Hormonal priming, induction of ovulation and in-vitro fertilization of the endangered Wyoming toad (Bufo baxteri)

PubMed Central

Browne, Robert K; Seratt, Jessica; Vance, Carrie; Kouba, Andrew

2006-01-01

The endangered Wyoming toad (Bufo baxteri) is the subject of an extensive captive breeding and reintroduction program. Wyoming toads in captivity rarely ovulate spontaneously and hormonal induction is used to ovulate females or to stimulate spermiation in males. With hormonal induction, ovulation is unreliable and egg numbers are low. The sequential administration of anovulatory doses of hormones (priming) has increased egg numbers and quality in both anurans and fish. Consequently, we tested the efficacy of a combination of human Chorionic Gonadotrophin (hCG) and Luteinizing Hormone Releasing Hormone analogue (LHRHa) administered as one dose, or two or three sequential doses to Bufo baxteri on egg numbers, fertilization and early embryo development. Spawning toads deposited eggs into Simplified Amphibian Ringers (SAR) solution to enable controlled in-vitro fertilization (IVF) with sperm from hormonally induced male toads. Unprimed females receiving a single mixed normally ovulatory dose of 500 IU hCG plus 4 micrograms of LHRHa produced no eggs. Whereas females primed with this dose and an anovulatory dose (100 IU hCG and 0.8 micrograms of LHRHa) of the same hormones, or primed only with an anovulatory dose, spawned after then receiving an ovulatory dose. Higher total egg numbers were produced with two primings than with one priming. Moreover, two primings produced significantly more eggs from each individual female than one priming. The cleavage rate of eggs was not found to differ between one or two primings. Nevertheless, embryo development with eggs from two primings gave a significantly greater percentage neurulation and swim-up than those from one priming. Of the male toads receiving a single dose of 300 IU hCG, 80% produced spermic urine with the greatest sperm concentration 7 hours post-administration (PA). However, peak sperm motility (95%) was achieved at 5 hours PA and remained relatively constant until declining 20 hours PA. In conclusion, Bufo baxteri egg numbers and quality benefited from sequential priming with LHRHa and hCG whereas spermic urine for IVF was produced from males with a single dose of hCG. The power of assisted reproduction technology in the conservation of endangered amphibians is shown by the release of nearly 2000 tadpoles produced by IVF during this study. PMID:16790071

Evaluation of ameliorative potential of supranutritional selenium on enrofloxacin-induced testicular toxicity.

PubMed

Rungsung, Soya; Khan, Adil Mehraj; Sood, Naresh Kumar; Rampal, Satyavan; Singh Saini, Simrat Pal

2016-05-25

The study was designed to assess the ameliorative potential of selenium (Se) on enrofloxacin-induced testicular toxicity in rats. There was a significant decrease in body weight and non-significant decrease in mean testicular weight of enrofloxacin treated rats. In enrofloxacin treated rats, total sperm count and viability decreased where as sperm abnormalities increased. Testicular histopathology revealed dose dependent dysregulation of spermatogenesis and presence of necrotic debris in seminiferous tubules which was marginally improved with Se. Enrofloxacin also produced a dose dependent decrease in testosterone level. The activity of testicular antioxidant enzymes decreased where as lipid peroxidation increased in a dose-dependent manner. Se supplementation partially restored oxidative stress and sperm damage and did not affect the plasma concentrations of enrofloxacin or ciprofloxacain. The results indicate that enrofloxacin produces a dose-dependent testicular toxicity in rats that is moderately ameliorated with supranutritional Se. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Contribution of adrenal hormones to nicotine-induced inhibition of synovial plasma extravasation in the rat.

PubMed

Miao, F J; Benowitz, N L; Heller, P H; Levine, J D

1997-01-01

1. In this study, we examined the mechanism(s) by which s.c. nicotine inhibits synovial plasma extravasation. We found that nicotine dose-dependently inhibited bradykinin (BK)- and platelet activating factor (PAF)-induced plasma extravasation. 2. The effect of nicotine on both BK- and PAF-induced plasma extravasation was attenuated by adrenal medullectomy. ICI-118,551 (a selective beta 2-adrenoceptor blocker) (30 micrograms ml-1, intra-articularly) significantly attenuated the inhibitory action of high-dose (1 mg kg-1) nicotine on BK-induced plasma extravasation without affecting the inhibition by low- (0.01 microgram kg-1) dose nicotine or that on PAF-induced plasma extravasation by nicotine at any dose. This suggested that beta 2-adrenoceptors mediate the inhibitory actions of high-dose, but not low-dose, nicotine. We also found that systemic naloxone (an opioid receptor antagonist) (two hourly injections of 1 mg kg-1, i.p.) attenuated the inhibitory action produced by all doses of nicotine on BK- or PAF-induced plasma extravasation, suggesting the contribution of endogenous opioids. 3. RU-38,486 (a glucocorticoid receptor antagonist) (30 mg kg-1, s.c.), and metyrapone (a glucocorticoid synthesis inhibitor) (two hourly injections of 100 mg kg-1, i.p.) both attenuated the action of high-dose nicotine without affecting that of low-dose nicotine. 4. Spinal mecamylamine (a nicotinic receptor antagonist) (0.025 mg kg-1, intrathecally, i.t.) attenuated the action of high-dose, but not low-dose, nicotine, suggesting that part of the action of high-dose nicotine is mediated by spinal nicotinic receptors. 5. Combined treatment with ICI-118,551, naloxone and RU-38,486 attenuated the action of low-dose nicotine by an amount similar to that produced by naloxone alone but produced significantly greater attenuation of the effect of high-dose nicotine when compared to the action of any of the three antagonists alone.

Contribution of adrenal hormones to nicotine-induced inhibition of synovial plasma extravasation in the rat

PubMed Central

Jia-Pei Miao, Frederick; Benowitz, Neal L; Heller, Philip H; Levine, Jon D

1997-01-01

In this study, we examined the mechanism(s) by which s.c. nicotine inhibits synovial plasma extravasation. We found that nicotine dose-dependently inhibited bradykinin (BK)- and platelet activating factor (PAF)-induced plasma extravasation. The effect of nicotine on both BK- and PAF-induced plasma extravasation was attenuated by adrenal medullectomy. ICI-118,551 (a selective β2-adrenoceptor blocker) (30 μg ml−1, intra-articularly) significantly attenuated the inhibitory action of high-dose (1 mg kg−1) nicotine on BK-induced plasma extravasation without affecting the inhibition by low- (0.01 μg kg−1) dose nicotine or that on PAF-induced plasma extravasation by nicotine at any dose. This suggested that β2-adrenoceptors mediate the inhibitory actions of high-dose, but not low-dose, nicotine. We also found that systemic naloxone (an opioid receptor antagonist) (two hourly injections of 1 mg kg−1, i.p.) attenuated the inhibitory action produced by all doses of nicotine on BK- or PAF-induced plasma extravasation, suggesting the contribution of endogenous opioids. RU-38,486 (a glucocorticoid receptor antagonist) (30 mg kg−1, s.c.) and metyrapone (a glucocorticoid synthesis inhibitor) (two hourly injections of 100 mg kg−1, i.p.) both attenuated the action of high-dose nicotine without affecting that of low-dose nicotine. Spinal mecamylamine (a nicotinic receptor antagonist) (0.025 mg kg−1, intrathecally, i.t.) attenuated the action of high-dose, but not low-dose, nicotine, suggesting that part of the action of high-dose nicotine is mediated by spinal nicotinic receptors. Combined treatment with ICI-118,551, naloxone and RU-38,486 attenuated the action of low-dose nicotine by an amount similar to that produced by naloxone alone but produced significantly greater attenuation of the effect of high-dose nicotine when compared to the action of any of the three antagonists alone. PMID:9117123

The effect of GABAmimetics on the duration of immobility in the forced swim test in albino mice.

PubMed

El Zahaf, Najwa Ahmed; Salem Elhwuegi, Abdalla

2014-01-01

Studies regarding the role of gamma aminobutyric acid (GABA) in depression are conflicting. Therefore, it was decided to examine the effect of different drugs that enhance the GABA system on the time of immobility induced by the forced swim test (FST). Adult albino mice were divided into several groups of six animals. Each group received an intraperitoneal injection of either imipramine (10, 20, or 30 mg/kg), diazepam (0.5, 1, or 2 mg/kg), vigabatrin (100, 200, or 300 mg/kg), zolpidem (2.5, 5, or 10 mg/kg), or alprazolam (1, 2.5, or 5 mg/kg). Control groups received the appropriate vehicle. One hour after injection, the duration of immobility was measured for 5 min in the FST. The percentage change in the duration of immobility from the control was calculated for each group. The statistical test of the difference between the treated and the control groups was calculated using unpaired Student's t-test. Imipramine produced a significant dose-dependent decrease in the duration of immobility (78, 74, and 56%, respectively). Different doses of diazepam, vigabatrin, and zolpidem produced a significant increase in the duration of immobility (119, 126, and 128%), (116, 124, and 128%), and (108, 109, and 119%), respectively. The two low doses of alprazolam produced a significant increase (115 and 120%), while the high dose produced a significant decrease in the duration of immobility (74%). Increasing central GABAergic activity by different mechanisms has resulted in a depressant-like activity measured as an increase in the duration of immobility in the FST model of depression.

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

Chang, Amy T.Y., E-mail: changty@ha.org.hk; Hung, Albert W.M.; Cheung, Fion W.K.

Purpose: Intensity modulated radiation therapy (IMRT) is widely used to achieve a highly conformal dose and improve treatment outcome. However, plan quality and planning time are institute and planner dependent, and no standardized tool exists to recognize an optimal plan. RapidPlan, a knowledge-based algorithm, can generate constraints to assist optimization and produce high-quality IMRT plans. This report evaluated the quality and efficiency of using RapidPlan in nasopharyngeal carcinoma (NPC) IMRT planning. Methods and Materials: RapidPlan was configured using 79 radical IMRT plans for NPC; 20 consecutive NPC patients indicated for radical radiation therapy between October 2014 and May 2015 weremore » then recruited to assess its performance. The ability of RapidPlan to produce acceptable plans was evaluated. For plans that could not achieve clinical acceptance, manual touch-up was performed. The IMRT plans produced without RapidPlan (manual plans) and with RapidPlan (RP-2 plans, including those with manual touch-up) were compared in terms of dosimetric quality and planning efficiency. Results: RapidPlan by itself could produce clinically acceptable plans for 9 of the 20 patients; manual touch-up increased the number of acceptable plans (RP-2 plans) to 19. The target dose coverage and conformity were very similar. No difference was found in the maximum dose to the brainstem and optic chiasm. RP-2 plans delivered a higher maximum dose to the spinal cord (46.4 Gy vs 43.9 Gy, P=.002) but a lower dose to the parotid (mean dose to right parotid, 37.3 Gy vs 45.4 Gy; left, 34.4 Gy vs 43.1 Gy; P<.001) and the right cochlea (mean dose, 48.6 Gy vs 52.6 Gy; P=.02). The total planning time for RP-2 plans was significantly less than that for manual plans (64 minutes vs 295 minutes, P<.001). Conclusions: This study shows that RapidPlan can significantly improve planning efficiency and produce quality IMRT plans for NPC patients.« less

Enhancement of natural background gamma-radiation dose around uranium microparticles in the human body.

PubMed

Pattison, John E; Hugtenburg, Richard P; Green, Stuart

2010-04-06

Ongoing controversy surrounds the adverse health effects of the use of depleted uranium (DU) munitions. The biological effects of gamma-radiation arise from the direct or indirect interaction between secondary electrons and the DNA of living cells. The probability of the absorption of X-rays and gamma-rays with energies below about 200 keV by particles of high atomic number is proportional to the third to fourth power of the atomic number. In such a case, the more heavily ionizing low-energy recoil electrons are preferentially produced; these cause dose enhancement in the immediate vicinity of the particles. It has been claimed that upon exposure to naturally occurring background gamma-radiation, particles of DU in the human body would produce dose enhancement by a factor of 500-1000, thereby contributing a significant radiation dose in addition to the dose received from the inherent radioactivity of the DU. In this study, we used the Monte Carlo code EGSnrc to accurately estimate the likely maximum dose enhancement arising from the presence of micrometre-sized uranium particles in the body. We found that although the dose enhancement is significant, of the order of 1-10, it is considerably smaller than that suggested previously.

Analgesic Activity of Tramadol and Buprenorphine after Voluntary Ingestion by Rats (Rattus norvegicus)

PubMed Central

Taylor, Bryan F; Ramirez, Harvey E; Battles, August H; Andrutis, Karl A; Neubert, John K

2016-01-01

Effective pain management for rats and mice is crucial due to the continuing increase in the use of these species in biomedical research. Here we used a recently validated operant orofacial pain assay to determine dose–response curves for buprenorphine and tramadol when mixed in nut paste and administered to male and female rats. Statistically significant analgesic doses of tramadol in nut paste included doses of 20, 30, and 40 mg/kg for female rats but only 40 mg/kg for male rats. For male rats receiving buprenorphine mixed in nut paste, a significant analgesic response was observed at 0.5 and 0.6 mg/kg. None of the doses tested produced a significant analgesic response in female rats. Our results indicate that at the doses tested, tramadol and buprenorphine produced an analgesic response in male rats. In female rats, tramadol shows a higher analgesic effect than buprenorphine. The analgesic effects observed 60 min after administration of the statistically significant oral doses of both drugs were similar to the analgesic effects of 0.03 mg/kg subcutaneous buprenorphine 30 min after administration. The method of voluntary ingestion could be effective, is easy to use, and would minimize stress to the rats during the immediate postoperative period. PMID:26817983

Dose-rate plays a significant role in synchrotron radiation X-ray-induced damage of rodent testes.

PubMed

Chen, Heyu; Wang, Ban; Wang, Caixia; Cao, Wei; Zhang, Jie; Ma, Yingxin; Hong, Yunyi; Fu, Shen; Wu, Fan; Ying, Weihai

2016-01-01

Synchrotron radiation (SR) X-ray has significant potential for applications in medical imaging and cancer treatment. However, the mechanisms underlying SR X-ray-induced tissue damage remain unclear. Previous studies on regular X-ray-induced tissue damage have suggested that dose-rate could affect radiation damage. Because SR X-ray has exceedingly high dose-rate compared to regular X-ray, it remains to be determined if dose-rate may affect SR X-ray-induced tissue damage. We used rodent testes as a model to investigate the role of dose-rate in SR X-ray-induced tissue damage. One day after SR X-ray irradiation, we determined the effects of the irradiation of the same dosage at two different dose-rates, 0.11 Gy/s and 1.1 Gy/s, on TUNEL signals, caspase-3 activation and DNA double-strand breaks (DSBs) of the testes. Compared to those produced by the irradiation at 0.11 Gy/s, irradiation at 1.1 Gy/s produced higher levels of DSBs, TUNEL signals, and caspase-3 activation in the testes. Our study has provided the first evidence suggesting that dose-rate could be a significant factor in SR X-ray-induced tissue damage, which may establish a valuable base for utilizing this factor to manipulate the tissue damage in SR X-ray-based medical applications.

Dose-rate plays a significant role in synchrotron radiation X-ray-induced damage of rodent testes

PubMed Central

Chen, Heyu; Wang, Ban; Wang, Caixia; Cao, Wei; Zhang, Jie; Ma, Yingxin; Hong, Yunyi; Fu, Shen; Wu, Fan; Ying, Weihai

2016-01-01

Synchrotron radiation (SR) X-ray has significant potential for applications in medical imaging and cancer treatment. However, the mechanisms underlying SR X-ray-induced tissue damage remain unclear. Previous studies on regular X-ray-induced tissue damage have suggested that dose-rate could affect radiation damage. Because SR X-ray has exceedingly high dose-rate compared to regular X-ray, it remains to be determined if dose-rate may affect SR X-ray-induced tissue damage. We used rodent testes as a model to investigate the role of dose-rate in SR X-ray-induced tissue damage. One day after SR X-ray irradiation, we determined the effects of the irradiation of the same dosage at two different dose-rates, 0.11 Gy/s and 1.1 Gy/s, on TUNEL signals, caspase-3 activation and DNA double-strand breaks (DSBs) of the testes. Compared to those produced by the irradiation at 0.11 Gy/s, irradiation at 1.1 Gy/s produced higher levels of DSBs, TUNEL signals, and caspase-3 activation in the testes. Our study has provided the first evidence suggesting that dose-rate could be a significant factor in SR X-ray-induced tissue damage, which may establish a valuable base for utilizing this factor to manipulate the tissue damage in SR X-ray-based medical applications. PMID:28078052

Acute effects of pentobarbital, thiopental and urethane on lung oedema induced by alpha-naphthythiourea (ANTU).

PubMed

Sipahi, Emine; Ustün, Hüseyin; Niyazi Ayoglu, Ferruh

2002-03-01

This study was designed to investigate the possible participation of urethane, pentobarbital sodium and thiopental sodium anaesthesia in the lung oedema induced by alpha-naphthylthiourea (ANTU), which is a well known noxious chemical agent in the lung. ANTU when injected intraperitoneally (i.p.) into rats (10 mg x kg (-1) i.p.) produced lung oedema as indicated by an increase in lung weight/body weight (LW/BW) ratio and pleural effusion (PE) reaching a maximum within 4 h. Administration of urethane prior to ANTU, at doses of 100 and 200mg(100g)(-1), elicited a significant and dose-dependent inhibition in LW/BW ratio and PE. Thiopental sodium at doses of 25, 50 mg x kg (-1), also produced a significant and dose-dependent inhibition of both parameters. Prior i.p. injection of pentobarbital sodium at a dose of 40 mg x kg (-1) elicited a significant inhibition in both parameters. These results suggest that i.p. urethane, thiopental sodium and pentobarbital sodium pretreatment have a prophylactic effect on ANTU-induced lung injury in rats. The possible role of the anaesthetics in lung oedema induced by ANTU and the possible underlying mechanisms are discussed. Copyright 2002 Elsevier Science Ltd.

Limiting the risk of cardiac toxicity with esophageal-sparing intensity modulated radiotherapy for locally advanced lung cancers.

PubMed

Woodford, Katrina; Panettieri, Vanessa; Ruben, Jeremy D; Senthi, Sashendra

2016-05-01

Intensity modulated radiotherapy (IMRT) is routinely utilized in the treatment of locally advanced non-small cell lung cancer (NSCLC). RTOG 0617 found that overall survival was impacted by increased low (5 Gy) and intermediate (30 Gy) cardiac doses. We evaluated the impact of esophageal-sparing IMRT on cardiac doses with and without the heart considered in the planning process and predicted toxicity compared to 3D-conventional radiotherapy (3DCRT). Ten consecutive patients with N2 Stage III NSCLC treated to 60 Gy in 30 fractions, between February 2012 and September 2014, were evaluated. For each patient, 3DCRT and esophageal-sparing IMRT plans were generated. IMRT plans were then created with and without the heart considered in the optimization process. To compare plans, the dose delivered to 95% and 99% of the target (D95% and D99%), and doses to the esophagus, lung and heart were compared by determining the volume receiving X dose (VXGy) and the normal tissue complication probability (NTCP) calculated. IMRT reduced maximum esophagus dose to below 60 Gy in all patients and produced significant reductions to V50Gy, V40Gy and esophageal NTCP. The cost of this reduction was a non-statistically, non-clinically significant increase in low dose (5 Gy) lung exposure that did not worsen lung NTCP. IMRT plans produced significant cardiac sparing, with the amount of improvement correlating to the amount of heart overlapping with the target. When included in plan optimization, for selected patients further sparing of the heart and improvement in heart NTCP was possible. Esophageal-sparing IMRT can significantly spare the heart even if it is not considered in the optimization process. Further sparing can be achieved if plan optimization constrains low and intermediate heart doses, without compromising lung doses.

Optimal precurarizing dose of rocuronium to decrease fasciculation and myalgia following succinylcholine administration.

PubMed

Kim, Kyu Nam; Kim, Kyo Sang; Choi, Hoon Il; Jeong, Ji Seon; Lee, Hee-Jong

2014-06-01

Succinylcholine commonly produces frequent adverse effects, including muscle fasciculation and myalgia. The current study identified the optimal dose of rocuronium to prevent succinylcholine-induced fasciculation and myalgia and evaluated the influence of rocuronium on the speed of onset produced by succinylcholine. This randomized, double-blinded study was conducted in 100 patients randomly allocated into five groups of 20 patients each. Patients were randomized to receive 0.02, 0.03, 0.04, 0.05 and 0.06 mg/kg rocuronium as a precurarizing dose. Neuromuscular monitoring after each precurarizing dose was recorded from the adductor pollicis muscle using acceleromyography with train-of-four stimulation of the ulnar nerve. All patients received succinylcholine 1.5 mg/kg at 2 minutes after the precurarization, and were assessed the incidence and severity of fasciculations, while myalgia was assessed at 24 hours after surgery. The incidence and severity of visible muscle fasciculation was significantly less with increasing the amount of precurarizing dose of rocuronium (P < 0.001). Those of myalgia tend to decrease according to increasing the amount of precurarizing dose of rocuronium, but there was no significance (P = 0.072). The onset time of succinylcholine was significantly longer with increasing the amount of precurarizing dose of rocuronium (P < 0.001). Precurarization with 0.04 mg/kg rocuronium was the optimal dose considering the reduction in the incidence and severity of fasciculation and myalgia with acceptable onset time, and the safe and effective precurarization.

“Stealth” Adenoviruses Blunt Cell-Mediated and Humoral Immune Responses against the Virus and Allow for Significant Gene Expression upon Readministration in the Lung

PubMed Central

Croyle, Maria A.; Chirmule, Narendra; Zhang, Yi; Wilson, James M.

2001-01-01

Most of the early gene therapy trials for cystic fibrosis have been with adenovirus vectors. First-generation viruses with E1a and E1b deleted are limited by transient expression of the transgene and substantial inflammatory responses. Gene transfer is also significantly curtailed following a second dose of virus. In an effort to reduce adenovirus-associated inflammation, capsids of first-generation vectors were modified with various activated monomethoxypolyethylene glycols. Cytotoxic T-lymphocyte production was significantly reduced in C57BL/6 mice after a single intratracheal administration of modified vectors, and length of gene expression was extended from 4 to 42 days. T-cell subsets from mice exposed to the conjugated vectors demonstrated a marked decrease in Th1 responses and slight enhancement of Th2 responses compared to animals dosed with native virus. Neutralizing antibodies (NAB) against adenovirus capsid proteins were reduced in serum and bronchoalveolar lavage fluid of animals after a single dose of modified virus, allowing significant levels of gene expression upon rechallenge with native adenovirus. Modification with polyethylene glycol (PEG) also allowed substantial gene expression from the new vectors in animals previously immunized with unmodified virus. However, gene expression was significantly reduced after two doses of the same PEG-conjugated vector. Alternating the activation group of PEG between doses did produce significant gene expression upon readministration. This technology in combination with second-generation or helper-dependent adenovirus could produce dosing strategies which promote successful readministration of vector in clinical trials and marked expression in patients with significant anti-adenovirus NAB levels and reduce the possibility of immune reactions against viral vectors for gene therapy. PMID:11312351

Anticlastogenic activity exhibited by botryosphaeran, a new exopolysaccharide produced by Botryosphaeria rhodina MAMB-05.

PubMed

Miranda, Carolina C B O; Dekker, Robert F H; Serpeloni, Juliana M; Fonseca, Eveline A I; Cólus, Ilce M S; Barbosa, Aneli M

2008-03-01

Biopolymers such as exopolysaccharides (EPS) are produced by microbial species and possess unusual properties known to modify biological responses, among them are antimutagenicity and immunomodulation. Botryosphaeran, a newly described fungal (1-->3; 1-->6)-beta-d-glucan produced by Botryosphaeria rhodina MAMB-05, was administered by gavage to mice at three doses (7.5, 15 and 30mg/kgb.w.per day) over 15 days, and found to be non-genotoxic by the micronucleus test in peripheral blood and bone marrow. Botryosphaeran administered at doses of 15 and 30mg EPS/kgb.w. decreased significantly (p<0.001) the clastogenic effect of cyclophosphamide-induced micronucleus formation resulting in a reduction of the frequency of micronucleated cells of 78 and 82% in polychromatic erythrocytes of bone marrow, and reticulocytes in peripheral blood, respectively. The protective effect was dose-dependent, and strong anticlastogenic activity was exerted at low EPS doses. Variance analysis (ANOVA) showed no significant differences (p<0.05) among the median body weights of the groups of mice treated with botryosphaeran during experiments evaluating genotoxic and protective activities of botryosphaeran. This is the first report on the biological activity attributed to botryosphaeran.

The effect of GABAmimetics on the duration of immobility in the forced swim test in albino mice.

PubMed

El Zahaf, Najwa Ahmed; Elhwuegi, Abdalla Salem

2014-01-01

Objectives Studies regarding the role of gamma aminobutyric acid (GABA) in depression are conflicting. Therefore, it was decided to examine the effect of different drugs that enhance the GABA system on the time of immobility induced by the forced swim test (FST). Materials and methods Adult albino mice were divided into several groups of six animals. Each group received an intraperitoneal injection of either imipramine (10, 20, or 30 mg/kg), diazepam (0.5, 1, or 2 mg/kg), vigabatrin (100, 200, or 300 mg/kg), zolpidem (2.5, 5, or 10 mg/kg), or alprazolam (1, 2.5, or 5 mg/kg). Control groups received the appropriate vehicle. One hour after injection, the duration of immobility was measured for 5 min in the FST. The percentage change in the duration of immobility from the control was calculated for each group. The statistical test of the difference between the treated and the control groups was calculated using unpaired Student's t-test. Results Imipramine produced a significant dose-dependent decrease in the duration of immobility (78, 74, and 56%, respectively). Different doses of diazepam, vigabatrin, and zolpidem produced a significant increase in the duration of immobility (119, 126, and 128%), (116, 124, and 128%), and (108, 109, and 119%), respectively. The two low doses of alprazolam produced a significant increase (115 and 120%), while the high dose produced a significant decrease in the duration of immobility (74%). Conclusion Increasing central GABAergic activity by different mechanisms has resulted in a depressant-like activity measured as an increase in the duration of immobility in the FST model of depression.

Interoceptive “Satiety” Signals Produced by Leptin and CCK

PubMed Central

Kanoski, Scott E.; Walls, Elwood K.; Davidson, T. L.

2007-01-01

The present studies assessed the extent to which the adiposity signal leptin and the brain-gut hormone cholecystokinin (CCK), administered alone or in combination, give rise to interoceptive sensory cues like those that are produced by a low (1 hr) level of food deprivation. Rats were trained with cues arising from1-hr and 24-hr food deprivation as discriminative stimuli. For one group, 24-hr food deprivation predicted the delivery of sucrose pellets, whereas 1-hr food deprivation did not. Another group received the reversed deprivation level-sucrose contingency. After asymptotic performance was achieved, the effects of leptin and CCK on food intake and on discrimination performance were tested under 24-hr food deprivation. In Experiment 1a, leptin administered into the third cerebroventricle (i3vt) at 3.5 or 7.0 μg doses had little effect, compared to saline on food intake or discriminative responding. In Experiment 1b, leptin (7.0 μg, i3vt) combined with CCK-8 (2 μg/kg, i.p.) reduced food intake significantly, but the findings indicated that CCK-8 alone produces interoceptive discriminative cues more like those produced by 1- than 24-hr food deprivation. Experiment 2a tested rats with i.p. leptin (0.3 and 0.5 mg/kg). Although neither dose suppressed intake, the 0.3 mg/kg dose produced interoceptive cues like 1-hr food deprivation. Experiment 2b tested two doses of CCK-8 (2 and 4mg/kg ,i.p.) and found significant intake suppression and generalization of discrimination with both doses of CCK-8. These findings suggest a role for both leptin and CCK in the production of sensory consequences that correspond to “satiety”. PMID:17408804

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.

Radiotherapy Dose Perturbation of Esophageal Stents Examined in an Experimental Model

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

Atwood, Todd F.; Hsu, Annie; Ogara, Maydeen M.

2012-04-01

Purpose: To investigate the radiotherapy dose perturbations caused by esophageal stents in patients undergoing external beam treatments for esophageal cancer. Methods and Materials: Four esophageal stents were examined (three metallic stents: WallFlex, Ultraflex, and Alveolus; one nonmetallic stent with limited radiopaque markers for visualization: Polyflex). All experiments were performed in a liquid water phantom with a custom acrylic stent holder. Radiochromic film was used to measure the dose distributions adjacent to the stents at locations proximal and distal to the radiation source. The stents were placed in an air-filled cavity to simulate the esophagus. Treatment plans were created and deliveredmore » for photon energies of 6 and 15 MV, and data analysis was performed on uniform regions of interest, according to the size and geometric placement of the films, to quantify the dose perturbations. Results: The three metallic stents produced the largest dose perturbations with distinct patterns of 'hot' spots (increased dose) measured proximal to the radiation source (up to 15.4%) and both 'cold' (decreased dose) and hot spots measured distal to the radiation source (range, -6.1%-5.8%). The polymeric Polyflex stent produced similar dose perturbations when the radiopaque markers were examined (range, -7.6%-15.4%). However, when the radiopaque markers were excluded from the analysis, the Polyflex stent produced significantly smaller dose perturbations, with maximum hot spots of 7.3% and cold spots of -3.2%. Conclusions: The dose perturbations caused by esophageal stents during the treatment of esophageal cancer using external beam radiotherapy should be understood. These perturbations will result in hot and cold spots in the esophageal mucosa, with varying magnitudes depending on the stent. The nonmetallic Polyflex stent appears to be the most suitable for patients undergoing radiotherapy, but further studies are necessary to determine the clinical significance of the dose perturbations.« less

Radiotherapy dose perturbation of esophageal stents examined in an experimental model.

PubMed

Atwood, Todd F; Hsu, Annie; Ogara, Maydeen M; Luba, Daniel G; Tamler, Bradley J; Disario, James A; Maxim, Peter G

2012-04-01

To investigate the radiotherapy dose perturbations caused by esophageal stents in patients undergoing external beam treatments for esophageal cancer. Four esophageal stents were examined (three metallic stents: WallFlex, Ultraflex, and Alveolus; one nonmetallic stent with limited radiopaque markers for visualization: Polyflex). All experiments were performed in a liquid water phantom with a custom acrylic stent holder. Radiochromic film was used to measure the dose distributions adjacent to the stents at locations proximal and distal to the radiation source. The stents were placed in an air-filled cavity to simulate the esophagus. Treatment plans were created and delivered for photon energies of 6 and 15 MV, and data analysis was performed on uniform regions of interest, according to the size and geometric placement of the films, to quantify the dose perturbations. The three metallic stents produced the largest dose perturbations with distinct patterns of "hot" spots (increased dose) measured proximal to the radiation source (up to 15.4%) and both "cold" (decreased dose) and hot spots measured distal to the radiation source (range, -6.1%-5.8%). The polymeric Polyflex stent produced similar dose perturbations when the radiopaque markers were examined (range, -7.6%-15.4%). However, when the radiopaque markers were excluded from the analysis, the Polyflex stent produced significantly smaller dose perturbations, with maximum hot spots of 7.3% and cold spots of -3.2%. The dose perturbations caused by esophageal stents during the treatment of esophageal cancer using external beam radiotherapy should be understood. These perturbations will result in hot and cold spots in the esophageal mucosa, with varying magnitudes depending on the stent. The nonmetallic Polyflex stent appears to be the most suitable for patients undergoing radiotherapy, but further studies are necessary to determine the clinical significance of the dose perturbations. Copyright © 2012 Elsevier Inc. All rights reserved.

Enhancement of natural background gamma-radiation dose around uranium microparticles in the human body

PubMed Central

Pattison, John E.; Hugtenburg, Richard P.; Green, Stuart

2010-01-01

Ongoing controversy surrounds the adverse health effects of the use of depleted uranium (DU) munitions. The biological effects of gamma-radiation arise from the direct or indirect interaction between secondary electrons and the DNA of living cells. The probability of the absorption of X-rays and gamma-rays with energies below about 200 keV by particles of high atomic number is proportional to the third to fourth power of the atomic number. In such a case, the more heavily ionizing low-energy recoil electrons are preferentially produced; these cause dose enhancement in the immediate vicinity of the particles. It has been claimed that upon exposure to naturally occurring background gamma-radiation, particles of DU in the human body would produce dose enhancement by a factor of 500–1000, thereby contributing a significant radiation dose in addition to the dose received from the inherent radioactivity of the DU. In this study, we used the Monte Carlo code EGSnrc to accurately estimate the likely maximum dose enhancement arising from the presence of micrometre-sized uranium particles in the body. We found that although the dose enhancement is significant, of the order of 1–10, it is considerably smaller than that suggested previously. PMID:19776147

A comparison of the abilities of chlorpromazine and molindone to interact adversely with guanethidine.

PubMed

Gilder, D A; Fain, W; Simpson, L L

1976-08-01

Chlorpromazine and molindone were tested for their abilities to impair conditioned avoidance behavior of rats. Chlorpromazine was effective within the dose range of 0.3 to 7.0 mg/kg (ID50approximately 2.0 mg/kg); molindone was effective within the range of 0.3 to 5.0 mg/kg (ID50 approximately 0.6 mg/kg). Behaviorally relevant doses of chlorpromazine and molindone were then tested for their effects on blood pressure and on adrenergic mechanisms. When given intravenously to anesthetized, hypertensive animals, both drugs (1.0 mg/kg) produced significant but transient vasodepression. When given intraperitoneally to anesthetized or to conscious hypertensive rats, the drugs did not produce significant effects on blood pressure. Both drugs (1.0 mg/kg) blocked responses to an alpha agonist (methoxamine), but chlorpromazine was significantly more potent than molindone. In addition, chlorpromazine produced a dose-dependent (1.0-10.0 mg/kg) inhibition of 3H-l-norepinephrine uptake into heart, but molindone at the same doses produced no inhibition of uptake. In related experiments, it was found that guanethidine (50 mg/kg) was an effective agent for lowering blood pressure of hypertensive rats. When chlorpromazine (3-10 mg/kg) was administered concomitantly with guanethidine, the blood pressure lowering properties of guanethidine were diminished or abolished. When molindone (1-10 mg/kg) was administered concomitantly with guanethidine, there was no loss of blood pressure control. It is concluded that molindone is an important drug, because it is an antipsychotic agent that does not interact adversely with guanethidine.

Nicotine enhancement and reinforcer devaluation: Interaction with opioid receptors.

PubMed

Kirshenbaum, Ari P; Suhaka, Jesse A; Phillips, Jessie L; Voltolini de Souza Pinto, Maiary

In rats, nicotine enhances responding maintained by non-pharmacological reinforcers, and discontinuation of nicotine devalues those same reinforcers. The goal of this study was to assess the interaction of nicotine and opioid receptors and to evaluate the degree to which nicotine enhancement and nicotine-induced devaluation are related to opioid activation. Nicotine (0.4mg/kg), or nicotine plus naloxone (0.3 or 3.0mg/kg), was delivered to rats prior to progressive ratio (PR) schedule sessions in which sucrose was used as a reinforcer. PR-schedule responding was assessed during ten daily sessions of drug delivery, and for three post-dosing days/sessions. Control groups for this investigation included a saline-only condition, and naloxone-only (0.3 or 3.0mg/kg) conditions. When administered in conjunction with nicotine, both naloxone doses attenuated nicotine enhancement of the sucrose reinforcer, and the combination of the larger dose of naloxone (3.0mg/kg) with nicotine produced significant impairments in sucrose reinforced responding. When administered alone, neither dose of naloxone (0.3 & 3.0mg/kg) significantly altered responding in comparison to saline. Furthermore, when dosing was discontinued after ten once-daily doses, all nicotine groups (nicotine-only and nicotine+naloxone combination) demonstrated significant decreases in sucrose reinforcement compared to the saline group. Although opioid antagonism attenuated reinforcement enhancement by nicotine, it did not prevent reinforcer devaluation upon discontinuation of nicotine dosing, and the higher dose of naloxone (3.0mg/kg) produced decrements upon discontinuation on its own in the absence of nicotine. Copyright © 2016 Elsevier Inc. All rights reserved.

Ethanol-induced analgesia

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

Pohorecky, L.A.; Shah, P.

1987-09-07

The effect of ethanol (ET) on nociceptive sensitivity was evaluated using a new tail deflection response (TDR) method. The IP injection of ET (0.5 - 1.5 g/kg) produced raid dose-dependent analgesia. Near maximal effect (97% decrease in TDR) was produced with the 1.5 g/kg dose of ET ten minutes after injection. At ninety minutes post-injection there was still significant analgesia. Depression of ET-induced nociceptive sensitivity was partially reversed by a 1 mg/kg dose of naloxone. On the other hand, morphine (0.5 or 5.0 mg/kg IP) did not modify ET-induced analgesia, while 3.0 minutes of cold water swim (known to producemore » non-opioid mediated analgesia) potentiated ET-induced analgesic effect. The 0.5 g/kg dose of ET by itself did not depress motor activity in an open field test, but prevented partially the depression in motor activity produced by cold water swim (CWS). Thus, the potentiation by ET of the depression of the TDR produced by CWS cannot be ascribed to the depressant effects of ET on motor activity. 21 references, 4 figures, 1 table.« less

Thermal antinociception after dexmedetomidine administration in cats: a dose-finding study.

PubMed

Slingsby, L S; Taylor, P M

2008-04-01

The optimum dose of dexmedetomidine for antinociception to a thermal stimulus was determined in a crossover study of 12 cats. In five treatment groups (n = 10 per group), dexmedetomidine was administered intramuscularly (i.m.) at 2, 5, 10, 20 and 40 microg/kg; positive and negative controls were administered buprenorphine (20 microg/kg, i.m.) and 0.9% saline (0.006 mL/kg, i.m.) respectively. Baseline thermal thresholds and visual analogue scale (VAS) sedation scores were obtained prior to drug treatment and then at regular intervals until 24 h after administration. The summary measures of overall mean thresholds and overall mean VAS scores were investigated using a univariate general linear model for multiple factors with post hoc Tukey's tests (P < 0.05). Only dexmedetomidine at 40 microg/kg displayed an analgesic effect (less than that of buprenorphine). The VAS for sedation did not significantly affect the thresholds obtained and treatment was the only significant factor to influence VAS. Dexmedetomidine resulted in higher VAS for sedation than saline and buprenorphine. Dexmedetomidine at 40 microg/kg significantly increased nociceptive thresholds compared with saline control, but less than buprenorphine. Dexmedetomidine produced dose-dependent sedation, but only the highest dose produced analgesia, suggesting that induction of analgesia requires the highest dose (or an additional analgesic) in the clinical setting.

Spinal antinociception of synthetic omega-conotoxin SO-3, a selective N-type neuronal voltage-sensitive calcium channel blocker, and its effects on morphine analgesia in chemical stimulus tests in rodent.

PubMed

Yan, Ling-Di; Liu, Yan-Li; Zhang, Lei; Dong, Hua-Jin; Zhou, Pei-Lan; Su, Rui-Bin; Gong, Ze-Hui; Huang, Pei-Tang

2010-06-25

SO-3, a novel Omega-superfamily conotoxin derived from Conus striatus, selectively inhibits N-type neuronal voltage-sensitive calcium channels. In current study, antinociception of SO-3 compared with MVIIA or morphine and its effects on morphine analgesia were investigated in rodent chemical stimulus tests after acute or repeated intrathecal administration. In mice acetic acid writhing test, similar to MVIIA, SO-3 caused dose- and time-dependent spinal antinociception with ED(50) of 0.25 microg/kg and t(1/2) of 4h, which was more potent and longer-acting than morphine. In rat formalin test after intrathecal bolus injection, SO-3 produced dose- and time-dependent antinociception by suppressing acute (ED(50), 1.79 microg/kg) and tonic phases (ED(50), 0.41 microg/kg), which was similar to MVIIA and approximately 10-fold potency and twice longer-acting of morphine in blocking tonic phase responses. After repeated intrathecal injections twice daily for 5 consecutive days, SO-3 produced analgesia without loss of potency whereas morphine produced analgesia tolerance in rat formalin test; further, SO-3 still produced potent analgesia in morphine-tolerant rats. SO-3 co-administered with morphine left-shift the dose-response curve of morphine in mice acetic acid writhing test and significantly potentiated morphine analgesia in rat formalin test. No changes in motor function were seen in mice or rats receiving antinociceptive doses of SO-3 whereas MVIIA caused motor dysfunction at doses of 1.0-2.0 microg/kg in rats. This study showed that (1) novel SO-3 produced potent and long-acting spinal antinociception without observable motor dysfunction, (2) SO-3 significantly potentiated morphine analgesia, (3) After repeated intrathecal administration, SO-3 produced neither tolerance nor cross-tolerance to morphine analgesia. (c) 2010 Elsevier B.V. All rights reserved.

Comparison of Planning Quality and Efficiency Between Conventional and Knowledge-based Algorithms in Nasopharyngeal Cancer Patients Using Intensity Modulated Radiation Therapy.

PubMed

Chang, Amy T Y; Hung, Albert W M; Cheung, Fion W K; Lee, Michael C H; Chan, Oscar S H; Philips, Helen; Cheng, Yung-Tang; Ng, Wai-Tong

2016-07-01

Intensity modulated radiation therapy (IMRT) is widely used to achieve a highly conformal dose and improve treatment outcome. However, plan quality and planning time are institute and planner dependent, and no standardized tool exists to recognize an optimal plan. RapidPlan, a knowledge-based algorithm, can generate constraints to assist optimization and produce high-quality IMRT plans. This report evaluated the quality and efficiency of using RapidPlan in nasopharyngeal carcinoma (NPC) IMRT planning. RapidPlan was configured using 79 radical IMRT plans for NPC; 20 consecutive NPC patients indicated for radical radiation therapy between October 2014 and May 2015 were then recruited to assess its performance. The ability of RapidPlan to produce acceptable plans was evaluated. For plans that could not achieve clinical acceptance, manual touch-up was performed. The IMRT plans produced without RapidPlan (manual plans) and with RapidPlan (RP-2 plans, including those with manual touch-up) were compared in terms of dosimetric quality and planning efficiency. RapidPlan by itself could produce clinically acceptable plans for 9 of the 20 patients; manual touch-up increased the number of acceptable plans (RP-2 plans) to 19. The target dose coverage and conformity were very similar. No difference was found in the maximum dose to the brainstem and optic chiasm. RP-2 plans delivered a higher maximum dose to the spinal cord (46.4 Gy vs 43.9 Gy, P=.002) but a lower dose to the parotid (mean dose to right parotid, 37.3 Gy vs 45.4 Gy; left, 34.4 Gy vs 43.1 Gy; P<.001) and the right cochlea (mean dose, 48.6 Gy vs 52.6 Gy; P=.02). The total planning time for RP-2 plans was significantly less than that for manual plans (64 minutes vs 295 minutes, P<.001). This study shows that RapidPlan can significantly improve planning efficiency and produce quality IMRT plans for NPC patients. Copyright © 2016 Elsevier Inc. All rights reserved.

Anti-inflammatory activity of Lippia dulcis.

PubMed

Pérez, S; Meckes, M; Pérez, C; Susunaga, A; Zavala, M A

2005-10-31

Lippia dulcis hexane and ethanol extracts were tested for its anti-inflammatory activity in several animal models. Hexane extract showed to be inactive, but the ethanol extract at doses of 400 mg/kg produced significant inhibition of carrageenan-induced paw oedema and reduced the weight of cotton pellet-induced granuloma, moreover, the topical application of 0.5 mg/ear of this extract inhibited the edema induced with TPA by 49.13%, an effect which is of less intensity than that produced by indomethacine at the same dose.

The Influence of Nicotine Dose and Nicotine Dose Expectancy on the Cognitive and Subjective Effects of Cigarette Smoking

PubMed Central

Juliano, Laura M.; Fucito, Lisa M.; Harrell, Paul T.

2013-01-01

This study investigated the independent and interactive effects of nicotine dose and nicotine dose expectancy on smoking outcomes using a 2 (given nicotine vs. placebo) × 2 (told nicotine vs. placebo) Balanced Placebo Design (BPD). Smokers (N = 148) completed the Rapid Visual Information Processing Task (RVIP) and measures of smoking urge, mood, and cigarette ratings (e.g., satisfying) after smoking a nicotine or placebo cigarette crossed with instructions that the cigarette contained either nicotine or no nicotine. Nicotine cigarettes (0.6 mg nicotine) produced better sustained attention performance than placebos as indicated by RVIP reaction time, hits, and sensitivity (A′). Nicotine cigarettes also produced better mood and greater rewarding subjective effects of the cigarettes on 11 of 11 dimensions compared to placebos. Nicotine instructions resulted in fewer RVIP false alarms, better mood, and greater rewarding subjective effects of the cigarettes on 9 of 11 dimensions compared to placebo instructions. Nicotine dose by nicotine dose expectancy interactions were also observed for urge and tension-anxiety, such that the dose expectancy manipulation produced differential effects only among those who smoked placebo cigarettes. In contrast a significant interaction for self-reported vigor-activity demonstrated that the dose expectancy manipulation produced effects only among those who smoked nicotine cigarettes. This study provides additional evidence that nicotine improves cognitive performance, and provides initial evidence that denicotinized cigarettes smoked under the guise that they contain nicotine influence cognitive performance, albeit with less robust effects than nicotine. These data may inform the development of expectancy-based interventions for tobacco dependence. PMID:21463067

Models of CNS radiation damage during space flight

NASA Astrophysics Data System (ADS)

Hopewell, J. W.

1994-10-01

The primary structural and functional arrangement of the different cell types within the CNS are reviewed. This was undertaken with a view to providing a better understanding of the complex interrelationships that may contribute to the pathogenesis of lesions in this tissue after exposure to ionizing radiation. The spectrum of possible CNS radiation-induced syndromes are discussed although not all have an immediate relevance to exposure during space flight. The specific characteristics of the lesions observed would appear to be dose related. Very high doses may produce an acute CNS syndrome that can cause death. Of the delayed lesions, selective coagulation necrosis of white matter and a later appearing vascular microangiopathy, have been reported in patients after cancer therapy doses. Lower doses, perhaps very low doses, may produce a delayed generalised CNS atrophy; this effect and the probability of the induction of CNS tumors could potentially have the greatest significance for space flight.

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

Effects of chronic delta-9-tetrahydrocannabinol (THC) administration on neurotransmitter concentrations and receptor binding in the rat brain

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

Ali, S.F.; Newport, G.D.; Scallet, A.C.

THC is the major psychoactive constituent of marijuana and is also known as an hallucinogenic compound. Numerous reports have shown that large doses of THC produce significant alterations in various neurotransmitter systems. The present study was designed to determine whether chronic exposure to THC produces significant alterations in selected neurotransmitter systems (dopamine, serotonin, acetylcholine, GABAergic, benzodiazepine, and opiate) in the rat brain. In Experiment 1, male Sprague-Dawley rats were gavaged with vehicle, 10 or 20 mg THC/kg body weight daily, 5 days/week for 90 days. Animals were killed either 24 hours or two months after the last dose. Brains weremore » dissected into different regions for neurochemical analyses. Two months after the cessation of chronic administration, there was a significant decrease in GABA receptor binding in the hippocampus of animals in the high dose group. However, no other significant changes were found in neurotransmitter receptor binding characteristics in the hippocampus or in neurotransmitter concentrations in the caudate nucleus, hypothalamus or septum after chronic THC administration. In an attempt to replicate the GABA receptor binding changes and also to determine the (35S)TBPS binding in hippocampus, we designed Experiment 2. In this experiment, we dosed the animals by gavage with 0, 5, 10 or 20 mg THC/kg daily, 5 days/week or with 20 mg THC/kg Monday through Thursday and 60 mg/kg on Friday for 90 days. Results from this experiment failed to replicate the dose-dependent effect of THC on GABA receptor binding in hippocampus. Modulation of (35S)TBPS binding by GABA or 3 alpha-OH-DHP or inhibition by cold TBPS in frontal cortex did not show any significant dose-related effects.« less

RANTES: a new prostaglandin dependent endogenous pyrogen in the rat.

PubMed

Tavares, E; Miñano, F J

2000-09-01

Fever, a hallmark of disease, is a highly complex process initiated by the action of a number of endogenous pyrogens on the thermosensitive cells of the brain. We describe the activity of RANTES, a chemotactic cytokine, as intrinsically pyrogenic in the rat, when it is delivered directly to the thermosensitive region of the rat's anterior hypothalamic, pre-optic area (AH/POA). RANTES, microinjected into the AH/POA in a dose of 1, 5, 10, 15, 25 or 50 pg, produces an immediate and intense dose-related fever following injection. Increasing the dose to 100 pg did not result in a further increase in the febrile response. No significant change in body temperature was produced by heat-inactivated RANTES. The intrahypothalamic injection of antibodies against RANTES (2.0 microg, 15 min prior to RANTES) significantly blocked the fever induced by this chemokine. Pretreatment with ibuprofen blocked the fever induced by RANTES. In order of potency, the magnitude of the febrile response induced by RANTES was greater than that produced with equipotent doses of either macrophage inflammatory protein-1beta or interleukin-6. The results thus demonstrate that RANTES is the most potent endopyrogen discovered thus far and exerts its action directly on pyrogen-sensitive cells of the AH/POA through a prostaglandin-dependent pathway.

High-precision γ -ray spectroscopy of the cardiac PET imaging isotope Rb 82 and its impact on dosimetry

DOE PAGES

Nino, M. N.; McCutchan, E. A.; Smith, S. V.; ...

2016-02-01

82Rb is a positron-emitting isotope used in cardiac positron emission tomography (PET) imaging which has been reported to deliver a significantly lower effective radiation dose than analogous imaging isotopes like 201Tl and 99mTc sestamibi. High-quality β-decay data are essential to accurately appraise the total dose received by the patients. A source of 82Sr was produced at the Brookhaven Linac Isotope Producer (BLIP), transported to Argonne National Laboratory, and studied with the Gammasphere facility. Significant revisions have been made to the level scheme of 82Kr including 12 new levels, 50 new γ-ray transitions, and the determination of many new spin assignmentsmore » through angular correlations. Lastly, these new high-quality data allow a precise reappraisal of the β-decay strength function and thus the consequent dose received by patients.« less

Acute and subchronic effects of bilastine (20 and 40 mg) and hydroxyzine (50 mg) on actual driving performance in healthy volunteers.

PubMed

Conen, Silke; Theunissen, Eef L; Van Oers, Anita C M; Valiente, Román; Ramaekers, Johannes G

2011-11-01

Bilastine is a new second-generation H1 antagonist. Although bilastine has been demonstrated to produce little or no performance impairment in laboratory tests, it cannot be excluded that it produces impairments in real-life performance such as driving. This study aims to assess the effects of two doses of bilastine (20 and 40 mg) on actual driving after single and repeated administration. Hydroxyzine 50 mg was included as an active control. Twenty-two participants (11 females, 11 males) were tested in a placebo-controlled, randomized, double-blind, four-way cross-over design. Participants were treated with once-daily doses for eight consecutive days. On day 1 and 8 of each treatment period participants performed an actual highway driving test. The primary variable was standard deviation of lateral position (SDLP), a measure of weaving. Results demonstrated that hydroxyzine significantly increased SDLP on days 1 and 8 of treatment. Bilastine did not affect SDLP. It is concluded that hydroxyzine produces severe driving impairment after single doses and that this impairment only partly mitigates over time due to a lack of complete tolerance. Bilastine did not produce any driving impairment after single and repeated doses and can be safely used in traffic in doses up to 40 mg.

