/70 kg/day) and high (5 mg/70 kg/day) dose folic acid supplement on endothelium-dependent relaxation in the isolated perfused mesenteric bed of heterozygous cystathionine beta-synthase deficient mice was investigated. Elevated total plasma homocysteine and impaired relaxation responses to methacholine were observed in heterozygous mice. In the presence of N(G)-nitro-L-arginine methyl ester relaxation responses in wild-type tissues were reduced, but in heterozygous tissues were abolished. Clotrimazole and 18alpha-glycyrrhetinic acid, both inhibitors of non-nitric oxide/non-prostanoid-induced endothelium-dependent relaxation, reduced responses to methacholine in wild-type but not heterozygous tissues. The combination of N(G)-nitro-L-arginine methyl ester and either clotrimazole or 18alpha-glycyrrhetinic acid completely inhibited relaxation responses in wild-type tissues. Both low and high dose folic acid increased plasma folate, reduced total plasma homocysteine and reversed endothelial dysfunction in heterozygous mice. A greater increase in plasma folate in the high dose group was accompanied by a more significant effect on endothelial function. In the presence of N(G)-nitro-L-arginine methyl ester, a significant residual relaxation response was evident in tissues from low and high dose folic acid treated heterozygous mice. These data suggest that the impaired mesenteric relaxation in heterozygous mice is largely due to loss of the non-nitric oxide/non-prostanoid component. While low dose folic acid may restore this response in a homocysteine-dependent manner, the higher dose has an additional effect on nitric oxide-mediated relaxation that would appear to be independent of homocysteine lowering.

Inhibition of Interferon-beta Responses in Multiple Sclerosis Immune Cells Associated With High-Dose Statins

PubMed Central

Feng, Xuan; Han, Diana; Kilaru, Bharat K.; Franek, Beverly S.; Niewold, Timothy B.; Reder, Anthony T.

2014-01-01

Objective To determine whether statins affect type 1 interferon responses in relapsing-remitting multiple sclerosis (RRMS). Design Study effects of atorvastatin on type 1 interferon responses in Jurkat cells, mononuclear cells (MNCs) from therapy-naive patients with RRMS in vitro, and MNCs from interferon-treated RRMS patients in vivo in 4 conditions: no drug, statin only, interferon-beta only, and statin added on to interferon-beta therapy. Patients The study examined clinically stable patients with RRMS: 21 therapy-naive patients and 14 patients receiving interferon-beta with a statin. Interventions Statin effects on in vitro and in vivo interferon-beta–induced STAT1 transcription factor activation, expression of interferon-stimulated proteins in MNCs, and serum type 1 interferon activity. Results In vitro, atorvastatin dose dependently inhibited expression of interferon-stimulated P-Y-STAT1 by 44% (P< .001), interferon regulatory factor 1 protein by 30% (P= .006), and myxovirus resistance 1 protein by 32% (P=.004) compared with no-statin control in MNCs from therapy-naive RRMS patients. In vivo, 9 of 10 patients who received high-dose statins (80 mg) had a significant reduction in interferon-beta therapy–induced serum interferon-α/β activity, whereas only 2 of 4 patients who received medium-dose statins (40 mg) had reductions. High-dose add-on statin therapy significantly blocked interferon-beta function, with less P-Y-STAT1 transcription factor activation, and reduced myxovirus resistance 1 protein and viperin protein production. Medium doses of statins did not change STAT1 activation. Conclusions High-dose add-on statin therapy significantly reduces interferon-beta function and type 1 interferon responses in RRMS patients. These data provide a putative mechanism for how statins could counteract the beneficial effects of interferon-beta and worsen disease. PMID:22801747

High dose Intravenous Anti-D Immune Globulin is More Effective and Safe in Indian Paediatric Patients of Immune Thrombocytopenic Purpura

PubMed Central

Jena, Rabindra Kumar; Swain, Kali Prasanna

2016-01-01

Introduction Immune Thrombocytopenia (ITP) is characterised by an autoimmune antibody-mediated destruction of platelets and impaired platelet production. Few controlled trials exist to guide management of patients with ITP in Indian scenario for which patients require an individualized approach. Anti-D (Rho (D) immune globulin) at a higher dose can prove to be a cost effective and safe alternative for Indian patients with ITP. Aim To compare the safety and efficacy of higher dose (75μg/kg) intravenous Anti-D immune globulin against the standard dose of 50μg/kg for the management of ITP in Indian patients. Materials and Methods One hundred and sixty four children with newly diagnosed ITP between 4-14 years were randomly selected for inclusion and were treated with 50μg/kg (standard dose) or 75μg /kg (higher dose) of Anti-D to compare the efficacy and safety of higher dose intravenous anti-D immune globulin. Efficacy of Anti-D was measured in terms of rate of response and median time to response for increase in platelet counts. Any adverse event was noted. A decrease in haemoglobin concentration suggested accompanying haemolysis. Results Seventy one out of 84 patients treated with Anti-D at 75μg/kg produced complete response (85%) with median time of response being 2.5 days. On the contrary, 45 patients (70%) patients treated with 50μg/kg had complete response. However, there was no significant increase in haemolysis with higher dose. A significant correlation was found between dose and peak increase in platelet count measured at 7th day following administration. However, there was no relationship between the decrease in haemoglobin and the dose given, or between the increase in platelet count and fall in haemoglobin. Conclusion A 75μg/kg dose of Anti-D is more effective with acceptable side effect in comparison to 50μg dose for treatment of newly diagnosed Indian patients of ITP. PMID:28208873

No-threshold dose-response curves for nongenotoxic chemicals: Findings and applications for risk assessment

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sheehan, Daniel M.

2006-01-15

We tested the hypothesis that no threshold exists when estradiol acts through the same mechanism as an active endogenous estrogen. A Michaelis-Menten (MM) equation accounting for response saturation, background effects, and endogenous estrogen level fit a turtle sex-reversal data set with no threshold and estimated the endogenous dose. Additionally, 31 diverse literature dose-response data sets were analyzed by adding a term for nonhormonal background; good fits were obtained but endogenous dose estimations were not significant due to low resolving power. No thresholds were observed. Data sets were plotted using a normalized MM equation; all 178 data points were accommodated onmore » a single graph. Response rates from {approx}1% to >95% were well fit. The findings contradict the threshold assumption and low-dose safety. Calculating risk and assuming additivity of effects from multiple chemicals acting through the same mechanism rather than assuming a safe dose for nonthresholded curves is appropriate.« less

The Effects of Low Dose Irradiation on Inflammatory Response Proteins in a 3D Reconstituted Human Skin Tissue Model

DOE Office of Scientific and Technical Information (OSTI.GOV)

Varnum, Susan M.; Springer, David L.; Chaffee, Mary E.

Skin responses to moderate and high doses of ionizing radiation include the induction of DNA repair, apoptosis, and stress response pathways. Additionally, numerous studies indicate that radiation exposure leads to inflammatory responses in skin cells and tissue. However, the inflammatory response of skin tissue to low dose radiation (<10 cGy) is poorly understood. In order to address this, we have utilized a reconstituted human skin tissue model (MatTek EpiDerm FT) and assessed changes in 23 cytokines twenty-four and forty eight hours following treatment of skin with either 3 or 10 cGy low-dose of radiation. Three cytokines, IFN-γ, IL-2, MIP-1α, weremore » significantly altered in response to low dose radiation. In contrast, seven cytokines were significantly altered in response to a high radiation dose of 200 cGy (IL-2, IL-10, IL-13, IFN-γ, MIP-1α, TNF α, and VEGF) or the tumor promoter 12-O-tetradecanoylphorbol 13-acetate (G-CSF, GM-CSF, IL-1α, IL-8, MIP-1α, MIP-1β, RANTES). Additionally, radiation induced inflammation appears to have a distinct cytokine response relative to the non-radiation induced stressor, TPA. Overall, these results indicate that there are subtle changes in the inflammatory protein levels following exposure to low dose radiation and this response is a sub-set of what is seen following a high dose in a human skin tissue model.« less

Optimization of radiation treatment of ginger ( Zingiber officinale) rhizomes using response surface methodology

NASA Astrophysics Data System (ADS)

Nketsia-Tabiri, Josephine

1998-06-01

The effects of pre-irradiation storage time (7-21 days), radiation dose (0-75 Gy) and post-irradiation storage time (2-20 weeks) on sprouting, wrinkling and weight loss of ginger was investigated using a central composite rotatable design. Predictive models developed for all three responses were highly significant. Weight loss and wrinkling decreased as pre-irradiation storage time increased. Dose and post-irradiation storage time had significant interactive effects on weight loss and sprouting. Processing conditions for achieving minimal sprouting resulted in maximum weight loss and wrinkling.

Statistical analysis of nonmonotonic dose-response relationships: research design and analysis of nasal cell proliferation in rats exposed to formaldehyde.

PubMed

Gaylor, David W; Lutz, Werner K; Conolly, Rory B

2004-01-01

Statistical analyses of nonmonotonic dose-response curves are proposed, experimental designs to detect low-dose effects of J-shaped curves are suggested, and sample sizes are provided. For quantal data such as cancer incidence rates, much larger numbers of animals are required than for continuous data such as biomarker measurements. For example, 155 animals per dose group are required to have at least an 80% chance of detecting a decrease from a 20% incidence in controls to an incidence of 10% at a low dose. For a continuous measurement, only 14 animals per group are required to have at least an 80% chance of detecting a change of the mean by one standard deviation of the control group. Experimental designs based on three dose groups plus controls are discussed to detect nonmonotonicity or to estimate the zero equivalent dose (ZED), i.e., the dose that produces a response equal to the average response in the controls. Cell proliferation data in the nasal respiratory epithelium of rats exposed to formaldehyde by inhalation are used to illustrate the statistical procedures. Statistically significant departures from a monotonic dose response were obtained for time-weighted average labeling indices with an estimated ZED at a formaldehyde dose of 5.4 ppm, with a lower 95% confidence limit of 2.7 ppm. It is concluded that demonstration of a statistically significant bi-phasic dose-response curve, together with estimation of the resulting ZED, could serve as a point-of departure in establishing a reference dose for low-dose risk assessment.

Modeling Rabbit Responses to Single and Multiple Aerosol ...

EPA Pesticide Factsheets

Journal Article Survival models are developed here to predict response and time-to-response for mortality in rabbits following exposures to single or multiple aerosol doses of Bacillus anthracis spores. Hazard function models were developed for a multiple dose dataset to predict the probability of death through specifying dose-response functions and the time between exposure and the time-to-death (TTD). Among the models developed, the best-fitting survival model (baseline model) has an exponential dose-response model with a Weibull TTD distribution. Alternative models assessed employ different underlying dose-response functions and use the assumption that, in a multiple dose scenario, earlier doses affect the hazard functions of each subsequent dose. In addition, published mechanistic models are analyzed and compared with models developed in this paper. None of the alternative models that were assessed provided a statistically significant improvement in fit over the baseline model. The general approach utilizes simple empirical data analysis to develop parsimonious models with limited reliance on mechanistic assumptions. The baseline model predicts TTDs consistent with reported results from three independent high-dose rabbit datasets. More accurate survival models depend upon future development of dose-response datasets specifically designed to assess potential multiple dose effects on response and time-to-response. The process used in this paper to dev

Dose and dose rate effects of whole-body proton-irradiation on lymphocyte blastogenesis and hematological variables: part II

NASA Technical Reports Server (NTRS)

Pecaut, Michael J.; Gridley, Daila S.; Smith, Anna L.; Nelson, Gregory A.

2002-01-01

The goal of part II of this study was to evaluate functional characteristics of leukocytes and circulating blood cell parameters after whole-body proton irradiation at varying doses and at low- and high-dose-rates (LDR and HDR, respectively). C57BL/6 mice (n=51) were irradiated and euthanized at 4 days post-exposure for assay. Significant radiation dose- (but not dose-rate-) dependent decreases were observed in splenocyte responses to T and B cell mitogens when compared to sham-irradiated controls (P<0.001). Spontaneous blastogenesis, also significantly dose-dependent, was increased in both blood and spleen (P<0.001). Red blood cell counts, hemoglobin concentration, and hematocrit were decreased in a dose-dependent manner (P<0.05), whereas thrombocyte numbers were only slightly affected. Comparison of proton- and gamma-irradiated groups (both receiving 3 Gy at HDR) showed a higher level of spontaneous blastogenesis in blood leukocytes and a lower splenocyte response to concanavalin A following proton irradiation (P<0.05). There were no dose rate effects. Collectively, the data demonstrate that the measurements in blood and spleen were largely dependent upon the total dose of proton radiation and that an 80-fold difference in the dose rate was not a significant factor. A difference, however, was found between protons and gamma-rays in the degree of change induced in some of the measurements.

A Reanalysis of Curvature in the Dose Response for Cancer and Modifications by Age at Exposure Following Radiation Therapy for Benign Disease

DOE Office of Scientific and Technical Information (OSTI.GOV)

Little, Mark P., E-mail: mark.little@nih.gov; Stovall, Marilyn; Smith, Susan A.

Purpose: To assess the shape of the dose response for various cancer endpoints and modifiers by age and time. Methods and Materials: Reanalysis of the US peptic ulcer data testing for heterogeneity of radiogenic risk by cancer endpoint (stomach, pancreas, lung, leukemia, all other). Results: There are statistically significant (P<.05) excess risks for all cancer and for lung cancer and borderline statistically significant risks for stomach cancer (P=.07), and leukemia (P=.06), with excess relative risks Gy{sup -1} of 0.024 (95% confidence interval [CI] 0.011, 0.039), 0.559 (95% CI 0.221, 1.021), 0.042 (95% CI -0.002, 0.119), and 1.087 (95% CI -0.018,more » 4.925), respectively. There is statistically significant (P=.007) excess risk of pancreatic cancer when adjusted for dose-response curvature. General downward curvature is apparent in the dose response, statistically significant (P<.05) for all cancers, pancreatic cancer, and all other cancers (ie, other than stomach, pancreas, lung, leukemia). There are indications of reduction in relative risk with increasing age at exposure (for all cancers, pancreatic cancer), but no evidence for quadratic variations in relative risk with age at exposure. If a linear-exponential dose response is used, there is no significant heterogeneity in the dose response among the 5 endpoints considered or in the speed of variation of relative risk with age at exposure. The risks are generally consistent with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers. Conclusions: There are excess risks for various malignancies in this data set. Generally there is a marked downward curvature in the dose response and significant reduction in relative risk with increasing age at exposure. The consistency of risks with those observed in the Japanese atomic bomb survivors and in groups of nuclear workers implies that there may be little sparing effect of fractionation of dose or low-dose-rate exposure.« less

Differences in carbachol dose, pain condition, and sex following lateral hypothalamic stimulation.

PubMed

Holden, J E; Wang, E; Moes, J R; Wagner, M; Maduko, A; Jeong, Y

2014-06-13

Lateral hypothalamic (LH) stimulation produces antinociception in female rats in acute, nociceptive pain. Whether this effect occurs in neuropathic pain or whether male-female sex differences exist is unknown. We examined the effect of LH stimulation in male and female rats using conditions of nociceptive and neuropathic pain. Neuropathic groups received chronic constriction injury (CCI) to induce thermal hyperalgesia, a sign of neuropathic pain. Nociceptive rats were naive for CCI, but received the same thermal stimulus following LH stimulation. To demonstrate that CCI ligation produced thermal hyperalgesia, males and females received either ligation or sham surgery for control. Both males and females demonstrated significant thermal hyperalgesia following CCI ligation (p<0.05), but male sham surgery rats also showed a significant left-right difference not present in female sham rats. In the second experiment, rats randomly assigned to CCI or nociceptive groups were given one of three doses of the cholinergic agonist carbachol (125, 250, or 500 nmol) or normal saline for control, microinjected into the left LH. Paw withdrawal from a thermal stimulus (paw withdrawal latency; PWL) was measured every 5 min for 45 min. Linear mixed models analysis showed that males and females in both pain conditions demonstrated significant antinociception, with the 500-nmol dose producing the greatest effect across groups compared with controls for the left paw (p<0.05). Female CCI rats showed equivalent responses to the three doses, while male CCI rats showed more variability for dose. However, nociceptive females responded only to the 500-nmol dose, while nociceptive males responded to all doses (p<0.05). For right PWL, only nociceptive males showed a significant carbachol dose response. These findings are suggestive that LH stimulation produces antinociception in male and female rats in both nociceptive and neuropathic pain, but dose response differences exist based on sex and pain condition. Copyright © 2014 IBRO. Published by Elsevier Ltd. All rights reserved.

Can Ayahuasca and sleep loss change sexual performance in male rats?

PubMed

Alvarenga, T A; Polesel, D N; Matos, G; Garcia, V A; Costa, J L; Tufik, S; Andersen, M L

2014-10-01

The ingestion of the beverage Ayahuasca usually occurs in religious ceremonies that are performed during the night leading to sleep deprivation. The purpose of the present study was to characterize the acute effects of Ayahuasca upon the sexual response of sleep deprived male rats. One group of sexually experienced male Wistar rats were submitted to a paradoxical sleep deprivation (PSD) protocol for 96h, while another group spent the same amount of time in the home cage (CTRL). After this period, either saline or Ayahuasca drink (250, 500 and 1000μgmL(-1)) was administered by gavage and sexual behavior and hormonal concentrations were measured. Ayahuasca alone significantly decreased sexual performance at all doses. However, in sleep deprived rats, the lower dose increased sexual performance while the intermediate dose produced a detrimental effect on sexual response compared to the CTRL rats at the same dose. Regarding the hormonal analyses, a lower testosterone concentration was observed in sleep-deprived saline rats in relation to the CTRL group. Progesterone was significantly lower only in PSD rats at the dose 500μgmL(-1) compared with CTRL-500μgmL(-1) group. Corticosterone was unchanged among the groups evaluated. Our results suggest that Ayahuasca intake markedly impaired sexual performance alone, but, when combined with sleep deprivation, had significant, but heterogeneous, effects on male sexual response. Copyright © 2014. Published by Elsevier B.V.

Opioid modulation of reflex versus operant responses following stress in the rat.

PubMed

King, C D; Devine, D P; Vierck, C J; Mauderli, A; Yezierski, R P

2007-06-15

In pre-clinical models intended to evaluate nociceptive processing, acute stress suppresses reflex responses to thermal stimulation, an effect previously described as stress-induced "analgesia." Suggestions that endogenous opioids mediate this effect are based on demonstrations that stress-induced hyporeflexia is enhanced by high dose morphine (>5 mg/kg) and is reversed by naloxone. However, reflexes and pain sensations can be modulated differentially. Therefore, in the present study direct comparisons were made of opioid agonist and antagonist actions, independently and in combination with acute restraint stress in Long Evans rats, on reflex lick-guard (L/G) and operant escape responses to nociceptive thermal stimulation (44.5 degrees C). A high dose of morphine (>8 mg/kg) was required to reduce reflex responding, but a moderate dose of morphine (1 mg/kg) significantly reduced escape responding. The same moderate dose (and also 5 mg/kg) of morphine significantly enhanced reflex responding. Naloxone (3 mg/kg) significantly enhanced escape responding but did not affect L/G responding. Restraint stress significantly suppressed L/G reflexes (hyporeflexia) but enhanced escape responses (hyperalgesia). Stress-induced hyperalgesia was significantly reduced by morphine and enhanced by naloxone. In contrast, stress-induced hyporeflexia was blocked by both naloxone and 1 mg/kg of morphine. Thus, stress-induced hyperalgesia was opposed by endogenous opioid release and by administration of morphine. Stress-induced hyporeflexia was dependent upon endogenous opioid release but was counteracted by a moderate dose of morphine. These data demonstrate a differential modulation of reflex and operant outcome measures by stress and by separate or combined opioid antagonism or administration of morphine.

Methylene Blue Facilitates Memory Retention in Zebrafish in a Dose-Dependent Manner.

PubMed

Echevarria, David J; Caramillo, Erika M; Gonzalez-Lima, Francisco

2016-12-01

Methylene blue (MB) is an FDA-grandfathered drug with memory-enhancing effects at low doses, but opposite effects at high doses. We investigated the effects of four MB doses (0.1, 0.5, 5.0, or 10.0 μM) on zebrafish memory retention in the T-maze task. After training fish to swim into a certain arm of the T-maze, the fish were placed into a tank containing one of the four MB doses or a control tank containing blue food dye. Subsequently, fish were placed into the T-maze for memory retention testing. Results indicated that MB produced hormetic dose-response effects on memory. Fish that received the 0.5 μM dose performed significantly better at the T-maze than those that received higher doses. Fish who received 5.0 μM did not exhibit a significant difference in performance from control fish, and the fish that received the 10.0 μM dose performed significantly worse than lower doses. These findings support the utility of zebrafish in comparative research and their potential value for testing of MB and other neuropsychopharmacological treatments in animal models of memory disorders.

Adjunctive aripiprazole in the treatment of risperidone-induced hyperprolactinemia: A randomized, double-blind, placebo-controlled, dose-response study.

PubMed

Chen, Jing-Xu; Su, Yun-Ai; Bian, Qing-Tao; Wei, Li-He; Zhang, Rong-Zhen; Liu, Yan-Hong; Correll, Christoph; Soares, Jair C; Yang, Fu-De; Wang, Shao-Li; Zhang, Xiang-Yang

2015-08-01

Hyperprolactinemia is an unwanted adverse effect associated with several antipsychotics. The addition of partial dopamine receptor agonist aripiprazole may attenuate antipsychotic-induced hyperprolactinemia effectively. However, the ideal dosing regimen for this purpose is unknown. We aimed to evaluate the dose effects of adjunctive treatment with aripiprazole on prolactin levels and hyperprolactinemia in schizophrenia patients. Stable subjects 18-45 years old with schizophrenia and hyperprolactinemia (i.e., >24 ng/ml for females and >20 ng/ml for males) were randomly assigned to receive 8 weeks of placebo (n=30) or oral aripiprazole 5mg/day (n=30), 10mg/day (n=29), or 20mg/day (n=30) added on to fixed dose risperidone treatment. Serum prolactin levels were measured at baseline and after 2, 4 and 8 weeks; clinical symptoms and side effects were assessed at baseline and week 8 using the Positive and Negative Syndrome Scale, Clinical Global Impressions Severity scale, Barnes Akathisia Scale, Simpson-Angus Scale and UKU Side Effects Rating Scale. Of 119 randomized patients, 107 (89.9%) completed the 8-week study. At study end, all three aripiprazole doses resulted in significantly lower prolactin levels (beginning at week 2), higher response rates (≥30% prolactin reduction) and higher prolactin normalization rates than placebo. Effects were significantly greater in the 10 and 20mg/day groups than the 5mg/day group. No significant changes were observed in any treatment groups regarding psychopathology and adverse effect ratings. Adjunctive aripiprazole treatment was effective and safe for resolving risperidone-induced hyperprolactinemia, producing significant and almost maximal improvements by week 2 without significant effects on psychopathology and side effects. Copyright © 2015 Elsevier Ltd. All rights reserved.

The effect of selective 5-hydroxytryptamine uptake inhibitors on 5-methoxy-N,N-dimethyltryptamine-induced ejaculation in the rat.

PubMed Central

Rényi, L.

1986-01-01

The ejaculatory response and the 5-hydroxytryptamine (5-HT) behavioural syndrome induced by 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) (3 mg kg-1 i.p.) were studied following acute and repeated treatment of rats with the selective uptake inhibitors of 5-HT, fluoxetine, zimeldine, alaproclate, and citalopram. The oral doses used were based on the respective ED50 values for uptake inhibition. Acute doses of fluoxetine and zimeldine significantly reduced the ejaculatory response when given 48 h before 5-MeODMT. This blockade was prevented by treatment of the rats with the postsynaptic 5-HT receptor antagonist methergoline. An acute dose of fluoxetine given 7 and 14 days before 5-MeODMT significantly enhanced the ejaculatory response. On day 24, the response returned to the control level. Repeated treatment every second day (5 times over 9 days and 10 times over 19 days) with fluoxetine caused a longer blockade of the ejaculatory response and the sensitization of the response came later than after an acute dose. Parallel with the ejaculatory response three other components of the 5-HT behavioural syndrome also decreased significantly. Acute doses of alaproclate and citalopram significantly blocked the ejaculatory response at 1 h, but they failed to affect the response at any other time point after either acute or repeated treatment. Neither did these drugs attentuate the 5-HT syndrome. It is concluded that acute and repeated treatment of rats with different selective 5-HT uptake inhibitors does not produce a common alteration in 5-HT2-receptor functions. PMID:2939912

American association of poison control centers database characterization of human tilmicosin exposures, 2001-2005.

PubMed

Oakes, Jennifer; Seifert, Steven

2008-12-01

Tilmicosin is a veterinary antibiotic with significant human toxicity at doses commonly used in animals, but the parenteral dose-response relationship has not been well characterized. Human exposures to tilmicosin in the database of the American Association of Poison Control Centers (AAPCC) from 2001 to 2005 were analyzed for demographic associations, exposure dose, clinical effects and outcomes. Over the 5-year period, there were 1,291 single-substance human exposures to tilmicosin. The mean age was 39.1 years, and 80% were male. By route there were 768 (54%) parenteral exposures. Patients with parenteral exposures had a significantly increased likelihood of being seen at a healthcare facility, admission, and admission to an ICU. With nonparenteral exposure, most had no clinical effects or minor effects, and there were no major effects or deaths. With parenteral exposure, moderate effects occurred in 46 (6%), major effects in 2 (0.3%) and there were 4 (0.5%) deaths, two of which were suicides. A dose-response relationship could be demonstrated. Clinical effect durations of up to a week occurred at even the lowest dose range. Over 250 cases of human tilmicosin exposure are reported to poison centers per year and over 150 of those are parenteral. Most exposures produce no or minor effects, but fatalities have occurred with parenteral exposure. The case fatality rate in parenteral exposures is 10 times the case fatality rate for all human exposures in the AAPCC database. Significant adverse and prolonged effects are reported at parenteral doses > 0.5 mL, suggesting that all parenteral exposures should be referred for healthcare facility evaluation.

Addition of cyclophosphamide and higher doses of dexamethasone do not improve outcomes of patients with AL amyloidosis treated with bortezomib.

PubMed

Kastritis, E; Gavriatopoulou, M; Roussou, M; Fotiou, D; Ziogas, D C; Migkou, M; Eleutherakis-Papaiakovou, E; Panagiotidis, I; Kanellias, N; Psimenou, E; Papadopoulou, E; Pamboucas, C; Manios, E; Gakiopoulou, H; Ntalianis, A; Tasidou, A; Giannouli, S; Terpos, E; Dimopoulos, M A

2017-06-16

Bortezomib, in combination with dexamethasone (VD) or with the addition of cyclophosphamide (VCD), is highly effective in patients with amyloid light-chain (AL) amyloidosis. Currently, VCD is considered as a primary regimen for patients with AL, but it is not clear whether the addition of cyclophosphamide to VD further and significantly improves efficacy, given the substantial activity of bortezomib itself. We retrospectively compared the outcomes of 101 patients with AL amyloidosis who received VD (n=59) or VCD (n=42) in two consecutive periods. Early mortality after adjustment for Mayo stage was similar. On intent to treat, a hematologic response rate was 68% for patients treated with VD and 78% for VCD (P=0.26), while complete response+very good partial response (CR+VGPR) rate was 47.5% and 35%, respectively. Higher doses of dexamethasone or twice-weekly bortezomib were not associated with significantly higher CR+VGPR rates. Organ responses occurred in similar rates between the two groups. Median survival was similar (33 vs 36 months, P=0.45) even after adjustment for Mayo stage and dose and schedule of bortezomib and dexamethasone. In conclusion, bortezomib even with low doses of dexamethasone is effective for the treatment of AL amyloidosis; higher doses of dexamethasone and addition of cyclophosphamide do not seem to have a profound effect on efficacy and survival.

Toxic effects of orally ingested oil from the Deepwater Horizon spill on laughing gulls.

PubMed

Horak, K E; Bursian, S J; Ellis, C K; Dean, K M; Link, J E; Hanson-Dorr, K C; Cunningham, F L; Harr, K E; Pritsos, C A; Pritsos, K L; Healy, K A; Cacela, D; Shriner, S A

2017-12-01

The explosion of the Deepwater Horizon oil rig released, millions of gallons of oil into the environment, subsequently exposing wildlife, including numerous bird species. To determine the effects of MC252 oil to species relevant to the Gulf of Mexico, studies were done examining multiple exposure scenarios and doses. In this study, laughing gulls (Leucophaeus atricilla, LAGU) were offered fish injected with MC252 oil at target doses of 5 or 10mL/kg bw per day. Dosing continued for 27 days. Of the adult, mixed-sex LAGUs used in the present study, ten of 20 oil exposed LAGUs survived to the end of the study; a total of 10 of the oil exposed LAGUs died or were euthanized within 20 days of initiation of the study. Endpoints associated with oxidative stress, hepatic total glutathione (tGSH), oxidized glutathione (GSSG) and reduced glutathione (rGSH) significantly increased as mean dose of oil increased, while the rGSH:GSSG ratio showed a non-significant negative trend with oil dose. A significant increase in 3-methyl histidine was found in oil exposed birds when compared to controls indicative of muscle wastage and may have been associated with the gross observation of diminished structural integrity in cardiac tissue. Consistent with previous oil dosing studies in birds, significant changes in liver, spleen, and kidney weight when normalized to body weight were observed. These studies indicate that mortality in response to oil dosing is relatively common and the mortality exhibited by the gulls is consistent with previous studies examining oil toxicity. Whether survival effects in the gull study were associated with weight loss, physiologic effects of oil toxicity, or a behavioral response that led the birds to reject the dosed fish is unknown. Published by Elsevier Inc.

A cumulative dose comparison between salbutamol and fenoterol metered dose aerosols in asthmatic patients.

PubMed Central

Bellamy, D.; Penketh, A.

1987-01-01

The potency and side effects of salbutamol and fenoterol inhalers have been compared in 8 asthmatic patients using a dose response curve. There was no significant difference in the absolute or percentage increase in FEV1 with the two treatments, but fenoterol caused a significantly greater (P less than 0.01) increase in heart rate than did salbutamol. A greater degree of bronchodilatation was observed with increased doses and we suggest that regular higher doses may provide better bronchodilatation and control of asthma in selected patients. PMID:3432172

Low-dose vaporized cannabis significantly improves neuropathic pain.

PubMed

Wilsey, Barth; Marcotte, Thomas; Deutsch, Reena; Gouaux, Ben; Sakai, Staci; Donaghe, Haylee

2013-02-01

We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling medium-dose (3.53%), low-dose (1.29%), or placebo cannabis with the primary outcome being visual analog scale pain intensity. Psychoactive side effects and neuropsychological performance were also evaluated. Mixed-effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the 2 active dose groups' results (P > .7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo versus low-dose, 2.9 for placebo versus medium-dose, and 25 for medium- versus low-dose. As these NNTs are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well tolerated, and neuropsychological effects were of limited duration and readily reversible within 1 to 2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain. The analgesia obtained from a low dose of delta-9-tetrahydrocannabinol (1.29%) in patients, most of whom were experiencing neuropathic pain despite conventional treatments, is a clinically significant outcome. In general, the effect sizes on cognitive testing were consistent with this minimal dose. As a result, one might not anticipate a significant impact on daily functioning. Published by Elsevier Inc.

A highly infective plant-associated bacterium influences reproductive rates in pea aphids

PubMed Central

Hendry, Tory A.; Clark, Kelley J.; Baltrus, David A.

2016-01-01

Pea aphids, Acyrthosiphon pisum, have the potential to increase reproduction as a defence against pathogens, though how frequently this occurs or how infection with live pathogens influences this response is not well understood. Here we determine the minimum infective dose of an environmentally common bacterium and possible aphid pathogen, Pseudomonas syringae, to determine the likelihood of pathogenic effects to pea aphids. Additionally, we used P. syringae infection to investigate how live pathogens may alter reproductive rates. We found that oral bacterial exposure decreased subsequent survival of aphids in a dose-dependent manner and we estimate that ingestion of less than 10 bacterial cells is sufficient to increase aphid mortality. Pathogen dose was positively related to aphid reproduction. Aphids exposed to low bacterial doses showed decreased, although statistically indistinguishable, fecundity compared to controls. Aphids exposed to high doses reproduced significantly more than low dose treatments and also more, but not significantly so, than controls. These results are consistent with previous studies suggesting that pea aphids may use fecundity compensation as a response to pathogens. Consequently, even low levels of exposure to a common plant-associated bacterium may therefore have significant effects on pea aphid survival and reproduction. PMID:26998321

A highly infective plant-associated bacterium influences reproductive rates in pea aphids.

PubMed

Hendry, Tory A; Clark, Kelley J; Baltrus, David A

2016-02-01

Pea aphids, Acyrthosiphon pisum, have the potential to increase reproduction as a defence against pathogens, though how frequently this occurs or how infection with live pathogens influences this response is not well understood. Here we determine the minimum infective dose of an environmentally common bacterium and possible aphid pathogen, Pseudomonas syringae, to determine the likelihood of pathogenic effects to pea aphids. Additionally, we used P. syringae infection to investigate how live pathogens may alter reproductive rates. We found that oral bacterial exposure decreased subsequent survival of aphids in a dose-dependent manner and we estimate that ingestion of less than 10 bacterial cells is sufficient to increase aphid mortality. Pathogen dose was positively related to aphid reproduction. Aphids exposed to low bacterial doses showed decreased, although statistically indistinguishable, fecundity compared to controls. Aphids exposed to high doses reproduced significantly more than low dose treatments and also more, but not significantly so, than controls. These results are consistent with previous studies suggesting that pea aphids may use fecundity compensation as a response to pathogens. Consequently, even low levels of exposure to a common plant-associated bacterium may therefore have significant effects on pea aphid survival and reproduction.

Impact of prior treatment and depth of response on survival in MM-003, a randomized phase 3 study comparing pomalidomide plus low-dose dexamethasone versus high-dose dexamethasone in relapsed/refractory multiple myeloma

PubMed Central

San Miguel, Jesus F.; Weisel, Katja C.; Song, Kevin W.; Delforge, Michel; Karlin, Lionel; Goldschmidt, Hartmut; Moreau, Philippe; Banos, Anne; Oriol, Albert; Garderet, Laurent; Cavo, Michele; Ivanova, Valentina; Alegre, Adrian; Martinez-Lopez, Joaquin; Chen, Christine; Renner, Christoph; Bahlis, Nizar Jacques; Yu, Xin; Teasdale, Terri; Sternas, Lars; Jacques, Christian; Zaki, Mohamed H.; Dimopoulos, Meletios A.

2015-01-01

Pomalidomide is a distinct oral IMiD® immunomodulatory agent with direct antimyeloma, stromal-support inhibitory, and immunomodulatory effects. The pivotal, multicenter, open-label, randomized phase 3 trial MM-003 compared pomalidomide + low-dose dexamethasone vs high-dose dexamethasone in 455 patients with refractory or relapsed and refractory multiple myeloma after failure of bortezomib and lenalidomide treatment. Initial results demonstrated significantly longer progression-free survival and overall survival with an acceptable tolerability profile for pomalidomide + low-dose dexamethasone vs high-dose dexamethasone. This secondary analysis describes patient outcomes by treatment history and depth of response. Pomalidomide + low-dose dexamethasone significantly prolonged progression-free survival and favored overall survival vs high-dose dexamethasone for all subgroups analyzed, regardless of prior treatments or refractory status. Both univariate and multivariate analyses showed that no variable relating to either the number (≤ or > 3) or type of prior treatment was a significant predictor of progression-free survival or overall survival. No cross-resistance with prior lenalidomide or thalidomide treatment was observed. Patients achieving a minimal response or better to pomalidomide + low-dose dexamethasone treatment experienced a survival benefit, which was even higher in those achieving at least a partial response (17.2 and 19.9 months, respectively, as compared with 7.5 months for patients with less than minimal response). These data suggest that pomalidomide + low-dose dexamethasone should be considered a standard of care in patients with refractory or relapsed and refractory multiple myeloma regardless of prior treatment. ClinicalTrials.gov: NCT01311687; EudraCT: 2010-019820-30. PMID:26160879

Comparison of the effects of maximal dose atorvastatin and rosuvastatin therapy on cholesterol synthesis and absorption markers

USDA-ARS?s Scientific Manuscript database

We measured plasma markers of cholesterol synthesis (lathosterol) and absorption (campesterol, sitosterol, and cholestanol) in order to compare the effects of maximal doses of rosuvastatin with atorvastatin and investigate the basis for the significant individual variation in lipid lowering response...

A dose related response of 6-OHDA on chicken spectral sensitivity and oscillatory potentials of recording electroretinograms.

PubMed

Li, X; Schaeffel, F; Konrad, K; Eberhart, Z

1996-10-01

To further study the contribution of dopamine system to the local growth controlling mechanisms, a dose related response of 6-hydroxydopamine (6-OHDA) was studied by recording electroretinograms (ERGs). The spectral sensitivity of the b-waves and spectral efficiency function of oscillatory potentials (OPs) including OP1, OP2 and OP3 in 4 different doses group were measured. The effect of ascorbate that must be contained in solution of 6-OHDA was first tested with the spectral sensitivity of the b-waves and a correlation between response of the OPs and age, as well as a difference in both own eyes was analyzed for determining an intra-subject and inter-subject variance. An enhanced response was found in OP1, OP2 with doses of 175 micrograms and OP3 with dose of 150 micrograms, and the effect of OPs was mainly in wavelength from 620 nm to 480 nm. No significant increase was found in the spectral sensitivity of the b-waves. The dose 200 micrograms seemed to be toxic to the retina estimated by both spectral sensitivity of the b-waves and spectral efficiency function of the OPs. The dose 175 micrograms and 150 micrograms of 6-OHDA yielded an effect on the chicken retina.

Heat Tolerance and the Peripheral Effects of Anticholinergics

DTIC Science & Technology

1988-01-30

0c. GENDER: Responses of 27 males and 12 females showed that both SR and AGD increased as a function of log MCh dose. SR was affected by gender only...at the 2 highest doses ( male SR slightly greater). At all but the lowest dose AGD was significantly greater for females. ACCLIMATION: Responses of 6... males to MCh were measured before and after 20. DISTRIBUTION /AVAILABILITY OF ABSTRACT 21. ABSTRACT SECURITY CLASSIFICATION 0 UNCLASSIFIED/UNLIMITED 0

Meta-analytic review of the effects of a single dose of intranasal oxytocin on threat processing in humans.

PubMed

Leppanen, Jenni; Ng, Kah Wee; Kim, Youl-Ri; Tchanturia, Kate; Treasure, Janet

2018-01-01

Heightened threat sensitivity is a transdiagnostic feature in several psychiatric disorders. The neuropeptide oxytocin has been shown to reduce fear related behaviours and facilitated fear extinction in animals. These findings have led to increasing interest to explore the effects of intranasal oxytocin on threat processing in humans. The review included 26 studies (N = 1173), nine of which included clinical populations (N = 234). The clinical groups included were people with borderline personality disorder (BPD), anorexia nervosa, bulimia nervosa, depression, anxiety, and alcohol dependence disorder. We examined the effects of a single dose of intranasal oxytocin on startle response, attentional responses, and behavioural responses to threat. A single dose of intranasal oxytocin significantly increased the physiological startle response to threat in healthy people with a small effect size. However, oxytocin did not have significant effects on attentional bias towards social or disorder-specific threat, fixation towards threatening stimuli among healthy or clinical populations, or on threat related behavioural approach or avoidance responses. No studies investigated the effects of oxytocin on the startle response to threat among clinical populations. Additionally, only one of the reviewed studies had sufficient power to detect at least a moderate effect of oxytocin according to our criterion. The synthesis of literature suggest that oxytocin may influence the salience of threatening stimuli among healthy individuals, increasing the startle response to threat. It would be of interest to investigate the effects of oxytocin on the startle response to threat among clinical populations. Copyright © 2017 Elsevier B.V. All rights reserved.

Peripheral NMDA Receptor/NO System Blockage Inhibits Itch Responses Induced by Chloroquine in Mice

PubMed Central

Haddadi, Nazgol-Sadat; Foroutan, Arash; Ostadhadi, Sattar; Azimi, Ehsan; Rahimi, Nastaran; Nateghpour, Mehdi; Lerner, Ethan A.; Dehpour, Ahmad Reza

2017-01-01

Intradermal administration of chloroquine (CQ) provokes scratching behavior in mice. Chloroquine-induced itch is histamine-independent and we have reported that the nitric oxide (NO)/cyclic guanosine monophosphate (cGMP) pathway is involved in CQ-induced scratching behavior in mice. Previous studies have demonstrated that activation of N-methyl-d-aspartate receptors (NMDARs) induces NO production. Here we show that NMDAR antagonists significantly decrease CQ-induced scratching in mice while a non-effective dose of an NMDAR agonist potentiates the scratching behavior provoked by sub-effective doses of CQ. In contrast, combined pre-treatment with sub-effective doses of an NMDAR antagonist, MK-801, and the NO synthase inhibitor, L-N-nitro arginine methyl ester (L-NAME), decreases CQ-induced scratching behavior. While intradermal administration of CQ significantly increases the concentration of intradermal nitrite, the end product of NO metabolism, effective doses of intraperitoneal and intradermal MK-801 significantly decrease intradermal nitrite levels. Likewise, administration of an effective dose of L-NAME significantly decreases CQ-induced nitrite production. We conclude that the NMDA/NO pathway in the skin modulates CQ-induced scratching behavior. PMID:28119997

Nitrogen Dioxide Exposure and Airway Responsiveness in ...

EPA Pesticide Factsheets

Controlled human exposure studies evaluating the effect of inhaled NO2 on the inherent responsiveness of the airways to challenge by bronchoconstricting agents have had mixed results. In general, existing meta-analyses show statistically significant effects of NO2 on the airway responsiveness of individuals with asthma. However, no meta-analysis has provided a comprehensive assessment of clinical relevance of changes in airway responsiveness, the potential for methodological biases in the original papers, and the distribution of responses. This paper provides analyses showing that a statistically significant fraction, 70% of individuals with asthma exposed to NO2 at rest, experience increases in airway responsiveness following 30-minute exposures to NO2 in the range of 200 to 300 ppb and following 60-minute exposures to 100 ppb. The distribution of changes in airway responsiveness is log-normally distributed with a median change of 0.75 (provocative dose following NO2 divided by provocative dose following filtered air exposure) and geometric standard deviation of 1.88. About a quarter of the exposed individuals experience a clinically relevant reduction in their provocative dose due to NO2 relative to air exposure. The fraction experiencing an increase in responsiveness was statistically significant and robust to exclusion of individual studies. Results showed minimal change in airway responsiveness for individuals exposed to NO2 during exercise. A variety of fa

Pupillometry as an indicator of L-DOPA dosages in Parkinson's disease patients.

PubMed

Bartošová, O; Bonnet, C; Ulmanová, O; Šíma, M; Perlík, F; Růžička, E; Slanař, O

2018-04-01

Dopamine was shown to induce mydriasis by excitation of alpha-adrenergic receptors at the dilator pupillae muscle. Pupilla diameter may thus serve as an indirect measure of peripheral pharmacokinetics of L-DOPA and dopamine. The aim of this study is to evaluate the effect of L-DOPA dosage on pupillometric parameters in Parkinson's disease (PD) patients. Sixteen PD patients and 14 healthy control subjects (CS) were studied. The statistical analysis revealed significant differences between CS and PD patients for the mean maximum and minimum pupil diameters (p = 0.017, p = 0.028, respectively), with higher values found in PD. Moreover, a significant dose-response relationship was found between the maximum pupil diameter and both the morning L-DOPA dose (R 2  = 0.78) and the total daily L-DOPA dose (R 2  = 0.93). A sigmoid-shaped curve best describes the dose-response relationship, with a ceiling effect at about 400 mg L-DOPA daily dose. In conclusion, measuring pupillometric parameters represents a sensitive tool for non-invasive evaluation of the peripheral effect of L-DOPA, especially with daily doses below 400 mg L-DOPA.

Antibody Secreting Cell Responses following Vaccination with Bivalent Oral Cholera Vaccine among Haitian Adults.

PubMed

Matias, Wilfredo R; Falkard, Brie; Charles, Richelle C; Mayo-Smith, Leslie M; Teng, Jessica E; Xu, Peng; Kováč, Pavol; Ryan, Edward T; Qadri, Firdausi; Franke, Molly F; Ivers, Louise C; Harris, Jason B

2016-06-01

The bivalent whole-cell (BivWC) oral cholera vaccine (Shanchol) is effective in preventing cholera. However, evaluations of immune responses following vaccination with BivWC have been limited. To determine whether BivWC induces significant mucosal immune responses, we measured V. cholerae O1 antigen-specific antibody secreting cell (ASC) responses following vaccination. We enrolled 24 Haitian adults in this study, and administered doses of oral BivWC vaccine 14 days apart (day 0 and day 14). We drew blood at baseline, and 7 days following each vaccine dose (day 7 and 21). Peripheral blood mononuclear cells (PBMCs) were isolated, and ASCs were enumerated using an ELISPOT assay. Significant increases in Ogawa (6.9 cells per million PBMCs) and Inaba (9.5 cells per million PBMCs) OSP-specific IgA ASCs were detected 7 days following the first dose (P < 0.001), but not the second dose. The magnitude of V. cholerae-specific ASC responses did not appear to be associated with recent exposure to cholera. ASC responses measured against the whole lipolysaccharide (LPS) antigen and the OSP moiety of LPS were equivalent, suggesting that all or nearly all of the LPS response targets the OSP moiety. Immunization with the BivWC oral cholera vaccine induced ASC responses among a cohort of healthy adults in Haiti after a single dose. The second dose of vaccine resulted in minimal ASC responses over baseline, suggesting that the current dosing schedule may not be optimal for boosting mucosal immune responses to V. cholerae antigens for adults in a cholera-endemic area.

Randomised, double blind trial of two loading dose regimens of diamorphine in ventilated newborn infants.

PubMed

Barker, D P; Simpson, J; Pawula, M; Barrett, D A; Shaw, P N; Rutter, N

1995-07-01

To compare the safety and efficacy of two loading doses of diamorphine in 27 ventilated newborn infants in a randomised double blind trial. Fifty or 200 mcg/kg were infused intravenously over 30 minutes, followed by a 15 mcg/kg/hour continuous infusion. Serial measurements were made of physiology, behaviour, and stress hormones. Both loading doses produced small but significant falls in blood pressure. The 200 mcg/kg dose produced greater respiratory depression, and two infants deteriorated clinically, requiring resuscitation. Loading reduced respiratory effort in most of the infants, but had little effect on behavioural activity. Stress hormone concentrations were reduced at six hours in both dosage groups; differences between loading doses were not significant. Morphine, morphine-3-glucuronide, and morphine-6-glucuronide were detected in the plasma of all patients. No significant differences in concentrations between loading doses were found. Diamorphine reduces the stress response in ventilated newborn infants. A high loading dose confers no benefit, and may produce undesirable physiological effects. A 50 mcg/kg loading dose seems to be safe and effective.

Randomised, double blind trial of two loading dose regimens of diamorphine in ventilated newborn infants.

PubMed Central

Barker, D. P.; Simpson, J.; Pawula, M.; Barrett, D. A.; Shaw, P. N.; Rutter, N.

1995-01-01

AIMS--To compare the safety and efficacy of two loading doses of diamorphine in 27 ventilated newborn infants in a randomised double blind trial. METHODS--Fifty or 200 mcg/kg were infused intravenously over 30 minutes, followed by a 15 mcg/kg/hour continuous infusion. Serial measurements were made of physiology, behaviour, and stress hormones. RESULTS--Both loading doses produced small but significant falls in blood pressure. The 200 mcg/kg dose produced greater respiratory depression, and two infants deteriorated clinically, requiring resuscitation. Loading reduced respiratory effort in most of the infants, but had little effect on behavioural activity. Stress hormone concentrations were reduced at six hours in both dosage groups; differences between loading doses were not significant. Morphine, morphine-3-glucuronide, and morphine-6-glucuronide were detected in the plasma of all patients. No significant differences in concentrations between loading doses were found. CONCLUSIONS--Diamorphine reduces the stress response in ventilated newborn infants. A high loading dose confers no benefit, and may produce undesirable physiological effects. A 50 mcg/kg loading dose seems to be safe and effective. PMID:7552591

Mitragyna speciosa Leaf Extract Exhibits Antipsychotic-Like Effect with the Potential to Alleviate Positive and Negative Symptoms of Psychosis in Mice

PubMed Central

Vijeepallam, Kamini; Pandy, Vijayapandi; Kunasegaran, Thubasni; Murugan, Dharmani D.; Naidu, Murali

2016-01-01

In this study, we investigated the antipsychotic-like effect of methanolic extract of Mitragyna speciosa leaf (MMS) using in vivo and ex vivo studies. In vivo studies comprised of apomorphine-induced climbing behavior, haloperidol-induced catalepsy, and ketamine-induced social withdrawal tests in mice whereas the ex vivo study was conducted utilizing isolated rat vas deferens preparation. Acute oral administration of MMS (50–500 mg/kg) showed an inverted bell-shaped dose-response in apomorphine-induced cage climbing behavior in mice. The effective inhibitory doses of MMS (75 and 100 mg/kg, p.o.) obtained from the apomorphine study was further tested on haloperidol (subcataleptic dose; 0.1 mg/kg, i.p.)-induced catalepsy in the mouse bar test. MMS (75 and 100 mg/kg, p.o.) significantly potentiated the haloperidol-induced catalepsy in mice. Interestingly, MMS at the same effective doses (75 and 100 mg/kg, p.o.) significantly facilitated the social interaction in ketamine-induced social withdrawal mice. Furthermore, MMS inhibited the dopamine-induced contractile response dose-dependently in the isolated rat vas deferens preparations. In conclusion, this investigation provides first evidence that MMS exhibits antipsychotic-like activity with potential to alleviate positive as well as negative symptoms of psychosis in mice. This study also suggests the antidopaminergic activity of MMS that could be responsible for alleviating positive symptoms of psychosis. PMID:27999544

Traditional Chinese medicine versus western medicine as used in China in the management of rheumatoid arthritis: a randomized, single-blind, 24-week study.

PubMed

He, Yi-Ting; Ou, Ai-Hua; Yang, Xiao-Bo; Chen, Wei; Fu, Li-Yuan; Lu, Ai-Ping; Yan, Xiao-Ping; Feng, Xing-Hua; Su, Li; Song, Yue-Jin; Zeng, Sheng-Ping; Liu, Wei; Qian, Xian; Zhu, Wan-Hua; Lao, Ying-Rong; Xu, Wei-Hua; Wen, Ze-Huai; He, Xiao-Hong; Wang, Bao-Juan; Chen, Geng-Xin; Xue, Su-Qin

2014-12-01

This study is designed to compare the efficacy and safety of traditional Chinese medicine (TCM) with western medicine (WM) in the management of rheumatoid arthritis (RA). This is a 24-week, randomized, multicenter, single-blind study comparing TCM with WM (as used in China) carried out between June 2002 and December 2004 in nine research centers in China, involving 489 patients. Patients were randomized to receive TCM (n = 247), MTX and SSZ (n = 242). MTX was started at a dose of 5 mg to a final dose of 7.5-15 mg weekly. The maintenance dose was 2.5-7.5 mg weekly. The starting dose of SSZ was 0.25 g bid, increasing by 0.25 g a day once a week to a final dose of 0.5-1 g qid. The maintenance dose was 0.5 g tid to qid. Primary end point was the proportion of patients with response according to the American College of Rheumatology 20 % improvement criteria (ACR20) at weeks 24. At 24 weeks, ACR20 responses were 53.0 % in TCM group and 66.5 % in WM group, (P < 0.001) at 24 weeks. ACR 50 responses were 31.6 % of TCM group and 42.6 % in WM group, (P = 0.01). ACR70 responses were 12.6 % in TCM group and 17.4 % in WM group, (P = 0.14). Side effects were observed more frequently in WM group. In this study, ACR20, ACR50 responses at 24 weeks were significantly better in the WM treated group, by intention to treat (ITT) and per protocol analysis. The ACR 70 response showed no significant difference between the two groups. TCM, while effective in treating RA, appears to be less effective than WM in controlling symptoms, but TCM is associated with fewer side effects.

Dose-response relationships in a microneutralization test for foot-and-mouth disease viruses.

PubMed Central

Booth, J. C.; Rweyemamu, M. M.; Pay, T. W.

1978-01-01

Two-dimensional quantal microneutralization tests on foot-and-mouth disease viruses, in which neutralizing antibody activity was titrated against a serial range of virus doses, demonstrated a variety of dose-response curves some of which were rectilinear, others clearly curvilinear. Moreover, in the case of the non-linear responses obtained with some antisera, the shape of the curve was such that antibody titres recorded with doses of virus ranging from 10(3)-10(5) TCD50 were closely similar. Studies were carried out on the effect of varying the conditions of the test on the shape of the dose-response curve: significant differences were obtained after treatment of the antiserum-virus mixtures with anti-species globulin, and when the test was assayed in cells of differing susceptibility to infection. PMID:202650

Human psychopharmacology of N,N-dimethyltryptamine.

PubMed

Strassman, R J

1996-01-01

We generated dose-response data for the endogenous and ultra-short-acting hallucinogen, N,N-dimethyltryptamine (DMT), in a cohort of experienced hallucinogen users, measuring multiple biological and psychological outcome measures. Subjective responses were quantified with a new rating scale, the HRS, which provided better resolution of dose effects than did the biological variables. A tolerance study then was performed, in which volunteers received four closely spaced hallucinogenic doses of DMT. Subjective responses demonstrated no tolerance, while biological measures were inconsistently reduced over the course of the sessions. Thus, DMT remains unique among classic hallucinogens in its inability to induce tolerance to its psychological effects. To assess the role of the 5-HT1A site in mediating DMT's effects, a pindolol pre-treatment study was performed. Pindolol significantly increased psychological responses to DMT, suggesting a buffering effect of 5-HT1A agonism on 5-HT2-mediated psychedelic effects. These data are opposite to those described in lower animal models of hallucinogens' mechanisms of action.

Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder.

PubMed

Jakubovski, Ewgeni; Varigonda, Anjali L; Freemantle, Nicholas; Taylor, Matthew J; Bloch, Michael H

2016-02-01

Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder. The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder. Forty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001-0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018-0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071-0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=-0.00093, 95% CI=-0.00165 to -0.00021, z=-2.54). Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.

Sex differences in the subjective effects of oral Δ9-THC in cannabis users.

PubMed

Fogel, Jessica S; Kelly, Thomas H; Westgate, Philip M; Lile, Joshua A

2017-01-01

Previous studies suggest that there are sex differences in endocannabinoid function and the response to exogenous cannabinoids, though data from clinical studies comparing acute cannabinoid effects in men and women under controlled laboratory conditions are limited. To further explore these potential differences, data from 30 cannabis users (N=18 M, 12 F) who completed previous Δ 9 -tetrahydrocannabinol (Δ 9 -THC) discrimination studies were combined for this retrospective analysis. In each study, subjects learned to discriminate between oral Δ 9 -THC and placebo and then received a range of Δ 9 -THC doses (0, 5, 15 and a "high" dose of either 25 or 30mg). Responses on a drug-discrimination task, subjective effects questionnaire, psychomotor performance tasks, and physiological measures were assessed. Δ 9 -THC dose-dependently increased drug-appropriate responding, ratings on "positive" Visual Analog Scale (VAS) items (e.g., good effects, like drug, take again), and items related to intoxication (e.g., high, stoned). Δ 9 -THC also dose-dependently impaired performance on psychomotor tasks and elevated heart rate. Sex differences on VAS items emerged as a function of dose. Women exhibited significantly greater subjective responses to oral drug administration than men at the 5mg Δ 9 -THC dose, whereas men were more sensitive to the subjective effects of the 15mg dose of Δ 9 -THC than women. These results demonstrate dose-dependent separation in the subjective response to oral Δ 9 -THC administration by sex, which might contribute to the differential development of problematic cannabis use. Copyright © 2015 Elsevier Inc. All rights reserved.

Non-Malignant Thyroid Diseases Following a Wide Range of Radiation Exposures

PubMed Central

Ron, Elaine; Brenner, Alina

2013-01-01

Background The thyroid gland is one of the most radiosensitive human organs. While it is well known that radiation exposure increases the risk of thyroid cancer, less is known about its effects in relation to non-malignant thyroid diseases. Objectives The aim of this review is to evaluate the effects of high and low dose radiation on benign structural and functional diseases of the thyroid. Methods We examined the results of major studies from cancer patients treated with high-dose radiotherapy or thyrotoxicosis patients treated with high doses of iodine-131, patients treated with moderate to high dose radiotherapy for benign diseases, persons exposed to low doses from environmental radiation and survivors of the atomic bombings who were exposed to a range of doses. We evaluated radiation effects on structural (tumors, nodules), functional (hyper- and hypothyroidism), and autoimmune thyroid diseases. Results Following a wide range of doses of ionizing radiation, an increased risk of thyroid adenomas and nodules was observed in a variety of populations and settings. The dose response appeared to be linear at low to moderate doses, but in one study there was some suggestion of a reduction in risk above 5 Gy. The elevated risk for benign tumors continues for decades following exposure. Considerably less consistent findings are available regarding functional thyroid diseases including autoimmune diseases. In general, associations for these outcomes were fairly weak and significant radiation effects were most often observed following high doses, particularly for hypothyroidism. Conclusions A significant radiation dose-response relation was demonstrated for benign nodules and follicular adenomas. The effects of radiation on functional thyroid diseases are less clear, partly due to the greater difficulties studying these diseases. PMID:21128812

Glyphosate rodent carcinogenicity bioassay expert panel review.

PubMed

Williams, Gary M; Berry, Colin; Burns, Michele; de Camargo, Joao Lauro Viana; Greim, Helmut

2016-09-01

Glyphosate has been rigorously and extensively tested for carcinogenicity by administration to mice (five studies) and to rats (nine studies). Most authorities have concluded that the evidence does not indicate a cancer risk to humans. The International Agency for Research on Cancer (IARC), however, evaluated some of the available data and concluded that glyphosate probably is carcinogenic to humans. The expert panel convened by Intertek assessed the findings used by IARC, as well as the full body of evidence and found the following: (1) the renal neoplastic effects in males of one mouse study are not associated with glyphosate exposure, because they lack statistical significance, strength, consistency, specificity, lack a dose-response pattern, plausibility, and coherence; (2) the strength of association of liver hemangiosarcomas in a different mouse study is absent, lacking consistency, and a dose-response effect and having in high dose males only a significant incidence increase which is within the historical control range; (3) pancreatic islet-cell adenomas (non-significant incidence increase), in two studies of male SD rats did not progress to carcinomas and lacked a dose-response pattern (the highest incidence is in the low dose followed by the high dose); (4) in one of two studies, a non-significant positive trend in the incidence of hepatocellular adenomas in male rats did not lead to progression to carcinomas; (5) in one of two studies, the non-significant positive trend in the incidence of thyroid C-cell adenomas in female rats was not present and there was no progression of adenomas to carcinomas at the end of the study. Application of criteria for causality considerations to the above mentioned tumor types and given the overall weight-of-evidence (WoE), the expert panel concluded that glyphosate is not a carcinogen in laboratory animals.

Effect of Spirulina (Arthrospira) supplementation on the immune response to tetanus toxoid vaccination in a mouse model.

PubMed

Chu, Wan-Loy; Quynh, Le Van; Radhakrishnan, Ammu Kutty

2013-09-01

The aim of this study was to investigate whether Spirulina (Arthrospira) supplementation could enhance the immune response to tetanus toxoid (TT) vaccine in a mouse model. Vaccination of TT was performed on day 7 and 21 in mice fed daily with Spirulina (50 and 150 mg/kg body weight). Both Spirulina supplementation and TT vaccination did not significantly affect body weight gain of the mice. Supplementation of Spirulina significantly enhanced IgG level (p = .01) after the first but not after the second TT vaccination. The anti-TT IgG levels of the groups that received low dose and high dose of Spirulina were not significantly different. Spirulina supplementation did not show significant effects on in vitro splenocyte proliferation and cytokine (IFN-γ and IL-4) production induced by Con A and TT. This study showed that Spirulina supplementation could enhance primary immune response in terms of antibody production, but not secondary immune response following TT vaccination in a mouse model.

Application of a computational decision model to examine acute drug effects on human risk taking.

PubMed

Lane, Scott D; Yechiam, Eldad; Busemeyer, Jerome R

2006-05-01

In 3 previous experiments, high doses of alcohol, marijuana, and alprazolam acutely increased risky decision making by adult humans in a 2-choice (risky vs. nonrisky) laboratory task. In this study, a computational modeling analysis known as the expectancy valence model (J. R. Busemeyer & J. C. Stout, 2002) was applied to individual-participant data from these studies, for the highest administered dose of all 3 drugs and corresponding placebo doses, to determine changes in decision-making processes that may be uniquely engendered by each drug. The model includes 3 parameters: responsiveness to rewards and losses (valence or motivation); the rate of updating expectancies about the value of risky alternatives (learning/memory); and the consistency with which trial-by-trial choices match expected outcomes (sensitivity). Parameter estimates revealed 3 key outcomes: Alcohol increased responsiveness to risky rewards and decreased responsiveness to risky losses (motivation) but did not alter expectancy updating (learning/memory); both marijuana and alprazolam produced increases in risk taking that were related to learning/memory but not motivation; and alcohol and marijuana (but not alprazolam) produced more random response patterns that were less consistently related to expected outcomes on the 2 choices. No significant main effects of gender or dose by gender interactions were obtained, but 2 dose by gender interactions approached significance. These outcomes underscore the utility of using a computational modeling approach to deconstruct decision-making processes and thus better understand drug effects on risky decision making in humans.

Dose-response study of N,N-dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects.

PubMed

Strassman, R J; Qualls, C R

1994-02-01

To begin applying basic neuropharmacological hypotheses of hallucinogenic drug actions to humans, we generated dose-response data for intravenously administered dimethyltryptamine fumarate's (DMT) neuroendocrine, cardiovascular, autonomic, and subjective effects in a group of experienced hallucinogen users. Dimethyltryptamine, an endogenous mammalian hallucinogen and drug of abuse, was administered intravenously at 0.05, 0.1, 0.2, and 0.4 mg/kg to 11 experienced hallucinogen users, in a double-blind, saline placebo-controlled, randomized design. Treatments were separated by at least 1 week. Peak DMT blood levels and subjective effects were seen within 2 minutes after drug administration, and were negligible at 30 minutes. Dimethyltryptamine dose dependently elevated blood pressure, heart rate, pupil diameter, and rectal temperature, in addition to elevating blood concentrations of beta-endorphin, corticotropin, cortisol, and prolactin. Growth hormone blood levels rose equally in response to all doses of DMT, and melatonin levels were unaffected. Threshold doses for significant effects relative to placebo were also hallucinogenic (0.2 mg/kg and higher). Subjects with five or more exposures to 3,4-methylenedioxymethamphetamine demonstrated less robust pupil diameter effects than those with two or fewer exposures. Dimethyltryptamine can be administered safely to experienced hallucinogen users and dose-response data generated for several measures hypothesized under serotonergic modulatory control. Additional studies characterizing the specific mechanisms mediating DMT's biological effects may prove useful in psychopharmacological investigations of drug-induced and endogenous alterations in brain function.

Reducing the dose of smallpox vaccine reduces vaccine-associated morbidity without reducing vaccination success rates or immune responses.

PubMed

Couch, Robert B; Winokur, Patricia; Edwards, Kathryn M; Black, Steven; Atmar, Robert L; Stapleton, Jack T; Kissner, Jennifer M; Shinefield, Henry; Denny, Thomas N; Bybel, Michael J; Newman, Frances K; Yan, Lihan

2007-03-15

When the decision was made to prepare for a deliberate release of smallpox, the United States had approximately 15 million doses of Wyeth Dryvax vaccine, which was known to induce significant morbidity when used undiluted; Sanofi Pasteur, Inc., later identified approximately 85 million additional doses in storage. Eleven vaccine-dose groups, each with 30 vaccinia-naive subjects, were given diluted Dryvax vaccine or 1 of 2 lots of Sanofi Pasteur smallpox vaccine and were evaluated for vaccination success rates, morbidity, and immune responses. Estimated doses of 10(6.6)-10(8.2) pfu of virus/mL induced major reactions (or "takes") in 93%-100% of subjects in each dose group. No differences in vaccination take rates, lesion size, erythema, and induration or in serum neutralizing-antibody response were detected between the groups. However, systemic reactogenicity and missed activities were significantly lower for the vaccine groups given doses of 10(6.6)-10(7.2) pfu/mL than for those given doses of 10(7.6)-10(8.2) pfu/mL. These findings support the use of a higher dilution of Wyeth Dryvax vaccine and Sanofi Pasteur smallpox vaccine, given that the resulting morbidity should be significantly lower without loss of vaccine effectiveness. A plan for use of higher dilutions would create an enormous stockpile of vaccine.

The lack of cytotoxic effect and radioadaptive response in splenocytes of mice exposed to low level internal β-particle irradiation through tritiated drinking water in vivo.

PubMed

Flegal, Matthew; Blimkie, Melinda; Roch-Lefevre, Sandrine; Gregoire, Eric; Klokov, Dmitry

2013-12-05

Health effects of tritium, a β-emitter and a by-product of the nuclear industry, is a subject of significant controversy. This mouse in vivo study was undertaken to monitor biological effects of low level tritium exposure. Mice were exposed to tritiated drinking water (HTO) at 10 KBq/L, 1 MBq/L and 20 MBq/L concentrations for one month. The treatment did not result in a significant increase of apoptosis in splenocytes. To examine if this low level tritium exposure alters radiosensitivity, the extracted splenocytes were challenged in vitro with 2 Gy γ-radiation, and apoptotic responses at 1 and 24 h were measured. No alterations in the radiosensitivity were detected in cells from mice exposed to tritium compared to sham-treated mice. In contrast, low dose γ-irradiation at 20 or 100 mGy, resulted in a significant increase in resistance to apoptotic cell death after 2 Gy irradiation; an indication of the radioadaptive response. Overall, our data suggest that low concentrations of tritium given to mice as HTO in drinking water do not exert cytotoxic effect in splenocytes, nor do they change cellular sensitivity to additional high dose γ-radiation. The latter may be considered as the lack of a radioadaptive response, typically observed after low dose γ-irradiation.

An Insecticide Further Enhances Experience-Dependent Increased Behavioural Responses to Sex Pheromone in a Pest Insect

PubMed Central

Abrieux, Antoine; Mhamdi, Amel; Rabhi, Kaouther K.; Egon, Julie; Debernard, Stéphane; Duportets, Line; Tricoire-Leignel, Hélène; Anton, Sylvia; Gadenne, Christophe

2016-01-01

Neonicotinoid insecticides are widely used to protect plants against pest insects, and insecticide residues remaining in the environment affect both target and non-target organisms. Whereas low doses of neonicotinoids have been shown to disturb the behaviour of pollinating insects, recent studies have revealed that a low dose of the neonicotinoid clothianidin can improve behavioural and neuronal sex pheromone responses in a pest insect, the male moth Agrotis ipsilon, and thus potentially improve reproduction. As male moth behaviour depends also on its physiological state and previous experience with sensory signals, we wondered if insecticide effects would be dependent on plasticity of olfactory-guided behaviour. We investigated, using wind tunnel experiments, whether a brief pre-exposure to the sex pheromone could enhance the behavioural response to this important signal in the moth A. ipsilon at different ages (sexually immature and mature males) and after different delays (2 h and 24 h), and if the insecticide clothianidin would interfere with age effects or the potential pre-exposure-effects. Brief pre-exposure to the pheromone induced an age-independent significant increase of sex pheromone responses 24 h later, whereas sex pheromone responses did not increase significantly 2 h after exposure. However, response delays were significantly shorter compared to naïve males already two hours after exposure. Oral treatment with clothianidin increased sex pheromone responses in sexually mature males, confirming previous results, but did not influence responses in young immature males. Males treated with clothianidin after pre-exposure at day 4 responded significantly more to the sex pheromone at day 5 than males treated with clothianidin only and than males pre-exposed only, revealing an additive effect of experience and the insecticide. Plasticity of sensory systems has thus to be taken into account when investigating the effects of sublethal doses of insecticides on behaviour. PMID:27902778

Direct effects of diazepam on emotional processing in healthy volunteers

PubMed Central

Murphy, S. E.; Downham, C.; Cowen, P. J.

2008-01-01

Rationale Pharmacological agents used in the treatment of anxiety have been reported to decrease threat relevant processing in patients and healthy controls, suggesting a potentially relevant mechanism of action. However, the effects of the anxiolytic diazepam have typically been examined at sedative doses, which do not allow the direct actions on emotional processing to be fully separated from global effects of the drug on cognition and alertness. Objectives The aim of this study was to investigate the effect of a lower, but still clinically effective, dose of diazepam on emotional processing in healthy volunteers. Materials and methods Twenty-four participants were randomised to receive a single dose of diazepam (5 mg) or placebo. Sixty minutes later, participants completed a battery of psychological tests, including measures of non-emotional cognitive performance (reaction time and sustained attention) and emotional processing (affective modulation of the startle reflex, attentional dot probe, facial expression recognition, and emotional memory). Mood and subjective experience were also measured. Results Diazepam significantly modulated attentional vigilance to masked emotional faces and significantly decreased overall startle reactivity. Diazepam did not significantly affect mood, alertness, response times, facial expression recognition, or sustained attention. Conclusions At non-sedating doses, diazepam produces effects on attentional vigilance and startle responsivity that are consistent with its anxiolytic action. This may be an underlying mechanism through which benzodiazepines exert their therapeutic effects in clinical anxiety. PMID:18581100

Beta-cell response during a meal test: a comparative study of incremental doses of repaglinide in type 2 diabetic patients.

PubMed

Cozma, Lawrence S; Luzio, Stephen D; Dunseath, Gareth J; Underwood, Paul M; Owens, David R

2005-05-01

To assess the effects of incremental doses of repaglinide on postprandial insulin and glucose profiles after a standard 500-kcal test meal. Sixteen diet-treated Caucasians with type 2 diabetes (mean HbA(1c) 8.4%) were enrolled in this randomized, open-label, crossover trial. Subjects received 0.5, 1, 2, and 4 mg repaglinide or placebo in a random fashion, followed by a standard 500-kcal test meal on 5 separate study days, 1 week apart. The insulinogenic index (DeltaI30/DeltaG30) and insulin area under the curve (AUC) from 0 to 30 min (AUC(0-30)) were higher with the 4-mg drug dose compared with the two lower doses and with 2 mg compared with 0.5 mg. On subgroup analysis, the incremental insulin responses were apparent only in the fasting plasma glucose (FPG) < 9-mmol/l subgroup of subjects and not in the FPG >9-mmol/l subgroup. There was a significant dose-related increase in the late postprandial insulin secretion (insulin AUC(120-240)), which resulted in hypoglycemia in four subjects. Proinsulin-to-insulin ratios at 30 and 60 min improved with increasing doses of repaglinide; higher drug doses (2 and 4 mg) were more effective than the 0.5- and 1-mg doses. Significant dose-related increases in early insulin secretion were found only in less advanced diabetic subjects. In advanced diabetic patients, only the maximum dose (4 mg) was significant compared with placebo. Better proinsulin-to-insulin processing was noted with increasing drug doses.

Dose-Effect Relationship in Chemoradiotherapy for Locally Advanced Rectal Cancer: A Randomized Trial Comparing Two Radiation Doses

DOE Office of Scientific and Technical Information (OSTI.GOV)

Jakobsen, Anders, E-mail: anders.jakobsen@slb.regionsyddanmark.dk; University of Southern Denmark, Odense; Ploen, John

2012-11-15

Purpose: Locally advanced rectal cancer represents a major therapeutic challenge. Preoperative chemoradiation therapy is considered standard, but little is known about the dose-effect relationship. The present study represents a dose-escalation phase III trial comparing 2 doses of radiation. Methods and Materials: The inclusion criteria were resectable T3 and T4 tumors with a circumferential margin of {<=}5 mm on magnetic resonance imaging. The patients were randomized to receive 50.4 Gy in 28 fractions to the tumor and pelvic lymph nodes (arm A) or the same treatment supplemented with an endorectal boost given as high-dose-rate brachytherapy (10 Gy in 2 fractions; armmore » B). Concomitant chemotherapy, uftoral 300 mg/m{sup 2} and L-leucovorin 22.5 mg/d, was added to both arms on treatment days. The primary endpoint was complete pathologic remission. The secondary endpoints included tumor response and rate of complete resection (R0). Results: The study included 248 patients. No significant difference was found in toxicity or surgical complications between the 2 groups. Based on intention to treat, no significant difference was found in the complete pathologic remission rate between the 2 arms (18% and 18%). The rate of R0 resection was different in T3 tumors (90% and 99%; P=.03). The same applied to the rate of major response (tumor regression grade, 1+2), 29% and 44%, respectively (P=.04). Conclusions: This first randomized trial comparing 2 radiation doses indicated that the higher dose increased the rate of major response by 50% in T3 tumors. The endorectal boost is feasible, with no significant increase in toxicity or surgical complications.« less

Effects of luteinizing hormone-releasing hormone and arginine-vasotocin on the sperm-release response of Günther's Toadlet, Pseudophryne guentheri

PubMed Central

2010-01-01

Background Luteinizing hormone-releasing hormone (LHRH) is an exogenous hormone commonly used to induce spermiation in anuran amphibians. Over the past few decades, the LHRH dose administered to individuals and the frequency of injection has been highly variable. The sperm-release responses reported have been correspondingly diverse, highlighting a need to quantify dose-response relationships on a species-specific basis. This study on the Australian anuran Pseudophryne guentheri first evaluated the spermiation response of males administered one of five LHRHa doses, and second, determined whether AVT administered in combination with the optimal LHRHa dose improved sperm-release. Methods Male toadlets were administered a single dose of 0, 1, 2, 4 or 8 micrograms/g body weight of LHRHa. A 4 micrograms/g dose of AVT was administered alone or in combination with 2 micrograms/g LHRHa. Spermiation responses were evaluated at 3, 7 and 12 h post hormone administration (PA), and sperm number and viability were quantified using fluorescent microscopy. Results LHRHa administration was highly effective at inducing spermiation in P. guentheri, with 100% of hormone-treated males producing sperm during the experimental period. The number of sperm released in response to 2 micrograms/g LHRHa was greater than all other doses administered and sperm viability was highest in the 1 microgram/g treatment. The administration of AVT alone or in combination with LHRHa resulted in the release of significantly lower sperm numbers. Conclusion Overall, results from this study suggest that in P. guentheri, LHRHa is effective at inducing spermiation, but that AVT inhibits sperm-release. PMID:21059269

A forced titration study of the antioxidant and immunomodulatory effects of Ambrotose AO supplement

PubMed Central

2010-01-01

Background Oxidative stress plays a role in acute and chronic inflammatory disease and antioxidant supplementation has demonstrated beneficial effects in the treatment of these conditions. This study was designed to determine the optimal dose of an antioxidant supplement in healthy volunteers to inform a Phase 3 clinical trial. Methods The study was designed as a combined Phase 1 and 2 open label, forced titration dose response study in healthy volunteers (n = 21) to determine both acute safety and efficacy. Participants received a dietary supplement in a forced titration over five weeks commencing with a no treatment baseline through 1, 2, 4 and 8 capsules. The primary outcome measurement was ex vivo changes in serum oxygen radical absorbance capacity (ORAC). The secondary outcome measures were undertaken as an exploratory investigation of immune function. Results A significant increase in antioxidant activity (serum ORAC) was observed between baseline (no capsules) and the highest dose of 8 capsules per day (p = 0.040) representing a change of 36.6%. A quadratic function for dose levels was fitted in order to estimate a dose response curve for estimating the optimal dose. The quadratic component of the curve was significant (p = 0.047), with predicted serum ORAC scores increasing from the zero dose to a maximum at a predicted dose of 4.7 capsules per day and decreasing for higher doses. Among the secondary outcome measures, a significant dose effect was observed on phagocytosis of granulocytes, and a significant increase was also observed on Cox 2 expression. Conclusion This study suggests that Ambrotose AO® capsules appear to be safe and most effective at a dosage of 4 capsules/day. It is important that this study is not over interpreted; it aimed to find an optimal dose to assess the dietary supplement using a more rigorous clinical trial design. The study achieved this aim and demonstrated that the dietary supplement has the potential to increase antioxidant activity. The most significant limitation of this study was that it was open label Phase 1/Phase 2 trial and is subject to potential bias that is reduced with the use of randomization and blinding. To confirm the benefits of this dietary supplement these effects now need to be demonstrated in a Phase 3 randomised controlled trial (RCT). Trial Registration Australian and New Zealand Clinical Trials Register: ACTRN12605000258651 PMID:20433711

Dose and dose rate effects of whole-body gamma-irradiation: II. Hematological variables and cytokines

NASA Technical Reports Server (NTRS)

Gridley, D. S.; Pecaut, M. J.; Miller, G. M.; Moyers, M. F.; Nelson, G. A.

2001-01-01

The goal of part II of this study was to evaluate the effects of gamma-radiation on circulating blood cells, functional characteristics of splenocytes, and cytokine expression after whole-body irradiation at varying total doses and at low- and high-dose-rates (LDR, HDR). Young adult C57BL/6 mice (n = 75) were irradiated with either 1 cGy/min or 80 cGy/min photons from a 60Co source to cumulative doses of 0.5, 1.5, and 3.0 Gy. The animals were euthanized at 4 days post-exposure for in vitro assays. Significant dose- (but not dose-rate-) dependent decreases were observed in erythrocyte and blood leukocyte counts, hemoglobin, hematocrit, lipopolysaccharide (LPS)-induced 3H-thymidine incorporation, and interleukin-2 (IL-2) secretion by activated spleen cells when compared to sham-irradiated controls (p < 0.05). Basal proliferation of leukocytes in the blood and spleen increased significantly with increasing dose (p < 0.05). Significant dose rate effects were observed only in thrombocyte counts. Plasma levels of transforming growth factor-beta 1 (TGF-beta 1) and splenocyte secretion of tumor necrosis factor-alpha (TNF-alpha) were not affected by either the dose or dose rate of radiation. The data demonstrate that the responses of blood and spleen were largely dependent upon the total dose of radiation employed and that an 80-fold difference in the dose rate was not a significant factor in the great majority of measurements.

Low Dose Vaporized Cannabis Significantly Improves Neuropathic Pain

PubMed Central

Wilsey, Barth; Marcotte, Thomas D.; Deutsch, Reena; Gouaux, Ben; Sakai, Staci; Donaghe, Haylee

2013-01-01

We conducted a double-blind, placebo-controlled, crossover study evaluating the analgesic efficacy of vaporized cannabis in subjects, the majority of whom were experiencing neuropathic pain despite traditional treatment. Thirty-nine patients with central and peripheral neuropathic pain underwent a standardized procedure for inhaling either medium dose (3.53%), low dose (1.29%), or placebo cannabis with the primary outcome being VAS pain intensity. Psychoactive side-effects, and neuropsychological performance were also evaluated. Mixed effects regression models demonstrated an analgesic response to vaporized cannabis. There was no significant difference between the two active dose groups’ results (p>0.7). The number needed to treat (NNT) to achieve 30% pain reduction was 3.2 for placebo vs. low dose, 2.9 for placebo vs. medium dose, and 25 for medium vs. low dose. As these NNT are comparable to those of traditional neuropathic pain medications, cannabis has analgesic efficacy with the low dose being, for all intents and purposes, as effective a pain reliever as the medium dose. Psychoactive effects were minimal and well-tolerated, and neuropsychological effects were of limited duration and readily reversible within 1–2 hours. Vaporized cannabis, even at low doses, may present an effective option for patients with treatment-resistant neuropathic pain. PMID:23237736

The differential effects of alprazolam and oxazepam on methamphetamine self-administration in rats.

PubMed

Spence, Allyson L; Guerin, Glenn F; Goeders, Nicholas E

2016-09-01

Methamphetamine is the second most commonly used illicit drug in the world, and despite recent attempts by the Drug Enforcement Administration to combat this epidemic, methamphetamine use is still on the rise. As methamphetamine use increases so does polydrug use, particularly that involving methamphetamine and benzodiazepines. The present study was designed to examine the effects of two benzodiazepines on methamphetamine self-administration. Five doses of methamphetamine (0.0075, 0.015, 0.03, 0.09, and 0.12mg/kg/infusion) were tested, producing an inverted U-shaped dose-response curve. Rats were then pretreated with oxazepam, alprazolam, or vehicle prior to methamphetamine self-administration. To determine if the effects of these drugs were due to the GABAA receptor and/or translocator protein (TSPO), we also pretreated rats with an antagonist for the benzodiazepine-binding site on the GABAA receptor (i.e., flumazenil) and a TSPO antagonist (i.e., PK11195) prior to alprazolam or oxazepam administration. Oxazepam significantly reduced methamphetamine self-administration as demonstrated by a downward shift of the dose-response curve. In contrast, alprazolam significantly enhanced methamphetamine self-administration as evidenced by a leftward shift of the dose-response curve. Flumazenil completely blocked the effects of alprazolam on methamphetamine self-administration. When administered individually, both flumazenil and PK11195 partially reversed the effects of oxazepam on methamphetamine self-administration. However, when these two antagonists were combined, the effects of oxazepam were completely reversed. The GABAA receptor is responsible for the alprazolam-induced enhancement of methamphetamine self-administration, while the activation of both the GABAA receptor and TSPO are responsible for the oxazepam-induced reduction of methamphetamine self-administration. Published by Elsevier Ireland Ltd.

Dose-response analysis of testosterone replacement therapy in patients with female to male gender identity disorder.

PubMed

Nakamura, Aya; Watanabe, Masami; Sugimoto, Morito; Sako, Tomoko; Mahmood, Sabina; Kaku, Haruki; Nasu, Yasutomo; Ishii, Kazushi; Nagai, Atsushi; Kumon, Hiromi

2013-01-01

Gender identity disorder (GID) is a conflict between a person's actual physical gender and the one they identify him or herself with. Testosterone is the key agent in the medical treatment of female to male GID patients. We conducted a dose-response analysis of testosterone replacement therapy (TRT) in 138 patients to determine the onset of the therapeutic effects. The TRT consisted of intramuscular injection of testosterone enanthate and patients were divided into three groups; 250 mg every two weeks, 250 mg every three weeks and 125 mg every two weeks. The onset of deepening of voice, increase in facial hair and cessation of menses was evaluated in each group. At one month after the start of TRT, the onset of these physical changes was more prevalent in the group receiving the higher dose of testosterone, and there were dose-dependent effects observed between the three treatment groups. On the other hand, at six months after the start of TRT, most of the patients had achieved treatment responses and there were no dose-dependent effects with regard to the percentage of patients with therapeutic effects. No significant side effects were observed in any of the treatment groups. We demonstrated that the early onset of the treatment effects of TRT is dose-dependent, but within six months of starting TRT, all three doses were highly effective. Current study provides useful information to determine the initial dose of TRT and to suggest possible changes that should be made in the continuous dosage for long term TRT.

Low- and high-dose laser irradiation effects on cell migration and destruction

NASA Astrophysics Data System (ADS)

Layton, Elivia; Gallagher, Kyra A.; Zukerman, Sara; Stevens, Brianna; Zhou, Feifan; Liu, Hong; Chen, Wei R.

2018-02-01

Metastases are the cause of more than 90 percent of cancer-related deaths. Current treatment methods, including chemotherapy, radiation, and surgery, fail to target the metastases effectively. One potential treatment for metastatic cancer is laser immunotherapy (LIT). LIT combines the use of a photothermal laser with an immunoadjuvant, Glycated Chitosan (GC). GC combined with single-walled carbon nanotubes (SWNTs) has proven to be a viable alternative to traditional cancer treatment methods, when under irradiation of laser with appropriate wavelength. In this study, the effects of low dose and high dose laser irradiation on metastatic pancreatic cancer cell migration were observed. It was found that low dose irradiation increased the migration rate, but the high dose irradiation significantly decreased the migration rate of the cancer cells. When using LIT, the goal is to kill tumor cells and to prompt the correct immune response. If the tumor were irradiated with a low dose, it would promote metastasis. If the dose of irradiation were too high, it would destroy the entire tumor and the immune response would not recognize the tumor. Therefore, the laser dose plays an important role in LIT, particularly when using SWNT as light absorbing agent. Our results from this study will delineate the optimal laser irradiation dose for destroying tumor cells and at the same time preserve and release tumor antigens as a precursor of antitumor immune response.

Sci—Fri PM: Topics — 06: The influence of regional dose sensitivity on salivary loss and recovery in the parotid gland

DOE Office of Scientific and Technical Information (OSTI.GOV)

Clark, H; BC Cancer Agency, Surrey, B.C.; BC Cancer Agency, Vancouver, B.C.

Purpose: The Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC 2010) survey of radiation dose-volume effects on salivary gland function has called for improved understanding of intragland dose sensitivity and the effectiveness of partial sparing in salivary glands. Regional dose susceptibility of sagittally- and coronally-sub-segmented parotid gland has been studied. Specifically, we examine whether individual consideration of sub-segments leads to improved prediction of xerostomia compared with whole parotid mean dose. Methods: Data from 102 patients treated for head-and-neck cancers at the BC Cancer Agency were used in this study. Whole mouth stimulated saliva was collected before (baseline), threemore » months, and one year after cessation of radiotherapy. Organ volumes were contoured using treatment planning CT images and sub-segmented into regional portions. Both non-parametric (local regression) and parametric (mean dose exponential fitting) methods were employed. A bootstrap technique was used for reliability estimation and cross-comparison. Results: Salivary loss is described well using non-parametric and mean dose models. Parametric fits suggest a significant distinction in dose response between medial-lateral and anterior-posterior aspects of the parotid (p<0.01). Least-squares and least-median squares estimates differ significantly (p<0.00001), indicating fits may be skewed by noise or outliers. Salivary recovery exhibits a weakly arched dose response: the highest recovery is seen at intermediate doses. Conclusions: Salivary function loss is strongly dose dependent. In contrast no useful dose dependence was observed for function recovery. Regional dose dependence was observed, but may have resulted from a bias in dose distributions.« less

The antinociceptive effect of intrathecal administration of epibatidine with clonidine or neostigmine in the formalin test in rats.

PubMed

Hama, A T; Lloyd, G K; Menzaghi, F

2001-03-01

The analgesic effect of intrathecal injection of epibatidine, clonidine and neostigmine, compounds that elevate ACh, was examined in the formalin test, a model of post-injury central sensitization in the rat. The compounds were injected alone and in combination. Intrathecal injection of epibatidine alone did not alter pain behaviors, compared to vehicle-treated rats. Intrathecal injection of clonidine dose-dependently reduced tonic pain behaviors (ED(50)+/-95% confidence limits=6.7+/-4.8 microg). The combination of clonidine and epibatidine (C:E), in the ratio of 26:1, dose-dependently reduced tonic pain behaviors; and the ED(50) of C:E was 1.1+/-0.98 microg a significant 6-fold leftward shift of the dose response curve, compared with clonidine alone. The antinociceptive effect of C:E (26:1) was attenuated by pre-treatment with the nAChR antagonist mecamylamine. Neostigmine dose-dependently reduced tonic pain behaviors (ED(50)=1.5+/-1.3 microg). The combination of neostigmine and epibatidine, in a ratio of 8:1, significantly shifted the dose response curve 4-fold to the left (ED(50)=0.4+/-0.3 microg). The effect is mediated in part by the activation of the nAChR and possibly by the enhanced release of ACh. These data demonstrate significant enhancement of the antinociceptive effects of spinally delivered analgesics by a nAChR agonist, suggesting that this class of compounds may have utility as adjuvants when combined with conventional therapeutics.

The alanine detector in BNCT dosimetry: Dose response in thermal and epithermal neutron fields

DOE Office of Scientific and Technical Information (OSTI.GOV)

Schmitz, T., E-mail: schmito@uni-mainz.de; Bassler, N.; Blaickner, M.

Purpose: The response of alanine solid state dosimeters to ionizing radiation strongly depends on particle type and energy. Due to nuclear interactions, neutron fields usually also consist of secondary particles such as photons and protons of diverse energies. Various experiments have been carried out in three different neutron beams to explore the alanine dose response behavior and to validate model predictions. Additionally, application in medical neutron fields for boron neutron capture therapy is discussed. Methods: Alanine detectors have been irradiated in the thermal neutron field of the research reactor TRIGA Mainz, Germany, in five experimental conditions, generating different secondary particlemore » spectra. Further irradiations have been made in the epithermal neutron beams at the research reactors FiR 1 in Helsinki, Finland, and Tsing Hua open pool reactor in HsinChu, Taiwan ROC. Readout has been performed with electron spin resonance spectrometry with reference to an absorbed dose standard in a {sup 60}Co gamma ray beam. Absorbed doses and dose components have been calculated using the Monte Carlo codes FLUKA and MCNP. The relative effectiveness (RE), linking absorbed dose and detector response, has been calculated using the Hansen and Olsen alanine response model. Results: The measured dose response of the alanine detector in the different experiments has been evaluated and compared to model predictions. Therefore, a relative effectiveness has been calculated for each dose component, accounting for its dependence on particle type and energy. Agreement within 5% between model and measurement has been achieved for most irradiated detectors. Significant differences have been observed in response behavior between thermal and epithermal neutron fields, especially regarding dose composition and depth dose curves. The calculated dose components could be verified with the experimental results in the different primary and secondary particle fields. Conclusions: The alanine detector can be used without difficulty in neutron fields. The response has been understood with the model used which includes the relative effectiveness. Results and the corresponding discussion lead to the conclusion that application in neutron fields for medical purpose is limited by its sensitivity but that it is a useful tool as supplement to other detectors and verification of neutron source descriptions.« less

Plasma growth hormone response to human growth hormone releasing factor in rats administered with chlorpromazine and antiserum against somatostatin. Effects of hypo- and hyperthyroidism.

PubMed

Wakabayashi, I; Tonegawa, Y; Ihara, T; Hattori, M; Shibasaki, T; Ling, N

1985-10-01

The effect of hypo- and hyperthyroidism on the plasma growth hormone (GH) response to synthetic human growth hormone releasing factor (GRF) was determined in conscious, freely moving rats pretreated with chlorpromazine and antiserum against somatostatin. Chlorpromazine plus somatostatin antiserum pretreated rats gave consistent response to GRF which was not observed in untreated rats. Chlorpromazine alone has no effect on GH secretion induced by GRF in rat pituitary monolayer culture. In rats made hypothyroid by thyroidectomy, both basal and peak plasma GH responses to a small (0.25 microgram/kg bw) and a moderate dose of GRF (1 microgram/kg bw) were significantly reduced as compared to controls. In rats made hyperthyroid by the administration of thyroxine, basal and peak plasma GH responses to a small but not to a moderate dose of GRF were significantly reduced as compared to controls. A reduced plasma GH response to a small dose of GRF was observed 8 days after the cessation of thyroxine administration. The pituitary GH reserve was markedly reduced in hypothyroid but not in hyperthyroid rats as compared to their respective controls. These results indicate that plasma GH response to GRF is reduced both in hypo- and hyperthyroidism. The mechanism involved in the phenomenon appears to be different between the two conditions.

Methamphetamine-Induced Locomotor Changes are Dependent on Age, Dose and Genotype

PubMed Central

Good, Renee L.; Radcliffe, Richard A.

2012-01-01

Adolescence is a critical age for addiction formation as a large percentage of pathological drug-seeking behaviors manifest during this time. The extent to which neurotoxic effects of drugs of abuse influence subsequent drug seeking behaviors and impulsivity is an understudied area of research. Methamphetamine (METH) is a widely abused drug that produces locomotor responses ranging from behavioral sensitization to tolerance, both of which are behaviors that may relate to risk of abuse. Here we investigated the effects of age, genotype, METH dose, including a neurotoxic dose, and METH metabolism on open-field activity (OFA) to gain insight into the complex disease of drug abuse. C57Bl/6 (B6), DBA/2 (D2), and 129S6SvEv/Tac (129) mouse strains were administered saline or either a high dose (4 × 5 mg/kg in 2h intervals for 2 days) or low dose (2 × 1 mg/kg in 24h intervals) METH pretreatment during adolescence (post natal day (PND) 40) or early adulthood (PND 80) followed by behavioral testing with a METH (1 mg/kg) or saline challenge 40 days later. Striatal concentrations of METH and AMPH were also determined. Significant findings include: 1) METH pretreated adolescent B6 mice displayed significant sensitization for horizontal locomotion due to high dose METH pretreatment; 2) METH pretreated B6 adults showed significant tolerance for the vertical activity measure caused by low dose METH pretreatment; 3) METH pretreated adult D2 mice exhibited significant sensitization for vertical activity induced by low dose METH pretreatment, and 4) 129 mice metabolized METH significantly faster than the B6 and D2 mice, but METH pretreatment did not alter metabolism. No significant behavioral responses to either METH pretreatment dose were observed for the D2 adolescent studies or either 129 age group. Our results highlight the importance of the interactions of age, strain and METH dose on locomotor behavioral outcomes. PMID:21163294

Predicting in vivo cardiovascular properties of β-blockers from cellular assays: a quantitative comparison of cellular and cardiovascular pharmacological responses

PubMed Central

Baker, Jillian G.; Kemp, Philip; March, Julie; Fretwell, Laurice; Hill, Stephen J.; Gardiner, Sheila M.

2011-01-01

β-Adrenoceptor antagonists differ in their degree of partial agonism. In vitro assays have provided information on ligand affinity, selectivity, and intrinsic efficacy. However, the extent to which these properties are manifest in vivo is less clear. Conscious freely moving rats, instrumented for measurement of heart rate (β1; HR) and hindquarters vascular conductance (β2; HVC) were used to measure receptor selectivity and ligand efficacy in vivo. CGP 20712A caused a dose-dependent decrease in basal HR (P<0.05, ANOVA) at 5 doses between 6.7 and 670 μg/kg (i.v.) and shifted the dose-response curve for isoprenaline to higher agonist concentrations without altering HVC responses. In contrast, at doses of 67 μg/kg (i.v.) and above, ICI 118551 substantially reduced the HVC response to isoprenaline without affecting HR responses. ZD 7114, xamoterol, and bucindolol significantly increased basal HR (ΔHR: +122±12, +129±11, and +59±11 beats/min, respectively; n=6), whereas other β-blockers caused significant reductions (all at 2 mg/kg i.v.). The agonist effects of xamoterol and ZD 7114 were equivalent to that of the highest dose of isoprenaline. Bucindolol, however, significantly antagonized the response to the highest doses isoprenaline. An excellent correlation was obtained between in vivo and in vitro measures of β1-adrenoceptor efficacy (R2=0.93; P<0.0001).—Baker, J. G., Kemp, P., March, J., Fretwell, L., Hill, S. J., Gardiner, S. M. Predicting in vivo cardiovascular properties of β-blockers from cellular assays: a quantitative comparison of cellular and cardiovascular pharmacological responses. PMID:21865315

An Adaptive Staggered Dose Design for a Normal Endpoint.