Exposure to heavy charged particles affects thermoregulation in rats

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

Kandasamy, S.B.; Hunt, W.A.; Dalton, T.K.

1994-09-01

Rats exposed to 0.1-5 Gy of heavy particles ({sup 56}Fe, {sup 40}Ar, {sup 20}Ne or {sup 4}He) showed dose-dependent changes in body temperature. Lower doses of all particles produced hyperthermia, and higher doses of {sup 20}Ne and {sup 56}Fe produced hypothermia. Of the four HZE particles, {sup 56}Fe particles were the most potent and {sup 4}He particles were the least potent in producing changes in thermoregulation. The {sup 20}Ne and {sup 40}Ar particles produced an intermediate level of change in body temperature. Significantly greater hyperthermia was produced by exposure to 1 Gy of {sup 20}Ne, {sup 40}Ar and {sup 56}Femore » particles than by exposure to 1 Gy of {sup 60}Co {gamma} rays. Pretreating rats with the cyclo-oxygenase inhibitor indomethacin attenuated the hyperthermia produced by exposure to 1 Gy of {sup 56}Fe particles, indicating that prostaglandins mediate {sup 56}Fe-particle-induced hyperthermia. The hypothermia produced by exposure to 5 Gy of {sup 56}Fe particles is mediated by histamine and can be attenuated by treatment with the antihistamines mepyramine and cimetidine. 15 refs., 4 figs.« less

Materials Degradation in the Jovian Radiation Environment

NASA Technical Reports Server (NTRS)

Miloshevsky, Gennady; Caffrey, Jarvis A.; Jones, Jonathan E.; Zoladz, Thomas F.

2017-01-01

The radiation environment of Jupiter represents a significant hazard for Europa Lander deorbit stage components, and presents a significant potential mission risk. The radiolytic degradation of ammonium perchlorate (AP) oxidizer in solid propellants may affect its properties and performance. The Monte Carlo code MONSOL was used for modeling of laboratory experiments on the electron irradiation of propellant samples. An approach for flattening dose profiles along the depth of irradiated samples is proposed. Depth-dose distributions produced by Jovian electrons in multi-layer slabs of materials are calculated. It is found that the absorbed dose in a particular slab is significantly affected by backscattered electrons and photons from neighboring slabs. The dose and radiolytic decomposition of AP crystals are investigated and radiation-induced chemical yields and weight percent of radical products are reported.

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.

Intravenously administered oxotremorine and atropine, in doses known to affect pain threshold, affect the intraspinal release of acetylcholine in rats.

PubMed

Abelson, Klas S P; Höglund, A Urban

2002-04-01

Both systemically and intrathecally administered cholinergic agonists produce antinociception while cholinergic antagonists decrease pain threshold. The mechanism and the site of action of these substances are not known. In the present study it was hypothesized that systemically administered muscarinic agonists and antagonists modify nociceptive threshold by affecting intraspinal release of acetylcholine (ACh). Catheters were inserted into the femoral vein in rats maintained on isoflurane anaesthesia for administration of oxotremorine (10-300 microg/kg) and atropine (0.1, 10, 5000 microg/kg). Spinal microdialysis probes were placed intraspinally at approximately the C2-C5 spinal level for sampling of acetylcholine and dialysis delivery of atropine (0.1, 1, 10 nM). Additionally, the tail-flick behaviour was tested on conscious rats injected intraperitoneally with saline, atropine (10, 100 and 5000 microg/kg), or subcutaneously with oxotremorine (30, 100, 300 microg/kg). Subcutaneous administration of oxotremorine (30, 100, 300 microg/kg) significantly increased the tail-flick latency. These doses of oxotremorine dose-dependently increased the intraspinal release of acetylcholine. Intravenously administered atropine, in a dose that produced hyperalgesia (5000 microg/kg) in the tail-flick test, significantly decreased the intraspinal release of acetylcholine. Our results suggest an association between pain threshold and acetylcholine release in spinal cord. It is also suggested that an approximately 30% increase in basal ACh release produces antinociception and that a 30% decrease in basal release produces hyperalgesia.

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

A comparison of dehydroepiandrosterone and 7-keto dehydroepiandrosterone with other drugs that modulate ethanol intake in rats responding under a multiple schedule

PubMed Central

Amato, Russell J.; Hulin, Mary W.; Winsauer, Peter J.

2012-01-01

Dehydroepiandrosterone (DHEA), 7-keto DHEA, and several comparison drugs (ethanol, chlordiazepoxide, rauwolscine, and RO15-4513) were administered to male rats responding under a multiple schedule of food and ethanol presentation to determine their selectively for decreasing ethanol-maintained responding. DHEA and 7-keto DHEA significantly decreased both ethanol- and food-maintained responding, compared to control, while also decreasing blood ethanol concentration (BEC). Acute ethanol administration also decreased responding for both food and ethanol; however, ethanol-maintained responding was more potently decreased than food-maintained responding. BEC remained relatively stable after increasing ethanol doses. Among the other drugs tested, RO15-4513 was the most selective for decreasing ethanol-maintained responding compared to food-maintained responding, and it decreased BECs as ethanol-maintained responding decreased. The largest dose of rauwolscine significantly decreased responding for food, while not affecting ethanol-maintained responding compared to control. Low to intermediate doses of rauwolscine produced small, non-significant increases in ethanol-maintained responding and BECs. Chlordiazepoxide produced significant decreases in food-maintained responding and the dose of ethanol presented, but only at the highest dose tested. Although DHEA and 7-keto DHEA did not decrease ethanol-maintained responding as selectively as ethanol or RO15-4513 under the multiple schedule, these neurosteroids may be valuable pharmacological tools in the development of new treatments for alcohol abuse and dependence. PMID:22473025

An inherent acceleratory effect of insulin on small intestinal transit and its pharmacological characterization in normal mice

PubMed Central

Peddyreddy, Murali Krishna Reddy; Dkhar, Steven Aibor; Ramaswamy, Subramanian; Naveen, Amrithraj Theophilus; Shewade, Deepak Gopal

2006-01-01

AIM: To study an inherent effect of insulin on small intestinal transit and to explore involvement of various systems/mechanisms in normal mice. METHODS: Insulin at the doses of 2 μU/kg, 2 mU/kg, 2 U/kg or vehicle was subcutaneously administered to four groups of overnight fasted normal male mice. Blood glucose (BG) levels were measured 2 min before insulin administration and 2 min before sacrificing the animals for the measurement of small intestinal transit (SIT). Charcoal meal was administered (0.3 mL) intragastrically 20 min after insulin administration and animals were sacrificed after 20 min and SIT was determined. For exploration of the various mechanisms involved in insulin-induced effect on SIT, the dose of insulin which can produce a significant acceleration of SIT without altering BG levels was determined. The following drugs, atropine (1 mg/kg), clonidine (0.1 mg/kg), ondansetron (1 mg/kg), naloxone (5 mg/kg), verapamil (8 mg/kg) and glibenclamide (10 mg/kg), were administered intravenously 10 min prior to the administration of insulin (2 μU/kg). RESULTS: The lower doses of insulin (2 μU/kg and 2 mU/kg) produced a significant acceleration of SIT from 52.0% to 70.7% and 73.5% without lowering blood glucose levels (P < 0.01), while the highest dose of insulin (2 U/kg) produced a fall in blood glucose levels which was also associated with significant acceleration of SIT (P < 0.01). After pretreatment of insulin (2 μU/kg) group with atropine, insulin could reverse 50% of the inhibition produced by atropine. In clonidine-pretreated group, insulin administration could reverse only 37% of the inhibition produced by clonidine and inhibition of SIT was significant compared with vehicle + insulin-treated group, i.e. from 74.7% to 27.7% (P < 0.01). In ondansetron-pretreated group, insulin administration could produce only mild acceleration of SIT (23.5%). In naloxone-pretreated group, insulin administration could significantly reverse the inhibition of SIT produced by naloxone when compared with naloxone per se group, i.e. from 32.3% to 53.9% (P < 0.01). In verapamil-pretreated group, insulin administration could only partially reverse the inhibition (65%). In glibenclamide-pretreated group, insulin administration produced further acceleration of SIT (12.2%). CONCLUSION: Insulin inherently possesses an acceleratory effect on SIT in normal mice. Adrenergic and cholinergic systems can play a significant role. Calcium channels and opioidergic system can play a supportive role; in addition, enhancement of endogenous insulin release can augment the effect of exogenously administered insulin on SIT. PMID:16688808

Pharmacokinetics and metabolism of all-trans- and 13-cis-retinoic acid in pulmonary emphysema patients.

PubMed

Muindi, Josephia R; Roth, Michael D; Wise, Robert A; Connett, John E; O'Connor, George T; Ramsdell, Joe W; Schluger, Neil W; Romkes, Marjorie; Branch, Robert A; Sciurba, Frank C

2008-01-01

Retinoids promote lung alveolarization in animal models and were administered to patients as part of the Feasibility of Retinoid Therapy for Emphysema (FORTE) study. This FORTE substudy investigated the pharmacokinetic profiles of 2 retinoic acid isomers-all-trans-retinoic acid (ATRA) and 13-cis-retinoic acid (13-cRA)-in subjects with emphysema, evaluated strategies to overcome self-induced ATRA catabolism, and identified pharmacodynamic relationships. Comprehensive and limited pharmacokinetics were obtained at multiple visits in emphysema subjects treated with placebo (n = 30), intermittent dosing (4 days/week) with low-dose ATRA (1 mg/kg/day, n = 21), or high-dose ATRA (2 mg/kg/day, n = 25) or daily administration of 13-cRA (1 mg/kg/day, n = 40). High-dose ATRA produced the highest peak plasma ATRA Cmax. However, at follow-up, plasma ATRA C(max) was significantly decreased from baseline in subjects whose day 1 levels exceeded 100 ng/mL (P < .0001). In contrast, administration of 13-cRA produced lower plasma ATRA C(max) (<100 ng/mL), but the levels were significantly higher at follow-up than those on day 1 (P < .001). Plasma ATRA levels as determined on day 1 correlated with changes in pulmonary diffusing capacity at 6 months, consistent with concentration-dependent biologic effects (r2 = -0.25). The authors conclude that intermittent therapy with high-dose ATRA produced the greatest ATRA exposure, but alternative approaches for limiting self-induced ATRA catabolism should be sought.

Locomotor activating effects of cocaine and scopolamine combinations in rats: isobolographic analysis

PubMed Central

Thomsen, Morgane

2014-01-01

Muscarinic cholinergic receptors are receiving renewed interest as viable targets for treating various psychiatric disorders. Dopaminergic and muscarinic systems interact in complex ways. The goal of this study was to quantify the interaction of a systemically administered psychomotor stimulant and muscarinic antagonist at the behavioral level. Using isobolographic analysis of locomotor activity data, we assessed the effects of three cocaine/scopolamine mixtures in terms of deviation from simple dose addition (additivity), at four effect levels. All three mixtures produced some more-than-additive (synergistic) effects, as lower doses were needed to produce given effects relative to the calculated effect of additive doses. A mixture with comparable contributions from cocaine and scopolamine produced significantly more-than-additive effects at all but the lowest effect level examined. A mostly-cocaine mixture was more-than-additive at low effect levels only, while a mostly-scopolamine mixture produced effects more consistent with additivity, with only the highest effect level barely reaching significant synergism. Our study confirms and quantifies previous findings that suggested synergistic effects of stimulants and muscarinic antagonists. The synergism implies that cocaine and scopolamine stimulate locomotor activity through non-identical pathways, and was most pronounced for a mixture containing cocaine and scopolamine in comparable proportions. PMID:24769455

Effects of intrathecal or intracerebroventricular administration of nonsteroidal anti-inflammatory drugs on a C-fiber reflex in rats.

PubMed

Bustamante, D; Paeile, C; Willer, J C; Le Bars, D

1997-06-01

A C-fiber reflex elicited by electrical stimulation within the territory of the sural nerve was recorded from the ipsilateral biceps femoris muscle in anesthetized rats. The temporal evolution of the response was studied using a constant stimulus intensity (3 times threshold), and recruitment curves were built by varying the stimulus intensity from 0 to 7 times threshold. The intrathecal (i.t.) but not i.c.v. administration of aspirin, indomethacin, ketoprofen and lysine clonixinate resulted in dose-dependent depressions of the C-fiber reflex. In contrast, saline was ineffective. Regardless of the route of administration, the drugs never produced disturbances in heart rate and/or acid-base equilibrium. When a constant level of stimulation was used, 500 microg of aspirin i.t. induced a blockade of the reflex immediately after the injection, followed by a partial recovery. Indomethacin produced a stable depression, which reached 80 to 90% with an i.t. dose of 500 microg. Ketoprofen and lysine clonixinate produced a more stable effect; the highest doses (500 microg) produced a steady-state depression of approximately 50% for approximately 30 min. When the recruitment curves were built with a range of nociceptive stimulus intensities, all of the drugs except for indomethacin produced a dose-dependent decrease in the slopes and the areas under the recruitment curves without major modifications in the thresholds; indomethacin also induced a significant dose-related increase in the threshold. The orders of potency for both stimulation paradigms with the i.t. route were the same, namely aspirin > indomethacin > lysine clonixinate > or = ketoprofen. It is concluded that nonsteroidal anti-inflammatory drugs elicit significant antinociceptive effects at a spinal level, which do not depend on the existence of a hyperalgesic or inflammatory state. Such effects were not seen after injections within the lateral ventricle.

Pleiotropic effects of fenofibrate therapy on rats with hypertriglycemia.

PubMed

Sun, Bing; Xie, Yuan; Jiang, Jinfa; Wang, Yiping; Xu, Xiaolin; Zhao, Cuimei; Huang, Feifei

2015-04-14

Cardio-protective effect of fibrate therapy is controversial and current research is to evaluate the effect of fenofibrate therapy on rats with hypertriglycemia. Rats with hypertriglycemia were produced by 10% fructose administration (10 ml daily) for 4 weeks. After model has been successfully produced as reflected by increased triglyceride level, different doses of fenofibrate, namely low dose (50 mg/kg body weight) and high dose (100 mg/kg body weight), were orally prescribed for 2 weeks. At baseline, 4 weeks of fructose administration and 2 weeks of fenofibrate therapy, parameters of interest were evaluated and compared. At baseline, no significant differences of parameter were observed between groups. After 4 weeks of fructose prescription, triglyceride level increased in company with high density lipoprotein cholesterol (HDL-C) and apoprotein A1 (ApoA1) decreased. C-reactive protein (CRP) and malondialdehyde (MDA) levels were also elevated. Endothelial function was impaired as reflected by reduced nitric oxide (NO) production and elevated serum asymmetric dimethylarginine (ADMA) level. All these changes were significant as compared to the control group (P<0.05), suggesting that short-term of triglyceride elevation could potently initiate atherosclerosis. With 2 weeks of fenofibrate therapy, in comparison to un-treated group, triglyceride level was significantly reduced in parallel with HDL-C and ApoA1 elevation. Inflammation and oxidation were also profoundly ameliorated as reflected by CRP and MDA reduction. Notably, NO production was enhanced in company with serum ADMA level decrease. Overall, these improvements manifested in a dose-dependent manner, which was supported by multivariate regression analysis showing that after adjusted to other variables, the dose of fenofibrate therapy remained significantly associated with NO production and serum ADMA level, with OR of 1.042 (high-dose versus low-dose, 95% CI 1.028-1.055, P<0.05). Fenofibrate therapy not only could reduce triglyceride level but also confer pleiotropic effects in terms of endothelium-protection and amelioration of inflammation and oxidation in a dose-dependent manner.

A Subanalgesic Dose of Morphine Eliminates Nalbuphine Anti-analgesia in Postoperative Pain

PubMed Central

Gear, Robert W.; Gordon, Newton C.; Hossaini-Zadeh, Mehran; Lee, Janice S.; Miaskowski, Christine; Paul, Steven M.; Levine, Jon D.

2008-01-01

The agonist-antagonist kappa-opioid nalbuphine administered for postoperative pain produces greater analgesia in females than in males. In fact, males administered nalbuphine (5 mg) experience pain greater than those receiving placebo, suggesting the existence of an anti-analgesic effect. These sexually dimorphic effects on postoperative pain can be eliminated by co-administration of a fixed ratio of the prototypical opioid receptor antagonist naloxone with nalbuphine, implying a role for opioid receptors in the anti-analgesic as well as analgesic effects of nalbuphine. In the present study, we further evaluated the role of opioid receptors in the sex-specific effects on pain produced by nalbuphine by co-administering a dose of morphine low enough that it does not produce analgesia. Following extraction of bony impacted third molar teeth, nalbuphine (5 mg) was administered alone or in combination with either of two low doses of morphine (2 mg or 4 mg). Both doses of morphine reversed nalbuphine-induced anti-analgesia in males, but only the lower dose (2 mg) reached statistical significance. Neither dose affected nalbuphine-induced analgesia in females, and when administered alone in either males or females, morphine (2 mg) had no analgesic effect. Though not observed in females, the effect of morphine in males argues that, like naloxone, low dose morphine may act as an anti-analgesia opioid receptor antagonist. Perspective Previously we reported that the nalbuphine produces both analgesic and anti-analgesic effects, and that the opioid antagonist naloxone can enhance nalbuphine analgesia by selectively antagonizing the anti-analgesic effect. Here we show that morphine, given in a subanalgesic dose, reverses nalbuphine-induced anti-analgesia in males, perhaps by a similar mechanism. PMID:18201935

High doses of dextromethorphan, an NMDA antagonist, produce effects similar to classic hallucinogens

PubMed Central

Carter, Lawrence P.; Johnson, Matthew W.; Mintzer, Miriam Z.; Klinedinst, Margaret A.; Griffiths, Roland R.

2013-01-01

Rationale Although reports of dextromethorphan (DXM) abuse have increased recently, few studies have examined the effects of high doses of DXM. Objective This study in humans evaluated the effects of supratherapeutic doses of DXM and triazolam. Methods Single, acute, oral doses of DXM (100, 200, 300, 400, 500, 600, 700, 800 mg/70 kg), triazolam (0.25, 0.5 mg/70kg), and placebo were administered to twelve healthy volunteers with histories of hallucinogen use, under double-blind conditions, using an ascending dose run-up design. Subjective, behavioral, and physiological effects were assessed repeatedly after drug administration for 6 hours. Results Triazolam produced dose-related increases in subject-rated sedation, observer-rated sedation, and behavioral impairment. DXM produced a profile of dose-related physiological and subjective effects differing from triazolam. DXM effects included increases in blood pressure, heart rate, and emesis, increases in observer-rated effects typical of classic hallucinogens (e.g. distance from reality, visual effects with eyes open and closed, joy, anxiety), and participant ratings of stimulation (e.g. jittery, nervous), somatic effects (e.g. tingling, headache), perceptual changes, end-of-session drug liking, and mystical-type experience. After 400 mg/70kg DXM, 11 of 12 participants indicated on a pharmacological class questionnaire that they thought they had received a classic hallucinogen (e.g. psilocybin). Drug effects resolved without significant adverse effects by the end of the session. In a 1-month follow up volunteers attributed increased spirituality and positive changes in attitudes, moods, and behavior to the session experiences. Conclusions High doses of DXM produced effects distinct from triazolam and had characteristics that were similar to the classic hallucinogen psilocybin. PMID:22526529

Esophageal cancer dose escalation using a simultaneous integrated boost technique.

PubMed

Welsh, James; Palmer, Matthew B; Ajani, Jaffer A; Liao, Zhongxing; Swisher, Steven G; Hofstetter, Wayne L; Allen, Pamela K; Settle, Steven H; Gomez, Daniel; Likhacheva, Anna; Cox, James D; Komaki, Ritsuko

2012-01-01

We previously showed that 75% of radiation therapy (RT) failures in patients with unresectable esophageal cancer are in the gross tumor volume (GTV). We performed a planning study to evaluate if a simultaneous integrated boost (SIB) technique could selectively deliver a boost dose of radiation to the GTV in patients with esophageal cancer. Treatment plans were generated using four different approaches (two-dimensional conformal radiotherapy [2D-CRT] to 50.4 Gy, 2D-CRT to 64.8 Gy, intensity-modulated RT [IMRT] to 50.4 Gy, and SIB-IMRT to 64.8 Gy) and optimized for 10 patients with distal esophageal cancer. All plans were constructed to deliver the target dose in 28 fractions using heterogeneity corrections. Isodose distributions were evaluated for target coverage and normal tissue exposure. The 50.4 Gy IMRT plan was associated with significant reductions in mean cardiac, pulmonary, and hepatic doses relative to the 50.4 Gy 2D-CRT plan. The 64.8 Gy SIB-IMRT plan produced a 28% increase in GTV dose and comparable normal tissue doses as the 50.4 Gy IMRT plan; compared with the 50.4 Gy 2D-CRT plan, the 64.8 Gy SIB-IMRT produced significant dose reductions to all critical structures (heart, lung, liver, and spinal cord). The use of SIB-IMRT allowed us to selectively increase the dose to the GTV, the area at highest risk of failure, while simultaneously reducing the dose to the normal heart, lung, and liver. Clinical implications warrant systematic evaluation. Copyright © 2012 Elsevier Inc. All rights reserved.

Esophageal Cancer Dose Escalation using a Simultaneous Integrated Boost Technique

PubMed Central

Welsh, James; Palmer, Matthew B.; Ajani, Jaffer A.; Liao, Zhongxing; Swisher, Steven G.; Hofstetter, Wayne L.; Allen, Pamela K.; Settle, Steven H.; Gomez, Daniel; Likhacheva, Anna; Cox, James D.; Komaki, Ritsuko

2014-01-01

Purpose We previously showed that 75% of radiation therapy (RT) failures in patients with unresectable esophageal cancer are in the gross tumor volume (GTV). We performed a planning study to evaluate if a simultaneous integrated boost (SIB) technique could selectively deliver a boost dose of radiation to the GTV in patients with esophageal cancer. Methods and Materials Treatment plans were generated using four different approaches (two-dimensional conformal RT [2D-CRT] to 50.4 Gy or 64.8 Gy, intensity-modulated RT [IMRT] to 50.4 Gy, and SIB-IMRT to 64.8 Gy) and optimized for 10 patients with distal esophageal cancer. All plans were constructed to deliver the target dose in 28 fractions using heterogeneity corrections. Isodose distributions were evaluated for target coverage and normal tissue exposure. Results The 50.4-Gy IMRT plan was associated with significant reductions in mean cardiac, pulmonary, and hepatic doses relative to the 50.4-Gy 2D-CRT plan. The 64.8-Gy SIB-IMRT plan produced a 28% increase in GTV dose and the same normal tissue doses as the 50.4-Gy IMRT plan; compared with the 50.4-Gy 2D-CRT plan, the 64.8-Gy SIB-IMRT produced significant dose reductions to all critical structures (heart, lung, liver, and spinal cord). Conclusions The use of SIB-IMRT allowed us to selectively increase the dose to the GTV, the area at highest risk of failure, while simultaneously reducing the dose to the normal heart, lung, and liver. Clinical implications warrant systematic evaluation. PMID:21123005

Experimental study of electrolysis-induced hepatic necrosis.

PubMed

Robertson, G S; Wemyss-Holden, S A; Dennison, A R; Hall, P M; Baxter, P; Maddern, G J

1998-09-01

One of the most promising but unexplored methods for treating patients with irresectable liver tumours is electrolysis. This study examined the effect of increasing 'current dose' on the volume of the lesion induced in normal rat liver. A direct current generator, connected to platinum electrodes implanted in the rat liver, was used to examine the effect of (1) varying current doses from 1 to 5 coulombs and (2) electrode separation (2 or 20 mm), on the volume of liver necrosis. There was a significant correlation (P < 0.001) between the current dose and the volume of necrosis produced for each electrode separation. Placing the electrodes 2 mm apart resulted in smaller total volumes of necrosis than placing them 20 mm apart when anode lesions were significantly larger than cathode lesions (P< 0.05). Liver enzymes (aspartate aminotransferase, alanine aminotransferase) were significantly raised 1 day after treatment (P < 0.001) and predicted the total volume of hepatic necrosis (P < 0.001). Predictable and reproducible areas of liver necrosis are produced with electrolysis. If these results extrapolate to larger animal models, this technique has potential for patients with irresectable primary and secondary liver tumours.

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.

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.

Effects of ionizing radiation on properties of monolayer and multilayer flexible food packaging materials

NASA Astrophysics Data System (ADS)

Riganakos, K. A.; Koller, W. D.; Ehlermann, D. A. E.; Bauer, B.; Kontominas, M. G.

1999-05-01

Volatile compounds produced in flexible food packaging materials (LDPE, EVAc, PET/PE/EVOH/PE) during electron beam irradiation were isolated by purge and trap technique and identified by combined gas chromatography-mass spectrometry (GC/MS), after thermal desorption and concentration. For comparison purposes non-irradiated films were also studied. Film samples were irradiated at low (5 kGy, corresponding to cold pasteurization), intermediate (20 kGy, corresponding to cold sterilization) and high (100 kGy) doses. It was observed that a number of volatile compounds are produced after irradiation in all cases. Furthermore the amounts of all volatile compounds increase with increasing irradiation dose. Both primary (methyl-derivatives etc.) as well as secondary i.e. oxidation products (ketones, aldehydes, alcohols, carboxylic acids etc.) are produced upon irradiation. These products may affect organoleptic properties and thus shelf-life of prepackaged irradiated foods. No significant changes were observed in the structure of polymer matrices as exhibited by IR spectra after irradiation of the materials at doses tested. Likewise, no significant changes were observed in O 2, H 2O and CO 2 permeability values of plastic packaging materials after irradiation.

Effects of denopamine (TA-064), a new positive inotropic agent, on myocardial oxygen consumption and left ventricular dimension in anesthetized dogs.

PubMed

Ikeo, T; Nagao, T

1985-10-01

We compared the effects of denopamine (TA-064) and isoproterenol on hemodynamics, myocardial oxygen consumption and the left ventricular (LV) dimension in halothane-N2O anesthetized dogs. Denopamine (0.25-1 micrograms/kg/min, i.v., infusion X 15 min) produced a maximum increase in LV dp/dtmax by 64% of the control, without affecting aortic pressure significantly. Doses of isoproterenol (0.01-0.04 micrograms/kg/min, i.v., infusion X 15 min) were selected to produce a positive inotropic action similar to that of denopamine. Denopamine produced significantly less increasing effects in heart rate, cardiac output and myocardial oxygen consumption and had more reducing effects in LV internal diameter than isoproterenol, while isoproterenol tended to produce a more potent increase in coronary blood flow, but a smaller decrease in LV end-diastolic pressure than denopamine. PQ interval was similarly reduced. Denopamine caused no substantial increase in myocardial oxygen consumption at a lower dose, at which LV dp/dtmax was significantly increased. A weak effect of denopamine on myocardial oxygen consumption may result partly from a weak positive chronotropic effect and partly from a reduction of preload and cardiac size.

Evaluation of the Anxiolytic Activity of NR-ANX-C (a Polyherbal Formulation) in Ethanol Withdrawal-Induced Anxiety Behavior in Rats.

PubMed

Mohan, L; Rao, U S C; Gopalakrishna, H N; Nair, V

2011-01-01

The present study investigates the anxiolytic activity of NR-ANX-C, a standardized polyherbal formulation containing the extracts of Withania somnifera, Ocimum sanctum, Camellia sinensis, Triphala, and Shilajit in ethanol withdrawal- (EW-) induced anxiety behavior in rats. Ethanol dependence in rats was produced by substitution of drinking water with 7.5% v/v alcohol for 10 days. Then, ethanol withdrawal was induced by replacing alcohol with drinking water, 12 hours prior to experimentation. After confirming induction of withdrawal symptoms in the alcohol deprived animals, the anxiolytic activity of the test compound in graded doses (10, 20, and 40 mg/kg) was compared to the standard drug alprazolam (0.08 mg/kg) in the elevated plus maze and bright and dark arena paradigms. In our study, single and repeated dose administration of NR-ANX-C reduced EW-induced anxiety in a dose-dependent manner. Even though the anxiolytic activity was not significant at lower doses, NR-ANX-C at the highest dose tested (40 mg/kg) produced significant anxiolytic activity that was comparable to the standard drug alprazolam. Based on our findings we believe that NR-ANX-C has the potential to be used as an alternative to benzodiazepines in the treatment of EW-induced anxiety.

Evaluation of the Anxiolytic Activity of NR-ANX-C (a Polyherbal Formulation) in Ethanol Withdrawal-Induced Anxiety Behavior in Rats

PubMed Central

Mohan, L.; Rao, U. S. C.; Gopalakrishna, H. N.; Nair, V.

2011-01-01

The present study investigates the anxiolytic activity of NR-ANX-C, a standardized polyherbal formulation containing the extracts of Withania somnifera, Ocimum sanctum, Camellia sinensis, Triphala, and Shilajit in ethanol withdrawal- (EW-) induced anxiety behavior in rats. Ethanol dependence in rats was produced by substitution of drinking water with 7.5% v/v alcohol for 10 days. Then, ethanol withdrawal was induced by replacing alcohol with drinking water, 12 hours prior to experimentation. After confirming induction of withdrawal symptoms in the alcohol deprived animals, the anxiolytic activity of the test compound in graded doses (10, 20, and 40 mg/kg) was compared to the standard drug alprazolam (0.08 mg/kg) in the elevated plus maze and bright and dark arena paradigms. In our study, single and repeated dose administration of NR-ANX-C reduced EW-induced anxiety in a dose-dependent manner. Even though the anxiolytic activity was not significant at lower doses, NR-ANX-C at the highest dose tested (40 mg/kg) produced significant anxiolytic activity that was comparable to the standard drug alprazolam. Based on our findings we believe that NR-ANX-C has the potential to be used as an alternative to benzodiazepines in the treatment of EW-induced anxiety. PMID:20953426

Human stem cell-derived cardiomyocytes detect drug-mediated changes in action potentials and ion currents.

PubMed

Gibson, John K; Yue, Yimei; Bronson, Jared; Palmer, Cassie; Numann, Randy

2014-01-01

It has been proposed that proarrhythmia assessment for safety pharmacology testing includes the use of human pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) to detect drug-induced changes in cardiac electrophysiology. This study measured the actions of diverse agents on action potentials (AP) and ion currents recorded from hiPSC-CM. During AP experiments, the hiPSC-CM were paced at 1Hz during a baseline period, and when increasing concentrations of test compound were administered at 4-minute intervals. AP parameters, including duration (APD60 and APD90), resting membrane potential, rate of rise, and amplitude, were measured throughout the entire experiment. Voltage clamp experiments with E-4031 and nifedipine were similarly conducted. E-4031 produced a dose-dependent prolongation of cardiac action potential and blocked the hERG/IKr current with an IC50 of 17nM. At 3nM, dofetilide significantly increased APD90. Astemizole significantly increased APD60 and APD90 at 30nM. Terfenadine significantly increased APD90 at concentrations greater than 10nM. Fexofenadine, a metabolite of terfenadine, did not produce any electrophysiologic changes in cardiac action potentials. Flecainide produced a dose-dependent prolongation of the cardiac action potential at 1 and 3μM. Acute exposure to nifedipine significantly decreased APD60 and APD90 and produced a dose-dependent block of calcium current with an IC50 of 0.039μM. Verapamil first shortened APD60 and APD90 in a dose-dependent manner, until a compensating increase in APD90, presumably via hERG blockade, was observed at 1 and 3μM. Following a chronic exposure (20-24h) to clinically relevant levels of pentamidine, a significant increase in action potential duration was accompanied by early afterdepolarizations (EADs). These experiments show the ability of AP measured from hiPSC-CM to record the interactions of various ion channels via AP recording and avoid the limitations of using several single ion channel assays in a noncardiac tissue. Copyright © 2014 Elsevier Inc. All rights reserved.

Relationship between cocaine-induced subjective effects and dopamine transporter occupancy

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

Volkow, N.D.; Fischman, M.; Wang, G.J.

The ability of cocaine to occupy the dopamine transporter has been linked to its reinforcing properties. However, such a relationship has not been demonstrated in humans. Methods: Positron Emission Tomography and [C-11]cocaine were used to estimate dopamine transporter occupancies after different doses of cocaine in 18 active cocaine abusers. The ratio of the distribution volume of [C-11]cocaine in striatum to that in cerebellum, which corresponds to Bmax/Kd +1 and is insensitive to changes in cerebral blood flow, was our measure of dopamine transporter availability. In parallel subjective effects were measured to assess the relationship between dopamine transporter occupancy and cocainesmore » behavioral effects. Intravenous cocaine produced a significant dose,-dependent blockade of dopamine transporters: 73 % for 0.6 mg/kg; 601/6 for 0.3 mg/kg; 48 % for 0.1 mg/kg iv and 40 % for 0.05 mg/kg. In addition, dopamine transporter occupancies were significantly correlated with cocaine plasma concentration (r = 0.55 p < 0.001). Cocaine also produced dose-dependent increases in self-reported ratings of {open_quotes}high{close_quotes} which were significantly correlated with the levels of dopamine transporter blockade. Discussion: These results provide the first documentation in humans that dopamine transporter occupancy is associated with cocaine induced subjective effects. They also suggest that dopamine transporter occupancies equal to or greater than 60% are required to produce significant effects on ratings of {open_quotes}high{close_quotes}.« less

Physical, proximate, functional and pasting properties of flour produced from gamma irradiated cowpea (Vigna unguiculata, L. Walp)

NASA Astrophysics Data System (ADS)

Darfour, B.; Wilson, D. D.; Ofosu, D. O.; Ocloo, F. C. K.

2012-04-01

Cowpeas are leguminous seeds widely produced and consumed in most developing countries of sub Saharan Africa. The aim of this study was to determine the physical, proximate, functional and pasting properties of flour obtained from gamma irradiated cowpea. Four cowpea cultivars were irradiated with gamma radiation at dose levels of 0.25, 0.5, 0.75, 1.0 and 1.5 kGy with the unirradiated cultivars serving as controls. The samples were hammer milled, sieved and stored at 4 °C for analysis. Physical, proximate, functional, pasting properties were determined using appropriate methods. In general, the irradiation dose applied to cowpea for insect control did not significantly affect the physical and proximate properties of the flour. However, significant increase (p<0.05) was achieved in paste bulk density, water and oil absorption capacities, foam capacities and least gelation concentrations of flour in general, which may be attributed to the irradiation. The radiation reduced the swelling power and water solubility index significantly. The peak temperature, peak viscosity and setback viscosity of the pastes were significantly (p<0.05) reduced while breakdown viscosity was significantly (p<0.05) increased by the radiation. It was established that the doses used on cowpea affected both the functional and pasting properties of the flour.

Intensity Modulated Radiotherapy Improves Target Coverage and Parotid Gland Sparing When Delivering Total Mucosal Irradiation in Patients With Squamous Cell Carcinoma of Head and Neck of Unknown Primary Site

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

Bhide, Shreerang; Clark, Catherine; Harrington, Kevin

2007-10-01

Head and neck squamous cell carcinoma with occult primary site represents a controversial clinical problem. Conventional total mucosal irradiation (TMI) maximizes local control, but at the expense of xerostomia. IMRT has been shown to spare salivary tissue in head and cancer patients. This study has been performed to investigate the potential of IMRT to perform nodal and TMI and also allow parotid gland sparing in this patient group. Conventional radiotherapy (CRT) and IMRT plans were produced for six patients to treat the ipsilateral (involved) post-operative neck (PTV1) and the un-operated contralateral neck and mucosal axis (PTV2). Plans were produced withmore » and without the inclusion of nasopharynx in the PTV2. The potential to improve target coverage and spare the parotid glands was investigated for the IMRT plans. There was no significant difference in the mean doses to the PTV1 using CRT and IMRT (59.7 and 60.0 respectively, p = 0.5). The maximum doses to PTV1 and PTV2 were lower for the IMRT technique as compared to CRT (P = 0.008 and P < 0.0001), respectively, and the minimum doses to PTV1 and PTV2 were significantly higher for IMRT as compared to CRT (P = 0.001 and P = 0.001), respectively, illustrating better dose homogeneity with IMRT. The mean dose to the parotid gland contralateral to PTV1 was significantly lower for IMRT (23.21 {+-} 0.7) as compared to CRT (50.5 {+-} 5.8) (P < 0.0001). There was a significant difference in parotid dose between plans with and without the inclusion of the nasopharynx. IMRT offers improved dose homogeneity in PTV1 and PTV2 and allows for parotid sparing.« less

Intrathecal Morphine Attenuates Recovery of Function after a Spinal Cord Injury

PubMed Central

Moreno, Georgina; Woller, Sarah; Puga, Denise; Hoy, Kevin; Balden, Robyn; Grau, James W.

2009-01-01

Abstract Prior work has shown that a high dose (20 mg/kg) of systemic morphine, required to produce significant analgesia in the acute phase of a contusion injury, undermines the long-term health of treated subjects and increases lesion size. Moreover, a single dose of systemic morphine in the early stage of injury (24 h post-injury) led to symptoms of neuropathic pain 3 weeks later, in the chronic phase. The present study examines the locus of the effects using intrathecal morphine administration. Subjects were treated with one of three doses (0, 30, or 90 μg) of intrathecal morphine 24 h after a moderate contusion injury. The 90-μg dose produced significant analgesia when subjects were exposed to noxious stimuli (thermal and incremented shock) below the level of injury. Yet, despite analgesic efficacy, intrathecal morphine significantly attenuated the recovery of locomotor function and increased lesion size rostral to the injury site. A single dose of 30 or 90 μg of intrathecal morphine also decreased weight gain, and more than doubled the incidence of mortality and autophagia when compared to vehicle-treated controls. Morphine is one of the most effective pharmacological agents for the treatment of neuropathic pain and, therefore, is indispensable for the spinally injured. Treatment can, however, adversely affect the recovery process. A morphine-induced attenuation of recovery may result from increases in immune cell activation and, subsequently, pro-inflammatory cytokine concentrations in the contused spinal cord. PMID:19388818

Effect of intravenously-administered putative and potential antagonists of ethanol on sleep time in ethanol-narcotized mice

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

Hatch, R.C.; Jernigan, A.D.

Groups of male CD-1 mice (n = 12/group) were injected intraperitoneally (IP) with 5 g ethanol/kg of body weight. After loss of righting reflex, they were given vehicle or one of 2-3 doses of reputed or potential antagonists of ethanol intravenously (IV). Sleep time was measured from loss to return of righting reflex. Mean sleep time (MST) was increased significantly by a large dose of dl-amphetamine and by 4-aminopyridine. Significant increases were also produced by small and large doses of aminophylline and by yohimbine. MST was not altered significantly by small and medium doses of dl-amphetamine, a medium dose ofmore » aminophylline, or by any doses of naloxone, thyrotropin-releasing hormone, propranolol, physostigmine, doxapram, or Ro 15-4513. When Ro 15-4513 was given IP 15 minutes before ethanol (n = 6/group), onset and duration of narcosis were not altered. None of the compounds tested was an effective IV antidote for deep ethanol narcosis because of drug side effects, toxicity, prolongation of MST, or insufficient shortening of MST. 36 references, 1 table.« less

(+/-)-3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') increases social interaction in rats.

PubMed

Morley, K C; McGregor, I S

2000-11-10

A series of experiments administered a low dose range (0, 1.25, 2.5 and 5 mg/kg) of (+/-)-3,4-methylenedioxymethamphetamine (MDMA, 'Ecstasy') to rats and assessed them in a variety of standard tests of anxiety. These tests included the emergence and elevated plus-maze tests, social interaction, cat odor avoidance and footshock-induced ultrasonic vocalizations. MDMA increased anxiety-related behaviours in the emergence and elevated plus-maze tests at all dose levels. A 5 mg/kg dose of MDMA also significantly reduced the time spent in close proximity to an anxiogenic cat odor stimulus. The 5 mg/kg dose also significantly reduced footshock-induced ultrasonic vocalizations. In the social interaction test, MDMA decreased aggressive behaviours at all doses tested, while the highest dose (5 mg/kg) also significantly increased the duration of social interaction. These results indicate that MDMA has both anxiogenic and anxiolytic effects depending upon the test situation employed. The facilitation of social interaction produced by MDMA in rats concurs with human experience of MDMA as a uniquely prosocial drug.

Contractile activity of ATP and diadenosine tetraphosphate on urinary bladder in the rats: role of superoxide anion and urothelium.

PubMed

Khattab, M M; Al-Hrasen, M N

2006-04-01

Both ATP and diadenosine tetraphosphate (AP(4)A) produced a dose-dependent contraction of rat isolated urinary bladder rings. The AP(4)A dose-response curve was to the left of that of ATP, and the maximum response was greater than that produced by ATP. Mechanical removal of the urothelium increased the contractile response to ATP by between 53% and 71%, and that to AP(4)A by 42% (at highest AP(4)A concentration) to 68% at lower concentration. Inhibition of Cu/Zn superoxide dismutase with diethylthiocarbamate (DETCA, 5 mm) significantly reduced the ATP-evoked contraction by 31% (at high ATP concentration) to 40% at low ATP concentration. Similarly, the AP(4)A-induced contractions were significantly decreased by 27% at low AP(4)A level to 38% at higher concentrations. Induction of exogenous superoxide anion stress by the use of the superoxide anion generator, pyrogallol (0.5 mm), significantly decreased both ATP- and AP(4)A-induced contractions of the rat urinary bladder over the whole dose range. Contractile responses to ATP decreased by 36-40%, and those to AP(4)A by 44-49%. In conclusion, the urinary bladder urothelium exerts an inhibitory control over the purinergic contractility produced by adenine mononucleotides and dinucleotides. Superoxide anion stress, whether endogenous or exogenous, attenuates the ATP-induced as well as AP(4)A-induced contractility.

The dichotomy of memantine treatment for ischemic stroke: dose-dependent protective and detrimental effects

PubMed Central

Trotman, Melissa; Vermehren, Philipp; Gibson, Claire L; Fern, Robert

2015-01-01

Excitotoxicity is a major contributor to cell death during the acute phase of ischemic stroke but aggressive pharmacological targeting of excitotoxicity has failed clinically. Here we investigated whether pretreatment with low doses of memantine, within the range currently used and well tolerated for the treatment of Alzheimer's disease, produce a protective effect in stroke. A coculture preparation exposed to modeled ischemia showed cell death associated with rapid glutamate rises and cytotoxic Ca2+ influx. Cell death was significantly enhanced in the presence of high memantine concentrations. However, low memantine concentrations significantly protected neurons and glia via excitotoxic cascade interruption. Mice were systemically administered a range of memantine doses (0.02, 0.2, 2, 10, and 20 mg/kg/day) starting 24 hours before 60 minutes reversible focal cerebral ischemia and continuing for a 48-hour recovery period. Low dose (0.2 mg/kg/day) memantine treatment significantly reduced lesion volume (by 30% to 50%) and improved behavioral outcomes in stroke lesions that had been separated into either small/striatal or large/striatocortical infarcts. However, higher doses of memantine (20 mg/kg/day) significantly increased injury. These results show that clinically established low doses of memantine should be considered for patients ‘at risk' of stroke, while higher doses are contraindicated. PMID:25407270

Analgesic use of inhaled methoxyflurane: Evaluation of its potential nephrotoxicity.

PubMed

Dayan, A D

2016-01-01

Methoxyflurane is a volatile, halogenated analgesic, self-administered in a controlled low dose from the Penthrox(®) inhaler for short-term pain relief. It was formerly used in significantly higher doses to produce anaesthesia, when it caused a specific type of dose-related renal tubular damage. The pathogenesis of the renal damage and clinical use of methoxyflurane are discussed here with evidence that a low but effective analgesic dose is not associated with the risk of renal adverse effects. The maximum dose employed to produce analgesia is limited to methoxyflurane 6 mL/day and 15 mL/week, producing a minimum alveolar concentration (MAC) of 0.59 MAC-hours. Renal damage is due to the metabolism of methoxyflurane and release of fluoride ions. Exposure of humans to methoxyflurane ≤2.0 MAC-hours, resulting in serum fluoride ≤40 µmol/L, has not been associated with renal tubular toxicity. The safety margin of analgesic use of methoxyflurane in the Penthrox ((®)) inhaler is at least 2.7- to 8-fold, based on methoxyflurane MAC-hours or serum fluoride level, with clinical experience suggesting it is higher. It is concluded from clinical experience in emergency medicine, surgical procedures and various experimental and laboratory investigations that the analgesic use of methoxyflurane in subanaesthetic doses in the Penthrox inhaler does not carry a risk of nephrotoxicity. © The Author(s) 2015.

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.

Effect of gamma irradiation on physical characteristics of Jordanian durum wheat and quality of semolina and lasagna products

NASA Astrophysics Data System (ADS)

Azzeh, F. S.; Amr, A. S.

2009-09-01

This study was conducted to determine the effect of using varying gamma irradiation doses on the physiochemical and rheological properties of semolina and its products. Ash, protein and water content were not influenced with gamma irradiation, while falling number and fungi counts decreased with increasing irradiation dose. Irradiation adversely affected wet gluten at 5 kGy dose. Dough stability was deteriorated vigorously with increasing irradiation dose. Sensory evaluation showed that lasagna produced from 0.25- and 1 kGy-irradiated semolina did not show any significant differences as compared with the control sample.

Effects of acute and repeated oral exposure to the organophosphate insecticide chlorpyrifos on open-field activity in chicks.

PubMed

Al-Badrany, Y M A; Mohammad, F K

2007-11-01

The effects of the organophosphate insecticide chlorpyrifos on 5min open-field activity were examined in a 7-15 days old chick model. Chlorpyrifos was acutely administered taking into account cholinesterase inhibition and determination of the acute (24h) median lethal dose (LD50). The oral LD50 value of chlorpyrifos in chicks was 18.14mg/kg, with cholinergic toxicosis observed on intoxicated chicks. Chlorpyrifos at the dose rates of 5,10 and 20mg/kg orally produced within 2h signs of cholinergic toxicosis in the chicks and significantly inhibited plasma (40-70%), whole brain (43-69%) and liver (31-46%) cholinesterase activities in a dose-dependent manner. Chlorpyrifos at 2 and 4mg/kg, orally did not produce overt signs of cholinergic toxicosis, but decreased (30, 60 and 90min after dosing) the general locomotor activity of the chicks as seen by a significant increase in the latency to move from the central square of the open-field arena, decreases in the numbers of lines crossed and vocalization score. Repeated daily chlorpyrifos treatments (2 and 4mg/kg, orally) for seven consecutive days also caused hypoactivity in chicks in the open-field behavioral paradigm. Only the high dose of chlorpyrifos (4mg/kg, orally) given repeatedly for 7 days caused significant cholinesterase inhibition in the whole brain (37%) and the liver (22%). In conclusion, chlorpyrifos at single or short-term repeated doses-induced behavioral changes in 7-15 days old chicks, in a model that could be used for further neurobehavioral studies involving subtle effects of organophosphates on chicks.

Effects of a new glucocorticoid, oxazacort, on some variables connected with bone metabolism in man: a comparison with prednisone.

PubMed

Caniggia, A; Marchetti, M; Gennari, C; Vattimo, A; Nicolis, F B

1977-03-01

The urinary elimination of calcium, other electrolytes, and hydroxyproline and the oral absorption of 47Ca have been evaluated in three groups of 8 patients before and during a 15-day treatment with prednisone at daily doses of 25 and 50 mg and with oxazacort, a new glucocorticoid, at a daily dose of 50 mg. The results obtained demonstrate that oxazacort in short-term teatment with a high dose has no significant effect on the urinary elimination of calcium and hydroxypyroline in experimental conditions in which prednisone produces statistically significant and clinically relevant increase, both when given at the same dose and when given at half that dose. On the other hand, the oral absorption of 47Ca is decreased by oxazacort, but less than by prednisone at the same dose. As the antirheumatic activity of oxazacort appears to be only slightly lower than that of prednisone (activity ratio of about 0.84: 1), these findings may have interesting therapeutic implications.

COCAINE AND PAVLOVIAN FEAR CONDITIONING: DOSE-EFFECT ANALYSIS

PubMed Central

Wood, Suzanne C.; Fay, Jonathon; Sage, Jennifer R.; Anagnostaras, Stephan G.

2007-01-01

Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1 – 15 mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15 mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1 mg/kg) showed significantly enhanced fear memory for both context and tone, compared to controls. These results were not due to cocaine’s anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine’s reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent fear conditioning. PMID:17098299

Cocaine and Pavlovian fear conditioning: dose-effect analysis.

PubMed

Wood, Suzanne C; Fay, Jonathan; Sage, Jennifer R; Anagnostaras, Stephan G

2007-01-25

Emerging evidence suggests that cocaine and other drugs of abuse can interfere with many aspects of cognitive functioning. The authors examined the effects of 0.1-15mg/kg of cocaine on Pavlovian contextual and cued fear conditioning in mice. As expected, pre-training cocaine dose-dependently produced hyperactivity and disrupted freezing. Surprisingly, when the mice were tested off-drug later, the group pre-treated with a moderate dose of cocaine (15mg/kg) displayed significantly less contextual and cued memory, compared to saline control animals. Conversely, mice pre-treated with a very low dose of cocaine (0.1mg/kg) showed significantly enhanced fear memory for both context and tone, compared to controls. These results were not due to cocaine's anesthetic effects, as shock reactivity was unaffected by cocaine. The data suggest that despite cocaine's reputation as a performance-enhancing and anxiogenic drug, this effect is seen only at very low doses, whereas a moderate dose disrupts hippocampus and amygdala-dependent fear conditioning.

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.

Development of parmesan cheese production from local cow milk

NASA Astrophysics Data System (ADS)

Aliwarga, Lienda; Christianti, Elisabeth Novi; Lazarus, Chrisella

2017-05-01

Parmesan cheese is one of the dairy products which is used in various foods, such as pasta, bakery product, and pizza. It has a hard texture due to aging process for at least two years. Long aging period inhibited the production of parmesan cheese while consumer demands were increasing gradually. This research was conducted to figure out the effect of starter culture and rennet dose to the production of parmesan cheese. This research consists of (1) pasteurization of 1,500 ml milk at 73°C; and (2) main cheese making process that comprised of fermentation process and the addition of rennet. In latter stage, milk was converted into curd. Variations were made for the dose of bacteria culture and rennet. Both variables correlated to the fermentation time and characteristics of the produced cheese. The analysis of the produced cheese during testing stage included measured protein and cheese yield, whey pH, water activity, and moisture content. Moreover, an organoleptic test was done in a qualitative manner. The results showed that the dose of bacteria culture has a significant effect to the fermentation time, protein yield, and cheese yield. Meanwhile, rennet dose significantly affected cheese yield, pH of whey, and water activity. The highest protein yield (93.1%) was obtained at 0.6 ml of culture and 0.5 ml of rennet while the maximum cheese yield (6.81%) was achieved at 0.4 ml of culture and 0.1 ml of rennet. The water activity of produced cheeses was lower compared to the water activity of common parmesan cheese (ca. 0.6). For the organoleptic test, 0.4 ml of bacterial culture and 0.5 ml of rennet produced the most preferred cheese flavor compared to other variations.

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

Fenoterol delivery by Respimat soft mist inhaler versus CFC metered dose inhaler: cumulative dose-response study in asthma patients.

PubMed

Vincken, Walter; Dewberry, Helen; Moonen, Diane

2003-09-01

Respimat (RMT) soft mist inhaler (SMI) is a novel, propellant-free alternative to chlorofluorocarbon metered-dose inhalers (CFC-MDIs). The aim of this study was to evaluate the safety and establish the equipotent dose of fenoterol delivered by RMT SMI vs. a conventional MDI. Double-blind, randomized, crossover, comparative study between fenoterol inhaled via RMT (either 50 microg/actuation, RMT50; or 100 microg/actuation. RMT100) and MDI (100 microg/actuation; MDI100). A total of 41 asthma patients received cumulative doses of fenoterol 600 microg (RMT50) or 1200 microg (RMT100 and MDI100) on 3 test days. The bronchodilator response (forced expiratory volume in 1 second [FEV1]) was considered therapeutically equivalent (i.e., noninferior) if the 95% confidence intervals for the difference in their mean changes from baseline were within limits of +/- 0.15L. Systemic exposure was evaluated from plasma fenoterol levels. Adverse events (AEs) were recorded. RMT50 and RMT100 produced noninferior bronchodilatation to MDI100 from 30minutes after the first dose. RMT50 showed equivalent safety and tolerability to MDI100, whereas RMT100 produced a higher incidence of AEs, a significantly greater plasma potassium reduction and a significant increase in pulse rate. Fenoterol plasma levels were twice as high with RMT100 as with RMT50 or MDI100. CONCLUSIONS; The nominal dose of fenoterol administered via RMT SMI can be at least halved to achieve equivalent efficacy, safety, and tolerability to a MDI.

Pharmacokinetics of detomidine administered to horses at rest and after maximal exercise.

PubMed

Hubbell, J A E; Sams, R A; Schmall, L M; Robertson, J T; Hinchcliff, K W; Muir, W W

2009-05-01

Increased doses of detomidine are required to produce sedation in horses after maximal exercise compared to calm or resting horses. To determine if the pharmacokinetics of detomidine in Thoroughbred horses are different when the drug is given during recuperation from a brief period of maximal exercise compared to administration at rest. Six Thoroughbred horses were preconditioned by exercising them on a treadmill. Each horse ran a simulated race at a treadmill speed that caused it to exercise at 120% of its maximal oxygen consumption. One minute after the end of exercise, horses were treated with detomidine. Each horse was treated with the same dose of detomidine on a second occasion a minimum of 14 days later while standing in a stocks. Samples of heparinised blood were obtained at various time points on both occasions. Plasma detomidine concentrations were determined by liquid chromatography-mass spectrometry. The plasma concentration vs. time data were analysed by nonlinear regression analysis. Median back-extrapolated time zero plasma concentration was significantly lower and median plasma half-life and median mean residence time were significantly longer when detomidine was administered after exercise compared to administration at rest. Median volume of distribution was significantly higher after exercise but median plasma clearance was not different between the 2 administrations. Detomidine i.v. is more widely distributed when administered to horses immediately after exercise compared to administration at rest resulting in lower peak plasma concentrations and a slower rate of elimination. The dose requirement to produce an equivalent effect may be higher in horses after exercise than in resting horses and less frequent subsequent doses may be required to produce a sustained effect.

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)

Effects of aqueous extracts of "Betel quid" and its constituents on testosterone production by dispersed mouse interstitial cells.

PubMed

Yang, Nai-Yen Jack; Kaphle, Krishna; Wang, Pei-Hwa; Jong, De-Shien; Wu, Leang-Shin; Lin, Jen-Hsou

2004-01-01

Betel quid (BQ) is a favorite chewing item among many communities in different parts of Asia where it is popular by different names. BQ is a unique combination of nut or fruit from the Areca catechu Linn. (AN) tree, leaf from the Piper betle Linn. (BL) vine, slaked lime, paste of bark from the Acacia catechu tree and other spices. AN has been used successfully in various traditional medicines by different civilizations over several ages. Initially condemned by the medical communities for its health hazards, identification and application of potent pharmacologically bioactive compounds from different constituents of BQ have rekindled growing interest in related investigations. Curious about the stimulating role of BQ, we investigated the potential steroidogenic activity of hot water extract from BQ and its constituents and arecoline on testosterone producing ability in an in vitro experiment. Enzyme dissociated interstitial cells from adult mouse testes (ICR strain) were cultured with/without different doses of the extracts and the level of testosterone produced was assayed by an enzyme immunoassay (EIA) technique. It was found that at lower doses of arecoline, AN and BL extracts had significantly stimulated testosterone production over the basal level (p < 0.05). BQ extract, on the other hand, did not show any significant effect on testosterone production. Combinations of arecoline at low doses with 10 ng/ml ovine leutinizing hormone (oLH) showed increases in testosterone produced, while cyclic adenosine monophosphate (cAMP) co-culture showed dose-related inhibition. Our current finding hints at the possible dose-dependent dualistic role of AN and BL extracts and arecoline for testosterone production employing possible non-cAMP-dependent pathway of steroidogenesis. However, the identity of the active compounds besides arecoline and the exact mechanism involved remains to be further investigated.

Histological analysis of the influence of certain extremal factors on the postradiational changes in the tissues of experimental animals

NASA Technical Reports Server (NTRS)

Sutulov, L. S.; Gaydamakin, N. A.; Sutulov, Y. L.

1975-01-01

Protons with energies of 120 MeV at a dose of 640 rads or gamma-neutron radiation at a dose of 300 rads produce radiation sickness of moderate severity in rats. The significance of toxemia and disturbances to the endocrine regulatory system in the development of metabolic processes in various stages of radiation sickness are discussed.

Effects of tartrazine on exploratory behavior in a three-generation toxicity study in mice.

PubMed

Tanaka, Toyohito; Takahashi, Osamu; Oishi, Shinshi; Ogata, Akio

2008-10-01

Tartrazine was given to mice in the diet at levels of 0 (control), 0.05%, 0.15%, and 0.45% from 5 weeks of age of the F(0) generation to 9 weeks of age of the F(2) generation, and selected reproductive and neurobehavioral parameters were measured. In the F(1) generation, the development of swimming direction at postnatal day (PND) 7 was accelerated significantly in male offspring in a dose-related manner. Surface righting at PND 7 was affected significantly in female offspring in dose-related manner. Several variables in exploratory behavior showed significant tendencies to be affected in the treatment groups in male offspring at 3 weeks of age. In the F(2) generation, the development of swimming direction at PND 7 was accelerated significantly in the high-dosed group in male offspring. Time taken of olfactory orientation at PND 14 was accelerated significantly in male offspring in a dose-related manner. Several variables in exploratory behavior showed significant tendencies to be affected in the treatment groups in male offspring at 3 weeks of age, and in males at 8 weeks of age. The dose levels of tartrazine in the present study produced a few adverse effects on neurobehavioral parameters throughout generations in mice.

Down-regulation of tryptamine binding sites following chronic molindone administration. A comparison with responses of dopamine and 5-hydroxytryptamine receptors.

PubMed

Nguyen, T V; Juorio, A V

1989-10-01

The present study assessed changes of tryptamine, dopamine D2, 5-HT1 and 5-HT2 binding sites in rat brain following chronic treatment with low (5 mg/kg/day) and high (40 mg/kg/day) doses of molindone, a clinically effective psychotropic drug. The high-dose molindone treatment produced a decrease in the number of tryptamine binding sites while both high and low doses caused an increase in the number of dopamine D2 binding sites in the striatum. No significant changes were observed in either 5-HT1 or 5-HT2 binding sites in the cerebral cortex. Competition binding experiments showed that molindone was a potent inhibitor at dopamine D2 but less effective at tryptamine, 5-HT1 and 5-HT2 binding sites. The inhibition activity of molindone towards type A monoamine oxidase produced a significant increase in endogenous tryptamine accumulation rate which was much higher than that of dopamine and 5-HT. These findings suggest that the reduction in the number of tryptamine binding sites produced by chronic molindone administration is related to monoamine oxidase inhibition and that the increase in the number of dopamine D2 binding sites is correlated to receptor blocking activity of the drug.

Postharvest Irradiation Treatment for Quarantine Control of Western Flower Thrips (Thysanoptera: Thripidae).

PubMed

Nicholas, Adrian H; Follett, Peter A

2018-04-05

The western flower thrips, Frankliniella occidentalis (Pergande) (Thysanoptera: Thripidae), is an important pest of fresh horticultural produce and as such is considered a biosecurity risk in many countries from which it is absent. Information is needed on the radiation tolerance of important surface pests of quarantine importance such as F. occidentalis so that phytosanitary irradiation treatments for exported fresh commodities can be lowered to below the 400 Gy generic treatment currently approved for most insects in the United States and Australia. Lowering the dose will help minimize any product quality problems, reduce costs, and shorten treatment time. In large-scale confirmatory trials conducted in two independent laboratories in Hawaii and Australia, a dose of 250 Gy (measured doses 222-279 Gy) applied to adult F. occidentalis on green beans resulted in no reproduction in 5,050 treated individuals. At 250 Gy, the effective dose is significantly below the 400 Gy generic dose, demonstrating that irradiation at this lowered level is an effective method for the disinfestation of F. occidentalis from fresh horticultural produce.

Efficacy and safety of oral lubiprostone in constipated patients with or without irritable bowel syndrome: a randomized, placebo-controlled and dose-finding study.

PubMed

Fukudo, S; Hongo, M; Kaneko, H; Ueno, R

2011-06-01

Lubiprostone is a prostone analog with a novel mechanism of action involving type-2 chloride channel activation. The aim of this work was to perform a dose-finding study for lubiprostone for the treatment of constipation with or without irritable bowel syndrome (IBS) in Japan. A total of 170 patients (128 without IBS and 42 with IBS) with chronic idiopathic constipation (CIC) randomly received a placebo (n=42) or 16μg (n=41), 32μg (n=43), or 48μg (n=44) of lubiprostone daily for 2weeks. There was a statistically significant and dose-dependent increase in change from baseline in the weekly average number of spontaneous bowel movements at week 1 (placebo: 1.5±0.4; 16μg: 2.3±0.4, 32μg: 3.5±0.5; and 48μg: 6.8±1.1, per week, mean±SE; P<0.0001). These primary endpoint results were significant on stratified analysis when patients were limited to those without IBS (P<0.0001). The primary endpoint in patients with IBS treated with 48μg of lubiprostone was significantly better than those given placebo (P=0.0086). Dose dependency was also seen for the secondary efficacy endpoints. Lubiprostone produced no serious side effects. Our results suggest that lubiprostone produced a steady and effective improvement in the symptoms of CIC with or without IBS in a dose-dependent manner with a good safety profile and tolerability in a Japanese population. © 2011 Blackwell Publishing Ltd.

Antidiarrhoeal Activity of Hydroethanolic Leaf Extract of Bryophyllum pinnatum Lam. Kurtz (Crassulaceae).

PubMed

Adeyemi, Olufunmilayo O; Ishola, Ismail O; Okoro, Uzodinma

2013-01-01

Bryophyllum pinnatum Lam. Kurtz (Crassulaceae) is used in traditional African medicine in the treatment of diarrhoea. To investigate the antidiarrhoeal action of the hydroethanolic leaf extract of Bryophyllum pinnatum (BP). Normal intestinal transit, castor oil-induced intestinal transit, castor oil-induced diarrhoea, gastric emptying and enteropooling models in rodents were used to investigate antidiarrhoeal effect. The possible mechanism of antidiarrhoeal activity was investigated using prazosin (1 mg/kg, s.c; α1, adrenoceptor antagonist), yohimbine (1 mg/kg, s.c; α2 adrenoceptor antagonist), propranolol (1 mg/kg, i.p; α- adrenoceptor non-selective antagonist), atropine (1 mg/kg, s.c; muscarinic cholinergic antagonist), pilocarpine (1 mg/kg, s.c; muscarinic cholinergic agonist), and isosorbide dinitrate (IDN) (150 mg/kg, p.o; nitric oxide donor). BP (25-100 mg/kg, p.o) produced dose-dependent and significant (P < 0.001) decrease in intestinal propulsion in normal and castor oil-induced intestinal transit models in comparison to distilled water (10 ml/kg, p.o.) treated control. This antidiarrhoeal effect was inhibited by propranolol pretreatment but yohimbine, prazosin, or atropine pretreatment failed to block this effect. BP treatment reduced the increased peristaltic activity induced by pilocarpine, however, co-treatment with IDN significantly (P < 0.001) enhanced the antidiarrhoeal effect of the extract. In castor oil-induced diarrhoea test, the extract produced a dose-dependent and significant (P < 0.001) increase in onset of diarrhoea, decreased diarrhoea score, the number and weight of wet stools when compared to control. The in vivo antidiarrhoeal index (ADI(in) vivo)) of 53.52 produced by the extract (50 mg/kg, p.o.) was similar to 76.28 ADI(in vivo) produced by morphine (10 mg/kg, s.c.). The extract produced dose- dependent and significant (P < 0.05; P < 0.001) decrease in the weight and volume of intestinal content in the intestinal fluid accumulation model. In gastric emptying test, BP treatment reduced the quantity of test meal emptied in 1 h but not significant. The results showed that the hydroethanolic leaf extract of Bryophyllum pinnatum possesses antidiarrhoeal activity possibly mediated by interaction with β adrenoceptor, muscarinic cholinergic receptor and nitric oxide pathway.

Central nervous system activity of Illicium verum fruit extracts.

PubMed

Chouksey, Divya; Upmanyu, Neeraj; Pawar, R S

2013-11-01

To research the acute toxicity of Illicium verum (I. verum) fruit extracts and its action on central nervous system. The TLC and HPTLC techniques were used as fingerprints to determine the chemical components present in I. verum. Male albino rats and mice were utilized for study. The powdered material was successively extracted with n-hexane, ethyl acetate and methanol using a Soxhlet extractor. Acute toxicity studies were performed as per OECD guidelines. The CNS activity was evaluated on parameters of general behavior, sleeping pattern, locomotor activity, anxiety and myocoordination activity. The animals were trained for seven days prior to experiments and the divided into five groups with six animals in each. The drug was administered by intraperitoneal route according to body weight. The dosing was done as prescribed in each protocol. Toxicity studies reported 2 000 mg/kg as toxicological dose and 1/10 of the same dose was taken as therapeutic dose Intraperitoneal injection of all extracts at dose of 200 mg prolonged phenobarbitone induced sleeping time, produced alteration in general behavior pattern, reduced locomotor activity and produced anxiolytic effects but the extracts do not significantly alter muscles coordination activity. The three extracts of I. verum at the dose of 200 mg, methanol extract was found to produce more prominent effects, then hexane and ethylacetate extracts. The observation suggested that the extracts of I. verum possess potent CNS depressant action and anxiolytic effect without interfering with motor coordination. Copyright © 2013 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

SU-E-T-504: Intensity-Modulated Radiosurgery Treatments Derived by Optimizing Delivery of Sphere Packing Treatment Plans

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

Hermansen, M; Bova, F; John, T St.

2015-06-15

Purpose To minimize the number of monitor units required to deliver a sphere packing stereotactic radiosurgery (SRS) plan by eliminating overlaps of individual beam projections. Methods An algorithm was written in C{sup ++} to calculate SRS treatment doses using sphere packing. Three fixed beams were used to approximate each arc in a typical SRS treatment plan. For cases involving multiple isocenters, at each gantry and table angle position beams directed to individual spheres overlap to produce regions of high dose, resulting in intensity modulated beams. These high dose regions were dampened by post-processing of the combined beam profile. The post-processmore » dampening involves removing the excess overlapping fluence from all but the highest contributing beam. The dampened beam profiles at each table and gantry angle position were then summed to produce the new total dose distribution. Results Delivery times for even the most complex multiple sphere plans can be reduced to consistent times of about 20 to 30 minutes. The total MUs required to deliver the plan can also be reduced by as much as 85% of the original plan’s MUs. Conclusion Regions of high dose are removed. Dampening overlapping radiation fluence can produce the new beam profiles that have more uniform dose distributions using less MUs. This results in a treatment that requires significantly fewer intensity values than traditional IMRT or VAMT planning.« less

A 13C(d,n)-based epithermal neutron source for Boron Neutron Capture Therapy.

PubMed

Capoulat, M E; Kreiner, A J

2017-01-01

Boron Neutron Capture Therapy (BNCT) requires neutron sources suitable for in-hospital siting. Low-energy particle accelerators working in conjunction with a neutron producing reaction are the most appropriate choice for this purpose. One of the possible nuclear reactions is 13 C(d,n) 14 N. The aim of this work is to evaluate the therapeutic capabilities of the neutron beam produced by this reaction, through a 30mA beam of deuterons of 1.45MeV. A Beam Shaping Assembly design was computationally optimized. Depth dose profiles in a Snyder head phantom were simulated with the MCNP code for a number of BSA configurations. In order to optimize the treatment capabilities, the BSA configuration was determined as the one that allows maximizing both the tumor dose and the penetration depth while keeping doses to healthy tissues under the tolerance limits. Significant doses to tumor tissues were achieved up to ∼6cm in depth. Peak doses up to 57Gy-Eq can be delivered in a fractionated scheme of 2 irradiations of approximately 1h each. In a single 1h irradiation, lower but still acceptable doses to tumor are also feasible. Treatment capabilities obtained here are comparable to those achieved with other accelerator-based neutron sources, making of the 13 C(d,n) 14 N reaction a realistic option for producing therapeutic neutron beams through a low-energy particle accelerator. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Image quality and dose differences caused by vendor-specific image processing of neonatal radiographs.

PubMed

Sensakovic, William F; O'Dell, M Cody; Letter, Haley; Kohler, Nathan; Rop, Baiywo; Cook, Jane; Logsdon, Gregory; Varich, Laura

2016-10-01

Image processing plays an important role in optimizing image quality and radiation dose in projection radiography. Unfortunately commercial algorithms are black boxes that are often left at or near vendor default settings rather than being optimized. We hypothesize that different commercial image-processing systems, when left at or near default settings, create significant differences in image quality. We further hypothesize that image-quality differences can be exploited to produce images of equivalent quality but lower radiation dose. We used a portable radiography system to acquire images on a neonatal chest phantom and recorded the entrance surface air kerma (ESAK). We applied two image-processing systems (Optima XR220amx, by GE Healthcare, Waukesha, WI; and MUSICA(2) by Agfa HealthCare, Mortsel, Belgium) to the images. Seven observers (attending pediatric radiologists and radiology residents) independently assessed image quality using two methods: rating and matching. Image-quality ratings were independently assessed by each observer on a 10-point scale. Matching consisted of each observer matching GE-processed images and Agfa-processed images with equivalent image quality. A total of 210 rating tasks and 42 matching tasks were performed and effective dose was estimated. Median Agfa-processed image-quality ratings were higher than GE-processed ratings. Non-diagnostic ratings were seen over a wider range of doses for GE-processed images than for Agfa-processed images. During matching tasks, observers matched image quality between GE-processed images and Agfa-processed images acquired at a lower effective dose (11 ± 9 μSv; P < 0.0001). Image-processing methods significantly impact perceived image quality. These image-quality differences can be exploited to alter protocols and produce images of equivalent image quality but lower doses. Those purchasing projection radiography systems or third-party image-processing software should be aware that image processing can significantly impact image quality when settings are left near default values.

Dimethyl Sulfoxide (DMSO) Produces Widespread Apoptosis in the Developing Central Nervous System

PubMed Central

Hanslick, Jennifer L.; Lau, Karen; Noguchi, Kevin K.; Olney, John W.; Zorumski, Charles F.; Mennerick, Steven; Farber, Nuri B.

2009-01-01

Dimethyl sulfoxide (DMSO) is a solvent that is routinely used as a cryopreservative in allogous bone marrow and organ transplantion. We exposed C57Bl/6 mice of varying postnatal ages (P0–P30) to DMSO in order to study whether DMSO could produce apoptotic degeneration in the developing CNS. DMSO produced widespread apoptosis in the developing mouse brain at all ages tested. Damage was greatest at P7. Significant elevations above the background rate of apoptosis occurred at the lowest dose tested, 0.3 ml/kg. In an in vitro rat hippocampal culture preparation, DMSO produced neuronal loss at concentrations of 0.5% and 1.0%. The ability of DMSO to damage neurons in dissociated cultures indicates that the toxicity likely results from a direct cellular effect. Because children, who undergo bone marrow transplantation, are routinely exposed to DMSO at doses higher than 0.3 ml/kg, there is concern that DMSO might be producing similar damage in human children. PMID:19100327

ABT-627, an endothelin ET(A) receptor-selective antagonist, attenuates tactile allodynia in a diabetic rat model of neuropathic pain.

PubMed

Jarvis, M F; Wessale, J L; Zhu, C Z; Lynch, J J; Dayton, B D; Calzadilla, S V; Padley, R J; Opgenorth, T J; Kowaluk, E A

2000-01-24

Tactile allodynia, the enhanced perception of pain in response to normally non-painful stimulation, represents a common complication of diabetic neuropathy. The activation of endothelin ET(A) receptors has been implicated in diabetes-induced reductions in peripheral neurovascularization and concomitant endoneurial hypoxia. Endothelin receptor activation has also been shown to alter the peripheral and central processing of nociceptive information. The present study was conducted to evaluate the antinociceptive effects of the novel endothelin ET(A) receptor-selective antagonist, 2R-(4-methoxyphenyl)-4S-(1,3-benzodioxol-5-yl)-1-(N, N-di(n-butyl)aminocarbonyl-methyl)-pyrrolidine-3R-carboxylic acid (ABT-627), in the streptozotocin-induced diabetic rat model of neuropathic pain. Rats were injected with 75 mg/kg streptozotocin (i. p.), and drug effects were assessed 8-12 weeks following streptozotocin treatment to allow for stabilization of blood glucose levels (>/=240 mg/dl) and tactile allodynia thresholds (

Diverse effects of a low dose supplement of lipidated curcumin in healthy middle aged people

PubMed Central

2012-01-01

Background Curcumin extracts of turmeric are proposed to produce health benefits. To date, human intervention studies have focused mainly on people with existing health problems given high doses of poorly absorbed curcumin. The purpose of the current study was to check whether in healthy people, a low dose of a lipidated curcumin extract could alter wellness-related measures. Methods The present study was conducted in healthy middle aged people (40–60 years old) with a low dose of curcumin (80 mg/day) in a lipidated form expected to have good absorption. Subjects were given either curcumin (N = 19) or placebo (N = 19) for 4 wk. Blood and saliva samples were taken before and after the 4 weeks and analyzed for a variety of blood and saliva measures relevant to health promotion. Results Curcumin, but not placebo, produced the following statistically significant changes: lowering of plasma triglyceride values, lowering of salivary amylase levels, raising of salivary radical scavenging capacities, raising of plasma catalase activities, lowering of plasma beta amyloid protein concentrations, lowering of plasma sICAM readings, increased plasma myeloperoxidase without increased c-reactive protein levels, increased plasma nitric oxide, and decreased plasma alanine amino transferase activities. Conclusion Collectively, these results demonstrate that a low dose of a curcumin-lipid preparation can produce a variety of potentially health promoting effects in healthy middle aged people. PMID:23013352

Hypoglycemic action of karanjin.

PubMed

Mandal, B; Maity, C R

1986-01-01

The hypoglycemic activity of karanjin, 3-methoxy flavono 7,8-furan, was investigated in normal and alloxan-induced diabetic albino rats. Oral administration of karanjin at a dose of 2 mg/kg/day for 7 days caused a significant reduction in blood sugar level both in normal and in alloxan-induced diabetic rats. Acute treatment with a single dose of karanjin, 0.5 mg/kg i.p., produced a significant fall in blood sugar level in normal rats while in alloxan-induced diabetic rats it was ineffective. Impaired glucose tolerance was also improved by karanjin treatment. It is concluded that karanjin has a significant hypoglycemic effect in albino rats.

Antidiarrhoeal activity of leaf methanolic extract of Rauwolfia serpentina.

PubMed

Ezeigbo, I I; Ezeja, M I; Madubuike, K G; Ifenkwe, D C; Ukweni, I A; Udeh, N E; Akomas, S C

2012-06-01

To evaluate the antidiarrhoeal property of methanol extract of the leaves of Rauwolfia serpentina (R. serpentina) in experimental diarrhoea induced by castor oil in mice. Doses of 100, 200 and 400 mg/kg R. serpentina leaf methanol extracts were administered to castor oil induced diarrhoea mice to determine its antidiarrhoeal activity. All doses of the extract and the reference drug atropine sulphate (3 mg/kg, i.p.) produced a dose-dependent reduction in intestinal weight and fluid volume. The extracts also significantly reduced the intestinal transit in charcoal meal test when compared to diphenoxylate Hcl (5 mg/kg, p.o.). The results show that the extract of R. serpentina leaves has a significant antidiarrhoeal activity and supports its traditional uses in herbal medicine.

Dose-response of intrathecal morphine when administered with intravenous ketorolac for post-cesarean analgesia: a two-center, prospective, randomized, blinded trial.

PubMed

Berger, J S; Gonzalez, A; Hopkins, A; Alshaeri, T; Jeon, D; Wang, S; Amdur, R L; Smiley, R

2016-12-01

The appropriate dose of intrathecal morphine for post-cesarean analgesia is unclear. With the inclusion of routine non-steroidal anti-inflammatory drugs, the required dose of morphine may be significantly less than the 200-300μg common a decade ago. We performed a two-center, prospective, randomized, blinded trial comparing three doses of intrathecal morphine, combined with routine intravenous ketorolac, in 144 healthy women undergoing elective cesarean delivery. Patients received an intrathecal injection of hyperbaric bupivacaine 12mg, fentanyl 15μg and a randomized dose of 50, 100, or 150μg morphine in a volume of 2.2mL. Patients received intravenous ketorolac 30mg before leaving the operating room and 15mg intravenously every 6h for the duration of the study (24h). All received postoperative patient-controlled intravenous morphine. The primary endpoint was total intravenous morphine administered postoperatively over 24h, analyzed using mixed model regression. There were no differences between dose groups (or institutions) in intravenous morphine use over 24h. Visual analog scale scores for pain and nausea did not differ. Pruritus was greater in the 100 and 150μg groups than the 50μg group at 6h and 12h, but there was no difference between groups in nausea or pruritus treatments. Respiratory depression or significant sedation did not occur. The dose-response relationship of intrathecal morphine for multimodal post-cesarean analgesia suggests that 50μg produces analgesia similar to that produced by either 100μg or 150μg. Copyright © 2016 Elsevier Ltd. All rights reserved.

Evaluation of a mixed beam therapy for post-mastectomy breast cancer patients: bolus electron conformal therapy combined with intensity modulated photon radiotherapy and volumetric modulated photon arc therapy.

PubMed

Zhang, Rui; Heins, David; Sanders, Mary; Guo, Beibei; Hogstrom, Kenneth

2018-05-10

The purpose of this study was to assess the potential benefits and limitations of a mixed beam therapy, which combined bolus electron conformal therapy (BECT) with intensity modulated photon radiotherapy (IMRT) and volumetric modulated photon arc therapy (VMAT), for left-sided post-mastectomy breast cancer patients. Mixed beam treatment plans were produced for nine post-mastectomy radiotherapy (PMRT) patients previously treated at our clinic with VMAT alone. The mixed beam plans consisted of 40 Gy to the chest wall area using BECT, 40 Gy to the supraclavicular area using parallel opposed IMRT, and 10 Gy to the total planning target volume (PTV) by optimizing VMAT on top of the BECT+IMRT dose distribution. The treatment plans were created in a commercial treatment planning system (TPS), and all plans were evaluated based on PTV coverage, dose homogeneity index (DHI), conformity index (CI), dose to organs at risk (OARs), normal tissue complication probability (NTCP), and secondary cancer complication probability (SCCP). The standard VMAT alone planning technique was used as the reference for comparison. Both techniques produced clinically acceptable PMRT plans but with a few significant differences: VMAT showed significantly better CI (0.70 vs. 0.53, p < 0.001) and DHI (0.12 vs. 0.20, p < 0.001) over mixed beam therapy. For normal tissues, mixed beam therapy showed better OAR sparing and significantly reduced NTCP for cardiac mortality (0.23% vs. 0.80%, p = 0.01) and SCCP for contralateral breast (1.7% vs. 3.1% based on linear model, and 1.2% vs. 1.9% based on linear-exponential model, p < 0.001 in both cases), but showed significantly higher mean (50.8 Gy vs. 49.3 Gy, p < 0.001) and maximum skin doses (59.7 Gy vs. 53.3 Gy, p < 0.001) compared with VMAT. Patients with more tissue (minimum distance between the distal PTV surface and lung approximately > 0.5 cm and volume of tissue between the distal PTV surface and heart or lung approximately > 250 cm 3 ) between distal PTV surface and lung may benefit the most from mixed beam therapy. This work has demonstrated that mixed beam therapy (BECT+IMRT : VMAT = 4 : 1) produces clinically acceptable plans having reduced OAR doses and risks of side effects compared with VMAT. Even though VMAT alone produces more homogenous and conformal dose distributions, mixed beam therapy remains as a viable option for treating post-mastectomy patients, possibly leading to reduced normal tissue complications. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Safety pharmacology of acute MDMA administration in healthy subjects.

PubMed

Vizeli, Patrick; Liechti, Matthias E

2017-05-01

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is being investigated in MDMA-assisted psychotherapy. The present study characterized the safety pharmacology of single-dose administrations of MDMA (75 or 125 mg) using data from nine double-blind, placebo-controlled, crossover studies performed in the same laboratory in a total of 166 healthy subjects. The duration of the subjective effects was 4.2 ± 1.3 h (range: 1.4-8.2 h). The 125 mg dose of MDMA produced greater 'good drug effect' ratings than 75 mg. MDMA produced moderate and transient 'bad drug effect' ratings, which were greater in women than in men. MDMA increased systolic blood pressure to >160 mmHg, heart rate >100 beats/min, and body temperature >38°C in 33%, 29% and 19% of the subjects, respectively. These proportions of subjects with hypertension (>160 mmHg), tachycardia, and body temperature >38°C were all significantly greater after 125 mg MDMA compared with the 75 mg dose. Acute and subacute adverse effects of MDMA as assessed by the List of Complaints were dose-dependent and more frequent in females. MDMA did not affect liver or kidney function at EOS 29 ± 22 days after use. No serious adverse events occurred. In conclusion, MDMA produced predominantly acute positive subjective drug effects. Bad subjective drug effects and other adverse effects were significantly more common in women. MDMA administration was overall safe in physically and psychiatrically healthy subjects and in a medical setting. However, the risks of MDMA are likely higher in patients with cardiovascular disease and remain to be investigated in patients with psychiatric disorders.

Effect of vitamin C on male fertility in rats subjected to forced swimming stress.

PubMed

Vijayprasad, Sanghishetti; Bb, Ghongane; Bb, Nayak

2014-07-01

Stress is defined as a general body response to initially threatening external or internal demands, involving the mobilization of physiological and psychological resources to deal with them. Recently, oxidative stress has become the focus of interest as a potential cause of male infertility. Normally, equilibrium exists between reactive oxygen species (ROS) production and antioxidant scavenging activities in the male reproductive organs. The ascorbic acid is a known antioxidant present in the testis with the precise role of protecting the latter from the oxidative damage. It also contributes to the support of spermatogensis at least in part through its capacity to maintain antioxidant in an active state. Group1: Normal Control animal received Distilled water, Group 2: Positive control (Only Stress), Group 3: Normal rats received an intermediate dose of Vitamin C (20mg/kg/day), Group 4: Stress + Low dose Vitamin C (10mg/kg/day), Group 5: Stress+ Intermediate dose Vitamin C (20mg/kg/day), Group 6: High dose Vitamin C (30mg/kg/day). On 16(th) day effect of stress on body weight, Reproductive organ weight, sperm parameters, and hormonal assay was studied. In the present context, in stress group the sperm count, motility, testicular weight declined significantly. The intermediate dose and high dose of vitamin C showed significantly increased effect on the sperm count and motility. Various physiological changes produced force swimming indicates that swimming is an effective model for producing stress in albino rats. The results suggest that Vitamin C supplementation improves the stress induced reproductive infertility due to both their testosterone increase effect and their antioxidant effect.

Enhanced renal prostaglandin production in the dog. I. Effects on renal function.

PubMed

Tannenbaum, J; Splawinski, J A; Oates, J A; Nies, A S

1975-01-01

The changes in renal function produced by endogenous synthesis of prostaglandins by the kidney were evaluated by infusing sodium arachidonate, the prescursor of the prostaglandins, into one renal artery of the dog. These changes were compared with those produced by similar infusions on performed prostaglandin (PG) E2 and F2alpha.PGE2given at 0.01-0.3 mug/kg min--1 produced dose-related increases in urine flow, sodium and potassium excretion, free water clearance, and renal blood flow. The glomerular filtration rage increased only at the lowest dose and the calculated filtration fraction fell. Arachidonic acid at 1.0-30.0 mug/kg min--1 similarly produced dose-related increases in electrolyte excretion, but the increase in renal blood flow was much less than that produced by PGE2 and there were no changes in glomerular filtration rate, filtration fraction, or free water clearances. PGF2alpha had essentially no effects at infusion rates of 0.03-1.0 mug/kg min--1. All renal effects of arachidonic acid were inhibited by simultaneous infusions of an inhibitor of prostaglandin synthetase, 5, 8, 11,14-eicosatetraynoic acid (20:4). None of the effects produced by PGE2 were inhibited by 20:4. These results indicate that enhanced endogenous renal prostaglandin synthesis, which can be produced by arachidonate infusion, results in significant alterations of renal function. This finding strengthens the hypothesis that renal prostaglandins formed in vivo have physiological importance as regulators of renal function.

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

Sub-Lethal Dose of Shiga Toxin 2 from Enterohemorrhagic Escherichia coli Affects Balance and Cerebellar Cytoarchitecture

PubMed Central

Pinto, Alipio; Cangelosi, Adriana; Geoghegan, Patricia A.; Tironi-Farinati, Carla; Brener, Gabriela J.; Goldstein, Jorge

2016-01-01

Shiga toxin producing Escherichia coli may damage the central nervous system before or concomitantly to manifested hemolytic–uremic syndrome symptoms. The cerebellum is frequently damaged during this syndrome, however, the deleterious effects of Shiga toxin 2 has never been integrally reported by ultrastructural, physiological and behavioral means. The aim of this study was to determine the cerebellar compromise after intravenous administration of a sub-lethal dose of Shiga toxin 2 by measuring the cerebellar blood–brain barrier permeability, behavioral task of cerebellar functionality (inclined plane test), and ultrastructural analysis (transmission electron microscope). Intravenous administration of vehicle (control group), sub-lethal dose of 0.5 and 1 ηg of Stx2 per mouse were tested for behavioral and ultrastructural studies. A set of three independent experiments were performed for each study (n = 6). Blood–brain barrier resulted damaged and consequently its permeability was significantly increased. Lower scores obtained in the inclined plane task denoted poor cerebellar functionality in comparison to their controls. The most significant lower score was obtained after 5 days of 1 ηg of toxin administration. Transmission electron microscope micrographs from the Stx2-treated groups showed neurons with a progressive neurodegenerative condition in a dose dependent manner. As sub-lethal intravenous Shiga toxin 2 altered the blood brain barrier permeability in the cerebellum the toxin penetrated the cerebellar parenchyma and produced cell damaged with significant functional implications in the test balance. PMID:26904009

Cardioprotective effects of gallic acid in diabetes-induced myocardial dysfunction in rats

PubMed Central

Patel, Snehal S.; Goyal, Ramesh K.

2011-01-01

Background: Normalization of hyperglycemia, hyperlipidemia, and oxidative stress is an important objective in preventing diabetes-induced cardiac dysfunction. Objective: This study was undertaken to examine the effects of gallic acid in myocardial dysfunctions associated with type-1 diabetes. Materials and Methods: Diabetes was induced by single intravenous injection of streptozotocin (STZ, 50 mg/kg i.v.). Gallic acid was administered daily at three different doses (100, 50, and 25 mg/kg p.o.) for 8 weeks at the end of which blood samples were collected and analyzed for various biochemical parameters. Results: Injection of STZ produced significant loss of body weight (BW), polyphagia, polydypsia, hyperglycemia, hypoinsulinemia, hyperlipidemia, hypertension, bradycardia, and myocardial functional alterations. Treatment with gallic acid significantly lowered fasting glucose, the AUCglucose level in a dose-dependent manner; however, the insulin level was not increased significantly at same the dose and prevented loss of BW, polyphagia, and polydypsia in diabetic rats. It also prevented STZ-induced hyperlipidemia, hypertension, bradycardia, structural alterations in cardiac tissue such as increase in force of contraction, left ventricular weight to body weight ratio, collagen content, protein content, serum lactate dehydrogenase, and creatinine kinase levels in a dose-dependent manner. Further, treatment also produced reduction in lipid peroxidation and increase in antioxidant parameters in heart of diabetic rats. Conclusion: The results of this study suggest that gallic acid to be beneficial for the treatment of myocardial damage associated with type-1 diabetes. PMID:22224046

Dose Control System in the Optima XE Single Wafer High Energy Ion Implanter

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

Satoh, Shu; Yoon, Jongyoon; David, Jonathan

2011-01-07

Photoresist outgassing can significantly compromise accurate dosimetry of high energy implants. High energy implant even at a modest beam current produces high beam powers which create significantly worse outgassing than low and medium energy implants and the outgassing continues throughout the implant due to the low dose in typical high energy implant recipes. In the previous generation of high energy implanters, dose correction by monitoring of process chamber pressure during photoresist outgassing has been used. However, as applications diversify and requirements change, the need arises for a more versatile photoresist correction system to match the versatility of a single wafermore » high energy ion implanter. We have successfully developed a new dosimetry system for the Optima XE single wafer high energy ion implanter which does not require any form of compensation due to the implant conditions. This paper describes the principles and performance of this new dose system.« less

The use of nicotinamide in the prevention of type 1 diabetes.

PubMed

Elliott, R B; Pilcher, C C; Stewart, A; Fergusson, D; McGregor, M A

1993-11-30

Nicotinamide can protect the NOD mouse from diabetes if given early enough and in sufficient dose. The effect partly wanes with time. There is reduced islet inflammation. Similar protective effects can be demonstrated in quasi-experimental interventions in humans--both diabetes related and unrelated deemed at risk of developing diabetes by reason of having islet cell antibodies. Nicotinamide protects isolated islets in vitro from the toxicity of a number of agents, but only in doses that produce significant PARP inhibition, and increased intracellular levels of NAD. It is unlikely that the protective effect demonstrated in humans is due to significant PARP inhibition, as the levels of nicotinamide achieved with the doses used are too low. Other effects of the vitamin are more likely, e.g., increase in NAD pool size by de novo synthesis, or inhibition of free radical generation. The drug appears to be safe in the doses employed in humans.

Benefits of High-dose Steroid + Hespander + Mannitol Administration in the Treatment of Bell's Palsy.

PubMed

Furukawa, Takatoshi; Abe, Yasuhiro; Ito, Tsukasa; Kubota, Toshinori; Kakehata, Seiji

2017-02-01

Large-scale investigations have not been recently conducted on the efficacy of high-dose steroid administration of prednisolone (PSL) for Bell's palsy. We compared treatment results between normal-dose steroid (PSL 60 mg/d) and high-dose steroid (PSL 200 mg/d) + Hespander + Mannitol administration. We also investigated the recovery rate for antiviral agents. Retrospective case review. Tertiary referral center. A total of 675 patients with Bell's palsy who had grade V and grade VI on the House-Brackmann (HB) scale were treated in our department between 1995 and 2014. These patients could be divided into a normal-dose group and high-dose group. We separately assessed treatment outcomes for HB grade V patients and HB grade VI patients. Logistic regression analysis was also performed to investigate factors that can impact treatment outcomes, i.e., sex, age, days to start of treatment, PSL dosage, and antiviral drug administration. Recovery rates were significantly better in the high-dose steroid + Hespander + Mannitol group in comparison with the normal-dose steroid group for HB grade V (100% versus 77.7%) and HB grade VI (92.5% versus 68.2%). Additional effects of antiviral agents were only shown in the normal-dose group. Significant factors for treatment outcomes were PSL 200 mg/d administration and early initiation of treatment. Insignificant factors were sex, age, and the antiviral agent. We showed the high-dose steroid + Hespander + Mannitol administration produced significantly better outcomes than normal-dose steroid administration in the treatment of patients with Bell's palsy.

Safety of Oral Dronabinol During Opioid Withdrawal in Humans

PubMed Central

Jicha, Crystal J.; Lofwall, Michelle R.; Nuzzo, Paul A.; Babalonis, Shanna; Elayi, Samy Claude; Walsh, Sharon L.

2015-01-01

Background Opioid dependence remains a significant public health problem worldwide with only three FDA-approved treatments, all targeting the mu-opioid receptor. Dronabinol, a cannabinoid (CB) 1 receptor agonist, is currently under investigation as a novel opioid withdrawal treatment. This study reports on safety outcomes of dronabinol among adults in opioid withdrawal. Methods Twelve adults physically dependent on short-acting opioids participated in this 5-week within-subject, randomized, double blind, placebo-controlled inpatient study. Volunteers were maintained on oral oxycodone 30mg qid. Double-blind placebo substitutions occurred for 21 hours before each of 7 experimental sessions in order to produce opioid withdrawal. A single oral test dose was administered each session (placebo, oxycodone 30 and 60mg, dronabinol 5, 10, 20, and 30mg [decreased from 40mg]). Heart rate, blood pressure, respiratory outcomes and pupil diameter were assessed repeatedly. Results Dronabinol 40mg produced sustained sinus tachycardia accompanied by anxiety and panic necessitating dose reduction to 30mg. Sinus tachycardia and anxiety also occurred in one volunteer after dronabinol 20mg. Compared to placebo, dronabinol 20 and 30mg produced significant increases in heart rate beginning 1 hour after drug administration that lasted approximately two hours (p<0.05). Dronabinol 5 and 10mg produced placebo-like effects. Oxycodone produced prototypic mu-opioid agonist effects (e.g., miosis). Conclusion Dronabinol 20mg and higher increased heart rate among healthy adults at rest who were in a state of opioid withdrawal, raising concern about its safety. These results have important implications for future dosing strategies and may limit the utility of dronabinol as a treatment for opioid withdrawal. PMID:26483357

Effects of medetomidine on serum glucose in cattle calves.

PubMed

Tariq, Muhammad; Kalhoro, Amir Bukhsh; Sarwar, Mian Saeed; Khan, Hamayun; Ahmad, Shakoor; Hassan, Sayed Mubashir; Zahoor, Arshad

2016-05-01

An experimental study was carried out to compare physiological effects (serum glucose level) of medetomidine in Red Sindhi cattle calves at three different doses i.e. 8, 10 and 12µg/kg body weight intravenously. Medetomidine produced a dose dependent significant (P<0.01) increase in serum glucose level with a maximum increase observed at 30 minutes with 8µg/kg, 10μg/kg and 12μg/kg body weight respectively. Start of sedation, degree of sedation and total duration of sedation were all dose dependent and the values obtained were significantly (P<0.01) different from each other. It was observed that the sedation was rapid, deep and longer with the higher doses of medetomidine i.e. 12μg/kg. The results of the present study shows that medetomidine is a very effective and safest drug use as sedative for calves which in lower doses (8μg/kg) can be used as a pre-anesthetic and for restraining of the animal, while higher calculated doses (10μg/kg, 12μg/kg) can be used to execute the minor surgical procedures.

Radiation effects on beta 10.6 of pure and europium doped KCl

NASA Technical Reports Server (NTRS)

Grimes, H. H.; Maisel, J. E.; Hartford, R. H.

1975-01-01

Changes in the optical absorption coefficient as a result of X-ray and electron bombardment of pure KCl (monocrystalline and polycrystalline), and divalent europium doped polycrystalline KCl were determined. The optical absorption coefficients were measured by a constant heat flow calorimetric method. Both 300 KV X-irradiation and 2 MeV electron irradiation produced significant increases in beta 10.6, measured at room temperature. The X-irradiation of pure moncrystalline KCl increased beta 10.6 by 0.005/cm for a 113 MR dose. For an equivalent dose, 2 MeV electrons were found less efficient in changing beta 10.6. However, electron irradiation of pure and Eu-doped polycrystalline KCl produced marked increases in adsorption. Beta increased to over 0.25/cm in Eu-doped material for a 30 x 10 to the 14th power electrons/sq cm dose, a factor of 20 increase over unirradiated material. Moreover, bleaching the electron irradiated doped KCl with 649 m light produced and additional factor of 1.5 increase. These findings will be discussed in light of known defect-center properties in KCl.

nNOS inhibitors attenuate methamphetamine-induced dopaminergic neurotoxicity but not hyperthermia in mice.

PubMed

Itzhak, Y; Martin, J L; Ail, S F

2000-09-11

Methamphetamine (METH)-induced dopaminergic neurotoxicity is associated with hyperthermia. We investigated the effect of several neuronal nitric oxide synthase (nNOS) inhibitors on METH-induced hyperthermia and striatal dopaminergic neurotoxicity. Administration of METH (5 mg/kg; q. 3 h x 3) to Swiss Webster mice produced marked hyperthermia and 50-60% depletion of striatal dopaminergic markers 72 h after METH administration. Pretreatment with the nNOS inhibitors S-methylthiocitrulline (SMTC; 10 mg/kg) or 3-bromo-7-nitroindazole (3-Br-7-NI; 20 mg/kg) before each METH injection did not affect the persistent hyperthermia produced by METH, but afforded protection against the depletion of dopaminergic markers. A low dose (25 mg/kg) of the nNOS inhibitor 7-nitroindazole (7-NI) did not affect METH-induced hyperthermia, but a high dose (50 mg/kg) produced significant hypothermia. These findings indicate that low dose of selective nNOS inhibitors protect against METH-induced neurotoxicity with no effect on body temperature and support the hypothesis that nitric oxide (NO) and peroxynitrite have a major role in METH-induced dopaminergic neurotoxicity.

Optimisation techniques in vaginal cuff brachytherapy.

PubMed

Tuncel, N; Garipagaoglu, M; Kizildag, A U; Andic, F; Toy, A

2009-11-01

The aim of this study was to explore whether an in-house dosimetry protocol and optimisation method are able to produce a homogeneous dose distribution in the target volume, and how often optimisation is required in vaginal cuff brachytherapy. Treatment planning was carried out for 109 fractions in 33 patients who underwent high dose rate iridium-192 (Ir(192)) brachytherapy using Fletcher ovoids. Dose prescription and normalisation were performed to catheter-oriented lateral dose points (dps) within a range of 90-110% of the prescribed dose. The in-house vaginal apex point (Vk), alternative vaginal apex point (Vk'), International Commission on Radiation Units and Measurements (ICRU) rectal point (Rg) and bladder point (Bl) doses were calculated. Time-position optimisations were made considering dps, Vk and Rg doses. Keeping the Vk dose higher than 95% and the Rg dose less than 85% of the prescribed dose was intended. Target dose homogeneity, optimisation frequency and the relationship between prescribed dose, Vk, Vk', Rg and ovoid diameter were investigated. The mean target dose was 99+/-7.4% of the prescription dose. Optimisation was required in 92 out of 109 (83%) fractions. Ovoid diameter had a significant effect on Rg (p = 0.002), Vk (p = 0.018), Vk' (p = 0.034), minimum dps (p = 0.021) and maximum dps (p<0.001). Rg, Vk and Vk' doses with 2.5 cm diameter ovoids were significantly higher than with 2 cm and 1.5 cm ovoids. Catheter-oriented dose point normalisation provided a homogeneous dose distribution with a 99+/-7.4% mean dose within the target volume, requiring time-position optimisation.

Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial

PubMed Central

Griffiths, Roland R; Johnson, Matthew W; Carducci, Michael A; Umbricht, Annie; Richards, William A; Richards, Brian D; Cosimano, Mary P; Klinedinst, Margaret A

2016-01-01

Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes. Trial Registration ClinicalTrials.gov identifier: NCT00465595 PMID:27909165

Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial.

PubMed

Griffiths, Roland R; Johnson, Matthew W; Carducci, Michael A; Umbricht, Annie; Richards, William A; Richards, Brian D; Cosimano, Mary P; Klinedinst, Margaret A

2016-12-01

Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes. ClinicalTrials.gov identifier: NCT00465595. © The Author(s) 2016.

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.

Once-daily atenolol in hypertensive Zimbabwean blacks. A double-blind trial using two different doses.

PubMed

Abson, C P; Levy, L M; Eyherabide, G

1981-07-11

A double-blind within-patient study was carried out on Zimbabwean Blacks to investigate the effect of once-daily atenolol on hypertension in doses of 100 and 200 mg/d. Atenolol 200 mg produced significant changes in diastolic pressure readings taken in the supine and standing positions and after exercise; with atenolol 100 mg modest but non-significant changes occurred. These findings are less impressive than those previously reported in White subjects. We conclude that beta-adrenoceptor blocking agents should not be used as drugs of first choice for hypertension in our Black population.

Assessment of glycemic potential ofMusa paradisiaca stem juice.

PubMed

Singh, Santosh Kumar; Kesari, Achyut Narayan; Rai, Prashant Kumar; Watal, Geeta

2007-09-01

The present study reveals the effect of Musa paradisiaca stem juice on blood glucose level (BGL) of normal & diabetic rats. The dose of 500 mg/kg bodyweight produces a significant rise of 28.3% in blood glucose level after 6h of oral administration in normal rats. Whereas, in sub diabetic rats the same dose produces a rise of 16.4% in blood glucose levels within 1h during glucose tolerance test (GTT) and a rise of 16% after 4 h in fasting blood glucose levels of severe diabetic cases. These results were unexpected and important to report as other species of Musa like Musa sapientum has been reported for its hypoglycemic effect.

Gamma and neutrino radiation dose from gamma ray bursts and nearby supernovae.