PubMed

Wu, Joseph; Menon, Sandeep; Chang, Mark

2015-01-01

In a clinical trial where several doses are compared to a control, a multi-stage design that combines both the selection of the best dose and the confirmation of this selected dose is desirable. An example is the two-stage drop-the-losers or pick-the-winner design, where inferior doses are dropped after interim analysis. Selection of target dose(s) can be based on ranking of observed effects, hypothesis testing with adjustment for multiplicity, or other criteria at interim stages. A number of methods have been proposed and have made significant gains in trial efficiency. However, many of these designs started off with all doses with equal allocation and did not consider prioritizing the doses using existing dose-response information. We propose an adaptive staggered dose procedure that allows explicit prioritization of doses and applies error spending scheme that favors doses with assumed better responses. This design starts off with only a subset of the doses and adaptively adds new doses depending on interim results. Using simulation, we have shown that this design performs better in terms of increased statistical power than the drop-the-losers design given strong prior information of dose response.

Effect of hypothalamic neuropeptides on corticotrophin release from quarters of rat anterior pituitary gland in vitro.

PubMed

Nicholson, S A; Adrian, T E; Gillham, B; Jones, M T; Bloom, S R

1984-02-01

The effect of six hypothalamic peptides on the basal release of ACTH and that induced by arginine vasopressin (AVP) or by ovine corticotrophin releasing factor (oCRF) from fragments of the rat anterior pituitary gland incubated in vitro was investigated. Dose-response curves to AVP and to oCRF were obtained, and the response to a low dose of oCRF was potentiated by a low dose of AVP. Basal release of ACTH was not affected by any of the peptides in concentrations in the range 10(-12) to 10(-6) mol/l, and only substance P (SP) and somatostatin (SRIF) inhibited significantly the response to oCRF in a dose-related manner. The responses to a range of doses of oCRF or AVP were reduced by 10(-8) and 10(-6) mol SP or SRIF/l, and to a greater extent by the higher dose. Except in the case of 10(-6) mol SRIF/l on the response to AVP, the response was not further diminished by preincubation of the tissue with the peptide before the stimulating agent was added. The inhibition of the responses to AVP or oCRF by 10(-9) mol SP/l was not potentiated by its combination with either 5 X 10(-10) or 10(-8) mol SRIF/l; the inhibitory effects were merely additive. The results suggest that although SRIF and SP are able to modulate the release of ACTH from the anterior pituitary gland, they do so only at a high concentration.(ABSTRACT TRUNCATED AT 250 WORDS)

Accounting for shared and unshared dosimetric uncertainties in the dose response for ultrasound-detected thyroid nodules after exposure to radioactive fallout.

PubMed

Land, Charles E; Kwon, Deukwoo; Hoffman, F Owen; Moroz, Brian; Drozdovitch, Vladimir; Bouville, André; Beck, Harold; Luckyanov, Nicholas; Weinstock, Robert M; Simon, Steven L

2015-02-01

Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semipalatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point "best estimates". In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5,000 population dose vectors reflect uncertainties in dosimetric parameters, partly shared and partly independent, among individual members of the study population. Risk estimates for thyroid nodules from internal irradiation were higher than those published in 2008, which results, to the best of our knowledge, from explicitly accounting for dose uncertainty. In contrast to earlier findings, the use of Bayesian methods led to the conclusion that the biological effectiveness for internal and external dose was similar. Estimates of excess relative risk per unit dose (ERR/Gy) for males (177 thyroid nodule cases) were almost 30 times those for females (571 cases) and were similar to those reported for thyroid cancers related to childhood exposures to external and internal sources in other studies. For confirmed cases of papillary thyroid cancers (3 in males, 18 in females), the ERR/Gy was also comparable to risk estimates from other studies, but not significantly different from zero. These findings represent the first reported dose response for a radiation epidemiologic study considering all known sources of shared and unshared errors in dose estimation and using a Bayesian model averaging (BMA) method for analysis of the dose response.

A study on comparison of Gafchromic EBT2 film response under single and cumulative exposure conditions

PubMed Central

Ganapathy, K.; Kurup, P.G.G.; Murali, V.; Muthukumaran, M.; Velmurugan, J.

2013-01-01

Gafchromic films are used as dosimeter for in vivo and in phantom dose measurements. The dose response of Gafchromic EBT2 film under single and repeated exposure conditions is compared in this study to analyze the usability of Gafchromic EBT2 films in cumulative dose measurements. The post-irradiation change in response of the film is studied for up to 4 days after irradiation. The effect of repeated exposure to scanner light on the response of the film is also studied. To check usability of Gafchromic EBT2 films in cumulative dose measurements, three EBT2 films were exposed to a daily fraction dose of 100 cGy, 150 cGy and 200 cGy, respectively, for 4 days. The dose response of the films exposed to cumulative irradiation was compared with the dose measured from films exposed to the same dose but in a single exposure. It is observed that the post-irradiation darkening of the film does not saturate and continue to take place even 4 days after irradiation. The dose measured from the EBT2 films after 4 days from irradiation was around 2% higher than the dose measured from the same films at 24 hours post-irradiation. It was also observed that the repeated exposure to scanner light does not produce any significant change in the film response. The dose response of films exposed to cumulative irradiation agrees with the dose response of films exposed to the same dose in a single irradiation with less than 3% difference. Gafchromic EBT2 films can be used to measure the cumulative dose delivered over multiple fractions, when the delivered dose is uniform across the film. PMID:24672151

A phantom-based JAFROC observer study of two CT reconstruction methods: the search for optimisation of lesion detection and effective dose

NASA Astrophysics Data System (ADS)

Thompson, John D.; Chakraborty, Dev P.; Szczepura, Katy; Vamvakas, Ioannis; Tootell, Andrew; Manning, David J.; Hogg, Peter

2015-03-01

Purpose: To investigate the dose saving potential of iterative reconstruction (IR) in a computed tomography (CT) examination of the thorax. Materials and Methods: An anthropomorphic chest phantom containing various configurations of simulated lesions (5, 8, 10 and 12mm; +100, -630 and -800 Hounsfield Units, HU) was imaged on a modern CT system over a tube current range (20, 40, 60 and 80mA). Images were reconstructed with (IR) and filtered back projection (FBP). An ATOM 701D (CIRS, Norfolk, VA) dosimetry phantom was used to measure organ dose. Effective dose was calculated. Eleven observers (15.11+/-8.75 years of experience) completed a free response study, localizing lesions in 544 single CT image slices. A modified jackknife alternative free-response receiver operating characteristic (JAFROC) analysis was completed to look for a significant effect of two factors: reconstruction method and tube current. Alpha was set at 0.05 to control the Type I error in this study. Results: For modified JAFROC analysis of reconstruction method there was no statistically significant difference in lesion detection performance between FBP and IR when figures-of-merit were averaged over tube current (F(1,10)=0.08, p = 0.789). For tube current analysis, significant differences were revealed between multiple pairs of tube current settings (F(3,10) = 16.96, p<0.001) when averaged over image reconstruction method. Conclusion: The free-response study suggests that lesion detection can be optimized at 40mA in this phantom model, a measured effective dose of 0.97mSv. In high-contrast regions the diagnostic value of IR, compared to FBP, is less clear.

Dose Response for Chromosome Aberrations in Human Lymphocytes and Fibroblasts After Exposure to Very Low Dose of High Let Radiation

NASA Technical Reports Server (NTRS)

Hada, M.; George, K.; Chappell, L.; Cucinotta, F. A.

2011-01-01

The relationship between biological effects and low doses of absorbed radiation is still uncertain, especially for high LET radiation exposure. Estimates of risks from low-dose and low-dose-rates are often extrapolated using data from Japanese atomic bomb survivor with either linear or linear quadratic models of fit. In this study, chromosome aberrations were measured in human peripheral blood lymphocytes and normal skin fibroblasts cells after exposure to very low dose (0.01 - 0.20 Gy) of 170 MeV/u Si-28 ions or 600 MeV/u Fe-56 ions, including doses where on average less than one direct ion traversal per cell nucleus occurs. Chromosomes were analyzed using the whole-chromosome fluorescence in situ hybridization (FISH) technique during the first cell division after irradiation, and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). The responses for doses above 0.1 Gy (more than one ion traverses a cell) showed linear dose responses. However, for doses less than 0.1 Gy, both Si-28 ions and Fe-56 ions showed a dose independent response above background chromosome aberrations frequencies. Possible explanations for our results are non-targeted effects due to aberrant cell signaling [1], or delta-ray dose fluctuations [2] where a fraction of cells receive significant delta-ray doses due to the contributions of multiple ion tracks that do not directly traverse cell nuclei where chromosome aberrations are scored.

Imatinib dose reduction in patients with chronic myeloid leukemia in sustained deep molecular response.

PubMed

Cervantes, Francisco; Correa, Juan-Gonzalo; Pérez, Isabel; García-Gutiérrez, Valentín; Redondo, Sara; Colomer, Dolors; Jiménez-Velasco, Antonio; Steegmann, Juan-Luis; Sánchez-Guijo, Fermín; Ferrer-Marín, Francisca; Pereira, Arturo; Osorio, Santiago

2017-01-01

To determine whether a lower imatinib dose could minimize toxicity while maintaining the molecular response (MR), imatinib dose was reduced to 300 mg daily in 43 patients with chronic myeloid leukemia (CML) in sustained deep molecular response to first-line imatinib 400 mg daily. At the time of dose reduction, median duration of the deep response was 4.1 (interquartile range (IQR) 2.2-5.9) years; molecular response was MR 4 , MR 4.5 , and MR 5 of the international scale in 6, 28, and 9 patients, respectively. Toxicity grade was 1, 2, and 3 in 28, 8, and 1 patients, respectively; 6 patients underwent dose reduction without having side effects. With a median of 1.6 (IQR 0.7-3.2) years on imatinib 300 mg daily, only one patient lost the deep molecular response to MR 3 . At the last follow-up, response was MR 3 , MR 4 , MR 4.5 , and MR 5 in 1, 3, 9, and 30 patients, respectively. Toxicity improvement was observed in 23 (62.2 %) of the 37 patients with side effects, decreasing to grade 0 in 20 of them. All but one anemic patients improved (p = 0.01), the median Hb increase in this subgroup of patients being 1 g/dL. In CML patients with sustained deep response to the standard imatinib dose, reducing to 300 mg daily significantly improves tolerability and preserves efficacy.

Contrasting actions of pressor agents in severe autonomic failure

NASA Technical Reports Server (NTRS)

Jordan, J.; Shannon, J. R.; Biaggioni, I.; Norman, R.; Black, B. K.; Robertson, D.

1998-01-01

BACKGROUND: Orthostatic hypotension is the most disabling symptom of autonomic failure. The choice of a pressor agent is largely empiric, and it would be of great value to define predictors of a response. PATIENTS AND METHODS: In 35 patients with severe orthostatic hypotension due to multiple system atrophy or pure autonomic failure, we determined the effect on seated systolic blood pressure (SBP) of placebo, phenylpropanolamine (12.5 mg and 25 mg), yohimbine (5.4 mg), indomethacin (50 mg), ibuprofen (600 mg), caffeine (250 mg), and methylphenidate (5 mg). In a subgroup of patients, we compared the pressor effect of midodrine (5 mg) with the effect of phenylpropanolamine (12.5 mg). RESULTS: There were no significant differences in the pressor responses between patients with multiple system atrophy or pure autonomic failure. When compared with placebo, the pressor response was significant for phenylpropanolamine, yohimbine, and indomethacin. In a subgroup of patients, we confirmed that this pressor effect of phenylpropanolamine, yohimbine, and indomethacin corresponded to a significant increase in standing SBP. The pressor responses to ibuprofen, caffeine, and methylphenidate were not significantly different from placebo. Phenylpropanolamine and midodrine elicited similar pressor responses. There were no significant associations between drug response and autonomic function testing, postprandial hypotension, or plasma catecholamine levels. CONCLUSIONS: We conclude that significant increases in systolic blood pressure can be obtained in patients with orthostatic hypotension due to primary autonomic failure with phenylpropanolamine in low doses or yohimbine or indomethacin in moderate doses. The response to a pressor agent cannot be predicted by autonomic function testing or plasma catecholamines. Therefore, empiric testing with a sequence of medications, based on the risk of side effects in the individual patient and the probability of a response, is a useful approach.

The effects of administration of monoamine oxidase-B inhibitors on rat striatal neurone responses to dopamine.

PubMed Central

Berry, M D; Scarr, E; Zhu, M Y; Paterson, I A; Juorio, A V

1994-01-01

1. (-)-Deprenyl has been shown to potentiate rat striatal neurone responses to dopamine agonists at doses not altering dopamine metabolism. Since there are a number of effects of (-)-deprenyl which could result in this phenomenon, we have investigated the effects of MDL 72,145 and Ro 19-6327, whose only common effect with (-)-deprenyl is an inhibition of monoamine oxidase-B (MAO-B), on rat striatal neurone responses to dopamine and on striatal dopamine metabolism. 2. Using in vivo electrophysiology, i.p. injection of either MDL 72,145 or Ro 19-6327 was found to produce a dose-dependent potentiation of striatal neurone responses to dopamine but not gamma-aminobutyric acid. 3. Neurochemical investigations revealed that this occurred at doses (0.25-1 mg kg-1) which, while not affecting levels of dopamine or its metabolites, 3,4-dihydroxyphenylacetic acid or homovanillic acid, did cause a significant, dose-dependent, elevation in striatal levels of the putative neuromodulator, 2-phenylethylamine (PE). 4. Inhibition of PE synthesis by i.p. injection of the aromatic L-amino acid decarboxylase inhibitor, NSD 1015, produced a reversal of the effects of MDL 72,145 and Ro 19-6327. 5. Neurochemical analysis revealed this to occur at a dose of NSD 1015 (10 mg kg-1) selective for reduction of elevated PE levels. 6. These results suggest that PE can act as a neuromodulator of dopaminergic responses and that MAO-B inhibitors may potentiate neuronal responses to dopamine via the indirect mechanism of elevation of PE following MAO-B inhibition. PMID:7889269

Caffeine and sleep-deprivation mediated changes in open-field behaviours, stress response and antioxidant status in mice.

PubMed

Onaolapo, J Olakunle; Onaolapo, Y Adejoke; Akanmu, A Moses; Olayiwola, Gbola

2016-01-01

Effects of daily caffeine consumption on open-field behaviours, serum corticosterone and brain antioxidant levels were investigated after six hours of total sleep-deprivation in prepubertal mice. We tested the hypothesis that daily caffeine consumption may significantly alter behaviour, stress and antioxidative response of prepubertal mice to an acute episode of total sleep-deprivation. Prepubertal Swiss mice of both sexes were assigned to two main groups of 120 each (subdivided into 6 groups of 10 each, based on sex), and administered vehicle or graded oral doses of caffeine (10, 20, 40, 80 and 120 mg/kg/day) for 14 days. On day 14, a main group was subjected to 6 h of total sleep-deprivation by 'gentle-handling'. Open-field behaviours were then assessed in both groups, after which animals were euthanized, and levels of corticosterone, superoxide dismutase and glutathione peroxidase assayed. Horizontal locomotion, rearing and grooming increased significantly, compared to control, with sleep-deprived (SD) mice showing stronger caffeine-driven responses at higher doses; and SD female mice showing sustained response to caffeine, compared to respective males. Plasma corticosterone increased with increasing doses of caffeine in both non sleep-deprived (NSD) and SD mice; although SD mice had higher corticosterone levels. Sleep-deprivation and/or higher doses of caffeine were associated with derangements in brain antioxidant levels. Repeated caffeine consumption and/or acute sleep-deprivation led to significant changes in pattern of open-field behaviour and stress/antioxidant response in mice. Responses seen in the study are probably due to modulatory effects of caffeine on the total body response to stressful stimuli.

Orexinergic Neurotransmission in Temperature Responses to Methamphetamine and Stress: Mathematical Modeling as a Data Assimilation Approach

PubMed Central

Behrouzvaziri, Abolhassan; Fu, Daniel; Tan, Patrick; Yoo, Yeonjoo; Zaretskaia, Maria V.; Rusyniak, Daniel E.; Molkov, Yaroslav I.; Zaretsky, Dmitry V.

2015-01-01

Experimental Data Orexinergic neurotransmission is involved in mediating temperature responses to methamphetamine (Meth). In experiments in rats, SB-334867 (SB), an antagonist of orexin receptors (OX1R), at a dose of 10 mg/kg decreases late temperature responses (t>60 min) to an intermediate dose of Meth (5 mg/kg). A higher dose of SB (30 mg/kg) attenuates temperature responses to low dose (1 mg/kg) of Meth and to stress. In contrast, it significantly exaggerates early responses (t<60 min) to intermediate and high doses (5 and 10 mg/kg) of Meth. As pretreatment with SB also inhibits temperature response to the stress of injection, traditional statistical analysis of temperature responses is difficult. Mathematical Modeling We have developed a mathematical model that explains the complexity of temperature responses to Meth as the interplay between excitatory and inhibitory nodes. We have extended the developed model to include the stress of manipulations and the effects of SB. Stress is synergistic with Meth on the action on excitatory node. Orexin receptors mediate an activation of on both excitatory and inhibitory nodes by low doses of Meth, but not on the node activated by high doses (HD). Exaggeration of early responses to high doses of Meth involves disinhibition: low dose of SB decreases tonic inhibition of HD and lowers the activation threshold, while the higher dose suppresses the inhibitory component. Using a modeling approach to data assimilation appears efficient in separating individual components of complex response with statistical analysis unachievable by traditional data processing methods. PMID:25993564

Long-Term Coffee Consumption Is Associated with Decreased Incidence of New-Onset Hypertension: A Dose-Response Meta-Analysis.

PubMed

Grosso, Giuseppe; Micek, Agnieszka; Godos, Justyna; Pajak, Andrzej; Sciacca, Salvatore; Bes-Rastrollo, Maira; Galvano, Fabio; Martinez-Gonzalez, Miguel A

2017-08-17

To perform a dose-response meta-analysis of prospective cohort studies investigating the association between long-term coffee intake and risk of hypertension. An online systematic search of studies published up to November 2016 was performed. Linear and non-linear dose-response meta-analyses were conducted; potential evidence of heterogeneity, publication bias, and confounding effect of selected variables were investigated through sensitivity and meta-regression analyses. Seven cohorts including 205,349 individuals and 44,120 cases of hypertension were included. In the non-linear analysis, there was a 9% significant decreased risk of hypertension per seven cups of coffee a day, while, in the linear dose-response association, there was a 1% decreased risk of hypertension for each additional cup of coffee per day. Among subgroups, there were significant inverse associations for females, caffeinated coffee, and studies conducted in the US with longer follow-up. Analysis of potential confounders revealed that smoking-related variables weakened the strength of association between coffee consumption and risk of hypertension. Increased coffee consumption is associated with a modest decrease in risk of hypertension in prospective cohort studies. Smoking status is a potential effect modifier on the association between coffee consumption and risk of hypertension.

Modulating effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin secretion in male rats.

PubMed Central

Matton, A.; Engelborghs, S.; Bollengier, F.; Finné, E.; Vanhaeist, L.

1996-01-01

1. The effect of the nootropic drug, piracetam on stress- and subsequent morphine-induced prolactin (PRL) secretion was investigated in vivo in male rats, by use of a stress-free blood sampling and drug administration method by means of a permanent indwelling catheter in the right jugular vein. 2. Four doses of piracetam were tested (20, 100, 200 and 400 mg kg-1), being given intraperitoneally 1 h before blood sampling; control rats received saline instead. After a first blood sample, rats were subjected to immobilization stress and received morphine, 6 mg kg-1, 90 min later. 3. Piracetam had no effect on basal plasma PRL concentration. 4. While in the non-piracetam-treated rats, stress produced a significant rise in plasma PRL concentration, in the piracetam-pretreated rats PRL peaks were attenuated, especially in the group given 100 mg kg-1 piracetam, where plasma PRL concentration was not significantly different from basal values. The dose-response relationship showed a U-shaped curve; the smallest dose had a minor inhibitory effect and the highest dose had no further effect on the PRL rise. 5. In unrestrained rats, morphine led to a significant elevation of plasma PRL concentration. After the application of immobilization stress it lost its ability to raise plasma PRL concentration in the control rats, but not in the piracetam-treated rats. This tolerance was overcome by piracetam in a significant manner but with a reversed dose-response curve; i.e. the smaller the dose of piracetam, the higher the subsequent morphine-induced PRL peak. 6. There is no simple explanation for the mechanism by which piracetam induces these contradictory effects. Interference with the excitatory amino acid system, which is also involved in opiate action, is proposed speculatively as a possible mediator of the effects of piracetam. PMID:8821540

Influence of environmental enrichment on hypothalamic-pituitary-adrenal (HPA) responses to single-dose nicotine, continuous nicotine by osmotic mini-pumps, and nicotine withdrawal by mecamylamine in male and female rats

PubMed Central

Skwara, Amanda J.; Karwoski, Tracy E.; Czambel, R. Kenneth; Rubin, Robert T.; Rhodes, Michael E.

2012-01-01

In the present study, we determined the effects of environmental enrichment (EE; Kong Toys® and Nestlets®) on sexually diergic HPA axis responses to single-dose nicotine (NIC), single-dose NIC following continuous NIC administration for two weeks, and NIC withdrawal by single-dose mecamylamine (MEC) in male and female rats. Blood sampling occurred before and after MEC and NIC administrations for the determination of adrenocorticotropic hormone (ACTH) and corticosterone (CORT). Supporting and extending our previous findings, EE appeared to produce anxiolytic effects by reducing hormone responses: Male and female rats housed with EE had lower baseline ACTH and significantly lower HPA axis responses to the mild stress of saline (SAL) injection than did those housed without EE. The sexually diergic responses to single dose NIC, continuous NIC, and MEC-induced NIC withdrawal were reduced by EE in many male and female groups. ACTH responses to continuous NIC and MEC-induced NIC withdrawal were blunted to a greater extent in female EE groups than in male EE groups, suggesting that females are more sensitive to the anxiolytic effects of EE. Because EE lowered stress-responsive hormones of the HPA axis in most groups, EE may be a useful intervention for stress reduction in animal models of NIC addiction. As well, the effectiveness of EE in animal studies of NIC withdrawal may enlighten human studies addressing coping styles and tobacco cessation in men and women. PMID:22705101

Effect of Brain Stem and Dorsal Vagus Complex Dosimetry on Nausea and Vomiting in Head and Neck Intensity-Modulated Radiation Therapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ciura, Katherine; McBurney, Michelle; Nguyen, Baongoc

Intensity-modulated radiation therapy (IMRT) is becoming the treatment of choice for many head and neck cancer patients. IMRT reduces some toxicities by reducing radiation dose to uninvolved normal tissue near tumor targets; however, other tissues not irradiated using previous 3D techniques may receive clinically significant doses, causing undesirable side effects including nausea and vomiting (NV). Irradiation of the brainstem, and more specifically, the area postrema and dorsal vagal complex (DVC), has been linked to NV. We previously reported preliminary hypothesis-generating dose effects associated with NV in IMRT patients. The goal of this study is to relate brainstem dose to NVmore » symptoms. We retrospectively studied 100 consecutive patients that were treated for oropharyngeal cancer with IMRT. We contoured the brainstem, area postrema, and DVC with the assistance of an expert diagnostic neuroradiologist. We correlated dosimetry for the 3 areas contoured with weekly NV rates during IMRT. NV rates were significantly higher for patients who received concurrent chemotherapy. Post hoc analysis demonstrated that chemoradiation cases exhibited a trend towards the same dose-response relationship with both brainstem mean dose (p = 0.0025) and area postrema mean dose (p = 0.004); however, both failed to meet statistical significance at the p {<=} 0.002 level. Duration of toxicity was also greater for chemoradiation patients, who averaged 3.3 weeks with reported Common Terminology Criteria for Adverse Events (CTC-AE), compared with an average of 2 weeks for definitive RT patients (p = 0.002). For definitive RT cases, no dose-response trend could be ascertained. The mean brainstem dose emerged as a key parameter of interest; however, no one dose parameter (mean/median/EUD) best correlated with NV. This study does not address extraneous factors that would affect NV incidence, including the use of antiemetics, nor chemotherapy dose schedule specifics before and during RT. A prospective study will be required to depict exactly how IMRT dose affects NV.« less

A dual inhibitor of FAAH and TRPV1 channels shows dose-dependent effect on depression-like behaviour in rats.

PubMed

Kirkedal, Christian; Wegener, Gregers; Moreira, Fabricio; Joca, Sâmia Regiane Lourenco; Liebenberg, Nico

2017-12-01

The cannabinoid receptor 1 (CB1) and transient receptor potential cation channel subfamily V member 1 (TRPV1) are proposed to mediate opposite behavioural responses. Their common denominator is the endocannabinoid ligand anandamide (AEA), which is believed to mediate antidepressant-like effect via CB1-R stimulation and depressive-like effect via TRPV1 activation. This is supposed to explain the bell-shaped dose-response curve for anandamide in preclinical models. We investigated this assumption by administering the dual inhibitor of AEA hydrolysis and TRPV1 activation N-arachidonoyl-serotonin (AA-5HT) into the medial prefrontal cortex of rats. AA-5HT was given in three different doses (0.125, 0.250, 0.500 nmol/0.4 µl/side) and rat behaviour was assessed in the forced swim test. Our results show significant antidepressant-like effect of AA-5HT (0.250 nmol) but no effects of low or high doses. The effect of 0.250 nmol AA-5HT was partially attenuated when coadministering the inverse CB1-agonist rimonabant (1.6 µg). A 0.250 nmol of AA-5HT administration into the medial prefrontal cortex induced a significant antidepressant-like effect that was partially attenuated by locally blocking CB1-receptor.

Polymer gel dosimeters with reduced toxicity: a preliminary investigation of the NMR and optical dose response using different monomers

NASA Astrophysics Data System (ADS)

Senden, R. J.; DeJean, P.; McAuley, K. B.; Schreiner, L. J.

2006-07-01

In this work, three new polymer gel dosimeter recipes were investigated that may be more suitable for widespread applications than polyacrylamide gel dosimeters, since the extremely toxic acrylamide has been replaced with the less harmful monomers N-isopropylacrylamide (NIPAM), diacetone acrylamide and N-vinylformamide. The new gel dosimeters studied contained gelatin (5 wt%), monomer (3 wt%), N,N'-methylene-bis-acrylamide crosslinker (3 wt%) and tetrakis (hydroxymethyl) phosphonium chloride antioxidant (10 mM). The NMR response (R2) of the dosimeters was analysed for conditions of varying dose, dose rate, time post-irradiation, and temperature during irradiation and scanning. It was shown that the dose-response behaviour of the NIPAM/Bis gel dosimeter is comparable to that of normoxic polyacrylamide gel (PAGAT) in terms of high dose-sensitivity and low dependence on dose rate and irradiation temperature, within the ranges considered. The dose-response (R2) of NIPAM/Bis appears to be linear over a greater dose range than the PAGAT gel dosimeter. The effects of time post-irradiation (temporal instability) and temperature during NMR scanning on the R2 response were more significant for NIPAM/Bis dosimeters. Diacetone acrylamide and N-vinylformamide gel dosimeters possessed considerably lower dose-sensitivities. The optical dose-response, measured in terms of the attenuation coefficient for each polymer gel dosimeter, showed potential for the use of optical imaging techniques in future studies.

Responsibility Study: Main Illicit Psychoactive Substances Among Car Drivers Involved in Fatal Road Crashes

PubMed Central

Gadegbeku, Blandine; Amoros, Emmanuelle; Laumon, Bernard

2011-01-01

In 1999, in France, before considering modifications in drug legislation, the government requested a study of the effect of illicit drugs on the risk of road crashes. It implemented a systematic screening of illicit drugs for all drivers involved in fatal crashes between October 2001 and September 2003. Within the European DRUID project, the study was restricted to car drivers. The project reported here is a responsibility analysis and, as such, it belongs to the framework of case-control studies; the outcome of interest is “being responsible for a fatal crash”. It was assessed with a method adapted from Robertson and Drummer. Cases are the 4,946 car drivers who are responsible for the crash; controls are the 1,986 car drivers selected from the non-responsible car drivers, in a way that makes the control group similar to the general driving population. The effect of cannabis on fatal crash responsibility is significant after adjustment for age, sex and alcohol: adjusted odds ratio is 1.89 [1.43–2.51]. The dose-response effect is significant (p=0.0001). For alcohol (≥0.1 g/l), the adjusted odds ratio for responsibility is 8.39 [6.95–10.11]. No interaction was found between alcohol and cannabis. For amphetamine, cocaine and opiates, adjusted odds ratios were not significantly different from 1. However the statistical power is low. The study finds similar odds ratios for alcohol as previously published. For cannabis, the significant odds ratio together with the significant dose-response effect indicates a causal relationship between cannabis and road crashes. A multiplicative effect between cannabis and alcohol was noted. PMID:22105404

Chronic prazosin attenuates the natriuretic response to a modest saline load in anaesthetized rats.

PubMed Central

Penner, S. B.; Smyth, D. D.

1988-01-01

1. The effect of chronic prazosin pretreatment (3 days) on the ability to excrete a modest saline load (i.v. saline, 0.097 ml min-1) was studied in the anaesthetized rat. Three days before the experiment, the drinking water was replaced with 0.5% dextrose (control), 0.015 mg ml-1 prazosin in 0.5% dextrose (low dose) or 0.15 mg ml-1 prazosin in 0.5% dextrose (high dose). 2. The selectivity of the prazosin for alpha 1-adrenoceptors was evaluated in pithed rats. The pressor response to phenylephrine was partially attenuated by the low dose of prazosin and completely attenuated by the high dose of prazosin. The pressor response to clonidine was slightly decreased by the 3 day prazosin pretreatment indicating a selectivity for alpha 1-adrenoceptors. 3. In rats pretreated with the low dose of prazosin, there was a significant decrease in sodium and water, but not potassium excretion as compared to the control group. Captopril failed to alter these effects of the low dose of prazosin. Blood pressure and creatinine clearance were the same in both groups. In rats pretreated with the high dose of prazosin, there was a further decrease in sodium and water but not potassium excretion. However, this dose of prazosin also significantly decreased blood pressure and increased creatinine clearance. A decrease in renal perfusion pressure with an aortic clamp to the same level as that observed with the high prazosin dose also decreased sodium and water but not potassium excretion. The decrease in sodium and water excretion was not as great as that observed with the high dose of prazosin.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2896036

Conventional and conformal technique of external beam radiotherapy in locally advanced cervical cancer: Dose distribution, tumor response, and side effects

NASA Astrophysics Data System (ADS)

Mutrikah, N.; Winarno, H.; Amalia, T.; Djakaria, M.

2017-08-01

The objective of this study was to compare conventional and conformal techniques of external beam radiotherapy (EBRT) in terms of the dose distribution, tumor response, and side effects in the treatment of locally advanced cervical cancer patients. A retrospective cohort study was conducted on cervical cancer patients who underwent EBRT before brachytherapy in the Radiotherapy Department of Cipto Mangunkusumo Hospital. The prescribed dose distribution, tumor response, and acute side effects of EBRT using conventional and conformal techniques were investigated. In total, 51 patients who underwent EBRT using conventional techniques (25 cases using Cobalt-60 and 26 cases using a linear accelerator (LINAC)) and 29 patients who underwent EBRT using conformal techniques were included in the study. The distribution of the prescribed dose in the target had an impact on the patient’s final response to EBRT. The complete response rate of patients to conformal techniques was significantly greater (58%) than that of patients to conventional techniques (42%). No severe acute local side effects were seen in any of the patients (Radiation Therapy Oncology Group (RTOG) grades 3-4). The distribution of the dose and volume to the gastrointestinal tract affected the proportion of mild acute side effects (RTOG grades 1-2). The urinary bladder was significantly greater using conventional techniques (Cobalt-60/LINAC) than using conformal techniques at 72% and 78% compared to 28% and 22%, respectively. The use of conformal techniques in pelvic radiation therapy is suggested in radiotherapy centers with CT simulators and 3D Radiotherapy Treatment Planning Systems (RTPSs) to decrease some uncertainties in radiotherapy planning. The use of AP/PA pelvic radiation techniques with Cobalt-60 should be limited in body thicknesses equal to or less than 18 cm. When using conformal techniques, delineation should be applied in the small bowel, as it is considered a critical organ according to RTOG consensus guidelines.

Dose rate mapping of VMAT treatments

NASA Astrophysics Data System (ADS)

Podesta, Mark; Antoniu Popescu, I.; Verhaegen, Frank

2016-06-01

Human tissues exhibit a varying response to radiation dose depending on the dose rate and fractionation scheme used. Dose rate effects have been reported for different radiations, and tissue types. The literature indicates that there is not a significant difference in response for low-LET radiation when using dose rates between 1 Gy min-1 and 12 Gy min-1 but lower dose rates have an observable sparing effect on tissues and a differential effect between tissues. In intensity-modulated radiotherapy such as volumetric modulated arc therapy (VMAT) the dose can be delivered with a wide range of dose rates. In this work we developed a method based on time-resolved Monte Carlo simulations to quantify the dose rate frequency distribution for clinical VMAT treatments for three cancer sites, head and neck, lung, and pelvis within both planning target volumes (PTV) and normal tissues. The results show a wide range of dose rates are used to deliver dose in VMAT and up to 75% of the PTV can have its dose delivered with dose rates  <1 Gy min-1. Pelvic plans on average have a lower mean dose rate within the PTV than lung or head and neck plans but a comparable mean dose rate within the organs at risk. Two VMAT plans that fulfil the same dose objectives and constraints may be delivered with different dose rate distributions, particularly when comparing single arcs to multiple arc plans. It is concluded that for dynamic plans, the dose rate range used varies to a larger degree than previously assumed. The effect of the dose rate range in VMAT on clinical outcome is unknown.

Effect of noni (Morinda citrifolia Linn.) fruit and its bioactive principles scopoletin and rutin on rat vas deferens contractility: an ex vivo study.

PubMed

Pandy, Vijayapandi; Narasingam, Megala; Kunasegaran, Thubasni; Murugan, Dharmani Devi; Mohamed, Zahurin

2014-01-01

This study examined the effect of methanolic extract of Morinda citrifolia Linn. (MMC) and its bioactive principles, scopoletin and rutin, on dopamine- and noradrenaline-evoked contractility in isolated rat vas deferens preparations. MMC (1-40 mg/mL), scopoletin (1-200 μg/mL), and rutin hydrate (0.6-312.6 μg/mL) dose-dependently inhibited the contractility evoked by submaximal concentrations of both dopamine and noradrenaline, respectively. Haloperidol and prazosin, reference dopamine D2, and α 1-adrenoceptors antagonists significantly reversed the dopamine- and noradrenaline-induced contractions, respectively, in a dose-dependent manner. Interestingly, MMC per se at higher doses (60-100 mg/mL) showed dose-dependent contractile response in rat vas deferens which was partially inhibited by high doses of haloperidol but not by prazosin. These results demonstrated the biphasic effects of MMC on dopaminergic system; that is, antidopaminergic effect at lower concentrations (<40 mg/mL) and dopaminergic agonistic effect at higher concentrations (>60 mg/mL). However, similar contractile response at high doses of scopoletin (0.5-5 mg/mL) and rutin hydrate (0.5-5 mg/mL) per se was not observed. Therefore, it can be concluded that the bioactive principles of MMC, scopoletin, and rutin might be responsible for the antidopaminergic and antiadrenergic activities of MMC.

High dose psilocybin is associated with positive subjective effects in healthy volunteers.

PubMed

Nicholas, Christopher R; Henriquez, Kelsey M; Gassman, Michele C; Cooper, Karen M; Muller, Daniel; Hetzel, Scott; Brown, Randall T; Cozzi, Nicholas V; Thomas, Chantelle; Hutson, Paul R

2018-06-01

The aim of the current study was to investigate the relationship between escalating higher doses of psilocybin and the potential psilocybin occasioned positive subjective effects. Healthy participants ( n=12) were given three escalating doses of oral psilocybin (0.3 mg/kg; 0.45 mg/kg; 0.6 mg/kg) or (18.8-36.6 mg; 27.1-54.0 mg; 36.3-59.2 mg) a minimum of four weeks apart in a supervised setting. Blood and urine samples, vital signs, and electrocardiograms were obtained. Subjective effects were assessed using the Mystical Experience Questionnaire and Persisting Effects Questionnaire. There was a significant linear dose-related response in Mystical Experience Questionnaire total score and the transcendence of time and space subscale, but not in the rate of a complete mystical experience. There was also a significant difference between dose 3 compared to dose 1 on the transcendence of time and space subscale, while no dose-related differences were found for Mystical Experience Questionnaire total scores or rate of a mystical experience. Persisting Effects Questionnaire positive composite scores 30 days after completion of the last dose were significantly higher than negative composite scores. Persisting Effects Questionnaire results revealed a moderate increase in sense of well-being or life satisfaction on average that was associated with the maximum Mystical Experience Questionnaire total score. Pharmacokinetic measures were associated with dose but not with Mystical Experience Questionnaire total scores or rate of a mystical experience. High doses of psilocybin elicited subjective effects at least as strong as the lower doses and resulted in positive persisting subjective effects 30 days after, indicating that a complete mystical experience was not a prerequisite for positive outcomes.

Blood phenylalanine concentrations in patients with PAH-deficient hyperphenylalaninaemia off diet without and with three different single oral doses of tetrahydrobiopterin: assessing responsiveness in a model of statistical process control.

PubMed

Lindner, M; Gramer, G; Garbade, S F; Burgard, P

2009-08-01

Tetrahydrobiopterin (BH(4)) cofactor loading is a standard procedure to differentiate defects of BH(4) metabolism from phenylalanine hydroxylase (PAH) deficiency. BH(4) responsiveness also exists in PAH-deficient patients with high residual PAH activity. Unexpectedly, single cases with presumed nil residual PAH activity have been reported to be BH(4) responsive, too. BH(4) responsiveness has been defined either by a >or=30% reduction of blood Phe concentration after a single BH(4) dose or by a decline greater than the individual circadian Phe level variation. Since both methods have methodological disadvantages, we present a model of statistical process control (SPC) to assess BH(4) responsiveness. Phe levels in 17 adult PKU patients of three phenotypic groups off diet were compared without and with three different single oral dosages of BH(4) applied in a double-blind randomized cross-over design. Results are compared for >or=30% reduction and SPC. The effect of BH(4) by >or=30% reduction was significant for groups (p < 0.01) but not for dose (p = 0.064), with no interaction of group with dose (p = 0.24). SPC revealed significant effects for group (p < 0.01) and the interaction for group with dose (p < 0.05) but not for dose alone (p = 0.87). After one or more loadings, seven patients would be judged to be BH(4) responsive either by the 30% criterion or by the SPC model, but only three by both. Results for patients with identical PAH genotype were not very consistent within (for different BH(4) doses) and between the two models. We conclude that a comparison of protein loadings without and with BH(4) combined with a standardized procedure for data analysis and decision would increase the reliability of diagnostic results.

Effects of propranolol on conversational reciprocity in autism spectrum disorder: a pilot, double-blind, single-dose psychopharmacological challenge study.

PubMed

Zamzow, Rachel M; Ferguson, Bradley J; Stichter, Janine P; Porges, Eric C; Ragsdale, Alexandra S; Lewis, Morgan L; Beversdorf, David Q

2016-04-01

Pharmacological intervention for autism spectrum disorder (ASD) is an important addition to treatment, yet currently available agents target co-morbid psychiatric concerns, such as aggression and irritability. Propranolol, a beta-adrenergic antagonist with anxiolytic effects, has been shown to improve verbal fluency and working memory in adults and adolescents with ASD in single-dose challenges. The present pilot study explores the acute effects of propranolol on a measure of conversational reciprocity in this population. We also examined whether autonomic activity and anxiety moderate or mediate response to the drug, given relationships between these variables and ASD, as well as the drug's effects. In a within-subject crossover design, 20 individuals with ASD received a single dose of propranolol or placebo during two sessions in a double-blinded, counterbalanced manner. After drug administration, participants performed a conversational reciprocity task by engaging in a short conversation with the researcher. Measurements of autonomic activity and anxiety were obtained before and after drug administration. Propranolol significantly improved performance on the conversational reciprocity task total [d = 0.40] and nonverbal communication domain scores when compared to the placebo condition. However, neither autonomic activity nor anxiety was significantly associated with drug response. Acute propranolol administration improved conversational reciprocity in ASD. Further exploration of these preliminary findings, as well as other potential treatment response predictors, with serial doses is warranted.

Comparison of increased aspirin dose versus combined aspirin plus clopidogrel therapy in patients with diabetes mellitus and coronary heart disease and impaired antiplatelet response to low-dose aspirin.

PubMed

Duzenli, Mehmet Akif; Ozdemir, Kurtulus; Aygul, Nazif; Soylu, Ahmet; Tokac, Mehmet

2008-08-15

The effects of therapy with aspirin 300 mg/day and with combined aspirin 100 mg/day plus clopidogrel 75 mg/day on platelet function were compared in patients with diabetes mellitus and coronary artery disease and impaired antiplatelet responses to aspirin 100 mg/day. The study population consisted of 151 outpatients with type II diabetes mellitus and coronary artery disease who were taking aspirin 100 mg/day. Of the 151 patients, a subgroup of subjects with impaired aspirin response were selected on the basis of the results of platelet aggregometry. Nonresponsiveness to aspirin was defined as mean aggregation > or =69% with 3 micromol/L adenosine diphosphate and mean aggregation > or =70% with 2 micromol/L collagen. Aspirin semiresponders were defined as meeting 1 but not both of these criteria. Nonresponders and semiresponders were randomized equally to aspirin 300 mg/day and aspirin 100 mg/day plus clopidogrel 75 mg/day, and aggregation tests were repeated after 2 weeks. Sixty of the 151 patients with diabetes (40%) were found to respond to aspirin inadequately. Platelet aggregation induced by adenosine diphosphate and collagen decreased significantly after aspirin 300 mg/day or combined therapy. Combined treatment was found to have a stronger inhibitory effect on platelet aggregation induced by adenosine diphosphate than aspirin 300 mg/day (p = 0.002). Impaired aspirin response was resolved by increasing the aspirin dose or adding clopidogrel to aspirin (p <0.0001 for each). However, desired platelet inhibition was achieved in significantly more patients by combined treatment than by aspirin 300 mg/day (p <0.05). In conclusion, aspirin 100 mg/day does not inhibit platelet function adequately in a significant number of patients with diabetes mellitus and coronary artery disease. Increasing the aspirin dose to 300 mg/day or adding clopidogrel to aspirin can provide adequate platelet inhibition in a significant number of those patients with impaired responses to low-dose aspirin.

The acute physiological and mood effects of tea and coffee: the role of caffeine level.

PubMed

Quinlan, P T; Lane, J; Moore, K L; Aspen, J; Rycroft, J A; O'Brien, D C

2000-05-01

The objective of this study was to determine the effect of caffeine level in tea and coffee on acute physiological responses and mood. Randomised full crossover design in subjects after overnight caffeine abstention was studied. In study 1 (n = 17) the caffeine level was manipulated naturalistically by preparing tea and coffee at different strengths (1 or 2 cups equivalent). Caffeine levels were 37.5 and 75 mg in tea, 75 and 150 mg in coffee, with water and no-drink controls. In study 2 (n = 15) caffeine level alone was manipulated (water, decaffeinated tea, plus 0, 25, 50, 100, and 200 mg caffeine). Beverage volume and temperature (55 degrees C) were constant. SBP, DBP, heart rate, skin temperature, skin conductance, and mood were monitored over each 3-h study session. In study 1, tea and coffee produced mild autonomic stimulation and an elevation in mood. There were no effects of tea vs. coffee or caffeine dose, despite a fourfold variation in the latter. Increasing beverage strength was associated with greater increases in DBP and energetic arousal. In study 2, caffeinated beverages increased SBP, DBP, and skin conductance and lowered heart rate and skin temperature compared to water. Significant dose-response relationships to caffeine were seen only for SBP, heart rate, and skin temperature. There were significant effects of caffeine on energetic arousal but no consistent dose-response effects. Caffeinated beverages acutely stimulate the autonomic nervous system and increase alertness. Although caffeine can exert dose-dependent effects on a number of acute autonomic responses, caffeine level is not an important factor. Factors besides caffeine may contribute to these acute effects.

Response to noise from modern wind farms in The Netherlands.

PubMed

Pedersen, Eja; van den Berg, Frits; Bakker, Roel; Bouma, Jelte

2009-08-01

The increasing number and size of wind farms call for more data on human response to wind turbine noise, so that a generalized dose-response relationship can be modeled and possible adverse health effects avoided. This paper reports the results of a 2007 field study in The Netherlands with 725 respondents. A dose-response relationship between calculated A-weighted sound pressure levels and reported perception and annoyance was found. Wind turbine noise was more annoying than transportation noise or industrial noise at comparable levels, possibly due to specific sound properties such as a "swishing" quality, temporal variability, and lack of nighttime abatement. High turbine visibility enhances negative response, and having wind turbines visible from the dwelling significantly increased the risk of annoyance. Annoyance was strongly correlated with a negative attitude toward the visual impact of wind turbines on the landscape. The study further demonstrates that people who benefit economically from wind turbines have a significantly decreased risk of annoyance, despite exposure to similar sound levels. Response to wind turbine noise was similar to that found in Sweden so the dose-response relationship should be generalizable.

Effect of Two Different Doses of Dexmedetomidine on Stress Response in Laparoscopic Pyeloplasty: A Randomized Prospective Controlled Study.

PubMed

Shamim, Rafat; Srivastava, Shashi; Rastogi, Amit; Kishore, Kamal; Srivastava, Aneesh

2017-01-01

Clonidine, opioids, β-blockers, and dexmedetomidine have been tried to attenuate stress responses during laparoscopic surgery. We evaluated the efficacy of dexmedetomidine in two different doses in attenuating stress responses on patients undergoing laparoscopic pyeloplasty. Ninety patients were assigned to one of the three groups: Group A, Group B, and Group C. Group B received dexmedetomidine 1 mcg/kg as loading dose, followed by 0.7 mcg/kg/h for maintenance; Group C received dexmedetomidine 0.7 mcg/kg as a loading dose, followed by 0.5 mcg/kg/h for maintenance. Group A received normal saline. Stress responses were assessed by the variations in heart rate (HR), mean arterial pressure (MAP), blood glucose levels, and serum cortisol levels. One-way analysis of variance test was applied. Multiple comparisons between groups were done with post hoc Bonferroni test. The HR and MAP were found to be higher in Group A. The difference was statistically significant ( P < 0.05) during intubation, carbon dioxide insufflation, and extubation when compared with Groups B and C. Blood glucose levels at postintubation and at extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. Serum cortisol levels at postintubation, during midsurgery, and 2 h after extubation were higher in Group A and statistically significant ( P < 0.05) when compared with Groups B and C. However, HR, MAP, blood glucose levels, and serum cortisol levels were similar in dexmedetomidine groups. Dexmedetomidine decreases stress response and provides good condition for maintenance of anesthesia. Dexmedetomidine when used in lower dose in Group C decreases stress response comparable to higher dose in Group B.

Pharmacology of o-chlorobenzylidene malononitrile (CS)

PubMed Central

Brimblecombe, R. W.; Green, D. M.; Muir, A. W.

1972-01-01

1. The effects of o-chlorobenzylidene malononitrile (CS) have been studied on several isolated organs and tissues, anaesthetized animals and cat encéphale isolé preparations. 2. On the isolated guinea-pig ileum an initial dose of CS produced a small, non-maintained contraction. Subsequent doses had reduced effects. There was no effect on peristalsis when the substance was given intraluminally. 3. No significant effects of CS were detected on the rat phrenic nerve-diaphragm preparation, the isolated perfused rabbit heart or on the contractor response of the indirectly stimulated cat tibialis muscle. 4. In the cat encéphale isolé preparation 1 mg/kg (i.v.) produced a brief period of electrocortical alerting but no abnormal activity in the electrocorticogram. Doses in excess of 10 mg/kg produced cortical depression. 5. Intravascular injection into the chloralose anaesthetized cat resulted typically in a pressor response accompanied by a brief period of apnoea. The threshold dose for the pressor response varied with the route of administration, but generally lay between 2·5 and 12·5 μg/kg; the threshold dose for apnoea was slightly higher. Small variations in this pattern of response were seen with different species and other anaesthetics. 6. When administered by stomach tube to chloralose anaesthetized cats, CS produced no measurable effects at doses of up to 100 mg/kg. 7. No changes in blood pressure or respiration were detected in anaesthetized cats given pure CS aerosol for 1 h in concentrations of between 345 mg/m3 and 1·39 g/m3 via a tracheal cannula or through the upper respiratory tract. Pure CS solution given by slow intravenous infusion at a similar dose and over a similar period produced significant effects on blood pressure and respiration. 8. Pyrotechnically generated (grenade) CS produced variable effects when given by inhalation in concentrations of between 460 and 1,040 mg/m3 for 1 hour. Respiratory depression, possibly reflex in nature, regularly occurred when the material was given via the upper respiratory tract, and respiratory stimulation occurred when it was given via a tracheal cannula. 9. Some cats were pre-exposed to a dose of 500 (mg/min)/m3 on 4 successive days and on the fifth day anaesthetized and exposed to high concentrations of grenade CS. Three out of six cats died during or after this final exposure compared to one out of six among animals not so pre-exposed. The general pattern of response to the final exposure to CS in the two groups was similar. PMID:5040666

Targeted nanoparticle delivery of therapeutic antisense microRNAs presensitizes glioblastoma cells to lower effective doses of temozolomide in vitro and in a mouse model.

PubMed

Malhotra, Meenakshi; Sekar, Thillai Veerapazham; Ananta, Jeyarama S; Devulapally, Rammohan; Afjei, Rayhaneh; Babikir, Husam A; Paulmurugan, Ramasamy; Massoud, Tarik F

2018-04-20

Temozolomide (TMZ) chemotherapy for glioblastoma (GBM) is generally well tolerated at standard doses but it can cause side effects. GBMs overexpress microRNA-21 and microRNA-10b, two known oncomiRs that promote cancer development, progression and resistance to drug treatment. We hypothesized that systemic injection of antisense microRNAs (antagomiR-21 and antagomiR-10b) encapsulated in cRGD-tagged PEG-PLGA nanoparticles would result in high cellular delivery of intact functional antagomiRs, with consequent efficient therapeutic response and increased sensitivity of GBM cells to lower doses of TMZ. We synthesized both targeted and non-targeted nanoparticles, and characterized them for size, surface charge and encapsulation efficiency of antagomiRs. When using targeted nanoparticles in U87MG and Ln229 GBM cells, we showed higher uptake-associated improvement in sensitivity of these cells to lower concentrations of TMZ in medium. Co-inhibition of microRNA-21 and microRNA-10b reduced the number of viable cells and increased cell cycle arrest at G2/M phase upon TMZ treatment. We found a significant increase in expression of key target genes for microRNA-21 and microRNA-10b upon using targeted versus non-targeted nanoparticles. There was also significant reduction in tumor volume when using TMZ after pre-treatment with loaded nanoparticles in human GBM cell xenografts in mice. In vivo targeted nanoparticles plus different doses of TMZ showed a significant therapeutic response even at the lowest dose of TMZ, indicating that preloading cells with antagomiR-21 and antagomiR-10b increases cellular chemosensitivity towards lower TMZ doses. Future clinical applications of this combination therapy may result in improved GBM response by using lower doses of TMZ and reducing nonspecific treatment side effects.

No regional difference in cisatracurium dose-response and time-course-of-action between patients in China and Bosnia.

PubMed

Dahaba, A A; Suljevic, I; Bornemann, H; Wu, X-M; Metzler, H

2011-03-01

Variability in drug response could result from a variety of genetic and environmental factors that are often hard to define or quantify. A number of studies demonstrated regional geographic variations in potency of neuromuscular blocking agents (NMBAs). The aim of our study was to compare dose-response and time-course-of-action of cisatracurium besylate, an NMBA eliminated via the Hoffman degradation, in two countries with different life habits, diet, and ambient conditions; being Han Chinese in China and Caucasians in Bosnia. Neuromuscular block of cisatracurium 20 µg kg(-1), followed by four incremental 10 µg kg(-1) doses, and the remainder of 100 µg kg(-1) was evaluated using the Relaxometer mechanomyograph (Groningen University, Groningen, The Netherlands). Dose-response curves were created using log-dose-probit-response transformation. There were no significant differences in cisatracurium mean (95% confidence intervals) ED(50), ED(90), and ED(95) (effective doses for 50%, 90%, and 95% first twitch depression) in Caucasian [39.1 (35.7-42.3), 50.6 (45.5-54.3), and 54.4 (49.8-58.9) µg kg(-1)] compared with Chinese patients [39.2 (35.1-43.1), 52.4 (47.9-56.8), and 56.9 (52.8-61.9) µg kg(-1)], respectively. There were no significant differences in mean (sd) Dur(25) and Dur(0.9) (time until 25% first twitch and 0.9 train-of-four ratio recoveries) in Caucasian [47.1 (6.4) and 77.5 (9.1) min)] compared with Chinese patients [(45.9 (4.7) and 72.3 (9.1) min)], respectively. Cisatracurium dose-response relationship and time-course-of-action were not influenced by geographic location. Thus, cisatracurium would not require dose adjustments between patients living in the two geographic locations.

Superoxide scavenging effects of N-acetylcysteine and vitamin C in subjects with essential hypertension.

PubMed

Schneider, Markus P; Delles, Christian; Schmidt, Bernhard M W; Oehmer, Sebastian; Schwarz, Thomas K; Schmieder, Roland E; John, Stefan

2005-08-01

It is not known whether the beneficial effects of N-acetylcysteine (NAC) in conditions associated with increased oxidative stress are caused by direct superoxide scavenging. We therefore compared the acute superoxide scavenging efficacy of NAC against vitamin C (VITC) on impaired endothelium-dependent vasodilation in subjects with essential hypertension. In a cross-over randomized study, the effects of intra-arterial administration of either NAC (48 mg/min) or VITC (18 mg/min) were examined in 15 subjects with essential hypertension and in 15 normotensive control subjects. Both endothelium-dependent and endothelium-independent vasodilation were determined as forearm blood flow (FBF) response to the intra-arterial administration of acetylcholine (Ach) and sodium nitroprusside (NP) in doses of 12 and 48 mug/min and 3.2 and 12.8 mug/min, respectively. Subjects with essential hypertension had impaired responses to both doses of Ach (Delta% FBF to higher dose of Ach: 325 +/- 146 in subjects with essential hypertension v 540 +/- 199 in control subjects; P = .02) and an impaired response to the higher dose of NP (330 +/- 108 v 500 +/- 199; P = .03). The intra-arterial administration of NAC had no effect on these responses (higher dose of Ach: 325 +/- 146 without v 338 +/- 112 with NAC, NS). In contrast, intra-arterial VITC improved both the response to Ach (320 +/- 132 without v 400 +/- 185 with VITC, P = .05) and to NP (383 +/- 162 v 447 +/- 170, P = .05). We found that NAC showed no statistically significant effect on either endothelium-dependent or endothelium-independent vasodilation in hypertensive subjects, whereas VITC did. We conclude that NAC is therefore not an effective superoxide scavenger in vivo. Other, nonimmediate effects such as the generation of glutathione may explain the beneficial effects of NAC in conditions associated with oxidative stress.

Low-dose right unilateral electroconvulsive therapy (ECT): effectiveness of the first treatment.

PubMed

Lapidus, Kyle A B; Shin, Joseph S W; Pasculli, Rosa M; Briggs, Mimi C; Popeo, Dennis M; Kellner, Charles H

2013-06-01

Electroconvulsive therapy (ECT) is a widely used, highly effective antidepressant treatment. Except for the most severely ill patients, right unilateral (RUL) electrode placement is the most frequent initial treatment choice. In current practice, RUL ECT is administered at several multiples of seizure threshold (ST) based on reports that lower stimulus intensity results in lower response/remission rates. Many patients, as part of an initial dose titration to determine ST, will receive a single treatment with low-dose RUL ECT and subsequent treatments with a stimulus at a multiple of ST. To assess response to the first ECT. A retrospective analysis of charts from clinical practice at Mount Sinai Medical Center was performed. A single treatment with low-dose (presumably near ST) RUL ECT had a significant and immediate antidepressant effect in our sample of patients with major depression. We determined that this response is similar to that of patients receiving a single initial treatment with high-dose RUL ECT (at a multiple of ST). These data suggest, contrary to commonly held belief, that RUL ECT may be effective at a low stimulus dose. This argues against restimulating at 6 times ST in the initial session, based on the belief that the near-threshold seizure has no antidepressant efficacy. Our findings suggest a need for further investigation of cases in which low-dose RUL ECT may be an effective antidepressant treatment. Further prospective studies, including larger numbers of patients who receive randomized treatment with low- or high-dose RUL with longer follow-up, are indicated.

Anti-inflammatory, analgesic and antipyretic effects of Lepidagathis anobrya Nees (Acanthaceae).

PubMed

Richard, Sawadogo Wamtinga; Marius, Lompo; Noya, Somé; Innocent Pierre, Guissou; Germaine, Nacoulma-Ouedraogo Odile

2011-01-01

This study investigated the general acute, anti-inflammatory, analgesic and antipyretic effects of methanol extract of Lepidagathis anobrya Nees (Acanthaceae). Carrageenan-induced rat paw edema and croton oil-induced ear edema in rats were used for the evaluation of general acute anti-inflammatory effects. Acetic acid-induced writhing response and yeast-induced hyperpyrexia in mice were used to evaluate the analgesic and antipyretic activities respectively. The extract at doses of 10, 25, 50 and 100 mgkg(-1) for carrageenan test and doses of 0.5 mg/ear for croton oil test induced a significant reduction (p < 0.001) of paw and ear edemas in rats. In the analgesic and antipyretic tests, the extract has shown a significant inhibition of writhes and hyperpyrexia with all the doses used when compared to the untreated control group. These results clearly show the anti-inflammatory, analgesic and antipyretic effects of the methanol extract of Lepidagathis anobrya and give the scientific basis for its traditional use. Further studies are needed to clarify the mechanism of action and the components responsible for these pharmacological effects.

Comparison of dehydroepiandrosterone (DHEA) and pregnanolone with existing pharmacotherapies for alcohol abuse on ethanol- and food-maintained responding in male rats.

PubMed

Hulin, Mary W; Lawrence, Michelle N; Amato, Russell J; Weed, Peter F; Winsauer, Peter J

2015-03-01

The present study compared two putative pharmacotherapies for alcohol abuse and dependence, dehydroepiandrosterone (DHEA) and pregnanolone, with two Food and Drug Administration (FDA)-approved pharmacotherapies, naltrexone and acamprosate. Experiment 1 assessed the effects of different doses of DHEA, pregnanolone, naltrexone, and acamprosate on both ethanol- and food-maintained responding under a multiple fixed-ratio (FR)-10 FR-20 schedule, respectively. Experiment 2 assessed the effects of different mean intervals of food presentation on responding for ethanol under a FR-10 variable-interval (VI) schedule, whereas Experiment 3 assessed the effects of a single dose of each drug under a FR-10 VI-80 schedule. In Experiment 1, all four drugs dose-dependently decreased response rate for both food and ethanol, although differences in the rate-decreasing effects were apparent among the drugs. DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding, whereas the reverse was true for naltrexone. Acamprosate decreased responding for both reinforcers with equal potency. In Experiment 2, different mean intervals of food presentation significantly affected the number of food reinforcers obtained per session; however, changes in the number of food reinforcements did not significantly affect responding for ethanol. Under the FR-10 VI-80 schedule in Experiment 3, only naltrexone significantly decreased both the dose of alcohol presented and blood ethanol concentration (BEC). Acamprosate and pregnanolone had no significant effects on any of the dependent measures, whereas DHEA significantly decreased BEC, but did not significantly decrease response rate or the dose presented. In summary, DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding under a multiple FR-10 FR-20 schedule, and were more selective for decreasing ethanol self-administration than either naltrexone or acamprosate under that schedule. Experiment 2 showed that ethanol intake was relatively independent of the interval of reinforcement in the food-maintained component, and Experiment 3 showed that naltrexone was the most effective drug at the doses tested when the interval for food reinforcement was low and maintained under a variable-interval schedule. Copyright © 2015 Elsevier Inc. All rights reserved.

Comparison of dehydroepiandrosterone (DHEA) and pregnanolone with existing pharmacotherapies for alcohol abuse on ethanol- and food-maintained responding in male rats

PubMed Central

Hulin, Mary W.; Lawrence, Michelle N.; Amato, Russell J.; Weed, Peter F.; Winsauer, Peter J.

2015-01-01

The present study compared two putative pharmacotherapies for alcohol abuse and dependence, dehydroepiandrosterone (DHEA) and pregnanolone, with two Food and Drug Administration (FDA)-approved pharmacotherapies, naltrexone and acamprosate. Experiment 1 assessed the effects of different doses of DHEA, pregnanolone, naltrexone, and acamprosate on both ethanol- and food-maintained responding under a multiple fixed-ratio (FR)-10 FR-20 schedule, respectively. Experiment 2 assessed the effects of different mean intervals of food presentation on responding for ethanol under an FR-10 variable-interval (VI) schedule, whereas Experiment 3 assessed the effects of a single dose of each drug under a FR-10 VI-80 schedule. In Experiment 1, all four drugs dose-dependently decreased response rate for both food and ethanol, although differences in the rate-decreasing effects were apparent among the drugs. DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding, whereas the reverse was true for naltrexone. Acamprosate decreased responding for both reinforcers with equal potency. In Experiment 2, different mean intervals of food presentation significantly affected the number of food reinforcers obtained per session; however, changes in the number of food reinforcements did not significantly affect responding for ethanol. Under the FR-10 VI-80 schedule in Experiment 3, only naltrexone significantly decreased both the dose of alcohol presented and blood ethanol concentration (BEC). Acamprosate and pregnanolone had no significant effects on any of the dependent measures, whereas DHEA significantly decreased BEC, but did not significantly decrease response rate or the dose presented. In summary, DHEA and pregnanolone decreased ethanol-maintained responding more potently than food-maintained responding under a multiple FR-10 FR-20 schedule, and were more selective for decreasing ethanol self-administration than either naltrexone or acamprosate under that schedule. Experiment 2 showed that ethanol intake was relatively independent of the density of reinforcement in the food-maintained component, and Experiment 3 showed that naltrexone was the most effective drug at the doses tested when the density for food reinforcement was low and maintained under a variable-interval schedule. PMID:25620274

Mumijo attenuates chemically induced inflammatory pain in mice.

PubMed

Malekzadeh, Golnaz; Dashti-Rahmatabadi, Mohammad Hossein; Zanbagh, Samira; Akhavi Mirab-bashii, Atefehsadat

2015-01-01

Mumijo (shilajit) has been well known in traditional medicine as a remedy for a number of diseases, such as bone fractures, wounds, inflammation, and headache. It is also widely used as an analgesic agent in folk medicine, but no scientific documentation exists concerning that effect. The current study was conducted to evaluate the ability of mumijo to reduce sensitivity to painful stimuli when compared with morphine sulfate and sodium diclofenac. A total of 176 animals were randomly and equally divided into 2 groups with 88 mice each-one for formalin test and the other for writhing test. For each test, the animals were allocated into 10 equal groups, based on the dosage of the analgesic, plus a negative control group, with 8 mice in each group. The analgesic effect of mumijo extract in doses of 0.75, 7.5, 75, and 750 mg/kg was assessed and compared witha group receiving distilled water-the negative control group, and that for groups receiving 1, 2, or 4 mg/kg of morphine sulfate or 10, 20, or 30 mg/kg of sodium diclofenac-the positive control groups. The results showed a significant decrease in pain intensity for all mice receiving doses of mumijo extract during a 1-h formalin test when compared with the distilled water group. For all the mumijo groups except the one receiving 750 mg/kg, the analgesic effect was significantly lower than that for the morphine sulfate group receiving 4 mg/kg. No significant differences existed between all mumijo and all diclofenac groups. In a writhing test, a significant inhibition of the pain response induced by acetic acid also occurred in all 4 mumijo-administered groups as opposed to the group receiving distilled water. No significant differences existed between the writhing response in groups receiving 75 and 750 mg/kg of mumijo and any doses of diclofenac or morphine. The comparison among the different doses of mumijo in the formalin test did not show any significant differences, but in the writhing test, the maximum dose showed a more effective analgesic action. The findings indicated a significant analgesic effect for mumijo extract on chronic pain in mice, occurring in a dose-independent manner.

Assessing dose-response effects of national essential medicine policy in China: comparison of two methods for handling data with a stepped wedge-like design and hierarchical structure.

PubMed

Ren, Yan; Yang, Min; Li, Qian; Pan, Jay; Chen, Fei; Li, Xiaosong; Meng, Qun

2017-02-22

To introduce multilevel repeated measures (RM) models and compare them with multilevel difference-in-differences (DID) models in assessing the linear relationship between the length of the policy intervention period and healthcare outcomes (dose-response effect) for data from a stepped-wedge design with a hierarchical structure. The implementation of national essential medicine policy (NEMP) in China was a stepped-wedge-like design of five time points with a hierarchical structure. Using one key healthcare outcome from the national NEMP surveillance data as an example, we illustrate how a series of multilevel DID models and one multilevel RM model can be fitted to answer some research questions on policy effects. Routinely and annually collected national data on China from 2008 to 2012. 34 506 primary healthcare facilities in 2675 counties of 31 provinces. Agreement and differences in estimates of dose-response effect and variation in such effect between the two methods on the logarithm-transformed total number of outpatient visits per facility per year (LG-OPV). The estimated dose-response effect was approximately 0.015 according to four multilevel DID models and precisely 0.012 from one multilevel RM model. Both types of model estimated an increase in LG-OPV by 2.55 times from 2009 to 2012, but 2-4.3 times larger SEs of those estimates were found by the multilevel DID models. Similar estimates of mean effects of covariates and random effects of the average LG-OPV among all levels in the example dataset were obtained by both types of model. Significant variances in the dose-response among provinces, counties and facilities were estimated, and the 'lowest' or 'highest' units by their dose-response effects were pinpointed only by the multilevel RM model. For examining dose-response effect based on data from multiple time points with hierarchical structure and the stepped wedge-like designs, multilevel RM models are more efficient, convenient and informative than the multilevel DID models. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

Ultraviolet radiation induces dose-dependent pigment dispersion in crustacean chromatophores.

PubMed

Gouveia, Glauce Ribeiro; Lopes, Thaís Martins; Neves, Carla Amorim; Nery, Luiz Eduardo Maia; Trindade, Gilma Santos

2004-10-01

Pigment dispersion in chromatophores as a response to UV radiation was investigated in two species of crustaceans, the crab Chasmagnathus granulata and the shrimp Palaemonetes argentinus. Eyestalkless crabs and shrimps maintained on either a black or a white background were irradiated with different UV bands. In eyestalkless crabs the significant minimal effective dose inducing pigment dispersion was 0.42 J/cm(2) for UVA and 2.15 J/cm(2) for UVB. Maximal response was achieved with 10.0 J/cm(2) UVA and 8.6 J/cm(2) UVB. UVA was more effective than UVB in inducing pigment dispersion. Soon after UV exposure, melanophores once again reached the initial stage of pigment aggregation after 45 min. Aggregated erythrophores of shrimps adapted to a white background showed significant pigment dispersion with 2.5 J/cm(2) UVA and 0.29 J/cm(2) UVC. Dispersed erythrophores of shrimps adapted to a black background did not show any significant response to UVA, UVB or UVC radiation. UVB did not induce any significant pigment dispersion in shrimps adapted to either a white or a black background. As opposed to the tanning response, which only protects against future UV exposure, the pigment dispersion response could be an important agent protecting against the harmful effects of UV radiation exposure.

Low dose radiation interactions with the transformation growth factor (TFG)-beta pathway

NASA Astrophysics Data System (ADS)

Maslowski, Amy Jesse

A major limiting factor for long-term, deep-space missions is the radiation dose to astronauts. Because the dose to the astronauts is a mixed field of low- and high-LET radiation, there is a need to understand the effects of both radiation types on whole tissue; however, there are limited published data on the effects of high-LET (linear-energy-transfer) radiation on tissue. Thus, we designed a perfusion chamber system for rat trachea in order to mimic in vivo respiratory tissue. We successfully maintained the perfused tracheal tissue ex vivo in a healthy and viable condition for up to three days. In addition, this project studied the effects of high-LET Fe particles on the overall transformation growth factor (TGF)-beta response after TGF-beta inactivation and compared the results to the TGF-beta response post x-ray irradiation. It was found that a TGF-beta response could be measured in the perfused tracheal tissue, for x-ray and Fe particle irradiations, despite the high autofluorescent background intrinsic to tissue. However, after comparing the TGF-beta response of x-ray irradiation to High-Z-High-energy (HZE) irradiation, there was not a significant difference in radiation types. The TGF-beta response in x-ray and HZE irradiated perfusion chambers was also measured over time post irradiation. It was found that for 6 hour and 8 hour post irradiation, the TGF-beta response was higher for lower doses of radiation than for higher doses. This is in contrast to the 0 hour fixation which found the TGF-beta response to increase with increased dose. The inverse relationship found for 6 hour and 8 hour fixation times may indicate a threshold response for TGF-beta response; i.e., for low doses, a threshold of dose must be reached for an immediate TGF-beta response, otherwise the tissue responds more slowly to the irradiation damage. This result was unexpected and will require further investigation to determine if the threshold can be determined for the 250 kVp x-rays and 1 Gev Fe particles.

Dose-dependent inhibition of gastric injury by hydrogen in alkaline electrolyzed drinking water

PubMed Central

2014-01-01

Background Hydrogen has been reported to relieve damage in many disease models, and is a potential additive in drinking water to provide protective effects for patients as several clinical studies revealed. However, the absence of a dose–response relationship in the application of hydrogen is puzzling. We attempted to identify the dose–response relationship of hydrogen in alkaline electrolyzed drinking water through the aspirin induced gastric injury model. Methods In this study, hydrogen-rich alkaline water was obtained by adding H2 to electrolyzed water at one atmosphere pressure. After 2 weeks of drinking, we detected the gastric mucosal damage together with MPO, MDA and 8-OHdG in rat aspirin induced gastric injury model. Results Hydrogen-dose dependent inhibition was observed in stomach mucosal. Under pH 8.5, 0.07, 0.22 and 0.84 ppm hydrogen exhibited a high correlation with inhibitory effects showed by erosion area, MPO activity and MDA content in the stomach. Gastric histology also demonstrated the inhibition of damage by hydrogen-rich alkaline water. However, 8-OHdG level in serum did not have significant hydrogen-dose dependent effect. pH 9.5 showed higher but not significant inhibitory response compared with pH 8.5. Conclusions Hydrogen is effective in relieving the gastric injury induced by aspirin-HCl, and the inhibitory effect is dose-dependent. The reason behind this may be that hydrogen-rich water directly interacted with the target tissue, while the hydrogen concentration in blood was buffered by liver glycogen, evoking a suppressed dose–response effect. Drinking hydrogen-rich water may protect healthy individuals from gastric damage caused by oxidative stress. PMID:24589018

Effect of a pre-exercise hydrocortisone dose on short-term physical performance in female patients with primary adrenal failure.

PubMed

Simunkova, Katerina; Jovanovic, Nevena; Rostrup, Espen; Methlie, Paal; Øksnes, Marianne; Nilsen, Roy Miodini; Hennø, Hanne; Tilseth, Mira; Godang, Kristin; Kovac, Ana; Løvås, Kristian; Husebye, Eystein S

2016-01-01

Many patients with primary adrenal insufficiency (Addison's disease) take extra doses of glucocorticoids during stressful events, but a benefit has not been demonstrated in controlled trials. Here, we investigated the effects of a pre-exercise hydrocortisone dose on cardiorespiratory, hormonal and metabolic parameters in response to short-term strenuous physical activity. This was a randomized placebo-controlled, two-week cross-over clinical trial. Ten women with Addison's disease and 10 age-matched healthy females participated in the study. All women in the study underwent maximal incremental exercise testing. A stress dose of 10 mg hydrocortisone or placebo was given 1 h prior to exercise on two occasions. Blood samples were drawn before, and 0, 15 and 30 min post exercise. Oxygen uptake, maximal aerobic capacity, endocrine and metabolic responses to physical activity, as well as health status by questionnaires were evaluated. Maximal aerobic capacity and duration of exercise were significantly lower in patients than in healthy subjects and did not improve with the treatment. After an extra hydrocortisone dose serum cortisol was significantly higher than in the healthy subjects (P<0.001). Post-exercise glucose and adrenaline levels were significantly lower and free fatty acids insignificantly higher in patients irrespective of stress dose. Stress dosing did not alter other metabolic or hormonal parameters or quality of life after the exercise. The patients did not benefit from an extra dose of hydrocortisone in short strenuous exercise. Stress dosing may not be justified in this setting. Whether stress dosing is beneficial in other types of physical activity will have to be examined further. © 2016 European Society of Endocrinology.

Dose-dependent effects of lesogaberan on reflux measures in patients with refractory gastroesophageal reflux disease: a randomized, placebo-controlled study.

PubMed

Miner, Philip B; Silberg, Debra G; Ruth, Magnus; Miller, Frank; Pandolfino, John

2014-11-18

The γ-aminobutyric acid type B-receptor agonist lesogaberan (AZD3355) has been developed for use in patients with gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy (partial responders). This study aimed to explore the dose-response effect of lesogaberan on reflux episodes in partial responders. In this randomized, single-centre, double-blind, crossover, placebo-controlled study, partial responders taking optimised PPI therapy were given 30, 90, 120 and 240 mg doses of lesogaberan. Each dose was given twice (12 h apart) during a 24-h period, during which impedance-pH measurements were taken. Twenty-five patients were included in the efficacy analysis and 27 in the safety analysis. The effect of lesogaberan on the mean number of reflux episodes was dose-dependent, and all doses significantly reduced the mean number of reflux episodes relative to placebo. Lesogaberan also dose-dependently reduced the mean number of acid reflux episodes (except the 30 mg dose) and weakly acid reflux episodes (all doses) significantly, relative to placebo. Regardless of dose, lesogaberan had a similar effect on the percentage of time with esophageal pH < 4 [mean reduction: 68.5% (30 mg), 54.2% (90 mg), 65.9% (120 mg), 72.1% (240 mg); p < 0.05 except 90 mg dose]. No adverse events led to discontinuation and no serious adverse events occurred during active treatment. Lesogaberan inhibited reflux in a dose-dependent manner in partial responders taking optimised PPI therapy, and these effects were significant versus placebo. All lesogaberan doses were well tolerated and were not associated with clinically relevant adverse events. ClinicalTrials.gov identifier: NCT01043185.

Hormones and Endocrine-Disrupting Chemicals: Low-Dose Effects and Nonmonotonic Dose Responses

PubMed Central

Colborn, Theo; Hayes, Tyrone B.; Heindel, Jerrold J.; Jacobs, David R.; Lee, Duk-Hee; Shioda, Toshi; Soto, Ana M.; vom Saal, Frederick S.; Welshons, Wade V.; Zoeller, R. Thomas

2012-01-01

For decades, studies of endocrine-disrupting chemicals (EDCs) have challenged traditional concepts in toxicology, in particular the dogma of “the dose makes the poison,” because EDCs can have effects at low doses that are not predicted by effects at higher doses. Here, we review two major concepts in EDC studies: low dose and nonmonotonicity. Low-dose effects were defined by the National Toxicology Program as those that occur in the range of human exposures or effects observed at doses below those used for traditional toxicological studies. We review the mechanistic data for low-dose effects and use a weight-of-evidence approach to analyze five examples from the EDC literature. Additionally, we explore nonmonotonic dose-response curves, defined as a nonlinear relationship between dose and effect where the slope of the curve changes sign somewhere within the range of doses examined. We provide a detailed discussion of the mechanisms responsible for generating these phenomena, plus hundreds of examples from the cell culture, animal, and epidemiology literature. We illustrate that nonmonotonic responses and low-dose effects are remarkably common in studies of natural hormones and EDCs. Whether low doses of EDCs influence certain human disorders is no longer conjecture, because epidemiological studies show that environmental exposures to EDCs are associated with human diseases and disabilities. We conclude that when nonmonotonic dose-response curves occur, the effects of low doses cannot be predicted by the effects observed at high doses. Thus, fundamental changes in chemical testing and safety determination are needed to protect human health. PMID:22419778

Experimental investigation of the 100 keV X-ray dose response of the high-temperature thermoluminescence in LiF:Mg,Ti (TLD-100): theoretical interpretation using the unified interaction model.

PubMed

Livingstone, J; Horowitz, Y S; Oster, L; Datz, H; Lerch, M; Rosenfeld, A; Horowitz, A

2010-03-01

The dose response of LiF:Mg,Ti (TLD-100) chips was measured from 1 to 50,000 Gy using 100 keV X rays at the European Synchroton Radiation Facility. Glow curves were deconvoluted into component glow peaks using a computerised glow curve deconvolution (CGCD) code based on first-order kinetics. The normalised dose response, f(D), of glow peaks 4 and 5 and 5b (the major components of composite peak 5), as well as peaks 7 and 8 (two of the major components of the high-temperature thermoluminescence (HTTL) at high levels of dose) was separately determined and theoretically interpreted using the unified interaction model (UNIM). The UNIM is a nine-parameter model encompassing both the irradiation/absorption stage and the thermally induced relaxation/recombination stage with an admixture of both localised and delocalised recombination mechanisms. The effects of radiation damage are included in the present modelling via the exponential removal of luminescent centres (LCs) at high dose levels. The main features of the experimentally measured dose response are: (i) increase in f(D)(max) with glow peak temperature, (ii) increase in D(max) (the dose level at which f(D)(max) occurs) with increasing glow peak temperature, and (iii) decreased effects of radiation damage with increasing glow peak temperature. The UNIM interpretation of this behaviour requires both strongly decreasing values of ks (the relative contribution of localised recombination) as a function of glow peak temperature and, as well, significantly different values of the dose-filling constants of the trapping centre (TC) and LC for peaks 7 and 8 than those used for peaks 4 and 5. This suggests that different TC/LC configurations are responsible for HTTL. The relative intensity of peak 5a (a low-temperature satellite of peak 5 arising from localised recombination) was found to significantly increase at higher dose levels due to preferential electron and hole population of the trapping/recombination complex giving rise to composite glow peak 5. It is also demonstrated that possible changes in the trapping cross section of the LC and the competitive centres due to increasing sample/glow peak temperature do not significantly influence these observations/conclusions.

Glycine inhibition of pupillary responses to pulses of light in conscious sheep.

PubMed

Seggie, J; Wright, N

1989-01-01

The use of a 1.5% glycine solution as a bladder irrigant during surgical removal of the prostate has been associated with transient visual impairment. Glycine is thought to be an inhibitory retinal transmitter. Adult female sheep were infused with a 1.5% glycine solution to provide a dose of 0, 7.5, 15, 30, or 60 g of glycine. The volume control was a solution of dextrose and saline. The degree of constriction of the pupil in response to 30 seconds of bright light following dilation in the dark was used as an index of visual response. Observations were made before and 2, 4, 6, 12, 24, 48, 96, and 192 hours after a single infusion. Significant inhibition of pupil response to light but not to the dark was apparent following systemically administered glycine resulting in plasma levels over 5000 mumol/L. Inhibition of pupil response was paralleled by behavioral indices of visual impairment but not by changes in plasma sodium, potassium, chloride or osmolality. The duration of the effect was dose dependent with visual impairment following a single high dose of glycine being detectable five days later and long after glycine levels had returned to normal. However, the relationship between dose, time, and effect appears to be complex. It is important to note that the present observations occurred at plasma glycine levels frequently experienced in routine surgical practice. The finding that significant long term detrimental effects of glycine could be detected should evoke a re-evaluation of the use of glycine as an irrigating solution for surgical procedures and stimulate further investigation of the effects of glycine on retinal function and the ability to perceive light.

Dose-Response Effects of Aerobic Exercise on Quality of Life in Postmenopausal Women: Results from the Breast Cancer and Exercise Trial in Alberta (BETA).

PubMed

Courneya, Kerry S; McNeil, Jessica; O'Reilly, Rachel; Morielli, Andria R; Friedenreich, Christine M

2017-06-01

Exercise generally improves quality of life (QoL) and psychosocial functioning in adult populations but few randomized trials have examined dose-response effects. The purpose of the present study was to report the QoL and psychosocial outcomes from the Breast Cancer and Exercise Trial in Alberta (BETA). Healthy but inactive postmenopausal women at risk for breast cancer were randomized to a year-long aerobic exercise intervention consisting of either 150 min/week (moderate volume group, n = 200) or 300 min/week (high volume group, n = 200). QoL was assessed at baseline and 1 year using the short form-36 health survey. Sleep quality, depression, anxiety, stress, self-esteem, and happiness were also assessed. Participant preference for group assignment (i.e., exercise volume) was assessed at baseline and tested as a moderator. There were no statistically significant dose-response effects of aerobic exercise on any QoL, sleep quality, or psychosocial outcome. Participant preference for group assignment did not moderate any QoL, sleep quality, or psychosocial responses. Marital status was a significant moderator (p for interaction = 0.01) and obesity showed a trend towards being a moderator (p for interaction = 0.08) of the dose-response effects of aerobic exercise on global sleep quality such that unmarried and obese women improved sleep quality with the higher volume of aerobic exercise. A higher volume of aerobic exercise, approximately double the minimum public health guideline, did not provide additional QoL or psychosocial benefits compared to the minimum public health guideline in inactive postmenopausal women, even for women who preferred the higher volume of exercise at baseline. Trial Registration clinicaltrials.gov identifier: NCT1435005.

Immunogenicity and safety of 1 vs 2 doses of quadrivalent meningococcal conjugate vaccine in youth infected with human immunodeficiency virus.

PubMed

Lujan-Zilbermann, Jorge; Warshaw, Meredith G; Williams, Paige L; Spector, Stephen A; Decker, Michael D; Abzug, Mark J; Heckman, Barb; Manzella, Adam; Kabat, Bill; Jean-Philippe, Patrick; Nachman, Sharon; Siberry, George K

2012-10-01

To compare the immunogenicity of 1 vs 2 doses of meningococcal polysaccharide conjugate vaccine (MCV4) in youth infected with human immunodeficiency virus (HIV). P1065 was a phase I/II immunogenicity and safety trial of MCV4 in 324 youth infected with HIV performed at 27 sites of the International Maternal Pediatric Adolescent AIDS Clinical Trials Group network in the US. At entry subjects received 1 dose of MCV4. At 24 weeks, those with screening cluster of differentiation 4 (CD4)% ≥ 15 were randomized to receive a second dose or not, and all with screening CD4% <15 received a second dose. Immunogenicity was evaluated as the proportion of subjects with a ≥ 4-fold rise from entry in serum bactericidal antibody against each meningococcal serogroup (SG) at weeks 28 and 72. Logistic regression models adjusting for HIV disease severity were used to evaluate the effect of 1 vs 2 MCV4 doses among those with screening CD4% ≥ 15. Subjects randomized to receive 2 vs 1 MCV4 dose had significantly higher response rates to all SGs at week 28 and to all except Neisseria meningitidis SG Y at week 72, with adjusted ORs of 2.5-5.6. In 31 subjects with screening CD4% <15 who received 2 MCV4 doses, response rates ranged from 22%-55% at week 28 and 6%-28% at week 72. In youth infected with HIV with a CD4% ≥ 15, a second dose of MCV4 given 6 months after the initial dose significantly improves response rates at 28 and 72 weeks. Subjects with CD4% <15 at entry had lower response rates despite 2 doses of MCV4. Copyright © 2012 Mosby, Inc. All rights reserved.

Intravenous Nicotine Self-Administration in Smokers: Dose-Response Function and Sex Differences.

PubMed

Jensen, Kevin P; DeVito, Elise E; Valentine, Gerald; Gueorguieva, Ralitza; Sofuoglu, Mehmet

2016-07-01

Sex differences in the sensitivity to nicotine may influence vulnerability to tobacco dependence. The goal of this study was to investigate the dose-response function for the reinforcing and subjective effects of intravenous nicotine in male and female smokers. Tobacco-dependent subjects (12 male and 14 female) participated in four experimental sessions in which they received sample infusions of saline and nicotine (0.1, 0.2, 0.3, or 0.4 mg doses) in a randomized double-blind crossover design. During each session, subjects first received the sample infusions, and heart rate (HR), blood pressure, and subjective stimulatory, pleasurable and aversive responses were monitored. Immediately following the sample infusions, subjects self-administered either nicotine or saline in six double-blind forced-choice trials. A sex by dose interaction was observed in the nicotine choice paradigm. Nicotine self-administration rate was negatively correlated with nicotine dose in males (males displayed choice preference for low doses of nicotine over high doses of nicotine), but no significant relationship between dose and choice preference was evident in females. Relative to placebo, sample doses of nicotine increased heart rate and blood pressure, and induced stimulatory, pleasurable, and aversive subjective effects. Diastolic blood pressure increased dose dependently in males, but not in females. These findings, which demonstrate sex differences in nicotine self-administration for doses that are near to the reinforcement threshold, suggest that male and female smokers may respond differently to the changes in nicotine doses available for self-administration.

Accounting for Shared and Unshared Dosimetric Uncertainties in the Dose Response for Ultrasound-Detected Thyroid Nodules after Exposure to Radioactive Fallout

PubMed Central

Hoffman, F. Owen; Moroz, Brian; Drozdovitch, Vladimir; Bouville, André; Beck, Harold; Luckyanov, Nicholas; Weinstock, Robert M.; Simon, Steven L.

2015-01-01

Dosimetic uncertainties, particularly those that are shared among subgroups of a study population, can bias, distort or reduce the slope or significance of a dose response. Exposure estimates in studies of health risks from environmental radiation exposures are generally highly uncertain and thus, susceptible to these methodological limitations. An analysis was published in 2008 concerning radiation-related thyroid nodule prevalence in a study population of 2,994 villagers under the age of 21 years old between August 1949 and September 1962 and who lived downwind from the Semi-palatinsk Nuclear Test Site in Kazakhstan. This dose-response analysis identified a statistically significant association between thyroid nodule prevalence and reconstructed doses of fallout-related internal and external radiation to the thyroid gland; however, the effects of dosimetric uncertainty were not evaluated since the doses were simple point “best estimates”. In this work, we revised the 2008 study by a comprehensive treatment of dosimetric uncertainties. Our present analysis improves upon the previous study, specifically by accounting for shared and unshared uncertainties in dose estimation and risk analysis, and differs from the 2008 analysis in the following ways: 1. The study population size was reduced from 2,994 to 2,376 subjects, removing 618 persons with uncertain residence histories; 2. Simulation of multiple population dose sets (vectors) was performed using a two-dimensional Monte Carlo dose estimation method; and 3. A Bayesian model averaging approach was employed for evaluating the dose response, explicitly accounting for large and complex uncertainty in dose estimation. The results were compared against conventional regression techniques. The Bayesian approach utilizes 5,000 independent realizations of population dose vectors, each of which corresponds to a set of conditional individual median internal and external doses for the 2,376 subjects. These 5,000 population dose vectors reflect uncertainties in dosimetric parameters, partly shared and partly independent, among individual members of the study population. Risk estimates for thyroid nodules from internal irradiation were higher than those published in 2008, which results, to the best of our knowledge, from explicitly accounting for dose uncertainty. In contrast to earlier findings, the use of Bayesian methods led to the conclusion that the biological effectiveness for internal and external dose was similar. Estimates of excess relative risk per unit dose (ERR/Gy) for males (177 thyroid nodule cases) were almost 30 times those for females (571 cases) and were similar to those reported for thyroid cancers related to childhood exposures to external and internal sources in other studies. For confirmed cases of papillary thyroid cancers (3 in males, 18 in females), the ERR/Gy was also comparable to risk estimates from other studies, but not significantly different from zero. These findings represent the first reported dose response for a radiation epidemiologic study considering all known sources of shared and unshared errors in dose estimation and using a Bayesian model averaging (BMA) method for analysis of the dose response. PMID:25574587

Evaluation of cytotoxicity and radiation enhancement using 1.9 nm gold particles: potential application for cancer therapy

PubMed Central

Butterworth, K T; Coulter, J A; Jain, S; Forker, J; McMahon, S J; Schettino, G; Prise, K M; Currell, F J; Hirst, D G

2010-01-01

High atomic number (Z) materials such as gold preferentially absorb kilovoltage x-rays compared to soft tissue and may be used to achieve local dose enhancement in tumours during treatment with ionizing radiation. Gold nanoparticles have been demonstrated as radiation dose enhancing agents in vivo and in vitro. In the present study, we used multiple endpoints to characterize the cellular cytotoxic response of a range of cell lines to 1.9 nm gold particles and measured dose modifying effects following transient exposure at low concentrations. Gold nanoparticles caused significant levels of cell type specific cytotoxicity, apoptosis and increased oxidative stress. When used as dose modifying agents, dose enhancement factors varied between the cell lines investigated with the highest enhancement being 1.9 in AGO-1522B cells at a nanoparticle concentration of 100 μg ml−1. This study shows exposure to 1.9 nm gold particles to induce a range of cell line specific responses including decreased clonogenic survival, increased apoptosis and induction of DNA damage which may be mediated through the production of reactive oxygen species. This is the first study involving 1.9 nm nanometre sized particles to report multiple cellular responses which impact on the radiation dose modifying effect. The findings highlight the need for extensive characterization of responses to gold nanoparticles when assessing dose enhancing potential in cancer therapy. PMID:20601762

Anti-inflammatory and antinociceptive effects of Chinese medicine SQ gout capsules and its modulation of pro-inflammatory cytokines focusing on gout arthritis.

PubMed

Kodithuwakku, Nandani Darshika; Pan, Min; Zhu, Yi-lin; Zhang, Yan-yan; Feng, Yi-dong; Fang, Wei-rong; Li, Yun-man

2013-12-12

Shuang-Qi gout capsule is a traditional Chinese medicine prescription, which has been used in the treatment of joint pain, inflammation and gout arthritis. This study evaluates anti-inflammatory and antinociceptive effects of Shuang-Qi gout capsule and its modulation of pro-inflammatory cytokines with special reference to gout arthritis. Anti-inflammatory effect of Shuang-Qi gout capsule was investigated bymice tail-flick response, acetic acid induced writhing response, Xylene-induced auricle inflammation and the hind paw volume of the monosodium urate (MSU) crystal induced rats with different time durations. To investigate the effects on gout arthritis, ankle joint of rats induced by MSU crystals and assessed for edema and histopathological changes. In vitro, prepared serum was incubated with urate crystal induced HUVE cells and the release of TNF-α and IL-1β determined by ELISA. Shuang-Qi gout capsule showed significant and dose dependent anti-inflammatory effect via reducing edema and pain, throughout all the models. The high dose of Shuang-Qi gout capsule and Indomethacin significantly attenuated the edema. Histopathological results showed that high and medium dose of Shuang-Qi gout capsule and Indomethacin reduced gouty joint inflammatory features, while the high dose of Shuang-Qi gout capsule showed a better therapeutic effect. High and medium dose of Shuang-Qi gout capsule significantly reduced the release of TNF-α and IL-1β (p<0.05). Shuang-Qi gout capsule can effectively inhibit the inflammation, analgesia, through the modulation of emission of pro-inflammatory cytokines and the curative effect is dose dependent. Conversely, these MSU induced in vivo and in vitro studies of Shuang-Qi gout capsule suggest that, Shuang-Qi gout capsule may be a potential agent for treatment in gouty arthritis. © 2013 Published by Elsevier Ireland Ltd.

Chronic naltrindole administration does not modify the inhibitory effect of morphine on vocalization responses in the tail electric stimulation test in rats.

PubMed

Fernández, B; Alberti, I; Kitchen, I; Paz Viveros, M

1999-01-29

To address the existence of possible functional interactions between delta- and mu- receptors in relation to the affective component of pain, we have studied the effects of functional blockade of delta-receptors by a chronic treatment with naltrindole (1 mg/kg, 8 consecutive days) on antinociceptive responses to morphine (2 and 5 mg/kg) in the tail electric stimulation test, in adult male rats. The thresholds for the motor response (tail withdrawal), vocalization during stimulus and vocalization afterdischarge were assessed. These responses are considered to be integrated at spinal, medulla oblongata and diencephalon-rhinencephalon levels, respectively. The results show that the vocalization during stimulus and the vocalization afterdischarge were significantly affected by morphine in a dose dependent manner, the latter response being the most sensitive to the effects of the mu-opioid agonist. However, no significant effect was observed on motor responses at the doses used in this study. Chronic naltrindole treatment did not modify the inhibitory effect of morphine on the vocalization responses. Since the vocalization afterdischarge is related to the affective component of pain, the data suggest that the delta-opioid receptor is not involved in the supraspinal mechanisms at which these responses are organized and that there is not a mu-delta interaction in the modulation of the affective responses to noxious electrical stimulation.

Agmatine attenuates methamphetamine-induced hyperlocomotion and stereotyped behavior in mice.

PubMed

Kitanaka, Nobue; Kitanaka, Junichi; Hall, F Scott; Uhl, George R; Watabe, Kaname; Kubo, Hitoshi; Takahashi, Hitoshi; Tanaka, Koh-ichi; Nishiyama, Nobuyoshi; Takemura, Motohiko

2014-04-01

We investigated whether pretreatment with the neurotransmitter/neuromodulator agmatine (decarboxylated L-arginine) affected methamphetamine (METH)-induced hyperlocomotion and stereotypy in male ICR mice. Agmatine pretreatment alone had no effects on locomotion or stereotypy, but it produced a dose-dependent attenuation of locomotion and the total incidence of stereotyped behavior induced by a low dose of METH (5 mg/kg). The stereotypy induced by this dose was predominantly characterized by stereotyped sniffing. By contrast, agmatine did not affect the total incidence of stereotypy induced by a higher dose of METH (10 mg/kg). However, the nature of stereotypy induced by this dose of METH was substantially altered; agmatine pretreatment significantly reduced stereotyped biting but significantly increased stereotyped sniffing and persistent locomotion. Agmatine pretreatment therefore appears to produce a rightward shift in the dose-response curve for METH. Pretreatment of mice with piperazine-1-carboxamidine (a putative agmatinase inhibitor) had no effect on locomotion or stereotypy induced by a low dose of METH, suggesting that endogenous agmatine may not regulate the METH action.

Monitoring exposure to atomic bomb radiation by somatic mutation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Akiyama, Mitoshi; Kyoizumi, Seishi; Kusunoki, Yoichiro

Atomic bomb survivors are a population suitable for studying the relationship between somatic mutation and cancer risk because their exposure doses are relatively well known and their dose responses in terms of cancer risk have also been thoroughly studied. An analysis has been made of erythrocyte glycophorin A (GPA) gene mutations in 1,226 atomic bomb survivors in Hiroshima and Nagasaki. The GPA mutation frequency (Mf) increased slightly but significantly with age at the time of measurement and with the number of cigarettes smoked. After adjustment for the effect of smoking, the Mf was significantly higher in males than in femalesmore » and higher in Hiroshima than in Nagasaki. All of these characteristics of the background GPA Mf were in accord with those of solid tumor incidence obtained from an earlier epidemiological study of A-bomb survivors. Analysis of the dose effect on Mf revealed the doubling dose to be about 1.20 Sv and the minimum dose for detection of a significant increase to be about 0.24 Sv. No significant dose effect for difference in sex, city, or age at the time of bombing was observed. Interestingly, the doubling dose for the GPA Mf approximated that for solid cancer incidence (1.59 Sv). And the minimum dose for detection was not inconsistent with the data for solid cancer incidence. The dose effect was significantly higher in those diagnosed with cancer before or after measurement than in those without a history of cancer. These findings are consistent with the hypothesis that somatic mutations are the main cause of excess cancer risk from radiation exposure. 27 refs., 2 figs.« less

Thyroid Dysfunction and Autoimmune Thyroid Diseases Among Atomic Bomb Survivors Exposed in Childhood.

PubMed

Imaizumi, Misa; Ohishi, Waka; Nakashima, Eiji; Sera, Nobuko; Neriishi, Kazuo; Yamada, Michiko; Tatsukawa, Yoshimi; Takahashi, Ikuno; Fujiwara, Saeko; Sugino, Keizo; Ando, Takao; Usa, Toshiro; Kawakami, Atsushi; Akahoshi, Masazumi; Hida, Ayumi

2017-07-01

The risk of thyroid cancer increases and persists for decades among individuals exposed to ionizing radiation in childhood, although the long-term effects of childhood exposure to medium to low doses of radiation on thyroid dysfunction and autoimmune thyroid diseases have remained unclear. To evaluate radiation dose responses for the prevalence of thyroid dysfunction and autoimmune thyroid disease among atomic bomb survivors exposed in childhood. Hiroshima and Nagasaki atomic bomb survivors who were younger than 10 years old at exposure underwent thyroid examinations at the Radiation Effects Research Foundation between 2007 and 2011, which was 62 to 66 years after the bombing. Data from 2668 participants (mean age, 68.2 years; 1455 women) with known atomic bomb thyroid radiation doses (mean dose, 0.182 Gy; dose range, 0 to 4.040 Gy) were analyzed. Dose-response relationships between atomic bomb radiation dose and the prevalence of hypothyroidism, hyperthyroidism (Graves' disease), and positive for antithyroid antibodies. Prevalences were determined for hypothyroidism (129 cases, 7.8%), hyperthyroidism (32 cases of Graves' disease, 1.2%), and positive for antithyroid antibodies (573 cases, 21.5%). None of these was associated with thyroid radiation dose. Neither thyroid antibody-positive nor -negative hypothyroidism was associated with thyroid radiation dose. Additional analyses using alternative definitions of hypothyroidism and hyperthyroidism found that radiation dose responses were not significant. Radiation effects on thyroid dysfunction and autoimmune thyroid diseases were not observed among atomic bomb survivors exposed in childhood, at 62 to 66 years earlier. The cross-sectional design and survival bias were limitations of this study. Copyright © 2017 Endocrine Society

Randomised controlled trials define shape of dose-response for Pollinex Quattro Birch allergoid immunotherapy.

PubMed

Worm, Margitta; Higenbottam, Tim; Pfaar, Oliver; Mösges, Ralph; Aberer, Werner; Gunawardena, Kulasiri; Wessiepe, Dorothea; Lee, Denise; Kramer, Matthias F; Skinner, Murray; Lees, Bev; Zielen, Stefan

2018-05-19

The Birch Allergoid, Tyrosine Adsorbate, Monophosphoryl Lipid A (POLLINEX ® Quattro Plus 1.0 ml Birch 100%) is an effective, well-tolerated short course subcutaneous immunotherapy. We performed two phase II studies to determine its optimal cumulative dose. The studies were conducted in Germany, Austria and Poland (EudraCT numbers: 2012-004336-28 PQBirch203 and 2015-000984-15 PQBirch204) using a wide range of cumulative doses. In both studies, subjects were administered 6 therapy injections weekly outside the pollen season. Conjunctival Provocation Tests were performed at screening, baseline and 3-4 weeks after completing treatment, to quantify the reduction of Total Symptom Scores (as the primary endpoint) with each cumulative dose. Multiple Comparison Procedure and Modelling analysis was used to test for the dose-response, shape of the curve, and estimation of the median effective dose (ED 50 ), a measure of potency. Statistically significant dose-responses (p<0.01 & 0.001) were seen respectively. The highest cumulative dose in PQBirch204 (27300 standardised units [SU]) approached a plateau. Potency of the PQ Birch was demonstrated by an ED 50 2723 SU, just over half the current dose. Prevalence of treatment-emergent adverse events was similar for active doses, most being short-lived and mild. Compliance was over 85% in all groups. Increasing the cumulative dose of PQ Birch 5.5-fold from 5100 to 27300 SU achieved an absolute point difference from placebo of 1.91, a relative difference 32.3% and an increase of efficacy of 50%, without compromising safety. The cumulative dose-response was confirmed to be curvilinear in shape. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Tier-2 studies on monocrotaline immunotoxicity in C57BL/6 mice.

PubMed

Deyo, J A; Kerkvliet, N I

1991-01-01

Monocrotaline (MCT) is a member of a class of naturally occurring phytotoxins known as pyrrolizidine alkaloids, and is a toxicological concern to both man and his livestock. The purpose of these studies was to evaluate the effect of a 14-day oral MCT (0-100 mg/kg per day) exposure on the functional integrity of various immunocyte effector systems in C57BL/6 mice, as well as to investigate potential mechanisms for its immunotoxicity. Decreases in lymphoid organ weights and cellularity, and resident peritoneal exudate cell (PEC) number were only observed after exposure to the highest dose of 100 mg/kg MCT. This dose also inhibited NK cell cytotoxicity, while the total number of NK lytic units per spleen was decreased (-53%) after exposure to 50 mg/kg MCT. Following i.p. injection of SRBC, the percentage of PEC macrophages containing engulfed SRBC was significantly increased in MCT-exposed mice, while the percentage of large vacuolated (activated) macrophages was decreased in a dose-dependent manner. Exposure to MCT significantly decreased the total number of Ig+ cells without altering the number of CD4+ and CD8+ cells. The antibody responses (PFC/10(6) spleen cells) to two T cell-independent antigens, TNP-LPS and DNP-Ficoll, were significantly decreased at all MCT doses, and the degree of suppression of both responses was identical at coincident doses. MCT exposure (25 mg/kg) significantly suppressed the blastogenic response to the T cell mitogen concanavalin A (-38%), and to the B cell mitogen lipopolysaccharide (-58%). These results indicate that exposure to MCT can alter the functional integrity of various immune effector responses in a dose-dependent manner, and suggest that the B cell may be a relatively more sensitive target of MCT immunotoxicity compared to T cells, macrophages and NK cells.

Effects of low doses of caffeine on cognitive performance, mood and thirst in low and higher caffeine consumers.

PubMed

Smit, H J; Rogers, P J

2000-10-01

Caffeine is present in many widely consumed drinks and some foods. In the fairly extensive literature on the psychostimulant effects of caffeine, there are few dose-response studies and even fewer studies of the effects of doses of caffeine lower than 50 mg (the range of the amounts of caffeine contained in, for example, a typical serving of tea or cola). This study measured the effects of 0, 12.5, 25, 50 and 100 mg caffeine on cognitive performance, mood and thirst in adults with low and moderate to high habitual caffeine intakes. This was a double-blind, within-subjects study. Following overnight caffeine abstinence, participants (n=23) completed a test battery once before and three times after placebo or caffeine administration. The test battery consisted of two performance tests, a long duration simple reaction time task and a rapid visual information processing task, and a mood questionnaire (including also an item on thirst). Effects on performance and mood confirmed a psychostimulant action of caffeine. All doses of caffeine significantly affected cognitive performance, and the dose-response relationships for these effects were rather flat. The effects on performance were more marked in individuals with a higher level of habitual caffeine intake, whereas caffeine increased thirst only in low caffeine consumers. After overnight caffeine abstinence, caffeine can significantly affect cognitive performance, mood and thirst at doses within and even lower than the range of amounts of caffeine contained in a single serving of popular caffeine-containing drinks. Regular caffeine consumers appear to show substantial tolerance to the thirst-increasing but not to the performance and mood effects of caffeine.

Behavioural profile of exendin-4/naltrexone dose combinations in male rats during tests of palatable food consumption.

PubMed

Wright, F L; Rodgers, R J

2014-09-01

The glucagon-like peptide 1 receptor (GLP-1R) agonist exendin-4 potently suppresses food intake in animals and humans. However, little is known about the behavioural specificity of this effect either when administered alone or when co-administered with another anorectic agent. The present study characterises the effects of exendin-4, both alone and in combination with naltrexone, on behaviours displayed by male rats during tests with palatable mash. Experiment 1 examined the dose-response effects of exendin-4 (0.025-2.5 μg/kg, IP), while experiment 2 profiled the effects of low-dose combinations of the peptide (0.025 and 0.25 μg/kg) and naltrexone (0.1 mg/kg). In experiment 1, exendin-4 dose dependently suppressed food intake as well as the frequency and rate of eating. However, these effects were accompanied by dose-dependent reductions in all active behaviours and, at 2.5 μg/kg, a large increase in resting and disruption of the behavioural satiety sequence (BSS). In experiment 2, while exendin-4 (0.25 μg/kg) and naltrexone each produced a significant reduction in intake and feeding behaviour (plus an acceleration in the BSS), co-treatment failed to produce stronger effects than those seen in response to either compound alone. Similarities between the behavioural signature of exendin-4 and that previously reported for the emetic agent lithium chloride would suggest that exendin-4 anorexia is related to the aversive effects of the peptide. Furthermore, as low-dose combinations of the peptide with naltrexone failed to produce an additive/synergistic anorectic effect, this particular co-treatment strategy would not appear to have therapeutic significance.

Analysis of the antinociceptive interactions in two-drug combinations of gabapentin, oxcarbazepine and amitriptyline in streptozotocin-induced diabetic mice.

PubMed

Tomić, Maja A; Vucković, Sonja M; Stepanović-Petrović, Radica M; Micov, Ana M; Ugresić, Nenad D; Prostran, Milica S; Bosković, Bogdan

2010-02-25

Antiepileptic and antidepressant drugs are the primary treatments for pain relief in diabetic neuropathy. Combination therapy is a valid approach in pain treatment, where a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of two-drug combinations of gabapentin, oxcarbazepine, and amitriptyline on nociception in diabetic mice and aimed to determine the type of interaction between components. The nociceptive responses in normal and diabetic mice were assessed by the tail-flick test. The testing was performed before and three weeks after the diabetes induction with streptozotocin (150mg/kg; i.p.), when the antinociceptive effects of gabapentin, oxcarbazepine, amitriptyline and their two-drug combinations were examined. Gabapentin (10-40mg/kg; p.o.) and oxcarbazepine (20-80mg/kg; p.o.) produced a significant, dose-dependent antinociception in diabetic mice while amitriptyline (5-60mg/kg; p.o.) produced weak antinociceptive effect. In normal mice, neither of the drugs produced antinociception. Gabapentin and oxcarbazepine, co-administered in fixed-dose fractions of the ED(50) to diabetic mice, induced significant, dose-dependent antinociception. Isobolographic analysis revealed synergistic interaction. Oxcarbazepine (10-60mg/kg; p.o.)+amitriptyline (5mg/kg; p.o.) and gabapentin (10-30mg/kg; p.o.)+amitriptyline (5mg/kg; p.o.) combinations significantly and dose-dependently reduced nociception in diabetic mice. Analysis of the log dose-response curves for oxcarbazepine or gabapentin in a presence of amitriptyline and oxcarbazepine or gabapentin applied alone, revealed a synergism in oxcarbazepine-amitriptyline and additivity in gabapentin-amitriptyline combination. These findings provide new information about the combination therapy of painful diabetic neuropathy and should be explored further in patients with diabetic neuropathy.

Characterization of ferrous-methylthymol blue-polyvinyl alcohol gel dosimeters using nuclear magnetic resonance and optical techniques

NASA Astrophysics Data System (ADS)

Rabaeh, Khalid A.; Eyadeh, Molham M.; Hailat, Tariq F.; Aldweri, Feras M.; Alheet, Samer M.; Eid, Rania M.

2018-07-01

A new composition of Ferrous sulphate-Metheylthymol blue (MTB)-Polyvinyl alcohol (PVA) dosimeter is introduced in this work and evaluated using nuclear magnetic resonance (NMR) and absorbance spectrophotometry techniques. The Fricke-MTB-PVA dosimeters were irradiated using a medical linear accelerator in a cubic water phantom. The dose response of the dosimeters was investigated using NMR in terms of spin-spin relaxation rate (R2), and ultraviolet and visible regions (UV-Vis) spectrophotometry in terms of absorbance. The dosimeter presents a linear dose response for doses up to 20 Gy with UV-Vis and 40 Gy with NMR method. The sample with 0.1 mM MTB, 5% PVA by weight showed highest dose sensitivity for both techniques. The Fricke-MTB-PVA dosimeter developed in this work has a significant advance over the Fricke-MTB-gelatin system: the NMR sensitivity was remarkably improved; the auto-oxidation rate was seven times lower, and no significant dose rate or photon energy effects were observed.

Effect of hydroalcoholic extract of Lavandula officinalis on nicotine-induced convulsion in mice.

PubMed

Arzi, A; Ahamehe, M; Sarahroodi, S

2011-06-01

Epilepsy an important CNS (central nervous system) problem that about 1% of world's population suffer of it. The aim of study was to evaluate of anticonvulsant effect of hydroalcoholic extract of Lavandula officinalis. In this study, anticonvulsant activity of the hydroalcoholic extract of Lavandula officinalis (L. officinalis) was studied against chemoconvulsant-induced seizures in male mice. Lavandula officinalis (100, 200, 400, 600 and 800 mg kg(-1)), diazepam (0.15 mg kg(-1)) and normal saline (10 mL kg(-1)) were injected intraperitoneally, respectively in different groups of mice, 30 min before nicotine (5 mg kg(-) i.p.). The onset time intensity and duration of convulsions and the percentage of death were recorded. Also the time-response (0, 15, 30, 45, 60 min before nicotine injection) for most effective dose of plant extract (600 mg kg(-1)) was investigated. The results showed that hydroalcoholic extract of Lavandula officinalis had anticonvulsant effect. The most effective dose of plant extract was 600 mg kg(-1). In time-response study for the most effective dose of extract (600 mg kg(-1)), the onset, duration and intensity of convulsion significantly (p < 0.05) increased, decreased and decreased, respectively for all tested times. The best response observed in 30, 45 and 60 min. The results showed significant anticonvulsant effect for hydroalcoholic extract of Lavandula.

Assessment of the risk of solar ultraviolet radiation to amphibians. III. Prediction of impacts in selected northern midwestern wetlands.

PubMed

Diamond, Stephen A; Peterson, Gregory S; Tietge, Joseph E; Ankley, Gerald T

2002-07-01

Solar ultraviolet radiation, especially UVB (280-320 nm), has been hypothesized to be at least partially responsible for adverse effects (e.g., declines and malformations) in amphibian species throughout the world. Evaluation of this hypothesis has been limited by the paucity of high-quality UV dose-response data and reliable estimates of typical UV doses that occur in amphibian habitats. In this preliminary risk assessment for effects of UV radiation on amphibians, dose-response relationships quantified in outdoor experiments were compared with UV exposure estimates for 26 wetlands in northern Minnesota and Wisconsin. A comparison of wetland doses, derived from model prediction, historical data, and dissolved organic carbon (DOC) characterization, with experimental effects levels for green (R. clamitans), northern leopard (R. pipiens), and mink (R. septentrionalis) frogs indicated that the risk of mortality and malformations due to UV exposure is low for the majority of wetlands evaluated. Wetland UV dose, averaged over the entire breeding season, exceeded effects doses for mortality for all three species in two of the 26 wetlands examined and for one species in an additional wetland. On the basis of evidence that shorter term doses caused mortality in amphibian larvae, 3-day doses were also evaluated. In three of the wetlands examined, 3-day doses in excess of 85% of full sunlight (the level that appeared to trigger effects in controlled experimentation) occurred at frequencies ranging 22-100% for all three species and at frequencies ranging from 15% to 58% for R. pipiens and R. septentrionalis in three additional wetlands. Risk of malformation in R. pipiens was apparent in five of the 26 wetlands evaluated. Overall, estimated UVB doses in 21 of the wetlands never exceeded experimental effects doses for mortality or malformations. These results suggest that most amphibians are not currently at significant risk for UVB effects in northern Minnesota and Wisconsin wetlands. However, continued reduction of ozone and other global climate change effects may increase UV doses in wetlands, suggesting that the risk of UV to amphibians should continue to be monitored and studied.

Involvement of a phosphoramidon-sensitive endopeptidase in the processing of big endothelin-1 in the guinea-pig.

PubMed

Pons, F; Touvay, C; Lagente, V; Mencia-Huerta, J M; Braquet, P

1992-06-24

In anaesthetized and ventilated guinea-pigs, i.v. injection of 1 nmol/kg big endothelin-1 (big ET-1) did not evoke significant changes in pulmonary inflation pressure (PIP) and mean arterial blood pressure (MBP), whereas injection of the same dose of endothelin-1 (ET-1) induced marked and rapid bronchoconstrictor and pressor responses. Administered at the dose of 10 nmol/kg, big ET-1 provoked significant increases in PIP and MBP, which developed slowly and were long-lasting as compared to those evoked by ET-1. When big ET-1 was incubated for 45 min at 37 degrees C with alpha-chymotrypsin (2 mU/nmol) or pepsin (1 microgram/nmol) and then injected into guinea-pigs at the dose of 1 nmol/kg, marked bronchoconstrictor and pressor responses were observed, with kinetics similar to those noted after administration of the same dose of ET-1. The magnitude of the alpha-chymotrypsin- or pepsin-treated big ET-1 responses was similar to that induced by ET-1, incubated or not with the enzymes. Injected i.v. at the dose of 5 mg/kg, 5 min before the challenge, phosphoramidon almost totally inhibited the bronchoconstrictor and pressor responses induced by 10 nmol/kg big ET-1, whereas thiorphan (5 mg/kg) partially reduced the increase in PIP and exerted a minimal effect on the changes in MBP. Administered at the dose of 20 mg/kg per os, 1 h before i.v. administration of 10 nmol/kg big ET-1, enalapril maleate and captopril did not significantly alter the bronchoconstriction and the hypertensive response evoked by the peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of radiation therapy on bronchial obstruction due to bronchogenic carcinoma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chetty, K.G.; Moran, E.M.; Sassoon, C.S.

1989-03-01

We evaluated the effect of radiation therapy in 57 patients with obstruction of a large bronchus with NSCC. Response with aeration of the atelectatic lung was seen in 12 patients (21 percent). Three patients (5 percent) showed partial response with persistent partial atelectasis, and nine patients (16 percent) showed good response with complete aeration of the atelectatic lung. In these patients the response appeared to be related to the dose of radiation. All of the patients who responded received more than 50 Gy. The difference in the response rate related to the dose of radiation was statistically significant (p lessmore » than 0.05). The rates were similar with all histologic types of NSCC. Regardless of the clinical response observed, bronchoscopy performed two to four months after completion of radiation therapy in 14 patients revealed persistent endobronchial tumor. There was no significant relationship between the persistence of endobronchial tumor, the dose of radiation therapy, and the tumor's histologic type. Of the 12 patients with radiographic improvement in atelectasis, fibrotic changes developed in four (33 percent) patients and pneumonitis in two (17 percent). Progression of disease with distant metastases occurred in 58 percent (seven) of the 12 patients who showed a clinical response of their bronchial obstruction. The median time to survival was nearly identical in responders and nonresponders.« less

Metabolic disruption in male mice due to fetal exposure to low but not high doses of bisphenol A (BPA): Evidence for effects on body weight, food intake, adipocytes, leptin, adiponectin, insulin and glucose regulation

PubMed Central

Angle, Brittany M.; Do, Rylee Phuong; Ponzi, Davide; Stahlhut, Richard W.; Drury, Bertram E.; Nagel, Susan C.; Welshons, Wade V.; Besch-Williford, Cynthia L; Palanza, Paola; Parmigiani, Stefano; vom Saal, Frederick S.; Taylor, Julia A.

2013-01-01

Exposure to bisphenol A (BPA) is implicated in many aspects of metabolic disease in humans and experimental animals. We fed pregnant CD-1 mice BPA at doses ranging from 5 to 50,000 μg/kg/day, spanning 10-fold below the reference dose to 10-fold above the currently predicted no adverse effect level (NOAEL). At BPA doses below the NOAEL that resulted in average unconjugated BPA between 2 and 200pg/ml in fetal serum (AUC0–24h),we observed significant effects in adult male offspring: an age-related change in food intake, an increase in body weight and liver weight, abdominal adipocyte mass, number and volume, and in serum leptin and insulin, but a decrease in serum adiponectin and in glucose tolerance. For most of these outcomes non-monotonic dose–response relationships were observed; the highest BPA dose did not produce a significant effect for any outcome. A 0.1-μg/kg/day dose of DES resulted in some but not all low-dose BPA outcomes. PMID:23892310

Effect of Noni (Morinda citrifolia Linn.) Fruit and Its Bioactive Principles Scopoletin and Rutin on Rat Vas Deferens Contractility: An Ex Vivo Study

PubMed Central

Narasingam, Megala; Murugan, Dharmani Devi; Mohamed, Zahurin

2014-01-01

This study examined the effect of methanolic extract of Morinda citrifolia Linn. (MMC) and its bioactive principles, scopoletin and rutin, on dopamine- and noradrenaline-evoked contractility in isolated rat vas deferens preparations. MMC (1–40 mg/mL), scopoletin (1–200 μg/mL), and rutin hydrate (0.6–312.6 μg/mL) dose-dependently inhibited the contractility evoked by submaximal concentrations of both dopamine and noradrenaline, respectively. Haloperidol and prazosin, reference dopamine D2, and α 1-adrenoceptors antagonists significantly reversed the dopamine- and noradrenaline-induced contractions, respectively, in a dose-dependent manner. Interestingly, MMC per se at higher doses (60–100 mg/mL) showed dose-dependent contractile response in rat vas deferens which was partially inhibited by high doses of haloperidol but not by prazosin. These results demonstrated the biphasic effects of MMC on dopaminergic system; that is, antidopaminergic effect at lower concentrations (<40 mg/mL) and dopaminergic agonistic effect at higher concentrations (>60 mg/mL). However, similar contractile response at high doses of scopoletin (0.5–5 mg/mL) and rutin hydrate (0.5–5 mg/mL) per se was not observed. Therefore, it can be concluded that the bioactive principles of MMC, scopoletin, and rutin might be responsible for the antidopaminergic and antiadrenergic activities of MMC. PMID:25045753

The anticonvulsant action of AHR-11748 on kindled amygdaloid seizures in rats.

PubMed

Albertson, T E; Walby, W F

1987-03-01

The anticonvulsant effectiveness of AHR-11748 (3-[3-(trifluoromethyl)phenoxy]-1-azetidinecarboxamide) was evaluated in the kindled amygdaloid seizure model in rats. Doses of AHR-11748 that did not cause prestimulation toxicity significantly attenuated elicited afterdischarge durations and the severity of the accompanying behavioral convulsive response in previously kindled rats. AHR-11748 (25-100 mg/kg i.p.) was evaluated at 30 min in previously kindled rats using both threshold (20 microA increments) and suprathreshold (400 microA) paradigms. AHR-11748 (50-100.mg/kg) reduced suprathreshold elicited after discharges and seizure severity. Utilizing a suprathreshold kindling paradigm, the maximum anticonvulsant effectiveness for the 100 mg/kg i.p. dose of AHR-11748 was seen at 180 min. AHR-11748 significantly elevated seizure thresholds only at the 100 mg/kg dose. AHR-11748 (25-100 mg/kg) significantly reduced the severity of threshold elicited seizures. When AHR-11748 (50 and 100 mg/kg i.p.) was administered daily during kindling acquisition, the number of daily trials necessary to complete kindling significantly increased. A reduction in both the duration and the severity of the responses induced by the daily stimulations during the acquisition period was seen with AHR-11748 treatment. This study has demonstrated that AHR-11748 significantly modifies both the acquisition of kindling and the fully kindled amygdaloid seizures at doses that do not cause behavioral toxicity.

Predictors of Local Control After Single-Dose Stereotactic Image-Guided Intensity-Modulated Radiotherapy for Extracranial Metastases

DOE Office of Scientific and Technical Information (OSTI.GOV)

Greco, Carlo; Zelefsky, Michael J., E-mail: zelefskm@mskcc.or; Lovelock, Michael

2011-03-15

Purpose: To report tumor local control after treatment with single-dose image-guided intensity-modulated radiotherapy (SD-IGRT) to extracranial metastatic sites. Methods and Materials: A total of 126 metastases in 103 patients were treated with SD-IGRT to prescription doses of 18-24 Gy (median, 24 Gy) between 2004 and 2007. Results: The overall actuarial local relapse-free survival (LRFS) rate was 64% at a median follow-up of 18 months (range, 2-45 months). The median time to failure was 9.6 months (range, 1-23 months). On univariate analysis, LRFS was significantly correlated with prescription dose (p = 0.029). Stratification by dose into high (23 to 24 Gy),more » intermediate (21 to 22 Gy), and low (18 to 20 Gy) dose levels revealed highly significant differences in LRFS between high (82%) and low doses (25%) (p < 0.0001). Overall, histology had no significant effect on LRFS (p = 0.16). Renal cell histology displayed a profound dose-response effect, with 80% LRFS at the high dose level (23 to 24 Gy) vs. 37% with low doses ({<=}22 Gy) (p = 0.04). However, for patients who received the high dose level, histology was not a statistically significant predictor of LRFS (p = 0.90). Target organ (bone vs. lymph node vs. soft tissues) (p = 0.5) and planning target volume size (p = 0.55) were not found to be associated with long-term LRFS probability. Multivariate Cox regression analysis confirmed prescription dose to be a significant predictor of LRFS (p = 0.003). Conclusion: High-dose SD-IGRT is a noninvasive procedure resulting in high probability of local tumor control. Single-dose IGRT may be effectively used to locally control metastatic deposits regardless of histology and target organ, provided sufficiently high doses (> 22 Gy) of radiation are delivered.« less

Metronidazole and 5-aminosalicylic acid enhance the contractile activity of histaminergic agonists on the guinea-pig isolated ileum

DOE Office of Scientific and Technical Information (OSTI.GOV)

Winbery, S.L.; Barker, L.A.

1986-03-01

The effects of metronidazole and 5-aminosalicylic acid (5-ASA) on histamine receptor-effector systems in the small intestine and right atrium of the guinea pig were studied. In an apparently all-or-none manner, both caused a sinistral shift in dose-response curves for the phasic component of the contractile response to histamine at H1 receptors on the ileum. In the presence of either, the EC50 value for histamine was reduced from 0.07 to about 0.03 microM. Similarly, in an apparently all-or-none fashion, both produced an elevation in the dose-response curve for the actions of dimaprit at H2-receptors in the ileum; the response to allmore » doses was increased about 30% with no significant change in the EC50 value. Metronidazole and 5-ASA did not alter dose-response curves for the tonic contractile response to histamine or curves generated by the cumulative addition of histamine. Also, neither altered the positive chronotropic response on isolated right atria or the phasic contractile response on isolated segments of jejunum and duodenum to histamine or dimaprit. Likewise, neither altered dose-response curves for the direct action of carbamylcholine at muscarinic receptors or for the indirect actions of dimethylphenylpiperazinium on the ileum. The effects of 5-ASA or metronidazole on the response to histamine could be prevented as well as reversed by scopolamine or tetrodotoxin. The results suggest that metronidazole and 5-ASA enhance the actions of histamine and dimaprit on the ileum by an action on myenteric plexus neurons.« less

Combined Exposure to Anti-Androgens Exacerbates Disruption of Sexual Differentiation in the Rat

PubMed Central

Hass, Ulla; Scholze, Martin; Christiansen, Sofie; Dalgaard, Majken; Vinggaard, Anne Marie; Axelstad, Marta; Metzdorff, Stine Broeng; Kortenkamp, Andreas

2007-01-01

Objective The aim of this study was to assess whether the joint effects of three androgen receptor antagonists (vinclozolin, flutamide, procymidone) on male sexual differentiation after in utero and postnatal exposures can be predicted based on dose–response data of the individual chemicals. Methods Test chemicals and mixtures were administered by gavage to time-mated nulliparous, young adult Wistar rats from gestational day 7 to the day before expected birth, and from postnatal days 1–16. Changes in anogenital distance (AGD) and nipple retention (NR) in male offspring rats were chosen as end points for extensive dose–response studies. Vinclozolin, flutamide, and procymidone were combined at a mixture ratio proportional to their individual potencies for causing retention of six nipples in male offspring. Results With AGD as the end point, the joint effects of the three anti-androgens were essentially dose additive. The observed responses for NR were slightly higher than those expected on the basis of dose addition. A combination of doses of each chemical, which on its own did not produce statistically significant AGD alterations, induced half-maximal mixture effects. At individual doses associated with only modest effects on NR, the mixture induced NR approaching female values in the males. Conclusions Effects of a mixture of similarly acting anti-androgens can be predicted fairly accurately on the basis of the potency of the individual mixture components by using the dose addition concept. Exposure to anti-androgens, which individually appears to exert only small effects, may induce marked responses in concert with, possibly unrecognized, similarly acting chemicals. PMID:18174960

Angiotensin I- and II- and norepinephrine-mediated pressor responses in an ancient holostean fish, the bowfin (Amia calva).

PubMed

Butler, D G; Oudit, G Y; Cadinouche, M Z

1995-06-01

Dorsal aortic blood pressure (PSYS, systolic; PDIAS, diastolic; and PDA, mean) and heart rate (HR) were measured in resting freshwater bowfins (n = 6), Amia calva L., before and after i.v. injections of 50, 100, 200, 500, and 1000 ng.kg-1 of synthetic [Asn1, Val5]-angiotensin II (ANG II). Baseline PSYS, PDIAS, and PDA were 27.7 +/- 2.8, 22.4 +/- 1.8, and 24.5 +/- 2 mm Hg, respectively. Bowfins were only moderately responsive to ANG II in a stepwise manner and the increase in blood pressure became significant only at the two highest doses; lower doses tended only to increase arterial pressure. Pressor responses due to 200 and 500 ng.kg-1 decayed over a greater time period compared with other doses. alpha-Adrenergic blockade abolished 70% of the ANG II-mediated pressor responses. Eel, salmon, and goosefish angiotensin I (ANG I; 500 ng.kg-1) elicited similar vasopressor responses (magnitude and time course) which were eliminated by prior angiotensin converting enzyme inhibition (captopril; 2-10 mg.kg-1). Bullfrog ANG I evoked a pressor effect, only at a higher dose (5000 ng.kg-1). Consecutive norepinephrine (NE) injections (100, 200, 500, and 1000 ng.kg-1) increased PSYS, PDIAS, and PDA in a dose-dependent manner which was dependent on alpha-adrenoceptors since phentolamine (1-3 mg.kg-1) abolished 80% of the pressor action of NE. PSYS was elevated by 100 ng.kg-1 of NE but PDIAS and PDA were significantly increased only at 200 ng.kg-1 ANG II and NE had no measurable chronotropic effect and resting HR (27.2 +/- 0.8 beats.min-1) was unchanged. Captopril and phentolamine treatments produced rapid hypotension and bradycardia (25-30%) which lasted from 15 to 30 and 20 to 40 min, respectively. The rising and decreasing phases of the NE-mediated pressor responses had shorter durations than ANG II effects. Tachyphylaxis occurred with the high doses of ANG II and NE. The data show that in the ancient bowfin, which evidently lacks renal juxtaglomerular cells, the cardiovascular system can be regulated by the renin-angiotensin system and NE.

Effects of low-dose light-emitting-diode therapy in combination with water bath for atopic dermatitis in NC/Nga mice.

PubMed

Kim, Chang-Hyun; Cheong, Kyung Ah; Lim, Won Suk; Park, Hyung-Moo; Lee, Ai-Young

2016-01-01

Light-emitting diode (LED) phototherapy and water bath therapy have beneficial effect on atopic dermatitis (AD)-like skin disease. However, not all current treatments work well and alternative therapies are need. The contribution of combination therapy with low-dose 850 nm LED and water bath was investigated on dermatophagoides farina (Df)-induced dermatitis in NC/Nga mice. Low-dose LED (10, 15, and 20 J/cm(2) ) irradiation, water bath (36 ± 1°C) were administered separately and together to the Df-induced NC/Nga mice in acrylic jar once a day for 2 weeks. Combined therapy with low-dose LED therapy and water bath therapy significantly ameliorated the development of AD-like skin lesions. These effects were correlated with the suppression of total IgE, NO, histamine, and Th2-mediated immune responses. Furthermore, combination therapy significantly reduced the infiltration of inflammatory cells and the induction of thymic stromal lymphopoietin (TSLP) in the skin lesions. The beneficial therapeutic effects of this combination therapy might regulate by the inhibition of various immunological responses including Th2-mediated immune responses, inflammatory mediators such as IgE, histamine, and NO, as well as inflammatory cells. The combination therapy of LED and water bath might be used as an efficacious, safe, and steroid-free alternative therapeutic strategy for the treatment of AD. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Relative Impact of Incorporating Pharmacokinetics on ...

EPA Pesticide Factsheets

The use of high-throughput in vitro assays has been proposed to play a significant role in the future of toxicity testing. In this study, rat hepatic metabolic clearance and plasma protein binding were measured for 59 ToxCast phase I chemicals. Computational in vitro-to-in vivo extrapolation was used to estimate the daily dose in a rat, called the oral equivalent dose, which would result in steady-state in vivo blood concentrations equivalent to the AC50 or lowest effective concentration (LEC) across more than 600 ToxCast phase I in vitro assays. Statistical classification analysis was performed using either oral equivalent doses or unadjusted AC50/LEC values for the in vitro assays to predict the in vivo effects of the 59 chemicals. Adjusting the in vitro assays for pharmacokinetics did not improve the ability to predict in vivo effects as either a discrete (yes or no) response or a low effect level (LEL) on a continuous dose scale. Interestingly, a comparison of the in vitro assay with the lowest oral equivalent dose with the in vivo endpoint with the lowest LEL suggested that the lowest oral equivalent dose may provide a conservative estimate of the point of departure for a chemical in a dose-response assessment. Furthermore, comparing the oral equivalent doses for the in vitro assays with the in vivo dose range that resulted in adverse effects identified more coincident in vitro assays across chemicals than expected by chance, suggesting that the approach ma

Salmonella Fecal Shedding and Immune Responses are Dose- and Serotype- Dependent in Pigs

PubMed Central

Ivanek, Renata; Österberg, Julia; Gautam, Raju; Sternberg Lewerin, Susanna

2012-01-01

Despite the public health importance of Salmonella infection in pigs, little is known about the associated dynamics of fecal shedding and immunity. In this study, we investigated the transitions of pigs through the states of Salmonella fecal shedding and immune response post-Salmonella inoculation as affected by the challenge dose and serotype. Continuous-time multistate Markov models were developed using published experimental data. The model for shedding had four transient states, of which two were shedding (continuous and intermittent shedding) and two non-shedding (latency and intermittent non-shedding), and one absorbing state representing permanent cessation of shedding. The immune response model had two transient states representing responses below and above the seroconversion level. The effects of two doses [low (0.65×106 CFU/pig) and high (0.65×109 CFU/pig)] and four serotypes (Salmonella Yoruba, Salmonella Cubana, Salmonella Typhimurium, and Salmonella Derby) on the models' transition intensities were evaluated using a proportional intensities model. Results indicated statistically significant effects of the challenge dose and serotype on the dynamics of shedding and immune response. The time spent in the specific states was also estimated. Continuous shedding was on average 10–26 days longer, while intermittent non-shedding was 2–4 days shorter, in pigs challenged with the high compared to low dose. Interestingly, among pigs challenged with the high dose, the continuous and intermittent shedding states were on average up to 10–17 and 3–4 days longer, respectively, in pigs infected with S. Cubana compared to the other three serotypes. Pigs challenged with the high dose of S. Typhimurium or S. Derby seroconverted on average up to 8–11 days faster compared to the low dose. These findings highlight that Salmonella fecal shedding and immune response following Salmonella challenge are dose- and serotype-dependent and that the detection of specific Salmonella strains and immune responses in pigs are time-sensitive. PMID:22523553

Adrenal hormones in rats before and after stress-experience: effects of ipsapirone.

PubMed

Korte, S M; Bouws, G A; Bohus, B

1992-06-01

The present study was designed to investigate the effects of the anxiolytic 5-HT1A receptor agonist ipsapirone on the hormonal responses in rats under nonstress and stress conditions by means of repeated blood sampling through an intracardiac catheter. Ipsapirone was given in doses of 2.5, 5, 10, and 20 mg/kg (IP) under nonstress conditions in the home cages of the rats. Plasma corticosterone levels increased in a dose-dependent way in the dose range of 5 to 20 mg/kg, whereas the plasma catecholamines were only significantly increased with the highest dose of the drug. The effect of ipsapirone in control and in stressed rats was studied with the selected dose of 5 mg/kg. Conditioned fear of inescapable electric footshock (0.6 mA, AC for 3 s) given one day earlier was used as stressor. Surprisingly, ipsapirone potentiated the magnitude of the neuroendocrine responses. Rats receiving an inescapable footshock 1 day earlier showed a further elevated corticosterone response to the 5-HT1A receptor agonist ipsapirone even before exposing them to the conditioned stress situation. The present findings suggest that if an animal has no possibilities to escape or avoid a noxious event, functional hypersensitivity will develop in the serotonergic neuronal system, which is reflected in the increased responsiveness of the HPA axis to a 5-HT1A agonist challenge.

Chemical modification of normal tissue damage induced by photodynamic therapy.

PubMed Central

Sigdestad, C. P.; Fingar, V. H.; Wieman, T. J.; Lindberg, R. D.

1996-01-01

One of the limitations of successful use of photodynamic therapy (PDT) employing porphyrins is the acute and long-term cutaneous photosensitivity. This paper describes results of experiments designed to test the effects of two radiation protective agents (WR-2721, 500 mg kg-1 or WR-3689, 700 mg kg-1) on murine skin damage induced by PDT. C3H mice were shaved and depilated three days prior to injection with the photosensitiser, Photofrin (5 or 10 mg kg-1). Twenty-four hours later, the mice were injected intraperitoneally with a protector 30 min prior to Argon dye laser (630 nm) exposure. The skin response was followed for two weeks post irradiation using an arbitrary response scale. A light dose response as well as a drug dose response was obtained. The results indicate that both protectors reduced the skin response to PDT, however WR-2721 was demonstrated to be the most effective. The effect of the protectors on vascular stasis after PDT was determined using a fluorescein dye exclusion assay. In mice treated with Photofrin (5 mg kg-1), and 630 nm light (180 J cm-2) pretreatment with either WR-2721 or WR-3689 resulted in significant protection of the vascular effects of PDT. These studies document the ability of the phosphorothioate class of radiation protective agents to reduce the effects of light on photosensitized skin. They do so in a drug dose-dependent fashion with maximum protection at the highest drug doses. PMID:8763855

Platelet reactivity in response to loading dose of atorvastatin or rosuvastatin in patients with stable coronary disease before percutaneous coronary intervention: The STATIPLAT randomized study.

PubMed

Godino, Cosmo; Pavon, Anna Giulia; Mangieri, Antonio; Salerno, Anna; Cera, Michela; Monello, Alberto; Chieffo, Alaide; Magni, Valeria; Cappelletti, Alberto; Margonato, Alberto; Colombo, Antonio

2017-08-01

The acute effects of statin loading dose (LD) on platelet reactivity in patients with chronic stable angina (CSA) are not completely clear. We hypothesized that LDs of atorvastatin and rosuvastatin have different pharmacodynamic acute effects on platelet aggregability in CSA patients with baseline normal platelet reactivity while on dual antiplatelet therapy (DAPT). From September 2011 to February 2014, all consecutive CSA patients on chronic DAPT (aspirin and clopidogrel) were evaluated before elective percutaneous coronary intervention (PCI). An initial assessment of platelet reactivity in response to thrombin receptor agonist, ADP, and ASP (respectively, indicative of the response to clopidogrel and aspirin) was performed with impedance aggregometry. Patients with high platelet reactivity to ADP test (area under the curve >47) were excluded. The remaining patients were randomized into 3 treatment groups: Group A, atorvastatin LD 80 mg; Group B, rosuvastatin LD 40 mg; and Group C, no statin LD (control group). A second assessment of platelet reactivity was performed ≥12 hours after statin LD. 682 patients were screened and 145 were randomized into the 3 groups. At baseline and after statin LD, no significant difference was found in platelet reactivity in response to 3 different agonists between the 3 groups. Subgroup analysis showed that platelet reactivity to ADP test was significantly lower in patients chronically treated with low-dose statins (n = 94) compared with statin-naïve patients (n = 51; 15.32 ± 1.50 vs 18.59 ± 1.30; P = 0.007). Loading dose of atorvastatin (80 mg) or rosuvastatin (40 mg) did not induce significant variation in platelet reactivity in CSA patients with baseline reduced platelet reactivity as in chronic DAPT. Our data confirm that chronic concomitant treatment with low-dose statins and clopidogrel resulted in significantly lower platelet reactivity compared with clopidogrel alone. © 2017 Wiley Periodicals, Inc.

Dose-Response Relationship between Dietary Magnesium Intake and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Regression Analysis of Prospective Cohort Studies.

PubMed

Fang, Xin; Han, Hedong; Li, Mei; Liang, Chun; Fan, Zhongjie; Aaseth, Jan; He, Jia; Montgomery, Scott; Cao, Yang

2016-11-19

The epidemiological evidence for a dose-response relationship between magnesium intake and risk of type 2 diabetes mellitus (T2D) is sparse. The aim of the study was to summarize the evidence for the association of dietary magnesium intake with risk of T2D and evaluate the dose-response relationship. We conducted a systematic review and meta-analysis of prospective cohort studies that reported dietary magnesium intake and risk of incident T2D. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to February 2016. We included cohort studies that provided risk ratios, i.e., relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs), for T2D. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. A total of 25 studies met the eligibility criteria. These studies comprised 637,922 individuals including 26,828 with a T2D diagnosis. Compared with the lowest magnesium consumption group in the population, the risk of T2D was reduced by 17% across all the studies; 19% in women and 16% in men. A statistically significant linear dose-response relationship was found between incremental magnesium intake and T2D risk. After adjusting for age and body mass index, the risk of T2D incidence was reduced by 8%-13% for per 100 mg/day increment in dietary magnesium intake. There was no evidence to support a nonlinear dose-response relationship between dietary magnesium intake and T2D risk. The combined data supports a role for magnesium in reducing risk of T2D, with a statistically significant linear dose-response pattern within the reference dose range of dietary intake among Asian and US populations. The evidence from Europe and black people is limited and more prospective studies are needed for the two subgroups.

The effect of labetalol and propranolol on the pressor response to sexual arousal in women.

PubMed Central

Riley, A J; Riley, E J

1981-01-01

1 The effect of a single oral dose of labetalol (100 mg), propranolol (80 mg) and placebo on the pressor response to sexual autostimulation has been studied in six female volunteers. 2 Labetalol but not propranolol significantly reduced the increase in blood pressure that occurred at orgasm. 3 The subjective features of the sexual response were assessed by each subject using visual analogue scales. 4 Subjects reported a significant reduction in vaginal lubrication with labetalol compared to both placebo and propranolol. 5 No other effects were noted. PMID:7295463

Antibody response to vaccines for rhinotracheitis, caliciviral disease, panleukopenia, feline leukemia, and rabies in tigers (Panthera tigris) and lions (Panthera leo).

PubMed

Risi, Emmanuel; Agoulon, Albert; Allaire, Franck; Le Dréan-Quénec'hdu, Sophie; Martin, Virginie; Mahl, Philippe

2012-06-01

This article presents the results of a study of captive tigers (Panthera tigris) and lions (Panthera leo) vaccinated with a recombinant vaccine against feline leukemia virus; an inactivated adjuvanted vaccine against rabies virus; and a multivalent modified live vaccine against feline herpesvirus, calicivirus, and panleukopenia virus. The aim of the study was to assess the immune response and safety of the vaccines and to compare the effects of the administration of single (1 ml) and double (2 ml) doses. The animals were separated into two groups and received either single or double doses of vaccines, followed by blood collection for serologic response for 400 days. No serious adverse event was observed, with the exception of abortion in one lioness, potentially caused by the incorrect use of the feline panleukopenia virus modified live vaccine. There was no significant difference between single and double doses for all vaccines. The recombinant vaccine against feline leukemia virus did not induce any serologic response. The vaccines against rabies and feline herpesvirus induced a significant immune response in the tigers and lions. The vaccine against calicivirus did not induce a significant increase in antibody titers in either tigers or lions. The vaccine against feline panleukopenia virus induced a significant immune response in tigers but not in lions. This report demonstrates the value of antibody titer determination after vaccination of nondomestic felids.

Caffeine Increases the Linearity of the Visual BOLD Response

PubMed Central

Liu, Thomas T.; Liau, Joy

2009-01-01

Although the blood oxygenation level dependent (BOLD) signal used in most functional magnetic resonance imaging (fMRI) studies has been shown to exhibit nonlinear characteristics, most analyses assume that the BOLD signal responds in a linear fashion to stimulus. This assumption of linearity can lead to errors in the estimation of the BOLD response, especially for rapid event-related fMRI studies. In this study, we used a rapid event-related design and Volterra kernel analysis to assess the effect of a 200 mg oral dose of caffeine on the linearity of the visual BOLD response. The caffeine dose significantly (p < 0.02) increased the linearity of the BOLD response in a sample of 11 healthy volunteers studied on a 3 Tesla MRI system. In addition, the agreement between nonlinear and linear estimates of the hemodynamic response function was significantly increased (p= 0.013) with the caffeine dose. These findings indicate that differences in caffeine usage should be considered as a potential source of bias in the analysis of rapid event-related fMRI studies. PMID:19854278

Cardiovascular and hypokalaemic effects of inhaled salbutamol, fenoterol, and isoprenaline.

PubMed Central

Crane, J; Burgess, C; Beasley, R

1989-01-01

The cardiovascular and hypokalaemic effects of equal doses of inhaled fenoterol, isoprenaline and salbutamol were compared in eight healthy male volunteers, in a double blind, placebo controlled study. Increasing doses of 400, 600, and 800 micrograms were given from a metered dose inhaler at 15 minute intervals, followed by measurements of heart rate, blood pressure, total electromechanical systole (as a measure of inotropic response), QTc interval, and plasma potassium concentration. After repeated inhalation, fenoterol resulted in significantly greater chronotropic, electrocardiographic, and hypokalaemic effects than either isoprenaline or salbutamol. The maximum inotropic effect of fenoterol was similar to that of isoprenaline. PMID:2928998

Dose-response relationship of cardiorespiratory fitness adaptation to controlled endurance training in sedentary older adults.

PubMed

Huang, Guoyuan; Wang, Ru; Chen, Peijie; Huang, Sunny C; Donnelly, Joseph E; Mehlferber, Jon P

2016-03-01

The purpose of this investigation was to identify a quantitative dose-response relationship for enhancing maximal oxygen consumption (VO2max) in healthy sedentary older adults after controlled endurance training. This meta-analysis of controlled clinical trials included 1257 exercisers and 845 controls with a mean age of 67.45 ± 5.25 years. Effect sizes were calculated for training-induced VO2max changes. Different training regimens were analyzed and compared. The weighted net change of the mean VO2max values showed a significant increase of 3.78 ml/kg per min (95% confidence interval = 3.29 to 4.27; p < 0.0001) in response to aerobic training. Interstudy differences in VO2max changes were significantly related to exercise intensity, and explained approximately 11% of the variance of the VO2max responses. VO2max improved significantly at 35%-50% heart rate reserve (HRR) and continued improving at a greater rate with increasing "dose". The largest VO2max-improvement adaptation was achieved with a mean intensity of 66%-73% HRR. The magnitudes of the VO2max adaptation are identical to exercise at 57%-65% HRR and at 75%-80% HRR. Higher intensity doses more than 75-80% HRR did not lead to greater enhancement of VO2max improvements but, conversely, resulted in large declines. Our data provide quantitative insight into the magnitude of VO2max alterations as affected by exercise intensity, duration, frequency, and program length. The shapes of the dose-response curves are not simply linear, but with many similar trends and noteworthy characteristics. Aerobic training at a mean intensity of 66%-73% HRR with 40-50 min per session for 3-4 day/week for 30-40 weeks appears to be effective and optimal for maximum cardiorespiratory benefits in healthy sedentary older adults. © The European Society of Cardiology 2015.

Comparative response to single or divided doses of parenteral iron for functional iron deficiency in hemodialysis patients receiving erythropoietin (EPO).

PubMed

Saltissi, D; Sauvage, D; Westhuyzen, J

1998-01-01

EPO treatment rapidly corrects anemia in patients with end-stage renal failure treated with hemodialysis, as long as sufficient iron is available. Absolute and relative (to demand) iron deficiency blunts the erythropoietic response and parenteral iron is frequently required during the course of therapy to restore EPO efficacy. Since the optimum time course of iron administration to restore EPO response in the short term is unknown, we compared three protocols of i.v. iron dextran administration in apparent functionally iron-deficient HD patients on oral iron therapy (hemoglobin < 10.0 g/dl plus ferritin < 100 micrograms/l and/or transferrin saturation < 20%). Intravenous iron (Imferon; Fisons Pty Ltd.) was given either as a single 600 mg dose (n = 15, Group I) or in divided doses of 100 mg administered on 6 successive dialyses (n = 14, Group II) or weekly for 6 weeks (n = 14, Group III). Response was monitored for 8 weeks. No adverse effects were observed. Collectively, mean hemoglobin increased (p < 0.01) by 0.4-0.5 g/dl plateauing at 4 weeks (between group comparison, p = 0.92). Mean ferritin concentrations changed with time (p < 0.01), peaking at 2 weeks in Groups I and II and at 4 weeks in Group III. Mean transferrin saturation levels also increased during the study (p < 0.001). The between group comparisons for the trends in iron indices were significant (p < 0.01 and 0.05 respectively). As there were no clinically significant differences in hemoglobin response at 4 weeks, single dose iron infusion would seem to be the most expedient in the short term, however frequent small doses are similarly effective.

Exposure to Silver Nanospheres Leads to Altered Respiratory Mechanics and Delayed Immune Response in an in Vivo Murine Model

PubMed Central

Botelho, Danielle; Leo, Bey F.; Massa, Christopher; Sarkar, Srijata; Tetley, Terry; Chung, Kian F.; Chen, Shu; Ryan, Mary P.; Porter, Alexandra; Atochina-Vasserman, Elena N.; Zhang, Junfeng; Schwander, Stephan; Gow, Andrew J.

2018-01-01

Here we examine the organ level toxicology of both carbon black (CB) and silver nanoparticles (AgNP). We aim to determine metal-specific effects to respiratory function, inflammation and potential interactions with lung lining fluid (LLF). C57Bl6/J male mice were intratracheally instilled with saline (control), low (0.05 μg/g) or high (0.5 μg/g) doses of either AgNP or CB 15 nm nanospheres. Lung histology, cytology, surfactant composition and function, inflammatory gene expression, and pulmonary function were measured at 1, 3, and 7 days post-exposure. Acutely, high dose CB resulted in an inflammatory response, increased neutrophilia and cytokine production, without alteration in surfactant composition or respiratory mechanics. Low dose CB had no effect. Neither low nor high dose AgNPs resulted in an acute inflammatory response, but there was an increase in work of breathing. Three days post-exposure with CB, a persistent neutrophilia was noted. High dose AgNP resulted in an elevated number of macrophages and invasion of lymphocytes. Additionally, AgNP treated mice displayed increased expression of IL1B, IL6, CCL2, and IL10. However, there were no significant changes in respiratory mechanics. At day 7, inflammation had resolved in AgNP-treated mice, but tissue stiffness and resistance were significantly decreased, which was accompanied by an increase in surfactant protein D (SP-D) content. These data demonstrate that the presence of metal alters the response of the lung to nanoparticle exposure. AgNP-surfactant interactions may alter respiratory function and result in a delayed immune response, potentially due to modified airway epithelial cell function. PMID:29632485

Effects of UV-B irradiation on isoforms of antioxidant enzymes and their activities in red alga Grateloupia filicina (Rhodophyta)

NASA Astrophysics Data System (ADS)

Zhao, Jiqiang; Li, Lixia

2014-11-01

Macroalgae in a littoral zone are inevitably exposed to UV-B irradiance. We analyzed the effects of UV-B on isoenzyme patterns and activities of superoxide dismutase (SOD), peroxidase (POX), catalase (CAT), and ascorbate peroxidase (APX) of red algae Grateloupia filicina (Lamour.) C. Agardh. The activities of SOD, CAT, and APX changed in response to UV-B in a time- and dose-dependent manner. POX activity increased significantly under all three UV-B treatments. The enzymatic assay showed three distinct bands of SODI (Mn-SOD), SODII (Fe-SOD), and SODIII (CuZn-SOD) under a low (Luv) and medium (Muv) dose of UV-B irradiation, while SODI and SODIII activities decreased significantly when exposed to a high dose of UV-B irradiation (Huv). The activity of POX isoenzymes increased significantly after exposure to UV-B, which is consistent with the total activity. In addition, a clear decrease in activity of CATIV was detected in response to all the three doses of UV treatments. Some bands of APX isoenzyme were also clearly influenced by UV-B irradiation. Correspondingly, the daily growth rate declined under all the three exposure doses, and was especially significant under Muv and Huv treatments. These data suggest that, although the protection mechanisms of antioxidant defense system are partly inducible by UV-B to prevent the damage, G. filicina has incomplete tolerance to higher UV-B irradiation stress.

Dose response effect of cement dust on respiratory muscles competence in cement mill workers.

PubMed

Meo, Sultan A; Azeem, Muhammad A; Qureshi, Aijaz A; Ghori, G Moinudin; Al-Drees, Abdul Majeed; Feisal Subhan, Mirza Muhammad

2006-12-01

Electromyography (EMG) of respiratory muscles is a reliable method of assessing the ventilatory muscle function, but still its use has not been fully utilized to determine the occupational and environmental hazards on respiratory muscles. Therefore, EMG of intercostal muscles was performed to determine the dose response effect of cement dust on respiratory muscles competence. Matched cross-sectional study of EMG in 50 non-smoking cement mill workers with an age range of 20 - 60 years, who worked without the benefit of cement dust control ventilation or respiratory protective devices. EMG was performed by using surface electrodes and chart recorder. Significant reduction was observed in number of peaks (p < 0.0005), maximum peak amplitude (p < 0.0005), peak-to-peak amplitude (p < 0.0005) and duration of response (p < 0.0005) in cement mill workers compared to their matched control. Cement dust impairs the intercostal muscle competence and stratification of results shows a dose-effect of years of exposure in cement mill.

Photodynamic therapy with 3-(1'-hexyloxyethyl) pyropheophorbide a for cancer of the oral cavity.

PubMed

Rigual, Nestor; Shafirstein, Gal; Cooper, Michele T; Baumann, Heinz; Bellnier, David A; Sunar, Ulas; Tracy, Erin C; Rohrbach, Daniel J; Wilding, Gregory; Tan, Wei; Sullivan, Maureen; Merzianu, Mihai; Henderson, Barbara W

2013-12-01

The primary objective was to evaluate safety of 3-(1'-hexyloxyethyl)pyropheophorbide-a (HPPH) photodynamic therapy (HPPH-PDT) for dysplasia and early squamous cell carcinoma of the head and neck (HNSCC). Secondary objectives were the assessment of treatment response and reporters for an effective PDT reaction. Patients with histologically proven oral dysplasia, carcinoma in situ, or early-stage HNSCC were enrolled in two sequentially conducted dose escalation studies with an expanded cohort at the highest dose level. These studies used an HPPH dose of 4 mg/m(2) and light doses from 50 to 140 J/cm(2). Pathologic tumor responses were assessed at 3 months. Clinical follow up range was 5 to 40 months. PDT induced cross-linking of STAT3 were assessed as potential indicators of PDT effective reaction. Forty patients received HPPH-PDT. Common adverse events were pain and treatment site edema. Biopsy proven complete response rates were 46% for dysplasia and carcinoma in situ and 82% for squamous cell carcinomas (SCC) lesions at 140 J/cm(2). The responses in the carcinoma in situ/dysplasia cohort are not durable. The PDT-induced STAT3 cross-links is significantly higher (P = 0.0033) in SCC than in carcinoma in situ/dysplasia for all light doses. HPPH-PDT is safe for the treatment of carcinoma in situ/dysplasia and early-stage cancer of the oral cavity. Early-stage oral HNSCC seems to respond better to HPPH-PDT in comparison with premalignant lesions. The degree of STAT3 cross-linking is a significant reporter to evaluate HPPH-PDT-mediated photoreaction. ©2013 AACR.

A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa

PubMed Central

Kang, Sang Bum; Marchelletta, Ronald R; Penrose, Harrison; Docherty, Michael J; McCole, Declan F

2015-01-01

Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (Isc). Subsequent Isc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. Isc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation. PMID:26038704

A comparison of linaclotide and lubiprostone dosing regimens on ion transport responses in human colonic mucosa.

PubMed

Kang, Sang Bum; Marchelletta, Ronald R; Penrose, Harrison; Docherty, Michael J; McCole, Declan F

2015-03-01

Linaclotide, a synthetic guanylyl cyclase C (GC-C) agonist, and the prostone analog, Lubiprostone, are approved to manage chronic idiopathic constipation and constipation-predominant irritable bowel syndrome. Lubiprostone also protects intestinal mucosal barrier function in ischemia. GC-C signaling regulates local fluid balance and other components of intestinal mucosal homeostasis including epithelial barrier function. The aim of this study was to compare if select dosing regimens differentially affect linaclotide and lubiprostone modulation of ion transport and barrier properties of normal human colonic mucosa. Normal sigmoid colon biopsies from healthy subjects were mounted in Ussing chambers. Tissues were treated with linaclotide, lubiprostone, or vehicle to determine effects on short-circuit current (I sc). Subsequent I sc responses to the cAMP agonist, forskolin, and the calcium agonist, carbachol, were also measured to assess if either drug caused desensitization. Barrier properties were assessed by measuring transepithelial electrical resistance. I sc responses to linaclotide and lubiprostone were significantly higher than vehicle control when administered bilaterally or to the mucosal side only. Single versus cumulative concentrations of linaclotide showed differences in efficacy while cumulative but not single dosing caused desensitization to forskolin. Lubiprostone reduced forskolin responses under all conditions. Linaclotide and lubiprostone exerted a positive effect on TER that was dependent on the dosing regimen. Linaclotide and lubiprostone increase ion transport responses across normal human colon but linaclotide displays increased sensitivity to the dosing regimen used. These findings may have implications for dosing protocols of these agents in patients with constipation.

Dose Response Data for Hormonally Active Chemicals: Estrogens, Antiandrogens and Androgens

EPA Science Inventory

The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects. For noncancer effects the defaul...

Effect of two doses of inhaled diltiazem on exercise-induced asthma.

PubMed

Foresi, A; Corbo, G M; Ciappi, G; Valente, S; Polidori, G

1987-01-01

Seven asthmatic children with moderately to severely increased bronchial responsiveness to methacholine took part in a double-blind placebo-controlled study to assess the effect of a calcium channel blocker, diltiazem, on exercise-induced asthma (EIA), and its duration. On the control day, bronchial response to exercise was found to be highly reproducible when performed 2 h apart (intraclass correlation coefficient 0.92). Normal saline and diltiazem at concentrations of 1.75 and 3.50 mg/ml (estimated nebulized doses 5 and 10 mg, respectively) were given in random order before exercise on a bicycle ergometer. Exercise challenge was performed 20 min and 2 h after each treatment, and bronchial response was expressed as percent fall in the forced expiratory volume in 1 s. In the overall group, diltiazem did not significantly change resting bronchial tone and produced no significant (p = 0.18) attenuation of EIA. An almost complete protection was detected only in two subjects 20 min after diltiazem 10 mg. This limited effect waned 2 h after the administration.

Variability of methacholine bronchoprovocation and the effect of inhaled corticosteroids in mild asthma

PubMed Central

Sumino, Kaharu; Sugar, Elizabeth A.; Irvin, Charles G.; Kaminsky, David A.; Shade, Dave; Wei, Christine Y.; Holbrook, Janet T.; Wise, Robert A.; Castro, Mario

2014-01-01

Background The methacholine challenge test quantifies airway hyper-responsiveness, which is measured by the provocative concentration of methacholine causing a 20% decrease in forced expiration volume in 1 second (PC20). The dose–response effect of inhaled corticosteroids (ICS) on PC20 has been inconsistent and within-patient variability of PC20 is not well established. Objectives To determine the effect of high- vs low-dose ICS on PC20 and within-patient variability in those with repeated measurements of PC20. Methods A randomized, double-masked, crossover trial was conducted in patients with asthma on controller medications with PC20 of 8 mg/mL or lower (n = 64) to evaluate the effect of high-dose (1,000 μg/d) vs low-dose (250 μg/d) fluticasone for 4 weeks on PC20. In addition, the variability of PC20 was assessed in participants who underwent 2 or 3 PC20 measurements on the same dose of ICS (n = 27) over a 4-week interval. Results Because there was a significant period effect, dose comparison of the change in PC20 was assessed in the first treatment period. There was no significant difference in the change in PC20 for high- vs low-dose ICS (39% vs 30% increase, respectively; P = .87). The within- and between-participant variances for log PC20 were 0.84 and 0.96, respectively, with an intra-class correlation of 0.53, and 37% of participants had more than 2 doubling dose changes in PC20 in those with repeated measurements. Conclusion The effect of ICS on PC20 is not dose dependent at fluticasone levels of 250 and 1,000 μg/d. Interpersonal variability for PC20 is large. A lack of precise measurements should be taken into account when interpreting any change in PC20. PMID:24507830

Extracellular vesicles have variable dose-dependent effects on cultured draining cells in the eye.

PubMed

Tabak, Saray; Schreiber-Avissar, Sofia; Beit-Yannai, Elie

2018-03-01

The role of extracellular vesicles (EVs) as signal mediators has been described in many biological fields. How many EVs are needed to deliver the desired physiological signal is yet unclear. Using a normal trabecular meshwork (NTM) cell culture exposed to non-pigmented ciliary epithelium (NPCE)-derived EVs, a relevant model for studying the human ocular drainage system, we addressed the EVs dose-response effects on the Wnt signaling. The objective of the study was to investigate the dosing effects of NPCE-derived EVs on TM Wnt signaling. EVs were isolated by PEG 8000 method from NPCE and RPE cells (used as controls) conditioned media. Concentrations were determined by Tunable Resistive Pulse Sensing method. Various exosomes concentration were incubated with TM cells, for the determination of mRNA (β-Catenin, Axin2 and LEF1) and protein (β-Catenin, GSK-3β) expression using real-time quantitative PCR and Western blot, respectively. Exposure of NTM cells for 8 hrs to low EVs concentrations was associated with a significant decreased expression of β-Catenin, GSK-3β, as opposed to exposure to high exosomal concentrations. Pro-MMP9 and MMP9 activities were significantly enhanced in NTM cells treated with high EV concentrations of (X10) as compared to low EV concentrations of either NPCE- or RPE-derived EVs and to untreated control. Our data support the concept that EVs biological effects are concentration-dependent at their target site. Specifically in the present study, we described a general dose-response at the gene and MMPs activity and a different dose-response regarding key canonical Wnt proteins expression. © 2018 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Treatment of yellow fever virus with an adenovirus-vectored interferon, DEF201, in a hamster model.

PubMed

Julander, Justin G; Ennis, Jane; Turner, Jeffrey; Morrey, John D

2011-05-01

Interferon (IFN) is an innate immune response protein that is involved in the antiviral response during viral infection. Treatment of acute viral infections with exogenous interferon may be effective but is generally not feasible for clinical use due to many factors, including cost, stability, and availability. To overcome these limitations, an adenovirus type 5-vectored consensus alpha IFN, termed DEF201, was constructed as a potential way to deliver sustained therapeutic levels of systemic IFN. To demonstrate the efficacy of DEF201 against acute flaviviral disease, various concentrations of the construct were administered as a single intranasal dose prior to virus infection, which resulted in a dose-responsive, protective effect in a hamster model of yellow fever virus (YFV) disease. A DEF201 dose of 5×10(7) PFU/animal administered intranasally just prior to YFV challenge protected 100% of the animals, while a 10-fold lower DEF201 dose exhibited lower, although significant, levels of protection. Virus titers in the liver and serum and levels of serum alanine aminotransferase were all significantly reduced as a result of DEF201 administration at all doses tested. No toxicity, as indicated by weight loss or gross morbidity, was observed in non-YFV-infected animals treated with DEF201. Protection of YFV-infected animals was observed when DEF201 was delivered as early as 7 days prior to virus challenge and as late as 2 days after virus challenge, demonstrating effective prophylaxis and therapy in a hamster model of disease. Overall, it appears that DEF201 is effective in the treatment of YFV in a hamster model.

[Induction of glutathione and activation of immune functions by low-dose, whole-body irradiation with gamma-rays].

PubMed

Kojima, Shuji

2006-10-01

We first examined the relation between the induction of glutathione and immune functions in mice after low-dose gamma-ray irradiation. Thereafter, inhibition of tumor growth by radiation was confirmed in Ehrlich solid tumor (EST)-bearing mice. The total glutathione level of the splenocytes transiently increased soon after irradiation and reached a maximum at around 4 h postirradiation. Thereafter, the level reverted to the 0 h value by 24 h postirradiation. A significantly high splenocyte proliferative response was also recognized 4 h postirradiation. Natural killer (NK) activity was also increased significantly in a similar manner. The time at which the response reached the maximum coincided well with that of maximum total glutathione levels of the splenocytes in the gamma-ray-irradiated mice. Reduced glutathione exogenously added to splenocytes obtained from normal mice enhanced the proliferative response and NK activity in a dose-dependent manner. The inhibitory effects of radiation on tumor growth was then examined in EST-bearing mice. Repeated low-dose irradiation (0.5 Gy, four times, before and within an early time after inoculation) significantly delayed the tumor growth. Finally, the effect of single low-dose (0.5 Gy), whole-body gamma-ray irradiation on immune balance was examined to elucidate the mechanism underlying the antitumor immunity. The percentage of B cells in blood lymphocytes was selectively decreased after radiation, concomitant with an increase in that of the helper T cell population. The IFN-gamma level in splenocyte culture prepared from EST-bearing mice was significantly increased 48 h after radiation, although the level of IL-4 was unchanged. IL-12 secretion from macrophages was also enhanced by radiation. These results suggest that low-dose gamma-rays induce Th1 polarization and enhance the activities of tumoricidal effector cells, leading to an inhibition of tumor growth.

Lipoic acid and Calligonum comosumon attenuate aroclor 1260-induced testicular toxicity in adult rats.

PubMed

Aly, Hamdy A A; Alahdal, Abdulrahman M; Nagy, Ayman A; Abdallah, Hossam M; Abdel-Sattar, Essam A; Azhar, Ahmad S

2017-04-01

Aroclor 1260 is one of the more representative polychlorinated biphenyls found in biota. This study was designed to delineate the testicular toxicity of Aroclor 1260 and to elucidate the potential protective role of Calligonum comosum (C. comosum) and lipoic acid in adult rats. Aroclor 1260 was dissolved in corn oil and given to rats by gavage at doses 0, 20, 40, or 60 mg/kg/day for 15 consecutive days (Groups I, II, III, and IV, respectively). Groups V and VI were pretreated with C. comosum (200 mg/kg/day) and lipoic acid (35 mg/kg/day) respectively 24 h before Aroclor 1260 (40 mg/kg/day) treatment for 15 consecutive days. Aroclor 1260 (20, 40 or 60 mg/kg/day) treatment significantly decreased testes weight, sperm count and motility and daily sperm production. Serum testosterone was significantly decreased in response to treatment with 40 and 60 mg/kg/day of Aroclor 1260. LDH-X activity was significantly decreased at the three dose levels. Hydrogen peroxide (H 2 O 2 ) production (in a dose-related manner) and lipid peroxidation were significantly increased in response to Aroclor 1260 (20, 40, or 60 mg/kg/day) treatment. Aroclor 1260 at the three dose levels decreased the activities of the antioxidant enzymes SOD, CAT, GPx, and GR and the non-enzymatic antioxidant GSH level. CAT, GPx and GSH showed a dose-response effect. These abnormalities were effectively attenuated by pretreatment with C. comosum (200 mg/kg/day) or lipoic acid (35 mg/kg/day). Histopathological examination showed a dose-related increase in morphological abnormalities of the testis in response to Aroclor 1260 treatment. In conclusion, Aroclor 1260 induced testicular toxicity at least, in part, by induction of oxidative stress. By reversal of biochemical and morphological changes towards normalcy, the cytoprotective role of C. comosum and lipoic acid is illuminated. In comparison, lipoic acid was more protective than C. comosum extract against testicular toxicity induced by Aroclor 1260. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1147-1157, 2017. © 2016 Wiley Periodicals, Inc.

Design considerations and analysis planning of a phase 2a proof of concept study in rheumatoid arthritis in the presence of possible non-monotonicity.

PubMed

Liu, Feng; Walters, Stephen J; Julious, Steven A

2017-10-02

It is important to quantify the dose response for a drug in phase 2a clinical trials so the optimal doses can then be selected for subsequent late phase trials. In a phase 2a clinical trial of new lead drug being developed for the treatment of rheumatoid arthritis (RA), a U-shaped dose response curve was observed. In the light of this result further research was undertaken to design an efficient phase 2a proof of concept (PoC) trial for a follow-on compound using the lessons learnt from the lead compound. The planned analysis for the Phase 2a trial for GSK123456 was a Bayesian Emax model which assumes the dose-response relationship follows a monotonic sigmoid "S" shaped curve. This model was found to be suboptimal to model the U-shaped dose response observed in the data from this trial and alternatives approaches were needed to be considered for the next compound for which a Normal dynamic linear model (NDLM) is proposed. This paper compares the statistical properties of the Bayesian Emax model and NDLM model and both models are evaluated using simulation in the context of adaptive Phase 2a PoC design under a variety of assumed dose response curves: linear, Emax model, U-shaped model, and flat response. It is shown that the NDLM method is flexible and can handle a wide variety of dose-responses, including monotonic and non-monotonic relationships. In comparison to the NDLM model the Emax model excelled with higher probability of selecting ED90 and smaller average sample size, when the true dose response followed Emax like curve. In addition, the type I error, probability of incorrectly concluding a drug may work when it does not, is inflated with the Bayesian NDLM model in all scenarios which would represent a development risk to pharmaceutical company. The bias, which is the difference between the estimated effect from the Emax and NDLM models and the simulated value, is comparable if the true dose response follows a placebo like curve, an Emax like curve, or log linear shape curve under fixed dose allocation, no adaptive allocation, half adaptive and adaptive scenarios. The bias though is significantly increased for the Emax model if the true dose response follows a U-shaped curve. In most cases the Bayesian Emax model works effectively and efficiently, with low bias and good probability of success in case of monotonic dose response. However, if there is a belief that the dose response could be non-monotonic then the NDLM is the superior model to assess the dose response.

Pharmacokinetics, pharmacodynamics, and dose-response relationship of repaglinide in type 2 diabetes.

PubMed

Strange, P; Schwartz, S L; Graf, R J; Polvino, W; Weston, I; Marbury, T C; Huang, W C; Goldberg, R B

1999-01-01

The pharmacodynamics and dose-response relationship of repaglinide, a novel oral hypoglycemic agent, were evaluated in steady-state treatment of patients with type 2 diabetes. Efficacy of repaglinide (0.25 mg, 0.5 mg, 1 mg, 2 mg, and 4 mg) was compared to that of placebo in a double-blind, randomized, parallel-group, 4-week dose-response clinical trial in 143 patients. Repaglinide was administered 15 minutes before meals (breakfast, lunch, and dinner). Efficacy of repaglinide therapy was assessed by measuring changes from baseline in mean levels of blood glucose (BGmean), fasting serum glucose (FSG), and mean levels of serum insulin (INSmean). Blood concentrations of repaglinide were proportional to the dose administered. INSmean values increased in all repaglinide treatment groups (by 6.7 to 12.9 microU/mL). All doses of repaglinide significantly decreased values of BGmean and FSG as compared with the placebo group. BGmean values stabilized between the second and third week of repaglinide treatment. A well-defined dose-response relationship was observed for BGmean and FSG values. All doses of repaglinide were well tolerated, and there were no serious adverse events. These findings show that the therapeutic reduction of serum glucose levels produced by repaglinide is dose-dependent for the 0.25- to 4-mg dose range. All doses of repaglinide tested were effective and well tolerated in patients with type 2 diabetes.

Assessment of low-dose cisplatin as a model of nausea and emesis in beagle dogs, potential for repeated administration.

PubMed

Kenward, Hannah; Pelligand, Ludovic; Elliott, Jonathan

2014-08-01

Cisplatin is a highly emetogenic cancer chemotherapy agent, which is often used to induce nausea and emesis in animal models. The cytotoxic properties of cisplatin also cause adverse events that negatively impact on animal welfare preventing repeated administration of cisplatin. In this study, we assessed whether a low (subclinical) dose of cisplatin could be utilized as a model of nausea and emesis in the dog while decreasing the severity of adverse events to allow repeated administration. The emetic, nausea-like behavior and potential biomarker response to both the clinical dose (70 mg/m2) and low dose (15 mg/m2) of cisplatin was assessed. Plasma creatinine concentrations and granulocyte counts were used to assess adverse effects on the kidneys and bone marrow, respectively. Nausea-like behavior and emesis was induced by both doses of cisplatin, but the latency to onset was greater in the low-dose group. No significant change in plasma creatinine was detected for either dose groups. Granulocytes were significantly reduced compared with baseline (P = 0.000) following the clinical, but not the low-dose cisplatin group. Tolerability of repeated administration was assessed with 4 administrations of an 18 mg/m2 dose cisplatin. Plasma creatinine did not change significantly. Cumulative effects on the granulocytes occurred, they were significantly decreased (P = 0.03) from baseline at 3 weeks following cisplatin for the 4th administration only. Our results suggest that subclinical doses (15 and 18 mg/m2) of cisplatin induce nausea-like behavior and emesis but have reduced adverse effects compared with the clinical dose allowing for repeated administration in crossover studies.

Association of radiation dose with prevalence of thyroid nodules among atomic bomb survivors exposed in childhood (2007-2011).

PubMed

Imaizumi, Misa; Ohishi, Waka; Nakashima, Eiji; Sera, Nobuko; Neriishi, Kazuo; Yamada, Michiko; Tatsukawa, Yoshimi; Takahashi, Ikuno; Fujiwara, Saeko; Sugino, Keizo; Ando, Takao; Usa, Toshiro; Kawakami, Atsushi; Akahoshi, Masazumi; Hida, Ayumi

2015-02-01

Few studies have evaluated the association of radiation dose with thyroid nodules among adults exposed to radiation in childhood. To evaluate radiation dose responses on the prevalence of thyroid nodules in atomic bomb survivors exposed in childhood. This survey study investigated 3087 Hiroshima and Nagasaki atomic bomb survivors who were younger than 10 years at exposure and participated in the thyroid study of the Adult Health Study at the Radiation Effects Research Foundation. Thyroid examinations including thyroid ultrasonography were conducted between October 2007 and October 2011, and solid nodules underwent fine-needle aspiration biopsy. Data from 2668 participants (86.4% of the total participants; mean age, 68.2 years; 1213 men; and 1455 women) with known atomic bomb thyroid radiation doses (mean dose, 0.182 Gy; median dose, 0.018 Gy; dose range, 0-4.040 Gy) were analyzed. The prevalence of all thyroid nodules having a diameter of 10 mm or more (consisting of solid nodules [malignant and benign] and cysts), prevalence of small thyroid nodules that were less than 10 mm in diameter detected by ultrasonography, and atomic bomb radiation dose-responses. Thyroid nodules with a diameter of 10 mm or more were identified in 470 participants (17.6%): solid nodules (427 cases [16.0%]), malignant tumors (47 cases [1.8%]), benign nodules (186 cases [7.0%]), and cysts (49 cases [1.8%]), and all were significantly associated with thyroid radiation dose. Excess odds ratios per gray unit were 1.65 (95% CI, 0.89-2.64) for all nodules, 1.72 (95% CI, 0.93-2.75) for solid nodules, 4.40 (95% CI, 1.75-9.97) for malignant tumors, 2.07 (95% CI, 1.16-3.39) for benign nodules, and 1.11 (95% CI, 0.15-3.12) for cysts. The interaction between age at exposure and the dose was significant for the prevalence of all nodules (P = .003) and solid nodules (P < .001), indicating that dose effects were significantly higher with earlier childhood exposure. No interactions were seen for sex, family history of thyroid disease, antithyroid antibodies, or seaweed intake. No dose-response relationships were observed for small (<10-mm diameter) thyroid nodules. Radiation effects on thyroid nodules exist in atomic bomb survivors 62 to 66 years after their exposure in childhood. However, radiation exposure is not associated with small thyroid nodules.

A model for evaluating radiological impacts on organisms other than man for use in post-closure assessments of geological repositories for radioactive wastes.

PubMed

Thorn, M C; Kelly, M; Rees, J H; Sánchez-Friera, P; Calvez, M

2002-09-01

Bioaccumulation and dosimetric models have been developed that allow the computation of dose rates to a wide variety of plants and animals in the context of the deep geological disposal of solid radioactive wastes. These dose rates can be compared with the threshold dose rates at which significant deleterious effects have been observed in field and laboratory observations. This provides a general indication of whether effects on ecosystems could be observable, but does not quantify the level of those effects. To address this latter issue, two indicator organisms were identified and exposure-response relationships were developed for endpoints of potential interest (mortality in conifers and the induction of skeletal malformations in rodents irradiated in utero). The bioaccumulation, dosimetry and exposure-response models were implemented and used to evaluate the potential significance of radionuclide releases from a proposed deep geological repository for radioactive wastes in France. This evaluation was undertaken in the context of a programme of assessment studies being performed by the Agence nationale pour la gestion des déchets radioactifs (ANDRA).

Effect of increasing radiation dose on pathologic complete response in rectal cancer patients treated with neoadjuvant chemoradiation therapy.

PubMed

Hall, Matthew D; Schultheiss, Timothy E; Smith, David D; Fakih, Marwan G; Wong, Jeffrey Y C; Chen, Yi-Jen

2016-12-01

Neoadjuvant chemoradiation therapy (CRT) increases pathological complete response (pCR) rates compared to radiotherapy alone in patients with stage II-III rectal cancer. Limited evidence addresses whether radiotherapy dose escalation further improves pCR rates. Our purpose is to measure the effects of radiotherapy dose and other factors on post-therapy pathologic tumor (ypT) and nodal stage in rectal cancer patients treated with neoadjuvant CRT followed by mesorectal excision. A non-randomized comparative effectiveness analysis was performed of rectal cancer patients treated in 2000-2013 from the National Oncology Data Alliance™ (NODA), a pooled database of cancer registries from >150 US hospitals. The NODA contains the same data submitted to state cancer registries and SEER combined with validated radiotherapy and chemotherapy records. Eligible patients were treated with neoadjuvant CRT followed by proctectomy and had complete data on treatment start dates, radiotherapy dose, clinical tumor (cT) and ypT stage, and number of positive nodes at surgery (n = 3298 patients). Multivariable logistic regression was used to assess the predictive value of independent variables on achieving a pCR. On multivariable regression, radiotherapy dose, cT stage, and time interval between CRT and surgery were significant predictors of achieving a pCR. After adjusting for the effect of other variates, patients treated with higher radiotherapy doses were also more likely to have negative nodes at surgery and be downstaged from cT3-T4 and/or node positive disease to ypT0-T2N0 after neoadjuvant CRT. Our study suggests that increasing dose significantly improved pCR rates and downstaging in rectal cancer patients treated with neoadjuvant CRT followed by surgery.

Phosphoramidon potentiates mammalian tachykinin-induced biting, licking and scratching behaviour in mice.

PubMed

Sakurada, T; Tan-No, K; Yamada, T; Sakurada, S; Kisara, K

1990-12-01

The effects of peptidase inhibitors were examined upon behavioural responses including scratch, bite and lick produced by intrathecal (IT) injection of substance P (SP) and neurokinin A (NK A) in mice. Phosphoramidon (0.002-2.0 nmol), an endopeptidase-24.11 inhibitor, simultaneously injected with SP or NK A, remarkably enhanced and prolonged SP- or NK A-induced behavioural response in a dose-dependent manner. The behavioural response to SP was significantly increased by 2.0 nmol of bestatin, an aminopeptidase inhibitor, but not by 1.0 nmol. Captopril, an angiotensin-converting enzyme inhibitor, was without effect on both tachykinin-induced responses. When phosphoramidon was injected together with bestatin and captopril which have no significant effect alone, SP- or NK A-induced behavioral response was significantly increased. These data suggest that endopeptidase-24.11 may be an important enzyme responsible for terminating of SP- or NK A-induced behavioral response at the spinal cord level.

Single and short-term dosing effects of levocetirizine on adenosine monophosphate bronchoprovocation in atopic asthma

PubMed Central

Lee, Daniel K C; Gray, Robert D; Wilson, Andrew M; Robb, Fiona M; Soutar, Patricia C; Lipworth, Brian J

2004-01-01

Aims Adenosine monophosphate (AMP) acts indirectly via primed airway mast cells to induce bronchial hyper-responsiveness, which in turn correlates with eosinophilic asthmatic inflammation and atopic disease expression. We evaluated single and short-term dosing effects of a modern histamine H1-receptor antagonist, levocetirizine, given at the usual clinically recommended dose, on the primary outcome of AMP bronchoprovocation. Methods Fifteen atopic asthmatics were randomized in double-blind, cross-over fashion to receive for 1 week either levocetirizine 5 mg or placebo. There was a 1-week washout period prior to each randomized treatment. The provocative concentration of AMP producing a 20% fall in FEV1 (PC20) was measured after each washout at baseline and at 4–6 h following the first and last doses of each randomized treatment. Results Baseline mean ± SEM values after washout prior to each randomized treatment comparing levocetirizine vs placebo were not significantly different for prechallenge FEV1 (% predicted) 83 ± 4 vs 82 ± 4, or AMP PC20 (mg ml−1) 45 ± 24 vs 45 ± 22, respectively. Airway calibre as prechallenge FEV1 for levocetirizine vs placebo was not significantly different following the first dose 86 ± 4 vs 82 ± 4, or the last dose 85 ± 4 vs 83 ± 4, respectively. There were significant improvements (P< 0.05) in AMP PC20 comparing levocetirizine vs placebo following the first dose 123 ± 73 vs 48 ± 24, a 1.4 doubling dilution difference (95% CI 0.8, 1.9), and the last dose 127 ± 74 vs 53 ± 29, a 1.2 doubling dilution difference (95% CI 0.5, 2.0). AMP PC20 was also improved (P< 0.05) by the first and last doses of levocetirizine but not placebo, vs respective baseline values, with there being no difference in the degree of protection between first and last doses. Conclusions Single and short-term dosing with levocetirizine conferred similar improvements in bronchial hyper-responsiveness to AMP challenge, which was unrelated to prechallenge airway calibre. Further studies are indicated to evaluate the longer-term effects of levocetirizine on asthma exacerbations. PMID:15206990

Dose-Response of Sodium Bicarbonate Ingestion Highlights Individuality in Time Course of Blood Analyte Responses.

PubMed

Jones, Rebecca Louise; Stellingwerff, Trent; Artioli, Guilherme Giannini; Saunders, Bryan; Cooper, Simon; Sale, Craig

2016-10-01

To defend against hydrogen cation accumulation and muscle fatigue during exercise, sodium bicarbonate (NaHCO 3 ) ingestion is commonplace. The individualized dose-response relationship between NaHCO 3 ingestion and blood biochemistry is unclear. The present study investigated the bicarbonate, pH, base excess and sodium responses to NaHCO 3 ingestion. Sixteen healthy males (23 ± 2 years; 78.6 ± 15.1 kg) attended three randomized order-balanced, nonblinded sessions, ingesting a single dose of either 0.1, 0.2 or 0.3 g·kg -1 BM of NaHCO 3 (Intralabs, UK). Fingertip capillary blood was obtained at baseline and every 10 min for 1 hr, then every 15 min for a further 2 hr. There was a significant main effect of both time and condition for all assessed blood analytes (p ≤ .001). Blood analyte responses were significantly lower following 0.1 g·kg -1 BM compared with 0.2 g·kg -1 BM; bicarbonate concentrations and base excess were highest following ingestion of 0.3 g·kg -1 BM (p ≤ .01). Bicarbonate concentrations and pH significantly increased from baseline following all doses; the higher the dose the greater the increase. Large interindividual variability was shown in the magnitude of the increase in bicarbonate concentrations following each dose (+2.0-5; +5.1-8.1; and +6.0-12.3 mmol·L -1 for 0.1, 0.2 and 0.3 g·kg -1 BM) and in the range of time to peak concentrations (30-150; 40-165; and 75-180 min for 0.1, 0.2 and 0.3 g·kg -1 BM). The variability in bicarbonate responses was not affected by normalization to body mass. These results challenge current practices relating to NaHCO 3 supplementation and clearly show the need for athletes to individualize their ingestion protocol and trial varying dosages before competition.

Incidence of salivary gland tumors among atomic bomb survivors, 1950-1987. Evaluation of radiation-related risk

DOE Office of Scientific and Technical Information (OSTI.GOV)

Land, C.E.; Saku, Takashi; Tokuoka, Shoji

1996-07-01

A wide-ranging seach for benign and malignant tumors of the major and minor salivary glands among members of the Life Span Study sample of the Radiation Effects Research Foundation identified 41 malignant and 94 benign incident tumors, including 14 malignant and 12 benign tumors of the minor salivary gland, plus 10 major gland tumors of unknown behavior. Dose-response analyses found statistically significant increases in risk with increasing A-bomb dose for both cancer and benign tumors. Estimated relative risks at 1 Sv weighted tissue kerma (RR{sub 1}Sv, with 90% confidence interval in parentheses) were 4.5 (2.5-8.5) for cancer and 1.7 (1.1-2.7)more » for benign tumors. When analyzed by histological subtype within these two broad groups, it appeared that most of the dose response for malignant tumors was provided by an exceptionally strong dose response for mucoepidermoid carcinoma [11 exposed cases with dose estimates, RR{sub 1Sv} - 9.3 (3.5-30.6)], and most or all of that for benign tumors corresponded to Warthin`s tumor [12 cases, RR{sub 1Sv} = 4.1 (1.6-11.3)]. There was a marginal dose response for malignant tumors other than mucoepidermoid carcinoma [RR{sub 1Sv} = 2.4 (0.99-5.7)] but no significant trend for benign tumors other than Warthin`s tumor [RR{sub 1Sv} = 1.3 (0.9-2.2)]. Re-examination of the original data from published studies of other irradiated populations may shed new light on the remarkable type specificity of the salivary tumor dose response observed in the present study. 33 refs., 3 figs., 7 tabs.« less

On the behavioural specificity of hypophagia induced in male rats by mCPP, naltrexone, and their combination.

PubMed

Wright, F L; Rodgers, R J

2014-02-01

Serotonergic (5-hydroxytryptamine, 5-HT) and opioidergic mechanisms are intimately involved in appetite regulation. In view of recent evidence of positive anorectic interactions between opioid and various non-opioid substrates, our aim was to assess the behavioural specificity of anorectic responses to the opioid receptor antagonist naltrexone, the 5-HT2C/1B receptor agonist mCPP and their combination. Behavioural profiling techniques, including the behavioural satiety sequence (BSS), were used to examine acute drug effects in non-deprived male rats tested with palatable mash. Experiment 1 characterised the dose-response profile of mCPP (0.1-3.0 mg/kg), while experiment 2 assessed the effects of combined treatment with a sub-anorectic dose of mCPP (0.1 mg/kg) and one of two low doses of naltrexone (0.1 and 1.0 mg/kg). Experiment 1 confirmed the dose-dependent anorectic efficacy of mCPP, with robust effects on intake and feeding-related measures observed at 3.0 mg/kg. However, that dose was also associated with other behavioural alterations including increased grooming, reductions in locomotion and sniffing, and disruption of the BSS. In experiment 2, naltrexone dose-dependently reduced food intake and time spent feeding, effects accompanied by a behaviourally selective acceleration in the BSS. However, the addition of 0.1 mg/kg mCPP did not significantly alter the behavioural changes observed in response to either dose of naltrexone given alone. In contrast to recently reported positive anorectic interactions involving low-dose combinations of opioid receptor antagonists or mCPP with cannabinoid CB1 receptor antagonists, present results would not appear to provide any support for potentially clinically relevant anorectic interactions between opioid and 5-HT2C/1B receptor mechanisms.

Radiation Pneumopathy in the Rat After Intravenous Application of {sup 188}Re-Labeled Microspheres

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liepe, Knut; Faulhaber, Diana; Wunderlich, Gerd

2011-10-01

Purpose: To determine the dose dependence and kinetics of pneumopathy after systemic administration of rhenium-188 ({sup 188}Re)-labeled microspheres in a rat model. Methods and Materials: {sup 188}Re-microspheres were injected intravenously into adult Wistar rats (n = 54, age, 8 {+-} 2 months). The rats were divided into 6 groups according to the intended absorbed dose in the lung (maximum 60 Gy). Gamma camera scans were used to estimate the individual whole lung doses. One control group (n = 5) received nonlabeled microspheres. The breathing rate was measured before and weekly after the treatment using whole body plethysmography until 24 weeks.more » An increase in the breathing rate by 20% compared with the individual pretreatment control value was defined as the quantal endpoint for dose-effect analyses. Results: A biphasic increase in the breathing rate was observed. The first impairment of lung function occurred in Weeks 3-6. For late changes, the interval to onset was clearly dose dependent and was 17 weeks (10-30 Gy) and 10 weeks (50-60 Gy), respectively. The incidence of the response was highly dependent on the estimated lung dose. The median effective dose for an early and late response was virtually identical (19.9 {+-} 0.6 Gy and 20.4 {+-} 3.1 Gy, respectively). A significant correlation was found between the occurrence of an early and a late effect in the same rat, suggesting a strong consequential component. Conclusions: The effects of radiolabeled microspheres can be studied longitudinally in a rat model, using changes in the breathing rate as the functional, clinically relevant response. The isoeffective doses from the present study using radionuclide administration and those from published investigations of homogeneous external beam radiotherapy are almost similar.« less

Single administration of intra-articular bupivacaine in arthroscopic knee surgery: a systematic review and meta-analysis.

PubMed

Sun, Qi-Bin; Liu, Shi-Dong; Meng, Qin-Jun; Qu, Hua-Zheng; Zhang, Zheng

2015-02-10

Single administration of intra-articular (IA) bupivacaine for pain relief after arthroscopic knee surgery is effective, but its active duration and dose-response relationship is unclear. We conducted this meta-analysis to summarize all published randomized controlled trials (RCTs), thus providing the most recent information on the safety and efficacy of single-administration IA bupivacaine for pain relief after arthroscopic knee surgery, and to determine whether a dose-response relationship exists. A systematic electronic literature search (through April 2014) was conducted to identify those RCTs that addressed the safety and efficacy of a single administration of IA bupivacaine for pain management after arthroscopic knee surgery. Subgroup analysis was conducted to determine changes in visual analog scale (VAS) scores at seven postoperative time points. Meta-regression and subgroup analyses were carried out to assess the effects of various treatment factors on efficacy and to evaluate the dose-response relationship of bupivacaine. Weighted mean differences or relative risks were calculated and pooled using a random-effects model. Twenty-eight trials involving 1,560 patients who underwent arthroscopic knee surgery met the inclusion criteria. The trials were subject to medium risk of bias. VAS scores at 2, 4, 6, 12, and 24 h postoperatively were significantly lower, the number of patients requiring supplementary analgesia was smaller, and the time to first request for analgesia was longer in the IA bupivacaine group than in the placebo group. The analgesic effect of single-administration IA bupivacaine may be associated with the effect of concomitant administration of epinephrine and concentration of bupivacaine, and no dose-response relationship was identified. No significant difference in side effects was detected between groups. Current evidence shows that the use of single-administration IA bupivacaine is effective for postoperative pain management in patients undergoing arthroscopic knee surgery, with satisfactory short-term safety. Low-dose administration of IA bupivacaine 0.5% combined with epinephrine adjuvant in clinical practice should be performed. Additional high-quality RCTs with longer follow-up periods are required to examine the safety of single-administration IA bupivacaine.

Acute toxicity, biochemical and histopathological responses of endosulfan in Chanos chanos.

PubMed

Kumar, Neeraj; Ambasankar, K; Krishnani, K K; Gupta, S K; Bhushan, Shashi; Minhas, P S

2016-09-01

This study investigated 96h median lethal concentration of endosulfan (99%, pure α: β ratio of 7:3) by conducting static non-renewable acute toxicity bio-assay in Chanos chanos juvenile with average weight (110±5.65g). Further, the effect of different definitive doses (18.5, 19.5, 20.5, 21.5 and 22.5µg/L) of endosulfan on metabolic, heamato-immunoligcal and histopathological response were probed. Anti-oxidative enzymes CAT, SOD and GST showed significant (p<0.01) increase of activity in the liver, gill and brain during exposure to endosulfan in a dose and time dependent manner. The brain AChE activity showed significant (p<0.01) inhibition from 18.5 to 22.5µg/L exposure of endosulfan than the control group. LDH and MDH activity gradually increased with consequent increasing dose of endosulfan exposure in the liver, gill and brain. Similarly, ALT, AST and G6PDH activities in both liver and gill increased with consequent increases in the dose of endosulfan exposure. Immunological profile such as blood glucose and serum cortisol level significantly enhanced while respiratory burst activity declined with consequent increasing doses of endosulfan exposure. Histopathological alteration in the gill demonstrated curling of secondary lamellae, thickening of primary epithelium, shorting of secondary lamellae, epithelial hyperplasia, fusion of secondary lamellae, aneurism, and collapsed secondary lamellae due to dose dependent exposure of endosulfan. Liver histology illustrated cloudy swelling and necrosis with pyknotic nuclei to the moderate dose of endosulfan, whereas higher dose of endosulfan (21.5µg/L) displayed severe necrosis of hepatic cells. Overall results clearly indicate that acute exposure of endosulfan led to pronounced deleterious alterations on biochemical, heamato-immunological, and histopathological responses of C. chanos juvenile. Copyright © 2016 Elsevier Inc. All rights reserved.

Continuous Exposure to Low-Dose-Rate Gamma Irradiation Reduces Airway Inflammation in Ovalbumin-Induced Asthma.