PubMed

Karam, P Andrew

2002-04-01

Supernovae and gamma ray bursts are exceptionally powerful cosmic events that occur randomly in space and time in our galaxy. Their potential to produce very high radiation levels has been discussed, along with speculation that they may have caused mass extinctions noted from the fossil record. It is far more likely that they have produced radiation levels that, while not lethal, are genetically significant, and these events may have influenced the course of evolution and the manner in which organisms respond to radiation insult. Finally, intense gamma radiation exposure from these events may influence the ability of living organisms to travel through space. Calculations presented in this paper suggest that supernovae and gamma ray bursts are likely to produce sea-level radiation exposures of about I Gy with a mean interval of about five million years and sea-level radiation exposures of about 0.2 Gy every million years. Comets and meteors traveling through space would receive doses in excess of 10 Gy at a depth of 0.02 m at mean intervals of 4 and 156 million years, respectively. This may place some constraints on the ability of life to travel through space either between planets or between planetary systems. Calculations of radiation dose from neutrino radiation are presented and indicate that this is not a significant source of radiation exposure for even extremely close events for the expected neutrino spectrum from these events.

Influence of dose rate on the induction of simple and complex chromosome exchanges by gamma rays.

PubMed

Loucas, Bradford D; Eberle, Richard; Bailey, Susan M; Cornforth, Michael N

2004-10-01

Single-color painting of whole chromosomes, or protocols in which only a few chromosomes are distinctively painted, will always fail to detect a proportion of complex exchanges because they frequently produce pseudosimple painting patterns that are indistinguishable from those produced by bona fide simple exchanges. When 24-color multi-fluor FISH (mFISH) was employed for the purpose of distinguishing (truly) simple from pseudosimple exchanges, it was confirmed that the acute low-LET radiation dose-response relationship for simple exchanges lacked significant upward curvature. This result has been interpreted to indicate that the formation of simple exchanges requires only one chromosome locus be damaged (e.g. broken) by radiation to initiate an exchange-not two, as classical cytogenetic theory maintains. Because a one-lesion mechanism implies single-track action, it follows that the production of simple exchanges should not be influenced by changes in dose rate. To examine this prediction, we irradiated noncycling primary human fibroblasts with graded doses of (137)Cs gamma rays at an acute dose rate of 1.10 Gy/min and compared, using mFISH, the yield of simple exchanges to that observed after exposure to the same radiation delivered at a chronic dose rate of 0.08 cGy/min. The shape of the dose response was found to be quasi-linear for both dose rates, but, counter to providing support for a one-lesion mechanism, the yield of simple aberrations was greatly reduced by protracted exposure. Although chronic doses were delivered at rates low enough to produce damage exclusively by single-track action, this did not altogether eliminate the formation of complex aberrations, an analysis of which leads to the conclusion that a single track of low-LET radiation is capable of inducing complex exchanges requiring up to four proximate breaks for their formation. For acute exposures, the ratio of simple reciprocal translocations to simple dicentrics was near unity.

A 3-lever discrimination procedure reveals differences in the subjective effects of low and high doses of MDMA.

PubMed

Harper, David N; Langen, Anna-Lena; Schenk, Susan

2014-01-01

Drug discrimination studies have suggested that the subjective effects of low doses of (±)3,4-methylenedioxymethamphetamine (MDMA) are readily differentiated from those of d-amphetamine (AMPH) and that the discriminative stimulus properties are mediated by serotonergic and dopaminergic mechanisms, respectively. Previous studies, however, have primarily examined responses to doses that do not produce substantial increases in extracellular dopamine. The present study determined whether doses of MDMA that produce increases in synaptic dopamine would also produce subjective effects that were more like AMPH and were sensitive to pharmacological manipulation of D1-like receptors. A three-lever drug discrimination paradigm was used. Rats were trained to respond on different levers following saline, AMPH (0.5mg/kg, IP) or MDMA (1.5mg/kg, IP) injections. Generalization curves were generated for a range of different doses of both drugs and the effect of the D1-like antagonist, SCH23390 on the discriminative stimulus effects of different doses of MDMA was determined. Rats accurately discriminated MDMA, AMPH and saline. Low doses of MDMA produced almost exclusive responding on the MDMA lever but at doses of 3.0mg/kg MDMA or higher, responding shifted to the AMPH lever. The AMPH response produced by higher doses of MDMA was attenuated by pretreatment with SCH23390. The data suggest that low doses and higher doses of MDMA produce distinct discriminative stimuli. The shift to AMPH-like responding following administration of higher doses of MDMA, and the decrease in this response following administration of SCH23390 suggests a dopaminergic component to the subjective experience of MDMA at higher doses. Copyright © 2013 Elsevier Inc. All rights reserved.

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 somatostatin on meal-induced gastric secretion in duodenal ulcer patients.

PubMed

Konturek, S J; Swierczek, J; Kwiecień, N; Mikoś, E; Oleksy, J; Wierzbicki, Z

1977-11-01

The effect of somatostatin, a growth hormone releasing-inhibiting hormone (GH-RIH) on basal and meal-, pentagastrin-, or histamine-stimulated gastric acid and pepsin secretion was studied in six duodenal ulcer patients. Intravenous GH-RIH infused in graded doses ranging from 0.62 to 5.0 microgram/kg/hr produced a dose-related inhibition of pentagastrin-induced acid secretion reaching about 15% of control level at the dose of 5.0 microgram/kg/hr. Acid inhibition was paralleled by a decrease in the pepsin output and accompanied by a dose-dependent reduction in serum growth hormone and insulin levels measured by radioimmunoassay. GH-RIH used in a single dose of 2.5 microgram/kg/hr produced about 85% inhibition of acid secretion induced by a meal (measured by intragastric titration) accompanied by a significant decrease in serum gastrin and insulin levels. The effect of GH-RIH on histamine-stimulated secretion was very modest and observed only after stopping the GH-RIH infusion. Thus GH-RIH suppressed acid and pepsin secretion induced by pentagastrin and a meal, and this effect was accompanied by a suppression of serum growth hormone and gastrin levels which may contribute to the inhibition of gastric secretion observed.

Early effects comparison of X-rays delivered at high-dose-rate pulses by a plasma focus device and at low dose rate on human tumour cells.

PubMed

Virelli, A; Zironi, I; Pasi, F; Ceccolini, E; Nano, R; Facoetti, A; Gavoçi, E; Fiore, M R; Rocchi, F; Mostacci, D; Cucchi, G; Castellani, G; Sumini, M; Orecchia, R

2015-09-01

A comparative study has been performed on the effects of high-dose-rate (DR) X-ray beams produced by a plasma focus device (PFMA-3), to exploit its potential medical applications (e.g. radiotherapy), and low-DR X-ray beams produced by a conventional source (XRT). Experiments have been performed at 0.5 and 2 Gy doses on a human glioblastoma cell line (T98G). Cell proliferation rate and potassium outward currents (IK) have been investigated by time lapse imaging and patch clamp recordings. The results showed that PFMA-3 irradiation has a greater capability to reduce the proliferation rate activity with respect to XRT, while it does not affect IK of T98G cells at any of the dose levels tested. XRT irradiation significantly reduces the mean IK amplitude of T98G cells only at 0.5 Gy. This work confirms that the DR, and therefore the source of radiation, is crucial for the planning and optimisation of radiotherapy applications. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Improved normal tissue sparing in head and neck radiotherapy using biological cost function based-IMRT.

PubMed

Anderson, N; Lawford, C; Khoo, V; Rolfo, M; Joon, D L; Wada, M

2011-12-01

Intensity-modulated radiotherapy (IMRT) has reduced the impact of acute and late toxicities associated with head and neck radiotherapy. Treatment planning system (TPS) advances in biological cost function based optimization (BBO) and improved segmentation techniques have increased organ at risk (OAR) sparing compared to conventional dose-based optimization (DBO). A planning study was undertaken to compare OAR avoidance in DBO and BBO treatment planning. Simultaneous integrated boost treatment plans were produced for 10 head and neck patients using both planning systems. Plans were compared for tar get coverage and OAR avoidance. Comparisons were made using the BBO TPS Monte Carlo dose engine to eliminate differences due to inherent algorithms. Target coverage (V95%) was maintained for both solutions. BBO produced lower OAR doses, with statistically significant improvement to left (12.3%, p = 0.005) and right parotid mean dose (16.9%, p = 0.004), larynx V50_Gy (71.0%, p = 0.005), spinal cord (21.9%, p < 0.001) and brain stem dose maximums (31.5%, p = 0.002). This study observed improved OAR avoidance with BBO planning. Further investigations will be undertaken to review any clinical benefit of this improved planned dosimetry.

Improved Normal Tissue Sparing in Head and Neck Radiotherapy Using Biological Cost Function Based-IMRT

PubMed Central

Anderson, N.; Lawford, C.; Khoo, V.; Rolfo, M.; Joon, D. Lim; Wada, M.

2011-01-01

Intensity-modulated radiotherapy (IMRT) has reduced the impact of acute and late toxicities associated with head and neck radiotherapy. Treatment planning system (TPS) advances in biological cost function based optimization (BBO) and improved segmentation techniques have increased organ at risk (OAR) sparing compared to conventional dose-based optimization (DBO). A planning study was undertaken to compare OAR avoidance in DBO and BBO treatment planning. Simultaneous integrated boost treatment plans were produced for 10 head and neck patients using both planning systems. Plans were compared for tar get coverage and OAR avoidance. Comparisons were made using the BBO TPS Monte Carlo dose engine to eliminate differences due to inherent algorithms. Target coverage (V95%) was maintained for both solutions. BBO produced lower OAR doses, with statistically significant improvement to left (12.3%, p = 0.005) and right parotid mean dose (16.9%, p = 0.004), larynx V50 Gy (71.0%, p = 0.005), spinal cord (21.9%, p < 0.001) and brain stem dose maximums (31.5%, p = 0.002). This study observed improved OAR avoidance with BBO planning. Further investigations will be undertaken to review any clinical benefit of this improved planned dosimetry. PMID:22066597

Substance P contributes to rapidly adapting receptor responses to pulmonary venous congestion in rabbits.

PubMed

Bonham, A C; Kott, K S; Ravi, K; Kappagoda, C T; Joad, J P

1996-05-15

1. This study tested the hypothesis that substance P stimulates rapidly adapting receptors (RARs), contributes to the increase in RAR activity produced by mild pulmonary congestion, and evokes an augmented response from RARs when combined with near-threshold levels of pulmonary congestion. 2. RAR activity, peak tracheal pressure, arterial blood pressure and left atrial pressure were measured in paralysed, anaesthetized and ventilated rabbits. Substance P was given i.v. in one-half log incremental doses to a maximum of 3 micrograms kg-1. Mild pulmonary congestion was produced by inflating a balloon in the left atrium to increase left atrial pressure by 5 mmHg. Near-threshold levels of pulmonary congestion were produced by increasing left atrial pressure by 2 mmHg. 3. Substance P produced dose-dependent increases in RAR activity. The highest dose given increased the activity from 1.3 +/- 0.5 to 11.0 +/- 3.1 impulses bin-1. Increases in left atrial pressure of 5 mmHg increased RAR activity from 3.8 +/- 1.4 to 14.7 +/- 3.9 impulses bin-1. Blockade of NK1 receptors with CP 96345 significantly attenuated RAR responses to substance P and to mild pulmonary congestion. 4. Doses of substance P, which alone had no effect, stimulated the RARs when delivered during near-threshold levels of pulmonary congestion. 5. The findings suggest that substance P augments the stimulatory effect of mild pulmonary congestion on RAR activity, most probably by enhancing hydraulically induced microvascular leak.

Evaluation of the RBC Pig-a and PIGRET assays using single doses of hydroxyurea and melphalan in rats.

PubMed

Adachi, Hideki; Uematsu, Yasuaki; Yamada, Toru

2016-11-15

To evaluate the suitability of the rat Pig-a assay on reticulocytes (PIGRET assay) as a short-term test, red blood cell (RBC) Pig-a and PIGRET assays after single doses with hydroxyurea (HU) and melphalan (L-PAM) were conducted and the results of both assays were compared. HU was administered once orally to male SD rats at 250, 500 and 1000mg/kg, and both assays were conducted using peripheral blood withdrawn from the jugular vein at 1, 2 and 4 weeks after dosing. L-PAM was administered at 1.25, 2.5 and 5mg/kg in the same manner. L-PAM produced significant dose-dependent increases in mutant frequencies in the PIGRET assay after single oral doses, but did not produce dose-dependent increases in mutant frequencies in the RBC Pig-a assay. These results suggest that the PIGRET assay is more sensitive for the evaluation of the mutagenic potential of L-PAM than the RBC Pig-a assay. In contrast, HU, a clastogenic but not DNA-reactive compound, gave negative results in both assays. The results with these 2 chemicals indicate that the single-dose PIGRET assay in rats has the potential to properly detect DNA-reactive compounds that directly cause DNA damage in a short-term assay. Copyright © 2016 Elsevier B.V. All rights reserved.

Direct comparison of the acute subjective, emotional, autonomic, and endocrine effects of MDMA, methylphenidate, and modafinil in healthy subjects.

PubMed

Dolder, Patrick C; Müller, Felix; Schmid, Yasmin; Borgwardt, Stefan J; Liechti, Matthias E

2018-02-01

3,4-Methylenedioxymethamphetamine (MDMA) is used recreationally and investigated as an adjunct to psychotherapy. Methylphenidate and modafinil are psychostimulants that are used to treat attention-deficit/hyperactivity disorder and narcolepsy, respectively, but they are also misused as cognitive enhancers. Little is known about differences in the acute effects of equally cardiostimulant doses of these stimulant-type substances compared directly within the same subjects. We investigated the acute autonomic, subjective, endocrine, and emotional effects of single doses of MDMA (125 mg), methylphenidate (60 mg), modafinil (600 mg), and placebo in a double-blind, cross-over study in 24 healthy participants. Acute drug effects were tested using psychometric scales, the Facial Emotion Recognition Task (FERT), and the Sexual Arousal and Desire Inventory (SADI). All active drugs produced comparable hemodynamic and adverse effects. MDMA produced greater increases in pupil dilation, subjective good drug effects, drug liking, happiness, trust, well-being, and alterations in consciousness than methylphenidate or modafinil. Only MDMA reduced subjective anxiety and impaired fear recognition and led to misclassifications of emotions as happy on the FERT. On the SADI, only MDMA produced sexual arousal-like effects. Only MDMA produced marked increases in cortisol, prolactin, and oxytocin. In contrast to MDMA, methylphenidate increased subjective anxiety, and methylphenidate and modafinil increased misclassifications of emotions as angry on the FERT. Modafinil had no significant subjective drug effects but significant sympathomimetic and adverse effects. MDMA induced subjective, emotional, sexual, and endocrine effects that were clearly distinct from those of methylphenidate and modafinil at the doses used.

In vivo tumor targeting of gold nanoparticles: effect of particle type and dosing strategy.

PubMed

Puvanakrishnan, Priyaveena; Park, Jaesook; Chatterjee, Deyali; Krishnan, Sunil; Tunnell, James W

2012-01-01

Gold nanoparticles (GNPs) have gained significant interest as nanovectors for combined imaging and photothermal therapy of tumors. Delivered systemically, GNPs preferentially accumulate at the tumor site via the enhanced permeability and retention effect, and when irradiated with near infrared light, produce sufficient heat to treat tumor tissue. The efficacy of this process strongly depends on the targeting ability of the GNPs, which is a function of the particle's geometric properties (eg, size) and dosing strategy (eg, number and amount of injections). The purpose of this study was to investigate the effect of GNP type and dosing strategy on in vivo tumor targeting. Specifically, we investigated the in vivo tumor-targeting efficiency of pegylated gold nanoshells (GNSs) and gold nanorods (GNRs) for single and multiple dosing. We used Swiss nu/nu mice with a subcutaneous tumor xenograft model that received intravenous administration for a single and multiple doses of GNS and GNR. We performed neutron activation analysis to quantify the gold present in the tumor and liver. We performed histology to determine if there was acute toxicity as a result of multiple dosing. Neutron activation analysis results showed that the smaller GNRs accumulated in higher concentrations in the tumor compared to the larger GNSs. We observed a significant increase in GNS and GNR accumulation in the liver for higher doses. However, multiple doses increased targeting efficiency with minimal effect beyond three doses of GNPs. These results suggest a significant effect of particle type and multiple doses on increasing particle accumulation and on tumor targeting ability.

Antidiarrhoeal activity of leaf methanolic extract of Rauwolfia serpentina

PubMed Central

Ezeigbo, II; Ezeja, MI; Madubuike, KG; Ifenkwe, DC; Ukweni, IA; Udeh, NE; Akomas, SC

2012-01-01

Objective To evaluate the antidiarrhoeal property of methanol extract of the leaves of Rauwolfia serpentina (R. serpentina) in experimental diarrhoea induced by castor oil in mice. Methods Doses of 100, 200 and 400 mg/kg R. serpentina leaf methanol extracts were administered to castor oil induced diarrhoea mice to determine its antidiarrhoeal activity. Results All doses of the extract and the reference drug atropine sulphate (3 mg/kg, i.p.) produced a dose-dependent reduction in intestinal weight and fluid volume. The extracts also significantly reduced the intestinal transit in charcoal meal test when compared to diphenoxylate Hcl (5 mg/kg, p.o.). Conclusions The results show that the extract of R. serpentina leaves has a significant antidiarrhoeal activity and supports its traditional uses in herbal medicine. PMID:23569944

Opioid withdrawal suppression efficacy of oral dronabinol in opioid dependent humans

PubMed Central

Lofwall, Michelle R.; Babalonis, Shanna; Nuzzo, Paul A.; Elayi, Samy Claude; Walsh, Sharon L.

2016-01-01

Background The cannabinoid (CB) system is a rational novel target for treating opioid dependence, a significant public health problem around the world. This proof-of-concept study examined the potential efficacy of a CB1 receptor partial agonist, dronabinol, in relieving signs and symptoms of opioid withdrawal. Methods Twelve opioid dependent adults participated in this 5-week, inpatient, double-blind, randomized, placebo-controlled study. Volunteers were maintained on double-blind oxycodone (30mg oral, four times/day) and participated in a training session followed by 7 experimental sessions, each testing a single oral test dose (placebo, oxycodone 30 and 60mg, dronabinol 5, 10, 20, and 30mg [decreased from 40mg]). Placebo was substituted for oxycodone maintenance doses for 21 hours before each session in order to produce measurable opioid withdrawal. Outcomes included observer- and participant-ratings of opioid agonist, opioid withdrawal and psychomotor/cognitive performance. Results Oxycodone produced prototypic opioid agonist effects (i.e., suppressing withdrawal and increasing subjective effects indicative of abuse liability). Dronabinol 5 and 10mg produced effects most similar to placebo, while the 20 and 30mg doses produced modest signals of withdrawal suppression that were accompanied by dose-related increases in high, sedation, bad effects, feelings of heart racing, and tachycardia. Dronabinol was not liked more than placebo, showed some impairment in cognitive performance, and was identified as marijuana with increasing dose. Conclusion CB1 receptor activation is a reasonable strategy to pursue for the treatment of opioid withdrawal; however, dronabinol is not a likely candidate given its modest withdrawal suppression effects of limited duration and previously reported tachycardia during opioid withdrawal. PMID:27234658

Image quality and radiation dose on digital chest imaging: comparison of amorphous silicon and amorphous selenium flat-panel systems.

PubMed

Bacher, Klaus; Smeets, Peter; Vereecken, Ludo; De Hauwere, An; Duyck, Philippe; De Man, Robert; Verstraete, Koenraad; Thierens, Hubert

2006-09-01

The aim of this study was to compare the image quality and radiation dose in chest imaging using an amorphous silicon flat-panel detector system and an amorphous selenium flat-panel detector system. In addition, the low-contrast performance of both systems with standard and low radiation doses was compared. In two groups of 100 patients each, digital chest radiographs were acquired with either an amorphous silicon or an amorphous selenium flat-panel system. The effective dose of the examination was measured using thermoluminescent dosimeters placed in an anthropomorphic Rando phantom. The image quality of the digital chest radiographs was assessed by five experienced radiologists using the European Guidelines on Quality Criteria for Diagnostic Radiographic Images. In addition, a contrast-detail phantom study was set up to assess the low-contrast performance of both systems at different radiation dose levels. Differences between the two groups were tested for significance using the two-tailed Mann-Whitney test. The amorphous silicon flat-panel system allowed an important and significant reduction in effective dose in comparison with the amorphous selenium flat-panel system (p < 0.0001) for both the posteroanterior and lateral views. In addition, clinical image quality analysis showed that the dose reduction was not detrimental to image quality. Compared with the amorphous selenium flat-panel detector system, the amorphous silicon flat-panel detector system performed significantly better in the low-contrast phantom study, with phantom entrance dose values of up to 135 muGy. Chest radiographs can be acquired with a significantly lower patient radiation dose using an amorphous silicon flat-panel system than using an amorphous selenium flat-panel system, thereby producing images that are equal or even superior in quality to those of the amorphous selenium flat-panel detector system.

Topical combinations aimed at treating microvascular dysfunction reduce allodynia in rat models of CRPS-I and neuropathic pain.

PubMed

Ragavendran, J Vaigunda; Laferrière, André; Xiao, Wen Hua; Bennett, Gary J; Padi, Satyanarayana S V; Zhang, Ji; Coderre, Terence J

2013-01-01

Growing evidence indicates that various chronic pain syndromes exhibit tissue abnormalities caused by microvasculature dysfunction in the blood vessels of skin, muscle, or nerve. We tested whether topical combinations aimed at improving microvascular function would relieve allodynia in animal models of complex regional pain syndrome type I (CRPS-I) and neuropathic pain. We hypothesized that topical administration of either α(2)-adrenergic (α(2)A) receptor agonists or nitric oxide (NO) donors combined with either phosphodiesterase (PDE) or phosphatidic acid (PA) inhibitors would effectively reduce allodynia in these animal models of chronic pain. Single topical agents produced significant dose-dependent antiallodynic effects in rats with chronic postischemia pain, and the antiallodynic dose-response curves of PDE and PA inhibitors were shifted 2.5- to 10-fold leftward when combined with nonanalgesic doses of α(2)A receptor agonists or NO donors. Topical combinations also produced significant antiallodynic effects in rats with sciatic nerve injury, painful diabetic neuropathy, and chemotherapy-induced painful neuropathy. These effects were shown to be produced by a local action, lasted up to 6 hours after acute treatment, and did not produce tolerance over 15 days of chronic daily dosing. The present results support the hypothesis that allodynia in animal models of CRPS-I and neuropathic pain is effectively relieved by topical combinations of α(2)A or NO donors with PDE or PA inhibitors. This suggests that topical treatments aimed at improving microvascular function may reduce allodynia in patients with CRPS-I and neuropathic pain. This article presents the synergistic antiallodynic effects of combinations of α(2)A or NO donors with PDE or PA inhibitors in animal models of CRPS-I and neuropathic pain. The data suggest that effective clinical treatment of chronic neuropathic pain may be achieved by therapies that alleviate microvascular dysfunction in affected areas. Copyright © 2013 American Pain Society. Published by Elsevier Inc. All rights reserved.

Anti-inflammatory activity and chemical composition of the essential oils from Senecio flammeus

PubMed Central

Xiao, Kai-Jun; Wang, Wen-Xia; Dai, Jia-Li; Zhu, Liang

2014-01-01

Many species from Senecio genus have been used in traditional medicine, and their pharmacological activities have been demonstrated. This study investigated the chemical composition and anti-inflammatory activities of essential oils from Senecio flammeus. A total of 48 components representing 98.41 % of the total oils were identified. The main compounds in the oils were α-farnesene (11.26 %), caryophyllene (8.69 %), n-hexadecanoic acid (7.23 %), and α-pinene (6.36 %). The anti-inflammatory activity of the essential oils was evaluated in rodents (10–90 mg/kg bw) in classical models of inflammation [carrageenan-induced paw edema, 12-O-tetradecanoyl-phorbol-13-acetate (TPA)-induced ear edema, and cotton pellet-induced granuloma]. The essential oils at doses of 10, 30, and 90 mg/kg bw significantly reduced carrageenan-induced paw edema by 17.42 % (P < 0.05), 52.90 % (P < 0.05), and 66.45 % (P < 0.05) 4 h after carrageenan injection, respectively, and significantly reduced myeloperoxidase activity (P < 0.05). The essential oils (10, 30, and 90 mg/kg) also produced a significant dose-dependent response to reduce TPA-induced ear edema by 20.27 % (P < 0.05), 33.06 % (P < 0.05), and 53.90 % (P < 0.05), respectively. The essential oils produced significant dose-response anti-inflammatory activity against cotton pellet-induced granuloma that peaked at the highest dose of 90 mg/kg (49.08 % wet weight and 47.29 % dry weight). Results demonstrate that the essential oils of S. flammeus were effective in the treatment of both acute and chronic inflammatory conditions, thereby supporting the traditional use of this herb. PMID:26417301

Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis

PubMed Central

Haney, Margaret; Malcolm, Robert J; Babalonis, Shanna; Nuzzo, Paul A; Cooper, Ziva D; Bedi, Gillinder; Gray, Kevin M; McRae-Clark, Aimee; Lofwall, Michelle R; Sparenborg, Steven; Walsh, Sharon L

2016-01-01

Cannabidiol (CBD), a constituent of cannabis with few psychoactive effects, has been reported in some studies to attenuate certain aspects of Δ9-tetrahydrocannabinol (THC) intoxication. However, most studies have tested only one dose of CBD in combination with one dose of oral THC, making it difficult to assess the nature of this interaction. Further, the effect of oral CBD on smoked cannabis administration is unknown. The objective of this multi-site, randomized, double-blind, within-subject laboratory study was to assess the influence of CBD (0, 200, 400, 800 mg, p.o.) pretreatment on the reinforcing, subjective, cognitive, and physiological effects of smoked cannabis (0.01 (inactive), 5.30–5.80% THC). Non-treatment-seeking, healthy cannabis smokers (n=31; 17M, 14 F) completed eight outpatient sessions. CBD was administered 90 min prior to cannabis administration. The behavioral and cardiovascular effects of cannabis were measured at baseline and repeatedly throughout the session. A subset of participants (n=8) completed an additional session to measure plasma CBD concentrations after administration of the highest CBD dose (800 mg). Under placebo CBD conditions, active cannabis (1) was self-administered by significantly more participants than placebo cannabis and (2) produced significant, time-dependent increases in ratings of ‘High', ‘Good Effect', ratings of the cannabis cigarette (eg, strength, liking), and heart rate relative to inactive cannabis. CBD, which alone produced no significant psychoactive or cardiovascular effects, did not significantly alter any of these outcomes. Cannabis self-administration, subjective effects, and cannabis ratings did not vary as a function of CBD dose relative to placebo capsules. These findings suggest that oral CBD does not reduce the reinforcing, physiological, or positive subjective effects of smoked cannabis. PMID:26708108

Oral Cannabidiol does not Alter the Subjective, Reinforcing or Cardiovascular Effects of Smoked Cannabis.

PubMed

Haney, Margaret; Malcolm, Robert J; Babalonis, Shanna; Nuzzo, Paul A; Cooper, Ziva D; Bedi, Gillinder; Gray, Kevin M; McRae-Clark, Aimee; Lofwall, Michelle R; Sparenborg, Steven; Walsh, Sharon L

2016-07-01

Cannabidiol (CBD), a constituent of cannabis with few psychoactive effects, has been reported in some studies to attenuate certain aspects of Δ(9)-tetrahydrocannabinol (THC) intoxication. However, most studies have tested only one dose of CBD in combination with one dose of oral THC, making it difficult to assess the nature of this interaction. Further, the effect of oral CBD on smoked cannabis administration is unknown. The objective of this multi-site, randomized, double-blind, within-subject laboratory study was to assess the influence of CBD (0, 200, 400, 800 mg, p.o.) pretreatment on the reinforcing, subjective, cognitive, and physiological effects of smoked cannabis (0.01 (inactive), 5.30-5.80% THC). Non-treatment-seeking, healthy cannabis smokers (n=31; 17M, 14 F) completed eight outpatient sessions. CBD was administered 90 min prior to cannabis administration. The behavioral and cardiovascular effects of cannabis were measured at baseline and repeatedly throughout the session. A subset of participants (n=8) completed an additional session to measure plasma CBD concentrations after administration of the highest CBD dose (800 mg). Under placebo CBD conditions, active cannabis (1) was self-administered by significantly more participants than placebo cannabis and (2) produced significant, time-dependent increases in ratings of 'High', 'Good Effect', ratings of the cannabis cigarette (eg, strength, liking), and heart rate relative to inactive cannabis. CBD, which alone produced no significant psychoactive or cardiovascular effects, did not significantly alter any of these outcomes. Cannabis self-administration, subjective effects, and cannabis ratings did not vary as a function of CBD dose relative to placebo capsules. These findings suggest that oral CBD does not reduce the reinforcing, physiological, or positive subjective effects of smoked cannabis.

Differential behavioral effects of the antidepressants reboxetine, fluoxetine, and moclobemide in a modified forced swim test following chronic treatment.

PubMed

Cryan, John F; Page, Michelle E; Lucki, Irwin

2005-11-01

The forced swim test (FST) is the most widely used model for assessing potential antidepressant activity in rodents following acute or short-term treatment. However, few studies have compared the effects of short- and long-term antidepressant treatment on behaviors in the test, despite the need to treat patients chronically to produce clinical effects. The current studies examined whether antidepressants from different classes produce different behavioral effects following short-term treatment and whether such effects change following administration for a longer duration. The effects of administering short-term (3 days) and long-term (14 days) treatments of antidepressants from three different chemical classes with distinct mechanisms of action via osmotic minipump were examined: the selective norepinephrine reuptake inhibitor reboxetine (10 and 60 mg kg(-1) day(-1)), the selective serotonin reuptake inhibitor fluoxetine (2.5 and 15 mg kg(-1) day(-1)), and the reversible inhibitor of monoamine oxidase moclobemide (2.5 and 15 mg kg(-1) day(-1)). All testing was carried out in a 15-min test with no preswim session in order to negate any confounding aspect of an induction procedure. The majority of antidepressant-sensitive behavioral changes were observed in the first 5 min of the test. The low dose of reboxetine failed to alter behavior in the test after 3 days but significantly decreased immobility and increased climbing behavior following administration for 14 days, whereas the high dose of reboxetine was equally effective following 3 and 14 days of treatment. In a similar fashion, the low dose of fluoxetine failed to alter behavior in the test following 3 days, but showed an augmented response on immobility and increased swimming following administration for 14 days. The high dose of fluoxetine was slightly more effective at reducing immobility following administration for 14 days than 3 days. The low dose of moclobemide decreased immobility and increased climbing behavior following treatment for 3 days, but increases in both swimming and climbing behaviors were measured following treatment for 14 days. Treatment with the high dose of moclobemide for 3 days decreased immobility and increased swimming, whereas treatment for 14 days significantly increased both active behaviors (swimming and climbing). Antidepressants from three different classes produce different effects on active behaviors in the FST. The effects of antidepressants were augmented following chronic administration for 14 days, especially when given at low doses. This suggests that modifications of the FST can be used to examine the onset of action of antidepressant agents produced by long-term administration.

Taste aversion learning produced by combined treatment with subthreshold radiation and lithium chloride

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

Rabin, B.M.; Hunt, W.A.; Lee, J.

1987-08-01

These experiments were designed to determine whether treatment with two subthreshold doses of radiation or lithium chloride, either alone or in combination, could lead to taste aversion learning. The first experiment determined the thresholds for a radiation-induced taste aversion at 15-20 rad and for lithium chloride at 0.30-0.45 mEq/kg. In the second experiment it was shown that exposing rats to two doses of 15 rad separated by up to 3 hr produced a taste aversion. Treatment with two injections of lithium chloride (0.30 mEq/kg) did not produce a significant reduction in preference. Combined treatment with radiation and lithium chloride didmore » produce a taste aversion when the two treatments were administered within 1 hr of each other. The results are discussed in terms of the implications of these findings for understanding the nature of the unconditioned stimuli leading to the acquisition of a conditioned taste aversion.« less

Taste aversion learning produced by combined treatment with subthreshold radiation and lithium chloride.

PubMed

Rabin, B M; Hunt, W A; Lee, J

1987-08-01

These experiments were designed to determine whether treatment with two subthreshold doses of radiation or lithium chloride, either alone or in combination, could lead to taste aversion learning. The first experiment determined the thresholds for a radiation-induced taste aversion at 15-20 rad and for lithium chloride at 0.30-0.45 mEq/kg. In the second experiment it was shown that exposing rats to two doses of 15 rad separated by up to 3 hr produced a taste aversion. Treatment with two injections of lithium chloride (0.30 mEq/kg) did not produce a significant reduction in preference. Combined treatment with radiation and lithium chloride did produce a taste aversion when the two treatments were administered within 1 hr of each other. The results are discussed in terms of the implications of these findings for understanding the nature of the unconditioned stimuli leading to the acquisition of a conditioned taste aversion.

Rivastigmine reduces "Likely to use methamphetamine" in methamphetamine-dependent volunteers.

PubMed

De La Garza, R; Newton, T F; Haile, C N; Yoon, J H; Nerumalla, C S; Mahoney, J J; Aziziyeh, A

2012-04-27

We previously reported that treatment with the cholinesterase inhibitor rivastigmine (3mg, PO for 5days) significantly attenuated "Desire for METH". Given that higher dosages of rivastigmine produce greater increases in synaptic ACh, we predicted that 6mg should have more pronounced effects on craving and other subjective measures. In the current study, we sought to characterize the effects of short-term exposure to rivastigmine (0, 3 or 6mg) on the subjective and reinforcing effects produced by administration of methamphetamine (METH) in non-treatment-seeking, METH-dependent volunteers. This was a double-blind, placebo-controlled, crossover study. Participants received METH on day 1, and were then randomized to placebo or rivastigmine on day 2 in the morning and treatment continued through day 8. METH dosing was repeated on day 6. The data indicate that METH (15 and 30mg), but not saline, increased several positive subjective effects, including "Any Drug Effect", "High", "Stimulated", "Desire METH", and "Likely to Use METH" (all p's<0.0001). In addition, during self-administration sessions, participants were significantly more likely to choose METH over saline (p<0.0001). Evaluating outcomes as peak effects, there was a trend for rivastigmine to reduce "Desire METH" (p=0.27), and rivastigmine significantly attenuated "Likely to Use METH" (p=0.01). These effects were most prominent for rivastigmine 6mg when participants were exposed to the low dose (15mg, IV), but not high dose (30mg, IV), of METH. The self-administration data reveal that rivastigmine did not alter total choices for METH (5mg, IV/choice). Overall, the results indicate some efficacy for rivastigmine in attenuating key subjective effects produced by METH, though additional research using higher doses and longer treatment periods is likely needed. These data extend previous findings and indicate that cholinesterase inhibitors, and other drugs that target acetylcholine systems, warrant continued consideration as treatments for METH dependence. Copyright © 2011 Elsevier Inc. All rights reserved.

Rivastigmine Reduces “Likely to Use Methamphetamine” in Methamphetamine-Dependent Volunteers

PubMed Central

De La Garza, R.; Newton, T.F.; Haile, C.N.; Yoon, J.H.; Nerumalla, C.S.; Mahoney, J.J.; Aziziyeh, A.

2012-01-01

We previously reported that treatment with the cholinesterase inhibitor rivastigmine (3 mg, PO for 5 days) significantly attenuated “Desire for METH”. Given that higher dosages of rivastigmine produce greater increases in synaptic ACh, we predicted that 6 mg should have more pronounced effects on craving and other subjective measures. In the current study, we sought to characterize the effects of short-term exposure to rivastigmine (0, 3 or 6 mg) on the subjective and reinforcing effects produced by administration of methamphetamine (METH) in non-treatment-seeking, METH-dependent volunteers. This was a double-blind, placebo-controlled, crossover study. Participants received METH on day 1, and were then randomized to placebo or rivastigmine on day 2 in the morning and treatment continued through day 8. METH dosing was repeated on day 6. The data indicate that METH (15 and 30 mg), but not saline, increased several positive subjective effects, including “Any Drug Effect”, “High”, “Stimulated”, “Desire METH”, and “Likely to Use METH” (all p’s<0.0001). In addition, during self-administration sessions, participants were significantly more likely to choose METH over saline (p<0.0001). Evaluating outcomes as peak effects, there was a trend for rivastigmine to reduce “Desire METH” (p=0.27), and rivastigmine significantly attenuated “Likely to Use METH” (p=0.01). These effects were most prominent for rivastigmine 6 mg when participants were exposed to the low dose (15 mg, IV), but not high dose (30 mg, IV), of METH. The self-administration data reveal that rivastigmine did not alter total choices for METH (5 mg, IV/choice). Overall, the results indicate some efficacy for rivastigmine in attenuating key subjective effects produced by METH, though additional research using higher doses and longer treatment periods is likely needed. These data extend previous findings and indicate that cholinesterase inhibitors, and other drugs that target acetylcholine systems, warrant continued consideration as treatments for METH dependence. PMID:22230648

Evaluation of Behavioral and Pharmacological Effects of Hydroalcoholic Extract of Valeriana prionophylla Standl. from Guatemala

PubMed Central

Holzmann, Iandra; Cechinel Filho, Valdir; Mora, Ticiana C.; Cáceres, Armando; Martínez, Jose Vicente; Cruz, Sully M.; de Souza, Márcia Maria

2011-01-01

There are few studies on the pharmacological properties of Valeriana prionophylla Standl. (VP), known as “Valeriana del monte”, and used in Mesoamerican folk medicine to treat sleep disorders. This study examines the pharmacological effects of the hydroalcoholic extract of the dry rhizome using the open field, rota rod, elevated plus-maze (EPM), forced swimming (FST), strychnine- and pentobarbital-induced sleeping time, PTZ-induced seizures, and the inhibitory avoidance tests. VP did not show any protective effect against PTZ-induced convulsions. In the EPM, exhibited an anxiolytic-like effect through the effective enhancement of the entries (38.5%) and time spent (44.7%) in the open arms, when compared with control group. Time spent and the numbers of entrances into the enclosed arms were decreased, similar to those effects observed with diazepam. In the FST, acute treatment with VP, produced a dose-dependent decrease in immobility time, similarly to imipramine. VP also produced a significant dose-dependent decrease in the latency of sleeping time, while producing an increase in total duration of sleep; influenced memory consolidation of the animals only at lower doses, unlike those that produced anti-depressant and anxiolytic effects. In summary, the results suggest that VP presents several psychopharmacological activities, including anxiolytic, antidepressant, and hypno-sedative effects. PMID:21754942

Aspirin, lysine, mifepristone and doxycycline combined can effectively and safely prevent and treat cancer metastasis: prevent seeds from gemmating on soil

PubMed Central

Xu, Huo; Ma, Ji; Zhu, Yewei; Lu, Yusheng; Wang, Jichuang; Zhang, Ting; Li, Tao; Xie, Jingjing; Xu, Bo; Xie, Fangwei; Gao, Yu; Shao, Jingwei; Tu, Xiaohuang; Jia, Lee

2015-01-01

Recent scientific advances have increased our understanding of the cancer metastatic complexities and provided further impetus for new combination therapies to prevent cancer metastasis. Here, we demonstrated that a combination (HAMPT) of aspirin, lysine, mifepristone and doxycycline can effectively and safely prevent cancer metastasis. The pharmaceutically-formulated HAMPT inhibited adhesion of cancer cells to either endothelial cells or extracellular matrix via down-regulating cell adhesion molecules ICAM-1 and α4-integrin. HAMPT inhibited the cloak effect by activated platelets on cancer cells, thereby interfering adhesion and invasion of cancer cells to the underlying stroma. At the effective concentration, HAMPT induced cancer cells into dormancy with minor inhibition on cell viability. Four-day pretreatment followed by 30-day oral administration of HAMPT (33.5-134 mg/kg) to the mice inoculated with cancer cells produced significant inhibition on cancer metastasis dose-dependently without marked side effects. Fifty-day rat toxicity study with HAMPT at doses (335-1340 mg/kg) 20-fold higher than its therapeutic dose produced no significant toxicity. Interestingly, the acute toxic death could not be reached at the maximum administrable dose (5 g/kg). This proof-of-concept study provides the first conceptual evidence that cancer metastasis can be controlled by using affordable old drugs to restrain circulating tumor cells from gemmating on the metastatic soil without the need for cytotoxicity. PMID:26459390

Bi-tangential hybrid IMRT for sparing the shoulder in whole breast irradiation.

PubMed

Farace, P; Deidda, M A; Iamundo de Cumis, I; Iamundo de Curtis, I; Deiana, E; Farigu, R; Lay, G; Porru, S

2013-11-01

A bi-tangential technique is proposed to reduce undesired doses to the shoulder produced by standard tangential irradiation. A total of 6 patients affected by shoulder pain and reduced functional capacity after whole-breast irradiation were retrospectively analysed. The standard tangential plan used for treatment was compared with (1) a single bi-tangential plan where, to spare the shoulder, the lateral open tangent was split into two half-beams at isocentre, with the superior portion rotated by 10-20° medially with respect to the standard lateral beam; (2) a double bi-tangential plan, where both the tangential open beams were split. The planning target volume (PTV) coverage and the dose to the portion of muscles and axilla included in the standard tangential beams were compared. PTV95 % of standard plan (91.9 ± 3.8) was not significantly different from single bi-tangential plan (91.8 ± 3.4); a small but significant (p < 0.01) decrease was observed with the double bi-tangential plan (90.1 ± 3.7). A marked dose reduction to the muscle was produced by the single bi-tangential plan around 30-40 Gy. The application of the double bi-tangential technique further reduced the volume receiving around 20 Gy, but did not markedly affect the higher doses. The dose to the axilla was reduced both in the single and the double bi-tangential plans. The single bi-tangential technique would have been able to reduce the dose to shoulder and axilla, without compromising target coverage. This simple technique is valuable for irradiation after axillary lymph node dissection or in patients without dissection due to negative or low-volume sentinel lymph node disease.

A study of the mechanisms involved in the neurotoxic action of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy') on dopamine neurones in mouse brain

PubMed Central

Colado, M Isabel; Camarero, Jorge; Mechan, Annis O; Sanchez, Veronica; Esteban, Blanca; Elliott, J Martin; Green, A Richard

2001-01-01

Administration of 3,4-methylenedioxymethamphetamine (MDMA, ‘ecstasy') to mice produces acute hyperthermia and long-term degeneration of striatal dopamine nerve terminals. Attenuation of the hyperthermia decreases the neurodegeneration. We have investigated the mechanisms involved in producing the neurotoxic loss of striatal dopamine. MDMA produced a dose-dependent loss in striatal dopamine concentration 7 days later with 3 doses of 25 mg kg−1 (3 h apart) producing a 70% loss. Pretreatment 30 min before each MDMA dose with either of the N-methyl-D-aspartate antagonists AR-R15896AR (20, 5, 5 mg kg−1) or MK-801 (0.5 mg kg−1×3) failed to provide neuroprotection. Pretreatment with clomethiazole (50 mg kg−1×3) was similarly ineffective in protecting against MDMA-induced dopamine loss. The free radical trapping compound PBN (150 mg kg−1×3) was neuroprotective, but it proved impossible to separate neuroprotection from a hypothermic effect on body temperature. Pretreatment with the nitric oxide synthase (NOS) inhibitor 7-NI (50 mg kg−1×3) produced neuroprotection, but also significant hypothermia. Two other NOS inhibitors, S-methyl-L-thiocitrulline (10 mg kg−1×3) and AR-R17477AR (5 mg kg−1×3), provided significant neuroprotection and had little effect on MDMA-induced hyperthermia. MDMA (20 mg kg−1) increased 2,3-dihydroxybenzoic acid formation from salicylic acid perfused through a microdialysis tube implanted in the striatum, indicating increased free radical formation. This increase was prevented by AR-R17477AR administration. Since AR-R17477AR was also found to have no radical trapping activity this result suggests that MDMA-induced neurotoxicity results from MDMA or dopamine metabolites producing radicals that combine with NO to form tissue-damaging peroxynitrites. PMID:11739248

A-1048400 is a novel, orally active, state-dependent neuronal calcium channel blocker that produces dose-dependent antinociception without altering hemodynamic function in rats.

PubMed

Scott, Victoria E; Vortherms, Timothy A; Niforatos, Wende; Swensen, Andrew M; Neelands, Torben; Milicic, Ivan; Banfor, Patricia N; King, Andrew; Zhong, Chengmin; Simler, Gricelda; Zhan, Cenchen; Bratcher, Natalie; Boyce-Rustay, Janel M; Zhu, Chang Z; Bhatia, Pramila; Doherty, George; Mack, Helmut; Stewart, Andrew O; Jarvis, Michael F

2012-02-01

Blockade of voltage-gated Ca²⁺ channels on sensory nerves attenuates neurotransmitter release and membrane hyperexcitability associated with chronic pain states. Identification of small molecule Ca²⁺ channel blockers that produce significant antinociception in the absence of deleterious hemodynamic effects has been challenging. In this report, two novel structurally related compounds, A-686085 and A-1048400, were identified that potently block N-type (IC₅₀=0.8 μM and 1.4 μM, respectively) and T-type (IC₅₀=4.6 μM and 1.2 μM, respectively) Ca²⁺ channels in FLIPR based Ca²⁺ flux assays. A-686085 also potently blocked L-type Ca²⁺ channels (EC₅₀=0.6 μM), however, A-1048400 was much less active in blocking this channel (EC₅₀=28 μM). Both compounds dose-dependently reversed tactile allodynia in a model of capsaicin-induced secondary hypersensitivity with similar potencies (EC₅₀=300-365 ng/ml). However, A-686085 produced dose-related decreases in mean arterial pressure at antinociceptive plasma concentrations in the rat, while A-1048400 did not significantly alter hemodynamic function at supra-efficacious plasma concentrations. Electrophysiological studies demonstrated that A-1048400 blocks native N- and T-type Ca²⁺ currents in rat dorsal root ganglion neurons (IC₅₀=3.0 μM and 1.6 μM, respectively) in a voltage-dependent fashion. In other experimental pain models, A-1048400 dose-dependently attenuated nociceptive, neuropathic and inflammatory pain at doses that did not alter psychomotor or hemodynamic function. The identification of A-1048400 provides further evidence that voltage-dependent inhibition of neuronal Ca²⁺ channels coupled with pharmacological selectivity vs. L-type Ca²⁺ channels can provide robust antinociception in the absence of deleterious effects on hemodynamic or psychomotor function. Copyright © 2011 Elsevier Inc. All rights reserved.

Is Slow-Onset Long-Acting Monoamine Transport Blockade to Cocaine as Methadone is to Heroin? Implication for Anti-Addiction Medications

PubMed Central

Peng, Xiao-Qing; Xi, Zheng-Xiong; Li, Xia; Spiller, Krista; Li, Jie; Chun, Lauren; Wu, Kuo-Ming; Froimowitz, Mark; Gardner, Eliot L

2010-01-01

The success of methadone in treating opiate addiction has suggested that long-acting agonist therapies may be similarly useful for treating cocaine addiction. Here, we examined this hypothesis, using the slow-onset long-acting monoamine reuptake inhibitor 31,345, a trans-aminotetralin analog, in a variety of addiction-related animal models, and compared it with methadone's effects on heroin's actions in the same animal models. Systemic administration of 31,345 produced long-lasting enhancement of electrical brain-stimulation reward (BSR) and extracellular nucleus accumbens (NAc) dopamine (DA). Pretreatment with 31,345 augmented cocaine-enhanced BSR, prolonged cocaine-enhanced NAc DA, and produced a long-term (24-48 h) reduction in cocaine self-administration rate without obvious extinction pattern, suggesting an additive effect of 31,345 with cocaine. In contrast, methadone pretreatment not only dose-dependently inhibited heroin self-administration with an extinction pattern but also dose-dependently inhibited heroin-enhanced BSR and NAc DA, suggesting functional antagonism by methadone of heroin's actions. In addition, 31,345 appears to possess significant abuse liability, as it produces dose-dependent enhancement of BSR and NAc DA, maintains a low rate of self-administration behavior, and dose-dependently reinstates drug-seeking behavior. In contrast, methadone only partially maintains self-administration with an extinction pattern, and fails to induce reinstatement of drug-seeking behavior. These findings suggest that 31,345 is a cocaine-like slow-onset long-acting monoamine transporter inhibitor that may act as an agonist therapy for cocaine addiction. However, its pattern of action appears to be significantly different from that of methadone. Ideal agonist substitutes for cocaine should fully emulate methadone's actions, that is, functionally antagonizing cocaine's action while blocking monoamine transporters to augment synaptic DA. PMID:20827272

Opioid agonist efficacy predicts the magnitude of tolerance and the regulation of mu-opioid receptors and dynamin-2.

PubMed

Pawar, Mohit; Kumar, Priyank; Sunkaraneni, Soujanya; Sirohi, Sunil; Walker, Ellen A; Yoburn, Byron C

2007-06-01

It has been proposed that opioid agonist efficacy may play a role in tolerance and the regulation of opioid receptor density. To address this issue, the present studies estimated the in vivo efficacy of three opioid agonists and then examined changes in spinal mu-opioid receptor density following chronic treatment in the mouse. In addition, tolerance and regulation of the trafficking protein dynamin-2 were determined. To evaluate efficacy, the method of irreversible receptor alkylation was employed and the efficacy parameter tau estimated. Mice were injected with the irreversible mu-opioid receptor antagonist clocinnamox (0.32-25.6 mg/kg, i.p), and 24 h later, the analgesic potency of s.c. morphine, oxycodone and etorphine were determined. Clocinnamox dose-dependently antagonized the analgesic effects of morphine, etorphine and oxycodone. The shift to the right of the dose-response curves was greater for morphine and oxycodone compared to etorphine and the highest dose of clocinnamox reduced the maximal effect of morphine and oxycodone, but not etorphine. The order of efficacy calculated from these results was etorphine>morphine>oxycodone. Other mice were infused for 7 days with oxycodone (10-150 mg/kg/day, s.c.) or etorphine (50-250 microg/kg/day, s.c.) and the analgesic potency of s.c. morphine determined. The low efficacy agonist (oxycodone) produced more tolerance than the high efficacy agonist (etorphine) at equi-effective infusion doses. In saturation binding experiments, the low efficacy opioid agonists (morphine, oxycodone) did not regulate the density of spinal mu-opioid receptors, while etorphine produced approximately 40% reduction in mu-opioid receptor density. Furthermore, etorphine increased spinal dynamin-2 abundance, while oxycodone did not produce any significant change in dynamin-2 abundance. Overall, these data indicate that high efficacy agonists produce less tolerance at equi-effective doses. Furthermore, increased efficacy was associated with mu-opioid receptor downregulation and dynamin-2 upregulation. Conversely, lower efficacy agonists produced more tolerance at equi-effective doses, but did not regulate mu-opioid receptor density or dynamin-2 abundance. Taken together, these studies indicate that agonist efficacy plays an important role in tolerance and regulation of receptors and trafficking proteins.

Nitrosamine-induced carcinogenesis. The alkylation of N-7 of guanine of nucleic acids of the rat by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate

PubMed Central

Swann, P. F.; Magee, P. N.