PubMed

Kim, Joong Sun; Son, Yeonghoon; Bae, Min Ji; Lee, Seung Sook; Park, Sun Hoo; Lee, Hae June; Lee, Soong In; Lee, Chang Geun; Kim, Sung Dae; Jo, Wol Soon; Kim, Sung Ho; Shin, In Sik

2015-01-01

Although safe doses of radiation have been determined, concerns about the harmful effects of low-dose radiation persist. In particular, to date, few studies have investigated the correlation between low-dose radiation and disease development. Asthma is a common chronic inflammatory airway disease that is recognized as a major public health problem. In this study, we evaluated the effects of low-dose-rate chronic irradiation on allergic asthma in a murine model. Mice were sensitized and airway-challenged with ovalbumin (OVA) and were exposed to continuous low-dose-rate irradiation (0.554 or 1.818 mGy/h) for 24 days after initial sensitization. The effects of chronic radiation on proinflammatory cytokines and the activity of matrix metalloproteinase-9 (MMP-9) were investigated. Exposure to low-dose-rate chronic irradiation significantly decreased the number of inflammatory cells, methylcholine responsiveness (PenH value), and the levels of OVA-specific immunoglobulin E, interleukin (IL)-4, and IL-5. Furthermore, airway inflammation and the mucus production in lung tissue were attenuated and elevated MMP-9 expression and activity induced by OVA challenge were significantly suppressed. These results indicate that low-dose-rate chronic irradiation suppresses allergic asthma induced by OVA challenge and does not exert any adverse effects on asthma development. Our findings can potentially provide toxicological guidance for the safe use of radiation and relieve the general anxiety about exposure to low-dose radiation.

Effects of sub-chronic oral cyanide on endothelial function in rabbit aortic rings.

PubMed

Ozolu, R I; Okolie, N P; Ebeigbe, A B; Karikari, N

2007-02-01

We have investigated how the endothelium affects vascular responses following sub-chronic low dose cyanide administration. Cyanide exists in low levels in cassava foods, which are widely consumed in tropical Africa. Adult rabbits were administered 0.38 mg/kg per day KCN po for 25 days, and responses of the isolated aortic rings to noradrenaline (NA), calcium chloride (Ca2+) and acetylcholine (ACh) were measured in vitro in the presence and absence of the endothelium. In order to establish that the dose was not toxic, animal weight, some haematological indices, plasma alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were measured. Results show that endothelium denudation significantly (P <0.05) attenuates NA-induced contraction in rings from cyanide-treated rabbits. There was a similar reduction in response in Ca2+-depleted NA-precontracted endothelium-denuded aortic rings from cyanide-treated rabbits. Endothelium-denuded rings from cyanide-treated rabbits showed significantly (P <0.05) enhanced relaxation to ACh. In rings from control animals, the responses to NA and Ca2+ were not significantly altered, whether in the presence or absence of the endothelium. There were no significant changes in the studied toxicological indices. We conclude that endothelial compromise is necessary for low-dose sub-chronic cyanide-induced to alter vascular reactivity to NA and ACh.

Diuretic effects of medetomidine compared with xylazine in healthy dogs.

PubMed

Talukder, Md Hasanuzzaman; Hikasa, Yoshiaki

2009-07-01

This study aimed to investigate and compare the effects of medetomidine and xylazine on diuretic and hormonal variables in healthy dogs. Five dogs, used in each of 11 groups, were injected intramuscularly with physiological saline solution (control), 5, 10, 20, 40, and 80 microg/kg of medetomidine, and 0.25, 0.5, 1, 2, and 4 mg/kg of xylazine. Urine and blood samples were taken 11 times over 24 h. Both medetomidine and xylazine increased urine production in a dose-dependent manner up to 4 h after injection, but the increase was much less with medetomidine than with xylazine at the tested doses. Urine specific gravity, pH, osmolality, and concentrations of creatinine, sodium, potassium, chloride, and arginine vasopressin (AVP) were decreased in a dose-dependent manner with both medetomidine and xylazine. Plasma osmolality and concentrations of sodium, potassium, and chloride were increased significantly with both drugs. Total amounts of urine AVP excreted and plasma AVP concentrations were significantly decreased by higher doses of medetomidine but were not significantly decreased by xylazine. Higher doses of both drugs significantly increased the plasma concentration of atrial natriuretic peptide (ANP), but the effect was greater with medetomidine than with xylazine. The results revealed that both drugs induce a profound diuresis, but medetomidine's effect is less dose-dependent than xylazine's effect. Although changes in plasma concentrations of AVP and ANP may partially influence the diuresis induced by medetomidine, other factors may be involved in the mechanism of the diuretic response to both drugs. Thus, both agents can be used clinically for transient but effective diuresis accompanied by sedation.

Dreaming, fenfluramine, and vitamin C.

PubMed

Mullen, A; Wilson, C W; Wilson, B P

1977-01-08

The effect of increasing doses of fenfluramine on dream patterns was studied in 20 patients receiving a reducing diet with or without a controlled dietary intake of vitamin C daily. The dream pattern was unchanged in six patients and dreams disappeared in another who normally dreamed often. In 13 patients dreams increased in frequency and intensity, and in five the dreams assumed frightening proportions. There was a significant straight-line relation between response and the size of the dose. When placebo tablets were given to four patients their dreams disappeared or assumed their pretreatment normal pattern. Absence of vitamin C from the diet did not significantly affect the dream pattern. That fenfluramine has dose-related cerebral effects should be remembered in patients with a history of mental illness.

Dreaming, fenfluramine, and vitamin C.

PubMed Central

Mullen, A; Wilson, C W; Wilson, B P

1977-01-01

The effect of increasing doses of fenfluramine on dream patterns was studied in 20 patients receiving a reducing diet with or without a controlled dietary intake of vitamin C daily. The dream pattern was unchanged in six patients and dreams disappeared in another who normally dreamed often. In 13 patients dreams increased in frequency and intensity, and in five the dreams assumed frightening proportions. There was a significant straight-line relation between response and the size of the dose. When placebo tablets were given to four patients their dreams disappeared or assumed their pretreatment normal pattern. Absence of vitamin C from the diet did not significantly affect the dream pattern. That fenfluramine has dose-related cerebral effects should be remembered in patients with a history of mental illness. PMID:318898

Effects of low-dose IV ketamine on peripheral and central pain from major limb injuries sustained in combat.

PubMed

Polomano, Rosemary C; Buckenmaier, Chester C; Kwon, Kyung H; Hanlon, Alexandra L; Rupprecht, Christine; Goldberg, Cynthia; Gallagher, Rollin M

2013-07-01

Examine response patterns to low-dose intravenous (IV) ketamine continuous infusions on multiple pain outcomes, and demonstrate effectiveness, safety, and tolerability of ketamine administration on general wards. Retrospective case series of consecutive patients given low-dose IV ketamine continuous infusions. Walter Reed Army Medical Center, Washington, DC. Nineteen eligible inpatients with neuropathic pain from major limb injuries sustained in combat with inadequate pain control from multimodal analgesia. A 3-day IV infusion of ketamine at doses ≤ 120 μg/kg/h. Daily present (PPI), average (API), and worst (WPI) pain intensity (0-10), global pain relief (GPR) (1 "no relief" to 5 "complete relief"), daily assessments of adverse events, and daily opioid requirements measured during therapy. A significant reduction in PPI (P < 0.001) and improvement in GPR (P = 0.031) was noted over time. Higher baseline WPI (≥ 7; N = 4) was associated with a significant decrease in WPI (P = 0.0388), but lower baseline WPI (N = 5) was not. Significant mean percent decreases in PPI with higher baseline PPI (N = 8; P = 0.0078) and WPI with no phantom limb pain (PLP) (N = 10; P = 0.0436) were observed. Mean percent increase in overall GPR was better for those reporting GPR scores ≤ 3 (N = 13) in the first 24 hours of therapy (P = 0.0153). While not significant, mean opioid requirement (IV morphine equivalents) decreased from 129.9 mgs ± 137.3 on day 1 to 112.14 ± 86.3 24 hours after therapy. Low-dose ketamine infusions for complex combat injury pain were safe and effective, and demonstrated response patterns over time and by baseline pain score stratification and presence or absence of PLP. Wiley Periodicals, Inc.

Pharmacokinetics and tolerability of human mouse chimeric anti-CD22 monoclonal antibody in Chinese patients with CD22-positive non-Hodgkin lymphoma.

PubMed

Li, Su; Zhang, Dongsheng; Sun, Jian; Li, Zhinming; Deng, Liting; Zou, Benyan; Zhan, Jing; Jiang, Wenqi

2012-01-01

The safety and pharmacokinetics assessment of antibodies targeting CD22 (e.g., epratuzumab) have been established in western Caucasian populations, but there are no reports of the effects in Chinese populations. This dose-escalation study examines the safety, pharmacokinetics and biologic effects of multiple doses of anti-CD22 human-murine chimeric monoclonal antibody SM03 in 21 Chinese patients with CD22-positive non-Hodgkin lymphoma. Most of drug-related adverse events (AEs) were mild and reversible. Two patients experienced serious AEs (hemorrhage); one patient had grade 4 neutropenia; one patient had asymptomatic grade III prolongation of activated partial thromboplastin time (APTT). Major AEs included fever (71%), prolongation of APTT (42.8%), leukocytopenia (44.4%), alanine transaminase elevation (28.6%), elevated serum creatinine (23.8%) and injection site skin redness (14.3%). Circulating B cells transiently decreased without significant effects on T cells or immunoglobulin levels. Pharmacokinetic data revealed that mean maximum observed SM03 concentration and mean AUC from time zero to infinity increased in a dose-dependent manner up to 360 mg/m (2) SM03. Mean clearance was similar at doses ≤ 360 mg/m (2) and decreased significantly at dose 480 mg/m (2), supporting saturation of B-cell binding at 360 mg/m (2). Across all dose levels and histologies, one patient achieved partial response at 480 mg/m (2) dose; 14 patients had stable disease as best response and four patients progressed. Overall, SM03 was tolerated at doses ranging from 60-480 mg/m (2) and had potential efficacy in Chinese patients with follicular lymphoma.

The effects of lower than conventional doses of oral nadolol on relative beta 1/beta 2-adrenoceptor blockade.

PubMed

Wheeldon, N M; McDevitt, D G; Lipworth, B J

1994-08-01

1. The aim of the present study was to evaluate the relative beta 1/beta 2 antagonist selectivity of the beta-adrenoceptor blocker nadolol, in lower than conventional clinical doses. 2. Eight normal volunteers received single oral doses of either placebo (PL), nadolol 5 mg (N5), 20 mg (N20) or 80 mg (N80) in a single-blind, randomised crossover design. beta 1-adrenoceptor antagonism was assessed by attenuation of exercise tachycardia, and beta 2-adrenoceptor blockade by effects on salbutamol-induced chronotropic, hypokalaemic and finger tremor responses. The relative percentage attenuation of beta 2 and beta 1-mediated responses was calculated and expressed as beta 2:beta 1 selectivity ratios. 3. Nadolol produced dose-related reductions in exercise tachycardia in keeping with increasing beta 1-adrenoceptor blockade; mean % reduction (95% CI) compared with placebo: N5 10.7 (6.6 to 14.8), N20 21.4 (17.3 to 25.4), N80 38.9 (34.8 to 42.9). However, even the lowest dose of nadolol (5 mg) produced almost complete blunting of beta 2-mediated effects and significantly increase exercise hyperkalaemia; peak exercise hyperkalaemia (mmol l-1) (means and 95% CI): PL 4.88 (4.68 to 5.07), N5 5.36 (5.17 to 5.55), N20 5.48 (5.28 to 5.67), N80 5.42 (5.22 to 5.61). beta 2:beta 1 selectivity ratios significantly increased as the dose of nadolol was reduced. 4. These data suggest that whereas in the clinical dose range nadolol behaves as a non-selective beta-adrenoceptor antagonist, as the dose is reduced this drug demonstrates an increasing degree of selectivity for the beta 2-adrenoceptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Dose-response study of sajabalssuk ethanol extract from Artemisia princeps Pampanini on blood glucose in subjects with impaired fasting glucose or mild type 2 diabetes.

PubMed

Choi, Ji-Young; Shin, Su-Kyung; Jeon, Seon-Min; Baek, Nam-In; Chung, Hae-Gon; Jeong, Tae-Sook; Lee, Kyung Tae; Lee, Mi-Kyung; Choi, Myung-Sook

2011-01-01

Previously we reported that an ethanol extract from Artemisia princeps Pampanini lowered blood glucose in db/db mice. Here we report a preliminary study in which the blood glucose-lowering effects of two different doses of sajabalssuk ethanol extract (SBE), containing eupatilin and jaseocidin, were examined in hyperglycemic subjects with fasting blood glucose (FBG) levels of 100-150 mg/dL. Subjects were randomized into four groups: negative control (2,000 mg of lactose /day), positive control (1,140 mg of pinitol/day), low-dose SBE (2,000 mg of SBE/day), and high-dose SBE (4,000 mg of SBE/day). After 8 weeks of supplementation, FBG and glycosylated hemoglobin levels were significantly lowered in low-and high-dose SBE groups compared to the baseline values; high-dose SBE also resulted in significantly lower plasma free fatty acid levels and systolic blood pressure. This study demonstrated that supplementation of 2 g or 4 g of SBE daily can significantly reduce blood glucose in hyperglycemic subjects, although high-dose SBE seemed to be more effective than low-dose SBE for lowering plasma free fatty acid level and systolic blood pressure.

Neutral endopeptidase activity and airway hyperresponsiveness to neurokinin A in asthmatic subjects in vivo.

PubMed

Cheung, D; Timmers, M C; Zwinderman, A H; den Hartigh, J; Dijkman, J H; Sterk, P J

1993-12-01

In a previous study we have shown that inhibition of the endogenous neuropeptide-degrading enzyme, neutral endopeptidase (NEP), potentiates airway narrowing to neurokinin A (NKA) in normal humans in vivo. In the present study, we tested the hypothesis that hyperresponsiveness to NKA in asthma is caused by a reduction in endogenous NEP activity. To that end, we used the NEP inhibitor, thiorphan, or placebo as inhaled pretreatment to NKA challenge in eight atopic asthmatic men, who were controlled by on-demand usage of beta 2-agonists alone. The dose of thiorphan pretreatment was obtained from pilot experiments in which 0.5 ml of a 2.5-mg/ml concentration appeared to be the maximally effective nebulized dose. Dose-response curves to inhaled NKA (1 to 125 micrograms/ml, 0.5 ml/dose) were recorded on 2 randomized days 1 wk apart, in a cross-over study. To detect any effects of thiorphan on bronchoconstriction per se, we also investigated the effect of thiorphan or placebo on the dose-response curve to inhaled methacholine in a separate set of experiments. The response was measured by FEV1 and by partial expiratory flow-volume curves (V40p). The position of the dose-response curves was expressed as the concentration causing a 20% fall in FEV1 (PC20FEV1) or a 40% fall in V40p (PC40V40p). Baseline FEV1 and V40p were not affected by either pretreatment (p > 0.06). PC20FEV1 and PC40V40p to NKA were significantly lower after thiorphan pretreatment as compared with placebo (mean difference +/- SEM: 2.3 +/- 0.6 and 1.6 +/- 0.5 doubling dose, respectively; p < 0.015).(ABSTRACT TRUNCATED AT 250 WORDS)

Ketamine modulation of the haemodynamic response to spreading depolarization in the gyrencephalic swine brain

PubMed Central

Santos, Edgar; Schöll, Michael; Kunzmann, Kevin; Stock, Christian; Silos, Humberto; Unterberg, Andreas W; Sakowitz, Oliver W

2016-01-01

Spreading depolarization (SD) generates significant alterations in cerebral haemodynamics, which can have detrimental consequences on brain function and integrity. Ketamine has shown an important capacity to modulate SD; however, its impact on SD haemodynamic response is incompletely understood. We investigated the effect of two therapeutic ketamine dosages, a low-dose of 2 mg/kg/h and a high-dose of 4 mg/kg/h, on the haemodynamic response to SD in the gyrencephalic swine brain. Cerebral blood volume, pial arterial diameter and cerebral blood flow were assessed through intrinsic optical signal imaging and laser-Doppler flowmetry. Our findings indicate that frequent SDs caused a persistent increase in the baseline pial arterial diameter, which can lead to a diminished capacity to further dilate. Ketamine infused at a low-dose reduced the hyperemic/vasodilative response to SD; however, it did not alter the subsequent oligemic/vasoconstrictive response. This low-dose did not prevent the baseline diameter increase and the diminished dilative capacity. Only infusion of ketamine at a high-dose suppressed SD and the coupled haemodynamic response. Therefore, the haemodynamic response to SD can be modulated by continuous infusion of ketamine. However, its use in pathological models needs to be explored to corroborate its possible clinical benefit. PMID:27126324

Ketamine modulation of the haemodynamic response to spreading depolarization in the gyrencephalic swine brain.

PubMed

Sánchez-Porras, Renán; Santos, Edgar; Schöll, Michael; Kunzmann, Kevin; Stock, Christian; Silos, Humberto; Unterberg, Andreas W; Sakowitz, Oliver W

2017-05-01

Spreading depolarization (SD) generates significant alterations in cerebral haemodynamics, which can have detrimental consequences on brain function and integrity. Ketamine has shown an important capacity to modulate SD; however, its impact on SD haemodynamic response is incompletely understood. We investigated the effect of two therapeutic ketamine dosages, a low-dose of 2 mg/kg/h and a high-dose of 4 mg/kg/h, on the haemodynamic response to SD in the gyrencephalic swine brain. Cerebral blood volume, pial arterial diameter and cerebral blood flow were assessed through intrinsic optical signal imaging and laser-Doppler flowmetry. Our findings indicate that frequent SDs caused a persistent increase in the baseline pial arterial diameter, which can lead to a diminished capacity to further dilate. Ketamine infused at a low-dose reduced the hyperemic/vasodilative response to SD; however, it did not alter the subsequent oligemic/vasoconstrictive response. This low-dose did not prevent the baseline diameter increase and the diminished dilative capacity. Only infusion of ketamine at a high-dose suppressed SD and the coupled haemodynamic response. Therefore, the haemodynamic response to SD can be modulated by continuous infusion of ketamine. However, its use in pathological models needs to be explored to corroborate its possible clinical benefit.

Hexamethonium attenuates sympathetic activity and blood pressure in spontaneously hypertensive rats.

PubMed

Li, Peng; Gong, Jue-Xiao; Sun, Wei; Zhou, Bin; Kong, Xiang-Qing

2015-11-01

Sympathetic activity is enhanced in heart failure and hypertensive rats. The aims of the current study were: i) To investigate the association between renal sympathetic nerve activity (RSNA) and mean arterial pressure (MAP) in response to intravenous injection of the ganglionic blocker hexamethonium; and ii) to determine whether normal Wistar rats and spontaneously hypertensive rats (SHRs) differ in their response to hexamethonium. RSNA and MAP were recorded in anaesthetized rats. Intravenous injection of four doses of hexamethonium significantly reduced the RSNA, MAP and heart rate (HR) in the Wistar rats and SHRs. There were no significant differences in the RSNA, MAP or HR between Wistar rats and SHRs at the two lowest doses of hexamethonium. However, the two highest doses of hexamethonium resulted in a greater reduction in the RSNA and MAP in SHRs compared with Wistar rats. There was a significant positive correlation between the alterations in RSNA and MAP in response to the intravenous injection of hexamethonium in the Wistar rats and SHRs. There were no significant differences in the timing of the maximal effects on RSNA, MAP or HR or in recovery following hexamethonium treatment. These results suggest that there is an association between the RSNA and MAP response to intravenous injection of hexamethonium and that the alterations in MAP in response to hexamethonium may be used to evaluate basal sympathetic nerve activity.

The effect of hypofractionated radiation and magnetic nanoparticle hyperthermia on tumor immunogenicity and overall treatment response

NASA Astrophysics Data System (ADS)

Hoopes, P. Jack; Wagner, Robert J.; Song, Ailin; Osterberg, Bjorn; Gladstone, David J.; Bursey, Alicea A.; Fiering, Steven N.; Giustini, Andrew J.

2017-02-01

It is now known that many tumors develop molecular signals (immune checkpoint modulators) that inhibit an effective tumor immune response. New information also suggest that even well-known cancer treatment modalities such as radiation and hyperthermia generate potentially beneficial immune responses that have been blocked or mitigated by such immune checkpoints, or similar molecules. The cancer therapy challenge is to; a) identify these treatment-based immune signals (proteins, antigens, etc.); b) the treatment doses or regimens that produce them; and c) the mechanisms that block or have the potential to promote them. The goal of this preliminary study, using the B6 mouse - B16 tumor model, clinically relevant radiation doses and fractionation schemes (including those used clinically in hypofractionated radiation therapy), magnetic nanoparticle hyperthermia (mNPH) and sophisticated protein, immune and tumor growth analysis techniques and modulators, is to determine the effect of specific radiation or hyperthermia alone and combined on overall treatment efficacy and immunologic response mechanisms. Preliminary analysis suggests that radiation dose (10 Gy vs. 2 Gy) significantly alters the mechanism of cell death (apoptosis vs. mitosis vs. necrosis) and the resulting immunogenicity. Our hypothesis and data suggest this difference is protein/antigen and immune recognition-based. Similarly, our evidence suggest that radiation doses larger than the conventional 2 Gy dose and specific hyperthermia doses and techniques (including mNP hyperthermia treatment) can be immunologically different, and potentially superior to, the radiation and heat therapy regimens that are typically used in research and clinical practice.

A Micronutrient Fortified Beverage Given at Different Dosing Frequencies Had Limited Impact on Anemia and Micronutrient Status in Filipino Schoolchildren.

PubMed

Angeles-Agdeppa, Imelda; Magsadia, Clarita R; Aaron, Grant J; Lloyd, Beate B; Hilmers, David C; Bhutta, Zulfiqar A

2017-09-12

This study evaluated the effects of a multi-micronutrient fortified juice drink given in different frequencies of consumption on hemoglobin (Hb) concentration of schoolchildren. Hb was measured in 2423 schoolchildren aged 6- to 9-years-old at baseline. All anemic children ( n = 246) were randomly allocated into groups: Daily dose (HD: high dose), 5X/week (MD: Moderate Dose), 3X/week (LD: Low Dose) and unfortified (Control). Pre- and post-study measurements of micronutrients were collected from 228 children. At the endpoint, significant Hb increases were observed in all groups, but there was no significant difference between groups. There was a significant reduction in anemia prevalence in all groups from 100% to 36% (Control), 30% (LD), 23% (MD) and 26% (HD). No dose-response effect was observed in Hb in this population. Most likely, this resulted from better than expected micronutrient status and lower than expected severity of anemia and micronutrient deficiencies in this cohort. It is unlikely that the addition of a fortified beverage to school feeding programs in this population would have a positive impact. Whether such an intervention would be cost-effective as a preventative approach needs to be assessed. This study demonstrates the importance of targeting such interventions to appropriate populations.

A Micronutrient Fortified Beverage Given at Different Dosing Frequencies Had Limited Impact on Anemia and Micronutrient Status in Filipino Schoolchildren

PubMed Central

Angeles-Agdeppa, Imelda; Magsadia, Clarita R.; Aaron, Grant J.; Lloyd, Beate B.; Hilmers, David C.; Bhutta, Zulfiqar A.

2017-01-01

This study evaluated the effects of a multi-micronutrient fortified juice drink given in different frequencies of consumption on hemoglobin (Hb) concentration of schoolchildren. Hb was measured in 2423 schoolchildren aged 6- to 9-years-old at baseline. All anemic children (n = 246) were randomly allocated into groups: Daily dose (HD: high dose), 5X/week (MD: Moderate Dose), 3X/week (LD: Low Dose) and unfortified (Control). Pre- and post-study measurements of micronutrients were collected from 228 children. At the endpoint, significant Hb increases were observed in all groups, but there was no significant difference between groups. There was a significant reduction in anemia prevalence in all groups from 100% to 36% (Control), 30% (LD), 23% (MD) and 26% (HD). No dose-response effect was observed in Hb in this population. Most likely, this resulted from better than expected micronutrient status and lower than expected severity of anemia and micronutrient deficiencies in this cohort. It is unlikely that the addition of a fortified beverage to school feeding programs in this population would have a positive impact. Whether such an intervention would be cost-effective as a preventative approach needs to be assessed. This study demonstrates the importance of targeting such interventions to appropriate populations. PMID:28895887

Response Inhibition Impairments Predict Alcohol-Induced Sedation

PubMed Central

Shannon, Erin E.; Staniforth, Elizabeth R.; McNamara, Juliette; Bernosky-Smith, Kimberly A.; Liguori, Anthony

2011-01-01

Aims: The aim of this study was to probe the relationship between the subjective effects of alcohol and impulsive behavior in social drinkers. Methods: Fifty social drinkers performed a response-inhibition task before consuming alcohol. A 0.8-g/kg dose of alcohol was administered in a binge-like fashion (0.2 g/kg every 30 min) to the participants over a 2-h time period. Participants then completed questionnaires measuring stimulation, sedation and mood following consumption of alcohol. Linear regression analyses were performed by examining the relationship between performance on the response inhibition impulsivity task and subjective responses to alcohol (i.e. stimulation, sedation and arousal). Results: There was a significant positive relationship found between impulsive responding and self-reported sedation following alcohol consumption. Additionally, there was a significant negative relationship between behavioral impulsivity and self-reported stimulation and arousal following alcohol consumption. Conclusion: These results suggest that higher levels of impulsivity are associated with experiencing greater sedating than stimulating effects of alcohol. Individuals with high levels of impulsivity may be less sensitive to the stimulating effects of a specified dose of alcohol, which could lead to these individuals consuming more alcohol to experience the stimulating effects of alcohol. PMID:21127353

Cardiovascular effects of the essential oil of Alpinia zerumbet leaves and its main constituent, Terpinen-4-ol, in rats: role of the autonomic nervous system.

PubMed

Lahlou, Saad; Galindo, Charles Antonio Barros; Leal-Cardoso, José Henrique; Fonteles, Manassés Claudino; Duarte, Gloria Pinto

2002-12-01

Cardiovascular effects of intravenous ( i. v.) treatment with the essential oil of Alpinia zerumbet (EOAZ) were investigated in rats. Additionally this study examined (I) whether the autonomic nervous system is involved in the mediation of EOAZ-induced changes in mean aortic pressure (MAP) and heart rate (HR), and (II) whether these changes could be, at least in part, attributed to the actions of terpinen-4-ol (Trp-4-ol), the major constituent of EOAZ. In both pentobarbitone-anaesthetised and conscious rats, i. v. bolus injections of EOAZ (1 to 20 mg/kg) elicited immediate and dose-dependent decreases in MAP. In anaesthetised rats, EOAZ decreased HR only at higher doses (10 and 20 mg/kg), while changes of this parameter were not uniform in conscious rats. Hypotensive responses to EOAZ were of the same order of magnitude or duration, irrespective of whether the animal was under general anaesthesia. Pretreatment of anaesthetised rats with bilateral vagotomy did not modify significantly the hypotensive and bradycardic responses to EOAZ. In conscious rats, i. v. injections of bolus doses (1 to 10 mg/kg) of Trp-4-ol also elicited immediate and dose-dependent decreases in MAP. However, these hypotensive effects were significantly greater than those evoked by the same doses of EOAZ (1 to 10 mg/kg). Intravenous pretreatment of conscious rats with either methylatropine (1 mg/kg) or hexamethonium (30 mg/kg) had no significant effects on the EOAZ-induced hypotension. These data show that i. v. treatment with the EOAZ in either anaesthetised or conscious rats induced an immediate and significant hypotension, an effect that could be partially attributed to the actions of Trp-4-ol. The hypotension appears independent of the presence of an operational sympathetic nervous system, suggesting that the EOAZ may be a direct vasorelaxant agent.

Sex- and dose-dependency in the pharmacokinetics and pharmacodynamics of (+)-methamphetamine and its metabolite (+)-amphetamine in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Milesi-Halle, Alessandra; Hendrickson, Howard P.; Laurenzana, Elizabeth M.

These studies investigated how (+)-methamphetamine (METH) dose and rat sex affect the pharmacological response to METH in Sprague-Dawley rats. The first set of experiments determined the pharmacokinetics of METH and its pharmacologically active metabolite (+)-amphetamine (AMP) in male and female Sprague-Dawley rats after 1.0 and 3.0 mg/kg METH doses. The results showed significant sex-dependent changes in METH pharmacokinetics, and females formed significantly lower amounts of AMP. While the area under the serum concentration-time curve in males increased proportionately with the METH dose, the females showed a disproportional increase. The sex differences in systemic clearance, renal clearance, volume of distribution, andmore » percentage of unchanged METH eliminated in the urine suggested dose-dependent pharmacokinetics in female rats. The second set of studies sought to determine the behavioral implications of these pharmacokinetic differences by quantifying locomotor activity in male and female rats after saline, 1.0, and 3.0 mg/kg METH. The results showed sex- and dose-dependent differences in METH-induced locomotion, including profound differences in the temporal profile of effects at higher dose. These findings show that the pharmacokinetic and metabolic profile of METH (slower METH clearance and lower AMP metabolite formation) plays a significant role in the differential pharmacological response to METH in male and female rats.« less

Increased Radioresistance to Lethal Doses of Gamma Rays in Mice and Rats after Exposure to Microwave Radiation Emitted by a GSM Mobile Phone Simulator

PubMed Central

Mortazavi, SMJ; Mosleh-Shirazi, MA; Tavassoli, AR; Taheri, M; Mehdizadeh, AR; Namazi, SAS; Jamali, A; Ghalandari, R; Bonyadi, S; Haghani, M; Shafie, M

2013-01-01

The aim of this study was to investigate the effect of pre-irradiation with microwaves on the induction of radioadaptive response. In the 1st phase of the study, 110 male mice were divided into 8 groups. The animals in these groups were exposed/sham-exposed to microwave, low dose rate gamma or both for 5 days. On day six, the animals were exposed to a lethal dose (LD). In the 2nd phase, 30 male rats were divided into 2 groups of 15 animals. The 1st group received microwave exposure. The 2nd group (controls) received the same LD but there was no treatment before the LD. On day 5, all animals were whole-body irradiated with the LD. Statistically significant differences between the survival rate of the mice only exposed to lethal dose of gamma radiation before irradiation with a lethal dose of gamma radiation with those of the animals pre-exposed to either microwave (p=0.02), low dose rate gamma (p=0.001) or both of these physical adapting doses (p=0.003) were observed. Likewise, a statistically significant difference between survival rates of the rats in control and test groups was observed. Altogether, these experiments showed that exposure to microwave radiation may induce a significant survival adaptive response. PMID:23930107

Critical target and dose and dose-rate responses for the induction of chromosomal instability by ionizing radiation

NASA Technical Reports Server (NTRS)

Limoli, C. L.; Corcoran, J. J.; Milligan, J. R.; Ward, J. F.; Morgan, W. F.

1999-01-01

To investigate the critical target, dose response and dose-rate response for the induction of chromosomal instability by ionizing radiation, bromodeoxyuridine (BrdU)-substituted and unsubstituted GM10115 cells were exposed to a range of doses (0.1-10 Gy) and different dose rates (0.092-17.45 Gy min(-1)). The status of chromosomal stability was determined by fluorescence in situ hybridization approximately 20 generations after irradiation in clonal populations derived from single progenitor cells surviving acute exposure. Overall, nearly 700 individual clones representing over 140,000 metaphases were analyzed. In cells unsubstituted with BrdU, a dose response was found, where the probability of observing delayed chromosomal instability in any given clone was 3% per gray of X rays. For cells substituted with 25-66% BrdU, however, a dose response was observed only at low doses (<1.0 Gy); at higher doses (>1.0 Gy), the incidence of chromosomal instability leveled off. There was an increase in the frequency and complexity of chromosomal instability per unit dose compared to cells unsubstituted with BrdU. The frequency of chromosomal instability appeared to saturate around approximately 30%, an effect which occurred at much lower doses in the presence of BrdU. Changing the gamma-ray dose rate by a factor of 190 (0.092 to 17.45 Gy min(-1)) produced no significant differences in the frequency of chromosomal instability. The enhancement of chromosomal instability promoted by the presence of the BrdU argues that DNA comprises at least one of the critical targets important for the induction of this end point of genomic instability.

Hydrocortisone infusion exerts dose- and sex-dependent effects on attention to emotional stimuli.

PubMed

Breitberg, Alaina; Drevets, Wayne C; Wood, Suzanne E; Mah, Linda; Schulkin, Jay; Sahakian, Barbara J; Erickson, Kristine

2013-03-01

Glucocorticoid administration has been shown to exert complex effects on cognitive and emotional processing. In the current study we investigated the effects of glucocorticoid administration on attention towards emotional words, using an Affective Go/No-go task on which healthy humans have shown an attentional bias towards positive as compared to negative words. Healthy volunteers received placebo and either low-dose (0.15mg/kg) or high-dose (0.45mg/kg) hydrocortisone intravenously during two separate visits in a double-blind, randomized design. Seventy-five minutes post-infusion, the subjects performed tests of attention (Rapid Visual Information Processing [RVIP]), spatial working memory (Spatial Span) and emotional processing (Affective Go/No-go task [AGNG]). On the attention task, performance was impaired under both hydrocortisone doses relative to placebo, though the effect on error rate was not significant after controlling for age; Spatial Span performance was unaffected by hydrocortisone administration. On the AGNG task, relative to the placebo condition the low-dose hydrocortisone infusion decreased response time to emotional words while high-dose hydrocortisone increased response time. In the females specifically, both high and low dose hydrocortisone administration attenuated the normal attentional bias toward positively valenced words. These data suggest that, in healthy women, the modulation of attention by the emotional salience of stimuli is influenced by glucocorticoid hormone concentrations. Copyright © 2012 Elsevier Inc. All rights reserved.

Effects of Family History of Alcohol Dependence on the Subjective Response to Alcohol using the Intravenous Alcohol Clamp

PubMed Central

Kerfoot, Karin; Pittman, Brian; Ralevski, Elizabeth; Limoncelli, Diana; Koretski, Julia; Newcomb, Jenelle; Arias, Albert J.; Petrakis, Ismene L

2013-01-01

Background Alcohol use disorders are well recognized to be common, debilitating, and the risk of developing them is influenced by family history. The subjective response to alcohol may be determined familialy and related to the risk of developing alcoholism. The aim of this study was to evaluate differences between family history positive (FHP) and family history negative (FHN) individuals in their response to alcohol within the domains of subjective, coordination, and cognitive effects using an IV clamping method of alcohol administration. Methods Two groups of healthy subjects, those with a FHP (n=65) vs. those who were FHN (n=115), between the ages of 21-30, participated in three test days. Subjects were scheduled to receive placebo, low dose ethanol (target BrAC=40mg%), and high dose ethanol (target BrAC=100mg%) on three separate test days at least three days apart in a randomized order under double-blind conditions. Outcome measures included subjective effects, measures of coordination and cognitive function. Results Both low and high dose alcohol led to dose-related stimulant and sedative subjective effects as measured the Biphasic Alcohol Effects Scale (BAES) and subjective measures of “high” and “drowsy” measured on a visual analog scale (VAS) However, there were no effects of family history. Similar dose-related effects were observed on cognitive and coordination related outcomes, but were not moderated family history. Conclusions Results from this study showed that healthy individuals responded to an IV alcohol challenge in a dose-related manner; however, there were no significant differences on subjective response, or on ethanol-induced impairment of coordination or cognition, between individuals with a positive family history for alcoholism and those with a negative family history. Results suggest that FH may not be a specific enough marker of risk, particularly in individuals who are beyond the age where alcohol use disorders often develop. PMID:23895557

A nicotinic acetylcholine receptor agonist affects honey bee sucrose responsiveness and decreases waggle dancing.

PubMed

Eiri, Daren M; Nieh, James C

2012-06-15

A nicotinic acetylcholine receptor agonist, imidacloprid, impairs memory formation in honey bees and has general effects on foraging. However, little is known about how this agonist affects two specific aspects of foraging: sucrose responsiveness (SR) and waggle dancing (which recruits nestmates). Using lab and field experiments, we tested the effect of sublethal doses of imidacloprid on (1) bee SR with the proboscis extension response assay, and (2) free-flying foragers visiting and dancing for a sucrose feeder. Bees that ingested imidacloprid (0.21 or 2.16 ng bee(-1)) had higher sucrose response thresholds 1 h after treatment. Foragers that ingested imidacloprid also produced significantly fewer waggle dance circuits (10.5- and 4.5-fold fewer for 50% and 30% sucrose solutions, respectively) 24 h after treatment as compared with controls. However, there was no significant effect of imidacloprid on the sucrose concentrations that foragers collected at a feeder 24 h after treatment. Thus, imidacloprid temporarily increased the minimum sucrose concentration that foragers would accept (short time scale, 1 h after treatment) and reduced waggle dancing (longer time scale, 24 h after treatment). The effect of time suggests different neurological effects of imidacloprid resulting from the parent compound and its metabolites. Waggle dancing can significantly increase colony food intake, and thus a sublethal dose (0.21 ng bee(-1), 24 p.p.b.) of this commonly used pesticide may impair colony fitness.

Differential response of two cell lines sequentially irradiated with low X-ray doses.

PubMed

Güerci, A M; Dulout, F N; Grillo, C A; Seoane, A I

2005-05-01

An experiment was designed to compare the effect of repeated low doses of X-rays in two different cell lines: one transformed, epithelial like and aneuploid Chinese hamster ovary K-1 (CHO-K1); the other originated from a human primary culture, fibroblast, diploid and non-transformed, MRC-5. CHO and MRC-5 cells were cultured for 14 or eight passages, respectively. Irradiation was performed once per passage when cells were in the quiescent state (90 - 95% in G1/G0). Cells were exposed to 10.0 mSv X-ray doses. Ionizing radiation did not induce apoptosis or necrosis in the exposed CHO cell population. Significant increases of low-level damaged cells (degrees 1 and 2) were found for the 14 cycles of radiation when compared with controls, except for the first irradiation cycle. No significant increases in the frequency of cells with severe damage were observed. The frequency of MRC-5 cells with low-level damage increased significantly when compared with controls for radiation cycles seven and eight. Significant increases of apoptosis, necrosis and severe damage were found only for the highest dose. Transformed and non-transformed cell types responded differently to direct and indirect damage using low-dose repeat exposures to ionizing radiation. Though more investigation is needed to understand the mechanisms of radiation effects in chronic low-dose-exposed cell populations, cellular type should be taken into account in the design of in vitro experiments for understanding low-dose-irradiation effects.

Transcriptome analysis of reproductive-stage Arabidopsis plants exposed gamma-ray irradiation at various doses.

PubMed

Hwang, Sun-Goo; Kim, Dong Sub; Kim, Jin-Baek; Hwang, Jung Eun; Park, Hyun Mi; Kim, Jin Hyuk; Jang, Cheol Seong

2016-08-01

Gamma rays (GR) induce significant changes in the structure and expression of genes involved in the regulation of diverse biochemical and physiological processes. Arabidopsis plants exhibit different growth and development patterns in response to exposure to GR. The effects on gene expression of different radiation doses of GR (100 and 800 Gy) administered to Arabidopsis plants were examined at the reproductive stage. We irradiated 26-day-old plants with three replications [developmental stages 5.1-6.0, according to Boyes et al. ( 2001 )] using a GR irradiator (60 Co, ca. 150 TBq capacity, Atomic Energy of Canada Limited, Ontario, Canada) at the Korea Atomic Energy Research Institute. Plants were treated with 100, 200, 300, 400, 800, 1200, 1600, or 2000 Gy, and the doses were made from varying the distance to the source. We conducted a high-throughput screening analysis and detected 883 GR-responsive genes that showed significant changes; these were involved in several putative metabolic pathways related to biotic stress. Additionally, five overrepresented cis-regulatory elements were identified in the 1-kb upstream regions of GR-responsive genes by using motif enrichment analysis. We also detected three GR-responsive genes associated with stamen development and confirmed their co-regulation with functionally interacting genes. This finding suggests that a network-based analysis is a viable approach to identify significant GR-responsive genes associated with the reproductive stage of Arabidopsis. Our results provide further insights into the complex biological systems involved in the response to different doses of GR in plants.

Sensory neuropeptides modulate cigarette smoke-induced decrease in neutral endopeptidase activity in guinea pig airways.

PubMed

Kuo, H P; Lu, L C

1995-01-01

Cigarette smoke (CS) inhalation stimulates C-fibers to release sensory neuropeptides which mediate airway reflex responses to prevent irritants from entering the lower airways. When CS is inhaled via the upper airways, these airway defense responses may modulate the effect of CS on airway NEP activity and related airway hyperresponsiveness. To examine this possibility, we exposed guinea pigs to 1:10 diluted mid-tar cigarette smoke 100 puffs per day for 7 days and recorded pulmonary resistance of cumulative doses of neurokinin A (NKA, 10(-12)-10(-8) mol/kg, i.v.) or methacholine (Mch, 1-50 micrograms/kg, i.v.). NEP activity in the tracheobronchi was measured using fluorometric assay. Exposure of CS alone failed to alter the dose-response to NKA or Mch compared with air control. NEP activity in the airways after CS exposure was slightly but significantly lower than that of air control. Capsaicin pretreatment 1 week before CS exposure significantly shifted the dose-response curves of NKA, but not Mch, to the left and decreased NEP activity in the airways to a greater extent compared with CS exposure alone group. Capsaicin pretreatment alone failed to alter the responsiveness to NKA or NEP activity. CS also induced a significant increase in neutrophil counts in airways. Capsaicin pretreatment enhanced the effect of CS on neutrophil recruitment. We conclude that sensory neuropeptides may have a protective role in modulation of airways NEP activity downregulation induced by CS, probably by preventing CS from entering the lower airways or the chronic release of sensory neuropeptides induced by CS providing increased amount of substrata for NEP upregulation, and therefore modify the direct effect of CS on NEP activity and related airway hyperresponsiveness.

Thermogenic effects of sibutramine and its metabolites

PubMed Central

Connoley, Ian P; Liu, Yong-Ling; Frost, Ian; Reckless, Ian P; Heal, David J; Stock, Michael J

1999-01-01

The thermogenic activity of the serotonin and noradrenaline reuptake inhibitor sibutramine (BTS 54524; Reductil) was investigated by measuring oxygen consumption (VO2) in rats treated with sibutramine or its two pharmacologically-active metabolites. Sibutramine caused a dose-dependent rise in VO2, with a dose of 10 mg kg−1 of sibutramine or its metabolites producing increases of up to 30% that were sustained for at least 6 h, and accompanied by significant increases (0.5–1.0°C) in body temperature. Based on the accumulation in vivo of radiolabelled 2-deoxy-[3H]-glucose, sibutramine had little or no effect on glucose utilization in most tissues, but caused an 18 fold increase in brown adipose tissue (BAT). Combined high, non-selective doses (20 mg kg−1) of the β-adrenoceptor antagonists, atenolol and ICI 118551, inhibited completely the VO2 response to sibutramine, but the response was unaffected by low, β1-adrenoceptor-selective (atenolol) or β2-adrenoceptor-selective (ICI 118551) doses (1 mg kg−1). The ganglionic blocking agent, chlorisondamine (15 mg kg−1), inhibited completely the VO2 response to the metabolites of sibutramine, but had no effect on the thermogenic response to the β3-adrenoceptor-selective agonist BRL 35135. Similar thermogenic responses were produced by simultaneous injection of nisoxetine and fluoxetine at doses (30 mg kg−1) that had no effect on VO2 when injected individually. It is concluded that stimulation of thermogenesis by sibutramine requires central reuptake inhibition of both serotonin and noradrenaline, resulting in increased efferent sympathetic activation of BAT thermogenesis via β3-adrenoceptor, and that this contributes to the compound's activity as an anti-obesity agent. PMID:10217544

Beta blocker therapy is associated with reduced depressive symptoms 12 months post percutaneous coronary intervention.

PubMed

Battes, Linda C; Pedersen, Susanne S; Oemrawsingh, Rohit M; van Geuns, Robert J; Al Amri, Ibtihal; Regar, Evelyn; de Jaegere, Peter P T; Serruys, Patrick; van Domburg, Ron T

2012-02-01

Beta blocker therapy may induce depressive symptoms, although current evidence is conflicting. We examined the association between beta blocker therapy and depressive symptoms in percutaneous coronary intervention (PCI) patients and the extent to which there is a dose-response relationship between beta blocker dose and depressive symptoms. Patients treated with PCI (N=685) completed the depression scale of the Hospital Anxiety and Depression Scale 1 and 12 months post PCI. Information about type and dose of beta blocker use was extracted from medical records. Of all patients, 68% (466/685) were on beta blocker therapy at baseline. In adjusted analysis, beta blocker use at 1 month post PCI (OR: 0.82; 95% CI: 0.53-1.26) was not significantly associated with depressive symptoms. At 12 months post PCI, there was a significant relationship between beta blocker use and depressive symptoms (OR: 0.51; 95% CI: 0.31-0.84), with beta blocker therapy associated with a 49% risk reduction in depressive symptoms. There was a dose-response relationship between beta blocker dose and depressive symptoms 12 months post PCI, with the risk reduction in depressive symptoms in relation to a low dose being 36% (OR: 0.64; 95% CI: 0.37-1.10) and 58% (OR: 0.42; 95% CI: 0.24-0.76) in relation to a high dose. Patients treated with beta blocker therapy were less likely to experience depressive symptoms 12 months post PCI, with there being a dose-response relationship with a higher dose providing a more pronounced protective effect. Copyright © 2011 Elsevier B.V. All rights reserved.

Protective effects of long-term administration of Ziziphus jujuba fruit extract on cardiovascular responses in L-NAME hypertensive rats.

PubMed

Mohebbati, Reza; Bavarsad, Kosar; Rahimi, Maryam; Rakhshandeh, Hasan; Khajavi Rad, Abolfazl; Shafei, Mohammad Naser

2018-01-01

Ziziphus jujuba stimulates the release of nitric oxide (NO). Because NO is involved in cardiovascular regulations, in this study the effects of hydroalcoholic extract of Z. jujuba on cardiovascular responses in acute NG-nitro-L-arginine methyl ester (L-NAME) hypertensive rats were evaluated. Rats were divided into 6 group (n=6): 1) saline, 2) L-NAME received (10mg/kg) intravenously, 3) sodium nitroprusside (SNP) (50µg/kg)+L-NAME group received SNP before L-NAME and 4-6) three groups of Z. jujuba (100, 200 and 400mg/kg) that treated for four weeks and on the 28 th day, L-NAME was injected. Femoral artery and vein were cannulated for recording cardiovascular responses and drug injection, respectively. Systolic blood pressure (SBP), Mean arterial pressure (MAP) and heart rate (HR) were recorded continuously. Maximal changes (∆) of SBP, MAP and HR were calculated and compared to control and L-NAME groups. In L-NAME group, maximal ΔSBP (L-NAME: 44.15±4.0 mmHg vs control: 0.71±2.1 mmHg) and ΔMAP (L-NAME: 40.8±4.0 mmHg vs control: 0.57±1.6 mmHg) significantly increased (p<0.001 in both) but ∆HR was not significant as compared to control (p>0.05). All doses of Z. jujuba attenuated maximal ∆SBP and ∆MAP induced by L-NAME but only the lowest dose (100 mg/kg) had significant effects (ΔSBP: 20.36±5.6 mmHg vs L-NAME: 44.1±4.0 mmHg and ΔMAP: 20.8±4.5 mmHg vs L-NAME: 40.8±3.8 mmHg (p<0.05 to p<0.01)). The ∆HR at three doses was not significantly different from that of L-NAME group (p>0.05). Because long-term consumption of Z. jujuba extract, especially its lowest dose, attenuated cardiovascular responses induced by L-NAME, we suggest that Z. jujuba has potential beneficial effects in prevention of hypertension induced by NO deficiency.

Influence of dosage, consciousness, and nifedipine on the acute pressor response to intraperitoneally administered cadmium. [Rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hall, C.E.; Hungerford, S.

1982-05-01

The acute pressor effect of intraperitoneally administered cadmium was explored over the dose range 0.015-2 mg/kg in both pentobarbital-anesthetized and conscious rats. The former first respondent at 0.031 mg/kg, and successive doublings of that dosage increased the highest pressures attained in a stepwise fashion until a dosage of 0.25 mg/kg, the maximally effective quantity, was reached. Arterial pressure did not rise in conscious rats until a dose of 1 mg/kg, which gave the maximum response within the range examined. Heart-rate changes with Cd were slight, and rarely significant at a given dosage, but pentobarbital invariably caused tachycardia. Anesthetized rats thusmore » gave a graded response, while conscious animals reacted in an all-or-none fashion. The increased pressor responsiveness of rats under pentobarbital can not be ascribed to its cardiac parasympatholytic effects, since sensitivity was not conferred upon conscious rats when pretreated with atropine at a dose producing even greater tachycardia than that caused by pentobarbital. Nifedipine, which blocks calcium entry into smooth muscle cells, prevented the pressor response to cadmium when given as pretreatment and terminated an ongoing response when give intercurrently. Possible mechanisms to account for the observed behavior are considered.« less

NOTE: Investigating the potential of polymer gel dosimetry for interventional radiology: first results

NASA Astrophysics Data System (ADS)

Antoniou, P. E.; Bousbouras, P.; Sandaltzopoulos, R.; Kaldoudi, E.

2008-04-01

Complex interventional radiology (IR) procedures contribute an increasing percentage of the overall medical radiation exposure of the population making accurate dosimetry a challenge. Magnetic resonance (MR) based polymer gel dosimetry has been widely employed in complex dosimetric problems in radiotherapy. The aim of this note is to investigate the feasibility of normoxic gel dosimetry in IR. Dose response, energy dependence and dose rate dependence were investigated in irradiation set-ups relevant to IR for a particular normoxic gel, based on methacrylic acid (MAA) as the monomer and including tetrakis-hydroxy-methyl-phosphonium chloride (THPC) as antioxidant. The gel presents a linear dose response beyond a 25 cGy threshold. No significant energy dependence was observed in the useful range of interventional radiology (80-110 kVp). A linear correlation between the gel response and dose rate was observed in the range of dose rates relevant to IR (5-8 cGy min-1). These results demonstrate a reduction of gel sensitivity at very low dose rate levels. A possible explanation of this effect is suggested.

Effects of zacopride and BMY25801 (batanopride) on radiation-induced emesis and locomotor behavior in the ferret

DOE Office of Scientific and Technical Information (OSTI.GOV)

King, G.L.; Landauer, M.R.

1990-06-01

The antiemetic and locomotor effects of two substituted benzamides, zacopride and batanopride (BMY25801), were compared in ferrets after bilateral 60Co irradiation at 2, 4 or 6 Gy. Both zacopride and BMY25801 were effective against emesis and related signs. Zacopride, tested at several doses (0.003, 0.03 and 0.3 mg/kg), appeared to be more potent because it abolished emesis at 100-fold lower doses than did BMY25801 (3 mg/kg). The ED50 value for the antiemetic effect of zacopride was 0.026 mg/kg (confidence levels = 0.0095, 0.072 mg/kg). However, analysis of emetic parameters recorded from vomiting animals (e.g., latency to first emesis) demonstrated thatmore » BMY25801 provided greater antiemetic protection in this population than zacopride without any apparent side effects. Locomotor activity was significantly depressed by both radiation (all doses) and zacopride alone (0.03 mg/kg and 0.3 mg/kg). BMY25801 alone did not affect locomotor activity, and protected against the radiation-induced locomotor decrement. Although zacopride potentiated the locomotor decrement to radiation, no clear dose-response relationship was evident. Bilateral abdominal vagotomy significantly increased the latency to the first emetic episode and significantly reduced the number of retches, but did not alter the duration of the prodromal response to 4-Gy irradiation. Unilateral vagotomies had no effect. Zacopride (at 0.03 mg/kg and 0.3 mg/kg) remained an effective antiemetic in animals that received a bilateral vagotomy, abolishing emesis in four of eight and two of eight ferrets, respectively. These data suggest that the antiemetic action of zacopride does not fully depend on intact vagal innervation and also acts via other pathways.« less

Contractile activity of ATP and diadenosine tetraphosphate on urinary bladder in the rat: role of A1- and P2X-purinoceptors and nitric oxide.

PubMed

Khattab, M M; Al-Hrasen, M N; El-Hadiyah, T M

2007-01-01

1. Both adenosine-5'-triphosphate (ATP) and diadenosine tetraphosphate (AP4A) produced a dose-dependent contraction of the isolated rat urinary bladder rings. AP(4)A dose-response curve was to the left of that of ATP, and maximum response was greater than that produced by ATP. 2. 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), the A1-purinergic receptor blocker (0.01 mm) significantly inhibited the ATP- and AP4A-induced contractions at the whole dose range. The inhibition was between 31-41%, and 15-25% for ATP and AP4A respectively. 3. Pyridoxal phosphate 6-azophenyl-2',4'-disulphonic acid (PPADS), the P2X-purinoceptor antagonist (0.01 mm) potently inhibited the bladder contractions in response to ATP and AP4A by around 75-80%. 4. The nitric oxide (NO) precursor L-arginine reduced the bladder contractile response to ATP by about 22-41% and that of AP4A to a lesser extent by around 20-32%. 5. The nitric oxide synthase inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 0.1 mM), did not produce any significant effect on ATP except for a weak inhibition of about 14% at the lowest dose of ATP. The contractions in response to AP4A were only slightly reduced by L-NAME by about 20%. 6. In conclusion, the contractile response of the bladder to ATP and to the dinucleotide AP4A is mediated mainly through P2X-purinoceptors and A1-purinergic receptors. In the detrusor muscle, NO donation possesses an inhibitory effect on ATP-mediated contractility more than that produced by the dinucleotide AP4A.

TH-E-BRF-03: A Multivariate Interaction Model for Assessment of Hippocampal Vascular Dose-Response and Early Prediction of Radiation-Induced Neurocognitive Dysfunction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farjam, R; Pramanik, P; Srinivasan, A

Purpose: Vascular injury could be a cause of hippocampal dysfunction leading to late neurocognitive decline in patients receiving brain radiotherapy (RT). Hence, our aim was to develop a multivariate interaction model for characterization of hippocampal vascular dose-response and early prediction of radiation-induced late neurocognitive impairments. Methods: 27 patients (17 males and 10 females, age 31–80 years) were enrolled in an IRB-approved prospective longitudinal study. All patients were diagnosed with a low-grade glioma or benign tumor and treated by 3-D conformal or intensity-modulated RT with a median dose of 54 Gy (50.4–59.4 Gy in 1.8− Gy fractions). Six DCE-MRI scans weremore » performed from pre-RT to 18 months post-RT. DCE data were fitted to the modified Toft model to obtain the transfer constant of gadolinium influx from the intravascular space into the extravascular extracellular space, Ktrans, and the fraction of blood plasma volume, Vp. The hippocampus vascular property alterations after starting RT were characterized by changes in the hippocampal mean values of, μh(Ktrans)τ and μh(Vp)τ. The dose-response, Δμh(Ktrans/Vp)pre->τ, was modeled using a multivariate linear regression considering integrations of doses with age, sex, hippocampal laterality and presence of tumor/edema near a hippocampus. Finally, the early vascular dose-response in hippocampus was correlated with neurocognitive decline 6 and 18 months post-RT. Results: The μh(Ktrans) increased significantly from pre-RT to 1 month post-RT (p<0.0004). The multivariate model showed that the dose effect on Δμh(Ktrans)pre->1M post-RT was interacted with sex (p<0.0007) and age (p<0.00004), with the dose-response more pronounced in older females. Also, the vascular dose-response in the left hippocampus of females was significantly correlated with memory function decline at 6 (r = − 0.95, p<0.0006) and 18 (r = −0.88, p<0.02) months post-RT. Conclusion: The hippocampal vascular response to radiation could be sex and age dependent. The early hippocampal vascular dose-response could predict late neurocognitive dysfunction. (Support: NIH-RO1NS064973)« less

Time- and dose-dependent differential regulation of copper-zinc superoxide dismutase and manganese superoxide dismutase enzymatic activity and mRNA level by vitamin E in rat blood cells.

PubMed

Hajiani, Maliheh; Razi, Farideh; Golestani, Aboualfazl; Frouzandeh, Mehdi; Owji, Ali Akbar; Khaghani, Shahnaz; Ghannadian, Naghmeh; Shariftabrizi, Ahmad; Pasalar, Parvin

2012-01-01

Vitamin E is the most important lipid-soluble antioxidant. Recently, it has been proposed as a gene regulator, and its gene modulation effects have been observed at different levels of gene expression and cell signaling. This study was performed to investigate the effects of vitamin E on the activity and expression of the most important endogenous antioxidant enzyme, superoxide dismutase (SOD), in rat plasma. Twenty-eight male Sprauge-Dawley rats were divided into four groups: control group and three dosing groups. The control group received the vehicle (liquid paraffin), and the dosing groups received twice-weekly intraperitoneal injections of 10, 30, and 100 mg/kg of vitamin E ((±)-α-Tocopherol) for 6 weeks. Quantitative real-time reverse transcription-polymerase chain reaction and enzyme assays were used to assess the levels of Cu/Zn-SOD and Mn-SOD mRNA and enzyme activity levels in blood cells at 0, 2, 4, and 6 weeks following vitamin E administration. Catalase enzyme activity and total antioxidant capacity were also assessed in plasma at the same time intervals. Mn-SOD activity was significantly increased in the 100 and 30 mg/kg dosing groups after 4 and 6 weeks, with corresponding significant increase in their mRNA levels. Cu/Zn-SOD activity was not significantly changed in response to vitamin E administration at any time points, whereas Cu/Zn-SOD mRNA levels were significantly increased after longer time points with high doses (30 and 100 mg/kg) of vitamin E. Catalase enzyme activity was transiently but significantly increased after 4 weeks of vitamin E treatment in 30 and 100 mg/kg dosing groups. Total antioxidant status was significantly increased after 4 and 6 weeks in the 100 mg/kg dosing group. Only the chronic administration of higher doses of alpha-tocopherol is associated with the increased activity and expression of Mn-SOD in rats. Cu/Zn-SOD activity and expression does not dramatically change in response to vitamin E.

Gamma rays induce DNA damage and oxidative stress associated with impaired growth and reproduction in the copepod Tigriopus japonicus.

PubMed

Han, Jeonghoon; Won, Eun-Ji; Lee, Bo-Young; Hwang, Un-Ki; Kim, Il-Chan; Yim, Joung Han; Leung, Kenneth Mei Yee; Lee, Yong Sung; Lee, Jae-Seong

2014-07-01

Nuclear radioisotope accidents are potentially ecologically devastating due to their impact on marine organisms. To examine the effects of exposure of a marine organism to radioisotopes, we irradiated the intertidal copepod Tigriopus japonicus with several doses of gamma radiation and analyzed the effects on mortality, fecundity, and molting by assessing antioxidant enzyme activities and gene expression patterns. No mortality was observed at 96h, even in response to exposure to a high dose (800Gy) of radiation, but mortality rate was significantly increased 120h (5 days) after exposure to 600 or 800Gy gamma ray radiation. We observed a dose-dependent reduction in fecundity of ovigerous females; even the group irradiated with 50Gy showed a significant reduction in fecundity, suggesting that gamma rays are likely to have a population level effect. In addition, we observed growth retardation, particularly at the nauplius stage, in individuals after gamma irradiation. In fact, nauplii irradiated with more than 200Gy, though able to molt to copepodite stage 1, did not develop into adults. Upon gamma radiation, T. japonicus showed a dose-dependent increase in reactive oxygen species (ROS) levels, the activities of several antioxidant enzymes, and expression of double-stranded DNA break damage genes (e.g. DNA-PK, Ku70, Ku80). At a low level (sub-lethal dose) of gamma irradiation, we found dose-dependent upregulation of p53, implying cellular damage in T. japonicus in response to sub-lethal doses of gamma irradiation, suggesting that T. japonicus is not susceptible to sub-lethal doses of gamma irradiation. Additionally, antioxidant genes, phase II enzyme (e.g. GSTs), and cellular chaperone genes (e.g. Hsps) that are involved in cellular defense mechanisms also showed the same expression patterns for sublethal doses of gamma irradiation (50-200Gy). These findings indicate that sublethal doses of gamma radiation can induce oxidative stress-mediated DNA damage and increase the expression of antioxidant enzymes and proteins with chaperone-related functions, thereby significantly affecting life history parameters such as fecundity and molting in the copepod T. japonicus. Copyright © 2014 Elsevier B.V. All rights reserved.

Escalating doses of transdermal nicotine in heavy smokers: effects on smoking behavior and craving.

PubMed

Selby, Peter; Andriash, Katherine; Zawertailo, Laurie; Persad, Desmond; Zack, Martin; Busto, Usoa E

2013-10-01

Fixed-dose nicotine replacement therapy (NRT) is efficacious for smoking cessation in the general population of smokers. However, it is less effective in populations with psychiatric comorbidities and/or severe tobacco dependence where the percent nicotine replacement is suboptimal. The objective of this pilot study was to determine the effectiveness of nicotine patch dose titration in response to continued smoking in heavily dependent smokers with psychiatric comorbidity. In a single-arm, open-label study adult smokers (mean cigarettes per day, 25.4 ± 13.4; range, 14-43; n = 12) willing to quit were treated with escalating doses of transdermal nicotine and brief counseling intervention if they continued to smoke over a 9-week treatment period. Plasma nicotine and cotinine, along with expired carbon monoxide levels, and the subjective effects of smoking, urge to smoke, demand elasticity, and mood symptoms were also assessed. The mean NRT dose was 32.7 (SD, 16.4) mg/d (range, 7-56 mg/d). Smokers reported significant reductions in both cigarettes per day (mean decrease, 18.4 ± 11.5) confirmed by expired carbon monoxide (mean decrease, 13.5 ± 13.0) with no significant changes in plasma nicotine concentrations during the course of NRT dose titration. There were significant effects on the subjective effects of smoking and measures of smoking behavior. Most commonly reported adverse events were respiratory infections, skin irritation at patch site, nausea, and sleep disturbances, which were generally mild and transient. Titrating doses of NRT to effect with brief intervention hold promise as an effective clinical strategy to assist heavily dependent psychiatrically ill smokers to change their smoking behavior.

Anti-Stress, Behavioural and Magnetoencephalography Effects of an L-Theanine-Based Nutrient Drink: A Randomised, Double-Blind, Placebo-Controlled, Crossover Trial.

PubMed

White, David J; de Klerk, Suzanne; Woods, William; Gondalia, Shakuntla; Noonan, Chris; Scholey, Andrew B

2016-01-19

L-theanine (γ-glutamylethylamide) is an amino acid found primarily in the green tea plant. This study explored the effects of an L-theanine-based nutrient drink on mood responses to a cognitive stressor. Additional measures included an assessment of cognitive performance and resting state alpha oscillatory activity using magnetoencephalography (MEG). Thirty-four healthy adults aged 18-40 participated in this double-blind, placebo-controlled, balanced crossover study. The primary outcome measure, subjective stress response to a multitasking cognitive stressor, was significantly reduced one hour after administration of the L-theanine drink when compared to placebo. The salivary cortisol response to the stressor was reduced three hours post-dose following active treatment. No treatment-related cognitive performance changes were observed. Resting state alpha oscillatory activity was significantly greater in posterior MEG sensors after active treatment compared to placebo two hours post-dose; however, this effect was only apparent for those higher in trait anxiety. This change in resting state alpha oscillatory activity was not correlated with the change in subjective stress response or the cortisol response, suggesting further research is required to assess the functional relevance of these treatment-related changes in resting alpha activity. These findings further support the anti-stress effects of L-theanine.

Reinforcing and neurochemical effects of cannabinoid CB1 receptor agonists, but not cocaine, are altered by an adenosine A2A receptor antagonist.

PubMed

Justinová, Zuzana; Ferré, Sergi; Redhi, Godfrey H; Mascia, Paola; Stroik, Jessica; Quarta, Davide; Yasar, Sevil; Müller, Christa E; Franco, Rafael; Goldberg, Steven R

2011-07-01

Several recent studies suggest functional and molecular interactions between striatal adenosine A(2A) and cannabinoid CB(1) receptors. Here, we demonstrate that A(2A) receptors selectively modulate reinforcing effects of cannabinoids. We studied effects of A(2A) receptor blockade on the reinforcing effects of delta-9-tetrahydrocannabinol (THC) and the endogenous CB(1) receptor ligand anandamide under a fixed-ratio schedule of intravenous drug injection in squirrel monkeys. A low dose of the selective adenosine A(2A) receptor antagonist MSX-3 (1 mg/kg) caused downward shifts of THC and anandamide dose-response curves. In contrast, a higher dose of MSX-3 (3 mg/kg) shifted THC and anandamide dose-response curves to the left. MSX-3 did not modify cocaine or food pellet self-administration. Also, MSX-3 neither promoted reinstatement of extinguished drug-seeking behavior nor altered reinstatement of drug-seeking behavior by non-contingent priming injections of THC. Finally, using in vivo microdialysis in freely-moving rats, a behaviorally active dose of MSX-3 significantly counteracted THC-induced, but not cocaine-induced, increases in extracellular dopamine levels in the nucleus accumbens shell. The significant and selective results obtained with the lower dose of MSX-3 suggest that adenosine A(2A) antagonists acting preferentially at presynaptic A(2A) receptors might selectively reduce reinforcing effects of cannabinoids that lead to their abuse. However, the appearance of potentiating rather than suppressing effects on cannabinoid reinforcement at the higher dose of MSX-3 would likely preclude the use of such a compound as a medication for cannabis abuse. Adenosine A(2A) antagonists with more selectivity for presynaptic versus postsynaptic receptors could be potential medications for treatment of cannabis abuse. Addiction Biology © 2010 Society for the Study of Addiction. No claim to original US government works.

Dose Calculations for [131I] Meta-Iodobenzylguanidine-Induced Bystander Effects

PubMed Central

Gow, M. D.; Seymour, C. B.; Boyd, M.; Mairs, R. J.; Prestiwch, W. V.; Mothersill, C. E.

2014-01-01

Targeted radiotherapy is a potentially useful treatment for some cancers and may be potentiated by bystander effects. However, without estimation of absorbed dose, it is difficult to compare the effects with conventional external radiation treatment. Methods: Using the Vynckier – Wambersie dose point kernel, a model for dose rate evaluation was created allowing for calculation of absorbed dose values to two cell lines transfected with the noradrenaline transporter (NAT) gene and treated with [131I]MIBG. Results: The mean doses required to decrease surviving fractions of UVW/NAT and EJ138/NAT cells, which received medium from [131I]MIBG-treated cells, to 25 – 30% were 1.6 and 1.7 Gy respectively. The maximum mean dose rates achieved during [131I]MIBG treatment were 0.09 – 0.75 Gy/h for UVW/NAT and 0.07 – 0.78 Gy/h for EJ138/NAT. These were significantly lower than the external beam gamma radiation dose rate of 15 Gy/h. In the case of control lines which were incapable of [131I]MIBG uptake the mean absorbed doses following radiopharmaceutical were 0.03 – 0.23 Gy for UVW and 0.03 – 0.32 Gy for EJ138. Conclusion: [131I]MIBG treatment for ICCM production elicited a bystander dose-response profile similar to that generated by external beam gamma irradiation but with significantly greater cell death. PMID:24659931

Safety and efficacy of cell-based therapy on critical limb ischemia: A meta-analysis.

PubMed

Ai, Min; Yan, Chang-Fu; Xia, Fu-Chun; Zhou, Shuang-Lu; He, Jian; Li, Cui-Ping

2016-06-01

Critical limb ischemia (CLI) is a major health problem worldwide, affecting approximately 500-1000 people per million per annum. Cell-based therapy has given new hope for the treatment of limb ischemia. This study assessed the safety and efficacy of cellular therapy CLI treatment. We searched the PubMed, Embase and Cochrane databases through October 20, 2015, and selected the controlled trials with cell-based therapy for CLI treatment compared with cell-free treatment. We assessed the results by meta-analysis using a variety of outcome measures, as well as the association of mononuclear cell dosage with treatment effect by dose-response meta-analysis. Twenty-five trials were included. For the primary evaluation index, cell-based therapy significantly reduced the rate of major amputation (odds ratio [OR] 0.44, 95% confidence interval [CI] 0.32-0.60, P = 0.000) and significantly increased the rate of amputation-free survival (OR 2.80, 95% CI 1.70-4.61, P = 0.000). Trial sequence analysis indicated that optimal sample size (n = 3374) is needed to detect a plausible treatment effect in all-cause mortality. Cell-based therapy significantly improves ankle brachial index, increases the rate of ulcer healing, increases the transcutaneous pressure of oxygen, reduces limb pain and improves movement ability. Subgroup analysis indicated heterogeneity is caused by type of control, design bias and transplant route. In the dose-response analysis, there was no significant correlation between cell dosage and the therapeutic effect. Cell-based therapy has a significant therapeutic effect on CLI, but randomized double-blind placebo-controlled trials are needed to improve the credibility of this conclusion. Assessment of all-cause mortality also requires a larger sample size to arrive at a strong conclusion. In dose-response analysis, increasing the dosage of cell injections does not significantly improve the therapeutic effects of cell-based therapy. Copyright © 2016 International Society for Cellular Therapy. Published by Elsevier Inc. All rights reserved.

Enhancing effect of menthol on nicotine self-administration in rats

PubMed Central

Biswas, Lisa; Harrison, Erin; Gong, Yongzhen; Avusula, Ramachandram; Lee, Jonathan; Zhang, Meiyu; Rousselle, Thomas; Lage, Janice; Liu, Xiu

2016-01-01

Rationale Tobacco smoking is a leading preventable cause of premature death in the United States. Menthol is a significant flavoring additive in tobacco products. Clinical evidence suggests that menthol may promote tobacco smoking and nicotine dependence. However, it is unclear whether menthol enhances the reinforcing actions of nicotine and thus facilitates nicotine consumption. This study employed a rat model of nicotine self-administration to examine the effects of menthol on nicotine-taking behavior. Methods Male Sprague-Dawley rats were trained in daily 1-h sessions to press a lever for intravenous nicotine self-administration under a fixed-ratio 5 schedule of reinforcement. In separate groups, rats self-administered nicotine at four different doses (0.0075, 0.015, 0.03, and 0.06 mg/kg/infusion). Five minutes prior to the two test sessions, menthol (5 mg/kg) or its vehicle was administered intraperitoneally in all rats in a counterbalanced design within each group. In separate rats that self-administered 0.015 mg/kg/infusion nicotine, menthol dose-response function was determined. Menthol was also tested on food self-administration. Results An inverted U-shaped nicotine dose-response curve was observed. Menthol pretreatment shifted the nicotine dose-response curve to the left. The facilitating effect of menthol on the self-administration of 0.015 mg/kg/infusion nicotine was dose-dependent, whereas it produced similar effects at doses above the threshold of 2.5 mg/kg. Menthol tended to suppress the self-administration of food pellets. Conclusions These data demonstrate that menthol enhances the reinforcing effects of nicotine, and the effect of menthol was specific to nicotine. The findings suggest that menthol directly facilitates nicotine consumption, thereby contributing to tobacco smoking. PMID:27473365

Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel Breath Powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial.

PubMed

Quintana, D S; Westlye, L T; Hope, S; Nærland, T; Elvsåshagen, T; Dørum, E; Rustan, Ø; Valstad, M; Rezvaya, L; Lishaugen, H; Stensønes, E; Yaqub, S; Smerud, K T; Mahmoud, R A; Djupesland, P G; Andreassen, O A

2017-05-23

The neuropeptide oxytocin has shown promise as a treatment for symptoms of autism spectrum disorders (ASD). However, clinical research progress has been hampered by a poor understanding of oxytocin's dose-response and sub-optimal intranasal delivery methods. We examined two doses of oxytocin delivered using a novel Breath Powered intranasal delivery device designed to improve direct nose-to-brain activity in a double-blind, crossover, randomized, placebo-controlled trial. In a randomized sequence of single-dose sessions, 17 male adults with ASD received 8 international units (IU) oxytocin, 24IU oxytocin or placebo followed by four social-cognitive tasks. We observed an omnibus main effect of treatment on the primary outcome measure of overt emotion salience as measured by emotional ratings of faces (η 2 =0.18). Compared to placebo, 8IU treatment increased overt emotion salience (P=0.02, d=0.63). There was no statistically significant increase after 24IU treatment (P=0.12, d=0.4). The effects after 8IU oxytocin were observed despite no significant increase in peripheral blood plasma oxytocin concentrations. We found no significant effects for reading the mind in the eyes task performance or secondary outcome social-cognitive tasks (emotional dot probe and face-morphing). To our knowledge, this is the first trial to assess the dose-dependent effects of a single oxytocin administration in autism, with results indicating that a low dose of oxytocin can significantly modulate overt emotion salience despite minimal systemic exposure.

A Unified Probabilistic Framework for Dose-Response Assessment of Human Health Effects.

PubMed

Chiu, Weihsueh A; Slob, Wout

2015-12-01

When chemical health hazards have been identified, probabilistic dose-response assessment ("hazard characterization") quantifies uncertainty and/or variability in toxicity as a function of human exposure. Existing probabilistic approaches differ for different types of endpoints or modes-of-action, lacking a unifying framework. We developed a unified framework for probabilistic dose-response assessment. We established a framework based on four principles: a) individual and population dose responses are distinct; b) dose-response relationships for all (including quantal) endpoints can be recast as relating to an underlying continuous measure of response at the individual level; c) for effects relevant to humans, "effect metrics" can be specified to define "toxicologically equivalent" sizes for this underlying individual response; and d) dose-response assessment requires making adjustments and accounting for uncertainty and variability. We then derived a step-by-step probabilistic approach for dose-response assessment of animal toxicology data similar to how nonprobabilistic reference doses are derived, illustrating the approach with example non-cancer and cancer datasets. Probabilistically derived exposure limits are based on estimating a "target human dose" (HDMI), which requires risk management-informed choices for the magnitude (M) of individual effect being protected against, the remaining incidence (I) of individuals with effects ≥ M in the population, and the percent confidence. In the example datasets, probabilistically derived 90% confidence intervals for HDMI values span a 40- to 60-fold range, where I = 1% of the population experiences ≥ M = 1%-10% effect sizes. Although some implementation challenges remain, this unified probabilistic framework can provide substantially more complete and transparent characterization of chemical hazards and support better-informed risk management decisions.

Effects of dexpanthenol with or without Aloe vera extract on radiation-induced oral mucositis: preclinical studies.

PubMed

Dörr, W; Schlichting, S; Bray, M A; Flockhart, I R; Hopewell, J W

2005-03-01

To define the effect of dexpanthenol with or without Aloe vera extract on radiation-induced oral mucositis. Mouse tongue mucosal ulceration was analysed as the clinically relevant endpoint. Graded single or fractionated dose irradiation (10 x 3 Gy/2 weeks, graded test doses on day 14) were combined with topical administration of dexpanthenol or a base, with or without Aloe vera extract. The formulations were applied for 14 days (single dose) or 24 days after the first fraction. Single dose irradiation resulted in an ED50 (dose at which a positive mucosal response was expected in 50% of the animals irradiated) of 11.9+/-1.2 Gy. None of the formulations yielded a significant change in incidence or time course of ulceration. Test irradiation after 10 x 3 Gy gave an ED50 of 9.0+/-0.1 Gy. Base treatment increased the ED50-values to 10.5+/-0.8 Gy (p = 0.0095) and 9.9+/-0.7 Gy (p = 0.0445) without or with Aloe vera. Dexpanthenol resulted in ED50 values of 9.5+/-0.1 Gy without Aloe vera (p > 0.05), and of 10.9+/-0.9 Gy (p = 0.0035) with Aloe vera. The latent time to ulceration was prolonged, compared to the control (6.3 days) without Aloe vera (8.0-8.2 days, p < 0.001) and with dexpanthenol and Aloe vera (7.3 days, p = 0.0239). With single dose irradiation, neither dexpanthenol nor Aloe vera extract significantly changed the oral mucosal radiation response. With fractionated irradiation, drug administration significantly increased the isoeffective radiation doses, independent of dexpanthenol or Aloe vera content. Neither dexpanthenol nor Aloe vera display a prophylactic potential.

The acute effects of a low and high dose of oral L-arginine supplementation in young active males at rest.

PubMed

Forbes, Scott C; Bell, Gordon J

2011-06-01

L-arginine (2-amino-5-guanidinovaleric acid) is a conditionally essential amino acid. Intravenous (IV) administration of l-arginine invokes a large metabolic (nitrate/nitrite (NO(x))) and hormonal (growth hormone (GH), insulin-like growth factor 1 (IGF-1), and insulin) response; however, research examining oral l-arginine supplementation is conflicting, potentially owing to dose. The purpose of this study was examine a low and high dose of oral l-arginine on blood l-arginine, NO(x), GH, IGF-1, and insulin response. Fourteen physically active males (age: 25 ± 5 years; weight: 78.0 ± 8.5 kg; height: 179.4 ± 4.7 cm) volunteered to be in a randomized, double-blind, repeated-measures study. Following an overnight fast, an IV catheter was placed in a forearm vein and a resting blood sample was drawn at ∼0800 hours. Each subject was then provided 1 of 3 treatment conditions (placebo, low (0.075 g·kg(-1) of body mass), or high (0.15 g·kg(-1) of body mass of l-arginine)). Blood samples were drawn at 30, 60, 90, 120, and 180 min after consumption. l-arginine plasma concentrations significantly increased (p < 0.001) to a similar level at any time point in both the low- and high-dose conditions; there was no change over time in the placebo condition. There was no significant difference between conditions for NO(x), GH, IGF-1, or insulin. Based on these findings, a low dose of l-arginine was just as effective at increasing plasma l-arginine concentrations as a high dose; however, neither dose was able to promote a significant increase in NO(x), GH, IGF-1, or insulin at rest.

Low-dose naltrexone for the treatment of fibromyalgia: findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels.

PubMed

Younger, Jarred; Noor, Noorulain; McCue, Rebecca; Mackey, Sean

2013-02-01

To determine whether low dosages (4.5 mg/day) of naltrexone reduce fibromyalgia severity as compared with the nonspecific effects of placebo. In this replication and extension study of a previous clinical trial, we tested the impact of low-dose naltrexone on daily self-reported pain. Secondary outcomes included general satisfaction with life, positive mood, sleep quality, and fatigue. Thirty-one women with fibromyalgia participated in the randomized, double-blind, placebo-controlled, counterbalanced, crossover study. During the active drug phase, participants received 4.5 mg of oral naltrexone daily. An intensive longitudinal design was used to measure daily levels of pain. When contrasting the condition end points, we observed a significantly greater reduction of baseline pain in those taking low-dose naltrexone than in those taking placebo (28.8% reduction versus 18.0% reduction; P = 0.016). Low-dose naltrexone was also associated with improved general satisfaction with life (P = 0.045) and with improved mood (P = 0.039), but not improved fatigue or sleep. Thirty-two percent of participants met the criteria for response (defined as a significant reduction in pain plus a significant reduction in either fatigue or sleep problems) during low-dose naltrexone therapy, as contrasted with an 11% response rate during placebo therapy (P = 0.05). Low-dose naltrexone was rated equally tolerable as placebo, and no serious side effects were reported. The preliminary evidence continues to show that low-dose naltrexone has a specific and clinically beneficial impact on fibromyalgia pain. The medication is widely available, inexpensive, safe, and well-tolerated. Parallel-group randomized controlled trials are needed to fully determine the efficacy of the medication. Copyright © 2013 by the American College of Rheumatology.

Tracheal smooth muscle responses to substance P and neurokinin A in the piglet.

PubMed

Haxhiu-Poskurica, B; Haxhiu, M A; Kumar, G K; Miller, M J; Martin, R J

1992-03-01

The tachykinins substance P (SP) and neurokinin A (NKA) have been shown to induce airway smooth muscle contraction in mature animals, and the enzyme neutral endopeptidase (NEP) modulates this effect. We evaluated maturation of SP- and NKA-induced tracheal smooth muscle contraction and modulation of their effects by NEP in anesthetized, paralyzed, and artificially ventilated piglets less than 4 days, 2-3 wk, and 10 wk of age. Tracheal smooth muscle tension was measured in vivo from an open tracheal segment by use of a force transducer. Intravenous SP caused a dose-dependent increase in tracheal tension in all three age groups; however, the response in less than 4-day-old piglets was significantly weaker than in 2- to 3- and 10-wk-old piglets. NKA caused a dose-dependent increase in tracheal tension only in 2- to 3- and 10-wk-old piglets. The response of tracheal tension to NKA was weaker than the response to SP in all age groups. Atropine (2 mg/kg) significantly diminished the responses of tracheal tension to SP and NKA, indicating a cholinergic contribution to these responses at all ages. Intravenous thiorphan, a known NEP inhibitor, potentiated the effects of SP only in 2- to 3- and 10-wk-old piglets and did not affect the response of tracheal tension to NKA at any age. Biochemical analyses demonstrated a significant increase in tracheal NEP activity in comparably aged piglets over the first 10 wk of life.(ABSTRACT TRUNCATED AT 250 WORDS)

Non-Targeted Effects Models Predict Significantly Higher Mars Mission Cancer Risk than Targeted Effects Models

DOE PAGES

Cucinotta, Francis A.; Cacao, Eliedonna

2017-05-12

Cancer risk is an important concern for galactic cosmic ray (GCR) exposures, which consist of a wide-energy range of protons, heavy ions and secondary radiation produced in shielding and tissues. Relative biological effectiveness (RBE) factors for surrogate cancer endpoints in cell culture models and tumor induction in mice vary considerable, including significant variations for different tissues and mouse strains. Many studies suggest non-targeted effects (NTE) occur for low doses of high linear energy transfer (LET) radiation, leading to deviation from the linear dose response model used in radiation protection. Using the mouse Harderian gland tumor experiment, the only extensive data-setmore » for dose response modelling with a variety of particle types (>4), for the first-time a particle track structure model of tumor prevalence is used to investigate the effects of NTEs in predictions of chronic GCR exposure risk. The NTE model led to a predicted risk 2-fold higher compared to a targeted effects model. The scarcity of data with animal models for tissues that dominate human radiation cancer risk, including lung, colon, breast, liver, and stomach, suggest that studies of NTEs in other tissues are urgently needed prior to long-term space missions outside the protection of the Earth’s geomagnetic sphere.« less

Non-Targeted Effects Models Predict Significantly Higher Mars Mission Cancer Risk than Targeted Effects Models

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cucinotta, Francis A.; Cacao, Eliedonna

Cancer risk is an important concern for galactic cosmic ray (GCR) exposures, which consist of a wide-energy range of protons, heavy ions and secondary radiation produced in shielding and tissues. Relative biological effectiveness (RBE) factors for surrogate cancer endpoints in cell culture models and tumor induction in mice vary considerable, including significant variations for different tissues and mouse strains. Many studies suggest non-targeted effects (NTE) occur for low doses of high linear energy transfer (LET) radiation, leading to deviation from the linear dose response model used in radiation protection. Using the mouse Harderian gland tumor experiment, the only extensive data-setmore » for dose response modelling with a variety of particle types (>4), for the first-time a particle track structure model of tumor prevalence is used to investigate the effects of NTEs in predictions of chronic GCR exposure risk. The NTE model led to a predicted risk 2-fold higher compared to a targeted effects model. The scarcity of data with animal models for tissues that dominate human radiation cancer risk, including lung, colon, breast, liver, and stomach, suggest that studies of NTEs in other tissues are urgently needed prior to long-term space missions outside the protection of the Earth’s geomagnetic sphere.« less

Photodynamic Therapy with 3-(1’-hexyloxyethyl) pyropheophorbide a (HPPH) for Cancer of the Oral Cavity

PubMed Central

Rigual, Nestor; Shafirstein, Gal; Cooper, Michele T.; Baumann, Heinz; Bellnier, David A.; Sunar, Ulas; Tracy, Erin C.; Rohrbach, Daniel J.; Wilding, Gregory; Tan, Wei; Sullivan, Maureen; Merzianu, Mihai; Henderson, Barbara W.

2013-01-01

Purpose The primary objective was to evaluate safety of 3-(1’-hexyloxyethyl)pyropheophorbide-a (HPPH) photodynamic therapy (HPPH-PDT) for dysplasia and early squamous cell carcinoma of the head and neck (HNSCC). Secondary objectives were the assessment of treatment response and reporters for an effective PDT reaction. Experimental Design Patients with histologically proven oral dysplasia, carcinoma in situ (CiS ) or early stage HNSCC were enrolled in two sequentially conducted dose escalation studies with an expanded cohort at the highest dose level. These studies employed an HPPH dose of 4 mg/m2 and light doses from 50 to 140 J/cm2. Pathologic tumor responses were assessed at 3 months. Clinical follow up range was 5 to 40 months. PDT induced cross-linking of signal transducer and activator of transcription 3 (STAT3) were assessed as potential indicators of PDT effective reaction. Results Forty patients received HPPH-PDT. Common adverse events were pain and treatment site edema. Biopsy proven complete response rates were 46% for dysplasia and CiS, and 82% for SCCs lesions at 140 J/cm2. The responses in the CiS/dysplasia cohort are not durable. The PDT induced STAT3 cross-links is significantly higher (P=0.0033) in SCC than in CiS/dysplasia for all light-doses. Conclusion HPPH-PDT is safe for the treatment of CiS/dysplasia and early stage cancer of the oral cavity. Early stage oral HNSCC appears to respond better to HPPH-PDT in comparison to premalignant lesions. The degree of STAT3 cross-linking is a significant reporter to evaluate HPPH-PDT mediated photoreaction. PMID:24088736

Fruit peel polyphenols demonstrate substantial anti-tumour effects in the model of breast cancer.

PubMed

Kubatka, Peter; Kapinová, Andrea; Kello, Martin; Kruzliak, Peter; Kajo, Karol; Výbohová, Desanka; Mahmood, Silvia; Murin, Radovan; Viera, Tischlerová; Mojžiš, Ján; Zulli, Anthony; Péč, Martin; Adamkov, Marián; Kassayová, Monika; Bojková, Bianka; Stollárová, Nadežda; Dobrota, Dušan

2016-04-01

Fruit and vegetable intake is inversely correlated with cancer; thus, it is proposed that an extract of phytochemicals as present in whole fruits, vegetables, or grains may have anti-carcinogenic properties. Thus, the anti-tumour effects of fruit peel polyphenols (Flavin7) in the chemoprevention of N-methyl-N-nitrosourea-induced mammary carcinogenesis in female rats were evaluated. Lyophilized substance of Flavin7 (F7) was administered at two concentrations of 0.3 and 3 % through diet. The experiment was terminated 14 weeks after carcinogen administration, and mammary tumours were removed and prepared for histopathological and immunohistochemical analysis. In addition, using an in vitro cytotoxicity assay, apoptosis and proliferation after F7 treatment in human breast adenocarcinoma (MCF-7) cells were performed. High-dose F7 suppressed tumour frequency by 58 % (P < 0.001), tumour incidence by 24 % (P < 0.05), and lengthened latency by 8 days (P > 0.05) in comparison with the control rats, whereas lower dose of F7 was less effective. Histopathological analysis of tumours showed significant decrease in the ratio of high-/low-grade carcinomas after high-dose F7 treatment. Immunohistochemical analysis of rat carcinoma cells in vivo found a significant increase in caspase-3 expression and significant decrease in Bcl-2, Ki67, and VEGFR-2 expression in the high-dose group. Both doses demonstrated significant positive effects on plasma lipid metabolism in rats. F7 significantly decreased survival of MCF-7 cells in vitro in MTT assay by dose- and time-dependent manner compared to control. F7 prevented cell cycle progression by significant enrichment in G1 cell populations. Incubation with F7 showed significant increase in the percentage of annexin V-/PI-positive MCF-7 cells and DNA fragmentation. Our results reveal a substantial tumour-suppressive effect of F7 in the breast cancer model. We propose that the effects of phytochemicals present in this fruit extract are responsible for observed potent anti-cancer activities.

Chromosomal Aberrations in DNA Repair Defective Cell Lines: Comparisons of Dose Rate and Radiation Quality

NASA Technical Reports Server (NTRS)

George, K. A.; Hada, M.; Patel, Z.; Huff, J.; Pluth, J. M.; Cucinotta, F. A.

2009-01-01

Chromosome aberration yields were assessed in DNA double-strand break repair (DSB) deficient cells after acute doses of gamma-rays or high-LET iron nuclei, or low dose-rate (0.018 Gy/hr) gamma-rays. We studied several cell lines including fibroblasts deficient in ATM (product of the gene that is mutated in ataxia telangiectasia patients) or NBS (product of the gene mutated in the Nijmegen breakage syndrome), and gliomablastoma cells that are proficient or lacking in DNA-dependent protein kinase, DNA-PK activity. Chromosomes were analyzed using the fluorescence in-situ hybridization (FISH) chromosome painting method in cells at the first division post-irradiation and chromosome aberrations were identified as either simple exchanges (translocations and dicentrics) or complex exchanges (involving >2 breaks in 2 or more chromosomes). Gamma radiation induced higher yields of both simple and complex exchanges in the DSB repair defective cells than in the normal cells. The quadratic dose-response terms for both chromosome exchange types were significantly higher for the ATM and NBS defective lines than for normal fibroblasts. However, the linear dose-response term was significantly higher only for simple exchanges in the NBS cells. Large increases in the quadratic dose response terms indicate the important roles of ATM and NBS in chromatin modifications that facilitate correct DSB repair and minimize aberration formation. Differences in the response of AT and NBS deficient cells at lower doses suggests important questions about the applicability of observations of radiation sensitivity at high dose to low dose exposures. For all iron nuclei irradiated cells, regression models preferred purely linear and quadratic dose responses for simple and complex exchanges, respectively. All the DNA repair defective cell lines had lower Relative biological effectiveness (RBE) values than normal cells, the lowest being for the DNA-PK-deficient cells, which was near unity. To further investigate the sensitivity differences for low and low high doses, we performed chronic low dose-rate irradiation, and have begun studies with ATM and Nibrin inhibitors and siRNA knockout of these proteins. Results support the conclusion that for the endpoint of simple chromosomal aberrations (translocation or dicentrics), the increased radiation sensitivity of AT cells found at high doses (>1 Gy) does not carry over to low doses or doserates, while NBS cells show increased sensitivity for both high and low dose exposures.

Prediction of Psilocybin Response in Healthy Volunteers

PubMed Central

Studerus, Erich; Gamma, Alex; Kometer, Michael; Vollenweider, Franz X.

2012-01-01

Responses to hallucinogenic drugs, such as psilocybin, are believed to be critically dependent on the user's personality, current mood state, drug pre-experiences, expectancies, and social and environmental variables. However, little is known about the order of importance of these variables and their effect sizes in comparison to drug dose. Hence, this study investigated the effects of 24 predictor variables, including age, sex, education, personality traits, drug pre-experience, mental state before drug intake, experimental setting, and drug dose on the acute response to psilocybin. The analysis was based on the pooled data of 23 controlled experimental studies involving 409 psilocybin administrations to 261 healthy volunteers. Multiple linear mixed effects models were fitted for each of 15 response variables. Although drug dose was clearly the most important predictor for all measured response variables, several non-pharmacological variables significantly contributed to the effects of psilocybin. Specifically, having a high score in the personality trait of Absorption, being in an emotionally excitable and active state immediately before drug intake, and having experienced few psychological problems in past weeks were most strongly associated with pleasant and mystical-type experiences, whereas high Emotional Excitability, low age, and an experimental setting involving positron emission tomography most strongly predicted unpleasant and/or anxious reactions to psilocybin. The results confirm that non-pharmacological variables play an important role in the effects of psilocybin. PMID:22363492

Prediction of psilocybin response in healthy volunteers.

PubMed

Studerus, Erich; Gamma, Alex; Kometer, Michael; Vollenweider, Franz X

2012-01-01

Responses to hallucinogenic drugs, such as psilocybin, are believed to be critically dependent on the user's personality, current mood state, drug pre-experiences, expectancies, and social and environmental variables. However, little is known about the order of importance of these variables and their effect sizes in comparison to drug dose. Hence, this study investigated the effects of 24 predictor variables, including age, sex, education, personality traits, drug pre-experience, mental state before drug intake, experimental setting, and drug dose on the acute response to psilocybin. The analysis was based on the pooled data of 23 controlled experimental studies involving 409 psilocybin administrations to 261 healthy volunteers. Multiple linear mixed effects models were fitted for each of 15 response variables. Although drug dose was clearly the most important predictor for all measured response variables, several non-pharmacological variables significantly contributed to the effects of psilocybin. Specifically, having a high score in the personality trait of Absorption, being in an emotionally excitable and active state immediately before drug intake, and having experienced few psychological problems in past weeks were most strongly associated with pleasant and mystical-type experiences, whereas high Emotional Excitability, low age, and an experimental setting involving positron emission tomography most strongly predicted unpleasant and/or anxious reactions to psilocybin. The results confirm that non-pharmacological variables play an important role in the effects of psilocybin.

"Curcumin-loaded Poly (d, l-lactide-co-glycolide) nanovesicles induce antinociceptive effects and reduce pronociceptive cytokine and BDNF release in spinal cord after acute administration in mice".

PubMed

Pieretti, Stefano; Ranjan, Amalendu P; Di Giannuario, Amalia; Mukerjee, Anindita; Marzoli, Francesca; Di Giovannandrea, Rita; Vishwanatha, Jamboor K

2017-10-01

Given the poor bioavailability of curcumin, its antinociceptive effects are produced after chronic intravenous administration of high doses, while poly (d,l-lactide-co-glycolide)-loaded vesicles (PLGA) can improve drug delivery. This paper investigates the antinociceptive effects of curcumin-loaded PLGA nanovesicles (PLGA-CUR) administered via intravenous (i.v.) or intrathecal (i.t.) routes at low and high doses. The following models of pain were used: formalin test, zymosan-induced hyperalgesia and sciatic nerve ligation inducing neuropathic allodynia and hyperalgesia. PLGA-CUR administered intravenously was able to reduce the response to nociceptive stimuli in the formalin test and hyperalgesia induced by zymosan. Curcumin, instead, was inactive. Low-dose i.t. administration of PLGA-CUR significantly reduced allodynia produced by sciatic nerve ligation, whereas low doses of curcumin did not change the response to nociceptive stimuli. Long-lasting antinociceptive effects were observed when high doses of PLGA-CUR were administered intrathecally. At high doses, i.t. administration of curcumin only exerted rapid and transient antinociceptive effects. Measurement of cytokine and BDNF in the spinal cord of neuropathic mice demonstrate that the antinociceptive effects of PLGA-CUR depend on the reduction in cytokine release and BDNF in the spinal cord. The results demonstrate the effectiveness of PLGA-CUR and suggest that PLGA-CUR nanoformulation might be a new potential drug in the treatment of pain. Copyright © 2017 Elsevier B.V. All rights reserved.