1971-01-01

1. The extent of ethylation of N-7 of guanine in the nucleic acids of rat tissue in vivo by diethylnitrosamine, N-ethyl-N-nitrosourea and ethyl methanesulphonate was measured. 2. All compounds produced measurable amounts of 7-ethyl-guanine. 3. A single dose of diethylnitrosamine or N-ethyl-N-nitrosourea produced tumours of the kidney in the rat. Three doses of ethyl methanesulphonate produced kidney tumours, but a single dose did not. 4. A single dose of diethylnitrosamine produced twice as much ethylation of N-7 of guanine in DNA of kidney as did N-ethyl-N-nitrosourea. A single dose of both compounds induced kidney tumours, although of a different histological type. 5. A single dose of ethyl methanesulphonate produced ten times as much ethylation of N-7 of guanine in kidney DNA as did N-ethyl-N-nitrosourea without producing tumours. 6. The relevance of these findings to the hypothesis that alkylation of a cellular component is the mechanism of induction of tumours by nitroso compounds is discussed. PMID:5145908

A comparison of the antinociceptive and temperature responses to morphine and fentanyl derivatives in rats.

PubMed

Savić Vujović, Katarina R; Vučković, Sonja; Srebro, Dragana; Ivanović, Milovan; Došen-Mićović, Ljiljana; Vučetić, Čedomir; Džoljić, Eleonora; Prostran, Milica

2013-04-01

In addition to producing antinociception, opioids exert profound effects on body temperature. This study aimed at comparing antinociceptive and hyperthermic responses between two groups of μ-opioid receptor agonists: fentanyl (4-anilinopiperidine-type) and morphine (phenanthrene-type) derivatives in rats. Analgesic activity was assessed by tail immersion test and the body temperature by insertion of a thermometer probe into the colon. Fentanyl (F), (±)-cis-3-methyl fentanyl (CM), (±)-cis-3-carbomethoxy fentanyl (C), (±)trans-3-carbomethoxy fentanyl (T) and (±)-cis-3 butyl fentanyl (B) produced dose-dependent increase in antinociception and hyperthermia. The relative order of analgesic potency was: CM(11.27)>F(1)>C(0.35)≥T(0.11)≥B(0.056). Similar to this, the relative order of hyperthermic potency was: CM(8.43)>F(1)>C(0.46)≥T(0.11)≥B(0.076). Morphine (M), oxycodone (O), thebacon (T) and 6,14-ethenomorphinan-7-methanol, 4,5-epoxy-6-fluoro-3-hydroxy-α,α,17-trimethyl-, (5α,7α) (E) also produced dose-dependent increase in antinociception and hyperthermia. Among morphine derivatives the relative order of analgesic potency was: E(56)>O(5)≥T(2.6)>M(1), and similar to this, the relative order of hyperthermic potency was: E(37)>O(3)≥T(2.3)>M(1). Morphine (phenanthrene-type) and fentanyl (4-anilinopiperidine-type) derivatives produced hyperthermia in rats at doses about 2 times lower, and 6-11 times higher, than their median antinociceptive doses, respectively. This study is first to identify difference between these two classes of opioid drugs in their potencies in producing hyperthermia. Further studies are needed to clarify the significance of these findings.

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.

Rasagiline for dysexecutive symptoms during wearing-off in Parkinson's disease: a pilot study.

PubMed

Rinaldi, Domiziana; Assogna, Francesca; Sforza, Michela; Tagliente, Stefania; Pontieri, Francesco E

2018-01-01

Wearing-off refers to the predictable worsening of motor and sometimes non-motor symptoms of Parkinson's disease occurring at the end of levodopa dose that improves with the next drug dose. Here, we investigated the efficacy of rasagiline on executive functions at the end of levodopa dose in patients displaying symptoms of wearing-off. Rasagiline was well-tolerated and produced a significant improvement at the Frontal Assessment Battery, together with improvement of motor symptoms at the end of levodopa dose. These results suggest that treatment of motor symptoms of wearing-off with rasagiline may be accompanied by improvement of executive functions, and further support the need for optimizing dopamine replacement therapy in fluctuating Parkinson's disease patients.

Sexual Competitiveness, Field Survival, and Dispersal of Anastrepha obliqua (Diptera: Tephritidae) Fruit Flies Irradiated at Different Doses.

PubMed

Gallardo-Ortiz, Uriel; Pérez-Staples, Diana; Liedo, Pablo; Toledo, Jorge

2018-04-02

The sterile insect technique (SIT) is used in area-wide pest management programs for establishing low pest prevalence and/or areas free of fruit flies (Diptera: Tephritidae). The aim of this technique is to induce high levels of sterility in the wild population, for this the released insects must have a high sexual competitiveness and field dispersal. However, radiation decreases these biological attributes that do not allow it to compete successfully with wild insects. In this study the sexual competitiveness, field survival and dispersal of Anastrepha obliqua (Macquart; Diptera: Tephritidae) irradiated at 0, 40, 50, 60, 70, and 80 Gy were evaluated in laboratory. A dose of 60 Gy produced 98% sterility, whereas doses of 70 and 80 Gy produced 99% sterility. Sexual competitiveness was assessed in field cages, comparing males irradiated at 0, 50, 60, 70, and 80 Gy against wild males for mating with wild fertile females. Males irradiated at 50 and 60 Gy achieved more matings than those irradiated at 70 and 80 Gy. Wild males were more competitive than mass-reared males, even when these were not irradiated (0 Gy). There was no effect of irradiation on mating latency, yet wild males showed significantly shorter mating latency than mass-reared males. Female remating did not differ among those that mated with wild males and those that mated with males irradiated with different doses. The relative sterility index (RSI) increased from 0.25 at 80 Gy to 0.37 at 60 Gy. The Fried competitiveness index was 0.69 for males irradiated at 70 Gy and 0.57 for those irradiated at 80 Gy, which indicates that a 10 Gy reduction in the irradiation dose produces greater induction of sterility in the wild population. There were no significant differences in field survival and dispersal between flies irradiated at 70 or 80 Gy. Reducing the irradiation dose to 60 or 70 Gy could improve the performance of sterile males and the effectiveness of the SIT. Our results also distinguish between the effects of irradiation and mass-rearing on the performance of sterile males.

Trovafloxacin in Combination with Vancomycin against Penicillin-Resistant Pneumococci in the Rabbit Meningitis Model

PubMed Central

Rodoni, Dina; Hänni, Fränzi; Gerber, Cynthia M.; Cottagnoud, Marianne; Neftel, Klaus; Täuber, Martin G.; Cottagnoud, Philippe

1999-01-01

Trovafloxacin, a new fluoroquinolone, produced bactericidal activity (−0.33 ± 0.13 Δlog10 CFU/ml · h; intravenously [i.v.] administered dose, 15 mg/kg) comparable to that of vancomycin (−0.39 ± 0.18 Δlog10 CFU/ml · h; i.v. administered dose, 20 mg/kg) in the treatment of experimental meningitis in rabbits due to a pneumococcal strain highly resistant to penicillin (MIC of penicillin G, 4 μg/ml). The combination of both drugs significantly increased (P < 0.05) the killing rate (−0.60 ± 0.23 Δlog10 CFU/ml · h) compared to that produced by either monotherapy. These results were also confirmed in vitro. PMID:10103211

Subjective and Cardiovascular Effects of Intravenous Methamphetamine during Perindopril Maintenance: A Randomized, Double-Blind, Placebo-Controlled Human Laboratory Study.

PubMed

Verrico, Christopher D; Haile, Colin N; De La Garza, Richard; Grasing, Kenneth; Kosten, Thomas R; Newton, Thomas F

2016-07-01

Our pilot study suggested that the angiotensin-converting enzyme inhibitor perindopril might reduce some subjective effects produced by i.v. methamphetamine. We characterized the impact of a wider range of perindopril doses on methamphetamine-induced effects in a larger group of non-treatment-seeking, methamphetamine-using volunteers. Before treatment, participants received 30mg methamphetamine. After 5 to 7 days of perindopril treatment (0, 4, 8, or 16mg/d), participants received 15 and 30mg of methamphetamine on alternate days. Before and after treatment, participants rated subjective effects and cardiovascular measures were collected. Prior to treatment with perindopril, there were no significant differences between treatment groups on maximum or peak subjective ratings or on peak cardiovascular effects. Following perindopril treatment, there were significant main effects of treatment on peak subjective ratings of "anxious" and "stimulated"; compared to placebo treatment, treatment with 8mg perindopril significantly reduced peak ratings of both anxious (P=.0009) and stimulated (P=.0070). There were no significant posttreatment differences between groups on peak cardiovascular effects. Moderate doses of perindopril (8mg) significantly reduced peak subjective ratings of anxious and stimulated as well as attenuated many other subjective effects produced by methamphetamine, likely by inhibiting angiotensin II synthesis. Angiotensin II is known to facilitate the effects of norepinephrine, which contributes to methamphetamine's subjective effects. The lack of a classic dose-response function likely results from either nonspecific effects of perindopril or from between-group differences that were not accounted for in the current study (i.e., genetic variations and/or caffeine use). The current findings suggest that while angiotensin-converting enzyme inhibitors can reduce some effects produced by methamphetamine, more consistent treatment effects might be achieved by targeting components of the renin-angiotensin system that are downstream of angiotensin-converting enzyme. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Alterations in cell migration and cell viability of wounded human skin fibroblasts following visible red light exposure

NASA Astrophysics Data System (ADS)

Prabhu, Vijendra; Rao, Bola Sadashiva S.; Mahato, Krishna Kishore

2014-02-01

The present study intended to examine the effect of visible red light on structural and cellular parameters on wounded skin fibroblast cells. To achieve the stated objective, uniform scratch was created on confluent monolayered human skin fibroblast cells, and were exposed to single dose of He-Ne laser (15 mm spot, 6.6808 mWcm-2) at 1, 2, 3, 4, 5, 6 and 7 Jcm-2 in the presence and absence of 10% fetal bovine serum (FBS). Beam profile measurements of the expanded laser beam were conducted to ensure the beam uniformity. The influence of laser dose on the change in temperature was recorded using sensitive temperature probe. Additionally, following laser exposure cell migration and cell survival were documented at different time intervals on wounded human skin fibroblast cells grown in vitro. Beam profile measurements indicated more or less uniform power distribution over the whole beam area. Temperature monitoring of sham irradiated control and laser treatment groups displayed negligible temperature change indicating the absence of thermal effect at the tested laser doses. In the absence of 10% FBS, single exposure of different laser doses failed to produce any significant effects on cell migration or cell survival. However, in the presence of serum single exposure of 5 J/cm2 on wounded skin fibroblasts significantly enhanced the cell migration (P<0.05) compared to the other tested doses (1, 2, 3, 4, 6 and 7 J/cm2) and sham irradiated controls. In conclusion, the LLLT acts by improving cell migration and cell proliferation to produce measurable changes in wounded fibroblast cells.

Effects of the H3 Antagonist, Thioperamide, on Behavioral Alterations Induced by Systemic MK-801 Administration in Rats

PubMed Central

Bardgett, Mark E.; Points, Megan; Roflow, John; Blankenship, Meredith; Griffith, Molly S.

2009-01-01

Rationale Recent studies have raised the possibility that antagonists of H3 histamine receptors possess cognitive-enhancing and antipsychotic properties. However, little work has assessed these compounds in classic animal models of schizophrenia. Objectives The purpose of this study was to determine if a prototypical H3 antagonist, thioperamide, could alter behavioral deficits caused by the NMDA receptor antagonist, MK-801, in adult male rats. MK-801 was chosen for study since it produces a state of NMDA receptor hypofunction in rats that may be analogous to the one hypothesized to occur in schizophrenia. Methods The interaction between thioperamide and MK-801 was measured in three behavioral tests: locomotor activity, prepulse inhibition (PPI), and delayed spatial alternation. In each test, rats received a subcutaneous injection of saline or thioperamide (3.0 & 10 mg/kg) followed 20 minutes later by a subcutaneous injection of saline or MK-801 (0.05, 0.10, & 0.30 mg/kg). Results Locomotor activity was significantly elevated by MK-801 in a dose-dependent manner. Thioperamide pretreatment alone did not alter locomotor activity, however its impact on MK-801 was dose-dependent. Each thioperamide dose enhanced the effects of two lower doses of MK801 but reduced the effect of a higher MK-801 dose. Clear deficits in PPI and delayed spatial alternation were produced by MK-801 treatment, but neither impairment was significantly modified by thioperamide pretreatment. Conclusions H3 receptors modulate responses to NMDA antagonists in behaviorally-specific ways and dependent upon the level of NMDA receptor blockade. PMID:19466392

Diethylene glycol-induced toxicities show marked threshold dose response in rats

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

Landry, Greg M., E-mail: Landry.Greg@mayo.edu; Dunning, Cody L., E-mail: cdunni@lsuhsc.edu; Abreo, Fleurette, E-mail: fabreo@lsuhsc.edu

Diethylene glycol (DEG) exposure poses risks to human health because of widespread industrial use and accidental exposures from contaminated products. To enhance the understanding of the mechanistic role of metabolites in DEG toxicity, this study used a dose response paradigm to determine a rat model that would best mimic DEG exposure in humans. Wistar and Fischer-344 (F-344) rats were treated by oral gavage with 0, 2, 5, or 10 g/kg DEG and blood, kidney and liver tissues were collected at 48 h. Both rat strains treated with 10 g/kg DEG had equivalent degrees of metabolic acidosis, renal toxicity (increased BUNmore » and creatinine and cortical necrosis) and liver toxicity (increased serum enzyme levels, centrilobular necrosis and severe glycogen depletion). There was no liver or kidney toxicity at the lower DEG doses (2 and 5 g/kg) regardless of strain, demonstrating a steep threshold dose response. Kidney diglycolic acid (DGA), the presumed nephrotoxic metabolite of DEG, was markedly elevated in both rat strains administered 10 g/kg DEG, but no DGA was present at 2 or 5 g/kg, asserting its necessary role in DEG-induced toxicity. These results indicate that mechanistically in order to produce toxicity, metabolism to and significant target organ accumulation of DGA are required and that both strains would be useful for DEG risk assessments. - Highlights: • DEG produces a steep threshold dose response for kidney injury in rats. • Wistar and F-344 rats do not differ in response to DEG-induced renal injury. • The dose response for renal injury closely mirrors that for renal DGA accumulation. • Results demonstrate the importance of DGA accumulation in producing kidney injury.« less

Cardiovascular and behavioral responses of gray wolves to ketamine-xylazine immobilization and antagonism by yohimbine

USGS Publications Warehouse

Kreeger, T.J.; Faggella, A.M.; Seal, U.S.; Mech, L.D.; Callahan, Margaret; Hall, B.

1987-01-01

Adult wolves (Canis lupus) were immobilized with 6.6 mg/kg ketamine hydrochloride (KET) and 2.2 mg/kg xylazine hydrochloride (XYL) administered intramuscularly. Induction time was 4.6 ± 0.3 min (x̄ ± SE). Immobilization resulted in significant bradycardia and hypertension (P < 0.05). Twenty min after induction, the wolves were given 0.05–0.60 mg/kg yohimbine hydrochloride (YOH). Yohimbine given intravenously produced dose-related increases in heart rate (HR) with doses >0.15 mg/kg resulting in extreme tachycardia (>300 bpm). All doses of YOH caused a temporary decrease in mean arterial blood pressure (MABP) with some individual animals manifesting profound hypotension (<30 torr) at doses >0.15 mg/kg. Increasing the dose of YOH above 0.15 mg/kg did not significantly decrease either arousal or ambulation times. Administering YOH at 40 or 60 min after induction resulted in decreased arousal and ambulation times. Stimulation by weighing and taking repeated blood samples during anesthesia did not shorten arousal times. We recommend that wolves immobilized with XYL-KET be antagonized with doses of YOH <0.15 mg/kg.

Effects of topical and systemic administration of Eugenia caryophyllata buds essential oil on corneal anesthesia and analgesia

PubMed Central

Khalilzadeh, Emad; Hazrati, Reza; Saiah, Gholamreza Vafaei

2016-01-01

Clinical studies suggest that essential oil of Eugenia caryophyllata (Clove) buds (EOEC) is efficacious in the treatment of dental pain. In the present study, we investigated the analgesic and local anesthetic effects of EOEC and its possible mechanisms of action in acute corneal pain in rats. EOEC was extracted by hydro-distillation in a Clevenger type apparatus from clove buds. The acute corneal pain was induced by applying a drop (40 µl) of 5 M NaCl solution on the corneal surface, and the numbers of eye wipes were counted during the first 30 s. The mechanical sensation of the cornea was evaluated by calibrated Von Frey filaments. Systemic administration of EOEC (100 and 200 mg/kg, SC) and morphine (2.5 and 5 mg/kg, IP) produced a significant antinociceptive effect in acute corneal pain. Pretreatment with naloxone or atropine prevented the EOEC-induced analgesia. However, L-arginine and methylene blue did not change the suppressive effect of EOEC on corneal pain response. Topical application of EOEC, eugenol and lidocaine significantly decreased corneal sensitivity. Combination treatments of eugenol (25 µg) with lidocaine (0.5%) and EOEC (50 µg) with lidocaine (0.5%) also significantly suppressed corneal sensitivity. Systemic administration of EOEC produced analgesia in the acute corneal pain through mechanisms that involved both opioidergic and cholinergic systems. In addition, topical instillation of EOEC, eugenol, and lidocaine produced local anesthesia in the rat cornea. Sub-anesthetic doses of EOEC or eugenol produced a significant local anesthetic effect when concurrently used with the sub-anesthetic dose of lidocaine. PMID:27651809

Randomized clinical trial on acute effects of i.v. iron sucrose during haemodialysis.

PubMed

Garcia-Fernandez, Nuria; Echeverria, Aitziber; Sanchez-Ibarrola, Alfonso; Páramo, José Antonio; Coma-Canella, Isabel

2010-03-01

Haemodialysis induces endothelial dysfunction by oxidation and inflammation. Intravenous iron administration during haemodialysis could worsen endothelial dysfunction. The aim of this study was to ascertain if iron produces endothelial dysfunction and the possible neutralizing effect of N-acetylcysteine when infused before iron. The oxidative and inflammatory effects of iron during haemodialysis were also assessed. Forty patients undergoing haemodialysis were studied in a randomized and cross-over design with and without N-acetylcysteine infused before iron sucrose (50 or 100 mg). Plasma Von Willebrand factor (vWF), soluble intercellular adhesion molecule-1 (sICAM-1) levels, malondialdehyde, total antioxidant capacity, CD11b/CD18 expression in monocytes, interleukin (IL)-8 in monocytes and plasma IL-8 were studied at baseline and during haemodialysis. Haemodialysis produced significant (P < 0.001) increase in plasma vWF, sICAM-1, malondialdehyde, IL-8 and CD11b/CD18 expression in monocytes, as well as decrease in total antioxidant capacity. Iron induced significant increase in plasma malondialdehyde and IL-8 in monocytes, but had no effect on total antioxidant capacity, CD11b/CD18 expression, plasma IL-8, vWF and sICAM-1. The addition of N-acetylcysteine to 50 mg of iron produced a significant (P = 0.040) decrease in malondialdehyde. Standard (100 mg) and low (50 mg) doses of iron during haemodialysis had no effects on endothelium. Iron only had minor effects on inflammation and produced an increase in oxidative stress, which was neutralized by N-acetylcysteine at low iron dose. Haemodialysis caused a significant increase in oxidative stress, inflammation and endothelial dysfunction markers.

76 FR 35672 - Revised Effectiveness Determination; Sunscreen Drug Products for Over-the-Counter Human Use

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-17

... are given ultraviolet (UV) radiation doses produced by a solar simulator (i.e., a UV lamp). Under... increasingly higher UV doses produced by the solar simulator. However, because the solar simulator can produce far higher UV radiation doses than a consumer would ever receive even under the most severe sun...

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.

Decrease of interleukin-10-producing T cells in the peripheral blood of severe unstable atopic asthmatics.

PubMed

Matsumoto, Koichiro; Inoue, Hiromasa; Fukuyama, Satoru; Tsuda, Miyuki; Ikegami, Tomomi; Kibe, Atsuko; Yoshiura, Yuki; Komori, Masashi; Hamasaki, Naotaka; Aizawa, Hisamichi; Nakanishi, Yoichi

2004-08-01

Although IL-10 is known as an immunoregulatory cytokine produced by various cells including T cells, its basic profile in atopic asthma remains uncertain. The profiles of IL-10 production in circulating CD4+ T cells of atopic asthmatics were investigated with respect to clinical severity. Forty atopic asthmatics were divided into three groups: mild, and severe but stable and severe unstable asthmatics. Eosinophils were counted in the peripheral blood and sputum, and exhaled nitric oxide was assessed. PBMCs were stimulated with or without anti-CD3 and anti-CD28 antibodies and then processed for detecting IL-10-producing CD4+ cells using flow cytometry. There was no difference in the eosinophil count in blood or sputum and in nitric oxide level among the three groups. IL-10-producing CD4+ cells were mainly detected in a CD45RO+ memory population. The frequency of IL-10-producing cells after stimulation was significantly lower in the severe unstable group compared to the mild group. In addition, the frequency of IL-10-producing cells in the severe unstable group was significantly lower than that in the severe stable group despite the fact that both groups received similar treatments with high-dose inhaled corticosteroids. The IL-10 production of CD4+CD45RO+ cells in response to dexamethasone did not differ among the three groups. IL-10-producing CD4+CD45RO+ cells in the peripheral blood are decreased in severe unstable asthmatics, which is not explained by the effect of high-dose inhaled corticosteroid medication. Copyright 2004 S. Karger AG, Basel

Dose response of CRM197 and tetanus toxoid-conjugated Haemophilus influenzae type b vaccines.

PubMed

Huebner, Robin E; Nicol, Mark; Mothupi, Rosalia; Käyhty, Helena; Mbelle, Nontombi; Khomo, Esther; Klugman, Keith P

2004-12-21

High vaccine cost has limited use of conjugate vaccines in the developing world where the disease burden is greatest. Fixed fractional doses of Haemophilus influenzae type b (Hib) vaccines have been shown to be immunogenic, but dose responses of these vaccines in humans are needed to determine the lowest immunogenic dose as an option for lowering vaccine cost. We randomized children to receive one of five doses (0.625, 1.25, 2.5, 5.0 and 10 microg) of either a diphtheria CRM197 or tetanus toxoid-conjugated Hib vaccine. The children received a primary three-dose series at 6, 10, and 14 weeks of age and a booster dose at 9 months. Anti-PRP IgG antibodies were measured at each vaccination, at 18 weeks, and at one week following the booster dose. Concentrations of > or =1.25 microg of HibCRM197 vaccine produced mean anti-PRP responses at 18 weeks of > or =5.72 microg/ml and > or =0.15 microg/ml was achieved in >98% of the children with at least 79% reaching anti-PRP concentrations of > or =1.0 microg/ml. Concentrations of > or =1.25 microg of Hib-tetanus vaccine produced mean anti-PRP responses at 18 weeks of > or =8.63 microg/ml and > or =0.15 microg/ml was achieved in 100% of the children with at least 88.9% reaching anti-PRP concentrations of > or =1.0 microg/ml. While mean antibody concentrations after either vaccine decreased over time, the proportion of children with antibody levels of > or =0.15 microg/ml had not changed significantly at the 9 month measurement. Immunologic memory was demonstrated by significant increases in mean antibody concentrations one week after the booster dose for doses > or =1.25 microg of HibCRM197 and Hib-tetanus to mean concentrations > or =37.71 and 16.07 microg/ml, respectively. There were no differences in antibody responses for vaccine doses > or =1.25 microg of the same vaccine or between the same concentrations of the two different vaccines. Our data suggest that doses of these vaccines of > or =1.25 microg may be sufficient to stimulate an immune response that offers both short and longer term protection from invasive Hib disease.

Evidence of thyroxine formation following iodine administration in Sprague-Dawley rats

NASA Technical Reports Server (NTRS)

Thrall, K. D.; Sauer, R. L.; Bull, R. J.

1992-01-01

Iodine (I2) has been proposed to be used as a water disinfectant on the manned space station. Previous work has shown that subchronic administration of I2 to Sprague-Dawley rats in drinking water significantly increases plasma thyroxine/triiodothyronine (T4/T3) levels. This is not observed with iodide (I-) treatment. The present study addresses the possibility that I2 reacts with deiodinated T4 metabolites in the gastrointestinal tract to resynthesize T4. Incubation of diiodothyronine (T2), T3, or reverse T3 with I2 in phosphate-buffered saline resulted in the formation of T4 as measured by radioimmunoassay. Washes from the initial segments of the small intestine of the rat show that substrates are present that react with I2 to produce T4. Single oral doses of I2 to rats produced significant dose-related increases in serum T4 and decreases in T3 concentrations after 2 h. Administration of an equivalent dose of I- did not alter significantly plasma T4 concentrations. Higher concentrations of a radioactive substance that bound a T4-specific antibody are present in plasma of animals treated with 125I2 compared to 125I-. These data support the hypothesis that I2 reacts with metabolites of thyroid hormone in the gastrointestinal tract to resynthesize T4 and elevate its levels in blood.

Use of gamma-irradiation technology in combination with edible coating to produce shelf-stable foods

NASA Astrophysics Data System (ADS)

Ouattara, B.; Sabato, S. F.; Lacroix, M.

2002-03-01

This research was undertaken to determine the effectiveness of low-dose gamma-irradiation combined with edible coatings to produce shelf-stable foods. Three types of commercially distributed food products were investigated: precooked shrimps, ready to cook pizzas, and fresh strawberries. Samples were coated with various formulations of protein-based solutions and irradiated at total doses between 0 and 3 kGy. Samples were stored at 4°C and evaluated periodically for microbial growth. Sensorial analysis was also performed using a nine-point hedonic scale to evaluate the organoleptic characteristics (odor, taste and appearance). The results showed significant ( p⩽0.05) combined effect of gamma-irradiation and coating on microbial growth (APCs and Pseudomonas putida). The shelf-life extension periods ranged from 3 to 10 days for shrimps and from 7 to 20 days for pizzas, compared to uncoated/unirradiated products. No significant ( p>0.05) detrimental effect of gamma-irradiation on sensorial characteristics (odor, taste, appearance) was observed. In strawberries, coating with irradiated protein solutions resulted in significant reduction of the percentage of mold contamination.

The effects of nicotine on ethanol-induced conditioned taste aversions in Long-Evans rats.

PubMed

Rinker, Jennifer A; Busse, Gregory D; Roma, Peter G; Chen, Scott A; Barr, Christina S; Riley, Anthony L

2008-04-01

Overall drug acceptability is thought to be a function of the balance between its rewarding and aversive effects, the latter of which is reportedly affected by polydrug use. Given that nicotine and alcohol are commonly co-used, the present experiments sought to assess nicotine's impact on ethanol's aversive effects within a conditioned taste aversion design. Experiment 1 examined various doses of nicotine (0, 0.4, 0.8, 1.2 mg/kg) to determine a behaviorally active dose, and experiment 2 examined various doses of ethanol (0, 0.5, 1.0, 1.5 g/kg) to determine a dose that produced intermediate aversions. Experiment 3 then examined the aversive effects of nicotine (0.8 mg/kg) and ethanol (1.0 g/kg) alone and in combination. Additionally, nicotine's effects on blood alcohol concentrations (BAC) and ethanol-induced hypothermia were examined. Nicotine and ethanol combined produced aversions significantly greater than those produced by either drug alone or the summed aversive effects of the individual compounds. These effects were unrelated to changes in BAC, but nicotine and ethanol combined produced a prolonged hypothermic effect which may contribute to the increased aversions induced by the combination. These data demonstrate that nicotine may interact with ethanol, increasing ethanol's aversive effects. Although the rewarding effects of concurrently administered nicotine and ethanol were not assessed, these data do indicate that the reported high incidence of nicotine and ethanol co-use is unlikely due to reductions in the aversiveness of ethanol with concurrently administered nicotine. It is more likely attributable to nicotine-related changes in ethanol's rewarding effects.

Substance P contributes to rapidly adapting receptor responses to pulmonary venous congestion in rabbits.

PubMed Central

Bonham, A C; Kott, K S; Ravi, K; Kappagoda, C T; Joad, J P

1996-01-01

1. This study tested the hypothesis that substance P stimulates rapidly adapting receptors (RARs), contributes to the increase in RAR activity produced by mild pulmonary congestion, and evokes an augmented response from RARs when combined with near-threshold levels of pulmonary congestion. 2. RAR activity, peak tracheal pressure, arterial blood pressure and left atrial pressure were measured in paralysed, anaesthetized and ventilated rabbits. Substance P was given i.v. in one-half log incremental doses to a maximum of 3 micrograms kg-1. Mild pulmonary congestion was produced by inflating a balloon in the left atrium to increase left atrial pressure by 5 mmHg. Near-threshold levels of pulmonary congestion were produced by increasing left atrial pressure by 2 mmHg. 3. Substance P produced dose-dependent increases in RAR activity. The highest dose given increased the activity from 1.3 +/- 0.5 to 11.0 +/- 3.1 impulses bin-1. Increases in left atrial pressure of 5 mmHg increased RAR activity from 3.8 +/- 1.4 to 14.7 +/- 3.9 impulses bin-1. Blockade of NK1 receptors with CP 96345 significantly attenuated RAR responses to substance P and to mild pulmonary congestion. 4. Doses of substance P, which alone had no effect, stimulated the RARs when delivered during near-threshold levels of pulmonary congestion. 5. The findings suggest that substance P augments the stimulatory effect of mild pulmonary congestion on RAR activity, most probably by enhancing hydraulically induced microvascular leak. Images Figure 6 PMID:8735708

Effect of time between x-irradiation and chemotherapy on the growth of three solid mouse tumors. IV. Actinomycin-d

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

Twentyman, P.R.; Kallman, R.F.; Brown, J.M.

1979-09-01

Experiments have been carried out to determine the effect of different intervals between the administration of x-radiation (1200 rad) and actinomycin-D (200 ..mu..g/kg) on the growth delay produced in three mouse tumors. The tumors used were the EMT6 tumor in BALB/c mice and the KHT and RIF-1 sarcomas in C3H mice. All tumors were grown intramuscularly in the gastrocnemius muscle, and treatment was carried out at a mean tumor weight of 450 mg. Time to reach 2 x (for KHT) or 4 x (for EMT6 and RIF-1) treatment volume was used as the endpoint of response. The drug was administeredmore » intraperitoneally either 24, 6, or 2 hr before radiation, immediately before the start of radiation, or 3, 6, or 24 hr after radiation. All irradiations were carried out in unanesthetized mice. For a single administration at this dose level (close to the maximum tolerated dose) actinomycin-D did not produce a significant delay in the growth of any of the tumors. For the RIF-1 and KHT tumors, the growth delays produced by drug/radiation combinations generally were not significantly greater than that produced by irradiation alone. For the EMT6 tumor, great variability in the growth delays of combined modality groups seen, with mean growth delays significantly longer than predicted by the radiation alone data. No consistent dependence on timing between irradiation and drug administration was seen.« less

Investigation of the Usability of Retrograded Flour in Meatball Production as A Structure Enhancer.

PubMed

Dinçer, Elif Aykin; Büyükkurt, Özlem Kiliç; Candal, Cihadiye; Bilgiç, Büşra Fatma; Erbaş, Mustafa

2018-02-01

This study aimed to research the possibilities of using retrograded flour produced in the laboratory environment in meatballs and the characteristics of these meatballs. In the use of retrograded flour to produce meatballs, it was ensured that the meatball properties, with respect to chemical, physical and sensorial aspects, were comparable to those of meatballs produced with bread (traditional) and rusk flour (commercial). The cooking loss of meatballs produced with using retrograded flour was similar to that of commercial meatballs. Doses of retrograded flour from 5% to 20% led to a significant decrease in cooking loss, from 21.95% to 6.19%, and in the diameter of meatballs, from 18.60% to 12.74%, but to an increase in the thickness of meatballs, from 28.82% to 41.39% compared to the control. The increase of a * and b * values was shown in that the meatballs were browned on cooking with increasing retrograded flour doses because of non-enzymatic reactions. The springiness of the traditional meatballs was significantly higher than that of the other meatballs. This might have been due to the bread crumbs having a naturally springy structure. Moreover, the addition of retrograded flour in the meatballs significantly ( p <0.05) affected the hardness, springiness and cohesiveness of the meatballs with respect to textural properties. Accordingly, it is considered that the use of 10% retrograded flour is ideal to improve the sensorial values of meatballs and the properties of their structure.

Investigation of the Usability of Retrograded Flour in Meatball Production as A Structure Enhancer

PubMed Central

2018-01-01

This study aimed to research the possibilities of using retrograded flour produced in the laboratory environment in meatballs and the characteristics of these meatballs. In the use of retrograded flour to produce meatballs, it was ensured that the meatball properties, with respect to chemical, physical and sensorial aspects, were comparable to those of meatballs produced with bread (traditional) and rusk flour (commercial). The cooking loss of meatballs produced with using retrograded flour was similar to that of commercial meatballs. Doses of retrograded flour from 5% to 20% led to a significant decrease in cooking loss, from 21.95% to 6.19%, and in the diameter of meatballs, from 18.60% to 12.74%, but to an increase in the thickness of meatballs, from 28.82% to 41.39% compared to the control. The increase of a* and b* values was shown in that the meatballs were browned on cooking with increasing retrograded flour doses because of non-enzymatic reactions. The springiness of the traditional meatballs was significantly higher than that of the other meatballs. This might have been due to the bread crumbs having a naturally springy structure. Moreover, the addition of retrograded flour in the meatballs significantly (p<0.05) affected the hardness, springiness and cohesiveness of the meatballs with respect to textural properties. Accordingly, it is considered that the use of 10% retrograded flour is ideal to improve the sensorial values of meatballs and the properties of their structure. PMID:29725226

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

Tobler, Matt; Watson, Gordon; Leavitt, Dennis

Radiotherapy plays a key role in the definitive or adjuvant management of patients with mesothelioma of the pleural surface. Many patients are referred for radiation with intact lung following biopsy or subtotal pleurectomy. Delivery of efficacious doses of radiation to the pleural lining while avoiding lung parenchyma toxicity has been a difficult technical challenge. Using opposed photon fields produce doses in lung that result in moderate-to-severe pulmonary toxicity in 100% of patients treated. Combined photon-electron beam treatment, at total doses of 4250 cGy to the pleural surface, results in two-thirds of the lung volume receiving over 2100 cGy. We havemore » developed a technique using intensity-modulated photon arc therapy (IMRT) that significantly improves the dose distribution to the pleural surface with concomitant decrease in dose to lung parenchyma compared to traditional techniques. IMRT treatment of the pleural lining consists of segments of photon arcs that can be intensity modulated with varying beam weights and multileaf positions to produce a more uniform distribution to the pleural surface, while at the same time reducing the overall dose to the lung itself. Computed tomography (CT) simulation is critical for precise identification of target volumes as well as critical normal structures (lung and heart). Rotational arc trajectories and individual leaf positions and weightings are then defined for each CT plane within the patient. This paper will describe the proposed rotational IMRT technique and, using simulated isodose distributions, show the improved potential for sparing of dose to the critical structures of the lung, heart, and spinal cord.« less

The preclinical pharmacological profile of WAY-132983, a potent M1 preferring agonist.

PubMed

Bartolomeo, A C; Morris, H; Buccafusco, J J; Kille, N; Rosenzweig-Lipson, S; Husbands, M G; Sabb, A L; Abou-Gharbia, M; Moyer, J A; Boast, C A

2000-02-01

Muscarinic M1 preferring agonists may improve cognitive deficits associated with Alzheimer's disease. Side effect assessment of the M1 preferring agonist WAY-132983 showed significant salivation (10 mg/kg i.p. or p.o.) and produced dose-dependent hypothermia after i. p. or p.o. administration. WAY-132983 significantly reduced scopolamine (0.3 mg/kg i.p.)-induced hyperswimming in mice. Cognitive assessment in rats used pretrained animals in a forced choice, 1-h delayed nonmatch-to-sample radial arm maze task. WAY-132983 (0.3 mg/kg i.p) significantly reduced scopolamine (0.3 mg/kg s.c.)-induced errors. Oral WAY-132983 attenuated scopolamine-induced errors; that is, errors produced after combining scopolamine and WAY-132983 (to 3 mg/kg p.o.) were not significantly increased compared with those of vehicle-treated control animals, whereas errors after scopolamine were significantly higher than those of control animals. With the use of miniosmotic pumps, 0.03 mg/kg/day (s.c.) WAY-132983 significantly reduced AF64A (3 nmol/3 microliter/lateral ventricle)-induced errors. Verification of AF64A cholinotoxicity showed significantly lower choline acetyltransferase activity in the hippocampi of AF64A-treated animals, with no significant changes in the striatal or frontal cortex. Cognitive assessment in primates involved the use of pretrained aged animals in a visual delayed match-to-sample procedure. Oral WAY-132983 significantly increased the number of correct responses during short and long delay interval testing. These effects were also apparent 24 h after administration. WAY-132983 exhibited cognitive benefit at doses lower than those producing undesirable effects; therefore, WAY-132983 is a potential candidate for improving the cognitive status of patients with Alzheimer's disease.

Endomorphin-2 analogs with C-terminal esterification produce potent systemic antinociception with reduced tolerance and gastrointestinal side effects.

PubMed

Wang, Chang-Lin; Qiu, Ting-Ting; Yang, Dai-Jun; Yuan, Bi-Yu; Han, Feng-Tong; Li, Li; Gu, Ning

2017-04-01

C-terminal esterification of opioid peptides may change their opioid activities due to the modified physicochemical properties. In the present study, the pharmacological activities of C-terminal esterified endomorphin-2 (EM-2) analogs 1-3 were characterized by in vitro metabolic stability and octanol/buffer distribution assays. Also, the antinociceptive profiles in the radiant heat paw withdrawal test and related side effects of these analogs were determined. Our results showed that all three analogs significantly increased the metabolic stability and lipophilicity. Moreover, analogs 1-3 displayed potent antinociceptive activities after intracerebroventricular (i.c.v.) administration. Analogs 1 and 3 exhibited about 2-fold higher antinociception than EM-2, and differential opioid mechanisms were involved. In addition, EM-2 at 50 μmol/kg failed to produce any significant antinociceptive activity after subcutaneous (s.c.) administration, whereas equimolar dose of analogs 1-3 produced significant analgesic effects. Analog 3 showed the highest antinociceptive activity after systemic administration, which was consistent with its in vitro stability and lipophilicity. We further evaluated the antinociceptive tolerance of analogs 1-3. In acute tolerance test, analogs 1-3 shifted the dose-response curves rightward by only 1.4-3.2 fold as determined by tolerance ratio, whereas EM-2 by 5.6-fold, demonstrating reduced antinociceptive tolerance. Also, analogs 1 and 2 decreased chronic antinociceptive tolerance by central and peripheral administration of drugs. In particular, analogs 3 displayed insignificant chronic antinociceptive tolerance. Furthermore, analogs 1-3 were less prone to induce gastrointestinal side effects at analgesic doses. The present investigation gave the evidence that C-terminal esterified modifications of EM-2 will facilitate the development of novel opioid analgesics with reduced side effects. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effect of sucrose and safflower oil preloads on short term appetite and food intake of young men.

PubMed

Woodend, D M; Anderson, G H

2001-12-01

The effects of carbohydrate and fat on satiety have been examined primarily through meal composition studies. The purpose of this study was to compare the effects of pure sucrose and safflower oil, isovolumetric beverage preloads, on appetite (measured every 15 minutes by visual analogue scales) and food intake 60 minutes later. Young men consumed 0, 418, 836 and 1254 kJ of sucrose in the first two experiments and these same doses of safflower oil in the third. Finally, the largest doses of sucrose and safflower oil were compared. Sucrose, but not safflower oil, suppressed average appetite compared with control. In experiment 2, food intake was reduced (p<0.05) by 518 kJ after the 418 and 836 kJ preloads and by 1129 kJ after the 1254 kJ sucrose preload. Only the 1254 kJ dose of safflower oil significantly suppressed food intake by 480 kJ in the third experiment. When the 1254 kJ doses were compared directly, sucrose suppressed food intake by 653 kJ compared with control where as safflower oil did not. It is concluded that, in the short-term, sucrose produces a dose dependent reduction in appetite and food intake that is greater than that produced by safflower oil.

Dose-dependent effects of β-phenylglutamic acid hydrochloride (RGPU-135, neuroglutam) on animal behavior.

PubMed

Tyurenkov, I N; Bagmetova, V V; Chernyshova, Yu V; Merkushenkova, O V

2014-12-01

β-Phenylglutamic acid hydrochloride (RGPU-135, neuroglutam) in doses of 13-650 mg/kg suppressed depressive behavior of animals in the Porsolt test (i.e. produced antidepressant properties), reduced anxiety in the open-field, elevated plus maze, and Vogel conflict tests (i.e. produced anxiolytic effects). RGPU-135 in doses of 26-130 mg/kg exhibited more pronounced antidepressant action and in doses of 26 and 52 mg/kg had more pronounced anxiolytic effects. RGPU-135 in doses of 13-78 mg/kg increased locomotor and exploratory activity of animals in the open-field test. Activating effects of this agent decreased with increasing the dose. RGPU-135 in the subtoxic dose (650 mg/kg) suppressed locomotor activity of animals (produced sedative effect).

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.

The acute effects of ethanol on acetanilide disposition in normal subjects, and in patients with liver disease.

PubMed Central

McKay, J; Rawlings, M D; Cobden, I; James, O F

1982-01-01

1 The effects of single doses (25 g and 50 g) oral ethanol on the disposition of acetanilide (50 mg/kg metabolic active mass) has been studied in normal subjects, and in patients with chronic non-alcoholic liver disease. 2 In normal subjects, ethanol produced a dose-dependent increase in acetanilide half-life, and a decrease in acetenilide clearance. There was a significant correlation (rs = 0.71, P less than 0.01) between the 90 min blood ethanol concentration and the reduction in acetanilide clearance. 3 In patients with liver disease, ethanol produced a similar proportional change in acetanilide half-life and clearance, but these were less consistent. Moreover, liver disease itself was associated with an increase in acetenilide half-life, and a reduction in clearance. 4 It is concluded that single oral doses of ethanol, comparable to those consumed during social drinking, may inhibit some forms of microsomal oxidation and thus have important clinical implications. PMID:7138735

The acute effects of ethanol on acetanilide disposition in normal subjects, and in patients with liver disease.

PubMed

McKay, J; Rawlings, M D; Cobden, I; James, O F

1982-10-01

1 The effects of single doses (25 g and 50 g) oral ethanol on the disposition of acetanilide (50 mg/kg metabolic active mass) has been studied in normal subjects, and in patients with chronic non-alcoholic liver disease. 2 In normal subjects, ethanol produced a dose-dependent increase in acetanilide half-life, and a decrease in acetenilide clearance. There was a significant correlation (rs = 0.71, P less than 0.01) between the 90 min blood ethanol concentration and the reduction in acetanilide clearance. 3 In patients with liver disease, ethanol produced a similar proportional change in acetanilide half-life and clearance, but these were less consistent. Moreover, liver disease itself was associated with an increase in acetenilide half-life, and a reduction in clearance. 4 It is concluded that single oral doses of ethanol, comparable to those consumed during social drinking, may inhibit some forms of microsomal oxidation and thus have important clinical implications.

The Effect of Sympathetic Antagonists on the Antidepressant Action of Alprazolam

PubMed Central

Al-Tubuly, RA; Aburawi, SM; Alghzewi, EA; Gorash, ZM; Errwami, S

2008-01-01

Alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam–induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor antagonists with benzodiazepines, which may impact the clinical use of alprazolam, was also studied. Behavioral despair was examined in six groups of albino mice. Drugs were administered intraperitoneally. The control group received only a single dose of 1% Tween 80. The second group received a single dose of alprazolam, and the third group received an antagonist followed by alprazolam. The fourth group was treated with imipramine, and the fifth group received an antagonist followed by imipramine. The sixth group was treated with a single dose of an antagonist alone (atenolol, a β1-selective adrenoceptor antagonist; propranolol, a non selective β-adrenoceptor antagonist; and prazocin, an α1-adrenoceptor antagonist). Results confirmed the antidepressant action of alprazolam and imipramine. Prazocin treatment alone produced depression, but it significantly potentiated the antidepressant actions of imipramine and alprazolam. Atenolol alone produced an antidepressant effect and potentiated the antidepressant action of alprazolam. Propranolol treatment alone produced depression, and antagonized the effects of alprazolam and imipramine, even producing depression in combined treatments.In conclusion, our results reveal that alprazolam may produce antidepressant effects through the release of noradrenaline, which stimulates β2 receptors to produce an antidepressant action. Imipramine may act by activating β2 receptors by blocking or down-regulating β1 receptors. PMID:21499463

Cardiovascular effects of constant rate infusions of lidocaine, lidocaine and dexmedetomidine, and dexmedetomidine in dogs anesthetized at equipotent doses of sevoflurane.

PubMed

Moran-Muñoz, Rafael; Valverde, Alexander; Ibancovichi, J A; Acevedo-Arcique, Carlos M; Recillas-Morales, Sergio; Sanchez-Aparicio, Pedro; Osorio-Avalos, Jorge; Chavez-Monteagudo, Julio Raul

2017-07-01

This study evaluated the cardiovascular effects of a constant rate infusion (CRI) of lidocaine, lidocaine and dexmedetomidine, and dexmedetomidine in dogs anesthetized with sevoflurane at equipotent doses. Treatments consisted of T1-Lidocaine [loading dose 2 mg/kg body weight (BW), IV, and CRI of 100 μg/kg BW per min] at 1.4% end-tidal of sevoflurane (FE SEV ); T2-Dexmedetomidine (loading dose 2 μg/kg BW, IV, and CRI of 2 μg/kg BW per hour) and FE SEV 1.1%; and T3-Lidocaine-Dexmedetomidine using the same doses of T1 and T2 and FE SEV 0.8%. Constant rate infusion of lidocaine did not induce any cardiovascular changes; lidocaine and dexmedetomidine resulted in cardiovascular effects similar to dexmedetomidine alone. These effects were characterized by a significant ( P < 0.001) decrease in heart rate, cardiac output, cardiac index, oxygen delivery, and pulmonary vascular resistance index, and a significant ( P < 0.001) increase in mean and diastolic arterial pressure, systemic vascular resistance index, pulmonary arterial occlusion pressure and oxygen extraction ratio, compared with baseline values. In conclusion, a CRI of lidocaine combined with dexmedetomidine produces significant cardiovascular changes similar to those observed with dexmedetomidine alone.

Effect of Withania somnifera on forced swimming test induced immobility in mice and its interaction with various drugs.

PubMed

Shah, P C; Trivedi, N A; Bhatt, J D; Hemavathi, K G

2006-01-01

The objective of the present study was to evaluate the antidepressant action of Withania somnifera (WS) as well as its interaction with the conventional antidepressant drugs and to delineate the possible mechanism of its antidepressant action using forced swimming model in mice. Effect of different doses of WS, fluoxetine and imipramine were studied on forced swimming test induced mean immobility time (MIT). Moreover effect of WS 100 mg/kg, i.p. was observed at different time intervals. Effect produced by combination of sub therapeutic doses of WS with imipramine (2.5 mg/kg, i.p.) as well as fluoxetine (2.5 mg/kg, i.p.) were also observed. Effect of WS (100 mg/kg, i.p.) as well as combination of WS (37.5 mg/kg, i.p.) with either imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.) were observed in mice pretreated with reserpine (2 mg/kg, i.p.) and clonidine (0.15 mg/kg, i.p.). Effects of prazosin (3 mg/kg, i.p.) or haloperidol (0.1 mg/kg, i.p.) pre-treatment were also observed on WS induced decrease in MIT. WS produced dose dependent decrease in MIT. Maximum effect in MIT was observed after 30 min of treatment with WS 100 mg/kg, i.p. Combination of WS (37.5 mg/kg, i.p.) with imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.) also produced significant decrease in the MIT. Clonidine and reserpine induced increase in MIT, was significantly reversed by treatment with WS (100 mg/kg, i.p.) as well as combination of WS (37.5 mg/kg, i.p.) with either imipramine (2.5 mg/kg, i.p.) or fluoxetine (2.5 mg/kg, i.p.). Pre-treatment with prazosin but not haloperidol, significantly antagonized the WS (100 mg/kg, i.p.) induced decrease in MIT. It is concluded that, WS produced significant decrease in MIT in mice which could be mediated partly through a adrenoceptor as well as alteration in the level of central biogenic amines.

CT dose reduction using Automatic Exposure Control and iterative reconstruction: A chest paediatric phantoms study.

PubMed

Greffier, Joël; Pereira, Fabricio; Macri, Francesco; Beregi, Jean-Paul; Larbi, Ahmed

2016-04-01

To evaluate the impact of Automatic Exposure Control (AEC) on radiation dose and image quality in paediatric chest scans (MDCT), with or without iterative reconstruction (IR). Three anthropomorphic phantoms representing children aged one, five and 10-year-old were explored using AEC system (CARE Dose 4D) with five modulation strength options. For each phantom, six acquisitions were carried out: one with fixed mAs (without AEC) and five each with different modulation strength. Raw data were reconstructed with Filtered Back Projection (FBP) and with two distinct levels of IR using soft and strong kernels. Dose reduction and image quality indices (Noise, SNR, CNR) were measured in lung and soft tissues. Noise Power Spectrum (NPS) was evaluated with a Catphan 600 phantom. The use of AEC produced a significant dose reduction (p<0.01) for all anthropomorphic sizes employed. According to the modulation strength applied, dose delivered was reduced from 43% to 91%. This pattern led to significantly increased noise (p<0.01) and reduced SNR and CNR (p<0.01). However, IR was able to improve these indices. The use of AEC/IR preserved image quality indices with a lower dose delivered. Doses were reduced from 39% to 58% for the one-year-old phantom, from 46% to 63% for the five-year-old phantom, and from 58% to 74% for the 10-year-old phantom. In addition, AEC/IR changed the patterns of NPS curves in amplitude and in spatial frequency. In chest paediatric MDCT, the use of AEC with IR allows one to obtain a significant dose reduction while maintaining constant image quality indices. Copyright © 2016 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.

Clonidine Reduces Nociceptive Responses in Mouse Orofacial Formalin Model: Potentiation by Sigma-1 Receptor Antagonist BD1047 without Impaired Motor Coordination.

PubMed

Yoon, Seo-Yeon; Kang, Suk-Yun; Kim, Hyun-Woo; Kim, Hyung-Chan; Roh, Dae-Hyun

2015-01-01

Although the administration of clonidine, an alpha-2 adrenoceptor agonist, significantly attenuates nociception and hyperalgesia in several pain models, clinical trials of clonidine are limited by its side effects such as drowsiness, hypotension and sedation. Recently, we determined that the sigma-1 receptor antagonist BD1047 dose-dependently reduced nociceptive responses in a mouse orofacial formalin model. Here we examined whether intraperitoneal injection of clonidine suppressed the nociceptive responses in the orofacial formalin test, and whether co-administration with BD1047 enhances lower-dose clonidine-induced anti-nociceptive effects without the disruption of motor coordination and blood pressure. Formalin (5%, 10 µL) was subcutaneously injected into the right upper lip, and the rubbing responses with the ipsilateral fore- or hind-paw were counted for 45 min. Clonidine (10, 30 or 100 µg/kg) was intraperitoneally administered 30 min before formalin injection. Clonidine alone dose-dependently reduced nociceptive responses in both the first and second phases. Co-localization for alpha-2A adrenoceptors and sigma-1 receptors was determined in trigeminal ganglion cells. Interestingly, the sub-effective dose of BD1047 (3 mg/kg) significantly potentiated the anti-nociceptive effect of lower-dose clonidine (10 or 30 µg/kg) in the second phase. In particular, the middle dose of clonidine (30 µg/kg) in combination with BD1047 produced an anti-nociceptive effect similar to that of the high-dose clonidine, but without a significant motor dysfunction or hypotension. In contrast, mice treated with the high dose of clonidine developed severe impairment in motor coordination and blood pressure. These data suggest that a combination of low-dose clonidine with BD1047 may be a novel and safe therapeutic strategy for orofacial pain management.