Dexmedetomidine in Attenuation of Haemodynamic Response and Dose Sparing Effect on Opioid and Anaesthetic Agents in Patients undergoing Laparoscopic Cholecystectomy- A Randomized Study

PubMed Central

Bhagat, Nandlal; Karim, Habib Md Reazaul; Hajong, Ranendra; Bhattacharyya, Prithwis; Singh, Manorama

2016-01-01

Introduction Perioperative procedures are stressful and lead to haemodynamic instability with potentially devastating consequences. Dexmedetomidine is found to have many of the desired characteristics that are required in perioperative period. Aim To evaluate the ability of pre and intraoperative dexmedetomidine to attenuate stress induced haemodynamic responses, quantifying the anaesthetic agents sparing as well as its cost-effectiveness in patients undergoing laparoscopic cholecystectomy. Materials and Methods The present single blind randomized study was conducted with 120 ASA I and II consented patients who underwent laparoscopic cholecystectomy. Patients were randomly divided into 2 groups (i.e., group D and group N). Prior to induction, group D received 1 μg/kg of Dexmedetomidine and group N received Normal saline infusion over 20 minutes. Group D also received maintenance Dexmedetomidine intraoperatively. Bispectral index and minimum alveolar concentration monitoring was done in both the groups. Haemodynamic parameters were noted till 100 minutes post laryngoscopy. Opioid and anaesthetic agent consumptions were also noted and cost analysis was done. Medcalc–Version 12.5.0.0 software was used for statistics and p <0.05 was considered significant. Results Dexmedetomidine attenuated the stress induced haemodynamics responses and produced stable, relatively non fluctuating haemodynamics throughout. The Minimum Alveolar Concentration (MAC) requirement and the consumptions of Fentanyl and Isoflurane were significantly less in the Dexmedetomidine group (p<0.0001). However, despite anaesthetic dose sparing effect the anaesthetic technique was not cost-effective. Conclusion Dexmedetomidine is effective in attenuating haemodynamic responses in laparoscopic surgery and having dose sparing effect on Fentanyl, Propofol and Isoflurane. However, overall this technique is not cost-effective. PMID:28050479

A Novel Highly Bioavailable Curcumin Formulation Improves Symptoms and Diagnostic Indicators in Rheumatoid Arthritis Patients: A Randomized, Double-Blind, Placebo-Controlled, Two-Dose, Three-Arm, and Parallel-Group Study.

PubMed

Amalraj, Augustine; Varma, Karthik; Jacob, Joby; Divya, Chandradhara; Kunnumakkara, Ajaikumar B; Stohs, Sidney J; Gopi, Sreeraj

2017-10-01

Rheumatoid arthritis (RA) is an autoimmune, chronic systemic inflammatory disorder. The long-term use of currently available drugs for the treatment of RA has many potential side effects. Natural phytonutrients may serve as alternative strategies for the safe and effective treatment of RA, and curcuminoids have been used in Ayurvedic medicine for the treatment of inflammatory conditions for centuries. In this study, a novel, highly bioavailable form of curcumin in a completely natural turmeric matrix was evaluated for its ability to improve the clinical symptoms of RA. A randomized, double-blind, placebo-controlled, three-arm, parallel-group study was conducted to evaluate the comparative efficacy of two different doses of curcumin with that of a placebo in active RA patients. Twelve patients in each group received placebo, 250 or 500 mg of the curcumin product twice daily for 90 days. The responses of the patients were assessed using the American College of Rheumatology (ACR) response, visual analog scale (VAS), C-reactive protein (CRP), Disease Activity Score 28 (DAS28), erythrocyte sedimentation rate (ESR), and rheumatoid factor (RF) values. RA patients who received the curcumin product at both low and high doses reported statistically significant changes in their clinical symptoms at the end of the study. These observations were confirmed by significant changes in ESR, CPR, and RF values in patients receiving the study product compared to baseline and placebo. The results indicate that this novel curcumin in a turmeric matrix acts as an analgesic and anti-inflammatory agent for the management of RA at a dose as low as 250 mg twice daily as evidenced by significant improvement in the ESR, CRP, VAS, RF, DAS28, and ACR responses compared to placebo. Both doses of the study product were well tolerated and without side effects.

The Immune Effects of an African Traditional Energy Tonic in In Vitro and In Vivo Models

PubMed Central

Ngcobo, Mlungisi; Naidoo, Vinny; Cele, Protus

2017-01-01

Most of the African traditional medicines (ATM) are formulated as energy tonics to boost and maintain immune defences. In this study, we aimed to evaluate the immune effects of a traditional energy tonic using peripheral blood mononuclear cells (PBMCs), THP-1 monocytes, and bacteria infected rats. When tested in mitogen and peptidoglycan stimulated PBMCs, this energy tonic showed minimal cytotoxicity, while in acute toxicity studies in rats it did not exhibit any significant toxicity at doses up to 2000 mg/mL/kg. The energy tonic doses between 100 and 10 μg/mL were shown to stimulate secretion of cytokines and increase sIL-2R levels in PHA-treated PBMCs. Similar doses in PG-S. aureus-stimulated PBMCs significantly (p < 0.05) increased IL-1α, IL-2, and GM-CSF while causing a significant (p < 0.05) decrease in sIL-2R levels. NF-κβ transcriptional activity was increased in LPS stimulated THP-1 cells. In Sprague Dawley rats pretreated with the energy tonic and then infected with S. aureus, there were insignificant increases in cytokines and sIL-2R when compared to bacteria infected only and 5% Enrofloxacin treated rats. Posttreatment with energy tonic doses after infection with S. aureus did not enhance inflammatory cytokines significantly but changed the immune response profile and decreased corticosterone levels. This ATM showed promising immunomodulatory effects on isolated immune cells and modulated the immune response of rat models infected with S. aureus. PMID:28408939

Dose Response Data for Hormonally Active Chemicals ...

EPA Pesticide Factsheets

The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects. For noncancer effects the default assumption is that noncancer effects generally display threshold rather than LNT responses. More recently, claims have arisen that the chemicals, like endocrine disrupters (EDS), which act via high affinity, low capacity nuclear receptors, may display LNT or nonmonotonic low dose responses: responses that could be missed in multigenerational guideline toxicity testing. This presentation will discuss LNT, threshold and nonmonotonic dose response relationships from case studies of chemicals that disrupt reproductive development and function via the ER, AR and AhR pathways and will include in vitro and in vivo multigenerational data. The in vivo studies in this discussion include only robust, well designed, comprehensive studies that administered the chemical via a relevant route(s) of exposure over a broad dose response range, including low dose(s) in the microgram/kg/d range. The chemicals include ethinyl estradiol, estradiol, genistein, bisphenol a, trenbolone, finasteride, flutamide, phthalate esters and 2,3,7,8 TCDD. The objective is to critically evaluate the data from well done studies in this field to address concerns that current multigenerational reproductive test gui

A Phase II, Randomized, Double-Blind, Placebo Controlled, Dose-Response Trial of the Melatonin Effect on the Pain Threshold of Healthy Subjects

PubMed Central

Stefani, Luciana Cadore; Muller, Suzana; Torres, Iraci L. S.; Razzolini, Bruna; Rozisky, Joanna R.; Fregni, Felipe; Markus, Regina; Caumo, Wolnei

2013-01-01

Background Previous studies have suggested that melatonin may produce antinociception through peripheral and central mechanisms. Based on the preliminary encouraging results of studies of the effects of melatonin on pain modulation, the important question has been raised of whether there is a dose relationship in humans of melatonin on pain modulation. Objective The objective was to evaluate the analgesic dose response of the effects of melatonin on pressure and heat pain threshold and tolerance and the sedative effects. Methods Sixty-one healthy subjects aged 19 to 47 y were randomized into one of four groups: placebo, 0.05 mg/kg sublingual melatonin, 0.15 mg/kg sublingual melatonin or 0.25 mg/kg sublingual melatonin. We determine the pressure pain threshold (PPT) and the pressure pain tolerance (PPTo). Quantitative sensory testing (QST) was used to measure the heat pain threshold (HPT) and the heat pain tolerance (HPTo). Sedation was assessed with a visual analogue scale and bispectral analysis. Results Serum plasma melatonin levels were directly proportional to the melatonin doses given to each subject. We observed a significant effect associated with dose group. Post hoc analysis indicated significant differences between the placebo vs. the intermediate (0.15 mg/kg) and the highest (0.25 mg/kg) melatonin doses for all pain threshold and sedation level tests. A linear regression model indicated a significant association between the serum melatonin concentrations and changes in pain threshold and pain tolerance (R2 = 0.492 for HPT, R2 = 0.538 for PPT, R2 = 0.558 for HPTo and R2 = 0.584 for PPTo). Conclusions The present data indicate that sublingual melatonin exerts well-defined dose-dependent antinociceptive activity. There is a correlation between the plasma melatonin drug concentration and acute changes in the pain threshold. These results provide additional support for the investigation of melatonin as an analgesic agent. Brazilian Clinical Trials Registry (ReBec): (U1111-1123-5109). IRB: Research Ethics Committee at the Hospital de Clínicas de Porto Alegre. PMID:25947930

Local tumor control probability modeling of primary and secondary lung tumors in stereotactic body radiotherapy.

PubMed

Guckenberger, Matthias; Klement, Rainer J; Allgäuer, Michael; Andratschke, Nicolaus; Blanck, Oliver; Boda-Heggemann, Judit; Dieckmann, Karin; Duma, Marciana; Ernst, Iris; Ganswindt, Ute; Hass, Peter; Henkenberens, Christoph; Holy, Richard; Imhoff, Detlef; Kahl, Henning K; Krempien, Robert; Lohaus, Fabian; Nestle, Ursula; Nevinny-Stickel, Meinhard; Petersen, Cordula; Semrau, Sabine; Streblow, Jan; Wendt, Thomas G; Wittig, Andrea; Flentje, Michael; Sterzing, Florian

2016-03-01

To evaluate whether local tumor control probability (TCP) in stereotactic body radiotherapy (SBRT) varies between lung metastases of different primary cancer sites and between primary non-small cell lung cancer (NSCLC) and secondary lung tumors. A retrospective multi-institutional (n=22) database of 399 patients with stage I NSCLC and 397 patients with 525 lung metastases was analyzed. Irradiation doses were converted to biologically effective doses (BED). Logistic regression was used for local tumor control probability (TCP) modeling and the second-order bias corrected Akaike Information Criterion was used for model comparison. After median follow-up of 19 months and 16 months (n.s.), local tumor control was observed in 87.7% and 86.7% of the primary and secondary lung tumors (n.s.), respectively. A strong dose-response relationship was observed in the primary NSCLC and metastatic cohort but dose-response relationships were not significantly different: the TCD90 (dose to achieve 90% TCP; BED of maximum planning target volume dose) estimates were 176 Gy (151-223) and 160 Gy (123-237) (n.s.), respectively. The dose-response relationship was not influenced by the primary cancer site within the metastatic cohort. Dose-response relationships for local tumor control in SBRT were not different between lung metastases of various primary cancer sites and between primary NSCLC and lung metastases. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Evaluation of zinc oxide nanoparticle toxicity in sludge products applied to agricultural soil using multispecies soil systems.

PubMed

Fernández, María Dolores; Alonso-Blázquez, María Nieves; García-Gómez, Concepción; Babin, Mar

2014-11-01

To study the environmental impact of nanoparticles, the sludges of wastewater (WWTS) and water treatment (WTS) plants enriched with ZnO nanoparticles were added to agricultural soil, and the toxic effects of the nanoparticles were studied using a microcosm system based on the soil. The WWTS treated soils were characterised by statistically significant decreases (p<0.05) in Vicia sativa germination at the lowest (76.2%) and medium (95.2%) application rates, decreases in the fresh biomass for Triticum aestivum (19.5%), Raphanus sativus (64.1%), V. sativa (37.4%) and Eisenia fetida (33.6%) at the highest application rate and a dose-related significant increase (p<0.05) in earthworm mortality. In WTS amended soils, significant reductions (p<0.05) of the fresh biomass (17.2%) and the chlorophyll index (24.4%) for T. aestivum and the fresh biomass for R. sativus (31.4%) were only recorded at the highest application doses. In addition, the soil phosphatase enzymatic activity decreased significantly (p<0.05) in both WWTS (dose related) and WTS treatments. For water organisms, a slight inhibition of the growth of Chlorella vulgaris was observed (WWTS treated soils), along with statistically significant dose-related inhibition responses on total glutathione cell content, and statistically significant dose-related induction responses on the glutathione S-transferase enzyme activity and the reactive oxygen species generation on the RTG-2 fish cell line. Copyright © 2014 Elsevier B.V. All rights reserved.

Chromosome translocations in T. scripta: the dose-rate effect and in vivo lymphocyte radiation response.

PubMed

Ulsh, B A; Whicker, F W; Congdon, J D; Bedford, J S; Hinton, T G

2001-01-01

Using a whole-chromosome FISH painting probe we previously developed for chromosome 1 of the yellow-bellied slider turtle (Trachemys scripta), we investigated the dose-rate effect for radiation-induced symmetrical translocations in T. scripta fibroblasts and lymphocytes. The dose rate below which no reduction in effect per unit dose is observed with further dose protraction was approximately 23 cGy h(-1). We estimated the whole-genome spontaneous background level of complete, apparently simple symmetrical translocations in T. scripta lymphocytes to be approximately 1.20 x 10(-3)/cell projected from aberrations occurring in chromosome 1. Similar spontaneous background levels reported for humans are some 6- to 25-fold higher, ranging from about 6 x 10(-3) to 3.4 x 10(-2) per cell. This relatively low background level for turtles would be a significant advantage for resolution of effects at low doses and dose rates. We also chronically irradiated turtles over a range of doses from 0-8 Gy delivered at approximately 5.5 cGy h(-1) and constructed a lymphocyte dose-response curve for complete, apparently simple symmetrical translocations suitable for use with animals chronically exposed to radiation in contaminated environments. The best-fitting calibration curve (not constrained through the zero dose estimate) was of the form Y(as) = c + aD + bD(2), where Y(as) was the number of apparently simple symmetrical translocations per cell, D was the dose (Gy), a = (0.0058 +/- 0.0009), b = (-0.00033 +/- 0.00011), and c = (0.0015 +/- 0.0013). With additional whole-chromosome probes to improve sensitivity, environmental biodosimetry using stable chromosome translocations could provide a practical and genetically relevant measurement end point for ecological risk assessments and biomonitoring programs.

Macrophage and tumor cell responses to repetitive pulsed X-ray radiation

NASA Astrophysics Data System (ADS)

Buldakov, M. A.; Tretyakova, M. S.; Ryabov, V. B.; Klimov, I. A.; Kutenkov, O. P.; Kzhyshkowska, J.; Bol'shakov, M. A.; Rostov, V. V.; Cherdyntseva, N. V.

2017-05-01

To study a response of tumor cells and macrophages to the repetitive pulsed low-dose X-ray radiation. Methods. Tumor growth and lung metastasis of mice with an injected Lewis lung carcinoma were analysed, using C57Bl6. Monocytes were isolated from a human blood, using CD14+ magnetic beads. IL6, IL1-betta, and TNF-alpha were determined by ELISA. For macrophage phenotyping, a confocal microscopy was applied. “Sinus-150” was used for the generation of pulsed X-ray radiation (the absorbed dose was below 0.1 Gy, the pulse repetition frequency was 10 pulse/sec). The irradiation of mice by 0.1 Gy pulsed X-rays significantly inhibited the growth of primary tumor and reduced the number of metastatic colonies in the lung. Furthermore, the changes in macrophage phenotype and cytokine secretion were observed after repetitive pulsed X-ray radiation. Conclusion. Macrophages and tumor cells had a different response to a low-dose pulsed X-ray radiation. An activation of the immune system through changes of a macrophage phenotype can result in a significant antitumor effect of the low-dose repetitive pulsed X-ray radiation.

Comparative Effectiveness of Two Oil Adjuvant-Inactivated Avian Influenza H9N2 Vaccines.

PubMed

Kilany, Walid H; Bazid, Abdel-Hamid I; Ali, Ahmed; El-Deeb, Ayman H; El-Abideen, Mohamed A Zain; Sayed, Magdy El; El-Kady, Magdy F

2016-05-01

Low pathogenic avian influenza H9N2 virus infection has been an important risk to the Egyptian poultry industry since 2011. Economic losses have occurred from early infection and co-infection with other pathogens. Therefore, H9N2 vaccination of broiler chicks as young as 7 days old was recommended. The current inactivated H9N2 vaccines (0.5 ml/bird) administered at a reduced dose (0.25 ml/bird) do not guarantee the delivery of an effective dose for broilers. In this study, the efficacy of the reduced-dose volume (0.3 ml/bird), compared with the regular vaccine dose (0.5 ml/bird) of inactivated H9N2 vaccines using two different commercially available adjuvants, was investigated. The vaccines were prepared from the local H9N2 virus (Ck/EG/114940v/NLQP/11) using the same antigen content: 300 hemagglutinating units. Postvaccination (PV) immune response was monitored using the hemagglutination inhibition test. At 4 wk PV, both vaccinated groups were challenged using the homologous H9N2 strain at a 50% egg infective dose (EID50) of 10(6) EID50/bird via the intranasal route. Clinical signs, mortality, and virus shedding in oropharyngeal swabs were monitored at 2, 4, 6, and 10 days postchallenge (DPC). The reduced-dose volume of vaccine induced a significantly faster and higher immune response than the regular volume of vaccine at 2 and 3 wk PV. No significant difference in virus shedding between the two vaccine formulas was found (P ≥ 0.05), and both vaccines were able to stop virus shedding by 6 DPC. The reduced-dose volume of vaccine using a suitable oil adjuvant and proper antigen content can be used effectively for early immunization of broiler chicks.

An update on the pharmacotherapy of attention-deficit/hyperactivity disorder in adults

PubMed Central

Wilens, Timothy E; Morrison, Nicholas R; Prince, Jefferson

2011-01-01

Adults with attention-deficit/hyperactivity disorder (ADHD) are more frequently presenting for diagnosis and treatment. Medication is considered to be appropriate among available treatments for ADHD; however, the evidence supporting the use of pharmacotherapeutics for adults with ADHD remains less established. In this article, the effectiveness and dosing parameters of the various agents investigated for adult ADHD are reviewed. In adults with ADHD, short-term improvements in symptomatology have been documented through the use of stimulants and antidepressants. Studies suggest that methylphenidate and amphetamine maintained an immediate onset of action, whereas the ADHD response to the nonstimulants appeared to be delayed. At a group level, there appears to be some, albeit not entirely consistent, dose-dependent responses to amphetamine and methylphenidate. Generally speaking, variability in diagnostic criteria, dosing parameters and response rates between the various studies was considerable, and most studies were of a relatively short duration. The aggregate literature shows that the stimulants and catecholaminergic nonstimulants investigated had a clinically significant beneficial effect on treating ADHD in adults. PMID:21955201

Acute effects of caffeine on several operant behaviors in rhesus monkeys.

PubMed

Buffalo, E A; Gillam, M P; Allen, R R; Paule, M G

1993-11-01

The acute effects of 1,3-trimethylxanthine (caffeine) were assessed using an operant test battery (OTB) of complex food-reinforced tasks that are thought to depend upon relatively specific brain functions, such as motivation to work for food (progressive ratio, PR), learning (incremental repeated acquisition, IRA), color and position discrimination (conditioned position responding, CPR), time estimation (temporal response differentiation, TRD), and short-term memory and attention (delayed matching-to-sample, DMTS). Endpoints included response rates (RR), accuracies (ACC), and percent task completed (PTC). Caffeine sulfate (0.175-20.0 mg/kg, IV), given 15 min pretesting, produced significant dose-dependent decreases in TRD percent task completed and accuracy at doses > or = 5.6 mg/kg. Caffeine produced no systematic effects on either DMTS or PR responding, but low doses tended to enhance performance in both IRA and CPR tasks. Thus, in monkeys, performance of an operant task designed to model time estimation is more sensitive to the disruptive effects of caffeine than is performance of the other tasks in the OTB.

Dose-Response Relationship between Dietary Magnesium Intake and Risk of Type 2 Diabetes Mellitus: A Systematic Review and Meta-Regression Analysis of Prospective Cohort Studies

PubMed Central

Fang, Xin; Han, Hedong; Li, Mei; Liang, Chun; Fan, Zhongjie; Aaseth, Jan; He, Jia; Montgomery, Scott; Cao, Yang

2016-01-01

The epidemiological evidence for a dose-response relationship between magnesium intake and risk of type 2 diabetes mellitus (T2D) is sparse. The aim of the study was to summarize the evidence for the association of dietary magnesium intake with risk of T2D and evaluate the dose-response relationship. We conducted a systematic review and meta-analysis of prospective cohort studies that reported dietary magnesium intake and risk of incident T2D. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to February 2016. We included cohort studies that provided risk ratios, i.e., relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs), for T2D. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. A total of 25 studies met the eligibility criteria. These studies comprised 637,922 individuals including 26,828 with a T2D diagnosis. Compared with the lowest magnesium consumption group in the population, the risk of T2D was reduced by 17% across all the studies; 19% in women and 16% in men. A statistically significant linear dose-response relationship was found between incremental magnesium intake and T2D risk. After adjusting for age and body mass index, the risk of T2D incidence was reduced by 8%–13% for per 100 mg/day increment in dietary magnesium intake. There was no evidence to support a nonlinear dose-response relationship between dietary magnesium intake and T2D risk. The combined data supports a role for magnesium in reducing risk of T2D, with a statistically significant linear dose-response pattern within the reference dose range of dietary intake among Asian and US populations. The evidence from Europe and black people is limited and more prospective studies are needed for the two subgroups. PMID:27869762

Cerebral radioprotection by pentobarbital: Dose-response characteristics and association with GABA agonist activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Olson, J.J.; Friedman, R.; Orr, K.

1990-05-01

Pentobarbital reduces cerebral radiation toxicity; however, the mechanism of this phenomenon remains unknown. As an anesthetic and depressant of cerebral metabolism, pentobarbital induces its effects on the central nervous system by stimulating the binding of gamma-aminobutyric acid (GABA) to its receptor and by inhibiting postsynaptic excitatory amino acid activity. The purpose of this study is to investigate the role of these actions as well as other aspects of the radioprotective activity of pentobarbital. Fischer 344 rats were separated into multiple groups and underwent two dose-response evaluations. In one set of experiments to examine the relationship of radioprotection to pentobarbital dose,more » a range of pentobarbital doses (0 to 75 mg/kg) were given intraperitoneally prior to a constant-level radiation dose (70 Gy). In a second series of experiments to determine the dose-response relationship of radiation protection to radiation dose, a range of radiation doses (10 to 90 Gy) were given with a single pentobarbital dose. Further groups of animals were used to evaluate the importance of the timing of pentobarbital administration, the function of the (+) and (-) isomers of pentobarbital, and the role of an alternative GABA agonist (diazepam). In addition, the potential protective effects of alternative methods of anesthesia (ketamine) and induction of cerebral hypometabolism (hypothermia) were examined. Enhancement of survival time from acute radiation injury due to high-dose single-fraction whole-brain irradiation was maximal with 60 mg/kg of pentobarbital, and occurred over the range of all doses examined between 30 to 90 Gy. Protection was seen only in animals that received the pentobarbital before irradiation. Administration of other compounds that enhance GABA binding (Saffan and diazepam) also significantly enhanced survival time.« less

Gestational exposure to perfluorooctanoic acid (PFOA): alterations in motor related behaviors

PubMed Central

Goulding, David R.; White, Sally S.; McBride, Sandra J.; Fenton, Suzanne E.; Harry, G. Jean

2016-01-01

Perfluoroalkyl and polyfluoroalkyl substances are used in commercial applications and developmental exposure has been implicated in alterations in neurobehavioral functioning. While associations between developmental perfluorooctanoic acid (PFOA) exposure and human outcomes have been inconsistent, studies in experimental animals suggest alterations in motor related behaviors. To examine a dose-response pattern of neurobehavioral effects following gestational exposure to PFOA, pregnant CD-1 mice received PFOA (0, 0.1, 0.3, 1.0 mg/kg/day) via oral gavage from gestational day 1–17 and the male offspring examined. Motor activity assessments on postnatal day (PND)18, 19, and 20 indicated a shift in the developmental pattern with an elevated activity level observed in the 1.0 mg/kg/day dose group on PND18. In the adult, no alterations were observed in body weights, activity levels, diurnal pattern of running wheel activity, startle response, or pre-pulse startle inhibition. In response to a subcutaneous injection of saline or nicotine (80 µg/kg), all animals displayed a transient increase in activity likely associated with handling with no differences observed across dose groups. Inhibition of motor activity over 18 days of 400µg/kg nicotine injection was not significantly different across dose groups. Hyperactivity induced by 2mg/kg (+)-methamphetamine hydrochloride intraperitoneal injection was significantly lower in the 1.0 mg/kg/day PFOA dose group as compared to controls. Taken together, these data suggest that the effects on motor-related behaviors with gestational PFOA exposure do not mimic those reported for acute postnatal exposure. Changes were not observed at dose level under 1.0 mg/kg/day PFOA. Further examination of pathways associated with methamphetamine-induced activity is warranted. PMID:27888120

Dizocilpine (MK-801) induces distinct changes of N-methyl-D-aspartic acid receptor subunits in parvalbumin-containing interneurons in young adult rat prefrontal cortex.

PubMed

Xi, Dong; Zhang, Wentong; Wang, Huai-Xing; Stradtman, George G; Gao, Wen-Jun

2009-11-01

N-methyl-D-aspartic acid receptor (NMDAR) hypofunction has long been implicated in schizophrenia and NMDARs on gamma-aminobutyric acid (GABA)ergic interneurons are proposed to play an essential role in the pathogenesis. However, controversial results have been reported regarding the regulation of NMDAR expression, and direct evidence of how NMDAR antagonists act on specific subpopulations of prefrontal interneurons is missing. We investigated the effects of the NMDAR antagonist dizocilpine (MK-801) on the expression of NMDAR subtypes in the identified interneurons in young adult rat prefrontal cortex (PFC) by using laser microdissection and real-time polymerase chain reaction, combined with Western blotting and immunofluorescent staining. We found that MK-801 induced distinct changes of NMDAR subunits in the parvalbumin-immunoreactive (PV-ir) interneurons vs. pyramidal neurons in the PFC circuitry. The messenger RNA (mRNA) expression of all NMDAR subtypes, including NR1 and NR2A to 2D, exhibited inverted-U dose-dependent changes in response to MK-801 treatment in the PFC. In contrast, subunit mRNAs of NMDARs in PV-ir interneurons were significantly down-regulated at low doses, unaltered at medium doses, and significantly decreased again at high doses, suggesting a biphasic dose response to MK-801. The differential effects of MK-801 in mRNA expression of NMDAR subunits were consistent with the protein expression of NR2A and NR2B subunits revealed with Western blotting and double immunofluorescent staining. These results suggest that PV-containing interneurons in the PFC exhibit a distinct responsiveness to NMDAR antagonism and that NMDA antagonist can differentially and dose-dependently regulate the functions of pyramidal neurons and GABAergic interneurons in the prefrontal cortical circuitry.

Low-dose priming before vaccination with the phase I chloroform-methanol residue vaccine against Q fever enhances humoral and cellular immune responses to Coxiella burnetii.

PubMed

Waag, David M; England, Marilyn J; Bolt, Christopher R; Williams, Jim C

2008-10-01

Although the phase I Coxiella burnetii cellular vaccine is completely efficacious in humans, adverse local and systemic reactions may develop if immune individuals are inadvertently vaccinated. The phase I chloroform-methanol residue (CMRI) vaccine was developed as a potentially safer alternative. Human volunteers with no evidence of previous exposure to C. burnetii received a subcutaneous vaccination with the CMRI vaccine in phase I studies under protocol IND 3516 to evaluate the safety and immunogenicity of the vaccine. This clinical trial tested escalating doses of the CMRI vaccine, ranging from 0.3 to 60 microg, followed by a booster dose of 30 microg, in a placebo-controlled study. Although priming doses of the CMRI vaccine did not induce a specific antibody detectable by enzyme-linked immunosorbent assay, booster vaccination stimulated the production of significant levels of anti-C. burnetii antibody. Peripheral blood cells (PBCs) of vaccinees responded to C. burnetii cellular antigen in vitro in a vaccine dose-dependent manner. After the booster dose, PBCs were activated by recall antigen in vitro, regardless of the priming dose. These findings suggest that vaccination with the CMRI vaccine can effectively prime the immune system to mount significant anamnestic responses after infection.

Low-Dose Priming before Vaccination with the Phase I Chloroform-Methanol Residue Vaccine against Q Fever Enhances Humoral and Cellular Immune Responses to Coxiella burnetii▿

PubMed Central

Waag, David M.; England, Marilyn J.; Bolt, Christopher R.; Williams, Jim C.

2008-01-01

Although the phase I Coxiella burnetii cellular vaccine is completely efficacious in humans, adverse local and systemic reactions may develop if immune individuals are inadvertently vaccinated. The phase I chloroform-methanol residue (CMRI) vaccine was developed as a potentially safer alternative. Human volunteers with no evidence of previous exposure to C. burnetii received a subcutaneous vaccination with the CMRI vaccine in phase I studies under protocol IND 3516 to evaluate the safety and immunogenicity of the vaccine. This clinical trial tested escalating doses of the CMRI vaccine, ranging from 0.3 to 60 μg, followed by a booster dose of 30 μg, in a placebo-controlled study. Although priming doses of the CMRI vaccine did not induce a specific antibody detectable by enzyme-linked immunosorbent assay, booster vaccination stimulated the production of significant levels of anti-C. burnetii antibody. Peripheral blood cells (PBCs) of vaccinees responded to C. burnetii cellular antigen in vitro in a vaccine dose-dependent manner. After the booster dose, PBCs were activated by recall antigen in vitro, regardless of the priming dose. These findings suggest that vaccination with the CMRI vaccine can effectively prime the immune system to mount significant anamnestic responses after infection. PMID:18701647

Diuretic effects of medetomidine compared with xylazine in healthy dogs

PubMed Central

Talukder, Md. Hasanuzzaman; Hikasa, Yoshiaki

2009-01-01

This study aimed to investigate and compare the effects of medetomidine and xylazine on diuretic and hormonal variables in healthy dogs. Five dogs, used in each of 11 groups, were injected intramuscularly with physiological saline solution (control), 5, 10, 20, 40, and 80 μg/kg of medetomidine, and 0.25, 0.5, 1, 2, and 4 mg/kg of xylazine. Urine and blood samples were taken 11 times over 24 h. Both medetomidine and xylazine increased urine production in a dose-dependent manner up to 4 h after injection, but the increase was much less with medetomidine than with xylazine at the tested doses. Urine specific gravity, pH, osmolality, and concentrations of creatinine, sodium, potassium, chloride, and arginine vasopressin (AVP) were decreased in a dose-dependent manner with both medetomidine and xylazine. Plasma osmolality and concentrations of sodium, potassium, and chloride were increased significantly with both drugs. Total amounts of urine AVP excreted and plasma AVP concentrations were significantly decreased by higher doses of medetomidine but were not significantly decreased by xylazine. Higher doses of both drugs significantly increased the plasma concentration of atrial natriuretic peptide (ANP), but the effect was greater with medetomidine than with xylazine. The results revealed that both drugs induce a profound diuresis, but medetomidine’s effect is less dose-dependent than xylazine’s effect. Although changes in plasma concentrations of AVP and ANP may partially influence the diuresis induced by medetomidine, other factors may be involved in the mechanism of the diuretic response to both drugs. Thus, both agents can be used clinically for transient but effective diuresis accompanied by sedation. PMID:19794896

Haloperidol dose combined with dexamethasone for PONV prophylaxis in high-risk patients undergoing gynecological laparoscopic surgery: a prospective, randomized, double-blind, dose-response and placebo-controlled study.

PubMed

Joo, Jin; Park, Yong Gyu; Baek, Jungwon; Moon, Young Eun

2015-07-08

Low-dose haloperidol is known to be effective for the prevention of postoperative nausea and vomiting (PONV). However, precise dose-response studies have not been completed, especially in patients at high risk for PONV who require combination therapy. This study sought to identify which dose of haloperidol 1mg or 2mg could be combined with dexamethasone without adverse effects in high-risk patients undergoing gynecological laparoscopic surgery. Female adults (n = 150) with three established PONV risk factors based on Apfel's score were randomized into one of three study groups. At the end of anesthesia, groups H0, H1, and H2 were given intravenous (IV) saline, haloperidol 1 mg, and haloperidol 2 mg, respectively. All patients were given dexamethasone 5 mg during the induction of anesthesia. The overall early (0-2 h) and late (2-24 h) incidences of nausea, vomiting, rescue anti-emetic administration, pain, and adverse effects (cardiac arrhythmias and extrapyramidal effects) were assessed postoperatively. The sedation score was recorded in the postanesthesia care unit (PACU). The total incidence of PONV over 24 h was significantly lower in groups H1 (29 %) and H2 (24 %) than in group H0 (54 %; P = 0.003), but there was no significant difference between groups H1 and H2. In the PACU, group H2 had a higher sedation score than groups H1 and H0 (P < 0.001). For high-risk PONV patients undergoing gynecological laparoscopic surgery, when used with dexamethasone, 1-mg haloperidol was equally effective as 2 mg in terms of preventing PONV with the less sedative effect. ClinicalTrials.gov ( NCT01639599 ).

Dose-response study of spinal hyperbaric ropivacaine for cesarean section

PubMed Central

Chen, Xin-zhong; Chen, Hong; Lou, Ai-fei; Lü, Chang-cheng

2006-01-01

Background: Spinal hyperbaric ropivacaine may produce more predictable and reliable anesthesia than plain ropivacaine for cesarean section. The dose-response relation for spinal hyperbaric ropivacaine is undetermined. This double-blind, randomized, dose-response study determined the ED50 (50% effective dose) and ED95 (95% effective dose) of spinal hyperbaric ropivacaine for cesarean section anesthesia. Methods: Sixty parturients undergoing elective cesarean section delivery with use of combined spinal-epidural anesthesia were enrolled in this study. An epidural catheter was placed at the L1~L2 vertebral interspace, then lumbar puncture was performed at the L3~L4 vertebral interspace, and parturients were randomized to receive spinal hyperbaric ropivacaine in doses of 10.5 mg, 12 mg, 13.5 mg, or 15 mg in equal volumes of 3 ml. Sensory levels (pinprick) were assessed every 2.5 min until a T7 level was achieved and motor changes were assessed by modified Bromage Score. A dose was considered effective if an upper sensory level to pin prick of T7 or above was achieved and no intraoperative epidural supplement was required. ED50 and ED95 were determined with use of a logistic regression model. Results: ED50 (95% confidence interval) of spinal hyperbaric ropivacaine was determined to be 10.37 (5.23~11.59) mg and ED95 (95% confidence interval) to be 15.39 (13.81~23.59) mg. The maximum sensory block levels and the duration of motor block and the rate of hypotension, but not onset of anesthesia, were significantly related to the ropivacaine dose. Conclusion: The ED50 and ED95 of spinal hyperbaric ropivacaine for cesarean delivery under the conditions of this study were 10.37 mg and 15.39 mg, respectively. Ropivacaine is suitable for spinal anesthesia in cesarean delivery. PMID:17111469

Physiological responses and toxin production of Microcystis aeruginosa in short-term exposure to solar UV radiation.

PubMed

Hernando, Marcelo; Minaglia, Melina Celeste Crettaz; Malanga, Gabriela; Houghton, Christian; Andrinolo, Darío; Sedan, Daniela; Rosso, Lorena; Giannuzzi, Leda

2018-01-17

The aim of this study was to evaluate the effects of short-term (hours) exposure to solar UV radiation (UVR, 280-400 nm) on the physiology of Microcystis aeruginosa. Three solar radiation treatments were implemented: (i) PAR (PAR, 400-700 nm), (ii) TUVA (PAR + UVAR, 315-700 nm) and (iii) TUVR (PAR + UVAR + UVBR, 280-700 nm). Differential responses of antioxidant enzymes and the reactive oxygen species (ROS) production to UVR were observed. Antioxidant enzymes were more active at high UVR doses. However, different responses were observed depending on the exposure to UVAR or UVBR and the dose level. No effects were observed on the biomass, ROS production or increased activity of superoxide dismutase (SOD) and catalase (CAT) compared to the control when UVR + PAR doses were lower than 9875 kJ m -2 . For intermediate doses, UVR + PAR doses between 9875 and 10 275 kJ m -2 , oxidative stress increased while resistance was imparted through SOD and CAT in the cells exposed to UVAR. Despite the increased antioxidant activity, biomass decrease and photosynthesis inhibition were observed, but no effects were observed with added exposure to UVBR. At the highest doses (UVR + PAR higher than 10 275 kJ m -2 ), the solar UVR caused decreased photosynthesis and biomass with only activation of CAT by UVBR and SOD and CAT by UVAR. In addition, for such doses, a significant decrease of microcystins (MCs, measured as MC-LR equivalents) was observed as a consequence of UVAR. This study facilitates our understanding of the SOD and CAT protection according to UVAR and UVBR doses and cellular damage and reinforces the importance of UVR as an environmental stressor. In addition, our results support the hypothesized antioxidant function of MCs.

The dose-response of salvage radiotherapy following radical prostatectomy: A systematic review and meta-analysis.

PubMed

King, Christopher R

2016-11-01

To date neither the optimal radiotherapy dose nor the existence of a dose-response has been established for salvage RT (SRT). A systematic review from 1996 to 2015 and meta-analysis was performed to identify the pathologic, clinical and treatment factors associated with relapse-free survival (RFS) after SRT (uniformly defined as a PSA>0.2ng/mL or rising above post-SRT nadir). A sigmoidal dose-response curve was objectively fitted and a non-parametric statistical test used to determine significance. 71 studies (10,034 patients) satisfied the meta-analysis criteria. SRT dose (p=0.0001), PSA prior to SRT (p=0.0009), ECE+ (p=0.039) and SV+ (p=0.046) had significant associations with RFS. Statistical analyses confirmed the independence of SRT dose-response. Omission of series with ADT did not alter results. Dose-response is well fit by a sigmoidal curve (p=0.0001) with a TCD 50 of 65.8Gy, with a dose of 70Gy achieving 58.4% RFS vs. 38.5% for 60Gy. A 2.0% [95% CI 1.1-3.2] improvement in RFS is achieved for each Gy. The SRT dose-response remarkably parallels that for definitive RT of localized disease. This study provides level 2a evidence for dose-escalated SRT>70Gy. The presence of an SRT dose-response for microscopic disease supports the hypothesis that prostate cancer is inherently radio-resistant. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Proton Radiotherapy for Solid Tumors of Childhood

PubMed Central

Cotter, Shane E.; McBride, Sean M.; Yock, Torunn I.

2012-01-01

The increasing efficacy of pediatric cancer therapy over the past four decades has produced many long-term survivors that now struggle with serious treatment related morbidities affecting their quality of life. Radiation therapy is responsible for a significant proportion of these late effects, but a relatively new and emerging modality, proton radiotherapy hold great promise to drastically reduce these treatment related late effects in long term survivors by sparing dose to normal tissues. Dosimetric studies of proton radiotherapy compared with best available photon based treatment show significant dose sparing to developing normal tissues. Furthermore, clinical data are now emerging that begin to quantify the benefit in decreased late treatment effects while maintaining excellent cancer control rates. PMID:22417062

NEUROTOXIC EFFECTS OF ENVIRONMENTAL AGENTS: DATA GAPS THAT CHALLENGE DOSE-RESPONSE ESTIMATION

EPA Science Inventory

Neurotoxic effects of environmental agents: Data gaps that challenge dose-response estimation
S Gutter*, P Mendola+, SG Selevan**, D Rice** (*UNC Chapel Hill; +US EPA, NHEERL; **US EPA, NCEA)

Dose-response estimation is a critical feature of risk assessment. It can be...

The antagonistic effects of atipamezole and yohimbine on stress-related neurohormonal and metabolic responses induced by medetomidine in dogs

PubMed Central

Ambrisko, T. D.; Hikasa, Y.

2003-01-01

This study aimed to compare the antagonistic effects of atipamezole (40, 120, and 320 μg/kg, IM), yohimbine (110 μg/kg, IM), and saline on neurohormonal and metabolic responses induced by medetomidine (20 μg/kg, IM). Five beagle dogs were used in each of the 5 experimental groups in randomized order. Blood samples were taken for 6 h. Medetomidine significantly decreased norepinephrine, epinephrine, insulin, and nonesterified fatty acid levels, and increased plasma glucose levels. Both atipamezole and yohimbine antagonized these effects. The reversal effect of atipamezole was dose-dependency, except on epinephrine. Yohimbine caused prolonged increases in plasma norepinephrine and insulin levels compared to atipamezole, possibly because of its longer half-life elimination. Only yohimbine increased the cortisol levels. Neither glucagon nor lactate levels changed significantly. Based on these findings, when medetomidine-induced sedation is antagonized in dogs, we recommend using atipamezole IM, from 2- to 6-fold the dose of medetomidine, unless otherwise indicated. PMID:12528832

Theoretical models and simulation codes to investigate bystander effects and cellular communication at low doses

NASA Astrophysics Data System (ADS)

Ballarini, F.; Alloni, D.; Facoetti, A.; Mairani, A.; Nano, R.; Ottolenghi, A.

Astronauts in space are continuously exposed to low doses of ionizing radiation from Galactic Cosmic Rays During the last ten years the effects of low radiation doses have been widely re-discussed following a large number of observations on the so-called non targeted effects in particular bystander effects The latter consist of induction of cytogenetic damage in cells not directly traversed by radiation most likely as a response to molecular messengers released by directly irradiated cells Bystander effects which are observed both for lethal endpoints e g clonogenic inactivation and apoptosis and for non-lethal ones e g mutations and neoplastic transformation tend to show non-linear dose responses This might have significant consequences in terms of low-dose risk which is generally calculated on the basis of the Linear No Threshold hypothesis Although the mechanisms underlying bystander effects are still largely unknown it is now clear that two types of cellular communication i e via gap junctions and or release of molecular messengers into the extracellular environment play a fundamental role Theoretical models and simulation codes can be of help in elucidating such mechanisms In the present paper we will review different available modelling approaches including one that is being developed at the University of Pavia The focus will be on the different assumptions adopted by the various authors and on the implications of such assumptions in terms of non-targeted radiobiological damage and more generally low-dose

Effect of terfenadine on nasal, eustachian tube, and pulmonary function after provocative intranasal histamine challenge.

PubMed

Skoner, D P; Doyle, W J; Boehm, S; Fireman, P

1991-12-01

Previous studies have documented that intranasal histamine challenge results in nasal and eustachian tube obstruction (ETO) in human volunteers. The purpose of the present study was to assess the effect of pretreatment with terfenadine, a nonsedating antihistamine on the pathophysiologic consequences of intranasal histamine challenge. Fifteen subjects with allergic rhinitis were challenged intranasally with saline and increasing histamine doses (0.01, 0.1, 0.5, 1.0, 5.0, and 10.0 mg) before pretreatment (baseline) and after 1 week of pretreatment with terfenadine, 60 mg b.i.d., terfenadine, 120 mg b.i.d., and placebo. Nasal conductance as measured by posterior rhinomanometry showed a dose-dependent, monotonic decrease following sequential administration of the histamine solutions, but there were no apparent differences in the average responses among the four challenge sessions. The frequency of ETO after histamine challenge was decreased by pretreatment with both doses of terfenadine, although this was not significant. Histamine-induced sneezing and rhinorrhea, but not congestion, were significantly reduced by terfenadine pretreatment. There was no evidence of extension of the histamine effects to the lower airway. The results of the present study suggest that terfenadine, a nonsedating antihistamine, had a favorable effect on sneezing and rhinorrhea after provocative intranasal histamine challenge, but did not significantly attenuate the subjective or objective nasal and ET obstructive responses.

The hydroalcoholic extract of Salvia elegans induces anxiolytic- and antidepressant-like effects in rats.

PubMed

Mora, S; Millán, R; Lungenstrass, H; Díaz-Véliz, G; Morán, J A; Herrera-Ruiz, M; Tortoriello, J

2006-06-15

Behavioral effects of a hydroalcoholic (60% ethanol) extract from the leaves of Salvia elegans Vahl (Lamiaceae) were studied in male Sprague-Dawley rats. The extract was administered intraperitoneally and its effects on spontaneous motor activity (total motility, locomotion, rearing and grooming behavior) were monitored. Putative anxiolytic and antidepressant properties of Salvia elegans were studied in the elevated plus-maze test (EPM) and in the forced swimming test (FST), respectively. Deleterious effects of Salvia elegans on learning and memory were also studied by using active and passive avoidance paradigms. The results revealed that all doses (3.12, 12.5, 25 and 50 mg/kg) of the extract caused a significant decrease in total motility, locomotion, rearing and grooming behavior. Only the dose of 12.5 mg/kg increased the exploration of the EPM open arms in a similar way to that of diazepam (1 mg/kg). In the FST, all doses of the extract induced a reduction of immobility, in a similar way to that of fluoxetine (10 mg/kg) and imipramine (12.5 mg/kg), along with a significant increase in the time spent in swimming behavior. Acquisition of active avoidance responses was disrupted by pre-treatment with the extract, but retention of a passive avoidance response was not significantly modified. These results suggest that some of the components of the hydroalcoholic extract of Salvia elegans have psychotropic properties, which deserve further investigation.

Early and long term anamnestic response to HBV booster dose among fully vaccinated Egyptian children during infancy.

PubMed

Salama, Iman I; Sami, Samia M; Said, Zeinab N; Salama, Somaia I; Rabah, Thanaa M; Abdel-Latif, Ghada A; Elmosalami, Dalia M; Saleh, Rehan M; Abdel Mohsin, Aida M; Metwally, Ammal M; Hassanin, Amal I; Emam, Hanaa M; Hemida, Samia A; Elserougy, Safaa M; Shaaban, Fatma A; Fouad, Walaa A; Mohsen, Amira; El-Sayed, Manal H

2018-04-05

To evaluate early and long term anamnestic response to a booster dose of HBV vaccine among non-seroprotected children. A national community based project was carried out on 3600 children aged 9 months to 16 years, fully vaccinated during infancy. They were recruited from 6 governorates representing Egypt. It revealed that 1535 children (42.8%) had non sero-protective anti-HBs (<10 IU/L) and were HBsAg or anti-HBc negative. A challenging dose of 10 μg of mono-valent Euvax HBV vaccine was given to 1121/1535 children. Quantitative assessment of anti-HBs was performed to detect early (2-4 weeks) and long term (one year) anamnestic responses. Early anamnestic response developed among 967/1070 children (90.3%).Children having detectable anti-HBs (1-9 IU/L) significantly developed early anamnestic response (90%) compared to 85% with undetectable anti-HBs (<1 IU/L), P < 0.001. Multiple logistic analysis revealed that undetectable anti-HBs, living in rural residence and children aged 15-16 years were the most significant predicting risk factors for the absence of early anamnestic response (<10 IU/L), with AOR 2.7, 2.7 & 4.7 respectively. After one year, long term anamnestic response was absent among 15% of children who previously showed early response. Poor early anamnestic response and undetectable pre-booster anti-HBs were the significant predicting risk factors for absent long term anamnestic response, with AOR 18.7 & 2.7 respectively. Immunological memory for HBV vaccine outlasts the presence of anti- HBs and HBV vaccination program provides effective long term protection even in children showing waning or undetectable concentrations of anti-HBs. This signifies no need for a booster dose especially to healthy children. Copyright © 2018 Elsevier Ltd. All rights reserved.

Photobiomodulation of distinct lineages of human dermal fibroblasts: a rational approach towards the selection of effective light parameters for skin rejuvenation and wound healing

NASA Astrophysics Data System (ADS)

Mignon, Charles; Uzunbajakava, Natallia E.; Raafs, Bianca; Moolenaar, Mitchel; Botchkareva, Natalia V.; Tobin, Desmond J.

2016-03-01

Distinct lineages of human dermal fibroblasts play complementary roles in skin rejuvenation and wound healing, which makes them a target of phototherapy. However, knowledge about differential responses of specific cell lineages to different light parameters and moreover the actual molecular targets remain to be unravelled. The goal of this study was to investigate the impact of a range of parameters of light on the metabolic activity, collagen production, and cell migration of distinct lineages of human dermal fibroblasts. A rational approach was used to identify parameters with high therapeutic potential. Fibroblasts exhibited both inhibitory and cytotoxic change when exposed to a high dose of blue and cyan light in tissue culture medium containing photo-reactive species, but were stimulated by high dose red and near infrared light. Cytotoxic effects were eliminated by refreshing the medium after light exposure by removing potential ROS formed by extracellular photo-reactive species. Importantly, distinct lineages of fibroblasts demonstrated opposite responses to low dose blue light treatment when refreshing the medium after exposure. Low dose blue light treatment also significantly increased collagen production by papillary fibroblasts; high dose significantly retarded closure of the scratch wound without signs of cytotoxicity, and this is likely to have involved effects on both cell migration and proliferation. We recommend careful selection of fibroblast subpopulations and their culture conditions, a systematic approach in choosing and translating treatment parameters, and pursuit of fundamental research on identification of photoreceptors and triggered molecular pathways, while seeking effective parameters to address different stages of skin rejuvenation and wound healing.

Hypoalgesia in response to transcutaneous electrical nerve stimulation (TENS) depends on stimulation intensity.

PubMed

Moran, Fidelma; Leonard, Tracey; Hawthorne, Stephanie; Hughes, Ciara M; McCrum-Gardner, Evie; Johnson, Mark I; Rakel, Barbara A; Sluka, Kathleen A; Walsh, Deirdre M

2011-08-01

Transcutaneous electrical nerve stimulation (TENS) is an electrophysical modality used for pain management. This study investigated the dose response of different TENS intensities on experimentally induced pressure pain. One hundred and thirty TENS naïve healthy individuals (18-64 years old; 65 males, 65 females) were randomly allocated to 5 groups (n = 26 per group): Strong Non Painful TENS; Sensory Threshold TENS; Below Sensory Threshold TENS; No Current Placebo TENS; and Transient Placebo TENS. Active TENS (80 Hz) was applied to the forearm for 30 minutes. Transient Placebo TENS was applied for 42 seconds after which the current amplitude automatically reset to 0 mA. Pressure pain thresholds (PPT) were recorded from 2 points on the hand and forearm before and after TENS to measure hypoalgesia. There were significant differences between groups at both the hand and forearm (ANOVA; P = .005 and .002). At 30 minutes, there was a significant hypoalgesic effect in the Strong Non Painful TENS group compared to: Below Sensory Threshold TENS, No Current Placebo TENS and Transient Placebo TENS groups (P < .0001) at the forearm; Transient Placebo TENS and No Current Placebo TENS groups at the hand (P = .001). There was no significant difference between Strong Non Painful TENS and Sensory Threshold TENS groups. The area under the curve for the changes in PPT significantly correlated with the current amplitude (r(2) = .33, P = .003). These data therefore show that there is a dose-response effect of TENS with the largest effect occurring with the highest current amplitudes. This study shows a dose response for the intensity of TENS for pain relief with the strongest intensities showing the greatest effect; thus, we suggest that TENS intensity should be titrated to achieve the strongest possible intensity to achieve maximum pain relief. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

Evaluation of the annual Canadian biodosimetry network intercomparisons

PubMed Central

Wilkins, Ruth C.; Beaton-Green, Lindsay A.; Lachapelle, Sylvie; Kutzner, Barbara C.; Ferrarotto, Catherine; Chauhan, Vinita; Marro, Leonora; Livingston, Gordon K.; Boulay Greene, Hillary; Flegal, Farrah N.

2015-01-01

Abstract Purpose: To evaluate the importance of annual intercomparisons for maintaining the capacity and capabilities of a well-established biodosimetry network in conjunction with assessing efficient and effective analysis methods for emergency response. Materials and methods: Annual intercomparisons were conducted between laboratories in the Canadian National Biological Dosimetry Response Plan. Intercomparisons were performed over a six-year period and comprised of the shipment of 10–12 irradiated, blinded blood samples for analysis by each of the participating laboratories. Dose estimates were determined by each laboratory using the dicentric chromosome assay (conventional and QuickScan scoring) and where possible the cytokinesis block micronucleus (CBMN) assay. Dose estimates were returned to the lead laboratory for evaluation and comparison. Results: Individual laboratories performed comparably from year to year with only slight fluctuations in performance. Dose estimates using the dicentric chromosome assay were accurate about 80% of the time and the QuickScan method for scoring the dicentric chromosome assay was proven to reduce the time of analysis without having a significant effect on the dose estimates. Although analysis with the CBMN assay was comparable to QuickScan scoring with respect to speed, the accuracy of the dose estimates was greatly reduced. Conclusions: Annual intercomparisons are necessary to maintain a network of laboratories for emergency response biodosimetry as they evoke confidence in their capabilities. PMID:25670072

Evaluation of growth hormone treatment efficacy in short Japanese children born small for gestational age: Five-year treatment outcome and impact on puberty

PubMed Central

Horikawa, Reiko; Tanaka, Toshiaki; Nishinaga, Hiromi; Ogawa, Yoshihisa; Yokoya, Susumu

2017-01-01

Abstract. Some children born small for gestational age (SGA) have short stature and are at an increased risk of developing psychosocial or behavioral problems. Here we evaluated the efficacy of GH and its effects on the timing of pubertal onset in a 3-yr extension of our previous 2-yr (total 5 yr) multicenter, randomized, double-blind, parallel-group clinical trial of 65 short Japanese children born SGA. Patients received low or high doses of GH (0.033 or 0.067 mg/kg/day, respectively). Age at onset of puberty was not statistically different for male and female patients receiving high- or low-dose GH. After the onset of puberty, no difference in height gain was observed between the two GH dose groups. At the onset of puberty, height standard deviation scores for chronological age of boys and girls improved significantly in both dose groups with evidence of a dose-response effect. Mean bone age/chronological age ratios in the low- and high-dose groups were significantly increased compared with baseline, being significantly greater in the high-dose group at 5 yr after treatment initiation. Delayed bone age at baseline was close to chronological age following GH treatment. GH treatment, especially high-dose GH, induced advanced bone age in short children born SGA. PMID:28458458

DOE Office of Scientific and Technical Information (OSTI.GOV)

Medin, Paul M., E-mail: Paul.medin@utsouthwestern.ed; Boike, Thomas P.

Clinical implementation of spinal radiosurgery has increased rapidly in recent years, but little is known regarding human spinal cord tolerance to single-fraction irradiation. In contrast, preclinical studies in single-fraction spinal cord tolerance have been ongoing since the 1970s. The influences of field length, dose rate, inhomogeneous dose distributions, and reirradiation have all been investigated. This review summarizes literature regarding single-fraction spinal cord tolerance in preclinical models with an emphasis on practical clinical significance. The outcomes of studies that incorporate uniform irradiation are surprisingly consistent among multiple small- and large-animal models. Extensive investigation of inhomogeneous dose distributions in the rat hasmore » demonstrated a significant dose-volume effect while preliminary results from one pig study are contradictory. Preclinical spinal cord dose-volume studies indicate that dose distribution is more critical than the volume irradiated suggesting that neither dose-volume histogram analysis nor absolute volume constraints are effective in predicting complications. Reirradiation data are sparse, but results from guinea pig, rat, and pig studies are consistent with the hypothesis that the spinal cord possesses a large capacity for repair. The mechanisms behind the phenomena observed in spinal cord studies are not readily explained and the ability of dose response models to predict outcomes is variable underscoring the need for further investigation. Animal studies provide insight into the phenomena and mechanisms of radiosensitivity but the true significance of animal studies can only be discovered through clinical trials.« less

Green tea polyphenol (−)-epigallocatechin-3-gallate triggered hepatotoxicity in mice: Responses of major antioxidant enzymes and the Nrf2 rescue pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Dongxu; Wang, Yijun; Wan, Xiaochun

(−)-Epigallocatechin-3-gallate (EGCG), a constituent of green tea, has been suggested to have numerous health-promoting effects. On the other hand, high-dose EGCG is able to evoke hepatotoxicity. In the present study, we elucidated the responses of hepatic major antioxidant enzymes and nuclear factor erythroid 2-related factor 2 (Nrf2) rescue pathway to high-dose levels of EGCG in Kunming mice. At a non-lethal toxic dose (75 mg/kg, i.p.), repeated EGCG treatments markedly decreased the levels of superoxide dismutase, catalase, and glutathione peroxidase. As a rescue response, the nuclear distribution of Nrf2 was significantly increased; a battery of Nrf2-target genes, including heme oxygenase 1more » (HO1), NAD(P)H:quinone oxidoreductase 1 (NQO1), glutathione S-transferase (GST), and those involved in glutathione and thioredoxin systems, were all up-regulated. At the maximum tolerated dose (45 mg/kg, i.p.), repeated EGCG treatments did not disturb the major antioxidant defense. Among the above-mentioned genes, only HO1, NQO1, and GST genes were significantly but modestly up-regulated, suggesting a comprehensive and extensive activation of Nrf2-target genes principally occurs at toxic levels of EGCG. At a lethal dose (200 mg/kg, i.p.), a single EGCG treatment dramatically decreased not only the major antioxidant defense but also the Nrf2-target genes, demonstrating that toxic levels of EGCG are able to cause a biphasic response of Nrf2. Overall, the mechanism of EGCG-triggered hepatotoxicity involves suppression of major antioxidant enzymes, and the Nrf2 rescue pathway plays a vital role for counteracting EGCG toxicity. - Highlights: • EGCG at maximum tolerated dose does not disturb hepatic major antioxidant defense. • EGCG at maximum tolerated dose modestly upregulates hepatic Nrf2 target genes. • EGCG at toxic dose suppresses hepatic major antioxidant enzymes. • EGCG at non-lethal toxic dose pronouncedly activates hepatic Nrf2 rescue response. • EGCG at lethal dose substantially suppresses hepatic Nrf2 pathway.« less

Egg intake and cancers of the breast, ovary and prostate: a dose-response meta-analysis of prospective observational studies.

PubMed

Keum, N; Lee, D H; Marchand, N; Oh, H; Liu, H; Aune, D; Greenwood, D C; Giovannucci, E L

2015-10-14

Evidence suggests that egg intake may be implicated in the aetiology of sex hormone-related cancers. However, dose-response relationships between egg intake and such cancers are unclear. Thus, we conducted a dose-response meta-analysis to summarise the dose-response relationships between egg consumption and the risk of breast, prostate and gynaecological cancers. A literature search was performed using PubMed and Embase up to April 2015 to identify relevant prospective observational studies. Summary relative risk (RR) and 95% CI were estimated using a random-effects model. For breast cancer, the linear dose-response meta-analysis found a non-significantly increased risk (RR for an increase of 5 eggs consumed/week: 1·05, 95% CI 0·99, 1·11, n 16,023 cases). Evidence for non-linearity was not statistically significant (P non-linearity= 0·50, n 15,415 cases) but consuming ≥ 5 eggs/week was significantly associated with an increased risk of breast cancer compared with no egg consumption, with the summary RR being 1·04 (95% CI 1·01, 1·07) for consuming 5 eggs/week and 1·09 (95% CI 1·03, 1·15) for consuming about 9 eggs/week. For other cancers investigated, the summary RR for an increase of 5 eggs consumed/week was 1·09 (95% CI 0·96, 1·24, n 2636 cases) for ovarian cancer; 1·47 (95% CI 1·01, 2·14, n 609 cases) for fatal prostate cancer, with evidence of small-study effects (P Egger= 0·04). No evidence was found for an association with the risk of total prostate cancer. While our conclusion was tempered by the potential for publication bias and confounding, high egg intake may be associated with a modestly elevated risk of breast cancer, and a positive association between egg intake and ovarian and fatal prostate cancers cannot be ruled out.

Dose-response-a challenge for allelopathy?

PubMed

Belz, Regina G; Hurle, Karl; Duke, Stephen O

2005-04-01

The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions.

Dose and dose rate effects of whole-body proton irradiation on leukocyte populations and lymphoid organs: part I

NASA Technical Reports Server (NTRS)

Gridley, Daila S.; Pecaut, Michael J.; Dutta-Roy, Radha; Nelson, Gregory A.

2002-01-01

The goal of part I of this study was to evaluate the effects of whole-body proton irradiation on lymphoid organs and specific leukocyte populations. C57BL/6 mice were exposed to the entry region of the proton Bragg curve to total doses of 0.5 gray (Gy), 1.5 Gy, and 3.0 Gy, each delivered at a low dose rate (LDR) of 1 cGy/min and high dose rate (HDR) of 80 cGy/min. Non-irradiated and 3 Gy HDR gamma-irradiated groups were included as controls. At 4 days post-irradiation, highly significant radiation dose-dependent reductions were observed in the mass of both lymphoid organs and the numbers of leukocytes and T (CD3(+)), T helper (CD3(+)/CD4(+)), T cytotoxic (CD3(+)/CD8(+)), and B (CD19(+)) cells in both blood and spleen. A less pronounced dose effect was noted for natural killer (NK1.1(+) NK) cells in spleen. Monocyte, but not granulocyte, counts in blood were highly dose-dependent. The numbers for each population generally tended to be lower with HDR than with LDR radiation; a significant dose rate effect was found in the percentages of T and B cells, monocytes, and granulocytes and in CD4(+):CD8(+) ratios. These data indicate that mononuclear cell response to the entry region of the proton Bragg curve is highly dependent upon the total dose and that dose rate effects are evident with some cell types. Results from gamma- and proton-irradiated groups (both at 3 Gy HDR) were similar, although proton-irradiation gave consistently lower values in some measurements.

Optimized dosing of a CCR2 antagonist for amplification of vaccine immunity.

PubMed

Mitchell, Leah A; Hansen, Ryan J; Beaupre, Adam J; Gustafson, Daniel L; Dow, Steven W

2013-02-01

We have recently discovered that inflammatory monocytes recruited to lymph nodes in response to vaccine-induced inflammation can function as potent negative regulators of both humoral and cell-mediated immune responses to vaccination. Monocyte depletion or migration blockade can significantly amplify both antibody titers and cellular immune responses to vaccination with several different antigens in mouse models. Thus, we hypothesized that the use of small molecule CCR2 inhibitors to block monocyte migration into lymph nodes may represent a broadly effective means of amplifying vaccine immunity. To address this question, the role of CCR2 in monocyte recruitment to vaccine draining lymph nodes was initially explored in CCR2-/- mice. Next, a small molecule antagonist of CCR2 (RS102895) was evaluated in mouse vaccination models. Initial studies revealed that a single intraperitoneal dose of RS102895 failed to effectively block monocyte recruitment following vaccination. Pharmacokinetic analysis of RS102895 revealed a short half-life (approximately 1h), and suggested that a multi-dose treatment regimen would be more effective. We found that administration of RS102895 every 6 h resulted in consistent plasma levels of 20 ng/ml or greater, which effectively blocked monocyte migration to lymph nodes following vaccination. Moreover, administration of RS102895 with concurrent vaccination markedly enhanced vaccine responses following immunization against the influenza antigen HA1. We concluded that administration of small molecule CCR2 antagonists such as RS102895 in the immediate post-vaccine period could be used as a novel means of significantly enhancing vaccine immunity. Copyright © 2012 Elsevier B.V. All rights reserved.

Sub-Chronic Safety Evaluation of Ayurvedic Immunostimulant Formulation ‘Immuforte’ in Rats in Reverse Pharmacology

PubMed Central

Dhumal, Rohit; Patil, Prakash; Selkar, Nilakash; Chawda, Mukesh; Vahlia, Mahesh; Vanage, Geeta

2013-01-01

Objective: The present study was undertaken to determine target organ safety of “Immuforte” to establish relationship between dose or exposure and response and also to identify potential parameters for monitoring adverse effects of “Immuforte” in clinical studies, if any. Materials and Methods: A total of 40 males and 40 females were randomly assigned to the four groups, namely group I (vehicle control; gum acacia), group II (120 mg/kg BW of Immuforte in gum acacia), group III (360 mg/kg BW of Immuforte in gum acacia), and group IV (600 mg/kg BW of Immuforte in gum acacia) consisting of 10 males and 10 females in each group. Additionally, a recovery group (600 mg/kg BW of Immuforte in gum acacia) containing 5 males and 5 females was included. Results: The results showed significant decrease in percent lymphocyte count of high and mid dose groups as compared to control group. The percent neutrophil counts in all the three treated groups of male and female rats were found to be significantly higher than that of control group (P < 0.05). In females MCV values in low dose and mid dose were significantly higher as compared to control (P < 0.05). The males from low dose group showed significant decrease in total serum protein, globulin, electrolytes, direct bilirubin, creatinine levels, whereas in mid dose group along with albumin, globulin. A significant decrease in AST and cholesterol was observed. In females, significant decrease was observed in total protein and globulin of low dose and mid dose of Immuforte-treated rats (P < 0.05). Though few hematological and biochemical parameters were different from control group, no does related response was observed and further, all these values were comparable with historical control data of the colony. Terminal body weight, organ weight, gross, and histopathology did not reveal any toxicity-related any adverse effects. Heavy metal analysis of the blood samples collected from terminally sacrificed animals did not show presence of heavy metals viz. lead (Pb), mercury (Hg), cadmium (Cd), and arsenic (As). Conclusion: The results of the present study demonstrated that Immuforte does not cause any observable toxicity at doses used in the study when administered for the period of 90 days and is safe for the human use and thus, Immuforte could be used safely for therapeutic use in humans. PMID:23833443

Pharmacokinetic–pharmacodynamic modelling in anaesthesia

PubMed Central

Gambús, Pedro L; Trocóniz, Iñaki F

2015-01-01

Anaesthesiologists adjust drug dosing, administration system and kind of drug to the characteristics of the patient. They then observe the expected response and adjust dosing to the specific requirements according to the difference between observed response, expected response and the context of the surgery and the patient. The approach above can be achieved because on one hand quantification technology has made significant advances allowing the anaesthesiologist to measure almost any effect by using noninvasive, continuous measuring systems. On the other the knowledge on the relations between dosing, concentration, biophase dynamics and effect as well as detection of variability sources has been achieved as being the benchmark specialty for pharmacokinetic–pharmacodynamic (PKPD) modelling. The aim of the review is to revisit the most common PKPD models applied in the field of anaesthesia (i.e. effect compartmental, turnover, drug–receptor binding and drug interaction models) through representative examples. The effect compartmental model has been widely used in this field and there are multiple applications and examples. The use of turnover models has been limited mainly to describe respiratory effects. Similarly, cases in which the dissociation process of the drug–receptor complex is slow compared with other processes relevant to the time course of the anaesthetic effect are not frequent in anaesthesia, where in addition to a rapid onset, a fast offset of the response is required. With respect to the characterization of PD drug interactions different response surface models are discussed. Relevant applications that have changed the way modern anaesthesia is practiced are also provided. PMID:24251846

Single dose x irradiation and concomitant hyperthermia on a murine fibroscarcoma. [Sensitizing effects of hyperthermia on tumors in mice subjected to local radiotherapy

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hahn, E.W.; Alfieri, A.A.; Kim, J.H.

1978-12-01

The objectives of this study were to quantitate the effects of local tumor hyperthermia (LTH) and concomitant x irradiation (RAD) on a moderately radioresistant murine fibrosarcoma in situ. Comparisons were made to the combined treatment response on the Ridgway osteogenic sarcoma, a radiosensitive tumor previously used in this laboratory and to establish the Meth-A fibrosarcoma as a model system for combined modality studies. 1.0 cm/sup 3/ tumors were exposed to single doses of RAD ranging from 0.5 to 3.8 krad alone or 0.5 to 2.3 krad in combination with LTH (water bath at 43.1 +- .05 C for 20 minutes)more » applied immediately postirradiation. LTH significantly enhanced the action of radiation as measured by tumor volume analysis, mean survival time and cures. The ratio of radiation doses vs. RAD + LTH required to produce an equivalent response ranged from 1.4 to 2.5 depending upon the endpoints evaluated. These findings are consistent with single dose studies on the radiosensitive Ridgway osteogenic sarcoma and suggest that the tumoricidal effectiveness of combination radiation and hyperthermia cannot be predicted on the basis of the radiation alone responsiveness of tumor.« less

Dose-Response Effect of Sunlight on Vitamin D2 Production in Agaricus bisporus Mushrooms.

PubMed

Urbain, Paul; Jakobsen, Jette

2015-09-23

The dose response effect of UV-B irradiation from sunlight on vitamin D2 content of sliced Agaricus bisporus (white button mushroom) during the process of sun-drying was investigated.Real-time UV-B and UV-A data were obtained using a high-performance spectroradiometer. During the first hour of sunlight exposure, the vitamin D2 content of the mushrooms increased in a linear manner, with concentrations increasing from 0.1 μg/g up to 3.9 ± 0.8 μg/g dry weight (DW). At the subsequent two measurements one and 3 h later, respectively, a plateau was reached. Two hours of additional exposure triggered a significant decline in vitamin D2 content. After just 15 min of sun exposure and an UV-B dose of 0.13 J/cm(2), the vitamin D2 content increased significantly to 2.2 ± 0.5 μg/g DW (P < 0.0001), which is equivalent to 17.6 μg (704 IU) vitamin D2 per 100 g of fresh mushrooms and comparable to levels found in fatty fish like the Atlantic salmon.

Neuroprotective Dose Response in RCS Rats Implanted with Microphotodiode Arrays

PubMed Central

Pardue, Machelle T.; Kim, Moon K.; Walker, Tiffany A.; Faulkner, Amanda E.; Chow, Alan Y.; Ciavatta, Vincent T.

2012-01-01

Purpose Neuropreservation of retinal function and structure in RCS rats following implantation of a microphotodiode array (MPA) has been shown in previous studies(Pardue et al. 2005a; Pardue et al. 2005b). Since microphotodiodes produce electrical currents in proportion to the intensity of incident light, increased light exposure may result in greater neuroprotective effects. Our previous studies suggested that the frequency of light exposure to electroretinogram (ERG) flash stimuli might provide increased neuroprotection. Thus, in this study, we examined the dose response of subretinal electrical stimulation by exposing RCS rats implanted with MPAs to variable durations and combinations of two different lighting regimens: pulsing incandescent bulbs and xenon stimuli from an ERG Ganzfeld. While incandescent light regimens did not produce any significant differences in ERG function, we found significantly greater dark-adapted ERG b-wave amplitudes in RCS rats that received weekly versus biweekly ERGs over the course of 8 weeks of follow-up. These results suggest that subretinal electrical stimulation may be optimized to produce greater neuroprotective effects by dosing with periodic higher current. PMID:22183323

Efficacy and Safety of OnabotulinumtoxinA Treatment of Forehead Lines: A Multicenter, Randomized, Dose-Ranging Controlled Trial.

PubMed

Solish, Nowell; Rivers, Jason K; Humphrey, Shannon; Muhn, Channy; Somogyi, Chris; Lei, Xiaofang; Bhogal, Meetu; Caulkins, Carrie

2016-03-01

Various onabotulinumtoxinA doses are effective in treating forehead lines (FHL), with a trend toward lower doses. To evaluate efficacy and safety of onabotulinumtoxinA dose-ranging treatment of FHL when the frontalis area and glabellar complex are treated together. Adults with moderate-to-severe FHL received onabotulinumtoxinA 40 U (FHL, 20 U; glabellar lines [GL], 20 U), 30 U (FHL, 10 U; GL, 20 U), or placebo. Response was assessed at weeks 1, 2, day 30, and monthly to day 180. Coprimary efficacy end points were investigator- and subject-assessed Facial Wrinkle Scale scores of none or mild (day 30). Patient-reported outcomes, onset/duration of effect, and adverse events (AEs) were evaluated. Responder rates (investigator/subject, respectively) were 40-U group, 91.2%/89.5%; 30-U group, 86.4%/81.4%; placebo, 1.7%/5.1%. OnabotulinumtoxinA resulted in significantly greater responder rates than placebo (p < .001). Adverse events were mild to moderate and similar between groups (most common AEs: nasopharyngitis [4.6%] and headache [4.0%]). Treatment of FHL with onabotulinumtoxinA 40 and 30 U (in frontalis and glabellar complex muscles) was tolerable, effective, and sustained. Both doses significantly reduced FHL severity; however, the 40-U dose demonstrated a trend toward greater sustained benefit and longer duration of effect versus the 30-U dose, with similar AE rates.

African Americans with LVH demonstrate depressed sensitivity of the coronary microcirculation to stimulated relaxation.

PubMed

Houghton, Jan Laws; Strogatz, David S; Torosoff, Mikhail T; Smith, Vivienne E; Fein, Steven A; Kuhner, Patricia A; Philbin, Edward F; Carr, Albert A

2003-09-01

Excess coronary heart disease morbidity and mortality among African Americans remains an important yet unexplained public health problem. We hypothesized that adverse outcome is in part due to intrinsic or acquired abnormalities in coronary endothelial function and vasoreactivity. We compared dose-response curves relating changes in coronary blood flow and epicardial diameter to graded infusions of acetylcholine in 50 African American and 65 white subjects with hypertensive left ventricular hypertrophy (LVH) and normal coronary arteries. These groups were similar for age, body mass index, mean arterial pressure, and indexed left ventricular mass. The same protocol was conducted in 24 normotensive African American and 56 similar white subjects. We found significant depression in the coronary blood flow dose-response curve relation among African Americans when compared with white subjects with similar LVH (P<0.03). Racial differences were observed at all doses of acetylcholine but were less precisely estimated at the highest dose. The same testing among normotensive subjects revealed similar dose-response curves with no significant effect of race. Qualitatively similar results were found with respect to coronary diameter. Adenosine responses, a measure of endothelium-independent function, were similar after partitioning by LVH. Our study demonstrates that there are racial differences in sensitivity of coronary arteries to acetylcholine-stimulated relaxation among those with LVH. These results provide a mechanism whereby racial differences in coronary vasoreactivity might contribute to adverse coronary heart disease outcome among African Americans, a group in whom LVH is prevalent.

Prenatal low-dose bisphenol A enhances behavioral responses induced by a predator odor.

PubMed

Fujimoto, Tetsuya; Kubo, Kazuhiko; Nishikawa, Yasuo; Aou, Shuji

2015-01-01

Bisphenol A (BPA) is an environmental endocrine disrupter (EED). Previous studies by our group showed that pre- and postnatal administration of low-level BPA induced depression-like behavior in rats. In this study, we evaluated the effects of prenatal BPA on behavioral responses to a predator odor by using a novel cross-form apparatus consisting of 4 plastic chambers. On the first day, nothing was placed into the chambers (Session 1). On the second day, a predator odor (fox odor) was located in separate chambers at 2 opposite corners of the apparatus (Session 2). Pregnant Wistar rats were exposed to low-dose BPA (less than the reference dose) during the 7 days just before birth, and the offspring of the treated rats were evaluated as adults. The locomotor activity and avoidance response of each rat on both test days were compared. The control and BPA groups showed reduced locomotor activity in the presence of the predator odor, but the odor-avoidance response was significant only in the BPA rats. The BPA-exposed rats were obviously sensitive to the predator odor. These results suggest that prenatal BPA exposure has an amplifying effect on avoidance responses to predator odor stress.

Predicting cancer rates in astronauts from animal carcinogenesis studies and cellular markers

NASA Technical Reports Server (NTRS)

Williams, J. R.; Zhang, Y.; Zhou, H.; Osman, M.; Cha, D.; Kavet, R.; Cuccinotta, F.; Dicello, J. F.; Dillehay, L. E.

1999-01-01

The radiation space environment includes particles such as protons and multiple species of heavy ions, with much of the exposure to these radiations occurring at extremely low average dose-rates. Limitations in databases needed to predict cancer hazards in human beings from such radiations are significant and currently do not provide confidence that such predictions are acceptably precise or accurate. In this article, we outline the need for animal carcinogenesis data based on a more sophisticated understanding of the dose-response relationship for induction of cancer and correlative cellular endpoints by representative space radiations. We stress the need for a model that can interrelate human and animal carcinogenesis data with cellular mechanisms. Using a broad model for dose-response patterns which we term the "subalpha-alpha-omega (SAO) model", we explore examples in the literature for radiation-induced cancer and for radiation-induced cellular events to illustrate the need for data that define the dose-response patterns more precisely over specific dose ranges, with special attention to low dose, low dose-rate exposure. We present data for multiple endpoints in cells, which vary in their radiosensitivity, that also support the proposed model. We have measured induction of complex chromosome aberrations in multiple cell types by two space radiations, Fe-ions and protons, and compared these to photons delivered at high dose-rate or low dose-rate. Our data demonstrate that at least three factors modulate the relative efficacy of Fe-ions compared to photons: (i) intrinsic radiosensitivity of irradiated cells; (ii) dose-rate; and (iii) another unspecified effect perhaps related to reparability of DNA lesions. These factors can produce respectively up to at least 7-, 6- and 3-fold variability. These data demonstrate the need to understand better the role of intrinsic radiosensitivity and dose-rate effects in mammalian cell response to ionizing radiation. Such understanding is critical in extrapolating databases between cellular response, animal carcinogenesis and human carcinogenesis, and we suggest that the SAO model is a useful tool for such extrapolation.

Effect of peptide YY on gastric, pancreatic, and biliary function in humans.

PubMed

Adrian, T E; Savage, A P; Sagor, G R; Allen, J M; Bacarese-Hamilton, A J; Tatemoto, K; Polak, J M; Bloom, S R

1985-09-01

The effect of peptide YY (PYY) on gastric and pancreatico-biliary secretion was studied in humans. Peptide YY was infused into groups of 6 healthy volunteers at doses of 0.59, 0.20, and 0.064 pmol X kg-1 X min-1. The two higher doses caused a significant suppression of gastric acid and pepsin output during background stimulation with pentagastrin. The middle dose of PYY (0.20 pmol X kg-1 X min-1) that increased plasma PYY levels by 27 +/- 2 pM caused a 90% +/- 18% (mean +/- SEM; p less than 0.001) reduction in the incremental gastric volume response to pentagastrin. Similarly this dose of PYY caused a substantial inhibition of the acid (77% +/- 14%; p less than 0.005) and pepsin (96% +/- 22%; p less than 0.01) response to pentagastrin; in 2 subjects, pepsin output fell to below basal levels. In contrast, the highest dose of PYY (0.62 pmol X kg-1 X min-1) had no significant influence on duodenal juice volume, output of bicarbonate, trypsin, or bilirubin during low dose stimulation with secretin (0.25 pmol X kg-1 X min-1) and cholecystokinin-8 (0.15 pmol X kg-1 X min-1). Thus PYY concentrations in the circulation similar to those seen after the ingestion of food cause a marked reduction in gastric secretion. This peptide should therefore be considered as one of the possible candidates for the classical enterogastrone.

Low doses of fludrocortisone and hydrocortisone, alone or in combination, on vascular responsiveness to phenylephrine in healthy volunteers

PubMed Central

Laviolle, Bruno; Donal, Erwan; Le Maguet, Pascale; Lainé, Fabrice; Bellissant, Eric

2013-01-01

Aims A single administration of hydrocortisone has been shown to enhance the pressor response to phenylephrine in healthy volunteers and to norepinephrine in septic shock patients. Similar data do not exist for fludrocortisone. Since there continues to be disagreement about the utility of fludrocortisone in septic shock, we assessed the effects of a single administration of low doses of hydrocortisone (50 mg intravenously) and fludrocortisone (50 μg orally), given either alone or in combination, on phenylephrine mean arterial pressure and cardiac systolic and diastolic function dose–response relationships in 12 healthy male volunteers with hypo-aldosteronism induced by intravenous sodium loading. Methods This was a placebo-controlled, randomized, double-blind, crossover study performed according to a 2 × 2 factorial design. Subjects received first a 2000 ml infusion of NaCl 0.9% during 2 h. Then fludrocortisone 50 μg (or its placebo) was administered orally and hydrocortisone 50 mg (or its placebo) was injected intravenously. At 1.5 h after treatment administration, incremental doses of phenylephrine were infused (from 0.01 to 3 μg kg−1 min−1), each dose being infused during 5 min. Results Both fludrocortisone (P < 0.001) and hydrocortisone (P = 0.002) induced a significant decrease in pressor response to phenylephrine, their effects being additive (fludrocortisone × hydrocortisone interaction, P = 0.792). The two drugs did not induce any detectable cardiac effect. Conclusions Single administrations of fludrocortisone and hydrocortisone decreased the pressor response to phenylephrine in healthy volunteers with hypo-aldosteronism. These similar effects of hydrocortisone and fludrocortisone probably express a rapid non-genomic vasodilating effect of the two steroids in the context of acute volume loading. PMID:22703532

Surgical Responses of Medial Rectus Muscle Recession in Thyroid Eye Disease-Related Esotropia

PubMed Central

Lyu, In Jeong; Lee, Ju-Yeun; Kong, Mingui; Park, Kyung-Ah; Oh, Sei Yeul

2016-01-01

We evaluate the surgical outcomes and surgical responses of medial rectus muscle (MR) recession patients with thyroid eye disease (TED)-related esotropia (ET). The surgical dose-response curves 1 week postoperatively and at the final visit were analyzed. Univariable and multivariable linear regression analyses were applied to investigate factors influencing surgical dose-response. A total of 43 patients with TED-related ET that underwent MR recession were included. The final success rate was 86.0% and the rate of undercorrection was 14.0%. The surgical dose-response curves of TED-related ET showed a gentle slope compared with those of standard surgical tables. In the univariable model, simultaneous vertical rectus muscle recession was the only significant factor influencing surgical dose-response of MR recession in TED-related ET (β = -0.397, P = 0.044). In a model adjusted for age, sex, type of surgery, and preoperative horizontal angle of deviation, simultaneous vertical rectus muscle recession showed marginal significance (β = -0.389, P = 0.064). The surgical dose-response curve of TED-related ET was unique. Simultaneous vertical rectus muscle recession was associated with increased surgical dose-response in TED-related ET. PMID:26796354

A group sequential adaptive treatment assignment design for proof of concept and dose selection in headache trials.

PubMed

Hall, David B; Meier, Ulrich; Diener, Hans-Cristoph

2005-06-01

The trial objective was to test whether a new mechanism of action would effectively treat migraine headaches and to select a dose range for further investigation. The motivation for a group sequential, adaptive, placebo-controlled trial design was (1) limited information about where across the range of seven doses to focus attention, (2) a need to limit sample size for a complicated inpatient treatment and (3) a desire to reduce exposure of patients to ineffective treatment. A design based on group sequential and up and down designs was developed and operational characteristics were explored by trial simulation. The primary outcome was headache response at 2 h after treatment. Groups of four treated and two placebo patients were assigned to one dose. Adaptive dose selection was based on response rates of 60% seen with other migraine treatments. If more than 60% of treated patients responded, then the next dose was the next lower dose; otherwise, the dose was increased. A stopping rule of at least five groups at the target dose and at least four groups at that dose with more than 60% response was developed to ensure that a selected dose would be statistically significantly (p=0.05) superior to placebo. Simulations indicated good characteristics in terms of control of type 1 error, sufficient power, modest expected sample size and modest bias in estimation. The trial design is attractive for phase 2 clinical trials when response is acute and simple, ideally binary, placebo comparator is required, and patient accrual is relatively slow allowing for the collection and processing of results as a basis for the adaptive assignment of patients to dose groups. The acute migraine trial based on this design was successful in both proof of concept and dose range selection.

Gene Profiling Characteristics of Radioadaptive Response in AG01522 Normal Human Fibroblasts

PubMed Central

Hou, Jue; Wang, Fan; Kong, Peizhong; Yu, Peter K. N.; Wang, Hongzhi; Han, Wei

2015-01-01

Radioadaptive response (RAR) in mammalian cells refers to the phenomenon where a low-dose ionizing irradiation alters the gene expression profiles, and protects the cells from the detrimental effects of a subsequent high dose exposure. Despite the completion of numerous experimental studies on RAR, the underlying mechanism has remained unclear. In this study, we aimed to have a comprehensive investigation on the RAR induced in the AG01522 human fibroblasts first exposed to 5 cGy (priming dose) and then followed by 2 Gy (challenge dose) of X-ray through comparisons to those cells that had only received a single 2 Gy dose. We studied how the priming dose affected the expression of gene transcripts, and to identify transcripts or pathways that were associated with the reduced chromosomal damages (in terms of the number of micronuclei) after application of the challenging dose. Through the mRNA and microRNA microarray analyses, the transcriptome alteration in AG01522 cells was examined, and the significantly altered genes were identified for different irradiation procedures using bioinformatics approaches. We observed that a low-dose X-ray exposure produced an alert, triggering and altering cellular responses to defend against subsequent high dose-induced damages, and accelerating the cell repair process. Moreover, the p53 signaling pathway was found to play critial roles in regulating DNA damage responses at the early stage after application of the challenging dose, particularly in the RAR group. Furthermore, microRNA analyses also revealed that cell communication and intercellular signaling transduction played important roles after low-dose irradiation. We conclude that RAR benefits from the alarm mechanisms triggered by a low-dose priming radation dose. PMID:25886619

Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression

NASA Technical Reports Server (NTRS)

Zeitzer, J. M.; Dijk, D. J.; Kronauer, R.; Brown, E.; Czeisler, C.

2000-01-01

Ocular exposure to early morning room light can significantly advance the timing of the human circadian pacemaker. The resetting response to such light has a non-linear relationship to illuminance. The dose-response relationship of the human circadian pacemaker to late evening light of dim to moderate intensity has not been well established. Twenty-three healthy young male and female volunteers took part in a 9 day protocol in which a single experimental light exposure6.5 h in duration was given in the early biological night. The effects of the light exposure on the endogenous circadian phase of the melatonin rhythm and the acute effects of the light exposure on plasma melatonin concentration were calculated. We demonstrate that humans are highly responsive to the phase-delaying effects of light during the early biological night and that both the phase resetting response to light and the acute suppressive effects of light on plasma melatonin follow a logistic dose-response curve, as do many circadian responses to light in mammals. Contrary to expectations, we found that half of the maximal phase-delaying response achieved in response to a single episode of evening bright light ( approximately 9000 lux (lx)) can be obtained with just over 1 % of this light (dim room light of approximately 100 lx). The same held true for the acute suppressive effects of light on plasma melatonin concentrations. This indicates that even small changes in ordinary light exposure during the late evening hours can significantly affect both plasma melatonin concentrations and the entrained phase of the human circadian pacemaker.

Effects of forskolin analogs, phosphodiesterase inhibitors and 8-bromo cyclic AMP on plasma exudations induced with bradykinin and prostaglandin E/sub 1/ in rat skin

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sugio, K.; Daly, J.W.

1984-01-09

The effects of forskolin analogs, phosphodiesterase inhibitors and 8-bromo cyclic AMP on plasma exudations induced with bradykinin and prostaglandin E/sub 1/ in rat skin were investigated using (/sup 125/I) bovine serum albumin (/sup 125/I-BSA). Forskolin, forskolin 7-ethyl carbonate and 7-desacetylforskolin, which are potent activators of adenylate cyclase, greatly potentiated the bradykinin-induced plasma exudation and inhibited the prostaglandin E/sub 1/-induced response. The phosphodiesterase inhibitors, ZK 627ll, dipyridamole, HL 725, and 3-isobutyl-1-methylxanthine potentiated the bradykinin-induced plasma exudation and inhibited and prostaglandin E/sub 1/-induced response. 8-Bromo cyclic AMP in the doses of 0.01 to 1 ..mu..g potentiated the bradykinin-induced plasma exudation, but hadmore » no effect at doses of 10 and 100 ..mu..g. 8-bromo cyclic AMP at all doses significantly inhibited the prostaglandin E/sub 1/-induced response. The results suggest that the effects of forskolin and its analogs on plasma exudations induced with bradykinin and prostaglandin E/sub 1/ in rat skin derive from activation of cyclic AMP-generating systems.« less

Enkephalinase inhibitor potentiates mammalian tachykinin-induced contraction in ferret trachea.

PubMed

Sekizawa, K; Tamaoki, J; Graf, P D; Basbaum, C B; Borson, D B; Nadel, J A

1987-12-01

To determine the roles of endogenous enkephalinase (EC.3.4.24.11) in regulating tachykinin-induced contraction of airway smooth muscle, the authors studied the effects of the enkephalinase inhibitor leucine-thiorphan on the contractile responses to substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) in isolated ferret tracheal smooth muscle segments. Leucine-thiorphan shifted, in concentration-dependent fashions, the dose-response curves to all tachykinins to lower concentrations. Leucine-thiorphan changed the rank order of tachykinin potency from NKA greater than SP greater than NKB to NKA = NKB greater than SP. Removal of the epithelium slightly enhanced the contractile responses to SP and NKA but not to NKB. Atropine shifted the dose-response curves of all tachykinins to higher concentrations. Each tachykinin increased the contractile response to electrical field stimulation (5 Hz, 20 sec of duration, 20 V) in a dose-dependent fashion. This effect was not altered by hexamethonium, indomethacin, BW755C or naloxone but was potentiated by leucine-thiorphan and inhibited by the tachykinin receptor antagonist (D-Pro2, D-Trp7,9)-SP and by atropine. Because tachykinins did not affect contractile responses to acetylcholine significantly, their effects were probably on presynaptic postganglionic nerves. Captopril, bestatin and leupeptin did not alter contractile responses, suggesting that angiotensin converting enzyme, aminopeptidases and serine proteinases did not modulate tachykinin-induced effects. Enkephalinase immunofluorescence was found in the smooth muscle and epithelium and confirmed the authors' finding of enkephalinase-like activity in the muscle. The results suggest that tracheal enkephalinase is an important modulator of tachykinin-induced effects.

Processing speed can monitor stimulant-medication effects in adults with attention deficit disorder with hyperactivity.

PubMed

Nielsen, Niels Peter; Wiig, Elisabeth H; Bäck, Svante; Gustafsson, Jan

2017-05-01

Treatment responses to methylphenidate by adults with ADHD are generally monitored against DSM-IV/DSM-V symptomatology, rating scales or interviews during reviews. To evaluate the use of single- and dual-dimension processing-speed and efficiency measures to monitor the effects of pharmacological treatment with methylphenidate after a short period off medication. A Quick Test of Cognitive Speed (AQT) monitored the effects of immediate-release methylphenidate in 40 previously diagnosed and medicated adults with ADHD. Processing speed was evaluated with prior prescription medication, without medication after a 2-day period off ADHD medication, and with low-dose (10/20 mg) and high-dose (20/40 mg) methylphenidate hydrochloride (Medikinet IR). Thirty-three participants responded to the experimental treatments. One-way ANOVA with post-hoc analysis (Scheffe) indicated significant main effects for single dimension colour and form and dual-dimension colour-form naming. Post-hoc analysis indicated statistical differences between the no- and high-dose medication conditions for colour and form, measures of perceptual speed. For colour-form naming, a measure of cognitive speed, there was a significant difference between no- and low-dose medication and between no- and high-dose medications, but not between low- and high-dose medications. Results indicated that the AQT tests effectively monitored incremental effects of the methylphenidate dose on processing speed after a 2-day period off medication. Thus, perceptual (colour and form) and cognitive speed (two-dimensional colour-form naming) and processing efficiency (lowered shift costs) increased measurably with high-dose medication. These preliminary findings warrant validation with added measures of associated behavioural and cognitive changes.

Sublethal pesticide doses negatively affect survival and the cellular responses in American foulbrood-infected honeybee larvae

NASA Astrophysics Data System (ADS)

López, Javier Hernández; Krainer, Sophie; Engert, Antonia; Schuehly, Wolfgang; Riessberger-Gallé, Ulrike; Crailsheim, Karl

2017-02-01

Disclosing interactions between pesticides and bee infections is of most interest to understand challenges that pollinators are facing and to which extent bee health is compromised. Here, we address the individual and combined effect that three different pesticides (dimethoate, clothianidin and fluvalinate) and an American foulbrood (AFB) infection have on mortality and the cellular immune response of honeybee larvae. We demonstrate for the first time a synergistic interaction when larvae are exposed to sublethal doses of dimethoate or clothianidin in combination with Paenibacillus larvae, the causative agent of AFB. A significantly higher mortality than the expected sum of the effects of each individual stressor was observed in co-exposed larvae, which was in parallel with a drastic reduction of the total and differential hemocyte counts. Our results underline that characterizing the cellular response of larvae to individual and combined stressors allows unmasking previously undetected sublethal effects of pesticides in colony health.

Sublethal pesticide doses negatively affect survival and the cellular responses in American foulbrood-infected honeybee larvae.

PubMed

López, Javier Hernández; Krainer, Sophie; Engert, Antonia; Schuehly, Wolfgang; Riessberger-Gallé, Ulrike; Crailsheim, Karl

2017-02-01

Disclosing interactions between pesticides and bee infections is of most interest to understand challenges that pollinators are facing and to which extent bee health is compromised. Here, we address the individual and combined effect that three different pesticides (dimethoate, clothianidin and fluvalinate) and an American foulbrood (AFB) infection have on mortality and the cellular immune response of honeybee larvae. We demonstrate for the first time a synergistic interaction when larvae are exposed to sublethal doses of dimethoate or clothianidin in combination with Paenibacillus larvae, the causative agent of AFB. A significantly higher mortality than the expected sum of the effects of each individual stressor was observed in co-exposed larvae, which was in parallel with a drastic reduction of the total and differential hemocyte counts. Our results underline that characterizing the cellular response of larvae to individual and combined stressors allows unmasking previously undetected sublethal effects of pesticides in colony health.

Effect of chemical mutagens and carcinogens on gene expression profiles in human TK6 cells.

PubMed

Godderis, Lode; Thomas, Reuben; Hubbard, Alan E; Tabish, Ali M; Hoet, Peter; Zhang, Luoping; Smith, Martyn T; Veulemans, Hendrik; McHale, Cliona M

2012-01-01

Characterization of toxicogenomic signatures of carcinogen exposure holds significant promise for mechanistic and predictive toxicology. In vitro transcriptomic studies allow the comparison of the response to chemicals with diverse mode of actions under controlled experimental conditions. We conducted an in vitro study in TK6 cells to characterize gene expression signatures of exposure to 15 genotoxic carcinogens frequently used in European industries. We also examined the dose-responsive changes in gene expression, and perturbation of biochemical pathways in response to these carcinogens. TK6 cells were exposed at 3 dose levels for 24 h with and without S9 human metabolic mix. Since S9 had an impact on gene expression (885 genes), we analyzed the gene expression data from cells cultures incubated with S9 and without S9 independently. The ribosome pathway was affected by all chemical-dose combinations. However in general, no similar gene expression was observed among carcinogens. Further, pathways, i.e. cell cycle, DNA repair mechanisms, RNA degradation, that were common within sets of chemical-dose combination were suggested by clustergram. Linear trends in dose-response of gene expression were observed for Trichloroethylene, Benz[a]anthracene, Epichlorohydrin, Benzene, and Hydroquinone. The significantly altered genes were involved in the regulation of (anti-) apoptosis, maintenance of cell survival, tumor necrosis factor-related pathways and immune response, in agreement with several other studies. Similarly in S9+ cultures, Benz[a]pyrene, Styrene and Trichloroethylene each modified over 1000 genes at high concentrations. Our findings expand our understanding of the transcriptomic response to genotoxic carcinogens, revealing the alteration of diverse sets of genes and pathways involved in cellular homeostasis and cell cycle control.