A biochemical method for assessing the neurotoxic effects of misonidazole in the rat.

PubMed Central

Rose, G. P.; Dewar, A. J.; Stratford, I. J.

1980-01-01

A proven biochemical method for assessing chemically induced neurotoxicity has been applied to the study of the toxic effects of misonidazole (MISO) in the rat. This involves the fluorimetric measurement of beta-glucuronidase and beta-galactosidase activities in homogenates of rat nervous tissue. The tissues analysed were sciatic/posterior tibial nerve (SPTN) cut into 4 sections, trigeminal ganglia and cerebellum. MISO administered i.p. to Wistar rats in doses greater than 300 mg/kg/day for 7 consecutive days produced maximal increases in both beta-glucuronidase and beta-galactosidase activities in th SPTN at 4 weeks (140-180% of control values). The highest increases were associated with the most distal secretion of the nerve. Significant enzyme-activity changes were also found in the trigeminal ganglia and cerebellum of MISO-dosed rats. The greatest activity occurred 4-5 weeks after dosing, and was dose-related. It is concluded that, in the rat, MISO can produce biochemical changes consistent with a dying-back peripheral neuropathy, and biochemical changes suggestive of cerebellar damage. This biochemical approach would appear to offer a convenient quantitative method for the detection of neurotoxic effects of other potential radio-sensitizing drugs. PMID:7459223

Development of a pharmacogenetic-guided warfarin dosing algorithm for Puerto Rican patients.

PubMed

Ramos, Alga S; Seip, Richard L; Rivera-Miranda, Giselle; Felici-Giovanini, Marcos E; Garcia-Berdecia, Rafael; Alejandro-Cowan, Yirelia; Kocherla, Mohan; Cruz, Iadelisse; Feliu, Juan F; Cadilla, Carmen L; Renta, Jessica Y; Gorowski, Krystyna; Vergara, Cunegundo; Ruaño, Gualberto; Duconge, Jorge

2012-12-01

This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy. A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors. The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better 'ideal dose' estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R(2) = 51%). Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients.

Antihyperalgesic/antinociceptive effects of ceftriaxone and its synergistic interactions with different analgesics in inflammatory pain in rodents.

PubMed

Stepanovic-Petrovic, Radica M; Micov, Ana M; Tomic, Maja A; Kovacevic, Jovana M; Boškovic, Bogdan D

2014-03-01

The β-lactam antibiotic ceftriaxone stimulates glutamate transporter GLT-1 expression and is effective in neuropathic and visceral pain models. This study examined the effects of ceftriaxone and its interactions with different analgesics (ibuprofen, celecoxib, paracetamol, and levetiracetam) in somatic and visceral pain models in rodents. The effects of ceftriaxone (intraperitoneally/intraplantarly), analgesics (orally), and their combinations were examined in the carrageenan-induced paw inflammatory hyperalgesia model in rats (n = 6-12) and in the acetic acid-induced writhing test in mice (n = 6-10). The type of interaction between ceftriaxone and analgesics was determined by isobolographic analysis. Pretreatment with intraperitoneally administered ceftriaxone (10-200 mg/kg per day) for 7 days produced a significant dose-dependent antihyperalgesia in the somatic inflammatory model. Acute administration of ceftriaxone, via either intraperitoneal (10-200 mg/kg) or intraplantar (0.05-0.2 mg per paw) routes, produced a significant and dose-dependent but less efficacious antihyperalgesia. In the visceral pain model, significant dose-dependent antinociception of ceftriaxone (25-200 mg/kg per day) was observed only after the 7-day pretreatment. Isobolographic analysis in the inflammatory hyperalgesia model revealed approximately 10-fold reduction of doses of both drugs in all examined combinations. In the visceral nociception model, more than 7- and 17-fold reduction of doses of both drugs was observed in combinations of ceftriaxone with ibuprofen/paracetamol and celecoxib/levetiracetam, respectively. Ceftriaxone exerts antihyperalgesia/antinociception in both somatic and visceral inflammatory pain. Its efficacy is higher after a 7-day pretreatment than after acute administration. The two-drug combinations of ceftriaxone and the nonsteroidal analgesics/levetiracetam have synergistic interactions in both pain models. These results suggest that ceftriaxone, particularly in combinations with ibuprofen, celecoxib, paracetamol, or levetiracetam, may provide useful approach to the clinical treatment of inflammation-related pain.

Direct Measurement of Perchlorate Exposure Biomarkers in a Highly Exposed Population: A Pilot Study

PubMed Central

Wong, Michelle; Copan, Lori; Olmedo, Luis; Patton, Sharyle; Haas, Robert; Atencio, Ryan; Xu, Juhua; Valentin-Blasini, Liza

2011-01-01

Exposure to perchlorate is ubiquitous in the United States and has been found to be widespread in food and drinking water. People living in the lower Colorado River region may have perchlorate exposure because of perchlorate in ground water and locally-grown produce. Relatively high doses of perchlorate can inhibit iodine uptake and impair thyroid function, and thus could impair neurological development in utero. We examined human exposures to perchlorate in the Imperial Valley among individuals consuming locally grown produce and compared perchlorate exposure doses to state and federal reference doses. We collected 24-hour urine specimen from a convenience sample of 31 individuals and measured urinary excretion rates of perchlorate, thiocyanate, nitrate, and iodide. In addition, drinking water and local produce were also sampled for perchlorate. All but two of the water samples tested negative for perchlorate. Perchlorate levels in 79 produce samples ranged from non-detect to 1816 ppb. Estimated perchlorate doses ranged from 0.02 to 0.51 µg/kg of body weight/day. Perchlorate dose increased with the number of servings of dairy products consumed and with estimated perchlorate levels in produce consumed. The geometric mean perchlorate dose was 70% higher than for the NHANES reference population. Our sample of 31 Imperial Valley residents had higher perchlorate dose levels compared with national reference ranges. Although none of our exposure estimates exceeded the U. S. EPA reference dose, three participants exceeded the acceptable daily dose as defined by bench mark dose methods used by the California Office of Environmental Health Hazard Assessment. PMID:21394205

Chernobyl doses. Volume 1. Analysis of forest canopy radiation response from multispectral imagery and the relationship to doses. Technical report, 29 July 1987-30 September 1993

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

McClennan, G.E.; Anno, G.H.; Whicker, F.W.

1994-09-01

This volume of the report Chernobyl Doses presents details of a new, quantitative method for remotely sensing ionizing radiation dose to vegetation. Analysis of Landsat imagery of the area within a few kilometers of the Chernobyl nuclear reactor station provides maps of radiation dose to pine forest canopy resulting from the accident of April 26, 1986. Detection of the first date of significant, persistent deviation from normal of the spectral reflectance signature of pine foliage produces contours of radiation dose in the 20 to 80 Gy range extending up to 4 km from the site of the reactor explosion. Themore » effective duration of exposure for the pine foliage is about 3 weeks. For this exposure time, the LD50 of Pinus sylvestris (Scotch pine) is about 23 Gy. The practical lower dose limit for the remote detection of radiation dose to pine foliage with the Landsat Thematic Mapper is about 5 Gy or 1/4 of the LD50.« less

A study on the dependence of exposure dose reduction and image evaluation on the distance from the dental periapical X-ray machine

NASA Astrophysics Data System (ADS)

Joo, Kyu-Ji; Shin, Jae-Woo; Dong, Kyung-Rae; Lim, Chang-Seon; Chung, Woon-Kwan; Kim, Young-Jae

2013-11-01

Reducing the exposure dose from a periapical X-ray machine is an important aim in dental radiography. Although the radiation exposure dose is generally low, any radiation exposure is harmful to the human body. Therefore, this study developed a method that reduces the exposure dose significantly compared to that encountered in a normal procedure, but still produces an image with a similar resolution. The correlation between the image resolution and the exposure dose of the proposed method was examined with increasing distance between the dosimeter and the X-ray tube. The results were compared with those obtained from the existing radiography method. When periapical radiography was performed once according to the recommendations of the International Commission on Radiological Protection (ICRP), the measured skin surface dose was low at 7 mGy or below. In contrast, the skin surface dose measured using the proposed method was only 1.57 mGy, showing a five-fold reduction. These results suggest that further decreases in dose might be achieved using the proposed method.

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

Anxiolytic activity of a standardized extract of Bacopa monniera: an experimental study.

PubMed

Bhattacharya, S K; Ghosal, S

1998-04-01

Bacopa monniera Wettst. (syn. Herpestis monniera L.; Hindi - Brahmi) is classified in Ayurveda, the classical Indian system of medicine, as Medhyarasayana, a group of plant derived drugs used as nervine tonics to promote mental health and improve memory and intellect. Earlier experimental and clinical studies have demonstrated the memory-promoting action of the plant extracts and that of its active saponins, bacoside A and B. The present study was designed to investigate the anxiolytic activity of a standardized extract (bacoside A content 25.5 ± 0.8%) of B. monniera (BM), since the plant is used in Ayurveda in clinical conditions resembling the modern concept of anxiety disorders. The animal models used have been extensively validated as experimental models of anxiety and included the open-field, elevated plusmaze, social interaction and novelty-suppressed feeding latency tests in rats. BM was used at doses of 5, 10 and 20 mg/kg, p.o. and the results were compared with those elicited by lorazepam, a well known benzodiazepine anxiolytic, used at a dose of 0.5 mg/kg, i.p. BM produced a dose-related anxiolytic activity, qualitatively comparable to that of lorazepam, in all the test parameters. However, statistically significant results were elicited usually by the higher two doses of BM. BM did not produce any significant motor deficit, at the doses used, as was evidenced by using the rota-rod test. The findings correlate with the clinical use of the plant in Ayurveda. The advantage of B. monniera over the widely used benzodiazepine anxiolytics lies in the fact that it promotes cognition unlike the amnesic action of the latter. Copyright © 1998 Gustav Fischer Verlag. Published by Elsevier GmbH.. All rights reserved.

Verticalization of behavior elicited by dopaminergic mobilization is qualitatively different between C57BL/6J and DBA/2J mice.

PubMed

Tirelli, E; Witkin, J M

1994-10-01

Behavioral effects of dopaminergic stimulation were evaluated in C57BL/6J mice and compared to the effects occurring in DBA/2J mice, an inbred strain with reduced densities of striatal dopamine receptors. Effects of apomorphine (0.5-64 mg/kg) alone and in combination with cocaine (30 mg/kg) were assessed using a time-sampling technique that classified climbing and leaning in separate categories. Locomotion was also assessed in a separate experiment. Climbing occurred in DBA/2J mice only at doses of apomorphine that were 16 times higher than the smallest effective dose in C57BL/6J mice; nevertheless, relative to baseline values, effects were fairly comparable. By contrast, whereas DBA/2J mice showed dose-dependent leaning under apomorphine, C57BL/6J mice exhibited little leaning even at doses not producing climbing, and only after the highest apomorphine dose was leaning significantly increased. Apomorphine was equipotent in inducing gnawing across strains, although somewhat less efficacious in DBA/2J mice. When given alone, cocaine produced significant climbing, but not leaning or gnawing, in either strain. Whereas cocaine potentiated apomorphine-induced climbing and gnawing in both strains, apomorphine-induced leaning was not consistently changed by cocaine in either strain. These effects were not indirectly due to hyperkinesia, since neither apomorphine alone nor apomorphine and cocaine in combination was stimulant; apomorphine alone reduced locomotor activity and attenuated cocaine-induced hyperkinesia. The present data do not support a unitary, purely quantitative, account of insensitivity to dopaminergic stimulation based upon low densities of striatal dopamine receptors in DBA/2J mice. Rather, this constellation of results is suggestive of qualitative interstrain dissimilarities in dopaminergic responsiveness that could reflect organizational differences in receptor populations.

Phentolamine Reverses Epinephrine-Enhanced Skin Antinociception of Dibucaine in Rats.

PubMed

Chou, An-Kuo; Chiu, Chong-Chi; Chen, Yu-Wen; Wang, Jhi-Joung; Hung, Ching-Hsia

2018-05-25

The objective of the experiment was to assess the antinociceptive effect of dibucaine, bupivacaine, and epinephrine. To assess the mechanism of action of the interaction between dibucaine and epinephrine, phentolamine, a nonselective α-adrenergic antagonist, was added to the mixture. We assessed sensory blockade with these drugs by injecting 0.6 mL of drug-in-saline in the dorsal thoracolumbar area of rats; pinprick of the "wheal" formed by the injectate was the area targeted for stimulation to elicit a cutaneous trunci muscle reflex. The sensory block of dibucaine was compared with that of bupivacaine or epinephrine. Drug-drug interactions were analyzed by isobologram. Phentolamine was added to investigate the antinociceptive effect of dibucaine coinjected with epinephrine. We demonstrated that dibucaine, epinephrine, and bupivacaine produced dose-dependent skin antinociception. On the median effective dose (ED50) basis, the potency was higher for epinephrine (mean, 0.011 [95% confidence interval {CI}, 0.007-0.015] μmol) than for dibucaine (mean, 0.493 [95% CI, 0.435-0.560] μmol) (P < .01), while there were no significant differences between dibucaine and bupivacaine (mean, 0.450 [95% CI, 0.400-0.505] μmol). On the equipotent basis (75% effective dose, median effective dose, and 25% effective dose), sensory block duration provoked by epinephrine was greater (P < .01) than that provoked by dibucaine or bupivacaine. Coadministration of dibucaine with epinephrine produced a synergistic nociceptive block, whereas phentolamine blocked that synergistic block. The preclinical data indicated that there is no statistically significant difference between the potency and duration of dibucaine and bupivacaine in this model. Epinephrine synergistically enhances the effects of dibucaine, while phentolamine partially blocked those effects. α-Adrenergic receptors play an important role in controlling synergistic analgesic effect of dibucaine combined with epinephrine.

Dynamic changes in metabolic profiles of rats subchronically exposed to mequindox.

PubMed

Jiang, Limiao; Zhao, Xiuju; Huang, Chongyang; Lei, Hehua; Tang, Huiru; Wang, Yulan

2014-11-01

Mequindox is widely used as an antibacterial veterinary drug and a feeding additive for farm animals in China. Although its toxicity has been widely studied, little is known regarding the metabolic effects of subchronic exposure to mequindox, which is vital for the health of meat producing livestock. Here, we characterized the dose- and time-dependent metabolic alterations in female Wistar rats subchronically exposed to mequindox through dietary supplementation at the level of 40, 110 and 280 mg kg(-1) for 13 weeks, employing a NMR based metabonomics approach with supplementary information from serum clinical chemistry. We found that urinary metabolic profiles were significantly affected in all dosed groups during the supplementation period; plasma and hepatic metabolic profiles were significantly affected only in rats dosed with moderate and high levels of mequindox. We also observed a return to control levels, for the profiles of urine and liver, at all dose levels after a two weeks washout period. However, this was not the case for the metabolic profiles of plasma from rats dosed at high levels. At the molecular level, we showed that subchronic exposure to mequindox resulted in tricarboxylic acid cycle (TCA cycle) stimulation, suppression of glycolysis, and promotion of gluconeogenesis and lipid oxidation in rats. In addition, subchronic exposure to mequindox induced oxidative stress in rats. Furthermore, a disturbance of gut microbiota, manifested by alterations in the urinary excretion of hippurate, phenylacetylglycine, 3-(3-hydroxyphenyl)propionate, p-cresol glucuronide, methylamine, dimethylamine, and formate, was associated with mequindox exposure. The present study provided important holistic metabolic information on the effects of subchronic dosage of mequindox on rats, which is useful for evaluating the safety of mequindox usage in meat producing animals.

Yohimbine Increases Opioid-Seeking Behavior in Heroin-Dependent, Buprenorphine-Maintained Individuals

PubMed Central

Greenwald, Mark K.; Lundahl, Leslie H.; Steinmiller, Caren L.

2012-01-01

Rationale In laboratory animals, the biological stressor yohimbine (α2-noradrenergic autoreceptor antagonist) promotes drug seeking. Human laboratory studies have demonstrated that psychological stressors can increase drug craving but not that stressors alter drug seeking. Objectives This clinical study tested whether yohimbine increases opioid seeking behavior. Methods Ten heroin-dependent, buprenorphine (8-mg/day) stabilized volunteers, sampled two doses of hydromorphone (12 and 24 mg IM in counterbalanced order, labeled Drug A [session 1] and Drug B [session 2]). During each of six later sessions (within-subject, double blind, randomized crossover design), volunteers could respond on a 12-trial choice progressive ratio task to earn units (1 or 2 mg) of the sampled hydromorphone dose (Drug A or B) vs. money ($2) following different oral yohimbine pretreatment doses (0, 16.2 and 32.4 mg). Results Behavioral economic demand intensity and peak responding (Omax) were significantly higher for hydromorphone 2-mg than 1-mg. Relative to placebo, yohimbine significantly increased hydromorphone demand inelasticity, more so for hydromorphone 1-mg units (Pmax = 909, 3647 and 3225 for placebo, 16.2 and 32.4 mg yohimbine doses, respectively) than hydromorphone 2-mg units (Pmax = 2656, 3193 and 3615, respectively). Yohimbine produced significant but clinically modest dose-dependent increases in blood pressure (systolic ≈15 and diastolic ≈10 mmHg) and opioid withdrawal symptoms, and decreased opioid agonist symptoms and elated mood. Conclusions These findings concur with preclinical data by demonstrating that yohimbine increases drug seeking; in this study, these effects occurred without clinically significant subjective distress or elevated craving, and partly depended on opioid unit dose. PMID:23161001

Side effects of antimotion sickness drugs

NASA Technical Reports Server (NTRS)

Wood, C. D.; Manno, J. E.; Manno, B. R.; Redetzki, H. M.; Wood, M. D.; Vekovius, W. A.

1984-01-01

The effects on operational proficiency of the antimotion sickness drugs scopolamine, promethazine and d-amphetamine are tested using a computerized pursuit meter. Proficiency is not significantly affected by oral doses of 0.25 mg or 0.50 mg scopolamine but is descreased by oral or I.M. doses of 25 mg promethazine. The performance decrement associated with 25 mg oral promethazine is prevented when combined with 10 mg oral d-amphetamine. The combination of 25 mg I.M. promethazine, 25 mg oral promethazine and 10 mg d-amphetamine produces less performance decrement than oral or I.M. doses of promethazine alone, though more performance decrement than a placebo. I.M. promethazine is adsorbed slowly and consequently may provoke drowsiness.

Effect of a delayed-action phenytoin preparation on blood phenytoin concentration

PubMed Central

Bochner, F.; Hooper, W. D.; Tyrer, J. H.; Eadie, M. J.

1972-01-01

In a cross-over study in a group of epileptic patients it was shown that replacement of the evening dose of an ordinary phenytoin preparation with the same phenytoin dose in a delayed-action preparation produced no significant change in the next morning's mean blood phenytoin concentration. However, replacement of the entire daily dose of an ordinary phenytoin preparation with the delayed-action preparation did increase mean blood phenytoin levels after some days, possibly because the latter preparation contained an additional 6% active drug, as compared with the former. In most circumstances, it seems doubtful if the delayed-action preparation offers any advantage over ordinary phenytoin in treating epilepsy. PMID:5084136

Shielding implications for secondary neutrons and photons produced within the patient during IMPT.

PubMed

DeMarco, J; Kupelian, P; Santhanam, A; Low, D

2013-07-01

Intensity modulated proton therapy (IMPT) uses a combination of computer controlled spot scanning and spot-weight optimized planning to irradiate the tumor volume uniformly. In contrast to passive scattering systems, secondary neutrons and photons produced from inelastic proton interactions within the patient represent the major source of emitted radiation during IMPT delivery. Various published studies evaluated the shielding considerations for passive scattering systems but did not directly address secondary neutron production from IMPT and the ambient dose equivalent on surrounding occupational and nonoccupational work areas. Thus, the purpose of this study was to utilize Monte Carlo simulations to evaluate the energy and angular distributions of secondary neutrons and photons following inelastic proton interactions within a tissue-equivalent phantom for incident proton spot energies between 70 and 250 MeV. Monte Carlo simulation methods were used to calculate the ambient dose equivalent of secondary neutrons and photons produced from inelastic proton interactions in a tissue-equivalent phantom. The angular distribution of emitted neutrons and photons were scored as a function of incident proton energy throughout a spherical annulus at 1, 2, 3, 4, and 5 m from the phantom center. Appropriate dose equivalent conversion factors were applied to estimate the total ambient dose equivalent from secondary neutrons and photons. A reference distance of 1 m from the center of the patient was used to evaluate the mean energy distribution of secondary neutrons and photons and the resulting ambient dose equivalent. For an incident proton spot energy of 250 MeV, the total ambient dose equivalent (3.6 × 10(-3) mSv per proton Gy) was greatest along the direction of the incident proton spot (0°-10°) with a mean secondary neutron energy of 71.3 MeV. The dose equivalent decreased by a factor of 5 in the backward direction (170°-180°) with a mean energy of 4.4 MeV. An 8 × 8 × 8 cm(3) volumetric spot distribution (5 mm FWHM spot size, 4 mm spot spacing) optimized to produce a uniform dose distribution results in an ambient dose equivalent of 4.5 × 10(-2) mSv per proton Gy in the forward direction. This work evaluated the secondary neutron and photon emission due to monoenergetic proton spots between 70 and 250 MeV, incident on a tissue equivalent phantom. Example calculations were performed to estimate concrete shield thickness based upon appropriate workload and shielding design assumptions. Although lower than traditional passive scattered proton therapy systems, the ambient dose equivalent from secondary neutrons produced by the patient during IMPT can be significant relative to occupational and nonoccupational workers in the vicinity of the treatment vault. This work demonstrates that Monte Carlo simulations are useful as an initial planning tool for studying the impact of the treatment room and maze design on surrounding occupational and nonoccupational work areas.

Lack of developmental and reproductive toxicity of 2,3,3',4,4'-pentachlorobiphenyl (PCB-105) in Ring-Necked Pheasants

USGS Publications Warehouse

Hornung, M.W.; Miller, L.; Goodman, B.; Melancon, M.J.; Peterson, R.E.

1998-01-01

Mono-ortho PCBs are global contaminants of wildlife with the potential to produce toxicity by an aryl hydrocarbon receptor (AhR)-mediated mechanism. To determine the potency of 2,3,3',4,4'pentachlorobiphenyl (PCB-105) for producing reproductive and developmental toxicity, adult ring-necked pheasant hens (Phasianus colchicus) were orally dosed with 0, 0.06, 0.6 or 6 mg PCB105/kg hen/week for 10 weeks to achieve cumulative doses of 0, 0.6, 6, or 60 mg PCB -105/hen after which hens were bred with untreated roosters once per week for 8 weeks. Except at week 6 of the egglaying period when cumulative egg production in the 6mg PCB 105/hen group was greater than controls, fertilized egg production was not significantly different between treatment groups. Embryo mortality and chick mortality were not significantly different between treatment groups. Total body and heart weights of all chicks 1 day posthatch (dph) were not different between groups, however liver weights of chicks from the 60mg/kg treatment groups were greater than controls at 1 dph. The first chick to hatch from each hen was reared to 21 dph and among these birds the total body, liver and heart weights were not different between groups. There were no dose-related malformations of the beak or limbs, and no signs of subcutaneous edema, ascites, or pericardial edema in chicks at 1 or 21 dph. Hepatic microsomal monooxygenase activities [ethoxyresorufin-O-dealkylase (EROD), benzyloxyresorufin-O-dealkylase (BROD), and methyloxyresorufin-O-dealkylase (MROD)] were significantly elevated in chicks at 1 dph from hens given a cumulative PCB105 dose of 6 mg/kg and in chicks at 21 dph from hens given a cumulative PCB dose of 60 mg/kg. These results indicate that a cumulative PCB-105 dose up to 60 mg/kg hen does not decrease the production of fertilized eggs or increase embryo or chick mortality in ring-necked pheasants, but does increase chick hepatic monooxygenase activity.

Paediatric dose reduction with the introduction of digital fluorography.

PubMed

Mooney, R B; McKinstry, J

2001-01-01

Fluoroscopy guided examinations in a paediatric X ray department were initially carried out on a unit that used a conventional screen-film combination for spot-films. A new fluoroscopy unit was installed with the facilities of digital fluorography and last image hold. Comparison of equipment performance showed that the dose per image for screen-film and digital fluorography was 3 microGy and 0.4 microGy, respectively. Although the screen-film had superior image quality, the department's radiologist confirmed that digital fluorography provided a diagnostic image. Patient dose measurements showed that introduction of the new unit caused doses to fall by an average of 70%, although fluoroscopy time had not changed significantly. The new unit produced 40% less air kerma during fluoroscopy. The remaining 30% reduction in dose was due to the introduction of digital fluorography and last image hold facilities. It is concluded that the use of digital fluorography can be an effective way of reducing paediatric dose.

Dissociation between the effects of P1, P4-diadenosine tetraphosphate (Ap4A) on renal haemodynamics and tubular function in anaesthetized rats.

PubMed

Jankowski, M; Angielski, S; Szczepańska-Konkel, M

2008-03-01

Previous studies from our laboratory have reported a marked reduction in glomerular filtration rate (GFR) and sodium reabsorption in renal proximal tubule during intravenous infusion of P(1),P(4)-diadenosine tetraphosphate (Ap(4)A) at dose of 1.0 micromol/kg + 10 nmol/kg/min (i.v., injection followed by infusion) in anaesthetized Wistar rats. In the present study, the changes of GFR and urine sodium excretion were investigated in response to systemic infusion of Ap(4)A at different doses. Ap(4)A at dose of 0.1 micromol/kg + 1.0 nmol/kg/min did not change GFR and sodium urinary excretion whereas 2-fold higher dose produced significant (3.4-fold) increase in sodium excretion without changes in GFR. Significant but transient reduction in GFR by approximately 21% was observed during infusion of Ap(4)A at dose of 0.5 micromol/kg + 5.0 nmol/kg/min. Higher doses of Ap(4)A (1.0 micromol/kg + 10 nmol/kg/min and 2.0 micromol/kg + 20 nmol/kg/min) reduction in GFR and marked natriuresis. Our results suggest that tubular sodium transport systems are more sensitive to Ap(4)A than systems involved in GFR regulation.

Predicted blood glucose from insulin administration based on values from miscoded glucose meters.

PubMed

Raine, Charles H; Pardo, Scott; Parkes, Joan Lee

2008-07-01

The proper use of many types of self-monitored blood glucose (SMBG) meters requires calibration to match strip code. Studies have demonstrated the occurrence and impact on insulin dose of coding errors with SMBG meters. This paper reflects additional analyses performed with data from Raine et al. (JDST, 2:205-210, 2007). It attempts to relate potential insulin dose errors to possible adverse blood glucose outcomes when glucose meters are miscoded. Five sets of glucose meters were used. Two sets of meters were autocoded and therefore could not be miscoded, and three sets required manual coding. Two of each set of manually coded meters were deliberately miscoded, and one from each set was properly coded. Subjects (n = 116) had finger stick blood glucose obtained at fasting, as well as at 1 and 2 hours after a fixed meal (Boost((R)); Novartis Medical Nutrition U.S., Basel, Switzerland). Deviations of meter blood glucose results from the reference method (YSI) were used to predict insulin dose errors and resultant blood glucose outcomes based on these deviations. Using insulin sensitivity data, it was determined that, given an actual blood glucose of 150-400 mg/dl, an error greater than +40 mg/dl would be required to calculate an insulin dose sufficient to produce a blood glucose of less than 70 mg/dl. Conversely, an error less than or equal to -70 mg/dl would be required to derive an insulin dose insufficient to correct an elevated blood glucose to less than 180 mg/dl. For miscoded meters, the estimated probability to produce a blood glucose reduction to less than or equal to 70 mg/dl was 10.40%. The corresponding probabilities for autocoded and correctly coded manual meters were 2.52% (p < 0.0001) and 1.46% (p < 0.0001), respectively. Furthermore, the errors from miscoded meters were large enough to produce a calculated blood glucose outcome less than or equal to 50 mg/dl in 42 of 833 instances. Autocoded meters produced zero (0) outcomes less than or equal to 50 mg/dl out of 279 instances, and correctly coded manual meters produced 1 of 416. Improperly coded blood glucose meters present the potential for insulin dose errors and resultant clinically significant hypoglycemia or hyperglycemia. Patients should be instructed and periodically reinstructed in the proper use of blood glucose meters, particularly for meters that require coding.

Studies To Examine Potential Tolerability Differences between the 5-HT2C Receptor Selective Agonists Lorcaserin and CP-809101.

PubMed

Higgins, Guy A; Silenieks, Leonardo B; Patrick, Amy; De Lannoy, Ines A M; Fletcher, Paul J; Parker, Linda A; MacLusky, Neil J; Sullivan, Laura C; Chavera, Teresa A; Berg, Kelly A

2017-05-17

Lorcaserin (LOR) is a selective 5-HT 2C receptor agonist that has been FDA approved as a treatment for obesity. The most frequently reported side-effects of LOR include nausea and headache, which can be dose limiting. We have previously reported that in the rat, while LOR produced unconditioned signs characteristic of nausea/malaise, the highly selective 5-HT 2C agonist CP-809101 (CP) produced fewer equivalent signs. Because this may indicate a subclass of 5-HT 2C agonists having better tolerability, the present studies were designed to further investigate this apparent difference. In a conditioned gaping model, a rodent test of nausea, LOR produced significantly higher gapes compared to CP consistent with it having higher emetogenic properties. Subsequent studies were designed to identify features of each drug that may account for such differences. In rats trained to discriminate CP-809101 from saline, both CP and LOR produced full generalization suggesting a similar interoceptive cue. In vitro tests of functional selectivity designed to examine signaling pathways activated by both drugs in CHO (Chinese hamster ovary) cells expressing h5-HT 2C receptors failed to identify evidence for biased signaling differences between LOR and CP. Thus, both drugs showed similar profiles across PLC, PLA 2 , and ERK signaling pathways. In studies designed to examine pharmacokinetic differences between LOR and CP, while drug plasma levels correlated with increasing dose, CSF levels did not. CSF levels of LOR increased proportionally with dose; however CSF levels of CP plateaued from 6 to 12 mg/kg. Thus, the apparently improved tolerability of CP likely reflects a limit to CNS levels attained at relatively high doses.

Novel quinazoline and acetamide derivatives as safe anti-ulcerogenic agent and anti-ulcerative colitis activity.

PubMed

Alasmary, Fatmah A S; Awaad, Amani S; Alafeefy, Ahmed M; El-Meligy, Reham M; Alqasoumi, Saleh I

2018-01-01

Two novel quinazoline derivatives named as; 3-[(4-hydroxy-3-methoxy-benzylidene)-amino]-2- p- tolyl-3 H -quinazolin-4-one ( 5 ) and 2- p -Tolyl-3-[3,4,5-trimethoxy-benzylidene-amino]-3 H -quinazolin-4-one ( 6 ) in addition to one acetamide derivative named as 2-(2-Hydroxycarbonylphenylamino)- N -(4-aminosulphonylphenyl) 11 were synthesized, and evaluated for their anti-ulcerogenic & Anti-Ulcerative colitis activities. All of the three compounds showed curative activity against acetic acid induced ulcer model at a dose of 50 mg/kg, they produced 65%, 85% & 57.74% curative ratio for compounds 5 , 6 & 11 respectively. The effect of the tested compounds 5 , 6 & 11 at dose 50 mg/kg were significantly (P < 0.01) more effective than dexamesathone (0.1 mg/kg) in reducing all parameters. Compounds showed curative activity of for peptic ulcer (induced by absolute alcohol (at a dose of 50 mg/kg, it produced Curative of control ulcer 56.00%, 61.70% & 87.1% for compounds 5 , 6 & 11 respectively at dose 50 mg/kg, while the standard drug (Omeprazole 20 mg/kg) produced 33.3%. In both tests, the activity of our target compounds were higher than the standard drugs used for treatment of peptic ulcer and ulcerative colitis. No side effects were reported on liver and kidney functions upon prolonged oral administration of this compounds.

SU-E-T-238: Monte Carlo Estimation of Cerenkov Dose for Photo-Dynamic Radiotherapy

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

Chibani, O; Price, R; Ma, C

Purpose: Estimation of Cerenkov dose from high-energy megavoltage photon and electron beams in tissue and its impact on the radiosensitization using Protoporphyrine IX (PpIX) for tumor targeting enhancement in radiotherapy. Methods: The GEPTS Monte Carlo code is used to generate dose distributions from 18MV Varian photon beam and generic high-energy (45-MV) photon and (45-MeV) electron beams in a voxel-based tissueequivalent phantom. In addition to calculating the ionization dose, the code scores Cerenkov energy released in the wavelength range 375–425 nm corresponding to the pick of the PpIX absorption spectrum (Fig. 1) using the Frank-Tamm formula. Results: The simulations shows thatmore » the produced Cerenkov dose suitable for activating PpIX is 4000 to 5500 times lower than the overall radiation dose for all considered beams (18MV, 45 MV and 45 MeV). These results were contradictory to the recent experimental studies by Axelsson et al. (Med. Phys. 38 (2011) p 4127), where Cerenkov dose was reported to be only two orders of magnitude lower than the radiation dose. Note that our simulation results can be corroborated by a simple model where the Frank and Tamm formula is applied for electrons with 2 MeV/cm stopping power generating Cerenkov photons in the 375–425 nm range and assuming these photons have less than 1mm penetration in tissue. Conclusion: The Cerenkov dose generated by high-energy photon and electron beams may produce minimal clinical effect in comparison with the photon fluence (or dose) commonly used for photo-dynamic therapy. At the present time, it is unclear whether Cerenkov radiation is a significant contributor to the recently observed tumor regression for patients receiving radiotherapy and PpIX versus patients receiving radiotherapy only. The ongoing study will include animal experimentation and investigation of dose rate effects on PpIX response.« less

"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.

Toxicology of brotizolam

PubMed Central

Hewett, C.; Kreuzer, H.; Köllmer, H.; Niggeschulze, A.; Stötzer, H.

1983-01-01

1 Acute studies. Following oral or intraperitoneal administration, toxicity was very low (LD50 in rodents > 10,000 and > 900 mg/kg, respectively). 2 Subacute and chronic studies in rodents. Signs of toxicity were seen only at doses of 400 mg/kg or more. Histopathological changes were found only in the 78-week study. 3 Subacute studies in dogs (intravenous) and primates (oral). In dogs, doses of 0.1 and 0.3 mg/kg produced ataxia, salivation, and diarrhoea. In monkeys doses of 7 mg/kg or higher produced ataxia, increased appetite, hyperreflexive muscular spasms, increase in liver weight, and lipid depletion of the adrenal cortex. 4 Reproductive studies in the rat and rabbit. Repeated doses of up to 30 mg/kg were not associated with any disturbance in fertility; nor were any embryotoxic or teratogenic effects observed. When dams were treated with 400 mg/kg, litter mortality was markedly increased. 5 Mutagenicity studies. The four different tests performed gave no indication of any mutagenic effect. 6 Local tolerance tests in the rabbit. Brotizolam was well tolerated when administered intramuscularly, intra-arterially, or intravenously. 7 Carcinogenicity studies in rodents. The mouse study showed no evidence of a tumourigenic effect. The rat study is still being evaluated. 8 The toxicological studies demonstrate that brotizolam has an unusually wide therapeutic range. Findings of toxicological significance, most of which were reversible, were first recorded at doses of 7-10 mg/kg, i.e. at more than 100-times the intended human therapeutic dose. PMID:6686462

Oral administration of the 5-HT6 receptor antagonists SB-357134 and SB-399885 improves memory formation in an autoshaping learning task.

PubMed

Perez-García, Georgina; Meneses, Alfredo

2005-07-01

In this work we aimed to re-examine the 5-HT6 receptor role, by testing the selective antagonists SB-357134 (1-30 mg/kg p.o.) and SB-399885 (1-30 mg/kg p.o.) during memory consolidation of conditioned responses (CR%), in an autoshaping Pavlovian/instrumental learning task. Bioavailability, half-life and minimum effective dose to induce inappetence for SB-357134 were 65%, 3.4 h, and 30 mg/kg p.o., and for SB-399885 were 52%, 2.2 h, and 50 mg/kg p.o., respectively. Oral acute and chronic administration of either SB-357134 or SB-399885 improved memory consolidation compared to control groups. Acute administration of SB-357134, at 1, 3, 10 and 30 mg/kg, produced a CR% inverted-U curve, eliciting the latter dose a 7-fold increase relative to saline group. Acute injection of SB-399885 produced significant CR% increments, being 1 mg/kg the most effective dose. Repeated administration (7 days) of either SB-357134 (10 mg/kg) or SB-399885 (1 mg/kg) elicited the most significant CR% increments. Moreover, modeling the potential therapeutic benefits of 5-HT6 receptor blockade, acute or repeated administration of SB-399885, at 10 mg/kg reversed memory deficits produced by scopolamine or dizocilpine, and SB-357134 (3 and 10 mg/kg) prevented amnesia and even improved performance. These data support the notion that endogenously 5-HT acting, via 5-HT6 receptor, improves memory consolidation.

Gastric anti-ulcer and cytoprotective effect of selenium in rats

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

Parmar, N.S.; Tariq, M.; Ageel, A.M.

1988-01-01

Selenium, a trace element, in the form of sodium selenite has been studied for its ability to protect the gastric mucosa against the injuries caused by hypothermic restraint stress, aspirin, indomethacin, reserpine, dimaprit, and various other gastric mucosal-damaging (necrotizing) agents in rats. The results demonstrate that oral administration of sodium selenite produces a significant inhibition of the gastric mucosal damage induced by all the procedures used in this study. Selenium, in a nonantisecretory dose, produced a marked cytoprotective effect against all the necrotizing agents. The cytoprotective effect of selenium against the effects of 80% ethanol and 0.6 M HCl wasmore » significantly reversed by prior treatment with a dose of indomethacin that inhibits prostaglandin biosynthesis. These data indicate that sodium selenite inhibits the formation of these lesions by the mucosal generation of prostaglandins. The concentrations of nonprotein sulfhydryls (NP-SH) were significantly decreased in the gastric mucosa following the administration of necrotizing agents--80% ethanol and 0.6 M HCl. Treatment with sodium selenite, which significantly reduced the intensity of gastric lesions, did not replenish the reduced levels of gastric mucosal NP-SH, thus ruling out the mediation of its protective effect through sulfhydryls. The antisecretory effect of sodium selenite, which becomes evident only in the high dose of 20 mumol/kg, may be responsible for the inhibition of gastric lesions induced by aspirin, indomethacin, reserpine, and dimaprit. Our findings show that selenium possesses significant anti-ulcer and adaptive cytoprotective effects. However, further detailed studies are required to confirm these effects, to establish its mechanism(s) of action, and to determine its role in the prophylaxis and treatment of peptic ulcer disease.« less

An evaluation of acute toxicity of colloidal silver nanoparticles.

PubMed

Maneewattanapinyo, Pattwat; Banlunara, Wijit; Thammacharoen, Chuchaat; Ekgasit, Sanong; Kaewamatawong, Theerayuth

2011-11-01

Tests for acute oral toxicity, eye irritation, corrosion and dermal toxicity of colloidal silver nanoparticles (AgNPs) were conducted in laboratory animals following OECD guidelines. Oral administration of AgNPs at a limited dose of 5,000 mg/kg produced neither mortality nor acute toxic signs throughout the observation period. Percentage of body weight gain of the mice showed no significant difference between control and treatment groups. In the hematological analysis, there was no significant difference between mice treated with AgNPs and controls. Blood chemistry analysis also showed no differences in any of the parameter examined. There was neither any gross lesion nor histopathological change observed in various organs. The results indicated that the LD(50) of colloidal AgNPs is greater than 5,000 mg/kg body weight. In acute eye irritation and corrosion study, no mortality and toxic signs were observed when various doses of colloidal AgNPs were instilled in guinea pig eyes during 72 hr observation period. However, the instillation of AgNPs at 5,000 ppm produced transient eye irritation during early 24 hr observation time. No any gross abnormality was noted in the skins of the guinea pigs exposed to various doses of colloidal AgNPs. In addition, no significant AgNPs exposure relating to dermal tissue changes was observed microscopically. In summary, these findings of all toxicity tests in this study suggest that colloidal AgNPs could be relatively safe when administered to oral, eye and skin of the animal models for short periods of time.

Single isotope evaluation of pulmonary capillary protein leak (ARDS model) using computerized gamma scintigraphy

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

Tatum, J.L.; Strash, A.M.; Sugerman, H.J.

Using a canine oleic acid model, a computerized gamma scintigraphic technique was evaluated to determine 1) ability to detect pulmonary capillary protein leak in a model temporally consistent with clinical adult respiratory distress syndrome (ARDS), 2) the possibility of providing a quantitative index of leak, and 3) the feasibility of closely spaced repeat evaluations. Study animals received oleic acid (controls, n . 10; 0.05 ml/kg, n . 10; 0.10 ml/kg, n . 12; 0.15 ml/kg, n . 6) 3 hours prior to a tracer dose of technetium-99m (/sup 99/mTc) HSA. One animal in each dose group also received two repeatmore » tracer injections spaced a minimum of 45 minutes apart. Digital images were obtained with a conventional gamma camera interfaced to a dedicated medical computer. Lung: heart ratio versus time curves were generated, and a slope index was calculated for each curve. Slope index values for all doses were significantly greater than control values (P(t) less than 0.0001). Each incremental dose increase was also significantly greater than the previous dose level. Oleic acid dose versus slope index fitted a linear regression model with r . 0.94. Repeat dosing produced index values with standard deviations less than the group sample standard deviations. We feel this technique may have application in the clinical study of pulmonary permeability edema.« less

Pharmacokinetics of testosterone cream applied to scrotal skin.

PubMed

Iyer, R; Mok, S F; Savkovic, S; Turner, L; Fraser, G; Desai, R; Jayadev, V; Conway, A J; Handelsman, D J

2017-07-01

Scrotal skin is thin and has high steroid permeability, but the pharmacokinetics of testosterone via the scrotal skin route has not been studied in detail. The aim of this study was to define the pharmacokinetics of testosterone delivered via the scrotal skin route. The study was a single-center, three-phase cross-over pharmacokinetic study of three single doses (12.5, 25, 50 mg) of testosterone cream administered in random sequence on different days with at least 2 days between doses to healthy eugonadal volunteers with endogenous testosterone suppressed by administration of nandrolone decanoate. Serum testosterone, DHT and estradiol concentrations were measured by liquid chromatograpy, mass spectrometry in extracts of serum taken before and for 16 h after administration of each of the three doses of testosterone cream to the scrotal skin. Testosterone administration onto the scrotal skin produced a swift (peak 1.9-2.8 h), dose-dependent (p < 0.0001) increase in serum testosterone with the 25 mg dose maintaining physiological levels for 16 h. Serum DHT displayed a time- (p < 0.0001), but not dose-dependent, increase in concentration reaching a peak concentration of 1.2 ng/mL (4.1 nm) at 4.9 h which was delayed by 2 h after peak serum testosterone. There were no significant changes in serum estradiol over time after testosterone administration. We conclude that testosterone administration to scrotal skin is well tolerated and produces dose-dependent peak serum testosterone concentration with a much lower dose relative to the non-scrotal transdermal route. © 2017 American Society of Andrology and European Academy of Andrology.

Comparative dosimetry of volumetric modulated arc therapy and limited-angle static intensity-modulated radiation therapy for early-stage larynx cancer

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

Riegel, Adam C.; Antone, Jeffrey; Schwartz, David L., E-mail: dschwartz3@nshs.edu

2013-04-01

To compare relative carotid and normal tissue sparing using volumetric-modulated arc therapy (VMAT) or intensity-modulated radiation therapy (IMRT) for early-stage larynx cancer. Seven treatment plans were retrospectively created on 2 commercial treatment planning systems for 11 consecutive patients with T1-2N0 larynx cancer. Conventional plans consisted of opposed-wedged fields. IMRT planning used an anterior 3-field beam arrangement. Two VMAT plans were created, a full 360° arc and an anterior 180° arc. Given planning target volume (PTV) coverage of 95% total volume at 95% of 6300 cGy and maximum spinal cord dose below 2500 cGy, mean carotid artery dose was pushed asmore » low as possible for each plan. Deliverability was assessed by comparing measured and planned planar dose with the gamma (γ) index. Full-arc planning provided the most effective carotid sparing but yielded the highest mean normal tissue dose (where normal tissue was defined as all soft tissue minus PTV). Static IMRT produced next-best carotid sparing with lower normal tissue dose. The anterior half-arc produced the highest carotid artery dose, in some cases comparable with conventional opposed fields. On the whole, carotid sparing was inversely related to normal tissue dose sparing. Mean γ indexes were much less than 1, consistent with accurate delivery of planned treatment. Full-arc VMAT yields greater carotid sparing than half-arc VMAT. Limited-angle IMRT remains a reasonable alternative to full-arc VMAT, given its ability to mediate the competing demands of carotid and normal tissue dose constraints. The respective clinical significance of carotid and normal tissue sparing will require prospective evaluation.« less

GDF-15 gene expression alterations in human lymphoblastoid cells and peripheral blood lymphocytes following exposure to ionizing radiation

PubMed Central

Li, Shuang; Zhang, Qing-Zhao; Zhang, De-Qin; Feng, Jiang-Bin; Luo, Qun; Lu, Xue; Wang, Xin-Ru; Li, Kun-Peng; Chen, De-Qing; Mu, Xiao-Feng; Gao, Ling; Liu, Qing-Jie

2017-01-01

The identification of rapid, sensitive and high-throughput biomarkers is imperative in order to identify individuals harmed by radiation accidents, and accurately evaluate the absorbed doses of radiation. DNA microarrays have previously been used to evaluate the alterations in growth/differentiation factor 15 (GDF15) gene expression in AHH-1 human lymphoblastoid cells, following exposure to γ-rays. The present study aimed to characterize the relationship between the dose of ionizing radiation and the produced effects in GDF-15 gene expression in AHH-1 cells and human peripheral blood lymphocytes (HPBLs). GDF-15 mRNA and protein expression levels following exposure to γ-rays and neutron radiation were assessed by reverse transcription-quantitative polymerase chain reaction and western blot analysis in AHH-1 cells. In addition, alterations in GDF-15 gene expression in HPBLs following ex vivo irradiation were evaluated. The present results demonstrated that GDF-15 mRNA and protein expression levels in AHH-1 cells were significantly upregulated following exposure to γ-ray doses ranging between 1 and 10 Gy, regardless of the dose rate. A total of 48 h following exposure to neutron radiation, a dose-response relationship was identified in AHH-1 cells at γ-ray doses between 0.4 and 1.6 Gy. GDF-15 mRNA levels in HPBLs were significantly upregulated following exposure to γ-ray doses between 1 and 8 Gy, within 4–48 h following irradiation. These results suggested that significant time- and dose-dependent alterations in GDF-15 mRNA and protein expression occur in AHH-1 cells and HPBLs in the early phases following exposure to ionizing radiation. In conclusion, alterations in GDF-15 gene expression may have potential as a biomarker to evaluate radiation exposure. PMID:28440431

CT image electron density quantification in regions with metal implants: implications for radiotherapy treatment planning

NASA Astrophysics Data System (ADS)

Jechel, Christopher Alexander

In radiotherapy planning, computed tomography (CT) images are used to quantify the electron density of tissues and provide spatial anatomical information. Treatment planning systems use these data to calculate the expected spatial distribution of absorbed dose in a patient. CT imaging is complicated by the presence of metal implants which cause increased image noise, produce artifacts throughout the image and can exceed the available range of CT number values within the implant, perturbing electron density estimates in the image. Furthermore, current dose calculation algorithms do not accurately model radiation transport at metal-tissue interfaces. Combined, these issues adversely affect the accuracy of dose calculations in the vicinity of metal implants. As the number of patients with orthopedic and dental implants grows, so does the need to deliver safe and effective radiotherapy treatments in the presence of implants. The Medical Physics group at the Cancer Centre of Southeastern Ontario and Queen's University has developed a Cobalt-60 CT system that is relatively insensitive to metal artifacts due to the high energy, nearly monoenergetic Cobalt-60 photon beam. Kilovoltage CT (kVCT) images, including images corrected using a commercial metal artifact reduction tool, were compared to Cobalt-60 CT images throughout the treatment planning process, from initial imaging through to dose calculation. An effective metal artifact reduction algorithm was also implemented for the Cobalt-60 CT system. Electron density maps derived from the same kVCT and Cobalt-60 CT images indicated the impact of image artifacts on estimates of photon attenuation for treatment planning applications. Measurements showed that truncation of CT number data in kVCT images produced significant mischaracterization of the electron density of metals. Dose measurements downstream of metal inserts in a water phantom were compared to dose data calculated using CT images from kVCT and Cobalt-60 systems with and without artifact correction. The superior accuracy of electron density data derived from Cobalt-60 images compared to kVCT images produced calculated dose with far better agreement with measured results. These results indicated that dose calculation errors from metal image artifacts are primarily due to misrepresentation of electron density within metals rather than artifacts surrounding the implants.

The effect of single large dose hydrocortisone treatment on IgM and IgG antibody production, morphological distribution of antibody producing cells and immunological memory

PubMed Central

Petrányi, Gy.; Benczúr, M.; Alföldy, P.

1971-01-01

The effect of a single subcutaneous dose of hydrocortisone (730 mg/kg ∼ 21-day LD50) on the haemolysin response of mice to sheep erythrocyte antigen was examined. Hydrocortisone was administered once at times varying from 5 days before immunization with sheep erythrocytes to 9 days after antigen. Total suppression of the 7S haemolysin titre was brought about by treatment with single dose of 750 mg/kg in the period 5 days prior to antigen until 2 days after antigen; at the same time, the titre of 19S haemolysin exceeded the control 19S titre. Microplaque assay on the 5th day failed to confirm total suppression of 7S antibody synthesis, as 4 per cent of the splenic plaque-forming cells produced 7S. The same assay failed to verify the augmentation of 19S production on a cellular level, as the number of 19S plaque-forming was significantly decreased. Hydrocortisone could be shown to influence the morphology of the 19S antibody producing cells by increasing the percentage of mature cell types. A selective depressing activity by hydrocortisone on 7S memory was found. The theoretical implications of these findings are discussed. PMID:4934137

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

Antinociceptive effects of JWH015 in female and male rats.