Verapamil Blocks Scopolamine Enhancement Effect on Memory Consolidation in Passive Avoidance Task in Rats

PubMed Central

Giménez De Béjar, Verónica; Caballero Bleda, María; Popović, Natalija; Popović, Miroljub

2017-01-01

Our recent data have indicated that scopolamine, a non-selective muscarinic receptor antagonist, improves memory consolidation, in a passive avoidance task, tested in rats. It has been found that verapamil, a phenylalkylamine class of the L-type voltage-dependent calcium channel antagonist, inhibits [3H] N-methyl scopolamine binding to M1 muscarinic receptors. However, there are no data about the effect of verapamil on memory consolidation in the passive avoidance task, in rats. The purpose of the present study was to examine the effects of verapamil (0.5, 1.0, 2.5, 5.0, 10, or 20 mg/kg i.p.) as well as the interaction between scopolamine and verapamil on memory consolidation in the step-through passive avoidance task, in Wistar rats. Our results showed that verapamil (1.0 and 2.5 mg/kg) administered immediately after the acquisition task significantly increased the latency of the passive avoidance response, on the 48 h retested trial, improving memory consolidation. On the other hand, verapamil in a dose of 5 mg/kg, that per se does not affect memory consolidation, significantly reversed the memory consolidation improvement induced by scopolamine (1 mg/kg, i.p., administered immediately after verapamil treatment) but did not change the passive avoidance response in rats treated by an ineffective dose of scopolamine (30 mg/kg). In conclusion, the present data suggest that (1) the post-training administration of verapamil, dose-dependently, improves the passive avoidance response; (2) verapamil, in ineffective dose, abolished the improvement of memory consolidation effect of scopolamine; and (3) exists interaction between cholinergic muscarinic receptors and calcium homeostasis-related mechanisms in the consolidation of emotional memory. PMID:28878678

The effect of peptidase inhibitors on bradykinin-induced bronchoconstriction in guinea-pigs in vivo.

PubMed Central

Ichinose, M.; Barnes, P. J.

1990-01-01

1. Bradykinin (BK) instilled directly into the airway lumen caused bronchoconstriction in anaesthetized, mechanically ventilated guinea-pigs in the presence of propranolol (1 mg kg-1 i.v.). The geometric mean dose of BK required to produce 100% increase in airway opening pressure (PD100) was 22.9 nmol (95% c.i. 11.7-44.6 nmol). 2. The dose-response curve for the effect of instilled BK was significantly shifted to the left by the angiotensin converting enzyme (ACE) inhibitor, captopril (5 and 50 nmol instillation, PD100 = 3.0, 95% c.i. 0.98-8.9, and 2.0 nmol, 95% c.i. 0.65-6.2 nmol, respectively). 3. The neutral endopeptidase (NEP) inhibitor, phosphoramidon (5 and 50 nmol instillation) also shifted the dose-response curve for the effect of instilled BK; the PD100 values = 2.2 (95% c.i. 0.40-11.7) and 1.8 nmol (95% c.i. 0.87-3.5 nmol), respectively. 4. After pretreatment with captopril (50 nmol) and phosphoramidon (50 nmol) in combination, the dose-response curve for the effect of instilled BK (PD100 = 1.1 nmol, 95% c.i. 0.37-3.2 nmol) was similar to that obtained in the presence of each inhibitor used alone. 5. The kinase I inhibitor, DL-2-mercaptomethyl-3-guanidinoethylthiopropionic acid (50 nmol instillation) failed to alter the dose-response curve to instilled BK (PD100 = 14.6 nmol, 95% c.i. 6.7-32.0 nmol). 6. These data suggest that both ACE and NEP degrade BK in the airway lumen, but that kininase I is not involved. PMID:2282470

Determining the behavioural dose-response relationship of marine mammals to air gun noise and source proximity.

PubMed

Dunlop, Rebecca A; Noad, Michael J; McCauley, Robert D; Scott-Hayward, Lindsay; Kniest, Eric; Slade, Robert; Paton, David; Cato, Douglas H

2017-08-15

The effect of various anthropogenic sources of noise (e.g. sonar, seismic surveys) on the behaviour of marine mammals is sometimes quantified as a dose-response relationship, where the probability of an animal behaviourally 'responding' (e.g. avoiding the source) increases with 'dose' (or received level of noise). To do this, however, requires a definition of a 'significant' response (avoidance), which can be difficult to quantify. There is also the potential that the animal 'avoids' not only the source of noise but also the vessel operating the source, complicating the relationship. The proximity of the source is an important variable to consider in the response, yet difficult to account for given that received level and proximity are highly correlated. This study used the behavioural response of humpback whales to noise from two different air gun arrays (20 and 140 cubic inch air gun array) to determine whether a dose-response relationship existed. To do this, a measure of avoidance of the source was developed, and the magnitude (rather than probability) of this response was tested against dose. The proximity to the source, and the vessel itself, was included within the one-analysis model. Humpback whales were more likely to avoid the air gun arrays (but not the controls) within 3 km of the source at levels over 140 re. 1 µPa 2  s -1 , meaning that both the proximity and the received level were important factors and the relationship between dose (received level) and response is not a simple one. © 2017. Published by The Company of Biologists Ltd.

An Exploratory Human Laboratory Experiment Evaluating Vaporized Cannabis in the Treatment of Neuropathic Pain from Spinal Cord Injury and Disease

PubMed Central

Wilsey, Barth; Marcotte, Thomas D.; Deutsch, Reena; Zhao, Holly; Prasad, Hannah; Phan, Amy

2016-01-01

Using eight hour human laboratory experiments, we evaluated the analgesic efficacy of vaporized cannabis in patients with neuropathic pain related to injury or disease of the spinal cord, the majority of whom were experiencing pain despite traditional treatment. After obtaining baseline data, 42 participants underwent a standardized procedure for inhaling 4 puffs of vaporized cannabis containing either placebo, 2.9%, or 6.7% delta-9-tetrahydrocannabinol on three separate occasions. A second dosing occurred 3 hours later; participants chose to inhale 4 to 8 puffs. This flexible dosing was utilized to attempt to reduce the placebo effect. Using an 11-point numerical pain intensity rating scale as the primary outcome, a mixed effects linear regression model demonstrated a significant analgesic response for vaporized cannabis. When subjective and psychoactive side effects (e.g., good drug effect, feeling high, etc.) were added as covariates to the model, the reduction in pain intensity remained significant above and beyond any effect of these measures (all p<0.0004). Psychoactive and subjective effects were dose dependent. Measurement of neuropsychological performance proved challenging because of various disabilities in the population studied. As the two active doses did not significantly differ from each other in terms of analgesic potency, the lower dose appears to offer the best risk-benefit ratio in patients with neuropathic pain associated with injury or disease of the spinal cord. PMID:27286745

Chronic methamphetamine exposure significantly decreases microglia activation in the arcuate nucleus.

PubMed

Lloyd, Steven A; Corkill, Beau; Bruster, Matthew C; Roberts, Rick L; Shanks, Ryan A

2017-07-01

Methamphetamine is a powerful psychostimulant drug and its use and abuse necessitates a better understanding of its neurobiobehavioral effects. The acute effects of binge dosing of methamphetamine on the neurons in the CNS are well studied. However, the long-term effects of chronic, low-dose methamphetamine are less well characterized, especially in other cell types and areas outside of the major dopamine pathways. Mice were administered 5mg/kg/day methamphetamine for ten days and brain tissue was analyzed using histochemistry and image analysis. Increased microglia activity in the striatum confirmed toxic effects of methamphetamine in this brain region using this dosing paradigm. A significant decrease in microglia activity in the arcuate nucleus of the hypothalamus was observed with no effect noted on dopamine neurons in the arcuate nucleus. Given the importance of this area in homeostatic and neuroendocrine regulation, the current study highlights the need to more fully understand the systemic effects of chronic, low-dose methamphetamine use. The novel finding of microglia downregulation after chronic methamphetamine could lead to advances in understanding neuroinflammatory responses towards addiction treatment and protection from psychostimulant-induced neurotoxicity. Copyright © 2017 Elsevier B.V. All rights reserved.

Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials.

PubMed

Del Gobbo, Liana C; Falk, Michael C; Feldman, Robin; Lewis, Kara; Mozaffarian, Dariush

2015-12-01

The effects of nuts on major cardiovascular disease (CVD) risk factors, including dose-responses and potential heterogeneity by nut type or phytosterol content, are not well established. We examined the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts) on blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein, and triglycerides], lipoproteins [apolipoprotein A1, apolipoprotein B (ApoB), and apolipoprotein B100], blood pressure, and inflammation (C-reactive protein) in adults aged ≥18 y without prevalent CVD. We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two investigators screened 1301 potentially eligible PubMed articles in duplicate. We calculated mean differences between nut intervention and control arms, dose-standardized to one 1-oz (28.4 g) serving/d, by using inverse-variance fixed-effects meta-analysis. Dose-response for nut intake was examined by using linear regression and fractional polynomial modeling. Heterogeneity by age, sex, background diet, baseline risk factors, nut type, disease condition, duration, and quality score was assessed with meta-regression. Publication bias was evaluated by using funnel plots and Egger's and Begg's tests. Sixty-one trials met eligibility criteria (n = 2582). Interventions ranged from 3 to 26 wk. Nut intake (per serving/d) lowered total cholesterol (-4.7 mg/dL; 95% CI: -5.3, -4.0 mg/dL), LDL cholesterol (-4.8 mg/dL; 95% CI: -5.5, -4.2 mg/dL), ApoB (-3.7 mg/dL; 95% CI: -5.2, -2.3 mg/dL), and triglycerides (-2.2 mg/dL; 95% CI: -3.8, -0.5 mg/dL) with no statistically significant effects on other outcomes. The dose-response between nut intake and total cholesterol and LDL cholesterol was nonlinear (P-nonlinearity < 0.001 each); stronger effects were observed for ≥60 g nuts/d. Significant heterogeneity was not observed by nut type or other factors. For ApoB, stronger effects were observed in populations with type 2 diabetes (-11.5 mg/dL; 95% CI: -16.2, -6.8 mg/dL) than in healthy populations (-2.5 mg/dL; 95% CI: -4.7, -0.3 mg/dL) (P-heterogeneity = 0.015). Little evidence of publication bias was found. Tree nut intake lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. The major determinant of cholesterol lowering appears to be nut dose rather than nut type. Our findings also highlight the need for investigation of possible stronger effects at high nut doses and among diabetic populations. © 2015 American Society for Nutrition.

A phase I safety and immunogenicity dose escalation trial of plague vaccine, Flagellin/F1/V, in healthy adult volunteers (DMID 08-0066).

PubMed

Frey, Sharon E; Lottenbach, Kathleen; Graham, Irene; Anderson, Edwin; Bajwa, Kanwaldeep; May, Ryan C; Mizel, Steven B; Graff, Aaron; Belshe, Robert B

2017-12-04

Intentional aerosolization of Yersinia pestis may result in pneumonic plague which is highly fatal if not treated early. We conducted a phase 1 randomized, double blind (within each group), placebo controlled, dose escalation trial to evaluate a plague vaccine, Flagellin/F1/V, in healthy adults aged 8 through 45years. Vaccine was administered intramuscularly on Days 0 and 28 at a dose of 1, 3, 6 or 10mcg. Subjects were observed for 4h after vaccination for cytokine release syndrome. Reactogenicity and adverse events (AE) were collected for 14 and 28days, respectively, after each vaccination. Serious AE were collected for the entire study. ELISA antibody and cytokines were measured at multiple time points. Subject's participation lasted 13months. Sixty healthy subjects were enrolled; 52% males, 100% non-Hispanic, 91.7% white and mean age 30.8years. No severe reactogenicity events occurred; most AE were mild. No serious AE related to vaccine occurred. A dose response effect was observed to F1, V and flagellin. The peak ELISA IgG antibody titers (95% CI) after two 10mcg doses of vaccine were 260.0 (102.6-659.0) and 983.6 (317.3-3048.8), respectively, against F1 and V antigens. The 6mcg dose group provided similar titers. Titers were low for the placebo, 1mcg and 3mcg recipients. A positive antibody dose response was observed to F1, V and flagellin. Vaccine antigen specific serum IgE was not detected. There were no significant rises in serum or cellular cytokine responses and no significant IgG increase to flagellin after the second dose. The Flagellin/F1/V vaccine exhibited a dose dependent increase in immunogenicity and was well tolerated at all doses. Antibody specific responses to F1, V and flagellin increased as dose increased. Given the results from this trial, testing higher doses of the vaccine may be merited. Copyright © 2017. Published by Elsevier Ltd.

External dose-rate conversion factors of radionuclides for air submersion, ground surface contamination and water immersion based on the new ICRP dosimetric setting.

PubMed

Yoo, Song Jae; Jang, Han-Ki; Lee, Jai-Ki; Noh, Siwan; Cho, Gyuseong

2013-01-01

For the assessment of external doses due to contaminated environment, the dose-rate conversion factors (DCFs) prescribed in Federal Guidance Report 12 (FGR 12) and FGR 13 have been widely used. Recently, there were significant changes in dosimetric models and parameters, which include the use of the Reference Male and Female Phantoms and the revised tissue weighting factors, as well as the updated decay data of radionuclides. In this study, the DCFs for effective and equivalent doses were calculated for three exposure settings: skyshine, groundshine and water immersion. Doses to the Reference Phantoms were calculated by Monte Carlo simulations with the MCNPX 2.7.0 radiation transport code for 26 mono-energy photons between 0.01 and 10 MeV. The transport calculations were performed for the source volume within the cut-off distances practically contributing to the dose rates, which were determined by a simplified calculation model. For small tissues for which the reduction of variances are difficult, the equivalent dose ratios to a larger tissue (with lower statistical errors) nearby were employed to make the calculation efficient. Empirical response functions relating photon energies, and the organ equivalent doses or the effective doses were then derived by the use of cubic-spline fitting of the resulting doses for 26 energy points. The DCFs for all radionuclides considered important were evaluated by combining the photon emission data of the radionuclide and the empirical response functions. Finally, contributions of accompanied beta particles to the skin equivalent doses and the effective doses were calculated separately and added to the DCFs. For radionuclides considered in this study, the new DCFs for the three exposure settings were within ±10 % when compared with DCFs in FGR 13.

External dose-rate conversion factors of radionuclides for air submersion, ground surface contamination and water immersion based on the new ICRP dosimetric setting

PubMed Central

Yoo, Song Jae; Jang, Han-Ki; Lee, Jai-Ki; Noh, Siwan; Cho, Gyuseong

2013-01-01

For the assessment of external doses due to contaminated environment, the dose-rate conversion factors (DCFs) prescribed in Federal Guidance Report 12 (FGR 12) and FGR 13 have been widely used. Recently, there were significant changes in dosimetric models and parameters, which include the use of the Reference Male and Female Phantoms and the revised tissue weighting factors, as well as the updated decay data of radionuclides. In this study, the DCFs for effective and equivalent doses were calculated for three exposure settings: skyshine, groundshine and water immersion. Doses to the Reference Phantoms were calculated by Monte Carlo simulations with the MCNPX 2.7.0 radiation transport code for 26 mono-energy photons between 0.01 and 10 MeV. The transport calculations were performed for the source volume within the cut-off distances practically contributing to the dose rates, which were determined by a simplified calculation model. For small tissues for which the reduction of variances are difficult, the equivalent dose ratios to a larger tissue (with lower statistical errors) nearby were employed to make the calculation efficient. Empirical response functions relating photon energies, and the organ equivalent doses or the effective doses were then derived by the use of cubic-spline fitting of the resulting doses for 26 energy points. The DCFs for all radionuclides considered important were evaluated by combining the photon emission data of the radionuclide and the empirical response functions. Finally, contributions of accompanied beta particles to the skin equivalent doses and the effective doses were calculated separately and added to the DCFs. For radionuclides considered in this study, the new DCFs for the three exposure settings were within ±10 % when compared with DCFs in FGR 13. PMID:23542764

Radiation-induced DNA damage and the relative biological effectiveness of 18F-FDG in wild-type mice

DOE PAGES

Taylor, Kristina; Lemon, Jennifer A.; Boreham, Douglas R.

2014-05-28

Clinically, the most commonly used positron emission tomography (PET) radiotracer is the glucose analog 2-[ 18F] fluoro-2-deoxy-d-glucose ( 18F-FDG), however little research has been conducted on the biological effects of 18F-FDG injections. The induction and repair of DNA damage and the relative biological effectiveness (RBE) of radiation from 18F-FDG relative to 662 keV γ-rays were investigated. The study also assessed whether low-dose radiation exposure from 18F-FDG was capable of inducing an adaptive response. DNA damage to the bone marrow erythroblast population was measured using micronucleus formation and lymphocyte γH2A.X levels. To test the RBE of 18F-FDG, mice were injected withmore » a range of activities of 18F-FDG (0–14.80 MBq) or irradiated with Cs-137 γ-rays (0–100 mGy). The adaptive response was investigated 24 h after the 18F-FDG injection by 1 Gy in vivo challenge doses for micronucleated reticulocyte (MN-RET) formation or 1, 2 and 4 Gy in vitro challenges doses for γH2A.X formation. A significant increase in MN-RET formation above controls occurred following injection activities of 3.70, 7.40 or 14.80 MBq (P < 0.001) which correspond to bone marrow doses of ~35, 75 and 150 mGy, respectively. Per unit dose, the Cs-137 radiation exposure induced significantly more damage than the 18F-FDG injections (RBE = 0.79 ± 0.04). A 20% reduction in γH2A.X fluorescence was observed in mice injected with a prior adapting low dose of 14.80 MBq 18F-FDG relative to controls (P < 0.019). A 0.74 MBq 18F-FDG injection, which gives mice a dose approximately equal to a typical human PET scan, did not cause a significant increase in DNA damage nor did it generate an adaptive response. Typical 18F-FDG injection activities used in small animal imaging (14.80 MBq) resulted in a decrease in DNA damage, as measured by γH2A.X formation, below spontaneous levels observed in control mice. Lastly, the 18F-FDG RBE was <1.0, indicating that the mixed radiation quality and/or low dose rate from PET scans is less damaging than equivalent doses of gamma radiation.« less

Radiation-induced DNA damage and the relative biological effectiveness of 18F-FDG in wild-type mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Taylor, Kristina; Lemon, Jennifer A.; Boreham, Douglas R.

Clinically, the most commonly used positron emission tomography (PET) radiotracer is the glucose analog 2-[ 18F] fluoro-2-deoxy-d-glucose ( 18F-FDG), however little research has been conducted on the biological effects of 18F-FDG injections. The induction and repair of DNA damage and the relative biological effectiveness (RBE) of radiation from 18F-FDG relative to 662 keV γ-rays were investigated. The study also assessed whether low-dose radiation exposure from 18F-FDG was capable of inducing an adaptive response. DNA damage to the bone marrow erythroblast population was measured using micronucleus formation and lymphocyte γH2A.X levels. To test the RBE of 18F-FDG, mice were injected withmore » a range of activities of 18F-FDG (0–14.80 MBq) or irradiated with Cs-137 γ-rays (0–100 mGy). The adaptive response was investigated 24 h after the 18F-FDG injection by 1 Gy in vivo challenge doses for micronucleated reticulocyte (MN-RET) formation or 1, 2 and 4 Gy in vitro challenges doses for γH2A.X formation. A significant increase in MN-RET formation above controls occurred following injection activities of 3.70, 7.40 or 14.80 MBq (P < 0.001) which correspond to bone marrow doses of ~35, 75 and 150 mGy, respectively. Per unit dose, the Cs-137 radiation exposure induced significantly more damage than the 18F-FDG injections (RBE = 0.79 ± 0.04). A 20% reduction in γH2A.X fluorescence was observed in mice injected with a prior adapting low dose of 14.80 MBq 18F-FDG relative to controls (P < 0.019). A 0.74 MBq 18F-FDG injection, which gives mice a dose approximately equal to a typical human PET scan, did not cause a significant increase in DNA damage nor did it generate an adaptive response. Typical 18F-FDG injection activities used in small animal imaging (14.80 MBq) resulted in a decrease in DNA damage, as measured by γH2A.X formation, below spontaneous levels observed in control mice. Lastly, the 18F-FDG RBE was <1.0, indicating that the mixed radiation quality and/or low dose rate from PET scans is less damaging than equivalent doses of gamma radiation.« less

Respiratory Toxicity of Dimethyl Sulfoxide.

PubMed

Takeda, Kotaro; Pokorski, Mieczyslaw; Sato, Yutaka; Oyamada, Yoshitaka; Okada, Yasumasa

2016-01-01

Dimethyl sulfoxide (DMSO) is one of the most commonly used solvents for hydrophobic substances in biological experiments. In addition, the compound exhibits a plethora of bioactivities, which makes it of potential pharmacological use of its own. The influence on respiration, and thus on arterial blood oxygenation, of DMSO is unclear, contentious, and an area of limited study. Thus, in the present investigation we set out to determine the influence on lung ventilation of cumulated doses of DMSO in the amount of 0.5, 1.5, 3.5, 7.5, and 15.5 g/kg; each dose given intraperitoneally at 1 h interval in conscious mice. Ventilation and its responses to 7 % hypoxia (N(2) balanced) were recorded in a whole body plethsymograph. We demonstrate a dose-dependent inhibitory effect of DMSO on lung ventilation and its hypoxic responsiveness, driven mostly by changes in the tidal component. The maximum safe dose of DMSO devoid of meaningful consequences for respiratory function was 3.5 g/kg. The dose of 7.5 g/kg of DMSO significantly dampened respiration, with yet well preserved hyperventilatory response to hypoxia. The highest dose of 15.5 g/kg severely impaired ventilation and its responses. The study delineates the safety profile of DMSO regarding the respiratory function which is essential for maintaining proper tissue oxygenation. Caution should be exercised concerning dose concentration of DMSO.

Caffeinated and decaffeinated coffee consumption and melanoma risk: a dose-response meta-analysis of prospective cohort studies.

PubMed

Micek, Agnieszka; Godos, Justyna; Lafranconi, Alessandra; Marranzano, Marina; Pajak, Andrzej

2018-06-01

To determine the association between total, caffeinated and decaffeinated coffee consumption and melanoma risk a dose-response meta-analysis on prospective cohort studies were performed. Eligible studies were identified searching PubMed and EMBASE databases from the earliest available online indexing year to March 2017. The dose-response relationship was assessed by random-effects meta-analysis and the shape of the exposure-outcome curve was modelled linearly and using restricted cubic splines. A total of seven studies eligible for meta-analysis were identified that comprised 1,418,779 participants and 9211 melanoma cases. A linear dose-response meta-analysis showed a significant association between total coffee consumption and melanoma risk. An increase in coffee consumption of one cup per day was associated with a 3% reduction in melanoma risk (RR 0.97; 95% CI 0.95-0.99). Our findings suggest that coffee intake may be inversely associated with incidence of melanoma. Nevertheless, further studies exploring also the role of confounding factors are needed to explain the heterogeneity among studies.

Dose-response relations between second-hand smoke exposure and depressive symptoms among middle-aged women.

PubMed

Ye, Xiaohua; Li, LiXia; Gao, Yanhui; Zhou, Shudong; Yang, Yi; Chen, Sidong

2015-09-30

A growing body of evidence indicates a strong association between smoking and depression. However, little is known about the possible effects of second-hand smoke (SHS) exposure on depression. This study aimed to examine the potential dose-response relation between SHS exposure and depressive symptoms among non-smoking middle-aged women. A cross-sectional survey was conducted using a stratified three-stage sampling method. Depressive symptoms were measured by the Center for Epidemiologic Studies Depression Scale with a cut-off point of 16. Self-reported SHS exposure was defined as non-smokers׳ inhalation of the smoke exhaled from smokers on at least one day a week. The multivariable logistic regression analysis was completed with adjustment for potential confounders. Among 1280 middle-aged women, 19.4% were classified as having depressive symptoms. There was a 104% increased odds of depressive symptoms corresponding to SHS exposure in general (OR=2.04, 95% CI 1.48-2.79) using no exposure as reference. There were significant positive relations between SHS exposure in general and depressive symptoms in a dose-response manner. These significant trends were observed consistently whether SHS exposure occurred in homes or workplaces. Our findings suggest that long-term and regular SHS exposure is associated with a significant, dose-dependent increase in risk of depressive symptoms. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Studies of the mortality of atomic bomb survivors, Report 14, 1950-2003: an overview of cancer and noncancer diseases.

PubMed

Ozasa, Kotaro; Shimizu, Yukiko; Suyama, Akihiko; Kasagi, Fumiyoshi; Soda, Midori; Grant, Eric J; Sakata, Ritsu; Sugiyama, Hiromi; Kodama, Kazunori

2012-03-01

This is the 14th report in a series of periodic general reports on mortality in the Life Span Study (LSS) cohort of atomic bomb survivors followed by the Radiation Effects Research Foundation to investigate the late health effects of the radiation from the atomic bombs. During the period 1950-2003, 58% of the 86,611 LSS cohort members with DS02 dose estimates have died. The 6 years of additional follow-up since the previous report provide substantially more information at longer periods after radiation exposure (17% more cancer deaths), especially among those under age 10 at exposure (58% more deaths). Poisson regression methods were used to investigate the magnitude of the radiation-associated risks, the shape of the dose response, and effect modification by gender, age at exposure, and attained age. The risk of all causes of death was positively associated with radiation dose. Importantly, for solid cancers the additive radiation risk (i.e., excess cancer cases per 10(4) person-years per Gy) continues to increase throughout life with a linear dose-response relationship. The sex-averaged excess relative risk per Gy was 0.42 [95% confidence interval (CI): 0.32, 0.53] for all solid cancer at age 70 years after exposure at age 30 based on a linear model. The risk increased by about 29% per decade decrease in age at exposure (95% CI: 17%, 41%). The estimated lowest dose range with a significant ERR for all solid cancer was 0 to 0.20 Gy, and a formal dose-threshold analysis indicated no threshold; i.e., zero dose was the best estimate of the threshold. The risk of cancer mortality increased significantly for most major sites, including stomach, lung, liver, colon, breast, gallbladder, esophagus, bladder and ovary, whereas rectum, pancreas, uterus, prostate and kidney parenchyma did not have significantly increased risks. An increased risk of non-neoplastic diseases including the circulatory, respiratory and digestive systems was observed, but whether these are causal relationships requires further investigation. There was no evidence of a radiation effect for infectious or external causes of death.

Stimulus specific effect of ibuprofen on chemiluminescence of sheep neutrophils

DOE Office of Scientific and Technical Information (OSTI.GOV)

Tahamont, M.V.; Margiotta, M.; Gee, M.H.

1986-03-05

The authors have shown that pretreatment with ibuprofen inhibits free radical release from complement stimulated neutrophils. To further examine the effect of ibuprofen on neutrophil free radical release, they stimulated neutrophils with the synthetic peptide, FMLP, phorbol myristate acetate (PMA), or zymosan-activated plasma (ZAP). Pure (>95%), viable (>95%) sheep neutrophils (2 x 10/sup 6/) were placed in HEPES buffer, luminol, drug or vehicle and stimulated in the luminometer with one of the stimuli. The chemiluminescence (CL) response was recorded and the drug treated samples were compared to vehicle treated controls. Ibuprofen had a dose dependent effect on CL in ZAPmore » stimulated neutrophils. At the highest dose (10/sup -2/M) these cells produced only 37 +/- 7% of the CL response observed in the control cells. In contrast, at the same dose, ibuprofen did not significantly attenuate CL seen in FMLP stimulated cells, with these cells producing 79 +/- 7% of the control cells; nor did ibuprofen effect PMA stimulated CL, as these cells produced a CL response that was 85 +/- 8% of the control cells. Ibuprofen appears to have a stimulus specific effect on free radical release in activated neutrophils. It is also apparent that ibuprofen inhibits complement stimulated free radical release by some mechanism independent of its cyclooxygenase inhibitory effect.« less

Cytogenetic damage analysis in mice chronically exposed to low-dose internal tritium beta-particle radiation.

PubMed

Roch-Lefèvre, Sandrine; Grégoire, Eric; Martin-Bodiot, Cécile; Flegal, Matthew; Fréneau, Amélie; Blimkie, Melinda; Bannister, Laura; Wyatt, Heather; Barquinero, Joan-Francesc; Roy, Laurence; Benadjaoud, Mohamed; Priest, Nick; Jourdain, Jean-René; Klokov, Dmitry

2018-06-08

The aim of this study was to carry out a comprehensive examination of potential genotoxic effects of low doses of tritium delivered chronically to mice and to compare these effects to the ones resulting from equivalent doses of gamma-irradiation. Mice were chronically exposed for one or eight months to either tritiated water (HTO) or organically bound tritium (OBT) in drinking water at concentrations of 10 kBq/L, 1 MBq/L or 20 MBq/L. Dose rates of internal β-particle resulting from such tritium treatments were calculated and matching external gamma-exposures were carried out. We measured cytogenetic damage in bone marrow and in peripheral blood lymphocytes (PBLs) and the cumulative tritium doses (0.009 - 181 mGy) were used to evaluate the dose-response of OBT in PBLs, as well as its relative biological effectiveness (RBE). Neither tritium, nor gamma exposures produced genotoxic effects in bone marrow. However, significant increases in chromosome damage rates in PBLs were found as a result of chronic OBT exposures at 1 and 20 M Bq/L, but not at 10 kBq/L. When compared to an external acute gamma-exposure ex vivo , the RBE of OBT for chromosome aberrations induction was evaluated to be significantly higher than 1 at cumulative tritium doses below 10 mGy. Although found non-existent at 10 kBq/L (the WHO limit), the genotoxic potential of low doses of tritium (>10 kBq/L), mainly OBT, may be higher than currently assumed.

Aqueous ethanol extract of the fruit of Xylopia aethiopica (Annonaceae) exhibits anti-anaphylactic and anti-inflammatory actions in mice.

PubMed

Obiri, David D; Osafo, Newman

2013-07-30

Xylopia aethiopica has been traditionally used in the form of the dried fruit decoction to treat bronchitis, asthma, arthritis and rheumatism in Ghana, Nigeria and Cameroon. Aim of the study is to evaluate the anti-anaphylactic and anti-inflammatory effects of a 70% aqueous ethanol extract of the fruits of Xylopia aethiopica. Systemic anaphylaxis was induced by the injection of either compound 48/80 or lipopolysaccharide, LPS and survival rates of mice monitored for 1 h or 7 days respectively while IgE-mediated anaphylaxis in a local allergic reaction was studied in the pinnal inflammation model in mice. Clonidine-induced catalepsy in mice was used to evaluate the indirect antihistamine effect of Xylopia aethiopica, XAE. The effects of XAE assessed on the maximal and total oedema responses in the carrageenan-induced paw oedema in mice was used to evaluate the anti-inflammatory action of the extract. Administered at 30, 100, 300 and 1000 mg kg(-1) p.o., XAE dose dependently suppressed compound 48/80-induced mouse systemic anaphylactic shock and offered 63% protection to mice against LPS-induced endotoxic shock at a dose of 300 mg kg(-1). In addition, the extract (30-300 mg kg(-1)) in a dose dependent manner significantly inhibited by 23-62% the mouse pinnal inflammation. Clonidine-induced catalepsy in mice was significantly suppressed in a dose and time dependent manner when administered both prophylactically and therapeutically. In the same doses, when administered before the induction of the mouse carrageenan-induced paw oedema, the mean maximal swelling attained during 6 h was reduced to 41.02±6.94%, 35.61±4.30%, and 29.09±4.90% of the inflamed control response respectively and total paw swellings induced over the 6 h were also dose-dependently and significantly suppressed to 74.84±14.84%, 63.95±9.37%, and 48.13±10.90% of the inflamed control response respectively. Administered after the induction of the carrageenan paw oedema the mean maximal swelling attained during 6 h was suppressed to 49.84±3.95%, 43.62±1.01%, and 35.97±1.34% of the inflamed control response respectively while the total paw swellings induced over the 6 h were also dose-dependently and significantly suppressed at 100 and 300 mg kg(-1) to 72.39±4.38% and 60.81±3.25% of the inflamed control response respectively. These findings suggest that XAE inhibits mast cell-dependent immediate allergic reactions and exhibit anti-inflammatory actions through the inhibition of histamine release from mast cells via stabilizing the cell membrane. Our results contribute towards validation of the traditional use of Xylopia aethiopica in the treatment of bronchitis, asthma, arthritis and rheumatism. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Efficacy and Tolerability of High-Dose Escitalopram in Posttraumatic Stress Disorder.

PubMed

Qi, Wei; Gevonden, Martin; Shalev, Arieh

2017-02-01

Open-label trials suggest that escitalopram (up to 20 mg/d) is an effective treatment for some, but not all posttraumatic stress disorder (PTSD) patients. Higher doses of escitalopram effectively reduced major depression symptoms in patients who had not responded to regular doses. The current study examines the efficacy, tolerability, and adherence to high-dose escitalopram in PTSD. Forty-five PTSD patients received 12 weeks of gradually increasing doses of escitalopram reaching 40 mg daily at 4 weeks. Among those, 12 participants received regular doses of antidepressants at study onset including escitalopram (n = 7). The Clinician-Administered PTSD Scale (CAPS) evaluated PTSD symptoms severity before treatment, at 3 months (upon treatment termination), and at 6 months (maintenance effect). A 20% reduction in CAPS scores was deemed clinically significant. Adverse events and medication adherence were monitored at each clinical session. Linear mixed-models analysis showed a significant reduction of mean CAPS scores (11.5 ± 18.1 points) at 3 months and maintenance of gains by 6 months (F2,34.56 = 8.15, P = 0.001). Eleven participants (34.3%) showed clinically significant improvement at 3 months. Only 9 participants (20%) left the study. There were no serious adverse events and few mild ones with only 2 adverse events (diarrhea, 11.1%; drowsiness, 11.1%) reported by more than 10% of participants. High doses of escitalopram are tolerable and well adhered to in PTSD. Their beneficial effect at a group level is due to a particularly good response in a subset of patients.Variability in prior pharmacological treatment precludes a definite attribution of the results to high doses of escitalopram.

Dose-response effects of Lepidium meyenii (Maca) aqueous extract on testicular function and weight of different organs in adult rats.

PubMed

Chung, Francisco; Rubio, Julio; Gonzales, Carla; Gasco, Manuel; Gonzales, Gustavo F

2005-04-08

Lepidium meyenii (Brassicaceae) known as Maca grows exclusively between 4000 and 4500 m over the sea level in the Peruvian central Andes. The dried hypocotyls of Maca are traditionally used as food and for its supposed fertility-enhancing properties. A dose-response study was performed to determine the effect of 7 days oral administration of an aqueous lyophilized extract of Maca at 0.01-5 g/kg (corresponding to 0.022-11 g dry hypocotyls of Maca/kg) on body and different organ weights, stages of the seminiferous tubules, epididymal sperm count and motility, and serum testosterone and estradiol levels in rats. In doses up to 5 g extract/kg, no toxicity was observed. Almost all organ weights were similar in controls and in the Maca extract-treated groups. Seminal vesicles weight was significantly reduced at 0.01 and 0.10 g extract/kg. Maca increased in length of stages VII-VIII of the seminiferous tubules in a dose-response fashion, with highest response at 1.0 g/kg, while caput/corpus epididymal sperm count increased at the 1.0 g dose. Cauda epididymal sperm count, sperm motility, and serum estradiol level were not affected at any of the doses studied. Serum testosterone was lower at 0.10 g extract/kg. Low-seminal vesicle weights correlated with low-serum testosterone levels (R2=0.33; P<0.0001) and low-testosterone/estradiol ratio (R2=0.35; P<0.0001). Increase in epididymal sperm count was related to lengths of stages VII-VIII. Highest effect on stages VII-VIII of the seminiferous tubules was observed at 1.0 g Maca aqueous extract/kg. The present study demonstrated that Maca extract in doses up to 5 g/kg (equivalent to the intake of 770 g hypocotyls in a man of 70 kg) was safe and that higher effect on reproductive parameters was elicited with a dose of 1 g extract/kg corresponding to 2.2 g dry Maca hypocotyls/kg.

Deviation from additivity in mixture toxicity: relevance of nonlinear dose-response relationships and cell line differences in genotoxicity assays with combinations of chemical mutagens and gamma-radiation.

PubMed

Lutz, Werner K; Vamvakas, Spyros; Kopp-Schneider, Annette; Schlatter, Josef; Stopper, Helga

2002-12-01

Sublinear dose-response relationships are often seen in toxicity testing, particularly with bioassays for carcinogenicity. This is the result of a superimposition of various effects that modulate and contribute to the process of cancer formation. Examples are saturation of detoxification pathways or DNA repair with increasing dose, or regenerative hyperplasia and indirect DNA damage as a consequence of high-dose cytotoxicity and cell death. The response to a combination treatment can appear to be supra-additive, although it is in fact dose-additive along a sublinear dose-response curve for the single agents. Because environmental exposure of humans is usually in a low-dose range and deviation from linearity is less likely at the low-dose end, combination effects should be tested at the lowest observable effect levels (LOEL) of the components. This principle has been applied to combinations of genotoxic agents in various cellular models. For statistical analysis, all experiments were analyzed for deviation from additivity with an n-factor analysis of variance with an interaction term, n being the number of components tested in combination. Benzo[a]pyrene, benz[a]anthracene, and dibenz[a,c]anthracene were tested at the LOEL, separately and in combination, for the induction of revertants in the Ames test, using Salmonella typhimurium TA100 and rat liver S9 fraction. Combined treatment produced no deviation from additivity. The induction of micronuclei in vitro was investigated with ionizing radiation from a 137Cs source and ethyl methanesulfonate. Mouse lymphoma L5178Y cells revealed a significant 40% supra-additive combination effect in an experiment based on three independent replicates for controls and single and combination treatments. On the other hand, two human lymphoblastoid cell lines (TK6 and WTK1) as well as a pilot study with human primary fibroblasts from fetal lung did not show deviation from additivity. Data derived from one cell line should therefore not be generalized. Regarding the testing of mixtures for deviation from additive toxicity, the suggested experimental protocol is easily followed by toxicologists.

Toxicogenomic profiling in maternal and fetal rodent brains following gestational exposure to chlorpyrifos

DOE Office of Scientific and Technical Information (OSTI.GOV)

Moreira, Estefania G.; Department of Physiological Sciences, State University of Londrina, Londrina, PR; Yu Xiaozhong

2010-06-15

Considering the wide variety of effects that have been reported to occur in the developmental neurotoxicity of chlorpyrifos (CP) and the lack of consensus on their dependence of brain acetylcholinesterase (AChE) activity inhibition, we applied microarray technology to explore dose-dependent alterations in transcriptional response in the fetal and maternal C57BL/6 mouse brain after daily gestational exposure (days 6 to 17) to CP (2, 4, 10, 12 or 15 mg/kg, sc). We identified significantly altered genes across doses and assessed for overrepresentation of Gene Ontology (GO) biological processes and KEGG pathways. We further clustered genes based on their expression profiles acrossmore » doses and repeated the GO/pathways analysis for each cluster. The dose-effect relationship of CP on gene expression, both at the gene and pathway levels was non-monotonic and not necessarily related to brain AChE inhibition. The largest impact was observed in the 10 mg/kg dose group which was also the LOAEL for brain AChE inhibition. In the maternal brain, lower doses (4 mg/kg) influenced GO categories and pathways such as cell adhesion, behavior, lipid metabolism, long-term potentiation, nervous system development, neurogenesis, synaptic transmission. In the fetal brain, lower doses (2 and/or 4 mg/kg) significantly altered cell division, translation, transmission of nerve impulse, chromatin modification, long-term potentiation. In addition, some genes involved in nervous system development and signaling were shown to be specifically influenced by these lower CP doses. Our approach was sensitive and reflected the diversity of responses known to be disrupted by CP and highlighted possible additional consequences of CP neurotoxicity, such as disturbance of the ubiquitin proteasome system.« less

Effects of 810 nm laser on mouse primary cortical neurons

NASA Astrophysics Data System (ADS)

Kharkwal, Gitika B.; Sharma, Sulbha K.; Huang, Ying-Ying; De Taboada, Luis; McCarthy, Thomas; Hamblin, Michael R.

2011-03-01

In the past four decades numerous studies have reported the efficacy of low level light (laser) therapy (LLLT) as a treatment for diverse diseases and injuries. Recent studies have shown that LLLT can biomodulate processes in the central nervous system and has been extensively studied as a stroke treatment. However there is still a lack of knowledge on the effects of LLLT at the cellular level in neurons. The present study aimed to study the effect of 810 nm laser on several cellular processes in primary cortical neurons cultured from mouse embryonic brains. Neurons were irradiated with light dose of 0.03, 0.3, 3, 10 and 30 J/cm2 and intracellular levels of reactive oxygen species, nitric oxide and calcium were measured. The changes in mitochondrial function in response to light were studied in terms of adenosine triphosphate (ATP) and mitochondrial membrane potential (MMP). Light induced a significant increase in calcium, ATP and MMP at lower fluences and a decrease at higher fluence. ROS was induced significantly by light at all light doses. Nitric oxide levels also showed an increase on treatment with light. The results of the present study suggest that LLLT at lower fluences is capable of inducing mediators of cell signaling process which in turn may be responsible for the biomodulatory effects of the low level laser. At higher fluences beneficial mediators are reduced but potentially harmful mediators are increased thus offering an explanation for the biphasic dose response.

Escitalopram dose-response revisited: an alternative psychometric approach to evaluate clinical effects of escitalopram compared to citalopram and placebo in patients with major depression.

PubMed

Bech, Per; Tanghøj, Per; Cialdella, Philippe; Andersen, Henning Friis; Pedersen, Anders Gersel

2004-09-01

In continuation of a previous psychometric analysis of dose-response data for citalopram in depression, the corresponding study data for escitalopram is of interest, since escitalopram is the active enantiomer of citalopram and because citalopram was used as the active control. Revisiting those corresponding data, the psychometric properties of the Montgomery-Asberg Depression Scale (MADRS) and the Hamilton Depression Scale (HAMD) were investigated by focusing on the unidimensional HAMD6 and MADRS6. Effect sizes were calculated and compared for two dosages of escitalopram (10 mg and 20 mg daily) and between each of these two dosages and 40 mg citalopram daily. The results showed that the three depression scales MADRS6, MADRS10 and HAMD6 were psychometrically acceptable (coefficient of homogeneity of 0.40 or higher). In the severely depressed patients (MADRS10> or =30) a rather clear dose-response relationship for escitalopram was seen on all three scales after 6 and 8 wk of therapy. Thus, the effect size for 10 mg escitalopram ranged from 0.28 to 0.38 while the effect sizes for 20 mg escitalopram ranged from 0.57 to 0.77. This difference was statistically significant (p<0.01). The effect size for 40 mg citalopram ranged from 0.36 to 0.47, which is within the range found for 40 mg citalopram in our previous dose-response analysis of citalopram after 6 wk of therapy. The numerically largest difference between 20 mg escitalopram and 40 mg citalopram was seen after 8 wk of therapy for MADRS10 (effect size 0.71 vs. 0.37). An item analysis identified 'suicidal thoughts' to be the most discriminating item in this respect. These results for the severely depressed patients were confirmed by the patients self-reported quality of life evaluation. When all included patients were analysed, however, no clear dose-response relationship was seen. In conclusion, a dose-response relationship for escitalopram was seen in the severely depressed patients on all outcome scales after 6 and 8 wk of treatment. After 8 wk of treatment 20 mg escitalopram was superior to 40 mg citalopram, but not after 2 wk of treatment.

Individualized Radiation Dose Escalation Based on the Decrease in Tumor FDG Uptake and Normal Tissue Constraints Improve Survival in Patients With Esophageal Carcinoma.

PubMed

Ma, Jinbo; Wang, Zhaoyang; Wang, Chengde; Chen, Ercheng; Dong, Yaozong; Song, Yipeng; Wang, Wei; You, Dong; Jiang, Wei; Zang, Rukun

2017-02-01

To determine whether individualized radiation dose escalation after planned chemoradiation based on the decrease in tumor and normal tissue constraints can improve survival in patients with esophageal carcinoma. From August 2005 to December 2010, 112 patients with squamous esophageal carcinoma were treated with radical concurrent chemoradiation. Patients received positron emission tomography-computer tomography scan twice, before radiation and after radiation dose of 50.4 Gy. All patients were noncomplete metabolic response groups according to the Response Evaluation Criteria in solid tumors. Only 52 patients with noncomplete metabolic response received individualized dose escalation based on tumor and normal tissue constraints. Survival and treatment failure were observed and analyzed using SPSS (13.0). The rate of complete metabolic response for patients with noncomplete metabolic response after dose escalation reached 17.3% (9 of 52). The 2-year overall survival rates for patients with noncomplete metabolic response in the conventional and dose-escalation groups were 20.5% and 42.8%, respectively( P = .001). The 2-year local control rates for patients were 35.7% and 76.2%, respectively ( P = .002). When patients were classified into partial metabolic response and no metabolic response, 2-year overall survival rates for patients with partial metabolic response were significantly different in conventional and dose-escalation groups (33.8% vs 78.4%; P = .000). The 2-year overall survival rates for patients with no metabolic response in two groups (8.6% vs 15.1%) did not significantly differ ( P = .917). Individualized radiation dose escalation has the potential to improve survival in patients with esophageal carcinoma according to increased rate of complete metabolic response. However, further trials are needed to confirm this and to identify patients who may benefit from dose escalation.

Substitution of starch by soluble fiber and Saccharomyces cerevisiae dose response on nutrient digestion and blood metabolites for precision-fed dairy heifers.

PubMed

Lascano, G J; Heinrichs, A J; Tricarico, J M

2012-06-01

The objective of this experiment was to determine the effects of 2 levels of dietary starch and the dose at which the effects of yeast culture (YC) derived from Saccharomyces cerevisiae (Yea-Sacc¹⁰²⁶, Alltech Inc., Nicholasville, KY) were maximized based on nutrient total-tract digestibility (AD), N utilization, and blood metabolites of precision-fed dairy heifers. A split-plot design with starch level as the whole plot and YC dose as subplot was administered in a 4-period (21 d), 4 × 4 Latin square. Eight Holstein heifers (432.49 ± 6.81 kg of body weight) were allocated to 2 starch treatments (28% starch, high starch, HS, or 17% starch, low starch, LS) and to a sequence of YC doses (0, 10, 30, and 50 g/d). Dry matter (DM) and neutral detergent fiber (NDF) AD were not different between HS and LS; however, HS decreased acid detergent fiber (ADF) and increased hemicellulose AD. Digestibility of DM and organic matter (OM) increased quadratically in response to increasing YC dose. Hemicellulose, NDF, and ADF AD increased or tended to increase quadratically with increasing YC dose. No significant effects were noted on fecal or urine output between dietary starch concentrations; YC decreased wet and dry fecal output corresponding to the effect in DM and OM. Apparent N digestibility was greater in the LS group. As YC dose increased, fecal N output decreased quadratically and was lowest at 30 g/d YC. A corresponding quadratic increase was observed for N retention expressed as a percentage of N digested: N output in urine tended to increase with increasing YC dose, resulting in no differences in retained N (g/d). Dietary starch concentration did not affect blood glucose, triglyceride, creatinine, or lactate concentration. However, HS increased plasma urea N concentration. Glucose concentration tended to increase quadratically with daily YC dose in both starch treatments, with the greatest response at 30 g/d. For triglycerides, dietary starch concentration and YC dose interacted, decreasing quadratically in the LS group and increasing in the HS group (lowest and highest value for 10 g/d respectively). We observed a significant time effect for all blood metabolites measured. We conclude that starch level did not affect DM AD, but influenced ADF and hemicellulose AD. Yeast culture had the greatest effect on DM, NDF, ADF, and hemicellulose AD when added at 30 g/d. Addition of YC influenced glucose and triglyceride concentrations differently according to the dietary starch concentration of the diet. Copyright © 2012 American Dairy Science Association. Published by Elsevier Inc. All rights reserved.

Testosterone influences spatial strategy preferences among adult male rats

PubMed Central

Spritzer, Mark D.; Fox, Elliott C.; Larsen, Gregory D.; Batson, Christopher G.; Wagner, Benjamin A.; Maher, Jack

2013-01-01

Males outperform females on some spatial tasks, and this may be partially due to the effects of sex steroids on spatial strategy preferences. Previous work with rodents indicates that low estradiol levels bias females toward a striatum-dependent response strategy, whereas high estradiol levels bias them toward a hippocampus-dependent place strategy. We tested whether testosterone influenced the strategy preferences in male rats. All subjects were castrated and assigned to one of three daily injection doses of testosterone (0.125, 0.250, or 0.500 mg/rat) or a control group that received daily injections of the drug vehicle. Three different maze protocols were used to determine rats’ strategy preferences. A low dose of testosterone (0.125 mg) biased males toward a motor-response strategy on a T-maze task. In a water maze task in which the platform itself could be used intermittently as a visual cue, a low testosterone dose (0.125 mg) caused a significant increase in the use of a cued-response strategy relative to control males. Results from this second experiment also indicated that males receiving a high dose of testosterone (0.500 mg) were biased toward a place strategy. A third experiment indicated that testosterone dose did not have a strong influence on the ability of rats to use a nearby visual cue (floating ball) in the water maze. For this experiment, all groups seemed to use a combination of place and cued-response strategies. Overall, the results indicate that the effects of testosterone on spatial strategy preference are dose dependent and task dependent. PMID:23597827

Testosterone influences spatial strategy preferences among adult male rats.

PubMed

Spritzer, Mark D; Fox, Elliott C; Larsen, Gregory D; Batson, Christopher G; Wagner, Benjamin A; Maher, Jack

2013-05-01

Males outperform females on some spatial tasks, and this may be partially due to the effects of sex steroids on spatial strategy preferences. Previous work with rodents indicates that low estradiol levels bias females toward a striatum-dependent response strategy, whereas high estradiol levels bias them toward a hippocampus-dependent place strategy. We tested whether testosterone influenced the strategy preferences in male rats. All subjects were castrated and assigned to one of three daily injection doses of testosterone (0.125, 0.250, or 0.500 mg/rat) or a control group that received daily injections of the drug vehicle. Three different maze protocols were used to determine rats' strategy preferences. A low dose of testosterone (0.125 mg) biased males toward a motor-response strategy on a T-maze task. In a water maze task in which the platform itself could be used intermittently as a visual cue, a low testosterone dose (0.125 mg) caused a significant increase in the use of a cued-response strategy relative to control males. Results from this second experiment also indicated that males receiving a high dose of testosterone (0.500 mg) were biased toward a place strategy. A third experiment indicated that testosterone dose did not have a strong influence on the ability of rats to use a nearby visual cue (floating ball) in the water maze. For this experiment, all groups seemed to use a combination of place and cued-response strategies. Overall, the results indicate that the effects of testosterone on spatial strategy preference are dose dependent and task dependent. Copyright © 2013 Elsevier Inc. All rights reserved.

Estradiol modulates the anorexic response to central glucagon-like peptide 1.

PubMed

Maske, Calyn B; Jackson, Christine M; Terrill, Sarah J; Eckel, Lisa A; Williams, Diana L

2017-07-01

Estrogens suppress feeding in part by enhancing the response to satiation signals. Glucagon-like peptide 1 (GLP-1) acts on receptor populations both peripherally and centrally to affect food intake. We hypothesized that modulation of the central GLP-1 system is one of the mechanisms underlying the effects of estrogens on feeding. We assessed the anorexic effect of 0, 1, and 10μg doses of GLP-1 administered into the lateral ventricle of bilaterally ovariectomized (OVX) female rats on a cyclic regimen of either 2μg β-estradiol-3-benzoate (EB) or oil vehicle 30min prior to dark onset on the day following hormone treatment. Central GLP-1 treatment significantly suppressed food intake in EB-treated rats at both doses compared to vehicle, whereas only the 10μg GLP-1 dose was effective in oil-treated rats. To follow up, we examined whether physiologic-dose cyclic estradiol treatment influences GLP-1-induced c-Fos in feeding-relevant brain areas of OVX females. GLP-1 significantly increased c-Fos expression in the area postrema (AP) and nucleus of the solitary tract (NTS), and the presence of estrogens may be required for this effect in the paraventricular nucleus of the hypothalamus (PVN). Together, these data suggest that modulation of the central GLP-1 system may be one of the mechanisms by which estrogens suppress food intake, and highlight the PVN as a region of interest for future investigation. Copyright © 2017 Elsevier Inc. All rights reserved.

Hepatitis B revaccination in healthy non-responder Chinese children: five-year follow-up of immune response and immunologic memory.

PubMed

Zhuang, Gui-Hua; Yan, Hong; Wang, Xue-Liang; Hwang, Lu-Yu; Wu, Qian; Wang, Li-Rong; Gao, Hai-Yan

2006-03-15

To assess persistence of anti-HBs and immunologic memory of non-responders after revaccination, 40 healthy non-responder children were given a three-dose recombinant hepatitis B vaccine revaccination randomly by intramuscular (10 microg per dose) or intradermal (2 microg per dose) route and followed up to five years. All 17 intramuscular and 22 of 23 intradermal children developed a seroprotective antibody response (anti-HBs>or=10 mIU/mL) after revaccination. Children of intramuscular group had significantly higher seroprotection rates and anti-HBs geometric mean titers than the intradermal group. At year 5, 50% of children in intramuscular group, but only 18.2% of intradermal group still maintained seroprotection (P=0.075). By the end of follow-up, a booster dose (5 microg) was given to those who had lost seroprotection. All the eight intramuscular children developed an anamnestic response with increase of anti-HBs level by 215 times, but two of the 18 intradermal children failed to produce seroprotective level. Three-routine-dose intramuscular revaccination was significantly more effective than low-dose intradermal revaccination with the same number of injections. No child seroconverted to HBsAg, and 11 had transient infections indicated by seroconversion to anti-HBc. These results demonstrated that non-responders could benefit from three doses intramuscular revaccination not only in high proportion of anti-HBs conversion but also in long-term persistence of seroprotection, and more importantly in preservation of the immunologic memory years after loss of protective anti-HBs.

Environmental standards for ionizing radiation: theoretical basis for dose-response curves.

PubMed Central

Upton, A C

1983-01-01

The types of injury attributable to ionizing radiation are subdivided, for purposes of risk assessment and radiological protection, into two broad categories: stochastic effects and nonstochastic effects. Stochastic effects are viewed as probablistic phenomena, varying in frequency but not severity as a function of the dose, without any threshold; nonstochastic effects are viewed as deterministic phenomena, varying in both frequency and severity as a function of the dose, with clinical thresholds. Included among stochastic effects are heritable effects (mutations and chromosome aberrations) and carcinogenic effects. Both types of effects are envisioned as unicellular phenomena which can result from nonlethal injury of individual cells, without the necessity of damage to other cells. For the induction of mutations and chromosome aberrations in the low-to-intermediate dose range, the dose-response curve with high-linear energy transfer (LET) radiation generally conforms to a linear nonthreshold relationship and varies relatively little with the dose rate. In contrast, the curve with low-LET radiation generally conforms to a linear-quadratic relationship, rising less steeply than the curve with high-LET radiation and increasing in slope with increasing dose and dose rate. The dose-response curve for carcinogenic effects varies widely from one type of neoplasm to another in the intermediate-to-high dose range, in part because of differences in the way large doses of radiation can affect the promotion and progression of different neoplasms. Information about dose-response relations for low-level irradiation is fragmentary but consistent, in general, with the hypothesis that the neoplastic transformation may result from mutation, chromosome aberration or genetic recombination in a single susceptible cell. PMID:6653536

Serum biomarkers for acute hepatotoxicity of Echis pyramidum snake venom in rats.

PubMed

Asmari, Abdulrahman K Al; Khan, Haseeb A; Banah, Faisal A; Buraidi, Ahmed A Al; Manthiri, Rajamohammed A

2015-01-01

Echis pyramidum is a venomous viper responsible for most cases of envenomation in Arabian Peninsula. We determined the acute phase (3-6 h) changes in serum markers of liver function including alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) and bilirubin in adult male Sprague Dawley rats injected with Echis pyramidum venom (EPV) in the doses of 0.00 (control), 0.25, 0.50 and 1.00 mg/kg bodyweight. We also analyzed markers of oxidative stress including superoxide dismutase (SOD), catalase (CAT), total thiols (T-SH) and thiobarbituric acids reactive substances (TBARS) in liver. The results showed significant and dose- and time-dependent increases in serum ALT, ALP and GGT activities after a single injection of EPV. Serum bilirubin was significantly increased by medium and high doses of EVP after 3 h post-injection and then decreased at 6 h. The low dose of EPV neither affected the activity of SOD nor altered the levels of liver T-SH and TBARS, however, it significantly decreased the activity of CAT at 6 h post-injection of EPV. The medium dose of EPV significantly reduced liver SOD activity after 6 h whereas the high dose significantly reduced the SOD activity at 3 h and 6 h post-dosing. Both medium and high doses of EPV caused significant as well as dose- and time-dependent reductions in liver CAT activities. The high dose significantly reduced T-SH and increased TBARS in rat liver. Further studies are warranted to test the pharmacological potential of early phase antioxidant therapy for neutralizing the toxic effects of EPV.

Modern dosimetric tools for 60Co irradiation at high containment laboratories

PubMed Central

Twardoski, Barri; Feldmann, Heinz; Bloom, Marshall E.; Ward, Joe

2011-01-01

Purpose To evaluate an innovative photo-fluorescent film as a routine dosimetric tool during 60Co irradiations at a high containment biological research laboratory, and to investigate whether manufacturer-provided chamber exposure rates can be used to accurately administer a prescribed dose to biological specimens. Materials and methods Photo-fluorescent, lithium fluoride film dosimeters and National Institutes of Standards and Technology (NIST) transfer dosimeters were co-located in a self-shielded 60Co irradiator and exposed to γ-radiation with doses ranging from 5–85 kGy. Film dose-response relationships were developed for varying temperatures simulating conditions present when irradiating infectious biological specimens. Dose measurement results from NIST transfer dosimeters were compared to doses predicted using manufacturer-provided irradiator chamber exposure rates. Results The film dosimeter exhibited a photo-fluorescent response signal that was consistent and nearly linear in relationship to γ-radiation exposure over a wide dose range. The dosimeter response also showed negligible effects from dose fractionization and humidity. Significant disparities existed between manufacturer-provided chamber exposure rates and actual doses administered. Conclusion This study demonstrates the merit of utilizing dosimetric tools to validate the process of exposing dangerous and exotic biological agents to γ-radiation at high containment laboratories. The film dosimeter used in this study can be utilized to eliminate potential for improperly administering γ-radiation doses. PMID:21961968

Dose-dependent social-cognitive effects of intranasal oxytocin delivered with novel Breath Powered device in adults with autism spectrum disorder: a randomized placebo-controlled double-blind crossover trial

PubMed Central

Quintana, D S; Westlye, L T; Hope, S; Nærland, T; Elvsåshagen, T; Dørum, E; Rustan, Ø; Valstad, M; Rezvaya, L; Lishaugen, H; Stensønes, E; Yaqub, S; Smerud, K T; Mahmoud, R A; Djupesland, P G; Andreassen, O A

2017-01-01

The neuropeptide oxytocin has shown promise as a treatment for symptoms of autism spectrum disorders (ASD). However, clinical research progress has been hampered by a poor understanding of oxytocin’s dose–response and sub-optimal intranasal delivery methods. We examined two doses of oxytocin delivered using a novel Breath Powered intranasal delivery device designed to improve direct nose-to-brain activity in a double-blind, crossover, randomized, placebo-controlled trial. In a randomized sequence of single-dose sessions, 17 male adults with ASD received 8 international units (IU) oxytocin, 24IU oxytocin or placebo followed by four social-cognitive tasks. We observed an omnibus main effect of treatment on the primary outcome measure of overt emotion salience as measured by emotional ratings of faces (η2=0.18). Compared to placebo, 8IU treatment increased overt emotion salience (P=0.02, d=0.63). There was no statistically significant increase after 24IU treatment (P=0.12, d=0.4). The effects after 8IU oxytocin were observed despite no significant increase in peripheral blood plasma oxytocin concentrations. We found no significant effects for reading the mind in the eyes task performance or secondary outcome social-cognitive tasks (emotional dot probe and face-morphing). To our knowledge, this is the first trial to assess the dose-dependent effects of a single oxytocin administration in autism, with results indicating that a low dose of oxytocin can significantly modulate overt emotion salience despite minimal systemic exposure. PMID:28534875

Modeling Effective Dosages in Hormetic Dose-Response Studies

PubMed Central

Belz, Regina G.; Piepho, Hans-Peter

2012-01-01

Background Two hormetic modifications of a monotonically decreasing log-logistic dose-response function are most often used to model stimulatory effects of low dosages of a toxicant in plant biology. As just one of these empirical models is yet properly parameterized to allow inference about quantities of interest, this study contributes the parameterized functions for the second hormetic model and compares the estimates of effective dosages between both models based on 23 hormetic data sets. Based on this, the impact on effective dosage estimations was evaluated, especially in case of a substantially inferior fit by one of the two models. Methodology/Principal Findings The data sets evaluated described the hormetic responses of four different test plant species exposed to 15 different chemical stressors in two different experimental dose-response test designs. Out of the 23 data sets, one could not be described by any of the two models, 14 could be better described by one of the two models, and eight could be equally described by both models. In cases of misspecification by any of the two models, the differences between effective dosages estimates (0–1768%) greatly exceeded the differences observed when both models provided a satisfactory fit (0–26%). This suggests that the conclusions drawn depending on the model used may diverge considerably when using an improper hormetic model especially regarding effective dosages quantifying hormesis. Conclusions/Significance The study showed that hormetic dose responses can take on many shapes and that this diversity can not be captured by a single model without risking considerable misinterpretation. However, the two empirical models considered in this paper together provide a powerful means to model, prove, and now also to quantify a wide range of hormetic responses by reparameterization. Despite this, they should not be applied uncritically, but after statistical and graphical assessment of their adequacy. PMID:22438929

Paradox effects of binge drinking on response inhibition processes depending on mental workload.

PubMed

Stock, Ann-Kathrin; Riegler, Lea; Chmielewski, Witold X; Beste, Christian

2016-06-01

Binge drinking is an increasing problem in Western societies, but we are still only beginning to unravel the effects of binge drinking on a cognitive level. While common sense suggests that all cognitive functions are compromised during high-dose ethanol intoxication, several studies suggest that the effects might instead be rather specific. Moreover, some results suggest that the degrees of automaticity and complexity of cognitive operations during response control modulate effects of binge drinking. However, this has not been tested in detail. In the current study, we therefore parametrically modulate cognitive/"mental" workload during response inhibition and examine the effects of high-dose ethanol intoxication (~1.1 ‰) in n = 18 male participants. The results suggest that detrimental effects of high-dose ethanol intoxication strongly depend on the complexity of processes involved in response inhibition. The results revealed strong effects (η (2) = .495) and are in line with findings showing that even high doses of ethanol have very specific effects on a cognitive level. Opposed to common sense, more complex cognitive operations seem to be less affected by a high-dose ethanol intoxication. Complementing this, high-dose ethanol intoxication is increasingly detrimental for action control, as stronger automated response tendencies are in charge and need to be controlled. Binge-like ethanol intoxication may take a heavier toll on cognitive control processes than on automated responses/response tendencies. Therefore, ethanol effects are more pronounced in supposedly "easier" control conditions because those facilitate the formation of automated response tendencies.

Oral desmopressin in central diabetes insipidus.

PubMed Central

Westgren, U; Wittström, C; Harris, A S

1986-01-01

Seven paediatric patients with central diabetes insipidus were studied in an open dose ranging study in hospital followed by a six month study on an outpatient basis to assess the efficacy and safety of peroral administration of DDAVP (desmopressin) tablets. In the dose ranging study a dose dependent antidiuretic response was observed. The response to 12.5-50 mcg was, however, less effective in correcting baseline polyuria than were doses of 100 mcg and above. Patients were discharged from hospital on a preliminary dosage regimen ranging from 100 to 400 mcg three times daily. After an initial adjustment in dosage in three patients at one week follow up, all patients were stabilised on treatment with tablets and reported an adequate water turnover at six months. As with the intranasal route of administration dosage requirements varied from patient to patient, and a dose range rather than standard doses were required. A significant correlation, however, was found for the relation between previous intranasal and present oral daily dosage. No adverse reactions were reported. No clinically significant changes were noted in blood chemistry and urinalysis. All patients expressed a preference for the oral over existing intranasal treatment. Treatment with tablets offers a beneficial alternative to the intranasal route, particularly in patients with chronic rhinitis or impaired vision. PMID:3963868

Does cocoa/dark chocolate supplementation have favorable effect on body weight, body mass index and waist circumference? A systematic review, meta-analysis and dose-response of randomized clinical trials.

PubMed

Kord-Varkaneh, Hamed; Ghaedi, Ehsan; Nazary-Vanani, Ali; Mohammadi, Hamed; Shab-Bidar, Sakineh

2018-03-19

Cocoa and dark chocolate (DC) have been reported to be effective for health promotion; however the exact effect of cocoa/DC on anthropometric measures have not been yet defined. A comprehensive search to identify randomized clinical trials investigating the impact of cocoa/DC on body weight, body mass index (BMI) and waist circumference (WC) was performed up to December 2017. A meta-analysis of eligible studies was performed using random effects model to estimate pooled effect size. Fractional polynominal modeling was used to explore dose-response relationships. A total of 35 RCTs investigated the effects of cocoa/DC on weight, BMI and WC were included. Meta-analysis did not suggest any significant effect of cocoa/DC supplementation on body weight (-0.108 kg, 95% CI -0.262, 0.046 P = 0.168), BMI (-0.014 kg/m 2 95% CI -0.105, 0.077, P: 0.759,) and WC (0.025 cm 95% CI -0.083, 0.129, P = 0.640). Subgroup analysis revealed that that weight and BMI were reduced with cocoa/DC supplementation ≥ 30 g chocolate per day in trials between 4-8 weeks. Cocoa/DC consumption resulted in WC reduction in non-linear fashion (r = 0.042, P-nonlinearity = 0.008). Cocoa/DC supplementation does not reduce anthropometric measures significantly. However subgroup analysis regarding dose (≥ 30 g/day) and duration (between 4 to 8 weeks) revealed significant reduction of body weight and BMI.

Initial results utilizing combination therapy for patients with a suboptimal response to either alprostadil or sildenafil monotherapy.

PubMed

Mydlo, J H; Volpe, M A; Macchia, R J

2000-07-01

Intraurethral alprostadil and oral sildenafil are useful in selected patients. However, there continues to be a significant treatment failure rate. Since their mechanisms of action are different, we wanted to evaluate the effectiveness of combination therapy. Of 214 patients treated for erectile dysfunction (ED), 65 were not fully satisfied with the firmness of their erections via monotherapy. Responses were evaluated using the International Index for Erectile Function (IIEF) questionnaire before and after treatment. Group I consisted of 33 patients who tried maximal dose intraurethral alprostadil monotherapy initially, followed by the maximal dose of sildenafil monotherapy, and were still unsatisfied. Group II consisted of 32 patients who tried the maximal dose sildenafil monotherapy initially, followed by the maximal dose of alprostadil monotherapy, and were also unsatisfied. There 65 patients then underwent combination therapy. 60 out of the 65 patients stated they were satisfied with combination therapy. Questionnaire scores for erectile function were 23.1+/-2.0 (114%) for combination therapy vs. 19.2+/-1.8 (77%) and 15.2+/-1.6 (41%) for sildenafil and alprostadil monotherapies (p<0.05). There were no significant differences in responses between the two groups. The men also reported improvement in intercourse and overall satisfaction. Combination therapy may be an option for motivated patients who have a suboptimal response from monotherapy.

Low dose radiation risks for women surviving the a-bombs in Japan: generalized additive model.

PubMed

Dropkin, Greg

2016-11-24

Analyses of cancer mortality and incidence in Japanese A-bomb survivors have been used to estimate radiation risks, which are generally higher for women. Relative Risk (RR) is usually modelled as a linear function of dose. Extrapolation from data including high doses predicts small risks at low doses. Generalized Additive Models (GAMs) are flexible methods for modelling non-linear behaviour. GAMs are applied to cancer incidence in female low dose subcohorts, using anonymous public data for the 1958 - 1998 Life Span Study, to test for linearity, explore interactions, adjust for the skewed dose distribution, examine significance below 100 mGy, and estimate risks at 10 mGy. For all solid cancer incidence, RR estimated from 0 - 100 mGy and 0 - 20 mGy subcohorts is significantly raised. The response tapers above 150 mGy. At low doses, RR increases with age-at-exposure and decreases with time-since-exposure, the preferred covariate. Using the empirical cumulative distribution of dose improves model fit, and capacity to detect non-linear responses. RR is elevated over wide ranges of covariate values. Results are stable under simulation, or when removing exceptional data cells, or adjusting neutron RBE. Estimates of Excess RR at 10 mGy using the cumulative dose distribution are 10 - 45 times higher than extrapolations from a linear model fitted to the full cohort. Below 100 mGy, quasipoisson models find significant effects for all solid, squamous, uterus, corpus, and thyroid cancers, and for respiratory cancers when age-at-exposure > 35 yrs. Results for the thyroid are compatible with studies of children treated for tinea capitis, and Chernobyl survivors. Results for the uterus are compatible with studies of UK nuclear workers and the Techa River cohort. Non-linear models find large, significant cancer risks for Japanese women exposed to low dose radiation from the atomic bombings. The risks should be reflected in protection standards.

Further assessment of the clinically effective dose range of etoricoxib: a randomized, double-blinded, placebo-controlled trial in rheumatoid arthritis.

PubMed

Greenwald, M; Peloso, P M; Mandel, D; Soto, O; Mehta, A; Frontera, N; Boice, J A; Zhan, X J; Curtis, S P

2011-10-01

To further assess the clinically active dose range of etoricoxib, a COX-2 selective inhibitor, in rheumatoid arthritis (RA). RA patients were randomized to etoricoxib 10, 30, 60, or 90 mg or placebo in a double-blind, 12-week study. DMARDs (methotrexate, biologics) or low-dose corticosteroids were allowed in stable doses. The primary endpoint was the proportion of patients completing the study and achieving an American College of Rheumatology 20% (ACR20) response. Secondary endpoints included individual components of the ACR index and Patient Global Assessment of Pain. Safety was assessed by physical exam and adverse experiences (AEs) occurrences. Etoricoxib 90 mg was the only dose to reach a statistically significant difference from placebo (p < 0.001) on the primary endpoint; etoricoxib 60 mg approached significance (p = 0.057). Significant pain improvement vs. placebo was observed with etoricoxib 90 mg (p < 0.001), 60 mg (p = 0.018), and 30 mg (p = 0.017). Despite the use of background biologics and corticosteroids, a dose response was still apparent. A higher proportion of etoricoxib 60 and 90 mg patients had renovascular AEs (i.e., edema and hypertension) compared with placebo, although discontinuations for renovascular AEs were rare. Etoricoxib 90 mg had a higher incidence of serious AEs (n = 5; 1 was considered drug-related) versus placebo (n = 0). The present study was not powered to detect differences in cardiovascular or gastrointestinal safety by dose. Additionally, further research is needed to clarify the role of doses less than the etoricoxib 90 mg dose for pain management in RA patients. Etoricoxib 90 mg demonstrated statistically superior efficacy (ACR20) compared with placebo and numerical superiority over the other doses of etoricoxib studied. Etoricoxib 30 and 60 mg demonstrated significant pain improvement versus placebo, suggesting utility for some patients.

Effects of aqueous, methanolic and chloroform extracts of rhizome and aerial parts of Valeriana officinalis L. on naloxone-induced jumping in morphine-dependent mice.

PubMed

Sharifzadeh, Mohammad; Hadjiakhoondi, Abbas; Khanavi, Mahnaz; Susanabadi, Maryam

2006-06-01

In the present study, the effects of rhizomes and aerial parts extracts of Valeriana officinalis L. on morphine dependence in mice have been investigated. Animals were treated subcutaneously with morphine (50, 50 and 75 mg/kg) three times daily (10 am, 1 pm and 4 pm) for 3 days, and a last dose of morphine (50 mg/kg) was administered on the fourth day. Withdrawal syndrome (jumping) was precipitated by naloxone (5 mg/kg) which was administered intraperitoneally 2 hours after the last dose of morphine. To study the effects of the aqueous, methanolic and chloroform extracts of both aerial parts and rhizome of the V. officinalis L. on naloxone-induced jumping in morphine-dependent animals, 10 injections of morphine (three administrations each day) for dependence and a dose of 5 mg/kg of naloxone for withdrawal induction were employed. Intraperitoneal injection of different doses (1, 5, 25 and 50 mg/kg) of aqueous, methanolic and chloroform extracts of the rhizome of V. officinalis L. 60 minutes before naloxone injection decreased the jumping response dose-dependently. Pre-treatment of animals with different doses (1, 5, 25, 50 and 100 mg/kg) of aqueous and methanolic extracts of aerial parts of V. officinalis L. 60 minutes before naloxone injection caused a significant decrease on naloxone-induced jumping. The chloroform extract of the aerial parts of V. officinalis L. did not show any significant changes on jumping response in morphine-dependent animals. It is concluded that the extracts of V. officinalis L. could affect morphine withdrawal syndrome via possible interactions with inhibitory neurotransmitters in nervous system.

Pharmacodynamics of Imipenem in Combination with β-Lactamase Inhibitor MK7655 in a Murine Thigh Model

PubMed Central

Mavridou, Eleftheria; Melchers, Ria J. B.; van Mil, Anita C. H. A. M.; Mangin, E.; Motyl, Mary R.

2014-01-01

MK7655 is a newly developed beta-lactamase inhibitor of class A and class C carbapenemases. Pharmacokinetics (PK) of imipenem-cilastatin (IMP/C) and MK7655 were determined for intraperitoneal doses of 4 mg/kg to 128 mg/kg of body weight. MIC and pharmacodynamics (PD) studies of MK7655 were performed against several beta-lactamase producing Pseudomonas aeruginosa and Klebsiella pneumoniae strains to determine its effect in vitro and in vivo. Neutropenic mice were infected in each thigh 2 h before treatment with an inoculum of approximately 5 × 106 CFU. They were treated with IMP/C alone (every 2 hours [q2h], various doses) or in combination with MK7655 in either a dose fractionation study or q2h for 24 h and sacrificed for CFU determinations. IMP/MK7655 decreased MICs regarding IMP MIC. The PK profiles of IMP/C and MK7655 were linear over the dosing range studied and comparable with volumes of distribution (V) of 0.434 and 0.544 liter/kg and half-lives (t1/2) of 0.24 and 0.25 h, respectively. Protein binding of MK7655 was 20%. A sigmoidal maximum effect (Emax) model was fit to the PK/PD index responses. The effect of the inhibitor was not related to the maximum concentration of drug in serum (Cmax)/MIC, and model fits for T>MIC and area under the concentration-time curve (AUC)/MIC were comparable (R2 of 0.7 and 0.75), but there appeared to be no significant relationship of effect with dose frequency. Escalating doses of MK7655 and IMP/C showed that the AUC of MK7655 required for a static effect was dependent on the dose of IMP/C and the MIC of the strain, with a mean area under the concentration-time curve for the free, unbound fraction of the drug (fAUC) of 26.0 mg · h/liter. MK7655 shows significant activity in vivo and results in efficacy of IMP/C in otherwise resistant strains. The exposure-response relationships found can serve as a basis for establishing dosing regimens in humans. PMID:25403667

Acceleration of atherogenesis in ApoE-/- mice exposed to acute or low-dose-rate ionizing radiation.

PubMed

Mancuso, Mariateresa; Pasquali, Emanuela; Braga-Tanaka, Ignacia; Tanaka, Satoshi; Pannicelli, Alessandro; Giardullo, Paola; Pazzaglia, Simonetta; Tapio, Soile; Atkinson, Michael J; Saran, Anna

2015-10-13

There is epidemiological evidence for increased non-cancer mortality, primarily due to circulatory diseases after radiation exposure above 0.5 Sv. We evaluated the effects of chronic low-dose rate versus acute exposures in a murine model of spontaneous atherogenesis. Female ApoE-/- mice (60 days) were chronically irradiated for 300 days with gamma rays at two different dose rates (1 mGy/day; 20 mGy/day), with total accumulated doses of 0.3 or 6 Gy. For comparison, age-matched ApoE-/- females were acutely exposed to the same doses and sacrificed 300 days post-irradiation. Mice acutely exposed to 0.3 or 6 Gy showed increased atherogenesis compared to age-matched controls, and this effect was persistent. When the same doses were delivered at low dose rate over 300 days, we again observed a significant impact on global development of atherosclerosis, although at 0.3 Gy effects were limited to the descending thoracic aorta. Our data suggest that a moderate dose of 0.3 Gy can have persistent detrimental effects on the cardiovascular system, and that a high dose of 6 Gy poses high risks at both high and low dose rates. Our results were clearly nonlinear with dose, suggesting that lower doses may be more damaging than predicted by a linear dose response.

Response of murine tumours to combinations of CCNU with misonidazole and other radiation sensitizers.

PubMed Central

Siemann, D. W.

1982-01-01

The effect of combinations of the conventional chemotherapeutic agent 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) and nitroimidazole radiation sensitizers was evaluated in female C3H mice. Tumour response to single-agent or combination therapy was assessed in a tumour growth-delay assay. In the KHT sarcoma the simultaneous addition of misonidazole (MISO) was found to increase significantly the tumour growth delay resulting from CCNU treatment. The observed enhancement ratios (ER) increased with MISO dose, and ranged from 1.3 to 1.9 for sensitizer doses of 0.25-1.0 mg/g. The combination of CCNU and 1.0 or 0.5 mg/g MISO in the RIF-1 tumour or the MT-1 tumour produced ERs of approximately 2.0 and approximately 1.5 respectively. In the KHT sarcoma a series of other nitroimidazole sensitizers, including Ro-05-9963, SR-2555, SR-2508 and metronidazole (METRO), were also evaluated at equimolar doses (5 mmol/kg) in combination with a 20mg/kg dose of CCNU. Unlike MISO, these compounds in general failed to enhance the CCNU cytotoxicity in this tumour model. However, SR-2508 did enhance the response of the RIF-1 tumour to large single doses of CCNU, though not as much as MISO. Normal-tissue toxicity was determined using peripheral white blood cell (WBC) counts 3 days after treatment. CCNU doses of 10-50 mg/kg given either alone or in simultaneous combination with 0.5 or 1.0 mg/g MISO were studied. WBC toxicity increased with CCNU dose, but the addition of MISO at either dose did not significantly enhance this normal-tissue toxicity. PMID:6460517

Brain volume changes over the first year of treatment in schizophrenia: relationships to antipsychotic treatment.

PubMed

Emsley, R; Asmal, L; du Plessis, S; Chiliza, B; Phahladira, L; Kilian, S

2017-09-01

Progressive brain volume reductions have been described in schizophrenia, and an association with antipsychotic exposure has been reported. We compared percentage changes in grey and white matter volume from baseline to month 12 in 23 previously antipsychotic-naïve patients with a first episode of schizophrenia or schizophreniform disorder who were treated with the lowest effective dose of flupenthixol decanoate depot formulation, with 53 matched healthy individuals. Total antipsychotic dose was precisely calculated and its relationship with brain volume changes investigated. Relationships between volumetric changes and treatment were further investigated in terms of treatment response (changes in psychopathology and functionality) and treatment-related adverse-events (extrapyramidal symptoms and weight gain). Excessive cortical volume reductions were observed in patients [-4.6 (6.6)%] v. controls [-1.12 (4.0)%] (p = 0.009), with no significant group differences for changes in subcortical grey matter and white matter volumes. In a multiple regression model, the only significant predictor of cortical volume change was total antipsychotic dose received (p = 0.04). Cortical volume change was not significantly associated with the changes in psychopathology, functionality, extrapyramidal symptoms and body mass index or age, gender and duration of untreated psychosis. Brain volume reductions associated with antipsychotic treatment are not restricted to poor outcome patients and occur even with the lowest effective dose of antipsychotic. The lack of an association with poor treatment response or treatment-related adverse effects counts against cortical volume reductions reflecting neurotoxicity, at least in the short term. On the other hand, the volume reductions were not linked to the therapeutic benefits of antipsychotics.

The evaluation of the novel pressor activity of gamma-piperidinobutyramide (WY 20051, DF480).

PubMed Central

Alps, B J; Devoy, P W; Waterfall, J F

1976-01-01

1 gamma-Piperidinobutyramide (Wy 20051, DF480) injected intravenously evoked pressor responses in the anaesthetized ganglion blocked rat preparation over the dose range 2.4 x 10(-6)-3.0 x 10(-4) mol/kg. 2 High doses (greater than 3.8 x 10(-5) mol/kg) or even repeated submaximal doses (1.9 x 10(-5) mol/kg) of Wy 20051 caused tachyphylaxis of this pressor response. 3 The noradrenaline pressor-response curve was shifted significantly to the right of the control curve following a dose of Wy 20051 (1.5 x 10(-4) mol/kg cumulative). 4 The dose-response curve for the pressor action of Wy 20051 was potentiated in reserpine-treated anaesthetized rats. In contrast, tyramine-induced pressor responses were abolished. 5 Wy 20051 contracted the guinea-pig isolated aortic spiral preparation (3.8 x 10(-5)-6.0 x 10(-4) mol) and evoked constrictor responses in the perfused mesenteric vasculature preparation of the rat (5.9 x 10(-7)-1.2 x 10(-5) mol). At higher doses the responses were reduced. 6 Wy 20051-induced constrictor responses of the perfused mesentery were unaffected by blockade of alpha-adrenoceptors or by tachyphylaxis of 5-hydroxytryptamine receptors. 7 The time for abolition of Wy 20051-induced constrictor responses of the mesentery in a calcium-free medium was not significantly different from that required for noradrenaline, but was significantly greater than that for KCl (P less than 0.001). 8 Wy 20051 and noradrenaline, but not KCl, evoked constrictor responses in the depolarized rat mesenteric vasculature. 9 The results indicate that Wy 20051 evokes pressor responses which have some of the characteristics of those of noradrenaline. However, the responses are not elicited by an alpha-adrenoceptor mechanism. PMID:3247

Bisphenol-A exposures and behavioural aberrations: median and linear spline and meta-regression analyses of 12 toxicity studies in rodents.

PubMed

Peluso, Marco E M; Munnia, Armelle; Ceppi, Marcello

2014-11-05

Exposures to bisphenol-A, a weak estrogenic chemical, largely used for the production of plastic containers, can affect the rodent behaviour. Thus, we examined the relationships between bisphenol-A and the anxiety-like behaviour, spatial skills, and aggressiveness, in 12 toxicity studies of rodent offspring from females orally exposed to bisphenol-A, while pregnant and/or lactating, by median and linear splines analyses. Subsequently, the meta-regression analysis was applied to quantify the behavioural changes. U-shaped, inverted U-shaped and J-shaped dose-response curves were found to describe the relationships between bisphenol-A with the behavioural outcomes. The occurrence of anxiogenic-like effects and spatial skill changes displayed U-shaped and inverted U-shaped curves, respectively, providing examples of effects that are observed at low-doses. Conversely, a J-dose-response relationship was observed for aggressiveness. When the proportion of rodents expressing certain traits or the time that they employed to manifest an attitude was analysed, the meta-regression indicated that a borderline significant increment of anxiogenic-like effects was present at low-doses regardless of sexes (β)=-0.8%, 95% C.I. -1.7/0.1, P=0.076, at ≤120 μg bisphenol-A. Whereas, only bisphenol-A-males exhibited a significant inhibition of spatial skills (β)=0.7%, 95% C.I. 0.2/1.2, P=0.004, at ≤100 μg/day. A significant increment of aggressiveness was observed in both the sexes (β)=67.9,C.I. 3.4, 172.5, P=0.038, at >4.0 μg. Then, bisphenol-A treatments significantly abrogated spatial learning and ability in males (P<0.001 vs. females). Overall, our study showed that developmental exposures to low-doses of bisphenol-A, e.g. ≤120 μg/day, were associated to behavioural aberrations in offspring. Copyright © 2014. Published by Elsevier Ireland Ltd.

A Radiation-Induced Hippocampal Vascular Injury Surrogate Marker Predicts Late Neurocognitive Dysfunction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Farjam, Reza; Pramanik, Priyanka; Aryal, Madhava P.

Purpose: We aimed to develop a hippocampal vascular injury surrogate marker for early prediction of late neurocognitive dysfunction in patients receiving brain radiation therapy (RT). Methods and Materials: Twenty-seven patients (17 males and 10 females, 31-80 years of age) were enrolled in an institutional review board-approved prospective longitudinal study. Patients received diagnoses of low-grade glioma or benign tumor and were treated by (3D) conformal or intensity-modulated RT with a median dose of 54 Gy (50.4-59.4 Gy in 1.8-Gy fractions). Six dynamic-contrast enhanced MRI scans were performed from pre-RT to 18-month post-RT, and quantified for vascular parameters related to blood-brain barrier permeability, K{sup trans},more » and the fraction of blood plasma volume, V{sub p}. The temporal changes in the means of hippocampal transfer constant K{sup trans} and V{sub p} after starting RT were modeled by integrating the dose effects with age, sex, hippocampal laterality, and presence of tumor or edema near a hippocampus. Finally, the early vascular dose response in hippocampi was correlated with neurocognitive dysfunction at 6 and 18 months post-RT. Results: The mean K{sup trans} Increased significantly from pre-RT to 1-month post-RT (P<.0004), which significantly depended on sex (P<.0007) and age (P<.00004), with the dose response more pronounced in older females. Also, the vascular dose response in the left hippocampus of females correlated significantly with changes in memory function at 6 (r=−0.95, P<.0006) and 18-months (r=−0.88, P<.02) post-RT. Conclusions: The early hippocampal vascular dose response could be a predictor of late neurocognitive dysfunction. A personalized hippocampus sparing strategy may be considered in the future.« less

Real-life effectiveness of canakinumab in cryopyrin-associated periodic syndrome.

PubMed

Kuemmerle-Deschner, Jasmin B; Hofer, Ferdinand; Endres, Theresa; Kortus-Goetze, Birgit; Blank, Norbert; Weißbarth-Riedel, Elisabeth; Schuetz, Catharina; Kallinich, Tilmann; Krause, Karoline; Rietschel, Christoph; Horneff, Gerd; Benseler, Susanne M

2016-04-01

Cryopyrin-associated periodic syndrome (CAPS) is a heterogeneous group of diseases characterized by excessive IL-1β release resulting in severe systemic and organ inflammation. Canakinumab targets IL-1β and is approved at standard dose for children and adults with all CAPS phenotypes. Limited data are available for the real-life effectiveness of canakinumab in patients living with CAPS. Therefore the aim of the study was to evaluate the real-life dosing and effectiveness of canakinumab in CAPS. A multi-centre study of consecutive children and adults with CAPS treated with canakinumab was performed. Demographics, CAPS phenotype and disease activity, inflammatory markers and canakinumab treatment strategy were recorded. Treatment response was assessed using CAPS disease activity scores, CRP and/or serum amyloid A levels. Comparisons between age groups, CAPS phenotypes and centres were conducted. A total of 68 CAPS patients at nine centres were included. All CAPS phenotypes were represented. Thirty-seven (54%) patients were females, the median age was 25 years and 27 (40%) were children, and the median follow-up was 28 months. Overall, complete response (CR) was seen in 72% of CAPS patients, significantly less often in severe (14%) than in mild CAPS phenotypes (79%). Only 53% attained CR on standard dose canakinumab. Dose increase was more commonly required in children (56%) than in adults (22%). Centres with a treat-to-target approach had significantly higher CR rates (94 vs 50%). Real-life effectiveness of canakinumab in CAPS was significantly lower than in controlled trials. Treat-to-target strategies may improve the outcome of children and adults living with CAPS. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Effect of tributyltin on antioxidant ability and immune responses of zebrafish (Danio rerio).

PubMed

Zhang, Chun-Nuan; Zhang, Ji-Liang; Ren, Hong-Tao; Zhou, Bian-Hua; Wu, Qiu-Jue; Sun, Ping

2017-04-01

Tributyltin (TBT) is a toxic compound released into aquatic ecosystems through antifouling paints. This study was designed to examine the effects of TBT on antioxidant ability and immune responses of zebrafish (Danio rerio). Three hundred sixty healthy zebrafish were randomly grouped into four groups and exposed to different doses of TBT (0, 1, 10 and 100ngL -1 ). At the end of 8 weeks, the fish were sampled, and antioxidant capability, immune parameters and immune-related genes were assessed. The results showed that with an increase in TBT dose, the concentration of malonaldehyde in the liver was significantly increased (p<0.05), whereas the activities of total superoxide dismutase, catalase and glutathione peroxidase were significantly decreased (p<0.05) compared to the control. The activity and expression of lysozyme and the content of immunoglobulin M were significantly decreased compared to those of the fish exposed to 0ngL -1 TBT (p<0.05). However, the expression of the HSP70, HSP90, tumor necrosis factor-α(TNF-α), interleukins (IL-1β, IL-6), and nuclear factor-kappa B p65 (NF-κ B p65) genes were all enhanced with an increase in TBT dose. The results indicated that TBT induced oxidative stress and had immunotoxic effects on zebrafish. Copyright © 2016 Elsevier Inc. All rights reserved.

TH-C-18A-09: Exam and Patient Parameters Affecting the DNA Damage Response Following CT Studies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Elgart, S; Adibi, A; Bostani, M

Purpose: To identify exam and patient parameters affecting the biological response to CT studies using in vivo and ex vivo blood samples. Methods: Blood samples were collected under IRB approval from 16 patients undergoing clinically-indicated CT exams. Blood was procured prior to, immediately after and 30minutes following irradiation. A sample of preexam blood was placed on the patient within the exam region for ex vivo analysis. Whole blood samples were fixed immediately following collection and stained for γH2AX to assess DNA damage response (DDR). Median fluorescence of treated samples was compared to non-irradiated control samples for each patient. Patients weremore » characterized by observed biological kinetic response: (a) fast — phosphorylation increased by 2minutes and fell by 30minutes, (b) slow — phosphorylation continued to increase to 30minutes and (c) none — little change was observed or irradiated samples fell below controls. Total dose values were normalized to exam time for an averaged dose-rate in dose/sec for each exam. Relationships between patient biological responses and patient and exam parameters were investigated. Results: A clearer dose response at 30minutes is observed for young patients (<61yoa; R2>0.5) compared to old patients (>61yoa; R{sup 2}<0.11). Fast responding patients were significantly younger than slow responding patients (p<0.05). Unlike in vivo samples, age did not significantly affect the patient response ex vivo. Additionally, fast responding patients received exams with significantly smaller dose-rate than slow responding patients (p<0.05). Conclusion: Age is a significant factor in the biological response suggesting that DDR may be more rapid in a younger population and slower as the population ages. Lack of an agerelated response ex vivo suggests a systemic response to radiation not present when irradiated outside the body. Dose-rate affects the biological response suggesting that patient response may be related to scan timing and dose delivery within an exam protocol. All authors receive(d) funding from a Master Research Agreement from Siemens Healthcare with UCLA Radiological Sciences.« less

The development of anthelmintic resistance with best practice control of nematodes on commercial sheep farms in the UK.

PubMed

Learmount, Jane; Stephens, Nathalie; Boughtflower, Valerie; Barrecheguren, Alba; Rickell, Kayleigh

2016-10-15

Antimicrobial resistance threatens the effective prevention and treatment of an ever-increasing range of infections. The widespread development of anthelmintic resistance is a major global issue affecting the effective control of parasite diseases in grazing livestock production. Sustainable control strategies that reduce dependence on antimicrobials have the potential to slow the further development of resistance but there is little data on the effect of control strategies on resistance development in the field. This report documents a study undertaken to measure the temporal effect of the UK sustainable control of parasites in sheep (SCOPS) guidelines on the development of anthelmintic resistance. Farms carrying out SCOPS or traditional worm control (TRADITIONAL) were tested for resistance to the benzimidazole and imidazothiazole anthelmintics in vitro using a discriminating dose (dd) larval development test (LDT) in year 1 and then 7 years later. In years 5 and 7, resistance was also measured using a dose-response LDT assay. There was a significant increase in Teladorsagia survivors at the benzimidazole dd assay between year 1 and year 7 for both treatment groups, but the increase in survivors was greater for the farms carrying out their traditional worm control compared to the SCOPS farms. There was also a significant difference between benzimidazole dd results generated across years for Trichostrongylus, but the year and treatment interaction was not significant. Only one of the farm Teladorsagia populations had survivors in the imidazothiazole dd assay in years 1 and 7 and none of the Trichostrongylus populations survived in year 1 compared to isolates from three of the farms in year 7. Dose-response data showed a significant effect for time for both the benzimidazole and imidazothiazole anthelmintics and the increase was again significantly higher for the Teladorsagia populations in the TRADITIONAL group compared to the SCOPS group. This data suggests an increased sensitivity both to detect and to measure changes in response to anthelmintics with the dose-response assay compared to the dd and this is important particularly when allele frequencies are low as might be the case when novel compounds are released to the market. Anthelmintic use across years 5-7 was significantly lower for the farms in the SCOPS group compared to the TRADITIONAL group and farmers in the SCOPS group had selected products from the benzimidazole group less often than farmers in the TRADITIONAL group. Both groups had made minimal use of the imidazothiazole anthelmintic classes and the majority of ewe treatments were selected from the macrocyclic lactone class. Further research is required to determine the effect of these anthelmintic choices on the development of resistance to the macrocyclic lactones. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

Risk of myelodysplastic syndromes in people exposed to ionizing radiation: a retrospective cohort study of Nagasaki atomic bomb survivors.

PubMed

Iwanaga, Masako; Hsu, Wan-Ling; Soda, Midori; Takasaki, Yumi; Tawara, Masayuki; Joh, Tatsuro; Amenomori, Tatsuhiko; Yamamura, Masaomi; Yoshida, Yoshiharu; Koba, Takashi; Miyazaki, Yasushi; Matsuo, Tatsuki; Preston, Dale L; Suyama, Akihiko; Kodama, Kazunori; Tomonaga, Masao

2011-02-01

The risk of myelodysplastic syndromes (MDS) has not been fully investigated among people exposed to ionizing radiation. We investigate MDS risk and radiation dose-response in Japanese atomic bomb survivors. We conducted a retrospective cohort study by using two databases of Nagasaki atomic bomb survivors: 64,026 people with known exposure distance in the database of Nagasaki University Atomic-Bomb Disease Institute (ABDI) and 22,245 people with estimated radiation dose in the Radiation Effects Research Foundation Life Span Study (LSS). Patients with MDS diagnosed from 1985 to 2004 were identified by record linkage between the cohorts and the Nagasaki Prefecture Cancer Registry. Cox and Poisson regression models were used to estimate relationships between exposure distance or dose and MDS risk. There were 151 patients with MDS in the ABDI cohort and 47 patients with MDS in the LSS cohort. MDS rate increased inversely with exposure distance, with an excess relative risk (ERR) decay per km of 1.2 (95% CI, 0.4 to 3.0; P < .001) for ABDI. MDS risk also showed a significant linear response to exposure dose level (P < .001) with an ERR per Gy of 4.3 (95% CI, 1.6 to 9.5; P < .001). After adjustment for sex, attained age, and birth year, the MDS risk was significantly greater in those exposed when young. A significant linear radiation dose-response for MDS exists in atomic bomb survivors 40 to 60 years after radiation exposure. Clinicians should perform careful long-term follow-up of irradiated people to detect MDS as early as possible.

Dose-response effects of oral guanidinoacetic acid on serum creatine, homocysteine and B vitamins levels.

PubMed

Ostojic, Sergej M; Stojanovic, Marko; Drid, Patrik; Hoffman, Jay R

2014-12-01

Guanidinoacetic acid (GAA) is an intermediate in the biosynthesis of creatine (Cr), yet its use in human nutrition is limited due to a lack of a clear understanding of its' dose-response effect. Thus, the purpose of this study was to investigate the effect of three different dosages of GAA (1.2, 2.4 and 4.8 g/day) administered for 6 weeks on serum and urinary variables related to GAA metabolism. Forty-eight healthy volunteers participated in the randomized, placebo-controlled, double-blind, repeated-measure study. At baseline, after 1, 2, 4 and 6 weeks, participants provided both fasting blood samples and 24-h urine. GAA intervention significantly increased serum and urinary GAA, Cr and creatinine as compared to placebo (P < 0.05). Differences were found for serum GAA and Cr responses between the three GAA dosages, with high-dose GAA resulting in a greater increase (P < 0.05) in the plasma concentration of both variables as compared to other GAA dosages. In GAA groups, fasting plasma total homocysteine (T-Hcy) increased by 3.5 μmol/L on average at post-administration, yet no dose-response differences were found between trials. Serum B vitamins were not affected by either placebo or GAA intervention (P > 0.05). Results indicate that low-to-high dosages of exogenous GAA can increase serum concentrations of Cr and T-Hcy while not depleting the B vitamins pool available for remethylation of homocysteine. ClinicalTrials.gov, identification number NCT01133899.

Somatic cell mutations at the glycophorin A locus in erythrocytes of atomic bomb survivors: Implications for radiation carcinogenesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kyoizumi, Seishi; Akiyama, Mitoshi; Tanabe, Kazumi

To clarify the relationship between somatic cell mutations and radiation exposure, the frequency of hemizygous mutant erythrocytes at the glycophorin A (GPA) locus was measured by flow cytometry for 1,226 heterozygous atomic bomb (A-bomb) survivors in HIroshima and Nagasaki. For statistical analysis, both GPA mutant frequency and radiation dose were log-transformed to normalize skewed distributions of these variables. The GPA mutant frequency increased slightly but significantly with age at testing and with the number of cigarettes smoked. Also, mutant frequency was significantly higher in males than in females even with adjustment for smoking and was higher to Hiroshima than inmore » Nagasaki. These characteristics of background GPA mutant frequency are qualitatively similar to those of background solid cancer incidence or mortality obtained from previous epidemiological studies of survivors. An analysis of the mutant frequency dose response using a descriptive model showed that the doubling dose is about 1.20 Sv [95% confidence interval (CI): 0.95-1.56], whereas the minimum dose for detecting a significant increase in mutant frequency is about 0.24 Sv (95% CI: 0.041-0.51). No significant effects of sex, city or age at the time of exposure on the dose response were detected. Interestingly, the doubling dose of the GPA mutant frequency was similar to that of solid cancer incidence in A-bomb survivors. This observation is in line with the hypothesis that radiation-induced somatic cell mutations are the major cause of excess cancer risk after radiation. 49 refs., 6 figs., 2 tabs.« less

Preliminary Analysis of the Multisphere Neutron Spectrometer

NASA Technical Reports Server (NTRS)

Goldhagen, P.; Kniss, T.; Wilson, J. W.; Singleterry, R. C.; Jones, I. W.; VanSteveninck, W.

2003-01-01

Crews working on present-day jet aircraft are a large occupationally exposed group with a relatively high average effective dose from galactic cosmic radiation. Crews of future high-speed commercial aircraft flying at higher altitudes would be even more exposed. To help reduce the significant uncertainties in calculations of such exposures, the Atmospheric Ionizing Radiation (AIR) Project, an international collaboration of 15 laboratories, made simultaneous radiation measurements with 14 instruments on five flights of a NASA ER-2 high-altitude aircraft. The primary AIR instrument was a highly sensitive extended-energy multisphere neutron spectrometer with lead and steel shells placed within the moderators of two of its 14 detectors to enhance response at high energies. Detector responses were calculated for neutrons and charged hadrons at energies up to 100 GeV using MCNPX. Neutron spectra were unfolded from the measured count rates using the new MAXED code. We have measured the cosmic-ray neutron spectrum (thermal to greater than 10 GeV), total neutron fluence rate, and neutron effective dose and dose equivalent rates and their dependence on altitude and geomagnetic cutoff. The measured cosmic-ray neutron spectra have almost no thermal neutrons, a large "evaporation" peak near 1 MeV and a second broad peak near 100 MeV which contributes about 69% of the neutron effective dose. At high altitude, geomagnetic latitude has very little effect on the shape of the spectrum, but it is the dominant variable affecting neutron fluence rate, which was 8 times higher at the northernmost measurement location than it was at the southernmost. The shape of the spectrum varied only slightly with altitude from 21 km down to 12 km (56 - 201 grams per square centimeter atmospheric depth), but was significantly different on the ground. In all cases, ambient dose equivalent was greater than effective dose for cosmic-ray neutrons.

γ irradiation with different dose rates induces different DNA damage responses in Petunia x hybrida cells.

PubMed

Donà, Mattia; Ventura, Lorenzo; Macovei, Anca; Confalonieri, Massimo; Savio, Monica; Giovannini, Annalisa; Carbonera, Daniela; Balestrazzi, Alma

2013-05-15

In plants, there is evidence that different dose rate exposures to gamma (γ) rays can cause different biological effects. The dynamics of DNA damage accumulation and molecular mechanisms that regulate recovery from radiation injury as a function of dose rate are poorly explored. To highlight dose-rate dependent differences in DNA damage, single cell gel electrophoresis was carried out on regenerating Petunia x hybrida leaf discs exposed to LDR (total dose 50 Gy, delivered at 0.33 Gy min(-1)) and HDR (total doses 50 and 100 Gy, delivered at 5.15 Gy min(-1)) γ-ray in the 0-24h time period after treatments. Significant fluctuations of double strand breaks and different repair capacities were observed between treatments in the 0-4h time period following irradiation. Dose-rate-dependent changes in the expression of the PhMT2 and PhAPX genes encoding a type 2 metallothionein and the cytosolic isoform of ascorbate peroxidase, respectively, were detected by Quantitative RealTime-Polymerase Chain Reaction. The PhMT2 and PhAPX genes were significantly up-regulated (3.0- and 0.7-fold) in response to HDR. The results are discussed in light of the potential practical applications of LDR-based treatments in mutation breeding. Copyright © 2013 Elsevier GmbH. All rights reserved.

Discerning strain effects in microbial dose-response data.

PubMed

Coleman, Margaret E; Marks, Harry M; Golden, Neal J; Latimer, Heejeong K

In order to estimate the risk or probability of adverse events in risk assessment, it is necessary to identify the important variables that contribute to the risk and provide descriptions of distributions of these variables for well-defined populations. One component of modeling dose response that can create uncertainty is the inherent genetic variability among pathogenic bacteria. For many microbial risk assessments, the "default" assumption used for dose response does not account for strain or serotype variability in pathogenicity and virulence, other than perhaps, recognizing the existence of avirulent strains. However, an examination of data sets from human clinical trials in which Salmonella spp. and Campylobacter jejuni strains were administered reveals significant strain differences. This article discusses the evidence for strain variability and concludes that more biologically based alternatives are necessary to replace the default assumptions commonly used in microbial risk assessment, specifically regarding strain variability.

A comparison of the transcriptome of Drosophila melanogaster in response to entomopathogenic fungus, ionizing radiation, starvation and cold shock.

PubMed

Moskalev, Alexey; Zhikrivetskaya, Svetlana; Krasnov, George; Shaposhnikov, Mikhail; Proshkina, Ekaterina; Borisoglebsky, Dmitry; Danilov, Anton; Peregudova, Darya; Sharapova, Irina; Dobrovolskaya, Eugenia; Solovev, Ilya; Zemskaya, Nadezhda; Shilova, Lyubov; Snezhkina, Anastasia; Kudryavtseva, Anna

2015-01-01

The molecular mechanisms that determine the organism's response to a variety of doses and modalities of stress factors are not well understood. We studied effects of ionizing radiation (144, 360 and 864 Gy), entomopathogenic fungus (10 and 100 CFU), starvation (16 h), and cold shock (+4, 0 and -4°C) on an organism's viability indicators (survival and locomotor activity) and transcriptome changes in the Drosophila melanogaster model. All stress factors but cold shock resulted in a decrease of lifespan proportional to the dose of treatment. However, stress-factors affected locomotor activity without correlation with lifespan. Our data revealed both significant similarities and differences in differential gene expression and the activity of biological processes under the influence of stress factors. Studied doses of stress treatments deleteriously affect the organism's viability and lead to different changes of both general and specific cellular stress response mechanisms.

Cyclooxygenase Expression and Platelet Function in Healthy Dogs Receiving Low Dose Aspirin

PubMed Central

Dudley, Alicia; Thomason, John; Fritz, Sara; Grady, Jesse; Stokes, John; Wills, Robert; Pinchuk, Lesya; Mackin, Andrew; Lunsford, Kari

2014-01-01

Background Low dose aspirin is used to prevent thromboembolic complications in dogs, but some animals are non-responsive to the anti-platelet effects of aspirin (‘aspirin resistance’). Hypothesis/Objectives That low dose aspirin would inhibit platelet function, decrease thromboxane synthesis, and alter platelet cyclooxygenase (COX) expression. Animals Twenty-four healthy dogs Methods A repeated measures study. Platelet function (PFA-100® closure time, collagen/epinephrine), platelet COX-1 and COX-2 expression, and urine 11-dehydro-thromboxane B2 (11-dTXB2) was evaluated prior to and during aspirin administration (1 mg/kg Q24 hours PO, 10 days). Based on prolongation of closure times after aspirin administration, dogs were divided into categories according to aspirin responsiveness: responders, non-responders, and inconsistent responders. Results Low dose aspirin increased closure times significantly (62% by Day 10, P<0.001), with an equal distribution among aspirin responsiveness categories, 8 dogs per group. Platelet COX-1 mean fluorescent intensity (MFI) increased significantly during treatment, 13% on Day 3 (range, −29.7%–136.1%) (P=0.047) and 72% on Day 10 (range, −0.37–210.36%) (P<0.001). Platelet COX-2 MFI increased significantly by 34% (range, −29.2–270.4%) on Day 3 (P = 0.003) and 74% (range, −19.7–226.2%) on Day 10 (P<0.001). Urinary 11-dTXB2 concentrations significantly (P=0.005, P<0.001) decreased at both time points. There was no difference between aspirin responsiveness and either platelet COX expression or thromboxane production. Conclusions and Clinical Importance Low dose aspirin consistently inhibits platelet function in approximately one third of healthy dogs, despite decreased thromboxane synthesis and increased platelet COX expression in most dogs. Pre-treatment COX isoform expression did not predict aspirin resistance. PMID:23278865

Optimization of Catheter Based rtPA Thrombolysis in a Novel In Vitro Clot Model for Intracerebral Hemorrhage

PubMed Central

Masomi-Bornwasser, Julia; Müller-Werkmeister, Hendrik; Kantelhardt, Sven Rainer; König, Jochem; Kempski, Oliver; Giese, Alf

2017-01-01

Hematoma lysis with recombinant tissue plasminogen activator (rtPA) has emerged as an alternative therapy for spontaneous intracerebral hemorrhage (ICH). Optimal dose and schedule are still unclear. The aim of this study was to create a reliable in vitro blood clot model for investigation of optimal drug dose and timing. An in vitro clot model was established, using 25 mL and 50 mL of human blood. Catheters were placed into the clots and three groups, using intraclot application of rtPA, placebo, and catheter alone, were analyzed. Dose-response relationship, repetition, and duration of rtPA treatment and its effectiveness in aged clots were investigated. A significant relative end weight difference was found in rtPA treated clots compared to catheter alone (p = 0.002) and placebo treated clots (p < 0.001). Dose-response analysis revealed 95% effective dose around 1 mg rtPA in 25 and 50 mL clots. Approximately 80% of relative clot lysis could be achieved after 15 min incubation. Lysis of aged clots was less effective. A new clot model for in vitro investigation was established. Our data suggest that current protocols for rtPA based ICH therapy may be optimized by using less rtPA at shorter incubation times. PMID:28459065

Optimization of Catheter Based rtPA Thrombolysis in a Novel In Vitro Clot Model for Intracerebral Hemorrhage.

PubMed

Keric, Naureen; Masomi-Bornwasser, Julia; Müller-Werkmeister, Hendrik; Kantelhardt, Sven Rainer; König, Jochem; Kempski, Oliver; Giese, Alf

2017-01-01

Hematoma lysis with recombinant tissue plasminogen activator (rtPA) has emerged as an alternative therapy for spontaneous intracerebral hemorrhage (ICH). Optimal dose and schedule are still unclear. The aim of this study was to create a reliable in vitro blood clot model for investigation of optimal drug dose and timing. An in vitro clot model was established, using 25 mL and 50 mL of human blood. Catheters were placed into the clots and three groups, using intraclot application of rtPA, placebo, and catheter alone, were analyzed. Dose-response relationship, repetition, and duration of rtPA treatment and its effectiveness in aged clots were investigated. A significant relative end weight difference was found in rtPA treated clots compared to catheter alone ( p = 0.002) and placebo treated clots ( p < 0.001). Dose-response analysis revealed 95% effective dose around 1 mg rtPA in 25 and 50 mL clots. Approximately 80% of relative clot lysis could be achieved after 15 min incubation. Lysis of aged clots was less effective. A new clot model for in vitro investigation was established. Our data suggest that current protocols for rtPA based ICH therapy may be optimized by using less rtPA at shorter incubation times.

Dose-response characteristics of an amorphous silicon EPID.

PubMed

Winkler, Peter; Hefner, Alfred; Georg, Dietmar

2005-10-01

Electronic portal imaging devices (EPIDs) were originally developed for the purpose of patient setup verification. Nowadays, they are increasingly used as dosimeters (e.g., for IMRT verification and linac-specific QA). A prerequisite for any clinical dosimetric application is a detailed understanding of the detector's dose-response behavior. The aim of this study is to investigate the dosimetric properties of an amorphous silicon EPID (Elekta IVIEWGT) with respect to three photon beam qualities: 6, 10, and 25 MV. The EPID showed an excellent temporal stability on short term as well as on long term scales. The stability throughout the day was strongly influenced by warming up, which took several hours and affected EPID response by 2.5%. Ghosting effects increased the sensitivity of the EPID. They became more pronounced with decreasing time intervals between two exposures as well as with increasing dose. Due to ghosting, changes in pixel sensitivity amounted up to 16% (locally) for the 25 MV photon beam. It was observed that the response characteristics of our EPID depended on dose as well as on dose rate. Doubling the dose rate increased the EPID sensitivity by 1.5%. This behavior was successfully attributed to a dose per frame effect, i.e., a nonlinear relationship between the EPID signal and the dose which was delivered to the panel between two successive readouts. The sensitivity was found to vary up to 10% in the range of 1 to 1000 monitor units. This variation was governed by two independent effects. For low doses, the EPID signal was reduced due to the linac's changing dose rate during startup. Furthermore, the detector reading was influenced by intrabeam variations of EPID sensitivity, namely, an increase of detector response during uniform exposure. For the beam qualities which were used, the response characteristics of the EPID did not depend on energy. Differences in relative dose-response curves resulted from energy dependent temporal output characteristics of the accelerator. If ghosting is prevented from affecting the results and all dose-response effects are properly corrected for, the EPID signal becomes independent of dose rate, dose, and exposure time.

European Academy of Allergy and Clinical Immunology task force report on 'dose-response relationship in allergen-specific immunotherapy'.

PubMed

Calderón, M A; Larenas, D; Kleine-Tebbe, J; Jacobsen, L; Passalacqua, G; Eng, P A; Varga, E M; Valovirta, E; Moreno, C; Malling, H J; Alvarez-Cuesta, E; Durham, S; Demoly, P

2011-10-01

For a century, allergen-specific immunotherapy (SIT) has proven to be an effective treatment for allergic rhinitis, asthma, and insect sting allergy. However, as allergen doses are frequently adapted to the individual patient, there are few data on dose-response relationship in SIT. Allergen products for SIT are being increasingly required to conform to regulatory requirements for human medicines, which include the need to demonstrate dose-dependent effects. This report, produced by a Task Force of the EAACI Immunotherapy Interest Group, evaluates the currently available data on dose-response relationships in SIT and aims to provide recommendations for the design of future studies. Fifteen dose-ranging studies fulfilled the inclusion criteria and twelve reported a dose-response relationship for clinical efficacy. Several studies also reported a dose-response relationship for immunological and safety endpoints. Due to the use of different reference materials and methodologies for the determination of allergen content, variations in study design, and choice of endpoints, no comparisons could be made between studies and, as a consequence, no general dosing recommendations can be made. Despite recently introduced guidelines on the standardization of allergen preparations and study design, the Task Force identified a need for universally accepted standards for the measurement of allergen content in SIT preparations, dosing protocols, and selection of clinical endpoints to enable dose-response effects to be compared across studies. © 2011 John Wiley & Sons A/S.

Delta receptor antagonism, ethanol taste reactivity, and ethanol consumption in outbred male rats.

PubMed

Higley, Amanda E; Kiefer, Stephen W

2006-11-01

Naltrexone, a nonspecific opioid antagonist, produces significant changes in ethanol responsivity in rats by rendering the taste of ethanol aversive as well as producing a decrease in voluntary ethanol consumption. The present study investigated the effect of naltrindole, a specific antagonist of delta opioid receptors, on ethanol taste reactivity and ethanol consumption in outbred rats. In the first experiment, rats received acute treatment of naltrexone, naltrindole, or saline followed by the measurement of ethanol consumption in a short-term access period. The second experiment involved the same treatments and investigated ethanol palatability (using the taste-reactivity test) as well as ethanol consumption. Results indicated that treatment with 3 mg/kg naltrexone significantly affected palatability (rendered ethanol more aversive, Experiment 2) and decreased voluntary ethanol consumption (Experiments 1 and 2). The effects of naltrindole were inconsistent. In Experiment 1, 8 mg/kg naltrindole significantly decreased voluntary ethanol consumption but this was not replicated in Experiment 2. The 8 mg/kg dose produced a significant increase in aversive responding (Experiment 2) but did not affect ingestive responding. Lower doses of naltrindole (2 and 4 mg/kg) were ineffective in altering rats' taste-reactivity response to and consumption of ethanol. While these data suggest that delta receptors are involved in rats' taste-reactivity response to ethanol and rats' ethanol consumption, it is likely that multiple opioid receptors mediate both behavioral responses.

Preventive effects of royal jelly against anaphylactic response in a murine model of cow's milk allergy.

PubMed

Guendouz, Malika; Haddi, Abir; Grar, Hadria; Kheroua, Omar; Saidi, Djamel; Kaddouri, Hanane

2017-12-01

Royal jelly (RJ) has long been used to promote human health. The current study investigated the preventive effects of RJ against the development of a systemic and intestinal immune response in mice allergic to cow's milk proteins. Balb/c mice treated orally for seven days with RJ at doses of 0.5, 1 and 1.5 g/kg were sensitized intraperitoneally with β-lactoglobulin (β-Lg). Serum IgG and IgE anti-β-Lg were determined by an enzyme-linked immunosorbent assay (ELISA). Plasma histamine levels, symptom scores and body temperature were determined after in vivo challenge to β-Lg. Jejunums were used for assessment of local anaphylactic responses by an ex vivo study in Ussing chambers and morphologic changes by histological analysis. RJ significantly decreased serum IgG (31.15-43.78%) and IgE (64.28-66.6%) anti-β-Lg and effectively reduced plasma histamine level (66.62-67.36%) (p < 0.001) at all the doses tested. Additionally, no clinical symptoms or body temperature drops were observed in RJ-pretreated mice. Interestingly, RJ significantly reduced (p < 0.001) intestinal dysfunction by abolishing the secretory response (70.73-72.23%) induced by sensitization and prevented length aberrations of jejunal villi by 44.32-59.01% (p < 0.001). We speculate that using RJ may help prevent systemic and anaphylactic response in allergic mice. These effects may be related to its inhibitory effects on the degranulation of mast cells.

Up-dosing with bilastine results in improved effectiveness in cold contact urticaria

PubMed Central

Krause, K; Spohr, A; Zuberbier, T; Church, M K; Maurer, M

2013-01-01

Background Cold contact urticaria (CCU) is characterized by itchy wheal and flare responses due to the release of histamine and other pro-inflammatory mediators after exposure to cold. The treatment of choice is nonsedating antihistamines, dosages of which may be increased up to fourfold if standard doses are ineffective. Here, we assess the effects of a standard 20 mg dose and up-dosing to 40 and 80 mg of bilastine in reducing the symptoms of CCU and inflammatory mediator release following cold challenge. Methods Twenty patients with CCU were included in this randomized, crossover, double-blind, placebo-controlled 12-week study. They received placebo, 20, 40 or 80 mg of bilastine daily each for 7 days with 14-day washout periods. The primary readout was change in critical temperature thresholds (CTT). Secondary readouts were changes in pruritus, levels of histamine IL-6, IL-8 and TNF-α collected by skin microdialysis and safety and tolerability of bilastine. Results Bilastine 20 mg was highly effective (P < 0.0001) in reducing CTT. Up-dosing to 80 mg significantly (P < 0.04) increased its effectiveness. At this dose, 19 of 20 (95%) patients responded to treatment, with 12 of 20 (60%) becoming symptom free. Only one patient was refractory to treatment. Microdialysis levels of histamine, IL-6 and IL-8 assessed 1–3 h after cold challenge were significantly (P < 0.05) decreased following up-dosing with 80 mg bilastine. Bilastine treat-ment was well tolerated without evidence of increased sedation with dose escala-tion. Conclusions Bilastine was effective in reducing the symptoms of patients with CCU. Increased efficacy of bilastine with fourfold up-dosing was without sedation and supports urticaria treatment guidelines. PMID:23742030

Up-dosing with bilastine results in improved effectiveness in cold contact urticaria.

PubMed

Krause, K; Spohr, A; Zuberbier, T; Church, M K; Maurer, M

2013-07-01

Cold contact urticaria (CCU) is characterized by itchy wheal and flare responses due to the release of histamine and other pro-inflammatory mediators after exposure to cold. The treatment of choice is nonsedating antihistamines, dosages of which may be increased up to fourfold if standard doses are ineffective. Here, we assess the effects of a standard 20 mg dose and up-dosing to 40 and 80 mg of bilastine in reducing the symptoms of CCU and inflammatory mediator release following cold challenge. Twenty patients with CCU were included in this randomized, crossover, double-blind, placebo-controlled 12-week study. They received placebo, 20, 40 or 80 mg of bilastine daily each for 7 days with 14-day washout periods. The primary readout was change in critical temperature thresholds (CTT). Secondary readouts were changes in pruritus, levels of histamine IL-6, IL-8 and TNF-α collected by skin microdialysis and safety and tolerability of bilastine. Bilastine 20 mg was highly effective (P < 0.0001) in reducing CTT. Up-dosing to 80 mg significantly (P < 0.04) increased its effectiveness. At this dose, 19 of 20 (95%) patients responded to treatment, with 12 of 20 (60%) becoming symptom free. Only one patient was refractory to treatment. Microdialysis levels of histamine, IL-6 and IL-8 assessed 1-3 h after cold challenge were significantly (P < 0.05) decreased following up-dosing with 80 mg bilastine. Bilastine treatment was well tolerated without evidence of increased sedation with dose escalation. Bilastine was effective in reducing the symptoms of patients with CCU. Increased efficacy of bilastine with fourfold up-dosing was without sedation and supports urticaria treatment guidelines. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Synergistic interaction between fentanyl and bupivacaine given intrathecally for labor analgesia.

PubMed

Ngan Kee, Warwick D; Khaw, Kim S; Ng, Floria F; Ng, Karman K L; So, Rita; Lee, Anna

2014-05-01

Lipophilic opioids and local anesthetics are often given intrathecally in combination for labor analgesia. However, the nature of the pharmacologic interaction between these drugs has not been clearly elucidated in humans. Three hundred nulliparous women randomly received 1 of 30 different combinations of fentanyl and bupivacaine intrathecally using a combined spinal-epidural technique for analgesia in the first stage of labor. Visual analogue scale pain scores were recorded for 30 min. Response was defined by percentage decrease in pain score from baseline at 15 and 30 min. Dose-response curves for individual drugs were fitted to a hyperbolic dose-response model using nonlinear regression. The nature of the drug interaction was determined using dose equivalence methodology to compare observed effects of drug combinations with effects predicted by additivity. The derived dose-response models for individual drugs (doses in micrograms) at 15 min were: Effect = 100 × dose / (13.82 + dose) for fentanyl, and Effect = 100 × dose / (1,590 + dose) for bupivacaine. Combinations of fentanyl and bupivacaine produced greater effects than those predicted by additivity at 15 min (P < 0.001) and 30 min (P = 0.015) (mean differences, 9.1 [95% CI, 4.1-14.1] and 6.4 [95% CI, 1.2-11.5] units of the normalized response, respectively), indicating a synergistic interaction. The pharmacologic interaction between intrathecal fentanyl and bupivacaine is synergistic. Characterization and quantification of this interaction provide a theoretical basis and support for the clinical practice of combining intrathecal opioids and local anesthetics.

Dose-Response—A Challenge for Allelopathy?

PubMed Central

Belz, Regina G.; Hurle, Karl; Duke, Stephen O.

2005-01-01

The response of an organism to a chemical depends, among other things, on the dose. Nonlinear dose-response relationships occur across a broad range of research fields, and are a well established tool to describe the basic mechanisms of phytotoxicity. The responses of plants to allelochemicals as biosynthesized phytotoxins, relate as well to nonlinearity and, thus, allelopathic effects can be adequately quantified by nonlinear mathematical modeling. The current paper applies the concept of nonlinearity to assorted aspects of allelopathy within several bioassays and reveals their analysis by nonlinear regression models. Procedures for a valid comparison of effective doses between different allelopathic interactions are presented for both, inhibitory and stimulatory effects. The dose-response applications measure and compare the responses produced by pure allelochemicals [scopoletin (7-hydroxy-6-methoxy-2H-1-benzopyran-2-one); DIBOA (2,4-dihydroxy-2H-1,4-benzoxaxin-3(4H)-one); BOA (benzoxazolin-2(3H)-one); MBOA (6-methoxy-benzoxazolin-2(3H)-one)], involved in allelopathy of grain crops, to demonstrate how some general principles of dose responses also relate to allelopathy. Hereupon, dose-response applications with living donor plants demonstrate the validity of these principles for density-dependent phytotoxicity of allelochemicals produced and released by living plants (Avena sativa L., Secale cereale L., Triticum L. spp.), and reveal the use of such experiments for initial considerations about basic principles of allelopathy. Results confirm that nonlinearity applies to allelopathy, and the study of allelopathic effects in dose-response experiments allows for new and challenging insights into allelopathic interactions. PMID:19330161

Mechanisms and biological importance of photon-induced bystander responses: do they have an impact on low-dose radiation responses

PubMed Central

Tomita, Masanori; Maeda, Munetoshi

2015-01-01

Abstract Elucidating the biological effect of low linear energy transfer (LET), low-dose and/or low-dose-rate ionizing radiation is essential in ensuring radiation safety. Over the past two decades, non-targeted effects, which are not only a direct consequence of radiation-induced initial lesions produced in cellular DNA but also of intra- and inter-cellular communications involving both targeted and non-targeted cells, have been reported and are currently defining a new paradigm in radiation biology. These effects include radiation-induced adaptive response, low-dose hypersensitivity, genomic instability, and radiation-induced bystander response (RIBR). RIBR is generally defined as a cellular response that is induced in non-irradiated cells that receive bystander signals from directly irradiated cells. RIBR could thus play an important biological role in low-dose irradiation conditions. However, this suggestion was mainly based on findings obtained using high-LET charged-particle radiations. The human population (especially the Japanese, who are exposed to lower doses of radon than the world average) is more frequently exposed to low-LET photons (X-rays or γ-rays) than to high-LET charged-particle radiation on a daily basis. There are currently a growing number of reports describing a distinguishing feature between photon-induced bystander response and high-LET RIBR. In particular, photon-induced bystander response is strongly influenced by irradiation dose, the irradiated region of the targeted cells, and p53 status. The present review focuses on the photon-induced bystander response, and discusses its impact on the low-dose radiation effect. PMID:25361549

Neurotoxicological and statistical analyses of a mixture of five organophosphorus pesticides using a ray design.

PubMed

Moser, V C; Casey, M; Hamm, A; Carter, W H; Simmons, J E; Gennings, C

2005-07-01

Environmental exposures generally involve chemical mixtures instead of single chemicals. Statistical models such as the fixed-ratio ray design, wherein the mixing ratio (proportions) of the chemicals is fixed across increasing mixture doses, allows for the detection and characterization of interactions among the chemicals. In this study, we tested for interaction(s) in a mixture of five organophosphorus (OP) pesticides (chlorpyrifos, diazinon, dimethoate, acephate, and malathion). The ratio of the five pesticides (full ray) reflected the relative dietary exposure estimates of the general population as projected by the US EPA Dietary Exposure Evaluation Model (DEEM). A second mixture was tested using the same dose levels of all pesticides, but excluding malathion (reduced ray). The experimental approach first required characterization of dose-response curves for the individual OPs to build a dose-additivity model. A series of behavioral measures were evaluated in adult male Long-Evans rats at the time of peak effect following a single oral dose, and then tissues were collected for measurement of cholinesterase (ChE) activity. Neurochemical (blood and brain cholinesterase [ChE] activity) and behavioral (motor activity, gait score, tail-pinch response score) endpoints were evaluated statistically for evidence of additivity. The additivity model constructed from the single chemical data was used to predict the effects of the pesticide mixture along the full ray (10-450 mg/kg) and the reduced ray (1.75-78.8 mg/kg). The experimental mixture data were also modeled and statistically compared to the additivity models. Analysis of the 5-OP mixture (the full ray) revealed significant deviation from additivity for all endpoints except tail-pinch response. Greater-than-additive responses (synergism) were observed at the lower doses of the 5-OP mixture, which contained non-effective dose levels of each of the components. The predicted effective doses (ED20, ED50) were about half that predicted by additivity, and for brain ChE and motor activity, there was a threshold shift in the dose-response curves. For the brain ChE and motor activity, there was no difference between the full (5-OP mixture) and reduced (4-OP mixture) rays, indicating that malathion did not influence the non-additivity. While the reduced ray for blood ChE showed greater deviation from additivity without malathion in the mixture, the non-additivity observed for the gait score was reversed when malathion was removed. Thus, greater-than-additive interactions were detected for both the full and reduced ray mixtures, and the role of malathion in the interactions varied depending on the endpoint. In all cases, the deviations from additivity occurred at the lower end of the dose-response curves.

Genetic effects on heavy ions in drosophila

NASA Technical Reports Server (NTRS)

Kale, P. G.

1986-01-01

Drosophila sex-linked recessive lethal mutation test was used to study the dose response relation and relative biological effectiveness of heavy ions. The experiments were performed using the heavy ion beams at BEVALAC of Lawrence Berkeley Laboratory. These experiments were undertaken according to the proposed milestones and included Ne-20, A-40 and Fe-65 ions with respective energies of 600 MeV, 840 MeV and 850 MeV. At these energies several doses of these radiations ranging from 20 to 1280 R were used. Space radiation exposure to astronauts is supposed to be quite low and therefore very low dose experiments i.e., 20 R, were also performed for the three ions. The mutation response was measured in all germ cell types i.e., spermatozoa, spermatids, spermatocytes and spermatogonia of treated Drosophila males. A linear dose frequency relation was observed for most of the range except at high doses where the saturation effect was observed. Also, a very significant difference was observed among the sensitivity of the four germ cell stages where spermatozoa and spermatids were more sensitive. At the higher doses of this range, most of the spermatogonia and spermatocytes were killed. Although comparative and identical experiments with X-rays or neutrons have not been performed, the compassion of our data with the ones available in literature suggest that the heavy ions have a high rbe and that they are several times more effective than low LET X-rays. The rbe compared to neutrons however appears to be only slightly higher.

Massage Therapy for Osteoarthritis of the Knee: A Randomized Dose-Finding Trial

PubMed Central

Perlman, Adam I.; Ali, Ather; Njike, Valentine Yanchou; Hom, David; Davidi, Anna; Gould-Fogerite, Susan; Milak, Carl; Katz, David L.

2012-01-01

Background In a previous trial of massage for osteoarthritis (OA) of the knee, we demonstrated feasibility, safety and possible efficacy, with benefits that persisted at least 8 weeks beyond treatment termination. Methods We performed a RCT to identify the optimal dose of massage within an 8-week treatment regimen and to further examine durability of response. Participants were 125 adults with OA of the knee, randomized to one of four 8-week regimens of a standardized Swedish massage regimen (30 or 60 min weekly or biweekly) or to a Usual Care control. Outcomes included the Western Ontario and McMaster Universities Arthritis Index (WOMAC), visual analog pain scale, range of motion, and time to walk 50 feet, assessed at baseline, 8-, 16-, and 24-weeks. Results WOMAC Global scores improved significantly (24.0 points, 95% CI ranged from 15.3–32.7) in the 60-minute massage groups compared to Usual Care (6.3 points, 95% CI 0.1–12.8) at the primary endpoint of 8-weeks. WOMAC subscales of pain and functionality, as well as the visual analog pain scale also demonstrated significant improvements in the 60-minute doses compared to usual care. No significant differences were seen in range of motion at 8-weeks, and no significant effects were seen in any outcome measure at 24-weeks compared to usual care. A dose-response curve based on WOMAC Global scores shows increasing effect with greater total time of massage, but with a plateau at the 60-minute/week dose. Conclusion Given the superior convenience of a once-weekly protocol, cost savings, and consistency with a typical real-world massage protocol, the 60-minute once weekly dose was determined to be optimal, establishing a standard for future trials. Trial Registration ClinicalTrials.gov NCT00970008 PMID:22347369

Toxic responses of microorganisms to nickel exposure in farmland soil in the presence of earthworm (Eisenia fetida).

PubMed

Xia, Xiaoqian; Lin, Siyuan; Zhao, Jun; Zhang, Wei; Lin, Kuangfei; Lu, Qiang; Zhou, Bingsheng

2018-02-01

Nickel (Ni)-contamination impairs soil ecosystem, threatening human health. A laboratory simulation of Ni-polluted farmland soil study, in the presence or absence of earthworm, was carried out to investigate the toxic responses of soil microorganisms, including microbial biomass C (MBC), soil basal respiration (SBR), metabolic quotient (qCO 2 ), urease (UA) and dehydrogenase activities (DHA). Additionally, the variations of Ni bioavailability were also explored. Results manifested that MBC and SBR were stimulated at 50 and 100 mg·kg -1 of Ni but inhibited by further increasing Ni level, showing a Hormesis effect. Earthworm input delayed the occurrence of a maximum SBR inhibition rate under the combined double-factors of time and dose. No specific effect of Ni concentration on the qCO 2 was observed. UA was significantly suppressed at 800 mg·kg -1 Ni (P < 0.05 or 0.01), whereas DHA was more sensitive and significantly inhibited throughout all the treatments (P < 0.01), indicating a pronounced dose-response relationship. The addition of earthworm facilitated all the biomarkers above. The time-dependent of dose-effect relationship (TDR) on MBC and SBR inhibition rates suggested that the peak responsiveness of microorganisms to Ni stress were approximate on the 21st day. The bioavailable form of per unit Ni concentration declined with time expanded and concentration increased, and the changeable process of the relative amount of bioavailability was mainly controlled by a physicochemical reactions. Copyright © 2017 Elsevier Ltd. All rights reserved.

Exjade® (deferasirox, ICL670) in the treatment of chronic iron overload associated with blood transfusion

PubMed Central

Cappellini, Maria Domenica

2007-01-01

Although blood transfusions are important for patients with anemia, chronic transfusions inevitably lead to iron overload as humans cannot actively remove excess iron. The cumulative effects of iron overload lead to significant morbidity and mortality, if untreated. Although the current reference standard iron chelator deferoxamine has been used clinically for over four decades, its effectiveness is limited by a demanding therapeutic regimen that leads to poor compliance. Deferasirox (Exjade®, ICL670, Novartis Pharma AG, Basel, Switzerland) is a once-daily, oral iron chelator approved for the treatment of transfusional iron overload in adult and pediatric patients. The efficacy and safety of deferasirox have been established in a comprehensive clinical development program involving patients with various transfusion-dependent anemias. Deferasirox has a dose-dependent effect on iron burden, and is as efficacious as deferoxamine at comparable therapeutic doses. Deferasirox therapy can be tailored to a patient’s needs, as response is related to both dose and iron intake. Since deferasirox has a long half-life and is present in the plasma for 24 hours with once-daily dosing, it is unique in providing constant chelation coverage with a single dose. The availability of this convenient, effective, and well tolerated therapy represents a significant advance in the management of transfusional iron overload. PMID:18360637

Cumulative Training Dose's Effects on Interrelationships Between Common Training-Load Models During Basketball Activity.

PubMed

Scanlan, Aaron T; Fox, Jordan L; Borges, Nattai R; Dascombe, Ben J; Dalbo, Vincent J

2017-02-01

The influence of various factors on training-load (TL) responses in basketball has received limited attention. This study aimed to examine the temporal changes and influence of cumulative training dose on TL responses and interrelationships during basketball activity. Ten state-level Australian male junior basketball players completed 4 × 10-min standardized bouts of simulated basketball activity using a circuit-based protocol. Internal TL was quantified using the session rating of perceived exertion (sRPE), summated heart-rate zones (SHRZ), Banister training impulse (TRIMP), and Lucia TRIMP models. External TL was assessed via measurement of mean sprint and circuit speeds. Temporal TL comparisons were performed between 10-min bouts, while Pearson correlation analyses were conducted across cumulative training doses (0-10, 0-20, 0-30, and 0-40 min). sRPE TL increased (P < .05) after the first 10-min bout of basketball activity. sRPE TL was only significantly related to Lucia TRIMP (r = .66-.69; P < .05) across 0-10 and 0-20 min. Similarly, mean sprint and circuit speed were significantly correlated across 0-20 min (r = .67; P < .05). In contrast, SHRZ and Banister TRIMP were significantly related across all training doses (r = .84-.89; P < .05). Limited convergence exists between common TL approaches across basketball training doses lasting beyond 20 min. Thus, the interchangeability of commonly used internal and external TL approaches appears dose-dependent during basketball activity, with various psychophysiological mediators likely underpinning temporal changes.

Effects of microwave (2.45 GHz) irradiation on some biological characters of Salmonella typhimurium.

PubMed

Nasri, Kaouther; Daghfous, Douraid; Landoulsi, Ahmed

2013-04-01

The present study was carried out to evaluate the effects of sub-lethal doses of microwave radiation on some biological characteristics in Salmonella typhimurium. The aim was to show the relationship between this treatment and the development of radiotolerance in this pathogen because there is a need for more information on physiological responses of pathogens to sub-lethal doses of microwave radiation. So, the bacterial strain was treated with a dose of 3600J (40-s exposure with power P=90 W) to cause cellular damage. The results have shown that the exposure of bacteria to microwaves resulted in a significant inhibition of cellular growth. This treatment has notably increased the effectiveness of the most tested antibiotics by the amelioration or the appearance of sensitivity in exposed bacteria. Gas chromatography (GC) analysis was performed to demonstrate the modification of the fatty acids (FA) composition. Results obtained have shown that this treatment had a significant effect on the FA content with an increase of unsaturated FA percentage. The acquisition of sensitivity to the sodium deoxycholate and the significant increase in the amount of extracellular proteins in exposed bacteria has confirmed the weakening of the bacterial membrane by microwaves. This study represents one of the few demonstrating the modifications on the bacterial membrane as a cellular response to survive the non-ionising radiation stress. Copyright © 2013 Académie des sciences. Published by Elsevier SAS. All rights reserved.

The characterization of oxotremorine-induced hypothermic response in the rat.

PubMed

Ryan, P M; Kelly, J P; Chambers, P L; Leonard, B E

1996-11-01

Oxotremorine is a muscarinic receptor agonist that induces a variety of physiological and behavioural effects including hypothermia in mice. These effects are antagonized dose-dependently by classical anticholinergic compounds such as atropine. Although the oxotremorine-induced hypothermic response has been demonstrated in mice, few studies of the effects of this muscarinic agonist have been made in the rat. The following studies were made in male Sprague Dawley rats: 1. an investigation of the dose-response relationship between oxotremorine and hypothermia; 2. an examination of the effect of housing on the oxotremorine-induced hypothermic response, and 3, an investigation of the acute administration of various doses of atropine sulphate on the hypothermia caused by oxotremorine. The results indicate that the dose-response relationship between oxotremorine and the antagonism of hypothermia is similar in rat as it is in mice. The results also showed that this effect did not occur in group-housed animals.

Low doses of ionizing radiation to mammalian cells may rather control than cause DNA damage

DOE Office of Scientific and Technical Information (OSTI.GOV)

Feinendegen, L.E.; Bond, V.P.; Sondhaus, C.A.

This report examines the origin of tissue effects that may follow from different cellular responses to low-dose irradiation, using published data. Two principal categories of cellular responses are considered. One response category relates to the probability of radiation-induced DNA damage. The other category consists of low-dose induced metabolic changes that induce mechanisms of DNA damage mitigation, which do not operate at high levels of exposure. Modeled in this way, tissue is treated as a complex adaptive system. The interaction of the various cellular responses results in a net tissue dose-effect relation that is likely to deviate from linearity in themore » low-dose region. This suggests that the LNT hypothesis should be reexamined. This paper aims at demonstrating tissue effects as an expression of cellular responses, both damaging and defensive, in relation to the energy deposited in cell mass, by use of microdosimetric concepts.« less

Effect of 3 Different Doses of Intrathecal Dexmedetomidine (2.5µg, 5µg, and 10 µg) on Subarachnoid Block Characteristics: A Prospective Randomized Double Blind Dose-Response Trial.

PubMed

Gupta, Mayank; Gupta, Priyanka; Singh, Dhananjay Kumar

2016-03-01

The extended analgesic efficacy of intrathecal dexmedetomidine (ITD) has been investigated in a few clinical trials; however, there is a lack of conclusive evidence upon its ideal dosage. To elucidate the dose-response relationship between ITD and subarachnoid block characteristics, particularly the duration of analgesia and differential analgesia (DA: defined as time difference from the offset of motor blockade to the first analgesic requirement on numerical rating scale = 4.0). Prospective, randomized double blind active control trial. Medical college teaching hospital. Ninety adult (18 - 60 years) patients undergoing elective lower abdominal and lower limb surgeries were randomized into 3 groups to receive intrathecal 0.5% bupivacaine 3 mL with 2.5 µg (group BD2.5), 5µg (group BD5), or 10 µg (group BD10) dexmedetomidine in 0.5 mL normal saline. The 2 segment sensory regression times (TSSRT), duration of motor blockade analgesia, DA, and perioperative adverse effects were assessed. The primary outcome was duration of analgesia and DA. ANOVA, Kruskal Wallis test, Chi-square (x2), and Fisher's exact test, significance: P < 0.05. The onset of sensory block was significantly earlier in group BD10 compared with group BD5 (P = 0.035) and BD2.5 (P = 0.010) while the onset of motor block was significantly earlier in group BD10 compared with BD2.5 (P = 0.020). There was a significant and dose-dependent prolongation of the duration of sensory block (127.50, 149.17, and 187.50 minutes; P < 0.001), motor block (258.50, 331, and 365 minutes; P < 0.001), analgesia (306.17, 396.50, and 512 minutes; P < 0.001), and DA (47.67, 65.50, and147 minutes; P < 0.001) with escalating doses of ITD, respectively. Group BD10 required significantly fewer rescue analgesics compared with other 2 groups (P = 0.001). Except for mild sedation which was significantly higher in group BD10; all the groups were comparable with respect to hemodynamic and other adverse effects. Lack of placebo group, exclusion of higher doses (15µg) of ITD, and short duration of postoperative follow-up. The addition of 10 µg compared with 2.5 µg or 5µg ITD to 0.5% hyperbaric bupivacaine is associated with significantly earlier onset of sensory and motor block as well as prolonged duration of sensory block, motor block, analgesia, and DA with a comparable adverse effect profile.

N-acetyl cysteine improves the effects of corticosteroids in a mouse model of chlorine-induced acute lung injury.

PubMed

Wigenstam, Elisabeth; Koch, Bo; Bucht, Anders; Jonasson, Sofia

2015-02-03

Chlorine (Cl2) causes tissue damage and a neutrophilic inflammatory response in the airways manifested by pronounced airway hyperreactivity (AHR). The importance of early anti-inflammatory treatment has previously been addressed. In the previous study, both high-dose and low-dose of dexamethasone (DEX) decreased the risk of developing delayed effects, such as persistent lung injuries, while only high-dose treatment could significantly counteract acute-phase effects. One aim of this study was to evaluate whether a low-dose of DEX in combination with the antioxidant N-acetyl cysteine (NAC) and if different treatments (Triptolide, Reparixin and Rolipram) administered 1h after Cl2-exposure could improve protection against acute lung injury in Cl2-exposed mice. BALB/c mice were exposed to 300 ppm Cl2 during 15 min. Assessment of AHR and inflammatory cells in bronchoalveolar lavage was analyzed 24h post exposure. Neither of DEX nor NAC reduced the AHR and displayed only minor effects on inflammatory cell influx when given as separate treatments. When given in combination, a protective effect on AHR and a significant reduction in inflammatory cells (neutrophils) was observed. Neither of triptolide, Reparixin nor Rolipram had an effect on AHR but Triptolide had major effect on the inflammatory cell influx. Treatments did not reduce the concentration of either fibrinogen or plasminogen activator inhibitor-1 in serum, thereby supporting the theory that the inflammatory response is not solely limited to the lung. These results provide a foundation for future studies aimed at identifying new concepts for treatment of chemical-induced lung injury. Studies addressing combination of anti-inflammatory and antioxidant treatment are highly motivated. Copyright © 2014. Published by Elsevier Ireland Ltd.

Once-daily high-dose pindolol for SSRI-refractory depression.

PubMed

Sokolski, Kenneth N; Conney, Janet C; Brown, Brenda J; DeMet, Edward M

2004-02-15

Selective serotonin reuptake inhibitor (SSRI) augmentation with the 5-HT1A antagonist pindolol has met with mixed results. Recent studies using positron emission tomography (PET) suggest that pindolol doses used in these studies were too low to effect 5-HT1A autoreceptor blockade. To test the hypothesis that a single higher dose of pindolol would effectively augment antidepressant responses in SSRI-refractory patients, nine subjects with major depression unresponsive to paroxetine 40 mg/day given for 2 months or more were randomized to AM pindolol 7.5 mg (n=4) or placebo (n=5). Subjects were administered the Hamilton Depression Scale (HAM-D), the Hamilton Anxiety Scale (HAM-A), the Bech-Rafaelsen Melancholia Scale, and the Zung Depression Inventory at baseline and weeks 1, 2, 3, and 4. Subjects receiving pindolol exhibited significant improvements in all ratings beginning at week 2 which continued through week 4. Aside from transient dizziness and a five-point decrease in systolic/diastolic blood pressure associated with pindolol, no adverse effects were reported. Although results must be verified in a larger sample, these findings support previous studies indicating that pindolol can accelerate antidepressant responses during SSRI therapy. In addition, results reported here suggest that a single high dose of pindolol (7.5 mg) is a more effective augmentation strategy in SSRI-refractory patients compared with the same total dose given at 2.5 mg tid.

Conformational Effects of UV Light on DNA Origami.

PubMed

Chen, Haorong; Li, Ruixin; Li, Shiming; Andréasson, Joakim; Choi, Jong Hyun

2017-02-01

The responses of DNA origami conformation to UV radiation of different wavelengths and doses are investigated. Short- and medium-wavelength UV light can cause photo-lesions in DNA origami. At moderate doses, the lesions do not cause any visible defects in the origami, nor do they significantly affect the hybridization capability. Instead, they help relieve the internal stress in the origami structure and restore it to the designed conformation. At high doses, staple dissociation increases which causes structural disintegration. Long-wavelength UV does not show any effect on origami conformation by itself. We show that this UV range can be used in conjunction with photoactive molecules for photo-reconfiguration, while avoiding any damage to the DNA structures.

[High-dose chemotherapy as a strategy to overcome drug resistance in solid tumors].

PubMed

Selle, Frédéric; Gligorov, Joseph; Soares, Daniele G; Lotz, Jean-Pierre

2016-10-01

The concept of high-doses chemotherapy was developed in the 1980s based on in vitro scientific observations. Exposure of tumor cells to increasing concentrations of alkylating agents resulted in increased cell death in a strong dose-response manner. Moreover, the acquired resistance of tumor cells could be overcome by dose intensification. In clinic, dose intensification of alkylating agents resulted in increased therapeutic responses, however associated with significant hematological toxicity. Following the development of autologous stem cells transplantation harvesting from peripheral blood, the high-doses of chemotherapy, initially associated with marked toxic effects, could be more easily tolerated. As a result, the approach was evaluated in different types of solid tumors, including breast, ovarian and germ cell tumors, small cell lung carcinoma, soft tissue sarcomas and Ewing sarcoma. To date, high-doses chemotherapy with hematopoietic stem cells support is only used as a salvage therapy to treat poor prognosis germ cell tumors patients with chemo-sensitive disease. Regarding breast and ovarian cancer, high-doses chemotherapy should be considered only in the context of clinical trials. However, intensive therapy as an approach to overcome resistance to standard treatments is still relevant. Numerous efforts are still ongoing to identify novel therapeutic combinations and active treatments to improve patients' responses. Copyright © 2016 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

Abuse liability assessment of eslicarbazepine acetate in healthy male and female recreational sedative users: A Phase I randomized controlled trial.

PubMed

Levy-Cooperman, Naama; Schoedel, Kerri A; Chakraborty, Bijan; Blum, David; Cheng, Hailong

2016-08-01

Eslicarbazepine acetate (ESL) is a once-daily oral antiepileptic drug for the treatment of partial-onset seizures. Adverse events such as dizziness and somnolence reported in clinical studies suggest that ESL has detectable central nervous system (CNS) effects in addition to its antiepileptic effects. This Phase I study evaluated the abuse liability of ESL compared with that of alprazolam (ALP) and placebo (PBO) in recreational CNS depressant users. In this single-dose, randomized, double-blind, PBO- and active-controlled crossover study, healthy recreational CNS depressant users who could discern between ALP 2mg and PBO received single oral doses of each of the following treatments with a washout interval of ≥7days between each treatment: ESL (800mg, 1600mg, 2000mg, and 2400mg); ALP (1.5mg and 3.0mg); and PBO. Subjective measures, including visual analog scales (VASs) e.g., Drug-Liking (primary endpoint), and Addiction Research Center Inventory (ARCI) Morphine-Benzedrine Group (MBG), Pentobarbital Chlorpromazine Alcohol Group (PCAG), and Lysergic Acid Diethylamide Group scales were evaluated at multiple time points up to 24h postdose. Cognitive effects were evaluated using the Choice Reaction Time (CRT), Divided Attention (DAT) and Hopkins Verbal Learning Task-Revised tests. Peak scores for Drug-Liking VAS (maximum effect [Emax]) were significantly higher for both ALP doses than for PBO (p<0.0001), thereby confirming study validity. Drug-Liking VAS Emax was significantly lower for all ESL doses than both ALP doses (p<0.0001). Drug-Liking VAS Emax for ESL 800mg was similar to that for PBO (least squares [LS] mean difference: 3.6; p=0.19). At the three higher ESL doses (1600mg and the supratherapeutic doses of 2000mg and 2400mg), Drug-Liking VAS Emax was significantly higher than for PBO, although the differences were minimal (LS mean difference: 9.3-13.3 out of 100). For most secondary subjective endpoints (i.e., Good Effects VAS and High VAS, ARCI-MBG, Take Drug Again VAS, Overall Drug-Liking VAS, and ARCI-PCAG; p<0.05), the effect of ESL (all doses) was significantly less than that of ALP (both doses). On most secondary measures, the dose-response relationship was relatively flat or showed saturation at higher ESL doses. Although significant differences were observed for ESL compared with those for PBO for some specific CRT and DAT endpoints (i.e., reaction time, manual tracking, hit latency), ALP demonstrated significant and dose-dependent impairment on the majority of cognitive endpoints when compared with PBO and ESL. Mean plasma concentrations of the active metabolite of ESL, eslicarbazepine, increased with increasing ESL dose. Pharmacokinetic parameters estimated for eslicarbazepine were generally comparable with results from previous studies in healthy volunteers. This study demonstrated that single doses of ESL may have less abuse liability than ALP in recreational sedative users. Although ESL had detectable subjective effects and showed some drug-'liking' at higher doses, the magnitude of these effects was small. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

The Effect of Evaporated Salt Solutions on the Optical Dating Properties of JSC Mars-1: "Seasoning" for a Mars Soil Simulant

NASA Astrophysics Data System (ADS)

Lepper, Kenneth

2009-08-01

Optically stimulated luminescence dating, or optical dating, is an established terrestrial geochronometric technique that is being adapted to date sedimentary deposits and landforms on the surface of Mars. Recent discoveries have highlighted the astrobiological significance and occurrence of halite on the surface of Mars. The objective of the experiments in this study was to create a simplistic analogue of the sedimentary material that would result from evaporation of ion-containing pore water out of martian regolith and evaluate the influence the evaporated salts would have on in situ optical dating of silicate sediments. The radiation dose response, as measured by infrared stimulated luminescence (IRSL), from evaporated mixtures of JSC Mars-1 and solutions of sodium chloride and calcium sulfate was documented. The results suggest that the presence of CaSO4 and NaCl within the aggregated particles does not have adverse effects on IRSL dose response and that aggregates of this type exhibit dose response characteristics that are appropriate for optical dating.

Effects of small-dose dexmedetomidine on hyperdynamic responses to electroconvulsive therapy.

PubMed

Li, Xiang; Tan, Fang; Jian, Chao-Jun; Guo, Na; Zhong, Zhi-Yong; Hei, Zi-Qing; Zhou, Shao-Li

2017-08-01

Acute hemodynamic responses to electroconvulsive therapy (ECT) may increase the risk of cardiovascular complications in vulnerable patients. The aim of the current study was to assess the effect of small-dose dexmedetomidine on hyperdynamic responses to ECT. Seventy-eight patients were enrolled and randomly allocated to receive either 0.2 μg/kg dexmedetomidine (Dex group, n = 39) or saline (Control group, n = 39) prior to ECT. Heart rate (HR) and mean arterial pressure (MAP) were recorded immediately after the administration of dexmedetomidine (T1), and 0, 1, 3, 5 and 10 min after the electrical stimuli ended (T2, T3, T4, T5 and T6). In addition, the peak HR after ECT, seizure duration, recovery time, and incidence rates of post-ECT adverse effects (agitation, headache and nausea) were also recorded. HR and MAP in the Dex group were significantly lower than those in the Control group from T2 to T5. In addition, peak HR was significantly lower in the Dex group compared with that in the Control group. Seizure length and time to spontaneous breathing, eye opening, and obeying commands in the Dex group were similar to those in the Control group. The incidence rates of post-ECT agitation and headache in the Dex group were significantly lower than that in the Control group. The administration of 0.2 μg/kg dexmedetomidine to patients receiving ECT leads to a significant reduction in HR, MAP, and peak HR responses to ECT without altering seizure duration or delaying recovery. Furthermore, dexmedetomidine effectively reduced the incidence rates of post-ECT adverse effects such as agitation and headache. Copyright © 2017. Published by Elsevier Taiwan LLC.

Low doses of six toxicants change plant size distribution in dense populations of Lactuca sativa.

PubMed

Belz, Regina G; Patama, Marjo; Sinkkonen, Aki

2018-08-01

Toxicants are known to have negligible or stimulatory, i.e. hormetic, effects at low doses below those that decrease the mean response of a plant population. Our earlier observations indicated that at such low toxicant doses the growth of very fast- and slow-growing seedlings is selectively altered, even if the population mean remains constant. Currently, it is not known how common these selective low-dose effects are, whether they are similar among fast- and slow-growing seedlings, and whether they occur concurrently with hormetic effects. We tested the response of Lactuca sativa in complete dose-response experiments to six different toxicants at doses that did not decrease population mean and beyond. The tested toxicants were IAA, parthenin, HHCB, 4-tert-octylphenol, glyphosate, and pelargonic acid. Each experiment consisted of 14,400-16,800 seedlings, 12-14 concentrations, 24 replicates per concentration and 50 germinated seeds per replicate. We analyzed the commonness of selective low-dose effects and explored if toxic effects and hormetic stimulation among fast- and slow-growing individuals occurred at the same concentrations as they occur at the population level. Irrespective of the observed response pattern and toxicant, selective low-dose effects were found. Toxin effects among fast-growing individuals usually started at higher doses compared to the population mean, while the opposite was found among slow-growing individuals. Very low toxin exposures tended to homogenize plant populations due to selective effects, while higher, but still hormetic doses tended to heterogenize plant populations. Although the extent of observed size segregation varied with the specific toxin tested, we conclude that a dose-dependent alteration in size distribution of a plant population may generally apply for many toxin exposures. Copyright © 2018 Elsevier B.V. All rights reserved.

Effect of some blocking drugs on the pressor response to physostigmine in the rat

PubMed Central

Gokhale, S. D.; Gulati, O. D.; Joshi, N. Y.

1963-01-01

Bretylium and guanethidine blocked the pressor effect of physostigmine and potentiated the responses to adrenaline and noradrenaline on the blood pressure of the rat. Morphine and atropine in small doses blocked the pressor effect of physostigmine without interfering with the actions of adrenaline and noradrenaline. Chlorpromazine in small doses (0.5 to 2.5 mg/kg) blocked the pressor effect of physostigmine and potentiated the responses to noradrenaline whilst those to adrenaline remained unaltered. 3,6-Di(3-diethylaminopropoxy)pyridazine di(methiodide) (Win 4981) blocked the pressor effect of physostigmine and, in its early stages, this block was partially reversed by choline chloride. N-Diethylaminoethyl-N-isopentyl-N'N'-diisopropylurea (P-286), in a dose that reduced the effect of dimethylphenylpiperazinium, had no effect on the pressor response to physostigmine or on the responses to adrenaline and noradrenaline. Hexamethonium, even in large doses (100 mg/kg), only blocked partially the effect of physostigmine while mecamylamine produced a complete block; the responses to adrenaline and noradrenaline were potentiated in both instances. ImagesFig. 1Fig. 2Fig. 3Fig. 4Fig. 5Fig. 6 PMID:14081658

Atomoxetine Increased Effect over Time in Adults with Attention-Deficit/Hyperactivity Disorder Treated for up to 6 Months: Pooled Analysis of Two Double-Blind, Placebo-Controlled, Randomized Trials.

PubMed

Wietecha, Linda A; Clemow, David B; Buchanan, Andrew S; Young, Joel L; Sarkis, Elias H; Findling, Robert L

2016-07-01

Changes in the magnitude of efficacy throughout 26 weeks of atomoxetine treatment, along with impact of dosing, were evaluated in adults with ADHD from two randomized, double-blind, placebo-controlled studies. Pooled placebo (n = 485) and atomoxetine (n = 518) patients, dosed 25, 40, 60, 80 (target dose), or 100 mg daily, were assessed. Change from baseline in Conners' Adult ADHD Rating Scale-Investigator Rated Scale: Screening Version (CAARS) total ADHD symptoms score and Adult ADHD Investigator Symptom Rating Scale (AISRS) total score were analyzed using mixed-model repeated measures, with least squares mean change, effect size, and response rate calculated at 1, 2, 4, 8, 12, 16, 22, and 26 weeks. Decreases on CAARS for atomoxetine- versus placebo-treated patients were consistently statistically significantly greater at every time point beginning at one week (P ≤ 0.006, 0.28 effect size). By 4 weeks, comparison was -13.19 compared with -8.84 (P < 0.0001, 0.45 effect size). By 26 weeks, mean change was -15.42 versus -9.71 (0.52 effect size); increase in effect size over time was most pronounced in the 80 mg group (0.82 effect size). AISRS demonstrated similar results. Atomoxetine response rate (CAARS 50% decrease) continued to increase throughout 26 weeks. Atomoxetine treatment in adults with ADHD was associated with small effect sizes after 4 weeks and moderate effect sizes by 6 months of treatment. The data support increased effect size and response rate over time during longer-term treatment at target dose. © 2016 Eli Lilly and Company. CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.

Contrasting effects of low versus high ascorbate doses on blood pressure responses to oral nitrite in L-NAME-induced hypertension.

PubMed

Pinheiro, Lucas C; Ferreira, Graziele C; Vilalva, Kelvin H; Toledo, José C; Tanus-Santos, Jose E

2018-04-01

Nitrite reduces blood pressure (BP) in both clinical and experimental hypertension. This effect is attributable to the formation of nitric oxide (NO) and other NO-related species, which may be improved by ascorbate or other antioxidants. However, the BP responses to oral nitrite result, at least in part, of increased gastric S-nitrosothiol formation. This study tested the hypothesis that ascorbate may destroy S-nitrosothiols and therefore not all doses of ascorbate enhance the BP responses to oral nitrite. We assessed the BP responses to oral sodim nitrite (0.2 mmol/kg) in L-NAME hypertensive rats pretreated with ascorbate (0, 0.02, 0.2, or 2 mmol/kg). Plasma and gastric wall concentrations of nitrite and nitroso compounds concentrations were determined using an ozone-based reductive chemiluminescence assay. Nitrate concentrations were determined using the Griess reaction. Free thiol concentrations were determined by a colorimetric assay. The BP responses to nitrite exhibited a bell-shape profile as they were not modified by ascorbate 0.02 mmol/l, whereas the 0.2 mmol/kg dose enhanced and the 2 mmol/kg dose attenuated BP responses. In parallel with BP responses, nitrite-induced increases in plasma nitrite and RSNO species were not modified by ascorbate 0.02 mmol/l, whereas the 0.2 mmol/kg dose enhanced and the 2 mmol/kg dose attenuated them. Similar experiments were carried out with an equimolar dose of S-nitrosogluthathione. Ascorbate dose-dependently impaired the BP responses to S-nitrosogluthathione, and the corresponding increases in plasma RSNO, but not in plasma nitrite concentrations. This is the first study to show that while ascorbate dose-dependently impairs the BP responses to oral S-nitrosogluthathione, there are contrasting effects when low versus high ascorbate doses are compared with respect to its effects on the blood pressure responses to oral nitrite administration. Our findings may have special implications to patients taking ascorbate, as high doses of this vitamin may impair protective mechanisms associated with nitrite or nitrate from dietary sources. Copyright © 2018 Elsevier Inc. All rights reserved.

Developmental and genetic toxicity of stannous chloride in mouse dams and fetuses.

PubMed

El-Makawy, Aida I; Girgis, Shenouda M; Khalil, Wagdy K B

2008-12-08

Humans are exposed to stannous chloride (SnCl2) present in packaged food, soft drinks, biocides, dentifrices, etc. Health effects in children exposed to tin and tin compounds have not been investigated yet. Therefore, we evaluated the possible teratogenic and genotoxic effects of SnCl2 in pregnant female mice and their fetuses. Teratogenic effects including morphological malformation of the fetus and its skeleton were observed. Exposures to environmental stressors including toxic chemicals that have the potential of modulating the immune system can often be linked to ecologically relevant endpoints, such as reduced resistance to disease. Therefore, the semi-quantitative reverse-transcription PCR (RT-PCR) assay was used to evaluate the expression of immune-response genes in the liver of SnCl2-treated dams and their fetuses. Bone-marrow cells of dams and fetuses were investigated for the presence of aberrant chromosomes. Three oral doses of SnCl2 (2, 10 and 20 mg/kg bw) were tested. The results of the teratological study show that SnCl2 induced a significant decrease in the number of living fetuses and a significant increase in the number of post-implantation losses. The high dose of SnCl2 induced complete post-implantation loss. Furthermore, SnCl2 caused reduction in the ossification of the fetal skeleton. The RT-PCR assay showed that the immune-response genes GARP and SIMP were not expressed in the liver of dams and fetuses in the controls or in the group treated with SnCl2 at 2 mg/kg bw. However, the expression of these genes was up-regulated in the groups treated with the other doses of SnCl2. Regarding the chromosome analysis, SnCl2 induced a dose-dependent increase in the frequency of individual and total chromosomal aberrations (P

A randomized comparative trial of two low-dose oral isotretinoin regimens in moderate to severe acne vulgaris

PubMed Central

Dhaked, Daulat Ram; Meena, Ram Singh; Maheshwari, Anshul; Agarwal, Uma Shankar; Purohit, Saroj

2016-01-01

Background: Oral isotretinoin is highly effective in all forms and grades of acne, even in lower dosages (<0.5 mg/kg/day). There is a paucity of comparative data on the various low-dose regimens of oral isotretinoin in the Indian literature. Objectives: To assess and compare the efficacy and tolerability of two low-dose oral isotretinoin treatment regimens (20 mg daily and 20 mg alternate days) in moderate to severe acne vulgaris. Materials and Methods: A total of 240 patients with moderate to severe acne vulgaris were selected and randomized into two groups and treated with a fixed dose of 20 mg of isotretinoin (Group A - daily and Group B - alternate days) for 24 weeks and followed up for 12 weeks post therapy. Results: A total of 234 patients completed the study. At the end of therapy, decrease in the total acne loads up to 98.99% (Group A) and 97.69% (Group B) was achieved from the baseline (P < 0.01), excellent response was observed in 98.3% (Group A) and 93.96% (Group B) patients (P = 0.166). In the severe acne, Group A performed significantly better than Group B until the end of 36 weeks. While in the moderate acne, significant difference in the response between both groups was observed only up to 12 weeks. No serious side effect was observed. Conclusion: Both isotretinoin regimens were well tolerated and found to be an effective treatment for moderate to severe acne vulgaris. However, in moderate acne 20 mg alternate day regimen may be preferred. A 20 mg daily regimen is a better choice for severe acne in terms of response. Limitation: Small sample size and short follow-up period. PMID:27730033

The effect of low dose rate on metabolomic response to radiation in mice

PubMed Central

Goudarzi, Maryam; Mak, Tytus D.; Chen, Congju; Smilenov, Lubomir B.; Brenner, David J.

2014-01-01

Metabolomics has been shown to have utility in assessing responses to exposure by ionizing radiation (IR) in easily accessible biofluids such as urine. Most studies to date from our laboratory and others have employed γ-irradiation at relatively high dose rates (HDR), but many environmental exposure scenarios will probably be at relatively low dose rates (LDR). There are well-documented differences in the biologic responses to LDR compared to HDR, so an important question is to assess LDR effects at the metabolomics level. Our study took advantage of a modern mass spectrometry approach in exploring the effects of dose rate on the urinary excretion levels of metabolites 2 days after IR in mice. A wide variety of statistical tools were employed to further focus on metabolites, which showed responses to LDR IR exposure (0.00309 Gy/min) distinguishable from those of HDR. From a total of 709 detected spectral features, more than 100 were determined to be statistically significant when comparing urine from mice irradiated with 1.1 or 4.45 Gy to that of sham-irradiated mice 2 days post-exposure. The results of this study show that LDR and HDR exposures perturb many of the same pathways such as TCA cycle and fatty acid metabolism, which also have been implicated in our previous IR studies. However, it is important to note that dose rate did affect the levels of particular metabolites. Differences in urinary excretion levels of such metabolites could potentially be used to assess an individual's exposure in a radiobiological event and thus would have utility for both triage and injury assessment. PMID:25047638

Effect of Retosiban on Cardiac Repolarization in a Randomized, Placebo- and Positive-controlled, Crossover Thorough QT/QTc Study in Healthy Men and Women.

PubMed

Stier, Brendt; Fossler, Michael; Liu, Feng; Caltabiano, Stephen

2015-07-01

Retosiban is a small molecule oxytocin receptor antagonist that is under evaluation in clinical studies for treatment of spontaneous preterm labor. A Thorough QT/QTc study was conducted to evaluate the effect of retosiban on cardiac repolarization according to International Conference on Harmonization E14 guidance. This was a randomized, placebo- and positive-controlled, single-dose, crossover study of healthy men and women. All study participants received a 100 mg dose of retosiban (therapeutic target exposure), a 800 mg dose of retosiban (supratherapeutic target exposure), a 400 mg dose of moxifloxacin (positive control), and placebo with an appropriate washout. Holter monitoring data at baseline (predose) and at 13 subsequent time points during the next 24 hours were extracted and manually read by a central ECG reader who was blinded to the treatment assignment and corrected for heart rate by using the Fridericia formula (QTcF). A linear exposure-QTc response model was developed: ΔΔQTcF=RI+Cp,R⋅RS+MI+Cp,M⋅MS, where RI and MI are intercept terms for retosiban and moxifloxacin, respectively, RS and MS are slope terms for retosiban and moxifloxacin, respectively, and Cp,R and Cp,M are plasma concentrations for retosiban and moxifloxacin, respectively. A total of 52 healthy men (n = 27) and women (n = 25), with a mean age of 32 years, were enrolled in the study, and 43 (83%) completed all treatment periods and assessments. Mean placebo-corrected change from baseline QT (ΔΔQTcF) for the 2 retosiban dose groups revealed statistically significant decreases in ΔΔQTcF between 2 and 3 hours after administration, reaching a value of -2.5 msec for both retosiban dose groups. The 400 mg moxifloxacin group had a statistically significant increase in the ΔΔQTcF value at 0.75 hours after administration, reaching a maximal increase of 11.10 msec at 4 hours after administration. Results of the exposure-QTc response modeling revealed that there was no significant effect of retosiban on the ΔΔQTcF at therapeutic exposures. For the supratherapeutic exposure of retosiban, there was a slight negative effect, with a mean decrease of -3.05 msec. The moxifloxacin arm had a mean increase in ΔΔQTcF of 10.7 msec. At therapeutic and supratherapeutic exposures, retosiban had no significant effect on cardiac repolarization, as estimated by the ΔΔQTcF. However, both doses of retosiban had a minor shortening effect. This is not considered to be clinically significant. CLINICALTRIALS. NCT01702376. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

A randomized study of rotigotine dose response on 'off' time in advanced Parkinson's disease.

PubMed

Nicholas, Anthony P; Borgohain, Rupam; Chaná, Pedro; Surmann, Erwin; Thompson, Emily L; Bauer, Lars; Whitesides, John; Elmer, Lawrence W

2014-01-01

Previous phase III studies in patients with advanced Parkinson's disease (PD) not adequately controlled on levodopa demonstrated significant reduction of 'off' time with rotigotine transdermal system up to 16 mg/24 h. However, the minimal effective dose has not been established. This international, randomized, double-blind, placebo-controlled study (SP921; NCT00522379) investigated rotigotine dose response up to 8 mg/24 h. Patients with advanced idiopathic PD (≥2.5 h of daily 'off' time on stable doses of levodopa) were randomized 1:1:1:1:1 to receive rotigotine 2, 4, 6, or 8 mg/24 h or placebo, titrated over 4 weeks and maintained for 12 weeks. The primary efficacy variable was change from baseline to end of maintenance in absolute time spent 'off'. 409/514 (80%) randomized patients completed maintenance. Mean (±SD) baseline daily 'off' times (h/day) were placebo: 6.4 (±2.5), rotigotine 2-8 mg/24 h: 6.4 (±2.6). Rotigotine 8 mg/24 h was the minimal dose to significantly reduce 'off' time versus placebo. LS mean (±SE) absolute change in daily 'off' time (h/day) from baseline was -2.4 (±0.28) with rotigotine 8 mg/24 h, and -1.5 (±0.26) with placebo; absolute change in 'off' time in the 8 mg/24 h group compared with placebo was -0.85 h/day (95% CI -1.59, -0.11; p = 0.024). There was an apparent dose-dependent trend. Adverse events (AEs) reported at a higher incidence in the rotigotine 8 mg/24 h group versus placebo included application site reactions, nausea, dry mouth, and dyskinesia; there was no worsening of insomnia, somnolence, orthostatic hypotension, confusional state or hallucinations, even in patients ≥75 years of age. The minimal statistically significant effective dose of rotigotine to reduce absolute 'off' time was 8 mg/24 h. The AE profile was similar to previous studies.

Effect of Temporal Pattern of Radiation in Intensity Modulated Radiotherapy on Cell Cycle Progression and Apoptosis of ACHN Renal Cell Carcinoma Cell Line.

PubMed

Khorramizadeh, Maryam; Saberi, Alihossein; Tahmasebi-Birgani, Mohammadjavad; Shokrani, Parvaneh; Amouhedari, Alireza

The existence of a hypersensitive radiation response to doses below 1 Gy is well established for many normal and tumor cell lines. The aim of this study was to ascertain the impact of temporal pattern modeling IMRT on survival, cell cycle and apoptosis of human RCC cell line ACHN, so as to provide radiobiological basis for optimizing IMRT plans for this disease. The ACHN renal cell carcinoma cell line was used in this study. Impact of the triangle, V, small-large or large-small temporal patterns in the presence and absence of threshold dose of hyper-radiosensitivity at the beginning of patterns were studied using soft agarclonogenic assays. Cell cycle and apoptosis analysis were performed after irradiation with the temporal patterns. For triangle and small-large dose sequences, survival fraction was significantly reduced after irradiation with or without threshold dose of hyper-radiosensitivity at the beginning of the patterns. In all of the dose patterns, cell cycle distributions and the percentage of apoptotic cells at 24 h after irradiation with or without priming dose of hyper-radiosensitivity showed no significant difference. However, apoptotic cells were increased when beams with the smallest dose applied at the beginning of dose pattern like triangle and small-large dose sequence. These data show that the biologic effects of single fraction may differ in clinical settings depending on the size and sequence of the partial fractions. Doses at the beginning but not at the end of sequences may change cytotoxicity effects of radiation.

PHYSIOLOCIGALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT

EPA Science Inventory

PHYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODELING AND MODE OF ACTION IN DOSE-RESPONSE ASSESSMENT. Barton HA. Experimental Toxicology Division, National Health and Environmental Effects Laboratory, ORD, U.S. EPA
Dose-response analysis requires quantitatively linking infor...

Flavonoid-rich cocoa consumption affects multiple cardiovascular risk factors in a meta-analysis of short-term studies.

PubMed

Shrime, Mark G; Bauer, Scott R; McDonald, Anna C; Chowdhury, Nubaha H; Coltart, Cordelia E M; Ding, Eric L

2011-11-01

A growing body of evidence suggests that the consumption of foods rich in polyphenolic compounds, particularly cocoa, may have cardioprotective effects. No review, however, has yet examined the effect of flavonoid-rich cocoa (FRC) on all major cardiovascular risk factors or has examined potential dose-response relationships for these effects. A systematic review and meta-analysis of randomized, controlled trials was performed to evaluate the effect of FRC on cardiovascular risk factors and to assess a dose-response relationship. Inclusion and exclusion criteria as well as dependent and independent variables were determined a priori. Data were collected for: blood pressure, pulse, total cholesterol, HDL cholesterol, LDL cholesterol, TG, BMI, C-reactive protein, flow-mediated vascular dilation (FMD), fasting glucose, fasting insulin, serum isoprostane, and insulin sensitivity/resistance indices. Twenty-four papers, with 1106 participants, met the criteria for final analysis. In response to FRC consumption, systolic blood pressure decreased by 1.63 mm Hg (P = 0.033), LDL cholesterol decreased by 0.077 mmol/L (P = 0.038), and HDL cholesterol increased by 0.046 mmol/L (P = 0.037), whereas total cholesterol, TG, and C-reactive protein remained the same. Moreover, insulin resistance decreased (HOMA-IR: -0.94 points; P < 0.001), whereas FMD increased (1.53%; P < 0.001). A nonlinear dose-response relationship was found between FRC and FMD (P = 0.004), with maximum effect observed at a flavonoid dose of 500 mg/d; a similar relationship may exist with HDL cholesterol levels (P = 0.06). FRC consumption significantly improves blood pressure, insulin resistance, lipid profiles, and FMD. These short-term benefits warrant larger long-term investigations into the cardioprotective role of FRC.

Oral oxybutynin for the treatment of hyperhidrosis: outcomes after one-year follow-up.

PubMed

Millán-Cayetano, José Francisco; Del Boz, Javier; Rivas-Ruiz, Francisco; Blázquez-Sánchez, Nuria; Hernández Ibáñez, Carlos; de Troya-Martín, Magdalena

2017-05-01

Although many treatments are available to address hyperhidrosis, the results are not always satisfactory. The aim of the study was to assess the effectiveness, optimal dosage regimen and long-term safety of oral oxybutynin in the treatment of hyperhidrosis. A retrospective review was performed on 110 patients who underwent treatment for hyperhidrosis between February 2007 and December 2013. Their response to treatment was evaluated using the hyperhidrosis disease severity scale at baseline, 3 and 12 months. Additionally, the safety and effectiveness of different up-dosing and fixed-dose regimens were compared. After 3 months of treatment, 87 of the 110 patients (79%) had responded (63%), which was considered excellent. After 12 months, 63 patients (62%) continued to respond, and the response was considered excellent in 50%. Nine patients were lost to follow up between month 3 and 12. In total, 77 and 70% of the patients who responded at 3 and 12 months, respectively, reported mild adverse events. No serious adverse events were observed. Treatment adherence was significantly higher among patients following the individualised up-dosing regimen. Oral oxybutynin may be an effective and safe option for the long-term treatment of hyperhidrosis. To improve treatment adherence, oxybutynin dosing regimens should be individualised on the basis of the patient's tolerance and response. © 2016 The Australasian College of Dermatologists.

[Combined internal-external radiotherapy (CIERT) in a cell model].

PubMed

Oehme, Liane; Bartzsch, Thomas; Maucksch, Ute; Freudenberg, Robert; Wunderlich, Gerd; Kotzerke, Jörg

2018-06-01

Combined internal-external radiotherapy (CIERT) requires a unified assessment of biologic radiation effects in addition to the total dose. The concept of biological effective dose (BED) was evaluated in a cell model. The thyroid NIS-positive cell line FRTL-5 was irradiated with X-ray and the radiotracer Tc-99m pertechnetate either alone or in combination. The cellular uptake of the radionuclide during the incubation time of 24 h was controlled by the presence or absence of perchlorate. Dose calculation was performed based on measured uptake values. Cell specific radiobiologic parameters were derived from dose effect curves using the colony forming assay as biological endpoint. For the combination of the radiation qualities the sequence and time difference were varied. Cell survival was compared with the prediction of the BED model. The radiobiologic parameters from X-ray dose response were α = (0.22 ± 0.02) Gy -1 and β = (0.021 ± 0.001) Gy -2 . The half life for repair was (1.51 ± 0.21) h. These values could also explain the dose response curves for Tc-99m-irradiation with exponential decreasing dose rate. CIERT experiments showed no significant differences in cell survival regarding sequence and irradiation break. When the radionuclide uptake was not prevented the cell survival for the combination of X-ray and Tc-99m was lower than the prediction by BED calculations. The validity of the BED formalism for different dose rates and radiation qualities was verified. Supraaddive effects measured in the combination of X-ray and intracellular Tc-99m might be caused by Auger and conversion electrons, however further experiments are necessary. Schattauer GmbH.

Pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of Δ9-THC in cannabis users

PubMed Central

Lile, Joshua A.; Kelly, Thomas H.; Charnigo, Richard J.; Stinchcomb, Audra L.; Hays, Lon R.

2013-01-01

Oral Δ9-tetrahydrocannabinol (Δ9-THC) has been evaluated as a medication for cannabis dependence, but repeated administration of acute oral doses up to 40 mg has not been effective at reducing drug-taking behavior. Larger doses might be necessary to affect cannabis use. The purpose of the present study was therefore to determine the physiological and behavioral effects of oral Δ9-THC at acute doses higher than those tested previously. The pharmacokinetic and pharmacodynamic profile of oral Δ9-THC, administered in ascending order in 15 mg increments across separate sessions, up to a maximum of 90 mg, was determined in seven cannabis users. Five subjects received all doses and two experienced untoward side effects at lower doses. Δ9-THC produced a constellation of effects consistent with previous clinical studies. Low cannabinoid concentrations were associated with significant effects on drug- sensitive measures, although progressively greater levels did not lead to proportionately larger drug effects. Considerable variability in Cmax and tmax was observed. Doses of oral Δ9-THC larger than those tested previously can be administered to individuals with a history of cannabis use, although given the pharmacokinetic variability of oral Δ9-THC and individual differences in sensitivity, individualized dose adjustment is needed to avoid side effects and maximize therapeutic response. PMID:23754596

Pharmacokinetic-Pharmacodynamic Modeling of the Effect of Varenicline on Nicotine Craving in Adult Smokers

PubMed Central

Ravva, Patanjali; Gastonguay, Marc R.; Lee, Theodore C.; Niaura, Raymond

2015-01-01

Introduction: Varenicline has been shown to significantly reduce craving and several aspects of smoking reinforcement in clinical trials, compared with placebo. This is the first report describing the concentration-effect relationship of varenicline on relief of craving. Methods: The pharmacokinetics (PK) and pharmacodynamics (PD) of a single 2mg dose of varenicline were investigated in 40 smokers in a randomized, crossover study comparing the effect of varenicline with placebo on ameliorating abstinence-and cue-induced craving and withdrawal symptoms. Subjects were asked to complete self-reported questionnaires (Smoking Urges Scale and Minnesota Nicotine Withdrawal Scale [MNWS]) and blood samples were simultaneously collected for measurement of varenicline concentrations. Only the data from the 4-hr postdose abstinence period (just prior to the cue session) were analyzed. Data were described by a 2-compartment PK model and a linear PD model with first-order onset/offset rate constants describing the placebo response “kinetics.” Response was described as the net effect of the baseline, placebo, and drug responses. Results: Varenicline significantly decreased mean craving score when compared with placebo and the magnitude of this response was related to varenicline concentration. The time-course and magnitude of both placebo and varenicline craving response were characterized by a large degree of unexplained variability. Simulations were used to illustrate the expected craving response over time and its associated random variability after chronic dosing. Conclusions: Craving reduction is associated with increased varenicline concentrations. The relatively rapid onset of this effect within 4hr postdose suggests that, smokers may experience some craving relief after acute administration of varenicline. PMID:25145377

Inhibitory Effects of Medium Molecular Weight Heparinyl Amino Acid Derivatives on Ischemic Paw Edema in Mice.

PubMed

Takeda, Seiichi; Toda, Takao; Nakamura, Kazuki

2016-01-01

We investigated the radical-scavenging effects of heparin (HE), medium molecular weight heparinyl phenylalanine (MHF), and medium molecular weight heparinyl leucine (MHL) using ischemic paw edema in mice. We also examined the activated partial thromboplastin time (APTT) of mice that were administered these compounds as an index of their side-effects. HE had a preventative effect and significant reduced ischemic paw edema. However, its effect was not dose-dependent and the dose-response curve was bell-shaped. The effective dose of HE also exhibited a prolonged APTT. Pretreatment using MHF and MHL were effective against ischemic paw edema without a prolonged APTT. Remarkably, the action of MHF was not only preventively, but also therapeutically active. These results suggest that MHF and MHL are superior to HE as safe radical scavengers in vivo. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Statistical strategies for averaging EC50 from multiple dose-response experiments.

PubMed

Jiang, Xiaoqi; Kopp-Schneider, Annette

2015-11-01

In most dose-response studies, repeated experiments are conducted to determine the EC50 value for a chemical, requiring averaging EC50 estimates from a series of experiments. Two statistical strategies, the mixed-effect modeling and the meta-analysis approach, can be applied to estimate average behavior of EC50 values over all experiments by considering the variabilities within and among experiments. We investigated these two strategies in two common cases of multiple dose-response experiments in (a) complete and explicit dose-response relationships are observed in all experiments and in (b) only in a subset of experiments. In case (a), the meta-analysis strategy is a simple and robust method to average EC50 estimates. In case (b), all experimental data sets can be first screened using the dose-response screening plot, which allows visualization and comparison of multiple dose-response experimental results. As long as more than three experiments provide information about complete dose-response relationships, the experiments that cover incomplete relationships can be excluded from the meta-analysis strategy of averaging EC50 estimates. If there are only two experiments containing complete dose-response information, the mixed-effects model approach is suggested. We subsequently provided a web application for non-statisticians to implement the proposed meta-analysis strategy of averaging EC50 estimates from multiple dose-response experiments.

Solid Cancer Incidence in the Techa River Incidence Cohort: 1956-2007.

PubMed

Davis, F G; Yu, K L; Preston, D; Epifanova, S; Degteva, M; Akleyev, A V

2015-07-01

Previously reported studies of the Techa River Cohort have established associations between radiation dose and the occurrence of solid cancers and leukemia (non-CLL) that appear to be linear in dose response. These analyses include 17,435 cohort members alive and not known to have had cancer prior to January 1, 1956 who lived in areas near the river or Chelyabinsk City at some time between 1956 and the end of 2007, utilized individualized dose estimates computed using the Techa River Dosimetry System 2009 and included five more years of follow-up. The median and mean dose estimates based on these doses are consistently higher than those based on earlier Techa River Dosimetry System 2000 dose estimates. This article includes new site-specific cancer risk estimates and risk estimates adjusted for available information on smoking. There is a statistically significant (P = 0.02) linear trend in the smoking-adjusted all-solid cancer incidence risks with an excess relative risk (ERR) after exposure to 100 mGy of 0.077 with a 95% confidence interval of 0.013-0.15. Examination of site-specific risks revealed statistically significant radiation dose effects only for cancers of the esophagus and uterus with an ERR per 100 mGy estimates in excess of 0.10. Esophageal cancer risk estimates were modified by ethnicity and sex, but not smoking. While the solid cancer rates are attenuated when esophageal cancer is removed (ERR = 0.063 per 100 mGy), a dose-response relationship is present and it remains likely that radiation exposure has increased the risks for most solid cancers in the cohort despite the lack of power to detect statistically significant risks for specific sites.

The Analgesic Effects of Different Extracts of Aerial Parts of Coriandrum Sativum in Mice

PubMed Central

Fatemeh Kazempor, Seyedeh; Vafadar langehbiz, Shabnam; Hosseini, Mahmoud; Naser Shafei, Mohammad; Ghorbani, Ahmad; Pourganji, Masoomeh

2015-01-01

Regarding the effects of Coriandrum sativum (C. sativum) on central nervous system, in the present study analgesic properties of different extracts of C. sativum aerial partswere investigated. The mice were treated by saline, morphine, three doses (20, 100 and 500 mg/kg) of aqueous, ethanolic, choloroformic extracts of C. sativum and one dose (100 mg/kg) of aqueous, two doses of ethanolic (100 and 500 mg/kg) and one dose of choloroformic (20 mg/kg) extracts of C. sativum pretreated by naloxone. Recording of the hot plate test was performed 10 min before injection of the drugs as a base and it was consequently repeated every 10 minutes after the extracts injection. The maximal percent effect (MPE) in the groups treated by three doses of aqueous, ethanolic and chloroformic extracts were significantly higher than saline group which were comparable to the effect of morphine. The effects of most effective doses of extracts were reversed by naloxone. The results of present study showed analgesic effect of aqueous, ethanolic and chloroformic extracts of C. sativum extract. These effects of the extracts may be mediated by opioid system. However, more investigations are needed to elucidate the exact responsible mechanism(s) and the effective compound(s).

Phosphoproteomics profiling of human skin fibroblast cells reveals pathways and proteins affected by low doses of ionizing radiation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Feng; Waters, Katrina M.; Miller, John H.

2010-11-30

Background: High doses of ionizing radiation result in biological damage, however the precise relationships between long term health effects, including cancer, and low dose exposures remain poorly understood and are currently extrapolated using high dose exposure data. Identifying the signaling pathways and individual proteins affected at the post-translational level by radiation should shed valuable insight into the molecular mechanisms that regulate dose dependent responses to radiation. Principle Findings: We have identified 6845 unique phosphopeptides (2566 phosphoproteins) from control and irradiated (2 and 50 cGy) primary human skin fibroblasts one hour post-exposure. Dual statistical analyses based on spectral counts and peakmore » intensities identified 287 phosphopeptides (from 231 proteins) and 244 phosphopeptides (from 182 proteins) that varied significantly following exposure to 2 and 50 cGy respectively. This screen identified phosphorylation sites on proteins with known roles in radiation responses including TP53BP1 as well as previously unidentified radiation responsive proteins such as the candidate tumor suppressor SASH1. Bioinformatics analyses suggest that low and high doses of radiation affect both overlapping and unique biological processes and suggest a role of MAP kinase and protein kinase A (PKA) signaling in the radiation response as well as differential regulation of p53 networks at low and high doses of radiation. Conlcusions: Our results represent the most comprehensive analysis of the phosphoproteomes of human primary fibroblasts exposed to multiple doses of ionizing radiation published to date and provides a basis for the systems level identification of biological processes, molecular pathways and individual proteins regulated in a dose dependent manner by ionizing radiation. Further study of these modified proteins and affected networks should help to define the molecular mechanisms that regulate biological responses to radiation at different radiation doses and elucidate the impact of low dose radiation exposure on human health.« less

Development of a home cage locomotor tracking system capable of detecting the stimulant and sedative properties of drugs in rats.

PubMed

Dunne, Fergal; O'Halloran, Ambrose; Kelly, John P

2007-10-01

The advent of automated locomotor activity methodologies has been extremely useful in removing the subjectivity and bias out of measuring this parameter in rodents. However, many of these behavioural studies are still conducted in novel environments, rather than in ones that the animals are familiar with, such as their home cage. The purpose of the present series of experiments was to develop an automated home cage tracking (HCT) profile using EthoVision software and assessing the acute effects of stimulant (amphetamine and methamphetamine, 0-5 mg/kg, sc) and sedative (diazepam, 0-20 mg/kg, sc and chlordiazepoxide, 0-50 mg/kg sc) drugs in this apparatus. Young adult male Sprague-Dawley rats were used, and the home cage locomotor activity was recorded for 11-60 min following administration (n=4 per group). For amphetamine and methamphetamine, a dose-dependent increase in home cage activity was evident for both drugs, with a plateau, followed by reduction at higher doses. Methamphetamine was more potent, whereas amphetamine produced greater maximal responses. Both diazepam and chlordiazepoxide dose-dependently reduced locomotor activity, with diazepam exhibiting a greater potency and having stronger sedative effects than chlordiazepoxide. Three doses of each drug were selected at the 31-40 min time period following administration, and compared to open field responses. Diazepam, chlordiazepoxide and amphetamine did not produce significant changes in the open field, whilst methamphetamine produced a significant increase in the 2.5 mg/kg group. In conclusion, these studies have successfully developed a sensitive HCT methodology that has been validated using drugs with stimulant and sedative properties in the same test conditions, with relatively small numbers of animals required to produce statistically significant results. It has proven superior to the open field investigations in allowing dose-response effects to be observed over a relatively short observation period (i.e. 10 min) for both stimulants and sedatives. In addition, the HCT system can determine differences in potency and efficacy between drugs of a similar chemical class.

External beam radiotherapy for palliation of painful bone metastases: pooled data bioeffect dose response analysis of dose fractionation

NASA Astrophysics Data System (ADS)

Naveen, T.; Supe, Sanjay S.; Ganesh, K. M.; Samuel, Jacob

2009-01-01

Bone metastases develop in up to 70% of newly diagnosed cancer patients and result in immobility, anxiety, and depression, severely diminishing the patients quality of life. Radiotherapy is a frequently used modality for bone metastasis and has been shown to be effective in reducing metastatic bone pain and in some instances, causing tumor shrinkage or growth inhibition. There is controversy surrounding the optimal fractionation schedule and total dose of external beam radiotherapy, despite many randomized trials and overviews addressing the issue. This study was undertaken to apply BED to clinical fractionation data of radiotherapeutic management of bone metastases in order to arrive at optimum BED values for acceptable level of response rate. A computerised literature search was conducted to identify all prospective clinical studies that addressed the issue of fractionation for the treatment of bone metastasis. The results of these studies were pooled together to form the database for the analysis. A total of 4111 number of patients received radiation dose ranging from 4 to 40.5 Gy in 1 to 15 fractions with dose per fraction ranging from 2 to 10 Gy. Single fraction treatments were delivered in 2013 patients and the dose varied from 4 to 10 Gy. Multifraction treatments were delivered in 2098 patients and the dose varied from 15 to 40.5 Gy. The biological effective dose (BED) was evaluated for each fractionation schedule using the linear quadratic model and an α/β value of 10 Gy. Response rate increased significantly beyond a BED value of 14.4 Gy (p < 0.01). Based on our analysis and indications from the literature about higher retreatment and fracture rate of single fraction treatments, minimum BED value of 14.4 Gy is recommended.

Single dosing comparison of the relative cardiac beta 1/beta 2 activity of inhaled fenoterol and salbutamol in normal subjects.

PubMed Central

Newnham, D M; Wheeldon, N M; Lipworth, B J; McDevitt, D G

1993-01-01

BACKGROUND--The aim of the present study was to compare the dose related effects of fenoterol and salbutamol on cardiac beta 1 and beta 2 receptors using the beta 1 selective antagonist atenolol, in order to dissect out relative beta 1/beta 2 mediated responses. METHODS--Fourteen normal volunteers were randomised to receive pretreatment with either atenolol 25 mg or placebo, followed by inhaled fenoterol or salbutamol in equal doses by weight (cumulative doses of 1 mg and 4 mg). Measurements were made 30 minutes after inhaling each dose of beta 2 agonist. Values (mean and 95% CI) were expressed as a change from baseline. RESULTS--At 4 mg fenoterol produced equivalent falls in serum potassium and increases in tremor to salbutamol. The mean (95% CI) increase in heart rate (beats/min) with fenoterol at 4 mg after placebo was 47 (41-53) and after atenolol was 34 (28-40), with values for salbutamol being 46 (40-52) after placebo and 30 (24-36) after atenolol. The inotropic response (stroke distance) after atenolol at the 4 mg dose was 5.0 (3.9-6.1) cm for fenoterol and 4.7 (3.5-5.9) cm for salbutamol. There were no significant differences in heart rate or stroke distance response between the two drugs after either placebo or atenolol. Furthermore, ECG effects (Q-Tc and T wave) of fenoterol and salbutamol were comparable at both doses. CONCLUSIONS--These results show that there is no difference in the respective chronotropic or inotropic activities of fenoterol and salbutamol on cardiac beta 1 or beta 2 receptors when given at higher than conventional doses. PMID:8102213

The effects of a 5-HT2 receptor antagonist (ICI 169,369) on changes in waking EEG, pupillary responses and state of arousal in human volunteers.