PubMed

Craft, Rebecca M; Greene, Nicholas Z; Wakley, Alexa A

2018-04-01

Despite greater chronic pain prevalence in females compared with males, and the analgesic potential of cannabinoid receptor type 2 (CB2) agonists, CB2 agonists have rarely been tested in females. The aim of the present study was to compare the antinociceptive effects of a CB2-preferring agonist, (2-methyl-1-propyl-1H-indol-3-yl)-1-naphthalenylmethanone (JWH015), in female and male rats against acute pain and persistent inflammatory pain. JWH015 (5-20 mg/kg, intraperitoneally) produced dose-dependent and time-dependent increases in latency to respond on the tail withdrawal and paw pressure tests that did not differ statistically between the sexes. JWH015 dose-dependently decreased locomotor activity in both sexes, but was more potent in females than males. JWH015 produced little catalepsy in either sex. In females, the antinociceptive effects of JWH015 against acute pain were blocked by rimonabant and SR144528, whereas locomotor suppression was antagonized by rimonabant. When administered 3 days after intraplantar injection of complete Freund's adjuvant, JWH015 produced a significantly greater antiallodynic effect in females at the highest dose tested (10 mg/kg, intraperitoneally). Antiallodynic effects of JWH015 were antagonized by rimonabant and SR144528 in both sexes. These studies indicate that systemically administered JWH015 produced antinociception that was both CB1 and CB2 receptor-mediated in both sexes. Unlike [INCREMENT]-9-tetrahydrocannabinol and other nonselective cannabinoid agonists, the CB2-preferring agonist JWH015 may produce more equivalent antinociception in females and males.

Dronabinol and marijuana in HIV-positive marijuana smokers. Caloric intake, mood, and sleep.

PubMed

Haney, Margaret; Gunderson, Erik W; Rabkin, Judith; Hart, Carl L; Vosburg, Suzanne K; Comer, Sandra D; Foltin, Richard W

2007-08-15

Individuals with HIV constitute the largest group using cannabinoids for medicinal reasons; yet, no studies have directly compared the tolerability and efficacy of smoked marijuana and oral dronabinol maintenance in HIV-positive marijuana smokers. This placebo-controlled within-subjects study evaluated marijuana and dronabinol across a range of behaviors: eating topography, mood, cognitive performance, physiologic measures, and sleep. HIV-positive marijuana smokers (n = 10) completed 2 16-day inpatient phases. Each dronabinol (5 and 10 mg) and marijuana (2.0% and 3.9% Delta9-tetrahydrocannabinol [THC]) dose was administered 4 times daily for 4 days, but only 1 drug was active per day, thereby maintaining double-blind dosing. Four days of placebo washout separated each active cannabinoid condition. As compared with placebo, marijuana and dronabinol dose dependently increased daily caloric intake and body weight in HIV-positive marijuana smokers. All cannabinoid conditions produced significant intoxication, except for low-dose dronabinol (5 mg); the intoxication was rated positively (eg, "good drug effect") with little evidence of discomfort and no impairment of cognitive performance. Effects of marijuana and dronabinol were comparable, except that only marijuana (3.9% THC) improved ratings of sleep. These data suggest that for HIV-positive marijuana smokers, both dronabinol (at doses 8 times current recommendations) and marijuana were well tolerated and produced substantial and comparable increases in food intake.

Increased interleukin-1β levels following low dose MDMA induces tolerance against the 5-HT neurotoxicity produced by challenge MDMA

PubMed Central

2011-01-01

Background Preconditioning is a phenomenon by which tolerance develops to injury by previous exposure to a stressor of mild severity. Previous studies have shown that single or repeated low dose MDMA can attenuate 5-HT transporter loss produced by a subsequent neurotoxic dose of the drug. We have explored the mechanism of delayed preconditioning by low dose MDMA. Methods Male Dark Agouti rats were given low dose MDMA (3 mg/kg, i.p.) 96 h before receiving neurotoxic MDMA (12.5 mg/kg, i.p.). IL-1β and IL1ra levels and 5-HT transporter density in frontal cortex were quantified at 1 h, 3 h or 7 days. IL-1β, IL-1ra and IL-1RI were determined between 3 h and 96 h after low dose MDMA. sIL-1RI combined with low dose MDMA or IL-1β were given 96 h before neurotoxic MDMA and toxicity assessed 7 days later. Results Pretreatment with low dose MDMA attenuated both the 5-HT transporter loss and elevated IL-1β levels induced by neurotoxic MDMA while producing an increase in IL-1ra levels. Low dose MDMA produced an increase in IL-1β at 3 h and in IL-1ra at 96 h. sIL-1RI expression was also increased after low dose MDMA. Coadministration of sIL-1RI (3 μg, i.c.v.) prevented the protection against neurotoxic MDMA provided by low dose MDMA. Furthermore, IL-1β (2.5 pg, intracortical) given 96 h before neurotoxic MDMA protected against the 5-HT neurotoxicity produced by the drug, thus mimicking preconditioning. Conclusions These results suggest that IL-1β plays an important role in the development of delayed preconditioning by low dose MDMA. PMID:22114930

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.

Chronic molindone treatment: relative inability to elicit dopamine receptor supersensitivity in rats.

PubMed

Meller, E

1982-01-01

Chronic treatment of rats with the antipsychotic drug molindone (2.5 mg/kg) did not elicit behavioral supersensitivity to apomorphine (AP) (0.25 mg/kg) or increased striatal 3H-spiroperidol binding, whereas treatment with haloperidol (0.5-1.0 mg/kg) produced manifestations of dopaminergic supersensitivity in both paradigms. Chronic treatment with a high dose of molindone (20 mg/kg) elicited a small, but significant increase in behavioral sensitivity to AP (57%) which was, however, significantly less than that produced by 1 mg/kg haloperidol (126%, P less than 0.01). Apparent tolerance to elevation of striatal and frontal cortical 3,4-dihydroxyphenylacetic acid (DOPAC) levels was obtained with chronic molindone treatment (5 or 20 mg/kg). None of the molindone doses used (2.5-50 mg/kg) increased striatal dopamine receptor binding. Scatchard analyses revealed no change in either maximal binding capacity (Bmax) or dissociation constant (Kd). A significant (P less than 0.001) correlation of receptor binding activity and stereotypy score was obtained for haloperidol-, but not molindone-treated rats. These results with molindone in an animal model of tardive dyskinesia suggest that this drug may have a lower potential for eliciting this disorder in humans.

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.

Detection and original dose assessment of egg powders subjected to gamma irradiation by using ESR technique

NASA Astrophysics Data System (ADS)

Aydın, Talat

2015-09-01

ESR (electron spin resonance) techniques were applied for detection and original dose estimation to radiation-processed egg powders. The un-irradiated (control) egg powders showed a single resonance line centered at g=2.0086±0.0005, 2.0081±0.0005, 2.0082±0.0005 (native signal) for yolk, white and whole egg, respectively. Irradiation induced at least one additional intense singlet overlapping to the control signal and caused a significant increase in signal intensity without any changes in spectral patterns. Responses of egg powders to different gamma radiation doses in the range 0-10 kGy were examined. The stability of the radiation-induced ESR signal of irradiated egg powders were investigated over a storage period of about 5 months. Additive reirradiation of the egg powders produces a reproducible dose response function, which can be used to assess the initial dose by back-extrapolation. The additive dose method gives an estimation of the original dose within ±12% at the end of the 720 h storage period.

Effects of nicotine in combination with drugs described as positive allosteric nicotinic acetylcholine receptor modulators in vitro: discriminative stimulus and hypothermic effects in mice.

PubMed

Moerke, Megan J; de Moura, Fernando B; Koek, Wouter; McMahon, Lance R

2016-09-05

Some drugs that are positive allosteric nAChR modulators in vitro, desformylflustrabromine (dFBr), PNU-120596 and LY 2087101, have not been fully characterized in vivo. These drugs were examined for their capacity to share or modify the hypothermic and discriminative stimulus effects of nicotine (1mg/kg s.c.) in male C57Bl/6J mice. Nicotine, dFBr, and PNU-120596 produced significant hypothermia, whereas LY 2087101 (up to 100mg/kg) did not. Nicotine dose-dependently increased nicotine-appropriate responding and decreased response rate; the respective ED50 values were 0.56mg/kg and 0.91mg/kg. The modulators produced no more than 38% nicotine-appropriate responding up to doses that disrupted operant responding. Rank order potency was the same for hypothermia and rate-decreasing effects: nicotine>dFBr>PNU-120596=LY 2087101. Mecamylamine and the α4β2 nAChR antagonist dihydro-β-erythroidine, but not the α7 antagonist methyllycaconitine, antagonized the hypothermic effects of nicotine. In contrast, mecamylamine did not antagonize the hypothermic effects of the modulators. The combined discriminative stimulus effects of DFBr and nicotine were synergistic, whereas the combined hypothermic effects of nicotine with either dFBr or PNU-120596 were infra-additive. PNU-120596 did not modify the nicotine discriminative stimulus, and LY 2087101 did not significantly modify either effect of nicotine. Positive modulation of nicotine at nAChRs by PNU-120596 and LY 2087101 in vitro does not appear to confer enhancement of the nAChR-mediated hypothermic or discriminative stimulus effects of nicotine. However, dFBr appears to be a positive allosteric modulator of some behavioral effects of nicotine at doses of dFBr smaller than the doses producing unwanted effects (e.g. hypothermia) through non-nAChR mechanisms. Copyright © 2016 Elsevier B.V. All rights reserved.

Effects of nicotine in combination with drugs described as positive allosteric nicotinic acetylcholine receptor modulators in vitro: discriminative stimulus and hypothermic effects in mice

PubMed Central

Moerke, Megan J.; de Moura, Fernando B.; Koek, Wouter; McMahon, Lance R.

2016-01-01

Some drugs that are positive allosteric nAChR modulators in vitro, desformylflustrabromine (dFBr), PNU-120596 and LY 2087101, have not been fully characterized in vivo. These drugs were examined for their capacity to share or modify the hypothermic and discriminative stimulus effects of nicotine (1 mg/kg s.c.) in male C57Bl/6J mice. Nicotine, dFBr, and PNU-120596 produced significant hypothermia, whereas LY 2087101 (up to 100 mg/kg) did not. Nicotine dose-dependently increased nicotine-appropriate responding and decreased response rate; the respective ED50 values were 0.56 mg/kg and 0.91 mg/kg. The modulators produced no more than 38% nicotine-appropriate responding up to doses that disrupted operant responding. Rank order potency was the same for hypothermia and rate-decreasing effects: nicotine>dFBr>PNU-120596=LY 2087101. Mecamylamine and the α4β2 nAChR antagonist dihydro-β-erythroidine, but not the α7 antagonist methyllycaconitine, antagonized the hypothermic effects of nicotine. In contrast, mecamylamine did not antagonize the hypothermic effects of the modulators. The combined discriminative stimulus effects of DFBr and nicotine were synergistic, whereas the combined hypothermic effects of nicotine with either dFBr or PNU-120596 were infra-additive. PNU-120596 did not modify the nicotine discriminative stimulus, and LY 2087101 did not significantly modify either effect of nicotine. Positive modulation of nicotine at nAChRs by PNU-120596 and LY 2087101 in vitro does not appear to confer enhancement of the nAChR-mediated hypothermic or discriminative stimulus effects of nicotine. However, dFBr appears to be a positive allosteric modulator of some behavioral effects of nicotine at doses of dFBr smaller than the doses producing unwanted effects (e.g. hypothermia) through non-nAChR mechanisms. PMID:27238974

A retrospective planning analysis comparing intensity modulated radiation therapy (IMRT) to volumetric modulated arc therapy (VMAT) using two optimization algorithms for the treatment of early-stage prostate cancer

PubMed Central

Elith, Craig A; Dempsey, Shane E; Warren-Forward, Helen M

2013-01-01

Introduction The primary aim of this study is to compare intensity modulated radiation therapy (IMRT) to volumetric modulated arc therapy (VMAT) for the radical treatment of prostate cancer using version 10.0 (v10.0) of Varian Medical Systems, RapidArc radiation oncology system. Particular focus was placed on plan quality and the implications on departmental resources. The secondary objective was to compare the results in v10.0 to the preceding version 8.6 (v8.6). Methods Twenty prostate cancer cases were retrospectively planned using v10.0 of Varian's Eclipse and RapidArc software. Three planning techniques were performed: a 5-field IMRT, VMAT using one arc (VMAT-1A), and VMAT with two arcs (VMAT-2A). Plan quality was assessed by examining homogeneity, conformity, the number of monitor units (MUs) utilized, and dose to the organs at risk (OAR). Resource implications were assessed by examining planning and treatment times. The results obtained using v10.0 were also compared to those previously reported by our group for v8.6. Results In v10.0, each technique was able to produce a dose distribution that achieved the departmental planning guidelines. The IMRT plans were produced faster than VMAT plans and displayed improved homogeneity. The VMAT plans provided better conformity to the target volume, improved dose to the OAR, and required fewer MUs. Treatments using VMAT-1A were significantly faster than both IMRT and VMAT-2A. Comparison between versions 8.6 and 10.0 revealed that in the newer version, VMAT planning was significantly faster and the quality of the VMAT dose distributions produced were of a better quality. Conclusion VMAT (v10.0) using one or two arcs provides an acceptable alternative to IMRT for the treatment of prostate cancer. VMAT-1A has the greatest impact on reducing treatment time. PMID:26229615

Proton radiography and proton computed tomography based on time-resolved dose measurements

NASA Astrophysics Data System (ADS)

Testa, Mauro; Verburg, Joost M.; Rose, Mark; Min, Chul Hee; Tang, Shikui; Hassane Bentefour, El; Paganetti, Harald; Lu, Hsiao-Ming

2013-11-01

We present a proof of principle study of proton radiography and proton computed tomography (pCT) based on time-resolved dose measurements. We used a prototype, two-dimensional, diode-array detector capable of fast dose rate measurements, to acquire proton radiographic images expressed directly in water equivalent path length (WEPL). The technique is based on the time dependence of the dose distribution delivered by a proton beam traversing a range modulator wheel in passive scattering proton therapy systems. The dose rate produced in the medium by such a system is periodic and has a unique pattern in time at each point along the beam path and thus encodes the WEPL. By measuring the time dose pattern at the point of interest, the WEPL to this point can be decoded. If one measures the time-dose patterns at points on a plane behind the patient for a beam with sufficient energy to penetrate the patient, the obtained 2D distribution of the WEPL forms an image. The technique requires only a 2D dosimeter array and it uses only the clinical beam for a fraction of second with negligible dose to patient. We first evaluated the accuracy of the technique in determining the WEPL for static phantoms aiming at beam range verification of the brain fields of medulloblastoma patients. Accurate beam ranges for these fields can significantly reduce the dose to the cranial skin of the patient and thus the risk of permanent alopecia. Second, we investigated the potential features of the technique for real-time imaging of a moving phantom. Real-time tumor tracking by proton radiography could provide more accurate validations of tumor motion models due to the more sensitive dependence of proton beam on tissue density compared to x-rays. Our radiographic technique is rapid (˜100 ms) and simultaneous over the whole field, it can image mobile tumors without the problem of interplay effect inherently challenging for methods based on pencil beams. Third, we present the reconstructed pCT images of a cylindrical phantom containing inserts of different materials. As for all conventional pCT systems, the method illustrated in this work produces tomographic images that are potentially more accurate than x-ray CT in providing maps of proton relative stopping power (RSP) in the patient without the need for converting x-ray Hounsfield units to proton RSP. All phantom tests produced reasonable results, given the currently limited spatial and time resolution of the prototype detector. The dose required to produce one radiographic image, with the current settings, is ˜0.7 cGy. Finally, we discuss a series of techniques to improve the resolution and accuracy of radiographic and tomographic images for the future development of a full-scale detector.

The effect of acetyl strophanthidin on the hearts of normal dogs.

PubMed

Hayes, A H; McShane, W P; Sidell, F R

1970-05-01

1. The ED50 of acetyl strophanthidin for producing ventricular arrhythmias in normal dogs was 54.5 mug/kg intravenously.2. Doses up to and including those which caused ventricular tachycardia did not produce either atrial arrhythmias or significant aberration of A-V conduction.3. Although the classic digitalis-induced rate and e.c.g. waveform changes may appear after administration of acetyl strophanthidin, their presence or absence have no value in predicting the subsequent development of ventricular arrhythmias.

Dose-response relationship of a new Timothy grass pollen allergoid in comparison with a 6-grass pollen allergoid.

PubMed

Pfaar, O; Hohlfeld, J M; Al-Kadah, B; Hauswald, B; Homey, B; Hunzelmann, N; Schliemann, S; Velling, P; Worm, M; Klimek, L

2017-11-01

Subcutaneous allergen immunotherapy with grass pollen allergoids has been proven to be effective and safe in the treatment of patients with allergic rhinoconjunctivitis. Based on the extensive cross-reactivity among Pooideae species, it has been suggested that grass pollen extracts could be prepared from a single species, rather than from a multiple species mixture. To find the optimal dose of a Phleum pratense (P. pratense) allergoid preparation and compare its efficacy and safety to a 6-grass pollen allergoid preparation. In this double-blind, placebo-controlled study (EudraCT: 2011-000674-58), three doses of P. pratense allergoid (1800 therapeutic units (TU), standard-dose 6000 TU and 18 000 TU) were compared with placebo and the marketed 6-grass pollen allergoid (6000 TU). In a pre-seasonal dosing regimen, 102 patients were randomized to five treatment groups and received nine subcutaneous injections. The primary efficacy endpoint was the change in weal size (late-phase reaction [LPR]) in response to the intracutaneous testing (ICT) before and after treatment, comparing the active allergoids to placebo. Secondary outcomes were the change in Total Nasal Symptom Score (TNSS) assessed in the allergen exposure chamber (AEC), the changes in P. pratense-serum-specific IgG 4 and the incidence of adverse events (AEs). All three doses of the P. pratense and the 6-grass pollen allergoid preparations were significantly superior to placebo for the primary outcome, whereas there were no significant differences in the change in TNSS. Compared to the standard-dose, the high-dose of P. pratense did not produce any additional significant benefit, but showed a slight increase in AEs. Yet this increase in AEs was lower than for the 6-grass pollen preparation. The standard-dose of the new P. pratense allergoid was comparable to the marketed 6-grass pollen preparation at equal dose for the parameters measured. © 2017 The Authors. Clinical & Experimental Allergy Published by John Wiley & Sons Ltd.

Comparison of immunogenicity between inactivated and live attenuated hepatitis A vaccines: a single-blind, randomized, parallel-group clinical trial among children in Xinjiang Uighur Autonomous Region, China.

PubMed

Liu, Xue-En; Wushouer, Fuerhati; Gou, Aili; Kuerban, Mahemuti; Li, Xinlan; Sun, Yubo; Zhang, Jiamin; Liu, Yan; Li, Jie; Zhuang, Hui

2013-07-01

To compare immunogenicity among an inactivated hepatitis A vaccine (Healive(®)) with one-dose and two-dose regimens, and three kinds of live attenuated vaccines in children. A single-blind, randomized, parallel-group clinical trial was conducted among healthy children aged 1.5-6 y in Xinjiang Uighur Autonomous Region, China. Subjects were randomly assigned to 5 groups. Two groups were administered one-dose or two-dose inactivated vaccine and the remaining groups were immunized with one of three kinds of attenuated vaccines, respectively. Serum samples were collected at 6- and 12-mo follow-ups. Anti-HAV IgG was measured with a microparticle enzyme immunoassay. No significant differences were observed in seroconversion rates (seroprotection rates) among the five groups at 6 or 12 mo (p>0.05). The geometric mean concentration (GMC) of anti-HAV IgG was significantly higher in the two-dose Healive(®) group than in the one-dose Healive(®) group and the attenuated vaccine groups at 12 mo (932.4 vs. 112.7, 135.8, 203.3, 212.8 mIU/ml, respectively, p<0.05). In the one-dose Healive(®) group, the GMC was significantly lower than that in the attenuated vaccine B and C groups at 6 mo (152.6 vs. 212, 204 mIU/ml, p<0.05) and at 12 mo (112.7 vs. 203.3, 212.8, p<0.05), but was similar to the attenuated vaccine A group at 12 mo (112.7 vs. 135.8 mIU/ml, p>0.05). The GMCs were significantly higher in the 1-2 y of age group than in the 3-6 y of age group for all types of vaccines except the attenuated vaccine C (p<0.05) at 12 mo. A higher GMC of anti-HAV IgG was induced in the two-dose Healive(®) than in the one-dose and the attenuated vaccines at 12 mo. The attenuated vaccine B or C produced higher GMCs than the one-dose Healive(®) at 6-12 mo after vaccination.

Effects of molindone and fluphenazine on the brain concentration of some phenolic and catecholic amines in the mouse and the rat.

PubMed

Juorio, A V

1980-11-01

1 The concentrations of p- and m-tyramine, dopamine, 3,4-dihydroxyphenylacetic acid and homo-vanillic acid were measured in the mouse or rat striatum following the subcutaneous injection of molindone or fluphenazine. The mouse hypothalamic levels of the m- or p-isomers of octopamine were also analysed. 2 Endogenous concentrations of p- and m-tyramine in the mouse striatum and p- and m-octopamine in the mouse hypothalamus were 20.6, 5.7, 9.4 and 1.2 ng/g respectively. The rat striatum concentrations of p- and m-tyramine were 12.8 and 3.8 ng/g. 3 The administration of low doses of molindone (1 to 10 mg/kg) produced a reduction in striatal p-tyramine, an increase in m-tyramine and an increase in dopamine turnover. Similar effects were produced by all doses of fluphenazine (0.1 to 5 mg/kg) employed. These findings are consistent with those observed after blockade of dopamine postsynaptic receptors. 4 With high doses of molindone (100 mg/kg) the effects on both tyramines and on dopamine metabolism were reversed. These results can be interpreted as molindone acting as a partial agonist. 5 The concentrations of hypothalamic p- and m-octopamine were increased by the higher doses of molindone (20 to 100 mg/kg) employed while lower doses produced no significant effects. All doses of fluphenazine reduced hypothalamic p-octopamine. These changes seem to depend on differences in the availability of p-tyramine to be converted into p-octopamine. 6 These results suggest that molindone acts as a blocker or a partial agonist of dopamine receptor sites and fit well with the proposal of a reciprocal relation between dopamine and tyramine. It is not possible yet to ascertain whether tyramine controls dopamine or vice versa or if it is a direct or a more remote relation.

Effects of molindone and fluphenazine on the brain concentration of some phenolic and catecholic amines in the mouse and the rat.

PubMed Central

Juorio, A. V.

1980-01-01

1 The concentrations of p- and m-tyramine, dopamine, 3,4-dihydroxyphenylacetic acid and homo-vanillic acid were measured in the mouse or rat striatum following the subcutaneous injection of molindone or fluphenazine. The mouse hypothalamic levels of the m- or p-isomers of octopamine were also analysed. 2 Endogenous concentrations of p- and m-tyramine in the mouse striatum and p- and m-octopamine in the mouse hypothalamus were 20.6, 5.7, 9.4 and 1.2 ng/g respectively. The rat striatum concentrations of p- and m-tyramine were 12.8 and 3.8 ng/g. 3 The administration of low doses of molindone (1 to 10 mg/kg) produced a reduction in striatal p-tyramine, an increase in m-tyramine and an increase in dopamine turnover. Similar effects were produced by all doses of fluphenazine (0.1 to 5 mg/kg) employed. These findings are consistent with those observed after blockade of dopamine postsynaptic receptors. 4 With high doses of molindone (100 mg/kg) the effects on both tyramines and on dopamine metabolism were reversed. These results can be interpreted as molindone acting as a partial agonist. 5 The concentrations of hypothalamic p- and m-octopamine were increased by the higher doses of molindone (20 to 100 mg/kg) employed while lower doses produced no significant effects. All doses of fluphenazine reduced hypothalamic p-octopamine. These changes seem to depend on differences in the availability of p-tyramine to be converted into p-octopamine. 6 These results suggest that molindone acts as a blocker or a partial agonist of dopamine receptor sites and fit well with the proposal of a reciprocal relation between dopamine and tyramine. It is not possible yet to ascertain whether tyramine controls dopamine or vice versa or if it is a direct or a more remote relation. PMID:6777007

Efficacy trial of Vi polysaccharide vaccine against typhoid fever in south-western China.

PubMed Central

Yang, H. H.; Wu, C. G.; Xie, G. Z.; Gu, Q. W.; Wang, B. R.; Wang, L. Y.; Wang, H. F.; Ding, Z. S.; Yang, Y.; Tan, W. S.; Wang, W. Y.; Wang, X. C.; Qin, M.; Wang, J. H.; Tang, H. A.; Jiang, X. M.; Li, Y. H.; Wang, M. L.; Zhang, S. L.; Li, G. L.

2001-01-01

OBJECTIVE: To test the efficacy of locally produced Vi vaccine over a time period of longer than one year. METHODS: A double-blinded, randomized field trial was performed in Guangxi Zhuang Autonomous Region in south-western China, using 30 micrograms doses of locally produced Vi. Enrolled subjects were 3-50 years of age, although the majority (92%) were school-aged children, who have the highest rate of typhoid fever in this setting. A total of 131,271 people were systematically allocated a single dose of 30 micrograms of Vi polysaccharide or saline placebo. The study population was followed for 19 months, with passive surveillance conducted in the Ministry of Health and the Regional Health and Anti-epidemic Centre (HAEC). Clinically suspected cases of typhoid fever were confirmed by blood culture, or by serological reaction with O-antigen (Widal tests). FINDINGS: After 19 months, there were 23 culture-confirmed cases of typhoid fever in the placebo group versus 7 cases in the Vi group (Protective efficacy (PE) = 69%; 95% CI = 28%, 87%). Most of the isolates were from school-aged children: 22 cases in the placebo group versus 6 in the Vi group (PE = 72%; 95% CI = 32%, 82%). No serious post-injection reactions were observed. The locally produced Vi polysaccharide vaccine showed levels of protective efficacy similar to those for Vi vaccine produced in industrial countries. CONCLUSION: The slightly higher dose of vaccine did not seem to alter efficacy significantly in China. PMID:11477965

Behavioral and biochemical effects of the antidepressant bupropion (Wellbutrin): evidence for selective blockade of dopamine uptake in vivo.

PubMed

Cooper, B R; Hester, T J; Maxwell, R A

1980-10-01

Bupropion (BW 323U; Wellbutrin), a novel compound with antidepressant effects in man, was found to reduce immobility in an "experimental helplessness" forced swimming antidepressant test in rats as did imipramine and amitriptyline. Higher doses produced elevated locomotor activity in an automated open field and produced stereotyped sniffing which was contrasted with apomorphine. When bupropion or desmethylimipramine was given before intracisternal injections of 6-hydroxydopamine, bupropion produced a dose-related selective antagonism of the destruction of dopamine neurons, while under the same conditions, desmethylimipramine produced a dose-related selective antagonism of the destruction of noradrenergic neurons. Studies in which the dose of bupropion and the dose of 6-hydroxydopamine were varied revealed that a dose-related selective antagonism of dopamine depletion by 6-hydroxydopamine occurred when doses up to and including 50 mg/kg i.p. to bupropion were administered. Some antagonism of norepinephrine depletion also occurred at 100 mg/kg of bupropion i.p. Bupropion also selectively reversed the dopamine depletion produced by alpha-methyl-m-tyrosine, a finding which is consistent with the view that bupropion is a dopamine uptake inhibitor in vivo. The importance of dopamine systems for the behavioral effects of bupropion were also studied. When the locomotor stimulant effects of bupropion were tested in rats with chronic destruction of dopamine neurons produced by 6-hydroxydopamine, bupropion failed to elevate locomotor activity. Rats treated with procedures using 6-hydroxydopamine to produce relatively selective norepinephrine depletions responded to bupropion with locomotor activity stimulation like controls. Rats with similar depletions of either dopamine or norepinephrine were also tested for the ability of low doses of bupropion to reduce immobility in the "experimental helplessness" forced swim antidepressant test. Prior destruction of dopamine neurons prevented activity of bupropion in this test. Results indicate that bupropion is a selective dopamine uptake inhibitor in vivo and that dopaminergic systems play an important role in its central nervous system pharmacology.

Effect of sublingual application of cannabinoids on intraocular pressure: a pilot study.

PubMed

Tomida, Ileana; Azuara-Blanco, Augusto; House, Heather; Flint, Maggie; Pertwee, Roger G; Robson, Philip J

2006-10-01

The purpose of this study was to assess the effect on intraocular pressure (IOP) and the safety and tolerability of oromucosal administration of a low dose of delta-9-tetrahydrocannabinol (Delta-9-THC) and cannabidiol (CBD). A randomized, double-masked, placebo-controlled, 4 way crossover study was conducted at a single center, using cannabis-based medicinal extract of Delta-9-THC and CBD. Six patients with ocular hypertension or early primary open angle glaucoma received a single sublingual dose at 8 AM of 5 mg Delta-9-THC, 20 mg CBD, 40 mg CBD, or placebo. Main outcome measure was IOP. Secondary outcomes included visual acuity, vital signs, and psychotropic effects. Two hours after sublingual administration of 5 mg Delta-9-THC, the IOP was significantly lower than after placebo (23.5 mm Hg vs. 27.3 mm Hg, P=0.026). The IOP returned to baseline level after the 4-hour IOP measurement. CBD administration did not reduce the IOP at any time. However, the higher dose of CBD (40 mg) produced a transient elevation of IOP at 4 hours after administration, from 23.2 to 25.9 mm Hg (P=0.028). Vital signs and visual acuity were not significantly changed. One patient experienced a transient and mild paniclike reaction after Delta-9-THC administration. A single 5 mg sublingual dose of Delta-9-THC reduced the IOP temporarily and was well tolerated by most patients. Sublingual administration of 20 mg CBD did not reduce IOP, whereas 40 mg CBD produced a transient increase IOP rise.

Long-term erythemal UV doses at Sodankylä estimated using total ozone, sunshine duration and snow depth

NASA Astrophysics Data System (ADS)

Lindfors, A. V.; Arola, A.; Kaurola, J.; Taalas, P.; Svenøe, T.

2003-04-01

A method for estimating daily erythemal UV doses using total ozone, sunshine duration and snow depth has been developed. The method consists of three steps: (1) daily clear-sky UV doses were simulated using the UVSPEC radiative transfer program, with daily values of total ozone as input data, (2) an empirical relationship was sought between the simulated clear-sky UV doses, the measured UV doses and the duration of bright sunshine, (3) daily erythemal UV doses were estimated using this relationship. The method accounts for the varying surface albedo by dividing the period of interest into winter and summer days, depending on the snow depth. Using this method, the daily erythemal UV doses at Sodankylä were estimated for the period 1950--99. This was done using Tromsø's total ozone together with Sodankylä's own sunshine duration and snow depth as input data. Although the method is fairly simple, the results are in good agreement, even on the daily scale, with the UV radiation measured with the Brewer spectrophotometer at Sodankylä. Statistically significant increasing trends in erythemal UV doses of a few percents per decade over the period 1950--99 were found for March and April, suggesting a connection to the stratospheric ozone depletion. For July, on the other hand, a significant decreasing trend of about 3% per decade, supported by the changes in both total ozone and sunshine duration, was found. The produced data set of erythemal UV doses is the longest time series of estimated UV known to the authors.

Correlates of individual differences in compensatory nicotine self-administration in rats following a decrease in nicotine unit dose

PubMed Central

Harris, Andrew C.; Pentel, Paul R.; LeSage, Mark G.

2013-01-01

Rationale The ability of tobacco harm reduction strategies to produce significant reductions in toxin exposure is limited by compensatory increases in smoking behavior. Characterizing factors contributing to the marked individual variability in compensation may be useful for understanding this phenomenon and assessing the feasibility of harm reduction interventions. Objective To use an animal model of human compensatory smoking that involves a decrease in unit dose supporting nicotine self-administration (NSA) to examine potential contributors to individual differences in compensation. Methods Rats were trained for NSA during daily 23 hr sessions at a unit dose of 0.06 mg/kg/inf until responding was stable. The unit dose was then reduced to 0.03 mg/kg/inf for at least 10 sessions. Following reacquisition of NSA at the training dose and extinction, single-dose nicotine pharmacokinetic parameters were determined. Results Decreases in nicotine intake following dose reduction were proportionally less than the decrease in unit dose, indicating partial compensation. Compensatory increases in infusion rates were observed across the course of the 23 hr sessions. The magnitude of compensation differed considerably between rats. Rats exhibiting the highest baseline infusion rates exhibited the lowest levels of compensation. Nicotine pharmacokinetic parameters were not significantly correlated with compensation. Infusion rates immediately returned to pre-reduction levels when baseline conditions were restored. Conclusions These findings provide initial insights into correlates of individual differences in compensation following a reduction in nicotine unit dose. The present assay may be useful for characterizing mechanisms and potential consequences of the marked individual differences in compensatory smoking observed in humans. PMID:19475400

Microcystins from tap water could be a risk factor for liver and colorectal cancer: a risk intensified by global change.

PubMed

Martínez Hernández, Juan; López-Rodas, V; Costas, E

2009-05-01

An increasing number of people drink water from fresh water supply reservoirs. However, with the global change a lot of reservoirs become eutrophic, which facilitates the occurrence of toxin-producing cyanobacterial blooms. Microcystins (powerful hepatotoxic water-soluble heptapeptides) are the most important cyanobacterial toxins affecting humans. High doses of microcystins produce hepatic necrosis. Consequently, WHO Guidelines limit microcystins to 1 ppb in drinking waters. However, microcystins are present frequently in tap water at lower doses. Here, we hypothesized that chronic consume of tap water containing low doses of microcystins may be a risk factor for liver and colorectal cancer. Two kinds of evidences support this hypothesis. On one hand some epidemiological data (mainly in China). On the other hand, the molecular mechanism of microcystins toxicity (inhibition of protein phosphatases PP1 and PP2) is just like okadaic acid (a potent tumor promoter). Cancer risk from drinking water is certainly less than smoking, occupational exposures or some foods. But it is significant and with a rapid increase of toxic cyanobacterial blooms by eutrophycation, become more frequent.

Inhibitory effect of heparin on neutrophil phagocytosis and burst production using a new whole-blood cytofluorometric method for determination.

PubMed

Salih, H; Husfeld, L; Adam, D

1997-12-31

The influence of heparin on Polymorphonuclear (PMN s) leukocytes was investigated using a new whole-blood cytofluorometric method (patent granted for the test with the number P 4334935.8-41) with Candida albicans and Staphylococcus aureus as test microorganisms. After comparing the effect of equal volumes of two widely used heparins we examined the influence of 5 different heparin-concentrations. Using both yeasts and bacteria, we found a significant, dose-depending decrease of the percentage of phagocyting PMN's and of phagocytized microorganisms as well as of the resulting percentage of PMN s producing respiratory burst along the kinetics. Furthermore we could demonstrate that heparin independently of phagocytosis produces a dose-dependent decrease of burst production of PMN's. Our results indicate that the use of heparins as anticoagulant for immunological investigations as well as clinically with patients under immunosuppressive therapy should be critically reconsidered. This applies even more because due to the evaluated dose-dependent decrease of phagocyte function no boundary for the inhibiting effect can be declared.

Effects of 100MeV protons delivered at 0.5 or 1cGy/min on the in vivo induction of early and delayed chromosomal damage.

PubMed

Rithidech, Kanokporn Noy; Honikel, Louise M; Reungpatthanaphong, Paiboon; Tungjai, Montree; Golightly, Marc; Whorton, Elbert B

2013-08-30

Little is known about in vivo cytogenetic effects of protons delivered at the dose and dose rates encountered in space. We determined the effects of 100MeV protons, one of the most abundant type of protons produced during solar particle events (SPE), on the induction of chromosome aberrations (CAs) in bone marrow (BM) cells collected at early (3 and 24h) and late (6 months) time-points from groups of BALB/cJ mice (a known radiosensitive strain) exposed whole-body to 0 (sham-controls), 0.5, or 1.0Gy of 100MeV protons, delivered at 0.5 or 1.0cGy/min. These doses and dose-rates are comparable to those produced during SPE events. Additionally, groups of mice were exposed to 0 or 1Gy of (137)Cs γ rays (delivered at 1cGy/min) as a reference radiation. The kinetics of formation/reduction of gamma-histone 2-AX (γH2AX) were determined in BM cells collected at 1.5, 3, and 24h post-irradiation to assess the early-response. There were five mice per treatment-group per harvest-time. Our data indicated that the kinetics of γH2AX formation/reduction differed, depending on the dose and dose rate of protons. Highly significant numbers of abnormal cells and chromatid breaks (p<0.01), related to those in sham-control groups, were detected in BM cells collected at each time-point, regardless of dose or dose-rate. The finding of significant increases in the frequencies of delayed non-clonal and clonal CAs in BM cells collected at a late time-point from exposed mice suggested that 0.5 or 1Gy of 100MeV protons is capable of inducing genomic instability in BM cells. However, the extent of effects induced by these two low dose rates was comparable. Further, the results showed that the in vivo cytogenetic effects induced by 1Gy of 100MeV protons or (137)Cs γ rays (delivered at 1cGy/min) were similar. Copyright © 2013 Elsevier B.V. All rights reserved.

Discriminative stimulus effects of alpidem, a new imidazopyridine anxiolytic.

PubMed

Sanger, D J; Zivkovic, B

1994-01-01

Alpidem in an imidazopyridine derivative which binds selectively to the omega 1 (BZ1) receptor subtype. It is active in some, but not all, behavioural tests sensitive to benzodiazepine anxiolytics and has clinical anti-anxiety effects. However, in a previous study, it was shown that alpidem did not substitute for chlordiazepoxide in rats trained to discriminate this benzodiazepine. The present experiments were carried out to investigate the discriminative stimulus properties of alpidem in greater detail. In the first experiment rats learned to discriminate a dose of 10 mg/kg alpidem from saline. Acquisition of the discrimination was long and performance unstable. Chlordiazepoxide, clorazepate and zolpidem substituted only partially for alpidem but the effects of the training dose of alpidem were blocked by 10 mg/kg flumazenil. The second experiment established stimulus control more rapidly to a dose of 30 mg/kg alpidem. Alpidem induced dose-related stimulus control, and dose-related and complete substitution for alpidem was produced by zolpidem, abecarnil, CL 218,872, triazolam and suriclone. Partial substitution occurred with chlordiazepoxide, clorazepate and pentobarbital. In most cases, high levels of substitution were produced only by doses which greatly reduced response rates even though the training dose of alpidem produced only modest decreases in rates. Ethanol, buspirone and bretazenil produced very little substitution for alpidem and both flumazenil and bretazenil antagonised the effects of alpidem. In two further experiments alpidem was found to substitute for the stimulus produced by zolpidem (2 mg/kg) but not for that produced by ethanol (1.5 g/kg).(ABSTRACT TRUNCATED AT 250 WORDS)

Comparing analgesia and μ-opioid receptor internalization produced by intrathecal enkephalin

PubMed Central

Chen, Wenling; Song, Bingbing; Lao, Lijun; Pérez, Orlando A.; Kim, Woojae; Marvizón, Juan Carlos G.

2007-01-01

Summary Opioid receptors in the spinal cord produce strong analgesia, but the mechanisms controlling their activation by endogenous opioids remain unclear. We have previously shown in spinal cord slices that peptidases preclude μ-opioid receptor (MOR) internalization by opioids. Our present goals were to investigate whether enkephalin-induced analgesia is also precluded by peptidases, and whether it is mediated by MORs or δ-opioid receptors (DORs). Tail-flick analgesia and MOR internalization were measured in rats injected intrathecally with Leu-enkephalin and peptidase inhibitors. Without peptidase inhibitors, Leu-enkephalin produced neither analgesia nor MOR internalization at doses up to 100 nmol, whereas with peptidase inhibitors it produced analgesia at 0.3 nmol and MOR internalization at 1 nmol. Leu-enkephalin was ten times more potent to produce analgesia than to produce MOR internalization, suggesting that DORs were involved. Selective MOR or DOR antagonists completely blocked the analgesia elicited by 0.3 nmol Leu-enkephalin (a dose that produced little MOR internalization), indicating that it involved these two receptors, possibly by an additive or synergistic interaction. The selective MOR agonist endomorphin-2 produced analgesia even in the presence of a DOR antagonist, but at doses substantially higher than Leu-enkephalin. Unlike Leu-enkephalin, endomorphin-2 had the same potencies to induce analgesia and MOR internalization. We concluded that low doses of enkephalins produce analgesia by activating both MORs and DORs. Analgesia can also be produced exclusively by MORs at higher agonist doses. Since peptidases prevent the activation of spinal opioid receptors by enkephalins, the coincident release of opioids and endogenous peptidase inhibitors may be required for analgesia. PMID:17845806

Alcohol Dose Effects on Brain Circuits During Simulated Driving: An fMRI Study

PubMed Central

Meda, Shashwath A.; Calhoun, Vince D.; Astur, Robert S.; Turner, Beth M.; Ruopp, Kathryn; Pearlson, Godfrey D.

2009-01-01

Driving while intoxicated remains a major public health hazard. Driving is a complex task involving simultaneous recruitment of multiple cognitive functions. The investigators studied the neural substrates of driving and their response to different blood alcohol concentrations (BACs), using functional magnetic resonance imaging (fMRI) and a virtual reality driving simulator. We used independent component analysis (ICA) to isolate spatially independent and temporally correlated driving-related brain circuits in 40 healthy, adult moderate social drinkers. Each subject received three individualized, separate single-blind doses of beverage alcohol to produce BACs of 0.05% (moderate), 0.10% (high), or 0% (placebo). 3 T fMRI scanning and continuous behavioral measurement occurred during simulated driving. Brain function was assessed and compared using both ICA and a conventional general linear model (GLM) analysis. ICA results replicated and significantly extended our previous 1.5T study (Calhoun et al. [2004a]: Neuropsychopharmacology 29:2097–2017). GLM analysis revealed significant dose-related functional differences, complementing ICA data. Driving behaviors including opposite white line crossings and mean speed independently demonstrated significant dose-dependent changes. Behavior-based factors also predicted a frontal-basal-temporal circuit to be functionally impaired with alcohol dosage across baseline scaled, good versus poorly performing drivers. We report neural correlates of driving behavior and found dose-related spatio-temporal disruptions in critical driving-associated regions including the superior, middle and orbito frontal gyri, anterior cingulate, primary/supplementary motor areas, basal ganglia, and cerebellum. Overall, results suggest that alcohol (especially at high doses) causes significant impairment of both driving behavior and brain functionality related to motor planning and control, goal directedness, error monitoring, and memory. PMID:18571794

Cathinone, an active principle of Catha edulis, accelerates oxidative stress in the limbic area of swiss albino mice.

PubMed

Safhi, Mohammed M; Alam, Mohammad Firoz; Hussain, Sohail; Hakeem Siddiqui, Mohammed Abdul; Khuwaja, Gulrana; Jubran Khardali, Ibrahim Abdu; Al-Sanosi, Rashad Mohammed; Islam, Fakhrul

2014-10-28

Cathinone hydrochloride is an active principle of the khat plant (Catha edulis) that produces pleasurable and stimulating effects in khat chewers. To the best of our knowledge no data of cathinone on oxidative stress in limbic areas of mice is available. This is the first study of cathinone on oxidative stress in limbic areas of the brain in Swiss albino male mice. The animals were divided into four groups. Group-I was the control group and received vehicle, while groups-II to IV received (-)-cathinone hydrochloride (0.125, 0.25 and 0.5 mg/kg body wt., i.p.) once daily for 15 days. The level of lipid peroxidation (LPO) was elevated dose-dependently and was significant (p<0.05, p<0.01) with doses of 0.25 and 0.5mg/kg body wt. of cathinone as compared to control group. In contrast, the content of reduced glutathione (GSH) was decreased significantly (p<0.01, p<0.001) with doses of 0.25 and 0.5mg/kg body wt. of cathinone as compared to control group. The activity of antioxidant enzymes (GPx, GR, GST, CAT, and SOD) was also decreased dose-dependently: the decreased activity of GPx, GR, catalase and SOD was significant with doses of 0.25 and 0.5 mg of cathinone as compared to control group, while the activity of GST was decreased dose-dependently and was significant with 0.5mg of cathinone as compared to control group. The results indicate that the cathinone generated oxidative stress hampered antioxidant enzymes, glutathione and lipid peroxidation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Six steps to a successful dose-reduction strategy

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

Bennett, M.

1995-03-01

The increased importance of demonstrating achievement of the ALARA principle has helped produce a proliferation of dose-reduction ideas. Across a company there may be many dose-reduction items being pursued in a variety of areas. However, companies have a limited amount of resource and, therefore, to ensure funding is directed to those items which will produce the most benefit and that all areas apply a common policy, requires the presence of a dose-reduction strategy. Six steps were identified in formulating the dose-reduction strategy for Rolls-Royce and Associates (RRA): (1) collating the ideas; (2) quantitatively evaluating them on a common basis; (3)more » prioritizing the ideas in terms of cost benefit, (4) implementation of the highest priority items; (5) monitoring their success; (6) periodically reviewing the strategy. Inherent in producing the dose-reduction strategy has been a comprehensive dose database and the RRA-developed dose management computer code DOMAIN, which allows prediction of dose rates and dose. The database enabled high task dose items to be identified, assisted in evaluating dose benefits, and monitored dose trends once items had been implemented. The DOMAIN code was used both in quantifying some of the project dose benefits and its results, such as dose contours, used in some of the dose-reduction items themselves. In all, over fifty dose-reduction items were evaluated in the strategy process and the items which will give greatest benefit are being implemented. The strategy has been successful in giving renewed impetus and direction to dose-reduction management.« less

The effect of methanol rhizome extract of Nymphaea lotus Linn. (Nymphaeaceae) in animal models of diarrhoea.

PubMed

Bello, Fatima Hauwa; Maiha, Bilkisu B; Anuka, Joseph A

2016-08-22

Nymphaea lotus, which is widely distributed throughout tropical Africa, enjoys a number of ethnomedical uses in Nigeria. Traditionally, the rhizomes of N. lotus are used to cure diarrhoea. This study aims to evaluate the antidiarrhoeal activity of the methanol rhizome extract of N. lotus plant in laboratory animals. The extract was screened for activity against castor oil-induced diarrhoea and magnesium sulphate-induced diarrhoea as well as effect on gastric transit time in mice. The effect of methanol rhizome extract of Nymphaea lotus on the perfused isolated tissue preparation was also determined. For castor oil-induced diarrhoea, the extract at doses of 200, 400 and 800mg/kg produced significant reduction in the frequency of diarrhoea (at p<0.001, p<0.001 and p<0.01 respectively). The extract at 800mg/kg produced a significant delay in onset of diarrhoea (p<0.05) comparable to loperamide (3mg/kg). The frequency of magnesium sulphate-induced diarrhoea was also significantly reduced in the groups treated with 200, 400 and 800mg/kg of the extract at p<0.001, p<0.001 and p<0.01 respectively. At doses of 200mg/kg and 400mg/kg, the protection produced was comparable to loperamide, 3mg/kg. All treated groups produced significant reduction in the transit of charcoal meal along the intestinal tract at p<0.001. The extract at low concentration (4×10(-4)-6.4×10(-2)mg/ml) had contractile effect on the tone of contraction of the rabbit jejunum while at higher concentrations (8×10(-2)-512×10(-2)mg/ml) produced significant reduction in the tone and rate of spontaneous contraction of rabbit jejunum. The extract at lower concentrations (4×10(-4)-2×10(-2)mg/ml) has no effect on contraction of the guinea pig ileum while higher concentrations (4×10(-2)-512×10(-2)mg/ml) produced significant relaxant activity on guinea pig ileum. This study has shown that the methanol rhizome extract of N. lotus has antidiarrhoeal properties thus justifying its use by the local population for this purpose. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Conditioned Reinforcement and Locomotor Activating Effects of Caffeine and Ethanol Combinations in Mice

PubMed Central

Hilbert, Megan L.T.; May, Christina E.; Griffin, William C.

2013-01-01

A growing trend among ethanol drinkers, especially young adults, is to combine caffeinated energy drinks with ethanol during a drinking episode. The primary active ingredient of these mixers is caffeine, which may significantly interact with ethanol. We tested the two hypotheses that caffeine would enhance ethanol-conditioned place preference and also enhance ethanol-stimulated locomotor activity. The interactive pharmacology of ethanol and caffeine was examined in C57BL/6J (B6) mice in a conditioned place preference procedure with 1.75 g/kg ethanol and 3 mg/kg caffeine. Additionally, we used B6 mice to evaluate ethanol/caffeine combinations on locomotor activity using 3 doses of ethanol (1.75, 2.5 and 3.25 g/kg) and 2 two doses of caffeine (3 and 15 mg/kg). Both ethanol and caffeine administered alone increased preference for the drug paired side, though the effect of caffeine was more modest than that of ethanol. The drug combination produced significant place preference itself, but this was not greater than that for ethanol alone. Additionally, the combination of caffeine and ethanol significantly increased locomotion compared to giving either drug alone. The effect was strongest with a stimulatory dose of ethanol (1.75 g/kg) and waned with increasing doses of ethanol. Thus, combinations of caffeine and ethanol had significant conditioned reinforcing and locomotor activating effects in mice. PMID:23872371

Caffeine expectancies influence the subjective and behavioral effects of caffeine.

PubMed

Harrell, Paul T; Juliano, Laura M

2009-12-01

This study investigated the independent and interactive effects of caffeine pharmacology and expected effects of caffeine on performance and subjective outcomes. Abstinent coffee drinkers (n = 60) consumed decaffeinated coffee with either 280 mg or 0 mg added caffeine. Caffeine dose was crossed with varying instructions that the coffee would either enhance or impair performance in a 2 x 2 factorial design. Performance, mood, caffeine withdrawal, and negative somatic effects were assessed. Relative to placebo, caffeine improved reaction time and accuracy on the rapid visual information processing task, a measure of vigilance. However, there was a significant dose by expectancy interaction that revealed that among participants given placebo coffee, "impair" instructions produced better performance than "enhance" instructions. Caffeine also improved psychomotor performance as indicated by a finger tapping task with no main effects of expectancy or interactions. Impair instructions produced greater reports of negative somatic effects than enhance instructions, but only when caffeine was administered. Manipulating the expected effects of caffeine altered the behavioral and subjective effects of caffeine. A significant dose by expectancy interaction revealed a somewhat paradoxical outcome in the placebo conditions whereby those told "impair" performed better than those told "enhance." This may reflect compensatory responding as has been observed in similar studies using alcohol (Fillmore et al. Psychopharmacology 115:383-388, 1994). Impair instructions led to greater negative somatic effects only when caffeine was administered supporting the active placebo hypothesis.

Evidence against the participation of a pharmacokinetic interaction in the protective effect of single-dose curcumin against gastrointestinal damage induced by indomethacin in rats.