PubMed Central

Millson, D S; Haworth, S J; Rushton, A; Wilkinson, D; Hobson, S; Harry, J

1991-01-01

1. ICI 169,369 (2-(2-dimethylamino ethylthio)-3-phenyl quinoline) is a potent selective competitive antagonist of the 5-HT2 receptor in animal models. Effects of ICI 169,369 as single oral doses (80 and 120 mg) separated by 1 week, on the power spectrum of waking EEG, dark adapted pupil responses and sedation score, were studied in a double-blind, placebo controlled, randomised cross over within subject comparison, in six healthy male volunteers. 2. Pupillary responses were measured using a portable infrared pupillometer following 15 min dark adaptation, assessing resting vertical pupil diameter (RPD), light constricted diameter (MPD) and recovered final diameter (FPD) at the end of a 3 s measurement cycle. 3. Both doses of ICI 169,369 produced a mean 36% (range 10-54%) decrease in log 10 power of the waking EEG alpha activity with eyes closed (P less than 0.02), and mean 38% (range 2-86%) increase in theta activity at 2 h compared with placebo. 4. Both 80 and 120 mg doses of ICI 169,369 reduced RPD by approximately 30% from a predose value of 6.25 mm (+/- 0.87; 95% CI) and from placebo values 6.41 mm (+/- 1.06) and 7.48 mm (+/- 1.49) at 3 and 5 h after dosing. MPD was reduced by 50% with the 120 mg dose at 5 h after dosing (placebo 5.2 mm; ICI 169,369 2.7 mm; P less than 0.05). FPD was significantly reduced (P less than 0.01) by both doses at 3 h after dosing.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1958438

[Dose-Response Dependences for Frequency of RET/PTC Gene Rearrangements in Papillary Thyroid Carcinoma after Irradiation. Simple Pooling Analysis of Molecular Epidemiological Data].

PubMed

Koterov, A N; Ushenkova, L N; Biryukov, A P

2016-01-01

On the basis of all possible publications on the theme included in the previously formed base of sources on molecular epidemiology of RET/PTC rearrangements in thyroid papillary carcinoma a pooled analysis ("simple pooling data") on determination of the dose-effect dependences for RET/PTC frequency in radiogenic carcinomas of various irradiated groups was performed. (They are groups subjected to radiotherapeutic exposure, residents near the Chernobyl nuclear power plant (CNPP) and victims of nuclear bombing). The tendency to Pearson linear correlation (r = 0.746; p = 0.148) between the frequency of RET/PTC and the estimated dose on thyroid in the regions affected by the CNPP accident was revealed. But this tendency was recognized to be random owing to abnormally low values of the indicator for the most contaminated Gomel region. The method tentatively called "case-control" showed reliable differences in thyroid dose values for carcinomas with RET/PTC and without those. The versatility of changes was found: the lack of RET/PTC for radiotherapeutic impacts was associated with higher doses, whereas in case of the CNPP accident and for nuclear bombing victims it was the opposite. Probably, in the first case the "cellular cleaning" phenomenon after exposure to very high doses took place. Search of direct Pearson correlations between average/median thyroid doses on groups and RET/PTC frequency in carcinomas of these groups showed a high reliability for the dose-effect dependences- at the continuous dose scale (for RET/PTC in total and RET/PTC1 respectively: r = 0.830; p = 0.002 and r = 0.906; p = 0.0003); while there was no significant correlation received for RET/PTC3. When using the weighting least square regression analysis (proceeding from the number of carcinomas in samples), the specified regularities remained. Attempts to influence the strength of correlation by exception ofthe data of all the samples connected with the accident on the CNPP did not significantly reduce the strength of associations for RET/PTC in total. On the basis of ordinal scale doses (background, "low" (0.1 Gy), "middle" (0.1-1 Gy) and "large" (1-10 Gy) dose) also found was a significant correlation (Spearman) with the dose for the frequency RET/PTC in total (r = 0.736; p = 0.0098), but for certain types of rearrangements the results were reverse to the previous analysis (the effect was significant only for the RET/PTC3: r = 0.731; p = 0.024). The linear dose-response trends of the Cochrane-Armitage-test for the frequency of RET/PTC in total, RET/PTC1 and RET/PTC3 depending on the dose to the thyroid in the ordinal scale were registered (p, respectively: < 0.0001 < 0.0001 and 0.007). Thus; after more than 20 years of the molecular and epidemiological research of RET/PTC in thyroid radiogenic carcinomas the comprehensive evidence of the dose-effect dependence existence indicating a real relationship between the studied parameters and a radiation factor was obtained for the first time.

Effects of a natural extract of Aronia Melanocarpa berry on endothelial cell nitric oxide production.

PubMed

Varela, Claudia Elena; Fromentin, Emilie; Roller, Marc; Villarreal, Francisco; Ramirez-Sanchez, Israel

2016-08-01

The effects of acute and chronic treatment with Aronia extracts on NO production and endothelial nitric oxide synthase (eNOS) phosphorylation in bovine coronary artery endothelial cells were investigated. Acute time-course and concentration-response experiments were performed to determine the time and concentration at which Aronia induced maximal NO synthesis and eNOS phosphorylation. The findings indicate that relatively low concentrations (0.1 μg/mL) of Aronia extract significantly induced NO synthesis and eNOS phosphorylation after 10 min of treatment. Increased sensitivity of eNOS and a significant increase in NO synthesis resulted from longer-term stimulation with Aronia (48 hr) and an acute re-treatment of the cells (10 min). These in vitro results may be translated into potential future clinical applications where Aronia extracts may be used for prevention and coadjuvant treatment of cardiovascular diseases via increases in endothelial NO synthesis and related improvements in vascular functions. Given the dose-response effect of Aronia extract in vitro and metabolism of polyphenols that occurs in humans, dose-response studies would be necessary to define the optimal daily amount to be consumed.

Effects of a natural extract of Aronia Melanocarpa berry on endothelial cell nitric oxide production

PubMed Central

Varela, Claudia Elena; Fromentin, Emilie; Roller, Marc; Villarreal, Francisco; Ramirez-Sanchez, Israel

2015-01-01

The effects of acute and chronic treatment with Aronia extracts on NO production and endothelial nitric oxide synthase (eNOS) phosphorylation in bovine coronary artery endothelial cells were investigated. Acute time-course and concentration-response experiments were performed to determine the time and concentration at which Aronia induced maximal NO synthesis and eNOS phosphorylation. The findings indicate that relatively low concentrations (0.1 μg/mL) of Aronia extract significantly induced NO synthesis and eNOS phosphorylation after 10 min of treatment. Increased sensitivity of eNOS and a significant increase in NO synthesis resulted from longer-term stimulation with Aronia (48 hr) and an acute re-treatment of the cells (10 min). PRACTICAL APPLICATIONS These in vitro results may be translated into potential future clinical applications where Aronia extracts may be used for prevention and coadjuvant treatment of cardiovascular diseases via increases in endothelial NO synthesis and related improvements in vascular functions. Given the dose-response effect of Aronia extract in vitro and metabolism of polyphenols that occurs in humans, dose-response studies would be necessary to define the optimal daily amount to be consumed. PMID:27616799

Aspirin as a potential modality for the chemoprevention of breast cancer: A dose-response meta-analysis of cohort studies from 857,831 participants

PubMed Central

Lu, Liming; Shi, Leiyu; Zeng, Jingchun; Wen, Zehuai

2017-01-01

Background Previous meta-analyses on the relationship between aspirin use and breast cancer risk have drawn inconsistent results. In addition, the threshold effect of different doses, frequencies and durations of aspirin use in preventing breast cancer have yet to be established. Results The search yielded 13 prospective cohort studies (N=857,831 participants) that reported an average of 7.6 cases/1,000 person-years of breast cancer during a follow-up period of from 4.4 to 14 years. With a random effects model, a borderline significant inverse association was observed between overall aspirin use and breast cancer risk, with a summarized RR = 0.94 (P = 0.051, 95% CI 0.87-1.01). The linear regression model was a better fit for the dose-response relationship, which displayed a potential relationship between the frequency of aspirin use and breast cancer risk (RR = 0.97, 0.95 and 0.90 for 5, 10 and 20 times/week aspirin use, respectively). It was also a better fit for the duration of aspirin use and breast cancer risk (RR = 0.86, 0.73 and 0.54 for 5, 10 and 20 years of aspirin use). Methods We searched MEDLINE, EMBASE and CENTRAL databases through early October 2016 for relevant prospective cohort studies of aspirin use and breast cancer risk. Meta-analysis of relative risks (RR) estimates associated with aspirin intake were presented by fixed or random effects models. The dose-response meta-analysis was performed by linear trend regression and restricted cubic spline regression. Conclusion Our study confirmed a dose-response relationship between aspirin use and breast cancer risk. For clinical prevention, long term (>5 years) consistent use (2-7 times/week) of aspirin appears to be more effective in achieving a protective effect against breast cancer. PMID:28418881

Aspirin as a potential modality for the chemoprevention of breast cancer: A dose-response meta-analysis of cohort studies from 857,831 participants.

PubMed

Lu, Liming; Shi, Leiyu; Zeng, Jingchun; Wen, Zehuai

2017-06-20

Previous meta-analyses on the relationship between aspirin use and breast cancer risk have drawn inconsistent results. In addition, the threshold effect of different doses, frequencies and durations of aspirin use in preventing breast cancer have yet to be established. The search yielded 13 prospective cohort studies (N=857,831 participants) that reported an average of 7.6 cases/1,000 person-years of breast cancer during a follow-up period of from 4.4 to 14 years. With a random effects model, a borderline significant inverse association was observed between overall aspirin use and breast cancer risk, with a summarized RR = 0.94 (P = 0.051, 95% CI 0.87-1.01). The linear regression model was a better fit for the dose-response relationship, which displayed a potential relationship between the frequency of aspirin use and breast cancer risk (RR = 0.97, 0.95 and 0.90 for 5, 10 and 20 times/week aspirin use, respectively). It was also a better fit for the duration of aspirin use and breast cancer risk (RR = 0.86, 0.73 and 0.54 for 5, 10 and 20 years of aspirin use). We searched MEDLINE, EMBASE and CENTRAL databases through early October 2016 for relevant prospective cohort studies of aspirin use and breast cancer risk. Meta-analysis of relative risks (RR) estimates associated with aspirin intake were presented by fixed or random effects models. The dose-response meta-analysis was performed by linear trend regression and restricted cubic spline regression. Our study confirmed a dose-response relationship between aspirin use and breast cancer risk. For clinical prevention, long term (>5 years) consistent use (2-7 times/week) of aspirin appears to be more effective in achieving a protective effect against breast cancer.

Investigations of putative reproductive toxicity of low-dose exposures to vinclozolin in Wistar rats.

PubMed

Flick, Burkhard; Schneider, Steffen; Melching-Kollmuss, Stephanie; Fussell, Karma C; Gröters, Sibylle; Buesen, Roland; Strauss, Volker; van Ravenzwaay, Bennard

2017-04-01

The current investigation examines whether the fungicide vinclozolin, which has an anti-androgenic mode of action, is capable of disrupting endocrine homeostasis at very low doses. The data generated clarify whether a non-monotonic dose-response relationship exists to enhance the current debate about the regulation of endocrine disruptors. Moreover, it is part of a series of investigations assessing the dose-response relationship of single and combined administration of anti-androgenic substances. A pre-postnatal in vivo study design was chosen which was compliant with regulatory testing protocols. The test design was improved by additional endpoints addressing hormone levels, morphology and histopathological examinations. Doses were chosen to represent an effect level (20 mg/kg bw/d), the current NOAEL (4 mg/kg bw/d), and a dose close to the "ADI" (0.005 mg/kg bw/d) for the detection of a possible non-monotonic dose-response curve. Anti-androgenic changes were observable at the effect level but not at lower exposures. Nipple/areola counts appeared to be the most sensitive measure of effect, followed by male sex organ weights at sexual maturation, and finally gross and histopathological findings. The results indicate the absence of evidence for effects at low or very low dose levels. A non-monotonic dose-response relationship was not evident.

Thrombomodulin exerts cytoprotective effect on low-dose UVB-irradiated HaCaT cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Iwata, Masahiro; Laboratory of Vascular Medicine, Department of Cardiovascular and Respiratory Disorders Advanced Therapeutics, Kagoshima University Graduate School of Medical and Dental Sciences, 8-35-1 Sakuragaoka, Kagoshima 890-8520; Kawahara, Ko-ichi

Thrombomodulin (TM) is an endothelial cell surface anticoagulant glycoprotein that performs antimetastatic, angiogenic, adhesive, and anti-inflammatory functions in various tissues. It is also expressed in epidermal keratinocytes. We found that a physiological dose (10 mJ/cm{sup 2}) of mid-wavelength ultraviolet irradiation (UVB) significantly induced TM expression via the p38mitogen-activated protein kinase (MAPK)/cyclic AMP response element (CRE) signaling pathway in the epidermal keratinocyte cell line HaCaT; this shows that TM regulates the survival of HaCaT cells. SB203580, a p38MAPK inhibitor, significantly decreased TM expression and the viability of cells exposed to UVB. Furthermore, overexpression of TM markedly increased cell viability, and itmore » was abrogated by TM small interfering RNA (siRNA), suggesting that TM may play an important role in exerting cytoprotective effect on epidermal keratinocytes against low-dose UVB.« less

Immunomodulatory effect of ganoderma lucidum polysaccharides (GLP) on long-term heavy-load exercising mice.

PubMed

Shi, Yali; Cai, Dehua; Wang, Xiaojie; Liu, Xinshen

2012-12-01

Long-term heavy-load exercise can lead to a decrease in the organism's immune response. In this study, we used 100 Kunming (KM) mice to investigate the immune-regulatory effects of Ganoderma lucidum polysaccharides (GLP) on long-term heavy-load exercising mice. Peripheral white blood cells (WBC), the absolute value of neutrophils (NEUT), the phagocytic function of macrophages, serum agglutination valence, and the number of plaque-forming cells (PFC) were evaluated 4 weeks after gavaging long-term heavy-load exercising mice with GLP. After exercise, the WBC count in peripheral blood, absolute neutrophil count, macrophage phagocytic index, serum agglutination valence, and the number of plaque-forming cells were significantly reduced in the mice not fed GLP. Both medium and high doses of GLP drastically increased peripheral WBC, absolute neutrophil count, macrophage phagocytic index, serum agglutination valence, and the number of plaque-forming cells in long-term heavy-load exercising mice. High doses of GLP increased peritoneal macrophage phagocytic rate considerably. With this study, we demonstrate that 4 weeks of heavy-load exercise can lead to exercise-induced immunosuppression in mice. A supplement of GLP fed to these mice improves both non-specific and specific immune responses among these mice. The effect for the high-dose GLP treatment is especially significant.

Differential respirable dust related lung function effects between current and former South African coal miners.

PubMed

Naidoo, Rajen N; Robins, Thomas G; Seixas, Noah; Lalloo, Umesh G; Becklake, Margaret

2005-05-01

Dust-related dose-response decrements in lung function among coal miners have been reported in several studies, with varying magnitudes across populations. Few studies have compared differences between current and former coal miners. No studies on dose response relationships with lung function have been conducted in South African coal mines, one of the top three producers of coal internationally. The objectives of this study were (1) to describe the relationship between respirable dust exposure and lung function among current and former South African coal miners and to determine whether differential dust related effects were present between these employment categories; (2) to examine dust related dose response relationships, controlling for potential confounding by smoking and a history of tuberculosis (TB). Six hundred and eighty-four current and 188 ex-miners from three bituminous coal mines in Mpumalanga Province were studied. Interviews assessing work histories, smoking profiles and other risk factors were conducted. Work histories were also obtained from company records. Standardised spirometry was performed by trained technicians. Cumulative respirable dust exposure (CDE) estimates were constructed from company-collected sampling and measurements conducted by the researchers. Regression models examined the associations of CDE with per cent predicted FEV(1) and FVC, controlling for smoking, past history of TB and employment status. A statistically significant decline in FEV(1) of 1.1 and 2.2 ml/mg-year/m(3) was found in representative 40-year-old, 1.7-m tall current and former miners, respectively. Significant differences were found between the highest and medium exposure categories. Ex-miners had a lower mean per cent predicted lung function than current miners for each cumulative exposure category, suggesting a "healthy worker" effect. Past history of TB contributed to 21 and 14% declines in per cent predicted FEV(1) and FVC, respectively. Thus, in this cohort, a dose-related decline in lung function was associated with respirable dust exposure, with a magnitude of effect similar to that seen in other studies and important differences between current and former employees. A "healthy worker" effect may have attenuated the magnitude of this relationship. TB was a significant contributor to lung function loss.

Evaluation of therapeutic effect of low dose naltrexone in experimentally-induced Crohn's disease in rats.

PubMed

Tawfik, Dina Ibrahim; Osman, Afaf Sayed; Tolba, Hedayat Mahmoud; Khattab, Aida; Abdel-Salam, Lubna O; Kamel, Mahmoud M

2016-10-01

Crohn's disease is a relapsing inflammatory condition afflicting the digestive tract. Drugs used for treatment of Crohn's disease may be associated with serious side effects. Endogenous opioid peptides modulate inflammatory cytokine production. Opioid antagonists have been shown to play a role in healing and repair of tissues. This work was designed to detect the possible beneficial effects of opioid antagonist naltrexone in indomethacin-induced Crohn's disease in rats. Enteritis was induced in male albino rats by two subcutaneous injection of indomethacin in a dose of 7.5mg/kg 24h apart started on day one. Salfasalazine, naltrexone and their combination were administered orally from day one of induction of enteritis to day 10. Disease activity index, serum levels of C-reactive protein and tumor necrosis factor-α, macroscopic and microscopic pathological scores and in vitro motility studies were evaluated. Induction of enteritis resulted in significant increase of disease activity index, significant elevation of serum levels of C-reactive protein and tumor necrosis factor-α, significant deterioration of pathological scores and significant increase in the mean contractility response of the isolated ileal segments compared with normal untreated rats. Treatment with sulfasalazine, low dose of natrexone or their combination resulted in significant improvement of all measured parameters compared with enteritis group. The current finding could provide new interesting opportunity for developing new therapeutic approaches for treatment of Crohn's disease. Use of naltrexone, especially in small dose, has little side effects making it of interest for treatment of Crohn's disease. Also, it provides the possibility of reduced doses of other drugs if it is used as combined therapy. Copyright © 2016 Elsevier Ltd. All rights reserved.

SU-F-T-329: Characteristic Study of a Rado-Photoluminescenct Glass Dosimeter with Accumulated Dose

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kim, D; Chung, W; Chung, M

Purpose: This study investigated the effect of accumulated dose on radiophotoluminescent glass dosimeter in megavoltage photon. Methods: 45 commercially-available radio-photoluminescence glass dosimeters (RPLGD; GD-302M, Asahi Techno Glass Co., Shizuoka, JAPAN) were irradiated to 10 × 10 cm{sup 2} open-field with 6, 10 and 15 MV photon beams at 100 cm of source to surface distance and dose maximum depths. Each energy has consists of five groups which is consists of three detectors. A group #1 and #2 was irradiated about 1 Gy to 100 Gy, and estimated the integral dose response with and without annealing procedure. A group #3 wasmore » read the dose after irradiated 10 Gy of dose by 10 times repeatedly to estimate the fading effect of RPLGD. A group #4 and #5 was produced same ways with different irradiation dose such as 50 Gy for group #4 and 100 Gy for group #5. Results: From the results of group #1 and #2, an annealed detector shows linear response to integral dose but other detectors without the annealing process, has supra linearity for integral dose especially close to 100 Gy dose. For group #3, #4 and #5, the dose response of repeated irradiation, the dose response was decreased about 15%, 12% and 7% for 6 MV, 10 MV and 15MV. Conclusion: It was found that RPLGD response to accumulated dose was supra linear and this respond was altered with amount of accumulated dose to the RPLGD. In addition, the fading effect need to be concern with RPLGD.« less

GENERAL CONSIDERATIONS OF DOSE-EFFECT AND DOSE-RESPONSE RELATIONSHIPS

EPA Science Inventory

ABSTRACT In 2003, the International Union of Pure and Applied chemistry (IUPAC) issued a glossary of terms that included the defi nition of dose-effect and doseresponse relationships (Nordberg et al., 2004). Dose effect relationship is defined as an association between dose and...

Genetic susceptibility: radiation effects relevant to space travel.

PubMed

Peng, Yuanlin; Nagasawa, Hatsumi; Warner, Christy; Bedford, Joel S

2012-11-01

Genetic variation in the capacity to repair radiation damage is an important factor influencing both cellular and tissue radiosensitivity variation among individuals as well as dose rate effects associated with such damage. This paper consists of two parts. The first part reviews some of the available data relating to genetic components governing such variability among individuals in susceptibility to radiation damage relevant for radiation protection and discusses the possibility and extent to which these may also apply for space radiations. The second part focuses on the importance of dose rate effects and genetic-based variations that influence them. Very few dose rate effect studies have been carried out for the kinds of radiations encountered in space. The authors present here new data on the production of chromosomal aberrations in noncycling low passage human ATM+/+ or ATM+/- cells following irradiations with protons (50 MeV or 1 GeV), 1 GeV(-1) n iron ions and gamma rays, where doses were delivered at a high dose rate of 700 mGy(-1) min, or a lower dose rate of 5 mGy min(-1). Dose responses were essentially linear over the dose ranges tested and not significantly different for the two cell strains. Values of the dose rate effectiveness factor (DREF) were expressed as the ratio of the slopes of the dose-response curves for the high versus the lower (5 mGy min(-1)) dose rate exposures. The authors refer to this as the DREF5. For the gamma ray standard, DREF5 values of approximately two were observed. Similar dose rate effects were seen for both energies of protons (DREF5 ≈ 2.2 in both cases). For 1 GeV(-1) n iron ions [linear energy transfer (LET) ≈ 150 keV μ(-1)], the DREF5 was not 1 as might have been expected on the basis of LET alone but was approximately 1.3. From these results and conditions, the authors estimate that the relative biological effectiveness for 1 GeV(-1) n iron ions for high and low dose rates, respectively, were about 10 and 15 rather than around 20 for low dose rates, as has been assumed by most recommendations from radiation protection organizations for charged particles of this LET. The authors suggest that similar studies using appropriate animal models of carcinogenesis would be valuable.

Tachykinin antagonist FK224 inhibits neurokinin A-, substance P- and capsaicin-induced human bronchial contraction.

PubMed

Honda, I; Kohrogi, H; Yamaguchi, T; Hamamoto, J; Hirata, N; Iwagoe, H; Fujii, K; Goto, E; Ando, M

1997-01-01

To determine the roles of endogenously released tachykinins (substance P [SP] and neurokinin A [NKA]) in the human bronchial tissues, we studied the effects of tachykinin antagonist FK224 on bronchial smooth muscle contraction induced by SP, NKA and capsaicin in an organ bath. FK224 (10(-6) M and 10(-5) M, respectively) significantly inhibited NKA-induced contraction and 10(-5) M FK224 shifted the dose-response curve to more than one log unit higher concentration. Because SP- and capsaicin-induced contractions were small, we pretreated the tissues with the neutral endopeptidase inhibitor phosphoramidon (10(-5) M), which inhibits degradation of exogenous tachykinins in order to potentiate the contractions. FK224 (10(-5) M) significantly inhibited SP-induced contraction and it shifted the dose-response curves to about one log unit higher concentration. FK224 (10(-5) M) also significantly inhibited capsaicin-induced contraction and it shifted the dose-response curves to more than one log unit higher concentration. In contrast, FK224 (10(-5) M) did not affect on acetylcholine-, histamine-, and leukotriene D4-induced contraction. These results suggest that FK224 is a tachykinin receptor antagonist in the human bronchial smooth muscle, and that capsaicin-induced contraction is due to endogenously released tachykinin-like substances in the human bronchus.

An evaluation of some pertinent parameters that influence the dosimetric performance of synthetic diamond detectors

NASA Astrophysics Data System (ADS)

Ade, N.; Nam, T. L.; Mhlanga, S. H.

2013-05-01

Although the near-tissue equivalence of diamond allows the direct measurement of dose for clinical applications without the need for energy-corrections, it is often cited that diamond detectors require pre-irradiation, a procedure necessary to stabilize the response or sensitivity of a diamond detector before dose measurements. In addition it has been pointed out that the relative dose measured with a diamond detector requires dose rate dependence correction and that the angular dependence of a detector could be due to its mechanical design or to the intrinsic angular sensitivity of the detection process. While the cause of instability of response has not been meticulously investigated, the issue of dose rate dependence correction is uncertain as some studies ignored it but reported good results. The aims of this study were therefore to investigate, in particular (1) the major cause of the unstable response of diamond detectors requiring pre-irradiation; (2) the influence of dose rate dependence correction in relative dose measurements; and (3) the angular dependence of the diamond detectors. The study was conducted with low-energy X-rays and electron therapy beams on HPHT and CVD synthesized diamonds. Ionization chambers were used for comparative measurements. Through systematic investigations, the major cause of the unstable response of diamond detectors requiring the recommended pre-irradiation step was isolated and attributed to the presence and effects of ambient light. The variation in detector's response between measurements in light and dark conditions could be as high as 63% for a CVD diamond. Dose rate dependence parameters (Δ values) of 0.950 and 1.035 were found for the HPHT and CVD diamond detectors, respectively. Without corrections based on dose rate dependence, the relative differences between depth-doses measured with the diamond detectors and a Markus chamber for exposures to 7 and 14 MeV electron beams were within 2.5%. A dose rate dependence correction using the Δ values obtained seemed to worsen the performance of the HPHT sample (up to about 3.3%) but it had a marginal effect on the performance of the CVD sample. In addition, the angular response of the CVD diamond detector was shown to be comparable with that of a cylindrical chamber. This study concludes that once the responses of the diamond detectors have been stabilised and they are properly shielded from ambient light, pre-irradiation prior to each measurement is not required. Also, the relative dose measured with the diamond detectors do not require dose rate dependence corrections as the required correction is only marginal and could have no dosimetric significance.

Nonmonotonic dose response curves (NMDRCs) are common after Estrogen or Androgen signaling pathway disruption. Fact or Falderal? ###SETAC

EPA Science Inventory

The shape of the dose response curve in the low dose region has been debated since the late 1940s. The debate originally focused on linear no threshold (LNT) vs threshold responses in the low dose range for cancer and noncancer related effects. Recently, claims have arisen tha...

Defibrotide for the treatment of severe hepatic veno-occlusive disease and multiorgan failure after stem cell transplantation: a multicenter, randomized, dose-finding trial.

PubMed

Richardson, Paul G; Soiffer, Robert J; Antin, Joseph H; Uno, Hajime; Jin, Zhezhen; Kurtzberg, Joanne; Martin, Paul L; Steinbach, Gideon; Murray, Karen F; Vogelsang, Georgia B; Chen, Allen R; Krishnan, Amrita; Kernan, Nancy A; Avigan, David E; Spitzer, Thomas R; Shulman, Howard M; Di Salvo, Donald N; Revta, Carolyn; Warren, Diane; Momtaz, Parisa; Bradwin, Gary; Wei, L J; Iacobelli, Massimo; McDonald, George B; Guinan, Eva C

2010-07-01

Therapeutic options for severe hepatic veno-occlusive disease (VOD) are limited and outcomes are dismal, but early phase I/II studies have suggested promising activity and acceptable toxicity using the novel polydisperse oligonucleotide defibrotide. This randomized phase II dose-finding trial determined the efficacy of defibrotide in patients with severe VOD following hematopoietic stem cell transplantation (HSCT) and identified an appropriate dose for future trials. Adult and pediatric patients received either lower-dose (arm A: 25 mg/kg/day; n = 75) or higher-dose (arm B: 40 mg/kg/day; n = 74) i.v. defibrotide administered in divided doses every 6 hours for > or =14 days or until complete response, VOD progression, or any unacceptable toxicity occurred. Overall complete response and day +100 post-HSCT survival rates were 46% and 42%, respectively, with no significant difference between treatment arms. The incidence of treatment-related adverse events was low (8% overall; 7% in arm A, 10% in arm B); there was no significant difference in the overall rate of adverse events between treatment arms. Early stabilization or decreased bilirubin was associated with better response and day +100 survival, and decreased plasminogen activator inhibitor type 1 (PAI-1) during treatment was associated with better outcome; changes were similar in both treatment arms. Defibrotide 25 or 40 mg/kg/day also appears effective in treating severe VOD following HSCT. In the absence of any differences in activity, toxicity or changes in PAI-1 level, defibrotide 25 mg/kg/day was selected for ongoing phase III trials in VOD.

Desvenlafaxine in major depressive disorder: an evidence-based review of its place in therapy

PubMed Central

Lieberman, Daniel Z; Massey, Suena H

2010-01-01

Introduction: Desvenlafaxine, the active metabolite of venlafaxine, is a serotonin norepinephrine reuptake inhibitor (SNRI) recently approved for the treatment of major depressive disorder. It is one of only three medications in this class available in the United States. Aims: The objective of this article is to review the published evidence for the safety and efficacy of desvenlafaxine, and to compare it to other antidepressants to delineate its role in the treatment of depression. Evidence review: At the recommended dose of 50 mg per day the rate of response and remission was similar to other SNRIs, as was the adverse effect profile. The rate of discontinuation was no greater than placebo, and a discontinuation syndrome was not observed at this dose. Higher doses were not associated with greater efficacy, but they did lead to more side effects, and the use of a taper prior to discontinuation. The most common side effects reported were insomnia, somnolence, dizziness, and nausea. Some subjects experienced clinically significant blood pressure elevation. Place in therapy: Like duloxetine, desvenlafaxine inhibits the reuptake of both norepinephrine and serotonin at the starting dose. Dual reuptake inhibitors have been shown to have small but statistically significantly greater rates of response and remission compared to selective serotonin reuptake inhibitors, and they have also shown early promise in the treatment of neuropathic pain. Desvenlafaxine may prove to be a valuable treatment option by expanding the limited number of available dual reuptake inhibitors. PMID:20694066

Exercise-Induced Dose-Response Alterations in Adiponectin and Leptin Levels Are Dependent on Body Fat Changes in Women at Risk for Breast Cancer.

PubMed

Sturgeon, Kathleen; Digiovanni, Laura; Good, Jerene; Salvatore, Domenick; Fenderson, Desiré; Domchek, Susan; Stopfer, Jill; Galantino, Mary Lou; Bryan, Cathy; Hwang, Wei-Ting; Schmitz, Kathryn

2016-08-01

Dysregulation of adipokines, such as adiponectin and leptin, is associated with a variety of chronic diseases, including cancer. Physical activity protects against breast cancer and one of the mechanisms which may underlie this association is exercise-induced changes in adipokine levels. The WISER Sister Trial was a three-armed randomized controlled trial in premenopausal women (n = 137) with an elevated risk for breast cancer. A 5-menstrual-cycle-long dosed aerobic exercise intervention compared low-dose exercise (150 min/wk; n = 44) or high-dose exercise (300 min/wk; n = 48) with a control group asked to maintain usual activity levels (n = 45). Exercise intensity progressed to and was maintained at 70% to 80% of age predicted heart rate max. Body composition and adipokine levels were measured at baseline and follow-up. We observed significant linear trends for increased fitness capacity (Δ%: -2.0% control, 10.1% low dose, 13.1% high dose), decreased fat tissue-to-total tissue mass (Δ%: 0.7% control, -2.9% low dose, -3.7% high dose), increased body fat adjusted adiponectin (Δ%: -0.6% control, 0.6% low dose, 0.9% high dose), and decreased body fat adjusted leptin (Δ%: 0.7% control, -8.2% low dose, -10.2% high dose). In this randomized clinical trial of premenopausal women at risk for breast cancer, we demonstrate a dose-response effect of exercise on adiponectin and leptin and that dose response is dependent on changes in body fat. Improved adipokine levels, achieved by aerobic exercise training-induced decreases in body fat, may decrease breast cancer risk for high-risk premenopausal women. Cancer Epidemiol Biomarkers Prev; 25(8); 1195-200. ©2016 AACR. ©2016 American Association for Cancer Research.

Cortisol Modulation by Ayahuasca in Patients With Treatment Resistant Depression and Healthy Controls

PubMed Central

Galvão, Ana C. de Menezes; de Almeida, Raíssa N.; Silva, Erick A. dos Santos; Freire, Fúlvio A. M.; Palhano-Fontes, Fernanda; Onias, Heloisa; Arcoverde, Emerson; Maia-de-Oliveira, João P.; de Araújo, Dráulio B.; Lobão-Soares, Bruno; Galvão-Coelho, Nicole L.

2018-01-01

Major depression is a highly prevalent mood disorder, affecting about 350 million people, and around 30% of the patients are resistant to currently available antidepressant medications. Recent evidence from a randomized controlled trial (RCT) supports the rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression. The aim of this study was to explore the effect of ayahuasca on plasma cortisol and awakening salivary cortisol response, in the same group of treatment-resistant patients (MD) and in healthy volunteers (C). Subjects received a single dose of ayahuasca or placebo (dosing session), and both plasma and awakening salivary cortisol response were measured at baseline (before dosing session) and 48 h after the dosing session. Baseline assessment (D0) showed blunted awakening salivary cortisol response and hypocortisolemia in patients, with respect to healthy controls. Salivary cortisol was also measured during dosing session, and we observed higher increases for both C and MD that ingested ayahuasca than placebo. After 48 h from the dosing session with ayahuasca, patients' awakening salivary cortisol response is similar to the ones detected in controls. No significant changes in plasma cortisol levels were observed 48 h after the sessions. Therefore, these findings point to new evidence on the modulation of salivary cortisol levels as a result of an ayahuasca session, both in healthy and depressive volunteers. Considering that cortisol acts in regulation of distinct physiological pathways, emotional and cognitive processes, it is assumed to be critically involved to the etiology of depression and its regulation seems to be important for the treatment and remission of major depression, ayahuasca use as antidepressant should be further investigated. Moreover, this study highlights the importance of psychedelics in the treatment of human mental disorders. PMID:29867608

Electroencephalographic response following midazolam-induced general anesthesia: relationship to plasma and effect-site midazolam concentrations.

PubMed

Miyake, Wakako; Oda, Yutaka; Ikeda, Yuko; Hagihira, Satoshi; Iwaki, Hiroyoshi; Asada, Akira

2010-06-01

To examine the relationships between effect-site concentrations and electroencephalographic parameters after the induction of general anesthesia with midazolam. Twenty-four patients with American Society of Anesthesiologists status I or II were randomly allocated to receive either an intravenous (i.v.) bolus of midazolam 0.2 mg kg(-1) (small-dose group, n = 12) or 0.3 mg kg(-1) (large-dose group, n = 12) for induction of general anesthesia in a double-blind experimental design. The bispectral index (BIS), 95% spectral edge frequency (SEF95), spectral power density, and plasma concentrations of midazolam were measured for 60 min following the induction of general anesthesia. Plasma and simulated effect-site concentrations of midazolam were significantly higher in the large-dose group than in the small-dose group (P = 0.005 and <0.001, respectively). There was a correlation between the relative beta ratio and BIS (r (2) = 0.30, P < 0.001; n = 168); however, effect-site concentrations of midazolam showed no association with BIS, relative beta ratio, or SEF95 (r (2) = 0.07, 0.11 and 0.01, respectively; n = 168). The electroencephalographic spectral power density in the beta-band (>/=13 and <30 Hz) was significantly increased after induction and was significantly larger in the large-dose group than in the small-dose group (P = 0.009). Following the induction of general anesthesia with i.v. midazolam 0.2 or 0.3 mg kg(-1), the BIS was positively correlated with the relative beta ratio. Despite a rapid decrease in the plasma and effect-site concentrations of midazolam, the average BIS remained >60 for 60 min after induction, reflecting an increased power of the electroencephalographic high-frequency band.

Dose-response relationship between dietary magnesium intake and cardiovascular mortality: A systematic review and dose-based meta-regression analysis of prospective studies.

PubMed

Fang, Xin; Liang, Chun; Li, Mei; Montgomery, Scott; Fall, Katja; Aaseth, Jan; Cao, Yang

2016-12-01

Although epidemiology studies have reported the relationship, including a dose-response relationship, between dietary magnesium intake and risk of cardiovascular disease (CVD), the risk for CVD mortality is inconclusive and the evidence for a dose-response relationship has not been summarized. We conducted a systematic review and meta-analysis of prospective studies to summarize the evidence regarding the association of dietary magnesium intake with risk of CVD mortality and describe their dose-response relationship. We identified relevant studies by searching major scientific literature databases and grey literature resources from their inception to August 2015, and reviewed references lists of retrieved articles. We included population-based studies that reported mortality risks, i.e. relative risks (RRs), odds ratios (ORs) or hazard ratios (HRs) of CVD mortality or cause-specific CVD death. Linear dose-response relationships were assessed using random-effects meta-regression. Potential nonlinear associations were evaluated using restricted cubic splines. Out of 3002 articles, 9 articles from 8 independent studies met the eligibility criteria. These studies comprised 449,748 individuals and 10,313 CVD deaths. Compared with the lowest dietary magnesium consumption group in the population, the risk of CVD mortality was reduced by 16% in women and 8% in men. No significant linear dose-response relationship was found between increment in dietary magnesium intake and CVD mortality across all the studies. After adjusting for age and BMI, the risk of CVD mortality was reduced by 24-25% per 100mg/d increment in dietary magnesium intake in women of all the participants and in all the US participants. Although the combined data confirm the role of dietary magnesium intake in reducing CVD mortality, the dose-response relationship was only found among women and in US population. Copyright © 2016 Elsevier GmbH. All rights reserved.

Optimal dose selection of N-methyl-N-nitrosourea for the rat comet assay to evaluate DNA damage in organs with different susceptibility to cytotoxicity.

PubMed

Kitamoto, Sachiko; Matsuyama, Ryoko; Uematsu, Yasuaki; Ogata, Keiko; Ota, Mika; Yamada, Toru; Miyata, Kaori; Funabashi, Hitoshi; Saito, Koichi

2015-07-01

The in vivo rodent alkaline comet assay (comet assay) is a promising technique to evaluate DNA damage in vivo. However, there is no agreement on a method to evaluate DNA damage in organs where cytotoxicity is observed. As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the comet assay, we examined DNA damage in the liver, stomach, and bone marrow of rats given three oral doses of N-methyl-N-nitrosourea (MNU) up to the maximum tolerated dose based on systemic toxicity. MNU significantly increased the % tail DNA in all the organs. Histopathological analysis showed no cytotoxic effect on the liver, indicating clearly that MNU has a genotoxic potential in the liver. In the stomach, however, the cytotoxic effects were very severe at systemically non-toxic doses. Low-dose MNU significantly increased the % tail DNA even at a non-cytotoxic dose, indicating that MNU has a genotoxic potential also in the stomach. Part of the DNA damage at cytotoxic doses was considered to be a secondary effect of severe cell damage. In the bone marrow, both the % tail DNA and incidence of micronucleated polychromatic erythrocytes significantly increased at non-hematotoxic doses, which were different from the non-cytotoxic doses for liver and stomach. These findings indicate that an optimal dose for detecting DNA damage may vary among organs and that careful attention is required to select an optimum dose for the comet assay based on systemic toxicity such as mortality and clinical observations. The present study shows that when serious cytotoxicity is suggested by increased % hedgehogs in the comet assay, histopathological examination should be included for the evaluation of a positive response. Copyright © 2015 Elsevier B.V. All rights reserved.

Split-course, high-dose palliative pelvic radiotherapy for locally progressive hormone-refractory prostate cancer.

PubMed

Gogna, Nirdosh Kumar; Baxi, Siddhartha; Hickey, Brigid; Baumann, Kathryn; Burmeister, Elizabeth; Holt, Tanya

2012-06-01

Local progression, in patients with hormone-refractory prostate cancer, often causes significant morbidity. Pelvic radiotherapy (RT) provides effective palliation in this setting, with most published studies supporting the use of high-dose regimens. The aim of the present study was to examine the role of split-course hypofractionated RT used at our institution in treating this group of patients. A total of 34 men with locoregionally progressive hormone-refractory prostate cancer, treated with a split course of pelvic RT (45-60 Gy in 18-24 fractions) between 2000 and 2008 were analyzed. The primary endpoints were the response rate and actuarial locoregional progression-free survival. Secondary endpoints included overall survival, compliance, and acute and late toxicity. The median age was 71 years (range, 53-88). Treatment resulted in an overall initial response rate of 91%, a median locoregional progression-free survival of 43 months, and median overall survival of 28 months. Compliance was excellent and no significant late toxicity was reported. The split course pelvic RT described has an acceptable toxicity profile, is effective, and compares well with other high-dose palliative regimens that have been previously reported. Copyright © 2012 Elsevier Inc. All rights reserved.

Study of pharmacological activities of methanol extract of Jatropha gossypifolia fruits.

PubMed

Apu, Apurba Sarker; Hossain, Faruq; Rizwan, Farhana; Bhuyan, Shakhawat Hossan; Matin, Maima; Jamaluddin, A T M

2012-12-01

The present study was carried out to investigate the possible in vivo analgesic, neuropharmacological and anti-diarrheal activities of the methanol extract of Jatropha gossypifolia fruits. The analgesic activity was measured by acetic acid induced writhing inhibition test. The neuropharmacological activities were evaluated by hole cross, hole-board, and elevated plus-maze (EPM) tests and the anti-diarrheal activity was assessed by castor oil induced diarrhea inhibition method. The extract showed highly significant (P < 0.001) analgesic activity with % inhibitions of writhing response at doses 200 and 400 mg/kg body weight were 77.86% and 71.25%, respectively. The extract at both doses showed significant (P < 0.05) sedative effect in-hole cross test. In-hole board test, the extract showed highly significant (P < 0.001) anxiolytic activity at lower dose whereas this activity was observed at higher dose in EPM test. The extract also showed highly significant (P < 0.001) anti-diarrheal activity. The findings of the study clearly indicate the presence of significant analgesic, neuropharmacological and anti-diarrheal properties of the plant, which demands further investigation including, compound isolation.

The linearized multistage model and the future of quantitative risk assessment.

PubMed

Crump, K S

1996-10-01

The linearized multistage (LMS) model has for over 15 years been the default dose-response model used by the U.S. Environmental Protection Agency (USEPA) and other federal and state regulatory agencies in the United States for calculating quantitative estimates of low-dose carcinogenic risks from animal data. The LMS model is in essence a flexible statistical model that can describe both linear and non-linear dose-response patterns, and that produces an upper confidence bound on the linear low-dose slope of the dose-response curve. Unlike its namesake, the Armitage-Doll multistage model, the parameters of the LMS do not correspond to actual physiological phenomena. Thus the LMS is 'biological' only to the extent that the true biological dose response is linear at low dose and that low-dose slope is reflected in the experimental data. If the true dose response is non-linear the LMS upper bound may overestimate the true risk by many orders of magnitude. However, competing low-dose extrapolation models, including those derived from 'biologically-based models' that are capable of incorporating additional biological information, have not shown evidence to date of being able to produce quantitative estimates of low-dose risks that are any more accurate than those obtained from the LMS model. Further, even if these attempts were successful, the extent to which more accurate estimates of low-dose risks in a test animal species would translate into improved estimates of human risk is questionable. Thus, it does not appear possible at present to develop a quantitative approach that would be generally applicable and that would offer significant improvements upon the crude bounding estimates of the type provided by the LMS model. Draft USEPA guidelines for cancer risk assessment incorporate an approach similar to the LMS for carcinogens having a linear mode of action. However, under these guidelines quantitative estimates of low-dose risks would not be developed for carcinogens having a non-linear mode of action; instead dose-response modelling would be used in the experimental range to calculate an LED10* (a statistical lower bound on the dose corresponding to a 10% increase in risk), and safety factors would be applied to the LED10* to determine acceptable exposure levels for humans. This approach is very similar to the one presently used by USEPA for non-carcinogens. Rather than using one approach for carcinogens believed to have a linear mode of action and a different approach for all other health effects, it is suggested herein that it would be more appropriate to use an approach conceptually similar to the 'LED10*-safety factor' approach for all health effects, and not to routinely develop quantitative risk estimates from animal data.

Angiotensin converting enzyme inhibitors potentiate the bronchoconstriction induced by substance P in the guinea-pig.

PubMed Central

Subissi, A.; Guelfi, M.; Criscuoli, M.

1990-01-01

1. The effects of intravenous captopril and enalaprilic acid on the increase in pulmonary inflation pressure induced by different bronchoconstrictor agents were evaluated in the anaesthetized guinea-pig. 2. Captopril and enalaprilic acid (1.6-200 micrograms kg-1) enhanced dose-dependently the bronchoconstriction (BC) induced by substance P. The threshold effective dose was 1.6 micrograms kg-1 and maximal potentiation over the control response was more than 400% for both agents. Enalaprilic acid was also assayed for serum and lung angiotensin converting enzyme (ACE) inhibition in anaesthetized guinea-pigs. This drug produced a dose-dependent inhibition of ACE in both tissues, with ED50 s of 7.6 and 9.4 micrograms kg-1, respectively: this inhibitory activity was positively correlated to substance P potentiation. 3. Captopril (8-1000 micrograms kg-1) enhanced dose-dependently the BC induced by capsaicin. The threshold effective dose was 40 micrograms kg-1 and maximal potentiation about 90%. 4. Captopril (200-1000 micrograms kg-1) did not affect BC induced by bradykinin. However, this response was markedly enhanced (about 200%) by captopril 200 micrograms kg-1 in propranolol-pretreated animals. 5. Captopril and enalaprilic acid (200-1000 micrograms kg-1) slightly (20-40%) but significantly enhanced the BC induced by 5-hydroxytryptamine. However, this response was potentiated to the same extent by a dose of prazosin, which produced a degree of hypotension similar to that observed after administration of the ACE inhibitors. 6. In conclusion, ACE inhibitors potentiate the BC induced by substance P and, to a minor extent, that induced by capsaicin in the anaesthetized guinea-pig.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1697196

Effects of a Multi-Ingredient Energy Supplement on Cognitive Performance and Cerebral-Cortical Activation.

PubMed

Daou, Marcos; Sassi, Julia Montagner; Miller, Matthew W; Gonzalez, Adam M

2018-03-13

This study assessed whether a multi-ingredient energy supplement (MIES) could enhance cerebral-cortical activation and cognitive performance during an attention-switching task. Cerebral-cortical activation was recorded in 24 young adults (12 males, 12 females; 22.8 ± 3.8 yrs) via electroencephalography (EEG) both at rest and during the attention-switching task before (pretest) and 30 min after (posttest) consumption of a single serving of a MIES (MIES-1), two servings of a MIES (MIES-2), or a placebo (PL) in a double-blinded, randomized crossover experimental design. EEG upper-alpha power was assessed at rest and during the task, wherein d' (Z[hit rate]-Z[false alarm rate]) and median reaction time (RT) for correct responses to targets on attention-hold and attention-switch trials were analyzed. For both d' and RT, the Session (MIES-1, MIES-2, PL) × Time (pretest, posttest) interaction approached statistical significance (p = .07, η 2 p = 0.106). Exploring these interactions with linear contrasts, a significant linear effect of supplement dose on the linear effect of time was observed (ps ≤.034), suggesting the pretest-to-posttest improvement in sensitivity to task target stimuli (d') and RT increased as a function of supplement dose. With respect to upper-alpha power, the Session × Time interaction was significant (p < .001, η 2 p = 0.422). Exploring this interaction with linear contrasts, a significant linear effect of supplement dose on the linear effect of time was observed (p < .001), suggesting pretest-to-posttest increases in cerebral-cortical activation were a function of supplement dose. In conclusion, our findings suggest that MIES can increase cerebral-cortical activation and RT during task performance while increasing sensitivity to target stimuli in a dose-dependent manner.

Renal uptake of radiolabeled octreotide in human subjects is efficiently inhibited by succinylated gelatin.

PubMed

Vegt, Erik; Wetzels, Jack F M; Russel, Frans G M; Masereeuw, Rosalinde; Boerman, Otto C; van Eerd, Juliette E; Corstens, Frans H M; Oyen, Wim J G

2006-03-01

Peptide receptor-mediated radiotherapy of neuroendocrine and other somatostatin receptor-positive tumors with radiolabeled somatostatin analogs has been applied in several experimental settings. The kidneys are the organs responsible for dose-limiting toxicity attributable to the retention of radiolabeled octreotide in the renal cortex, leading to a relatively high radiation dose that may result in irreversible loss of kidney function. The administration of basic amino acids reduces renal uptake but does have significant side effects. We observed that gelatin-based plasma expanders induced tubular low-molecular-weight proteinuria in healthy volunteers, suggesting that components in these solutions can interfere with the tubular reabsorption of proteins and peptides. Here, we studied the effects of infusion of low doses of the plasma expander succinylated gelatin (GELO) on the renal uptake of 111In-labeled octreotide (111In-OCT). Five healthy volunteers were given 111In-OCT, first in combination with normal saline and 2 wk later in combination with GELO. Scintigraphic images of the kidneys as well as blood and urine samples were analyzed. To exclude a nonspecific hemodynamic effect of the plasma expander, the procedure was repeated with 5 other volunteers who received the carbohydrate-based plasma expander hydroxyethyl starch (HES). Low doses of GELO were able to effectively reduce the kidney retention of 111In-OCT. The renal radiation dose was significantly reduced by 45% +/- 10% (mean +/- SD) (P = 0.006), whereas HES showed no significant effect (0% +/- 12%). The infusion of GELO did not cause any side effects. GELO effectively reduces the renal uptake of 111In-OCT. In contrast to currently used mixtures of amino acids, GELO does not cause any side effects.

Effects of VX on Acoustic Startle Response and Acquisition of Operant Behavior in Rats

DTIC Science & Technology

2008-02-01

spontaneous motor activity , fore- and hind-limb grip strength, thermal sensitivity (paw-lick latency), rectal temperature, acoustic startle response, and...whereas spontaneous motor activity and avoidance responding were affected at doses at or above 123 µg/kg, and acoustic startle response was affected...The 60- and 70-dB stimuli were stimulus control conditions presented to ensure that there was not significant activity within the recording chamber

Ocular lesions in canine mucopolysaccharidosis I and response to enzyme replacement therapy.

PubMed

Newkirk, Kim M; Atkins, Rosalie M; Dickson, Patti I; Rohrbach, Barton W; McEntee, Michael F

2011-07-11

Mucopolysaccharidosis I (MPS I) is an inherited metabolic disorder resulting from deficiency of α-L-iduronidase and lysosomal accumulation of glycosaminoglycans (GAG) in multiple tissues. Accumulation of GAG in corneal stromal cells causes corneal opacity and reduced vision. The purpose of this study was to determine the extent of ocular GAG accumulation and investigate the effectiveness of intravenous enzyme replacement therapy (ERT) on corneal GAG accumulation in dogs. Ocular tissues were obtained from 58 dogs with mucopolysaccharidosis I and four unaffected controls. Affected dogs received either low-dose ERT, high-dose ERT, or no treatment; some low-dose dogs also received intrathecal treatments. Histologic severity of corneal stromal GAG accumulation was scored. Accumulation of GAG was found in corneal stromal cells and scleral fibroblasts but not in corneal epithelium, endothelium, ciliary epithelium, choroid, retina, retinal pigment epithelium, or optic nerve. Corneal GAG accumulation increased in severity with increasing age. Although low-dose ERT did not significantly reduce corneal stromal GAG accumulation in comparison with untreated animals, high-dose ERT did result in significantly less GAG accumulation compared with the untreated dogs (adjusted P = 0.0143) or the low-dose ERT group (adjusted P = 0.0031). Intrathecal treatments did not significantly affect GAG accumulation. Dogs that began ERT shortly after birth also had significantly less (P < 0.0001) GAG accumulation in the corneal stroma than dogs with a later onset of treatment. These data suggest that high-dose, intravenous ERT is effective at preventing and/or clearing corneal stromal GAG accumulation, particularly if initiated early after birth.

Mal-Development of the Penis and Loss of Fertility in Male Rats Treated Neonatally with Female Contraceptive 17α-Ethinyl Estradiol: A Dose-Response Study and a Comparative Study with a Known Estrogenic Teratogen Diethylstilbestrol

PubMed Central

Mathews, Ensa; Braden, Tim D.; Williams, Carol S.; Williams, John W.; Bolden-Tiller, Olga; Goyal, Hari O.

2009-01-01

The objectives of this study were to find a minimal dose of 17α-ethinyl estradiol (EE) that is detrimental to the developing penis and fertility and to compare estrogenic effects between EE and diethylstilbestrol (DES). Neonatal rats received EE at 10 ng (1 μg/kg), 100 ng, 1 μg, or 10 μg per pup on alternate days from postnatal days 1 to 11 (dose-response study) or received EE or DES at 100 ng per pup daily from postnatal days 1 to 6 (comparative study). Effects of EE were dose dependent, with ≥ 100-ng dose inducing significant (p < 0.05) reductions in penile length, weight, and diameter. Additionally, the penis was malformed, characterized by underdeveloped os penis and accumulation of fat cells. Fertility was 0% in the ≥ 1-μg groups, in contrast to 60% in the 100-ng group and 100% in the 10-ng and control groups. Animals treated with ≥ 10 ng had significant reductions in the weight of bulbospongious muscle, testis, seminal vesicle, epididymal fat pad, and in epididymal sperm numbers. A comparison of EE and DES effects showed similar reductions in penile weight and length and the weight of bulbospongiosus muscle, testis, seminal vesicle, epididymis, and epididymal fat pad in both adolescent and adult rats. While 5/6 control males sired, only 1/6 in the EE group and 0/6 in the DES group sired. Hence, neonatal exposure to EE at 10 ng (environmentally relevant dose) adversely affects male reproductive organs. A dose ten times higher than this leads to permanently mal-developed penis and infertility. Furthermore, EE and DES exposures show similar level of toxicity to male reproductive organs. PMID:19729556

The effect of aspirin dosing on platelet function in diabetic and nondiabetic patients: an analysis from the aspirin-induced platelet effect (ASPECT) study.

PubMed

DiChiara, Joseph; Bliden, Kevin P; Tantry, Udaya S; Hamed, Miruais S; Antonino, Mark J; Suarez, Thomas A; Bailon, Oscar; Singla, Anand; Gurbel, Paul A

2007-12-01

Diabetic patients may have a higher prevalence of platelet aspirin resistance than nondiabetic patients. Our goal was to analyze platelet aspirin responsiveness to various aspirin doses in diabetic and nondiabetic patients. We examined the effect of aspirin (81, 162, and 325 mg/day for 4 weeks each) on platelet aspirin responsiveness in 120 stable outpatients (30 diabetic patients and 90 nondiabetic patients) with coronary artery disease (CAD) using light transmittance aggregometry (LTA), VerifyNow, platelet function analyzer (PFA)-100, and levels of urinary 11-dehydro-thromboxane B(2) (11-dh-TxB(2)). In the total group, a low prevalence (0-2%) of aspirin resistance was observed with all aspirin doses as determined by arachidonic acid-induced LTA. Aspirin resistance was higher at the 81-mg dose in diabetic versus nondiabetic patients using collagen-induced LTA (27 vs. 4%, P = 0.001), VerifyNow (13 vs. 3%, P = 0.05), and urinary 11-dh-TxB(2) (37 vs. 17%, P = 0.03). Diabetic patients treated with 81 mg exhibited higher platelet function measured by VerifyNow, collagen- and ADP-induced LTA, and 11-dh-TxB(2) levels (P

EFFECTS OF 2,3,7,8-TETRACHLORODIBENZO-P-DIOXIN ...

EPA Pesticide Factsheets

While the effect that TCDD has on humoral immunity in the mouse has been well documented, it has not been for the rat. n this study, the effect that TCDD has on the antibody plaque-forming cell (PFC) response to sheep red blood cells (SRBC) in adult female B6C3F1 mice and F344 rats was compared. ice or rats were given a single intraperitoneal injection of TCDD at doses ranging from 0.1 to 30 ug/kg, 7 days prior to intravenous immunization with SRBC. our days later the PFC response to SRBC was determined. ice showed a dose related suppression of the PFC response, with an ED50 of 0.71 ug/kg TCDD. n contrast, TCDD failed to suppress and in fact enhanced the PFC response to SRBC in rats at doses as high as 30 ug/kg. he inability of TCDD to suppress the PFC response in rats was unrelated to hepatic CYP1A1 and CYP1A2 induction which was detectable at doses of 1 and 0.3 ug/kg TCDD, respectively. here was no shift in the time to peak PFC response in rats dosed with TCDD, nor was the failure of TCDD to suppress the PFC response in rats related to gender or strain. henotypic analysis of thymocytes and splenic lymphocytes from TCDD-dosed (i.e., 3, 10 or 30 ug/kg) and SREC-immunized mice and rats revealed that CD4-CD8+ splenocytes were reduced in a dose related manner in rats only and that this reduction in CD4-CD8+ was accompanied by a dose related increase in IgM+ splenocytes. hese results demonstrate species differences in the effect of TCDD on the PFC response to SRBC w

Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials123

PubMed Central

Del Gobbo, Liana C; Falk, Michael C; Feldman, Robin; Lewis, Kara; Mozaffarian, Dariush

2015-01-01

Background: The effects of nuts on major cardiovascular disease (CVD) risk factors, including dose-responses and potential heterogeneity by nut type or phytosterol content, are not well established. Objectives: We examined the effects of tree nuts (walnuts, pistachios, macadamia nuts, pecans, cashews, almonds, hazelnuts, and Brazil nuts) on blood lipids [total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein, and triglycerides], lipoproteins [apolipoprotein A1, apolipoprotein B (ApoB), and apolipoprotein B100], blood pressure, and inflammation (C-reactive protein) in adults aged ≥18 y without prevalent CVD. Design: We conducted a systematic review and meta-analysis following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Two investigators screened 1301 potentially eligible PubMed articles in duplicate. We calculated mean differences between nut intervention and control arms, dose-standardized to one 1-oz (28.4 g) serving/d, by using inverse-variance fixed-effects meta-analysis. Dose-response for nut intake was examined by using linear regression and fractional polynomial modeling. Heterogeneity by age, sex, background diet, baseline risk factors, nut type, disease condition, duration, and quality score was assessed with meta-regression. Publication bias was evaluated by using funnel plots and Egger’s and Begg’s tests. Results: Sixty-one trials met eligibility criteria (n = 2582). Interventions ranged from 3 to 26 wk. Nut intake (per serving/d) lowered total cholesterol (−4.7 mg/dL; 95% CI: −5.3, −4.0 mg/dL), LDL cholesterol (−4.8 mg/dL; 95% CI: −5.5, −4.2 mg/dL), ApoB (−3.7 mg/dL; 95% CI: −5.2, −2.3 mg/dL), and triglycerides (−2.2 mg/dL; 95% CI: −3.8, −0.5 mg/dL) with no statistically significant effects on other outcomes. The dose-response between nut intake and total cholesterol and LDL cholesterol was nonlinear (P-nonlinearity < 0.001 each); stronger effects were observed for ≥60 g nuts/d. Significant heterogeneity was not observed by nut type or other factors. For ApoB, stronger effects were observed in populations with type 2 diabetes (−11.5 mg/dL; 95% CI: −16.2, −6.8 mg/dL) than in healthy populations (−2.5 mg/dL; 95% CI: −4.7, −0.3 mg/dL) (P-heterogeneity = 0.015). Little evidence of publication bias was found. Conclusions: Tree nut intake lowers total cholesterol, LDL cholesterol, ApoB, and triglycerides. The major determinant of cholesterol lowering appears to be nut dose rather than nut type. Our findings also highlight the need for investigation of possible stronger effects at high nut doses and among diabetic populations. PMID:26561616

The anticonvulsant action of nafimidone on kindled amygdaloid seizures in rats.

PubMed

Albertson, T E; Walby, W F

1988-01-01

The anticonvulsant effectiveness of nafimidone (1-[2-naphthoylmethyl]imidazole hydrochloride) was evaluated in the kindled amygdaloid seizure model in rats. Nafimidone (3.1-120 mg/kg i.p.) was evaluated at 30 min in previously kindled rats using both threshold (20 microA increments) and supranthreshold (400 microA) paradigms. Nafimidone (25-50 mg/kg) significantly reduced supranthreshold elicited afterdischarge length and seizure severity only at doses with some prestimulation toxicity. The maximum anticonvulsant effectiveness for the 25 mg/kg i.p. dose of nafimidone was seen between 15 and 30 min utilizing a suprathreshold kindling paradigm. Nafimidone did not significantly elevate seizure thresholds at the doses tested; however, nafimidone (3.1-50 mg/kg) reduced the severity and afterdischarge duration of threshold elicited seizures in a non-dose response manner. Drug-induced electroencephalographic spikes were seen in both cortex and amygdala in most kindled rats receiving 100-120 mg/kg i.p. within 30 min of dosing before electrical stimulation. The frequency of spike and wave complexes increased in most of these animals leading to drug-induced spontaneous seizures and death in approximately 25% before electrical stimulation. This study has demonstrated that although nafimidone can modify both threshold and suprathreshold elicited kindled amygdaloid seizures, it lacks significant specificity in this model of epilepsy.

Shorter Exposures to Harder X-Rays Trigger Early Apoptotic Events in Xenopus laevis Embryos

PubMed Central

Dong, JiaJia; Mury, Sean P.; Drahos, Karen E.; Moscovitch, Marko

2010-01-01

Background A long-standing conventional view of radiation-induced apoptosis is that increased exposure results in augmented apoptosis in a biological system, with a threshold below which radiation doses do not cause any significant increase in cell death. The consequences of this belief impact the extent to which malignant diseases and non-malignant conditions are therapeutically treated and how radiation is used in combination with other therapies. Our research challenges the current dogma of dose-dependent induction of apoptosis and establishes a new parallel paradigm to the photoelectric effect in biological systems. Methodology/Principal Findings We explored how the energy of individual X-ray photons and exposure time, both factors that determine the total dose, influence the occurrence of cell death in early Xenopus embryo. Three different experimental scenarios were analyzed and morphological and biochemical hallmarks of apoptosis were evaluated. Initially, we examined cell death events in embryos exposed to increasing incident energies when the exposure time was preset. Then, we evaluated the embryo's response when the exposure time was augmented while the energy value remained constant. Lastly, we studied the incidence of apoptosis in embryos exposed to an equal total dose of radiation that resulted from increasing the incoming energy while lowering the exposure time. Conclusions/Significance Overall, our data establish that the energy of the incident photon is a major contributor to the outcome of the biological system. In particular, for embryos exposed under identical conditions and delivered the same absorbed dose of radiation, the response is significantly increased when shorter bursts of more energetic photons are used. These results suggest that biological organisms display properties similar to the photoelectric effect in physical systems and provide new insights into how radiation-mediated apoptosis should be understood and utilized for therapeutic purposes. PMID:20126466

Prostacyclin and milrinone by aerosolization improve pulmonary hemodynamics in newborn lambs with experimental pulmonary hypertension.

PubMed

Kumar, Vasanth H; Swartz, Daniel D; Rashid, Nasir; Lakshminrusimha, Satyan; Ma, Changxing; Ryan, Rita M; Morin, Frederick C

2010-09-01

Aerosolized prostacyclin (PGI2) produces selective pulmonary vasodilation in patients with pulmonary hypertension (PH). The response to PGI2 may be increased by phosphodiesterase type 3 inhibitors such as milrinone. We studied the dose response effects of aerosolized PGI2 and aerosolized milrinone both alone and in combination on pulmonary and systemic hemodynamics in newborn lambs with Nomega-nitro-L-arginine methyl ester (L-NAME)-induced PH. We hypothesized that coaerosolization of PGI2 with milrinone would additively decrease pulmonary vascular resistance (PVR), prolong the duration of action of PGI2, and selectively dilate the pulmonary vasculature. Near-term lambs were delivered by C-section and instrumented and PH was induced by L-NAME (bolus 25 mg/kg; infusion 10 mg.kg(-1).h(-1)) and indomethacin. In the first set of experiments, PGI2 was aerosolized at random doses of 2, 20, 100, 200, 500, and 1,000 ng.kg(-1).min(-1) followed by milrinone at doses of 0.1, 1, and 10 microg.kg(-1).min(-1) over 10 min. In the second set of experiments, milrinone at 1 microg.kg(-1).min(-1) was aerosolized in combination with PGI2 at doses of 20, 100, and 200 ng.kg(-1).min(-1) over 10 min. Pulmonary arterial pressures (PAP) and PVR decreased significantly with increasing doses of aerosolized PGI2 and milrinone. The combination of PGI2 and milrinone significantly reduced PAP and PVR more than either of the drugs aerosolized alone. Addition of milrinone significantly increased the duration of action of PGI2. When aerosolized independently, PGI2 and milrinone selectively dilated the pulmonary vasculature but the combination did not. Milrinone enhances the vasodilatory effects of PGI2 on the pulmonary vasculature but caution must be exercised regarding systemic hypotension.

Preliminary evaluation of safety and activity of recombinant human interleukin 11 in patients with active Crohn's disease.

PubMed

Sands, B E; Bank, S; Sninsky, C A; Robinson, M; Katz, S; Singleton, J W; Miner, P B; Safdi, M A; Galandiuk, S; Hanauer, S B; Varilek, G W; Buchman, A L; Rodgers, V D; Salzberg, B; Cai, B; Loewy, J; DeBruin, M F; Rogge, H; Shapiro, M; Schwertschlag, U S

1999-07-01

Recombinant human interleukin 11 (rhIL-11) is a cytokine with thrombocytopoietic activity and anti-inflammatory and mucosal protective effects. The objectives of this study were to investigate the safety and tolerability of rhIL-11 in patients with Crohn's disease and to explore the effects of dose and schedule on platelet count and Crohn's disease activity. A multicenter, double-masked, placebo-controlled, dose-escalation study of 76 patients with active Crohn's disease was performed. Patients were randomized to receive subcutaneous placebo or rhIL-11 at doses of 5, 16, or 40 microgram. kg-1. wk-1 given 2 or 5 times weekly for 3 weeks. Clinical and laboratory safety data were recorded, and disease activity was measured at each visit. Subcutaneous injection of rhIL-11 generally was well tolerated. Significantly greater increases in platelet counts were found among patients receiving rhIL-11 40 microgram. kg-1. wk-1 as 2 or 5 weekly doses and 16 microgram. kg-1. week-1 as 5 weekly doses compared with patients receiving placebo (P < 0.05). Patients receiving 16 microgram. kg-1. wk-1 had the highest clinical response rates, with a response seen in 42% of patients (5/12) receiving 5 weekly doses and 33% of patients (4/12) receiving 2 weekly doses, compared with 7% of patients (1/15) receiving placebo. Short-term treatment with rhIL-11 is well tolerated in patients with active Crohn's disease. The thrombocytopoietic effect of rhIL-11 seems to be both dose and schedule dependent and may be minimized with retained clinical benefit in Crohn's disease at 16 microgram. kg-1. wk-1 given in 2 equal doses.

Evaluation of putative allelochemicals in rice root exudates for their role in the suppression of arrowhead root growth.

PubMed

Seal, Alexa N; Haig, Terry; Pratley, James E

2004-08-01

In previous studies, 15 putative allelopathic compounds detected in rice root exudates were quantified by GC/MS/MS. In this study, multiple regression analysis on these compounds determined that five selected phenolics, namely caffeic, p-hydroxybenzoic, vanillic, syringic, and p-coumaric acids, from rice exudates were best correlated with the observed allelopathic effect on arrowhead (Sagittaria montevidensis) root growth. Despite this positive association, determination of the phenolic acid dose-response curve established that the amount quantified in the exudates was much lower than the required threshold concentration for arrowhead inhibition. A similar dose-response curve resulted from a combination of all 15 quantified compounds. Significant differences between the amounts of trans-ferulic acid, abietic acid, and an indole also existed between allelopathic and non-allelopathic rice cultivars. The potential roles of these three compounds in rice allelopathy were examined by chemoassay. Overall, neither the addition of trans-ferulic acid nor 5-hydroxyindole-3-acetic acid to the phenolic mix significantly contributed to phytotoxicity, although at higher concentrations, trans-ferulic acid appeared to act antagonistically to the phytotoxic effects of the phenolic mix. The addition of abietic acid also decreased the inhibitory effect of the phenolic mix. These studies indicate that the compounds quantified are not directly responsible for the observed allelopathic response. It is possible that the amount of phenolic acids may be indirectly related to the chemicals finally responsible for the observed allelopathic effect.

The comparative gastrointestinal responses of children and adults following consumption of sweets formulated with sucrose, isomalt and lycasin HBC.

PubMed

Lee, A; Wils, D; Zumbé, A; Storey, D M

2002-08-01

To determine the gastrointestinal responses of children and adults following consumption of sucrose, isomalt and lycasin HBC and to compare these at two different dose levels in adults. Both studies were randomised, double-blind, cross-over designs. Fifty-one children aged 6-9 y were recruited from primary schools in the Salford area of Greater Manchester. Forty-eight children completed the study. Fifty healthy adult volunteers aged 18-24 y were recruited from the student population of the University of Salford. All subjects completed the study. Children consumed either 25 g of sucrose, isomalt or lycasin HBC and adults 25 and 40 g in hard boiled sweets per day for two consecutive test days. Test periods of 2 days were separated by 7 day washout periods. Children consumed sweets throughout test days and adults in no less than 30 min but no more than 90 min. Subjects reported the prevalence and magnitude of flatulence, borborygmi, bloating, colic, bowel movements and watery faeces. Consumption of 25 g isomalt provoked a mild laxative effect in children but not in adults. Consumption of 25 g isomalt significantly increased the prevalence and magnitude of gastrointestinal responses in both children and adults. Consumption of 25 g lycasin HBC significantly increased borborygml in children and adults but no other gastrointestinal responses. Consumption of 40 g lycasin HBC or isomalt by adults significantly increased the mean frequency of bowel movements and the number of subjects passing watery faeces. In adults, 40 g isomalt and lycasin HBC provoked significantly more gastrointestinal responses compared to 25 g of either product. Consumption of 25 g lycasin HBC does not provoke an unacceptable laxative effect or gastrointestinal response in children or adults compared to 25 g isomalt, which is associated with a mild laxative effect and increase in gastrointestinal responses. In adults gastrointestinal responses following consumption of products were found to be dose dependent.

Low-Dose Epinephrine Plus Tranexamic Acid Reduces Early Postoperative Blood Loss and Inflammatory Response: A Randomized Controlled Trial.

PubMed

Zeng, Wei-Nan; Liu, Jun-Li; Wang, Fu-You; Chen, Cheng; Zhou, Qiang; Yang, Liu

2018-02-21

The reductions of perioperative blood loss and inflammatory response are important in total knee arthroplasty. Tranexamic acid reduced blood loss and the inflammatory response in several studies. However, the effect of epinephrine administration plus tranexamic acid has not been intensively investigated, to our knowledge. In this study, we evaluated whether the combined administration of low-dose epinephrine plus tranexamic acid reduced perioperative blood loss or inflammatory response further compared with tranexamic acid alone. This randomized placebo-controlled trial consisted of 179 consecutive patients who underwent primary total knee arthroplasty. Patients were randomized into 3 interventions: Group IV received intravenous low-dose epinephrine plus tranexamic acid, Group TP received topical diluted epinephrine plus tranexamic acid, and Group CT received tranexamic acid alone. The primary outcome was perioperative blood loss on postoperative day 1. Secondary outcomes included perioperative blood loss on postoperative day 3, coagulation and fibrinolysis parameters (measured by thromboelastography), inflammatory cytokine levels, transfusion values (rate and volume), thromboembolic complications, length of hospital stay, wound score, range of motion, and Hospital for Special Surgery (HSS) score. The mean calculated total blood loss (and standard deviation) in Group IV was 348.1 ± 158.2 mL on postoperative day 1 and 458.0 ± 183.4 mL on postoperative day 3, which were significantly reduced (p < 0.05) compared with Group TP at 420.5 ± 188.4 mL on postoperative day 1 and 531.1 ± 231.4 mL on postoperative day 3 and Group CT at 520.4 ± 228.4 mL on postoperative day 1 and 633.7 ± 237.3 mL on postoperative day 3. Intravenous low-dose epinephrine exhibited a net anti-inflammatory activity in total knee arthroplasty and did not induce an obvious hypercoagulable status. Transfusion values were significantly reduced (p < 0.05) in Group IV, but no significant differences were observed in the incidence of thromboembolic complications, wound score, range of motion, and HSS score among the 3 groups (p > 0.05). The combined administration of low-dose epinephrine and tranexamic acid demonstrated an increased effect in reducing perioperative blood loss and the inflammatory response compared with tranexamic acid alone, with no apparent increased incidence of thromboembolic and other complications. Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Mammalian Tissue Response to Low Dose Ionizing Radiation: The Role of Oxidative Metabolism and Intercellular Communication

DOE Office of Scientific and Technical Information (OSTI.GOV)

Azzam, Edouard I

2013-01-16

The objective of the project was to elucidate the mechanisms underlying the biological effects of low dose/low dose rate ionizing radiation in organs/tissues of irradiated mice that differ in their susceptibility to ionizing radiation, and in human cells grown under conditions that mimic the natural in vivo environment. The focus was on the effects of sparsely ionizing cesium-137 gamma rays and the role of oxidative metabolism and intercellular communication in these effects. Four Specific Aims were proposed. The integrated outcome of the experiments performed to investigate these aims has been significant towards developing a scientific basis to more accurately estimatemore » human health risks from exposures to low doses ionizing radiation. By understanding the biochemical and molecular changes induced by low dose radiation, several novel markers associated with mitochondrial functions were identified, which has opened new avenues to investigate metabolic processes that may be affected by such exposure. In particular, a sensitive biomarker that is differentially modulated by low and high dose gamma rays was discovered.« less

A distributed lag approach to fitting non-linear dose-response models in particulate matter air pollution time series investigations.

PubMed

Roberts, Steven; Martin, Michael A

2007-06-01

The majority of studies that have investigated the relationship between particulate matter (PM) air pollution and mortality have assumed a linear dose-response relationship and have used either a single-day's PM or a 2- or 3-day moving average of PM as the measure of PM exposure. Both of these modeling choices have come under scrutiny in the literature, the linear assumption because it does not allow for non-linearities in the dose-response relationship, and the use of the single- or multi-day moving average PM measure because it does not allow for differential PM-mortality effects spread over time. These two problems have been dealt with on a piecemeal basis with non-linear dose-response models used in some studies and distributed lag models (DLMs) used in others. In this paper, we propose a method for investigating the shape of the PM-mortality dose-response relationship that combines a non-linear dose-response model with a DLM. This combined model will be shown to produce satisfactory estimates of the PM-mortality dose-response relationship in situations where non-linear dose response models and DLMs alone do not; that is, the combined model did not systemically underestimate or overestimate the effect of PM on mortality. The combined model is applied to ten cities in the US and a pooled dose-response model formed. When fitted with a change-point value of 60 microg/m(3), the pooled model provides evidence for a positive association between PM and mortality. The combined model produced larger estimates for the effect of PM on mortality than when using a non-linear dose-response model or a DLM in isolation. For the combined model, the estimated percentage increase in mortality for PM concentrations of 25 and 75 microg/m(3) were 3.3% and 5.4%, respectively. In contrast, the corresponding values from a DLM used in isolation were 1.2% and 3.5%, respectively.

Safety and reactogenicity of an MSP-1 malaria vaccine candidate: a randomized phase Ib dose-escalation trial in Kenyan children.

PubMed

Withers, Mark R; McKinney, Denise; Ogutu, Bernhards R; Waitumbi, John N; Milman, Jessica B; Apollo, Odika J; Allen, Otieno G; Tucker, Kathryn; Soisson, Lorraine A; Diggs, Carter; Leach, Amanda; Wittes, Janet; Dubovsky, Filip; Stewart, V Ann; Remich, Shon A; Cohen, Joe; Ballou, W Ripley; Holland, Carolyn A; Lyon, Jeffrey A; Angov, Evelina; Stoute, José A; Martin, Samuel K; Heppner, D Gray

2006-11-24

Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine. This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2:1 fashion to receive either the test product or a comparator. The study was conducted in a rural population in Kombewa Division, western Kenya. Subjects were 135 children, aged 12-47 mo. Subjects received 10, 25, or 50 microg of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 microL, respectively, of AS02A, or they received a comparator (Imovax (rabies vaccine). We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination. Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 microg of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 microg of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F(3,1047) = 10.78, or F(3, 995) = 11.22, p < 0.001); however, the comparison of 25 microg and 50 microg recipients indicated no significant difference (F(1,1047) = 0.05; p = 0.82). The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 microg doses was superior to that of the 10 microg dose.

Safety and Reactogenicity of an MSP-1 Malaria Vaccine Candidate: A Randomized Phase Ib Dose-Escalation Trial in Kenyan Children

PubMed Central

Withers, Mark R; McKinney, Denise; Ogutu, Bernhards R; Waitumbi, John N; Milman, Jessica B; Apollo, Odika J; Allen, Otieno G; Tucker, Kathryn; Soisson, Lorraine A; Diggs, Carter; Leach, Amanda; Wittes, Janet; Dubovsky, Filip; Stewart, V. Ann; Remich, Shon A; Cohen, Joe; Ballou, W. Ripley; Holland, Carolyn A; Lyon, Jeffrey A; Angov, Evelina; Stoute, José A; Martin, Samuel K; Heppner, D. Gray

2006-01-01

Objective: Our aim was to evaluate the safety, reactogenicity, and immunogenicity of an investigational malaria vaccine. Design: This was an age-stratified phase Ib, double-blind, randomized, controlled, dose-escalation trial. Children were recruited into one of three cohorts (dosage groups) and randomized in 2:1 fashion to receive either the test product or a comparator. Setting: The study was conducted in a rural population in Kombewa Division, western Kenya. Participants: Subjects were 135 children, aged 12–47 mo. Interventions: Subjects received 10, 25, or 50 μg of falciparum malaria protein 1 (FMP1) formulated in 100, 250, and 500 μL, respectively, of AS02A, or they received a comparator (Imovax® rabies vaccine). Outcome Measures: We performed safety and reactogenicity parameters and assessment of adverse events during solicited (7 d) and unsolicited (30 d) periods after each vaccination. Serious adverse events were monitored for 6 mo after the last vaccination. Results: Both vaccines were safe and well tolerated. FMP1/AS02A recipients experienced significantly more pain and injection-site swelling with a dose-effect relationship. Systemic reactogenicity was low at all dose levels. Hemoglobin levels remained stable and similar across arms. Baseline geometric mean titers were comparable in all groups. Anti-FMP1 antibody titers increased in a dose-dependent manner in subjects receiving FMP1/AS02A; no increase in anti-FMP1 titers occurred in subjects who received the comparator. By study end, subjects who received either 25 or 50 μg of FMP1 had similar antibody levels, which remained significantly higher than that of those who received the comparator or 10 μg of FMP1. A longitudinal mixed effects model showed a statistically significant effect of dosage level on immune response (F3,1047 = 10.78, or F3, 995 = 11.22, p < 0.001); however, the comparison of 25 μg and 50 μg recipients indicated no significant difference (F1,1047 = 0.05; p = 0.82). Conclusions: The FMP1/AS02A vaccine was safe and immunogenic in malaria-exposed 12- to 47-mo-old children and the magnitude of immune response of the 25 and 50 μg doses was superior to that of the 10 μg dose. PMID:17124529

DOE Office of Scientific and Technical Information (OSTI.GOV)

Blanck, Oliver, E-mail: oliver.blanck@uksh.de; CyberKnife Center Northern Germany, Guestrow; Bode, Frank

Purpose: To perform a proof-of-principle dose-escalation study to radiosurgically induce scarring in cardiac muscle tissue to block veno-atrial electrical connections at the pulmonary vein antrum, similar to catheter ablation. Methods and Materials: Nine mini-pigs underwent pretreatment magnetic resonance imaging (MRI) evaluation of heart function and electrophysiology assessment by catheter measurements in the right superior pulmonary vein (RSPV). Immediately after examination, radiosurgery with randomized single-fraction doses of 0 and 17.5-35 Gy in 2.5-Gy steps were delivered to the RSPV antrum (target volume 5-8 cm{sup 3}). MRI and electrophysiology were repeated 6 months after therapy, followed by histopathologic examination. Results: Transmural scarringmore » of cardiac muscle tissue was noted with doses ≥32.5 Gy. However, complete circumferential scarring of the RSPV was not achieved. Logistic regressions showed that extent and intensity of fibrosis significantly increased with dose. The 50% effective dose for intense fibrosis was 31.3 Gy (odds ratio 2.47/Gy, P<.01). Heart function was not affected, as verified by MRI and electrocardiogram evaluation. Adjacent critical structures were not damaged, as verified by pathology, demonstrating the short-term safety of small-volume cardiac radiosurgery with doses up to 35 Gy. Conclusions: Radiosurgery with doses >32.5 Gy in the healthy pig heart can induce circumscribed scars at the RSPV antrum noninvasively, mimicking the effect of catheter ablation. In our study we established a significant dose-response relationship for cardiac radiosurgery. The long-term effects and toxicity of such high radiation doses need further investigation in the pursuit of cardiac radiosurgery for noninvasive treatment of atrial fibrillation.« less

A swinging seesaw as a novel model mechanism for time-dependent hormesis under dose-dependent stimulatory and inhibitory effects: A case study on the toxicity of antibacterial chemicals to Aliivibrio fischeri.

PubMed

Sun, Haoyu; Calabrese, Edward J; Zheng, Min; Wang, Dali; Pan, Yongzheng; Lin, Zhifen; Liu, Ying

2018-08-01

Hormesis occurs frequently in broadly ranging biological areas (e.g. plant biology, microbiology, biogerontology), toxicology, pharmacology and medicine. While numerous mechanisms (e.g. receptor and pathway mediated pathway responses) account for stimulatory and inhibitory features of hormetic dose responses, the vast majority emphasizes the inclusion of many doses but only one timepoint or use of a single optimized dose that is assessed over a broad range of timepoints. In this paper, a toxicity study was designed using a large number of properly spaced doses with responses determined over a large number of timepoints, which could help us reveal the underlying mechanism of hormesis. We present the results of a dose-time-response study on hormesis using five antibacterial chemicals on the bioluminescence of Aliivibrio fischeri, measuring expression of protein mRNA based on quorum sensing, simulating bioluminescent reaction and analyzing toxic actions of test chemicals. The findings show dose-time-dependent responses conforming to the hormetic dose-response model, while revealing unique response dynamics between agent induced stimulatory and inhibitory effects within bacterial growth phase dynamics. These dynamic dose-time features reveal a type of biological seesaw model that integrates stimulatory and inhibitory responses within unique growth phase, dose and time features, which has faultlessly explained the time-dependent hormetic phenomenon induced by five antibacterial chemicals (characterized by low-dose stimulation and high-dose inhibition). This study offers advances in understanding cellular dynamics, the biological integration of diverse and opposing responses and their role in evolutionary adaptive strategies to chemicals, which can provide new insight into the mechanistic investigation of hormesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

Evaluation of methyl methanesulfonate, 2,6-diaminotoluene and 5-fluorouracil: Part of the Japanese center for the validation of alternative methods (JaCVAM) international validation study of the in vivo rat alkaline comet assay.

PubMed

Plappert-Helbig, Ulla; Junker-Walker, Ursula; Martus, Hans-Joerg

2015-07-01

As a part of the Japanese Center for the Validation of Alternative Methods (JaCVAM)-initiative international validation study of the in vivo rat alkaline comet assay (comet assay), we examined methyl methanesulfonate, 2,6-diaminotoluene, and 5-fluorouracil under coded test conditions. Rats were treated orally with the maximum tolerated dose (MTD) and two additional descending doses of the respective compounds. In the MMS treated groups liver and stomach showed significantly elevated DNA damage at each dose level and a significant dose-response relationship. 2,6-diaminotoluene induced significantly elevated DNA damage in the liver at each dose and a statistically significant dose-response relationship whereas no DNA damage was obtained in the stomach. 5-fluorouracil did not induce DNA damage in either liver or stomach. Copyright © 2015 Elsevier B.V. All rights reserved.

The impact of different dose response parameters on biologically optimized IMRT in breast cancer

NASA Astrophysics Data System (ADS)

Costa Ferreira, Brigida; Mavroidis, Panayiotis; Adamus-Górka, Magdalena; Svensson, Roger; Lind, Bengt K.

2008-05-01

The full potential of biologically optimized radiation therapy can only be maximized with the prediction of individual patient radiosensitivity prior to treatment. Unfortunately, the available biological parameters, derived from clinical trials, reflect an average radiosensitivity of the examined populations. In the present study, a breast cancer patient of stage I II with positive lymph nodes was chosen in order to analyse the effect of the variation of individual radiosensitivity on the optimal dose distribution. Thus, deviations from the average biological parameters, describing tumour, heart and lung response, were introduced covering the range of patient radiosensitivity reported in the literature. Two treatment configurations of three and seven biologically optimized intensity-modulated beams were employed. The different dose distributions were analysed using biological and physical parameters such as the complication-free tumour control probability (P+), the biologically effective uniform dose (\\bar{\\bar{D}} ), dose volume histograms, mean doses, standard deviations, maximum and minimum doses. In the three-beam plan, the difference in P+ between the optimal dose distribution (when the individual patient radiosensitivity is known) and the reference dose distribution, which is optimal for the average patient biology, ranges up to 13.9% when varying the radiosensitivity of the target volume, up to 0.9% when varying the radiosensitivity of the heart and up to 1.3% when varying the radiosensitivity of the lung. Similarly, in the seven-beam plan, the differences in P+ are up to 13.1% for the target, up to 1.6% for the heart and up to 0.9% for the left lung. When the radiosensitivity of the most important tissues in breast cancer radiation therapy was simultaneously changed, the maximum gain in outcome was as high as 7.7%. The impact of the dose response uncertainties on the treatment outcome was clinically insignificant for the majority of the simulated patients. However, the jump from generalized to individualized radiation therapy may significantly increase the therapeutic window for patients with extreme radio sensitivity or radioresistance, provided that these are identified. Even for radiosensitive patients a simple treatment technique is sufficient to maximize the outcome, since no significant benefits were obtained with a more complex technique using seven intensity-modulated beams portals.

Radiobiological effectiveness of laser accelerated electrons in comparison to electron beams from a conventional linear accelerator.

PubMed

Laschinsky, Lydia; Baumann, Michael; Beyreuther, Elke; Enghardt, Wolfgang; Kaluza, Malte; Karsch, Leonhard; Lessmann, Elisabeth; Naumburger, Doreen; Nicolai, Maria; Richter, Christian; Sauerbrey, Roland; Schlenvoigt, Hans-Peter; Pawelke, Jörg

2012-01-01

The notable progress in laser particle acceleration technology promises potential medical application in cancer therapy through compact and cost effective laser devices that are suitable for already existing clinics. Previously, consequences on the radiobiological response by laser driven particle beams characterised by an ultra high peak dose rate have to be investigated. Therefore, tumour and non-malignant cells were irradiated with pulsed laser accelerated electrons at the JETI facility for the comparison with continuous electrons of a conventional therapy LINAC. Dose response curves were measured for the biological endpoints clonogenic survival and residual DNA double strand breaks. The overall results show no significant differences in radiobiological response for in vitro cell experiments between laser accelerated pulsed and clinical used electron beams. These first systematic in vitro cell response studies with precise dosimetry to laser driven electron beams represent a first step toward the long term aim of the application of laser accelerated particles in radiotherapy.

Is there an ideal way to initiate antiplatelet therapy with aspirin? A crossover study on healthy volunteers evaluating different dosing schemes with whole blood aggregometry

PubMed Central

2011-01-01

Background Guidelines recommend an early initiation of aspirin treatment in patients with acute cerebral ischemia. Comparative studies on the best starting dose for initiating aspirin therapy to achieve a rapid antiplatelet effect do not exist. This study evaluated the platelet inhibitory effect in healthy volunteers by using three different aspirin loading doses to gain a model for initiating antiplatelet treatment in acute strokes patients. Methods Using whole blood aggregometry, this study with a prospective, uncontrolled, open, crossover design examined 12 healthy volunteers treated with three different aspirin loading doses: intravenous 500 mg aspirin, oral 500 mg aspirin, and a course of 200 mg aspirin on two subsequent days followed by a five-day course of 100 mg aspirin. Aspirin low response was defined as change of impedance exceeding 0 Ω after stimulation with arachidonic acid. Results Sufficient antiplatelet effectiveness was gained within 30 seconds when intravenous 500 mg aspirin was used. The mean time until antiplatelet effect was 74 minutes for 500 mg aspirin taken orally and 662 minutes (11.2 hours) for the dose scheme with 200 mg aspirin with a high inter- and intraindividual variability in those two regimes. Platelet aggregation returned to the baseline range during the wash-out phase within 4 days. Conclusion Our study reveals that the antiplatelet effect differs significantly between the three different aspirin starting dosages with a high inter- and intraindividual variability of antiplatelet response in our healthy volunteers. To ensure an early platelet inhibitory effect in acute stroke patients, it could be advantageous to initiate the therapy with an intravenous loading dose of 500 mg aspirin. However, clinical outcome studies must still define the best way to initiate antiplatelet treatment with aspirin. PMID:21466682

Probability Distribution of Dose and Dose-Rate Effectiveness Factor for use in Estimating Risks of Solid Cancers From Exposure to Low-Let Radiation.

PubMed

Kocher, David C; Apostoaei, A Iulian; Hoffman, F Owen; Trabalka, John R

2018-06-01

This paper presents an analysis to develop a subjective state-of-knowledge probability distribution of a dose and dose-rate effectiveness factor for use in estimating risks of solid cancers from exposure to low linear energy transfer radiation (photons or electrons) whenever linear dose responses from acute and chronic exposure are assumed. A dose and dose-rate effectiveness factor represents an assumption that the risk of a solid cancer per Gy at low acute doses or low dose rates of low linear energy transfer radiation, RL, differs from the risk per Gy at higher acute doses, RH; RL is estimated as RH divided by a dose and dose-rate effectiveness factor, where RH is estimated from analyses of dose responses in Japanese atomic-bomb survivors. A probability distribution to represent uncertainty in a dose and dose-rate effectiveness factor for solid cancers was developed from analyses of epidemiologic data on risks of incidence or mortality from all solid cancers as a group or all cancers excluding leukemias, including (1) analyses of possible nonlinearities in dose responses in atomic-bomb survivors, which give estimates of a low-dose effectiveness factor, and (2) comparisons of risks in radiation workers or members of the public from chronic exposure to low linear energy transfer radiation at low dose rates with risks in atomic-bomb survivors, which give estimates of a dose-rate effectiveness factor. Probability distributions of uncertain low-dose effectiveness factors and dose-rate effectiveness factors for solid cancer incidence and mortality were combined using assumptions about the relative weight that should be assigned to each estimate to represent its relevance to estimation of a dose and dose-rate effectiveness factor. The probability distribution of a dose and dose-rate effectiveness factor for solid cancers developed in this study has a median (50th percentile) and 90% subjective confidence interval of 1.3 (0.47, 3.6). The harmonic mean is 1.1, which implies that the arithmetic mean of an uncertain estimate of the risk of a solid cancer per Gy at low acute doses or low dose rates of low linear energy transfer radiation is only about 10% less than the mean risk per Gy at higher acute doses. Data were also evaluated to define a low acute dose or low dose rate of low linear energy transfer radiation, i.e., a dose or dose rate below which a dose and dose-rate effectiveness factor should be applied in estimating risks of solid cancers.

Mathematical models of cytotoxic effects in endpoint tumor cell line assays: critical assessment of the application of a single parametric value as a standard criterion to quantify the dose-response effects and new unexplored proposal formats.

PubMed

Calhelha, Ricardo C; Martínez, Mireia A; Prieto, M A; Ferreira, Isabel C F R

2017-10-23

The development of convenient tools for describing and quantifying the effects of standard and novel therapeutic agents is essential for the research community, to perform more precise evaluations. Although mathematical models and quantification criteria have been exchanged in the last decade between different fields of study, there are relevant methodologies that lack proper mathematical descriptions and standard criteria to quantify their responses. Therefore, part of the relevant information that can be drawn from the experimental results obtained and the quantification of its statistical reliability are lost. Despite its relevance, there is not a standard form for the in vitro endpoint tumor cell lines' assays (TCLA) that enables the evaluation of the cytotoxic dose-response effects of anti-tumor drugs. The analysis of all the specific problems associated with the diverse nature of the available TCLA used is unfeasible. However, since most TCLA share the main objectives and similar operative requirements, we have chosen the sulforhodamine B (SRB) colorimetric assay for cytotoxicity screening of tumor cell lines as an experimental case study. In this work, the common biological and practical non-linear dose-response mathematical models are tested against experimental data and, following several statistical analyses, the model based on the Weibull distribution was confirmed as the convenient approximation to test the cytotoxic effectiveness of anti-tumor compounds. Then, the advantages and disadvantages of all the different parametric criteria derived from the model, which enable the quantification of the dose-response drug-effects, are extensively discussed. Therefore, model and standard criteria for easily performing the comparisons between different compounds are established. The advantages include a simple application, provision of parametric estimations that characterize the response as standard criteria, economization of experimental effort and enabling rigorous comparisons among the effects of different compounds and experimental approaches. In all experimental data fitted, the calculated parameters were always statistically significant, the equations proved to be consistent and the correlation coefficient of determination was, in most of the cases, higher than 0.98.

Potential implications of the bystander effect on TCP and EUD when considering target volume dose heterogeneity.

PubMed

Balderson, Michael J; Kirkby, Charles

2015-01-01

In light of in vitro evidence suggesting that radiation-induced bystander effects may enhance non-local cell killing, there is potential for impact on radiotherapy treatment planning paradigms such as the goal of delivering a uniform dose throughout the clinical target volume (CTV). This work applies a bystander effect model to calculate equivalent uniform dose (EUD) and tumor control probability (TCP) for external beam prostate treatment and compares the results with a more common model where local response is dictated exclusively by local absorbed dose. The broad assumptions applied in the bystander effect model are intended to place an upper limit on the extent of the results in a clinical context. EUD and TCP of a prostate cancer target volume under conditions of increasing dose heterogeneity were calculated using two models: One incorporating bystander effects derived from previously published in vitro bystander data ( McMahon et al. 2012 , 2013a); and one using a common linear-quadratic (LQ) response that relies exclusively on local absorbed dose. Dose through the CTV was modelled as a normal distribution, where the degree of heterogeneity was then dictated by changing the standard deviation (SD). Also, a representative clinical dose distribution was examined as cold (low dose) sub-volumes were systematically introduced. The bystander model suggests a moderate degree of dose heterogeneity throughout a target volume will yield as good or better outcome compared to a uniform dose in terms of EUD and TCP. For a typical intermediate risk prostate prescription of 78 Gy over 39 fractions maxima in EUD and TCP as a function of increasing SD occurred at SD ∼ 5 Gy. The plots only dropped below the uniform dose values for SD ∼ 10 Gy, almost 13% of the prescribed dose. Small, but potentially significant differences in the outcome metrics between the models were identified in the clinically-derived dose distribution as cold sub-volumes were introduced. In terms of EUD and TCP, the bystander model demonstrates the potential to deviate from the common local LQ model predictions as dose heterogeneity through a prostate CTV varies. The results suggest, at least in a limiting sense, the potential for allowing some degree of dose heterogeneity within a CTV, although further investigation of the assumptions of the bystander model are warranted.