PubMed

Zazueta-Beltrán, Liliana; Medina-Aymerich, Lorena; Estela Díaz-Triste, Nadia; Chávez-Piña, Aracely Evangelina; Castañeda-Hernández, Gilberto; Cruz-Antonio, Leticia

2017-03-01

To determine the role of a pharmacokinetic interaction in the protective effect of curcumin against the gastric damage induced by indomethacin administration as such or as its prodrug acemetacin. Wistar rats orally received single dose of indomethacin (30 mg/kg) with and without curcumin (30 mg/kg); gastric injury was evaluated by determining the total damaged area. Additional groups of rats received an oral single dose of indomethacin (30 mg/kg) or its prodrug acemetacin (34.86 mg/kg) in the presence or absence of curcumin (30 mg/kg). Indomethacin and acemetacin concentrations in plasma from blood draws were determined by high-performance liquid chromatography.Plasma concentration-against-time curves were constructed, and bioavailability parameters, maximal concentration (C max ) and area under the curve to the last sampling time (AUC 0-t ) were estimated. Concomitant administration of indomethacin and curcumin resulted in a significantly reduced gastric damage compared to indomethacin alone. However, co-administration of curcumin did not produce any significant alteration in the bioavailability parameters of indomethacin and acemetacin after administration of either the active compound or the prodrug. Curcumin exhibits a protective effect against indomethacin-induced gastric damage, but does not produce a reduction of the bioavailability of this nonsteroidal anti-inflammatory drug, indomethacin. Data thus suggest that a pharmacokinetic mechanism of action is not involved in curcumin gastroprotection.

Biopesticide-induced behavioral and morphological alterations in the stingless bee Melipona quadrifasciata.

PubMed

Barbosa, Wagner F; Tomé, Hudson Vaner V; Bernardes, Rodrigo C; Siqueira, Maria Augusta L; Smagghe, Guy; Guedes, Raul Narciso C

2015-09-01

Because of their natural origin, biopesticides are assumed to be less harmful to beneficial insects, including bees, and therefore their use has been widely encouraged for crop protection. There is little evidence, however, to support this ingrained notion of biopesticide safety to pollinators. Because larval exposure is still largely unexplored in ecotoxicology and risk assessment on bees, an investigation was performed on the lethal and sublethal effects of a diet treated with 2 bioinsecticides, azadirachtin and spinosad, on the stingless bee, Melipona quadrifasciata, which is one of the most important pollinators in the Neotropics. Survival of stingless bee larvae was significantly compromised at doses above 210 ng a.i./bee for azadirachtin and 114 ng a.i./bee for spinosad. No sublethal effect was observed on larvae developmental time, but doses of both compounds negatively affected pupal body mass. Azadirachtin produced deformed pupae and adults as a result of its insect growth regulator properties, but spinosad was more harmful and produced greater numbers of deformed individuals. Only spinosad compromised walking activity of the adult workers at doses as low as 2.29 ng a.i./bee, which is 1/5000 of the maximum field recommended rate. In conclusion, the results demonstrated that bioinsecticides can pose significant risks to native pollinators with lethal and sublethal effects; future investigations are needed on the likelihood of such effects under field conditions. © 2015 SETAC.

In vivo hemodynamic and electrocardiographic changes following Crataegus aronia syn. Azarolus L administration to normotensive Wistar rats.

PubMed

Shatoor, Abdullah S

2013-02-01

To evaluate the effects of the whole plant aqueous extract of Crataegus aronia (C. aronia) syn. Azarolus (L) on the hemodynamic and electrocardiographic intervals in albino rats. This study was carried out in 2 stages at the Research Laboratory, Physiology Department, Medical College of King Khalid University, Abha, Kingdom of Saudi Arabia between February and June 2012. First, the effects of C. aronia syn. Azarolus (L) on the hemodynamics and electrocardiograph in 54 Wistar male rats were assessed, then the mechanisms underlying the hemodynamic and electrocardiographic changes observed in the first stage were evaluated in 48 rats of the same species. The C. aronia administered at escalating doses (0.05-20 microgram/kg) produced a dose-time-dependent decrease in heart rate (HR) and mean arterial pressure (MAP). Higher doses (15 and 20 microgram/kg) produced the most significant reduction in both HR and MAP, and induced sinus node suppression and progressive atrio-ventricular blockade. The underlying mechanism of the induced bradyarrhythmia appeared to be due to the direct stimulation of the muscarinic receptor M2 and possible blockade of beta-receptors, while the hypotension was caused by enhanced nitric oxide release. No significant alterations in the electrocardiogram (ECG) components were observed. The administration of the C. aronia syn. Azarolus extract induced bradyarrhythmia and hypotension, without alteration in the ECG components.

Cimetidine enhancement of cyclophosphamide antitumour activity.

PubMed Central

Dorr, R. T.; Alberts, D. S.

1982-01-01

Male DBA2 mice were given 10(6) P-388 leukaemic cells i.p. and cimetidine (CMT) at 100 mg/kg 1 day for 10 days, or as a single 100 mg/kg injection 30 min before cyclophosphamide (CTX). CMT significantly prolonged the survival of groups of mice receiving 50, 100 and 200 mg/kg of CTX 3 days after tumour inoculation. Median survival increased by 5.5 days (P less than 0.05), 10 days (P less than 0.05) and 13 days (P less than 0.05) respectively. The addition of CMT had the effect of roughly doubling the CTX dose, without increasing the lethality. CMT produced the only long-term survival seen in the study (1-2/10) CMT alone had no apparent antitumour activity. CMT significantly prolonged mean pentobarbital sleep to 28.6-60 min vs only 10 min for phenobarbital treated mice. Both CMT regimens increased the plasma concentration time products for CTX-induced metabolites (NBP) by about 1.3 fold (in contrast to a 33% reduction with phenobarbital). On average the single-dose CMT regimen produced the greatest effect on survival, on pentobarbital sleep duration and on total NBP reactive species. Probable mechanisms for the CMT-CTX interaction include competitive microsomal enzyme inhibition and/or acutely depressed hepatic blood flow. Caution should be used in combining CMT with full doses of CTX and any other highly metabolized antineoplastic agents in man. PMID:7059463

Dose planning objectives in anal canal cancer IMRT: the TROG ANROTAT experience

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

Brown, Elizabeth, E-mail: elizabeth@mebrown.net; Cray, Alison; Haworth, Annette

2015-06-15

Intensity modulated radiotherapy (IMRT) is ideal for anal canal cancer (ACC), delivering high doses to irregular tumour volumes whilst minimising dose to surrounding normal tissues. Establishing achievable dose objectives is a challenge. The purpose of this paper was to utilise data collected in the Assessment of New Radiation Oncology Treatments and Technologies (ANROTAT) project to evaluate the feasibility of ACC IMRT dose planning objectives employed in the Australian situation. Ten Australian centres were randomly allocated three data sets from 15 non-identifiable computed tomography data sets representing a range of disease stages and gender. Each data set was planned by twomore » different centres, producing 30 plans. All tumour and organ at risk (OAR) contours, prescription and dose constraint details were provided. Dose–volume histograms (DVHs) for each plan were analysed to evaluate the feasibility of dose planning objectives provided. All dose planning objectives for the bone marrow (BM) and femoral heads were achieved. Median planned doses exceeded one or more objectives for bowel, external genitalia and bladder. This reached statistical significance for bowel V30 (P = 0.04), V45 (P < 0.001), V50 (P < 0.001), external genitalia V20 (P < 0.001) and bladder V35 (P < 0.001), V40 (P = 0.01). Gender was found to be the only significant factor in the likelihood of achieving the bowel V50 (P = 0.03) and BM V30 constraints (P = 0.04). The dose planning objectives used in the ANROTAT project provide a good starting point for ACC IMRT planning. To facilitate clinical implementation, it is important to prioritise OAR objectives and recognise factors that affect the achievability of these objectives.« less

Monomeric DR2/MOG-35-55 recombinant TCR ligand treats relapses of experimental encephalomyelitis in DR2 transgenic mice.

PubMed

Link, Jason M; Rich, Cathleen M; Korat, Maya; Burrows, Gregory G; Offner, Halina; Vandenbark, Arthur A

2007-04-01

Treatment of human autoimmune diseases such as multiple sclerosis (MS) will likely require agents that can prevent or reverse the inflammatory process that results in clinical relapses and disease progression. We evaluated the ability of a newly designed monomeric recombinant TCR ligand (RTL342M) containing HLA-DR2 peptide-binding domains covalently linked to MOG-35-55 peptide to prevent and treat both the initial episode and subsequent relapses of experimental autoimmune encephalomyelitis (EAE) in HLA-DR2 transgenic mice. Single doses of RTL342M given either i.v. or s.c. to HLA-DR2 mice produced a rapid (within 24 h) and dose-dependent reversal of clinical signs of paralytic EAE, and even a single dose < or = 2 microg could produce a significant treatment effect. Multiple daily doses were even more effective than the same total amount of RTL given as a single dose. By establishing the minimal effective dose, we determined that RTLs may be 50 times more potent than molar equivalent doses of myelin peptide alone. RTL342M given prior to induction of EAE prevented disease in most mice, and the remainder could be successfully retreated with RTL. Most important for clinical application, RTL342M was highly effective for treating EAE relapses when given periodically prior to the relapse or even after relapses had occurred. These data demonstrate the rapid and potent clinical effects of RTL342M at disease onset and during relapses in EAE and establish important principles governing the application of this novel approach as a possible therapy for patients with MS.

Tailored on demand anti-coagulant dosing: an in vitro and in vivo evaluation of 3D printed purpose-designed oral dosage forms.

PubMed

Arafat, Basel; Qinna, Nidal; Cieszynska, Milena; Forbes, Robert T; Alhnan, Mohamed A

2018-04-16

Coumarin therapy has been associated with high levels of inter- and intra-individual variation in the required dose to reach a therapeutic anticoagulation outcome. Therefore, a dynamic system that is able to achieve accurate delivery of a warfarin dose is of significant importance. Here we assess, the ability of 3D printing to fabricate and deliver tailored individualised precision dosing using an in-vitro model. Sodium warfarin loaded filaments were compounded using hot melt extrusion (HME) and further fabricated via fused deposition modelling (FDM) 3D printing to produce capsular-ovoid-shaped dosage forms loaded at 200 and 400 µg dose. The solid dosage forms and comparator warfarin aqueous solutions were administered by oral gavage to Sprague-Dawley rats. In vitro, warfarin release was faster at pH 1.2 in comparison to pH 2. A novel UV imaging approach indicated that the erosion of the methacrylate matrix was at a rate of 16.4 and 15.2 µm/min for horizontal and vertical planes respectively. In vivo, 3D printed forms were as proportionately effective as their comparative solution form in doubling plasma exposure following a doubling of warfarin dose (184% versus 192% respectively). The 3D printed ovoids showed a lower C max of warfarin (1.51 and 3.33 mg/mL versus 2.5 and 6.44 mg/mL) and a longer T max (6 and 3.7 versus 4 and 1.5 h) in comparison to liquid formulation. This work demonstrates for the first time in vivo, the potential of FDM 3D printing to produce a tailored specific dosage form and to accurately titrate coumarin dose response to an individual patient. Copyright © 2018. Published by Elsevier B.V.

Increase in cocaine- and amphetamine-regulated transcript (CART) in specific areas of the mouse brain by acute caffeine administration.

PubMed

Cho, Jin Hee; Cho, Yun Ha; Kim, Hyo Young; Cha, Seung Ha; Ryu, Hyun; Jang, Wooyoung; Shin, Kyung Ho

2015-04-01

Caffeine produces a variety of behavioral effects including increased alertness, reduced food intake, anxiogenic effects, and dependence upon repeated exposure. Although many of the effects of caffeine are mediated by its ability to block adenosine receptors, it is possible that other neural substrates, such as cocaine- and amphetamine-regulated transcript (CART), may be involved in the effects of caffeine. Indeed, a recent study demonstrated that repeated caffeine administration increases CART in the mouse striatum. However, it is not clear whether acute caffeine administration alters CART in other areas of the brain. To explore this possibility, we investigated the dose- and time-dependent changes in CART immunoreactivity (CART-IR) after a single dose of caffeine in mice. We found that a high dose of caffeine (100 mg/kg) significantly increased CART-IR 2 h after administration in the nucleus accumbens shell (AcbSh), dorsal bed nucleus of the stria terminalis (dBNST), central nucleus of the amygdala (CeA), paraventricular hypothalamic nucleus (PVN), arcuate hypothalamic nucleus (Arc), and locus coeruleus (LC), and returned to control levels after 8 h. But this increase was not observed in other brain areas. In addition, caffeine administration at doses of 25 and 50 mg/kg appears to produce dose-dependent increases in CART-IR in these brain areas; however, the magnitude of increase in CART-IR observed at a dose of 50 mg/kg was similar or greater than that observed at a dose of 100 mg/kg. This result suggests that CART-IR in AcbSh, dBNST, CeA, PVN, Arc, and LC is selectively affected by caffeine administration. Copyright © 2015 Elsevier Ltd. All rights reserved.

A comprehensive dosimetric evaluation of using RapidArc volumetric‐modulated arc therapy for the treatment of early‐stage nasopharyngeal carcinoma

PubMed Central

Wong, Wicger; Leung, Lucullus H.T.; Yu, Peter K.N.; So, Ronald W.K.; Cheng, Ashley C.K.

2012-01-01

The purpose of this study was to investigate the potential benefits of using triple‐arc volumetric‐intensity modulated arc radiotherapy (RapidArc (RA)) for the treatment of early‐stage nasopharyngeal carcinoma (NPC). A comprehensive evaluation was performed including plan quality, integral doses, and peripheral doses. Twenty cases of stage I or II NPC were selected for this study. Nine‐field sliding window IMRT, double‐arc, and triple‐arc RA treatment plans were compared with respect to target coverage, dose conformity, critical organ sparing, and integral doses. Measurement of peripheral doses was performed using thermoluminescent dosimeters in an anthropomorphic phantom. While similar conformity and target coverage were achieved by the three types of plans, triple‐arc RA produced better sparing of parotid glands and spinal cord than double‐arc RA or IMRT. Double‐arc RA plans produced slightly inferior parotid sparing and dose homogeneity than the other two delivery methods. The monitor units (MU) required for triple‐arc were about 50% less than those of IMRT plans, while there was no significant difference in the required MUs between triple‐arc and double‐arc RA plans. The peripheral dose in triple‐arc RA was found to be 50% less compared to IMRT near abdominal and pelvic region. Triple‐arc RA improves both the plan quality and treatment efficiency compared with IMRT for the treatment of early stage NPC. It has become the preferred choice of treatment delivery method for early stage NPC at our center. PACS numbers: 87.53.Bn, 87.55.D, 87.55.de, 87.55.dk, 87.56.ng PMID:23149781

Bioavailability and Pharmacokinetics of Oral Cocaine in Humans.

PubMed

Coe, Marion A; Jufer Phipps, Rebecca A; Cone, Edward J; Walsh, Sharon L

2018-06-01

The pharmacokinetic profile of oral cocaine has not been fully characterized and prospective data on oral bioavailability are limited. A within-subject study was performed to characterize the bioavailability and pharmacokinetics of oral cocaine. Fourteen healthy inpatient participants (six males) with current histories of cocaine use were administered two oral doses (100 and 200 mg) and one intravenous (IV) dose (40 mg) of cocaine during three separate dosing sessions. Plasma samples were collected for up to 24 h after dosing and analyzed for cocaine and metabolites by gas chromatography-mass spectrometry. Pharmacokinetic parameters were calculated by non-compartmental analysis, and a two-factor model was used to assess for dose and sex differences. The mean ± SEM oral cocaine bioavailability was 0.32 ± 0.04 after 100 and 0.45 ± 0.06 after 200 mg oral cocaine. Volume of distribution (Vd) and clearance (CL) were both greatest after 100 mg oral (Vd = 4.2 L/kg; CL = 116.2 mL/[min kg]) compared to 200 mg oral (Vd = 2.9 L/kg; CL = 87.5 mL/[min kg]) and 40 mg IV (Vd = 1.3 L/kg; CL = 32.7 mL/[min kg]). Oral cocaine area-under-thecurve (AUC) and peak concentration increased in a dose-related manner. AUC metabolite-to-parent ratios of benzoylecgonine and ecgonine methyl ester were significantly higher after oral compared to IV administration and highest after the lower oral dose. In addition, minor metabolites were detected in higher concentrations after oral compared to IV cocaine. Oral cocaine produced a pharmacokinetic profile different from IV cocaine, which appears as a rightward and downward shift in the concentration-time profile. Cocaine bioavailability values were similar to previous estimates. Oral cocaine also produced a unique metabolic profile, with greater concentrations of major and minor metabolites.

Effect of a single dose of dextromethorphan on psychomotor performance and working memory capacity.

PubMed

Al-Kuraishy, Hayder M; Al-Gareeb, Ali I; Ashor, Ammar Waham

2012-04-01

Previous studies show that the prolonged use of dextromethorphan produces cognitive deterioration in humans. The aim of this study was to investigate the effect of a single dose of dextroemthrophan on psychomotor performance and working memory capacity. This is a randomized, double-blind, controlled, and prospective study. Thirty-six (17 women, 19 men) medical students enrolled in the study; half of them (7 women, 11 men) were given placebo, while the other half (10 women, 8 men) received dextromethorphan. The choice reaction time, critical flicker fusion threshold, and N-back working memory task were measured before and after 2 h of taking the drugs. Dextromethorphan showed a significant deterioration in the 3-back working memory task (P<0.05). No significant changes were seen as regards the choice reaction time components (total, recognition, motor) and critical flicker fusion threshold (P>0.05). On the other hand, placebo showed no significant changes as regards the choice reaction time, critical flicker fusion threshold, and N-back working memory task (P>0.05). A single dose of dextromethorphan has no effect on attention and arousal but may significantly impair the working memory capacity.

Augmentation of aluminum-induced oxidative stress in rat cerebrum by presence of pro-oxidant (graded doses of ethanol) exposure.

PubMed

Nayak, Prasunpriya; Sharma, Shiv Bhushan; Chowdary, Nadella Vijaya Subbaraya

2010-11-01

Both aluminum and ethanol are pro-oxidants and neurotoxic. Considering the possibilities of co-exposure and sharing mechanisms of producing neurotoxicity, the present study was planned to identify the level of aluminum-induced oxidative stress in altered pro-oxidant (ethanol exposure) status of cerebrum. Male rats were coexposed to aluminum and ethanol for 4 weeks. After the exposure period, cerebral levels of protein, reduced glutathione (GSH), lipid peroxidation (TBARS) were measured. Activities of catalase, superoxide dismutase (SOD), glutathione reductase (GR) and glutathione perioxidase (GPx) of cerebrum were estimated. In most of the cases significant correlations were observed between the alterations and graded ethanol doses, suggesting a dose-dependency in pushing the oxidant equilibrium toward pro-oxidants. Aluminum is found to influence significantly all the studied parameters of oxidative stress. Likewise, ethanol also influenced these parameters significantly, except GR, while the interaction between ethanol and aluminum could significantly influence only the GSH content and GR activity of cerebrum. Present study demonstrate that coexposure of aluminum with pro-oxidant might favor development of aluminum-induced oxidative stress in cerebrum. This observation might be helpful in understanding of mechanism of neurodegenerative disorders and ameliorate them.

Retrospective evaluation of a method to predict fresh-frozen plasma dosage in anticoagulated patients.

PubMed

Frazee, Lawrence A; Bourguet, Claire C; Gutierrez, Wilson; Elder-Arrington, Jacinta; Elackattu, Alphi E P; Haller, Nairmeen Awad

2008-01-01

In the United States, fresh-frozen plasma (FFP) is commonly used for urgent reversal of warfarin; however, dosage recommendations are difficult to find. If validated, a proposed method that uses a nonlinear relationship between international normalized ratio (INR) and clotting factor activity (CFa) would be useful. This study retrospectively evaluated a proposed equation with adult medical inpatients who received FFP for warfarin reversal. For each patient the equation was used to predict the dose of FFP required to achieve the observed change in INR, which was then compared to the actual dose. The equation was considered successful if the predicted dose was within +/-20% of the actual dose. Subgroup analyses included subjects who received concomitant vitamin K; subjects with supratherapeutic INRs (>3); and subjects with significantly elevated INRs (>5). Of the 209 patients screened, 91 met criteria for inclusion in the study. Use of the equation to calculate the predicted dose of FFP was successful in 11 patients (12.1%) with use of actual body weight for prediction and in 23 patients (25.3%) with use of ideal body weight (P = 0.02). The equation performed similarly in all subgroups analyzed. The mean predicted FFP dose was significantly greater than the actual dose in all patients when actual body weight was used (925.2 mL vs. 620.6 mL; P < 0.001). Least-squares regression modeling of repeat INR (converted to CFa) produced a model that accounted for 57% of the variance in repeat INR. The value predicted from the model was closer to the actual CFa than was the value predicted from the published equation in every comparison, but it was statistically different only when actual body weight was used. This study revealed that a published equation for calculation of FFP dose to reverse oral anticoagulation resulted in doses that were significantly higher than the actual dose. Use of ideal body weight improved accuracy but was still not successful for the majority of patients. Until trials are able to prospectively demonstrate the accuracy of a dose-prediction model for FFP, dosing will remain largely empiric.

Microbial quality evaluation and effective decontamination of nutraceutically valued lotus seeds by electron beams and gamma irradiation

NASA Astrophysics Data System (ADS)

Bhat, Rajeev; Sridhar, K. R.; Karim, A. A.

2010-09-01

Lotus seeds are nutraceutically valued natural plant produce, which succumbs to microbial contamination, predominantly to toxigenic moulds. Results of the present study revealed seed coat portion to harbor higher proportion of microbial load, particularly fungi than cotyledon portion. Among the mycotoxins analyzed, aflatoxins (B 1, B 2, G 1 and G 2) were below detectable limits, while the seeds were devoid of Ochratoxin-A (OTA). Application of different doses of electron beam and gamma irradiation (0, 2.5, 5, 7.5, 10, 15 and 30 kGy) for decontamination purpose revealed significant dose-dependent decrease in the fungal contaminants ( P<0.05). However, the contaminant yeasts could survive up to 10 kGy dose, which could be completely eliminated at 15 kGy. From the results obtained, a dose range between 10 and 15 kGy is recommended for complete decontamination, as these doses have also been shown earlier to have minimal effects on nutritional and functional properties of lotus seeds.

Electron beam therapy with coil-generated magnetic fields.

PubMed

Nardi, Eran; Barnea, Gideon; Ma, Chang-Ming

2004-06-01

This paper presents an initial study on the issues involved in the practical implementation of the use of transverse magnetic fields in electron beam therapy. By using such magnetic fields the dose delivered to the tumor region can increase significantly relative to that deposited to the healthy tissue. Initially we calculated the magnetic fields produced by the Helmholtz coil and modified Helmholtz coil configurations. These configurations, which can readily be used to generate high intensity magnetic fields, approximate the idealized magnetic fields studied in our previous publications. It was therefore of interest to perform a detailed study of the fields produced by these configurations. Electron beam dose distributions for 15 MeV electrons were calculated using the ACCEPTM code for a 3T transverse magnetic field produced by the modified Helmholtz configuration. The dose distribution was compared to those obtained with no magnetic field. The results were similar to those obtained in our previous work, where an idealized step function magnetic field was used and a 3T field was shown to be the optimal field strength. A simpler configuration was also studied in which a single external coil was used to generate the field. Electron dose distributions are also presented for a given geometry and given magnetic field strength using this configuration. The results indicate that this method is more difficult to apply to radiotherapy due to its lack of symmetry and its irregularity. For the various configurations dealt with here, a major problem is the need to shield the magnetic field in the beam propagation volume, a topic that must be studied in detail.

Pharmacodynamic evaluation of Lys5, MeLeu9, Nle10-NKA(4–10) prokinetic effects on bladder and colon activity in acute spinal cord transected and spinally intact rats

PubMed Central

Kullmann, F. Aura; Katofiasc, M.; Thor, K.B.; Marson, L.

2017-01-01

Purpose To determine feasibility of a novel therapeutic approach to drug-induced voiding after spinal cord injury (SCI) using a well-characterized, peptide, neurokinin 2 receptor (NK2 receptor) agonist, Lys5, MeLeu9, Nle10-NKA(4–10) (LMN-NKA). Methods Cystometry and colorectal pressure measurements were performed in urethane anesthetized, intact and acutely spinalized, female rats. Bladder pressure and voiding were monitored in response to intravenous LMN-NKA given with the bladder filled to 70% capacity. Results LMN-NKA (0.1–300 µg/kg) produced dose dependent, rapid (< 60 s), short duration (< 15 min) increases in bladder pressure. In intact rats, doses above 0.3–1 µg/kg induced urine release (voiding efficiency of ~ 70% at ≥ 1 µg/kg). In spinalized rats, urine release required higher doses (≥ 10 µg/kg) and was less efficient (30–50%). LMN-NKA (0.1–100 µg/kg) also produced dose dependent increases in colorectal pressure. No tachyphylaxis was observed, and the responses were blocked by an NK2 receptor antagonist (GR159897, 1 mg/kg i.v.). No obvious cardiorespiratory effects were noted. Conclusions These results suggest that rapid-onset, short duration, drug-induced voiding is possible in acute spinal and intact rats with intravenous administration of an NK2 receptor agonist. Future challenges remain in regards to finding alternative routes of administration that produce clinically significant voiding, multiple times per day, in animal models of chronic SCI. PMID:27889808

Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors.

PubMed

Griffiths, Roland R; Johnson, Matthew W; Richards, William A; Richards, Brian D; Jesse, Robert; MacLean, Katherine A; Barrett, Frederick S; Cosimano, Mary P; Klinedinst, Maggie A

2018-01-01

Psilocybin can occasion mystical-type experiences with participant-attributed increases in well-being. However, little research has examined enduring changes in traits. This study administered psilocybin to participants who undertook a program of meditation/spiritual practices. Healthy participants were randomized to three groups (25 each): (1) very low-dose (1 mg/70 kg on sessions 1 and 2) with moderate-level ("standard") support for spiritual-practice (LD-SS); (2) high-dose (20 and 30 mg/70 kg on sessions 1 and 2, respectively) with standard support (HD-SS); and (3) high-dose (20 and 30 mg/70kg on sessions 1 and 2, respectively) with high support for spiritual practice (HD-HS). Psilocybin was administered double-blind and instructions to participants/staff minimized expectancy confounds. Psilocybin was administered 1 and 2 months after spiritual-practice initiation. Outcomes at 6 months included rates of spiritual practice and persisting effects of psilocybin. Compared with low-dose, high-dose psilocybin produced greater acute and persisting effects. At 6 months, compared with LD-SS, both high-dose groups showed large significant positive changes on longitudinal measures of interpersonal closeness, gratitude, life meaning/purpose, forgiveness, death transcendence, daily spiritual experiences, religious faith and coping, and community observer ratings. Determinants of enduring effects were psilocybin-occasioned mystical-type experience and rates of meditation/spiritual practices. Psilocybin can occasion enduring trait-level increases in prosocial attitudes/behaviors and in healthy psychological functioning. Trial Registration ClinicalTrials.gov Identifier NCT00802282.

Psilocybin-occasioned mystical-type experience in combination with meditation and other spiritual practices produces enduring positive changes in psychological functioning and in trait measures of prosocial attitudes and behaviors

PubMed Central

Griffiths, Roland R; Johnson, Matthew W; Richards, William A; Richards, Brian D; Jesse, Robert; MacLean, Katherine A; Barrett, Frederick S; Cosimano, Mary P; Klinedinst, Maggie A

2017-01-01

Psilocybin can occasion mystical-type experiences with participant-attributed increases in well-being. However, little research has examined enduring changes in traits. This study administered psilocybin to participants who undertook a program of meditation/spiritual practices. Healthy participants were randomized to three groups (25 each): (1) very low-dose (1 mg/70 kg on sessions 1 and 2) with moderate-level (“standard”) support for spiritual-practice (LD-SS); (2) high-dose (20 and 30 mg/70 kg on sessions 1 and 2, respectively) with standard support (HD-SS); and (3) high-dose (20 and 30 mg/70kg on sessions 1 and 2, respectively) with high support for spiritual practice (HD-HS). Psilocybin was administered double-blind and instructions to participants/staff minimized expectancy confounds. Psilocybin was administered 1 and 2 months after spiritual-practice initiation. Outcomes at 6 months included rates of spiritual practice and persisting effects of psilocybin. Compared with low-dose, high-dose psilocybin produced greater acute and persisting effects. At 6 months, compared with LD-SS, both high-dose groups showed large significant positive changes on longitudinal measures of interpersonal closeness, gratitude, life meaning/purpose, forgiveness, death transcendence, daily spiritual experiences, religious faith and coping, and community observer ratings. Determinants of enduring effects were psilocybin-occasioned mystical-type experience and rates of meditation/spiritual practices. Psilocybin can occasion enduring trait-level increases in prosocial attitudes/behaviors and in healthy psychological functioning. Trial Registration ClinicalTrials.gov Identifier NCT00802282 PMID:29020861

Comparing gold nano-particle enhanced radiotherapy with protons, megavoltage photons and kilovoltage photons: a Monte Carlo simulation.

PubMed

Lin, Yuting; McMahon, Stephen J; Scarpelli, Matthew; Paganetti, Harald; Schuemann, Jan

2014-12-21

Gold nanoparticles (GNPs) have shown potential to be used as a radiosensitizer for radiation therapy. Despite extensive research activity to study GNP radiosensitization using photon beams, only a few studies have been carried out using proton beams. In this work Monte Carlo simulations were used to assess the dose enhancement of GNPs for proton therapy. The enhancement effect was compared between a clinical proton spectrum, a clinical 6 MV photon spectrum, and a kilovoltage photon source similar to those used in many radiobiology lab settings. We showed that the mechanism by which GNPs can lead to dose enhancements in radiation therapy differs when comparing photon and proton radiation. The GNP dose enhancement using protons can be up to 14 and is independent of proton energy, while the dose enhancement is highly dependent on the photon energy used. For the same amount of energy absorbed in the GNP, interactions with protons, kVp photons and MV photons produce similar doses within several nanometers of the GNP surface, and differences are below 15% for the first 10 nm. However, secondary electrons produced by kilovoltage photons have the longest range in water as compared to protons and MV photons, e.g. they cause a dose enhancement 20 times higher than the one caused by protons 10 μm away from the GNP surface. We conclude that GNPs have the potential to enhance radiation therapy depending on the type of radiation source. Proton therapy can be enhanced significantly only if the GNPs are in close proximity to the biological target.

Toxicity of dietary Heliotropium circinatum to rats.

PubMed

Eröksüz, H; Eröksüz, Y; Ozer, H; Ceribasi, A O; Tosun, F; Tamer, U; Kizilay, C Akyüz

2003-08-01

Pyrrolizidine alkaloid intoxication was produced in adult, male rats by feeding different levels (0, 1, 3, 5 or 10%) of Heliotropium circinatum for 20 w. Combined GC-MS revealed 0.15% total alkaloid content in the plant material of which 12% and 88% were basic and N-oxide forms, respectively. The specific alkaloids identified were europine (67.33%), heliotrine (16.34%), lasiocarpine (8.12%), heleurine (4.18%), echinatine (1.56%), 7-angeylheliotrine (1.19%), and an unknown alkaloid (1.28%). Neither mortality nor significant clinical changes occurred in test groups. Mild to moderate, dose-related hepatic megalocytosis was the most prominent histopathological finding. In addition to chronic hepatotoxicity, notable medial thickening occurred in the pulmonary arterioles and arteries of the high-dosed groups. This study indicated that H. circinatum plant has limited toxic potential in rats with mild to moderate histological changes and no mortality at the dosing levels, total doses, or time of exposure employed.

Peripheral opioid analgesia in teeth with symptomatic inflamed pulps.

PubMed Central

Uhle, R. A.; Reader, A.; Nist, R.; Weaver, J.; Beck, M.; Meyers, W. J.

1997-01-01

The purpose of this study was to investigate the ability of low-dose fentanyl to produce analgesia when administered via the periodontal ligament injection in teeth with symptomatic, inflamed pulps. All subjects presented for emergency treatment with moderate to severe pain and had a posterior tooth with a clinical diagnosis of irreversible pulpitis. Twenty subjects randomly received either 10 micrograms fentanyl citrate or saline placebo via the periodontal ligament injection in a double-blind manner. The subjects rated their pain prior to injection and rated pain intensity and pain half gone for 59 min postinjection. Low-dose fentanyl delivered via the periodontal ligament injection in inflamed teeth provided significantly greater analgesia than the saline placebo (P < 0.05). Since the dose of fentanyl used was less than the dose required to provide analgesia by a central mechanism, the results of this study may be consistent with a peripheral opioid mechanism of action. PMID:9481968

Acute Biological Effects of Simulating the Whole-Body Radiation Dose Distribution from a Solar Particle Event Using a Porcine Model

PubMed Central

Wilson, Jolaine M.; Sanzari, Jenine K.; Diffenderfer, Eric S.; Yee, Stephanie S.; Seykora, John T.; Maks, Casey; Ware, Jeffrey H.; Litt, Harold I.; Reetz, Jennifer A.; McDonough, James; Weissman, Drew; Kennedy, Ann R.; Cengel, Keith A.

2011-01-01

In a solar particle event (SPE), an unshielded astronaut would receive proton radiation with an energy profile that produces a highly inhomogeneous dose distribution (skin receiving a greater dose than internal organs). The novel concept of using megavoltage electron-beam radiation to more accurately reproduce both the total dose and the dose distribution of SPE protons and make meaningful RBE comparisons between protons and conventional radiation has been described previously. Here, Yucatan minipigs were used to determine the effects of a superficial, SPE-like proton dose distribution using megavoltage electrons. In these experiments, dose-dependent increases in skin pigmentation, ulceration, keratinocyte necrosis and pigment incontinence were observed. Five of 18 animals (one each exposed to 7.5 Gy and 12.5 Gy radiation and three exposed to 25 Gy radiation) developed symptomatic, radiation-associated pneumonopathy approximately 90 days postirradiation. The three animals from the highest dose group showed evidence of mycoplasmal pneumonia along with radiation pneumonitis. Moreover, delayed-type hypersensitivity was found to be altered, suggesting that superficial irradiation of the skin with ionizing radiation might cause immune dysfunction or dysregulation. In conclusion, using total doses, patterns of dose distribution, and dose rates that are compatible with potential astronaut exposure to SPE radiation, animals experienced significant toxicities that were qualitatively different from toxicities previously reported in pigs for homogeneously delivered radiation at similar doses. PMID:21859326

Chromosome aberrations in workers occupationally exposed to tritium.

PubMed

Tawn, E Janet; Curwen, Gillian B; Riddell, Anthony E

2018-06-01

This paper reports the findings of an historical chromosome analysis for unstable aberrations, undertaken on 34 nuclear workers with monitored exposure to tritium. The mean recorded β-particle dose from tritium was 9.33 mGy (range 0.25-79.71 mGy) and the mean occupational dose from external, mainly γ-ray, irradiation was 1.94 mGy (range 0.00-7.71 mGy). The dicentric frequency of 1.91 ± 0.53 × 10 -3 per cell was significantly raised, in comparison with that of 0.61 ± 0.30 × 10 -3 per cell for a group of 66 comparable worker controls unexposed to occupational radiation. The frequency of total aberrations was also significantly higher in the tritium workers. Comparisons with in vitro studies indicate that at these dose levels an increase in aberration frequency is not expected. However, the available historical tritium dose records were produced for the purposes of radiological protection and based on a methodology that has since been updated, so tritium doses are subject to considerable uncertainty. It is therefore recommended that, if possible, tritium doses are reassessed using information on historical recording practices in combination with current dosimetry methodology, and that further chromosome studies are undertaken using modern FISH techniques to establish stable aberration frequencies, as these will provide information on a cumulative biological effect.

Determining the Optimal Dose of Adenosine for Unmasking Dormant Pulmonary Vein Conduction Following Atrial Fibrillation Ablation: Electrophysiological and Hemodynamic Assessment. DORMANT-AF Study.

PubMed

Prabhu, Sandeep; Mackin, Vincent; McLellan, Alex J A; Phan, Tuong; McGlade, Desmond; Ling, Liang-Han; Peck, Kah Y; Voskoboinik, Alexandr; Pathik, Bupesh; Nalliah, Chrishan J; Wong, Geoff R; Azzopardi, Sonia M; Lee, Geoffrey; Mariani, Justin; Taylor, Andrew J; Kalman, Jonathan M; Kistler, Peter M

2017-01-01

ELECTROPHYSIOLOGICAL AND HEMODYNAMIC ASSESSMENT. The significance of adenosine induced dormant pulmonary vein (PV) conduction in atrial fibrillation (AF) ablation remains controversial. The optimal dose of adenosine to determine dormant PV conduction is yet to be systematically explored. ELECTROPHYSIOLOGICAL AND HEMODYNAMIC ASSESSMENT. Consecutive patients undergoing index AF ablation received 3 adenosine doses (12, 18, and 24 mg) in a randomized blinded order, immediately after pulmonary vein isolation (PVI). Electrophysiological (PR prolongation, AV block (AVB) and PV reconnection) and hemodynamic (BP) parameters were measured. A total, 339 doses (113/dose) assessed 191 PVs in 50 patients (66% male, 72% PAF, 52% hypertensive). Dormant PV conduction occurred in 28% of patients (16.5% [32] of PVs). All cases were associated with AVB (AVB: PV reconnection vs. no PV reconnection 100% vs. 83%, P = 0.007). AVB occurred more frequently at 24 mg versus 12 mg (92% vs. 82%, P = 0.019) but not versus 18 mg (91%, P = 0.62). AVB duration progressed between 12 mg (12.0 ± 8.9 seconds), 18 mg (16.1 ± 9.1 seconds, P = 0.001), and 24 mg (19.0 ± 9.3 seconds, P < 0.001) doses. MBP fell further at 24 mg (ΔMBP: 27 ± 12 mmHg) and 18 mg (26 ± 13 mmHg) doses compared to 12 mg (22 ± 10 mmHg vs., P < 0.001). A significant reduction in AVB in patients >110 kg (65% vs. 91% in 70-110 kg group, P < 0.001) in response to adenosine was seen. ELECTROPHYSIOLOGICAL AND HEMODYNAMIC ASSESSMENT. An adenosine dose producing AVB is required to unmask dormant PV conduction. AVB is significantly reduced in patients >110 kg. Weight and dosing variability may in part explain the conflicting results of studies evaluating the clinical utility of adenosine in PVI. © 2016 Wiley Periodicals, Inc.

A New Method for Synthesizing Radiation Dose-Response Data From Multiple Trials Applied to Prostate Cancer

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

Diez, Patricia; Vogelius, Ivan S.; Department of Human Oncology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792

2010-07-15

Purpose: A new method is presented for synthesizing dose-response data for biochemical control of prostate cancer according to study design (randomized vs. nonrandomized) and risk group (low vs. intermediate-high). Methods and Materials: Nine published prostate cancer dose escalation studies including 6,539 patients were identified in the MEDLINE and CINAHL databases and reviewed to assess the relationship between dose and biochemical control. A novel method of analysis is presented in which the normalized dose-response gradient, {gamma}{sub 50}, is estimated for each study and subsequently synthesized across studies. Our method does not assume that biochemical control rates are directly comparable between studies.more » Results: Nonrandomized studies produced a statistically significantly higher {gamma}{sub 50} than randomized studies for intermediate- to high-risk patients ({gamma}{sub 50} = 1.63 vs. {gamma}{sub 50} = 0.93, p = 0.03) and a borderline significantly higher ({gamma}{sub 50} = 1.78 vs. {gamma}{sub 50} = 0.56, p = 0.08) for low-risk patients. No statistically significant difference in {gamma}{sub 50} was found between low- and intermediate- to high-risk patients (p = 0.31). From the pooled data of low and intermediate- to high-risk patients in randomized trials, we obtain the overall best estimate of {gamma}{sub 50} = 0.84 with 95% confidence interval 0.54-1.15. Conclusions: Nonrandomized studies overestimate the steepness of the dose-response curve as compared with randomized trials. This is probably the result of stage migration, improved treatment techniques, and a shorter follow-up in higher dose patients that were typically entered more recently. This overestimation leads to inflated expectations regarding the benefit from dose-escalation and could lead to underpowered clinical trials. There is no evidence of a steeper dose response for intermediate- to high-risk compared with low-risk patients.« less

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.

Use of tomotherapy in treatment of synchronous bilateral breast cancer: dosimetric comparison study

PubMed Central

Wadasadawala, T; Sarin, R; Upreti, R R; Paul, S; Phurailatpam, R

2015-01-01

Objective: Synchronous malignancy in both breasts is a rare incidence. The present study aims at dosimetric comparison of conventional bitangential radiotherapy (RT) technique with conventional [field-in-field (FIF)] and rotational [Helical TomoTherapy® and TomoDirect™ (TD); Accuray Inc., Sunnyvale, CA] intensity-modulated RT for patients with synchronous bilateral breast cancer (SBBC). Methods: CT data sets of 10 patients with SBBC were selected for the present study. RT was planned for all patients on both sides to whole breast and/or chest wall using the above-mentioned techniques. Six females with breast conservation on at least one side also had a composite plan along with tumour bed (TB) boost using sequential electrons for bitangential and FIF techniques or sequential helical tomotherapy (HT) boost (for TD) or simultaneous integrated boost (SIB) for HT. Results: All techniques produced acceptable target coverage. The hotspot was significantly lower with FIF technique and HT but higher with TD. For the organs at risk doses, HT resulted in significant reduction of the higher dose volumes. Similarly, TD resulted in significant reduction of the mean dose to the heart and total lung by reducing the lower dose volumes. All techniques of delivering boost to the TB were comparable in terms of target coverage. HT-SIB markedly reduced mean doses to the total lung and heart by specifically lowering the higher dose volumes. Conclusion: This study demonstrates the cardiac and pulmonary sparing ability of tomotherapy in the setting of SBBC. Advances in knowledge: This is the first study demonstrating feasibility of treatment of SBBC using tomotherapy. PMID:25605345

Dose-rate effect was observed in T98G glioma cells following BNCT.

PubMed

Kinashi, Yuko; Okumura, Kakuji; Kubota, Yoshihisa; Kitajima, Erika; Okayasu, Ryuichi; Ono, Koji; Takahashi, Sentaro

2014-06-01

It is generally said that low LET radiation produce high dose-rate effect, on the other hand, no significant dose rate effect is observed in high LET radiation. Although high LET radiations are produced in BNCT, little is known about dose-rate effect of BNCT. T98G cells, which were tumor cells, were irradiated by neutron mixed beam with BPA. As normal tissue derived cells, Chinese hamster ovary (CHO-K1) cells and DNA double strand breaks (DNA-DSBs) repair deficient cells, xrs5 cells were irradiated by the neutrons (not including BPA). To DNA-DSBs analysis, T98G cells were stained immunochemically with 53BP1 antibody. The number of DNA-DSBs was determined by counting 53BP1 foci. There was no dose-rate effect in xrs5 cells. D0 difference between 4cGy/min and 20cGy/min irradiation were 0.5 and 5.9 at the neutron and gamma-ray irradiation for CHO-K1, and 0.3 at the neutron for T98G cells. D0 difference between 20cGy/min and 80cGy/min irradiation for T98G cells were 1.2 and 0.6 at neutron irradiation plus BPA and gamma-ray. The differences between neutron irradiations at the dose rate in T98G cells were supported by not only the cell viability but also 53BP1 foci assay at 24h following irradiation to monitor DNA-DSBs. Dose-rate effect of BNCT when T98G cells include 20ppm BPA was greater than that of gamma-ray irradiation. Moreover, Dose-rate effect of the neutron beam when CHO-K1 cells did not include BPA was less than that of gamma-ray irradiation These present results may suggest the importance of dose-rate effect for more efficient BNCT and the side effect reduction. © 2013 Published by Elsevier Ltd.

DISRUPTION OF CONDITIONED REWARD ASSOCIATION BY TYPICAL AND ATYPICAL ANTIPSYCHOTICS

PubMed Central

Danna, C.L.; Elmer, G.I.

2013-01-01

Antipsychotic drugs are broadly classified into typical and atypical compounds; they vary in their pharmacological profile however a common component is their antagonist effects at the D2 dopamine receptors (DRD2). Unfortunately, diminished DRD2 activation is generally thought to be associated with the severity of neuroleptic-induced anhedonia. The purpose of this study was to determine the effect of the atypical antipsychotic olanzapine and typical antipsychotic haloperidol in a paradigm that reflects the learned transfer of incentive motivational properties to previously neutral stimuli, namely autoshaping. In order to provide a dosing comparison to a therapeutically relevant endpoint, both drugs were tested against amphetamine-induced disruption of prepulse inhibition as well. In the autoshaping task, rats were exposed to repeated pairings of stimuli that were differentially predictive of reward delivery. Conditioned approach to the reward predictive cue (sign-tracking) and to the reward (goal-tracking) increased during repeated pairings in the vehicle treated rats. Haloperidol and olanzapine completely abolished this behavior at relatively low doses (100 μg/kg). This same dose was the threshold dose for each drug to antagonize the sensorimotor gating deficits produced by amphetamine. At lower doses (3–30 μg/kg) both drugs produced a dose-dependent decrease in conditioned approach to the reward predictive cue. There was no difference between drugs at this dose range which indicates that olanzapine disrupts autoshaping at a significantly lower proposed DRD2 receptor occupancy. Interestingly, neither drug disrupted conditioned approach to the reward at the same dose range that disrupted conditioned approach to the reward predictive cue. Thus, haloperidol and olanzapine, at doses well below what is considered therapeutically relevant, disrupts the attribution of incentive motivational value to previously neutral cues. Drug effects on this dimension of reward processing are an important consideration in the development of future pharmacological treatments for schizophrenia. PMID:20416333

Pavor nocturnus: a complication of single daily tricyclic or neuroleptic dosage.

PubMed

Flemenbaum, A

1976-05-01

The author tested the hypothesis that a single bedtime dosage schedule of tricyclic or neuroleptic medication produces increased frequency of night terrors by administering a questionnaire to 30 medical patients who were not receiving such medications and 100 psychiatric patients on either multiple- or single-dosage schedules. Psychiatric patients on multiple-dosage schedules reported no more frightening dreams than the medical patients, whereas almost three-fourths of those receiving single bedtime doses had frightening dreams, a significant difference from the medical sample. This preliminary report is presented to call attention to the possible undesirable effects of a single dose schedule.

Anti-oxidants show an anti-hypertensive effect in diabetic and hypertensive subjects.

PubMed

Ceriello, A; Giugliano, D; Quatraro, A; Lefebvre, P J

1991-12-01

1. In this study an acute anti-hypertensive effect of three anti-oxidant agents (vitamin C, thiopronine and glutathione) in hypertensive subjects and in both hypertensive and non-hypertensive diabetic patients is reported. 2. The anti-oxidants had no effect on blood pressure in healthy normal subjects at a dose of 6 mmol, but thiopronine and glutathione produced a significant hypotensive effect at a dose of 12 mmol. 3. These data suggest that anti-oxidants might have a dilatatory effect and that an imbalance of the nitric oxide-free radical interaction might facilitate the development of hypertension in humans.

Two dose Augmentin treatment of acute gonorrhoea in men.

PubMed Central

Lim, K B; Rajan, V S; Giam, Y C; Lui, E O; Sng, E H; Yeo, K L

1984-01-01

We studied 192 men with acute gonococcal urethritis, 97 of whom received two oral doses of Augmentin (amoxycillin 3 g and clavulanic acid 250 mg) separated by a four hour interval; the remaining 95 received 2 g kanamycin in a single intramuscular injection. Of the patients treated with Augmentin, 93 (95.9%) were cured, which was significantly more than the 83 (87.4%) patients treated with kanamycin. Augmentin was equally effective in the treatment of penicillinase producing Neisseria gonorrhoeae (PPNG) and non-PPNG infections, the cure rates for which were 96.6% and 95.6% respectively. PMID:6428699

Protective role of Delphinium denudatum (Jadwar) against morphine induced tolerance and dependence in mice.

PubMed

Zafar, S; Ahmad, M A; Siddiqui, T A

2001-11-01

Chronic treatment with Delphinium denudatum (Dd) (Jadwar) (family: Ranunculaceae, 200-1600 mg/kg) suppressed morphine withdrawal jumps in a dose-dependent manner, a sign of the development of dependence to opiate as assessed by naloxone (2 mg/kg) precipitation withdrawal on day 10 of testing in mice. Repeated administration of Dd (200-1600 mg/kg) for 9 days attenuated the development of tolerance to the analgesic effect of morphine (10 mg/kg), also produces significant change in tail-flick latency from the saline pretreated group in a dose-dependent manner.

Sex differences in antinociceptive tolerance to delta-9-tetrahydrocannabinol in the rat

PubMed Central

Wakley, Alexa A.; Wiley, Jenny L.; Craft, Rebecca M.

2014-01-01

Background Sex differences in cannabinoid effects have been reported in rodents, with adult females typically being more sensitive than adult males. The present study compared the development of antinociceptive tolerance to delta-9-tetrahydrocannabinol (THC) in adult, gonadally intact female vs. male rats. Methods Cumulative dose-effect curves were obtained for THC (1.0–18 mg/kg i.p.) on warm water tail withdrawal and paw pressure tests. Vehicle or the sex-specific ED80 dose for THC was administered twice daily for 9 days; THC dose-effect curves were then re-determined. Results On the pre-chronic test day, THC was significantly more potent in females than males in producing antinociception on the tail withdrawal and paw pressure tests. After 9 days of twice-daily THC treatment (5.4 mg/kg/injection in females, 7.6 mg/kg/injection in males), THC potency on both tests decreased more in females than males. On the tail withdrawal test, chronic THC produced 4.2- vs. 2.8-fold increases in ED50 values in females vs. males, respectively. On the paw pressure test, chronic THC produced 4.4- vs. 2.9-fold increases in ED50 values in females vs. males, respectively. Chronic THC treatment did not significantly disrupt estrous cycling in females. Conclusions These results demonstrate that – even when sex differences in acute THC potency are controlled for – females develop more antinociceptive tolerance to THC than males. Given the importance of drug tolerance in the development of drug dependence, these results suggest that females may be more vulnerable than males to developing dependence after chronic cannabinoid exposure. PMID:25131716

Evaluation of the anti-diarrheal activity of the hydromethanolic root extract of Rhus tripartita (Ucria) (Anacardiacae).

PubMed

Ben Barka, Zaineb; Aouadhi, Chedia; Tlili, Mounira; Alimi, Hichem; Ben Miled, Hanene; Ben Rhouma, Khémais; Sakly, Mohsen; Ksouri, Riadh; Schneider, Yves Jacques; Maaroufi, Abderrazek; Tebourbi, Olfa

2016-10-01

Rhus tripartita (Anacardiacae) is a plant which is traditionally used for the treatment of ulcer and diarrhea in Tunisia. However, the scientific basis for this usage has not been well established. The core aim of the present study is to evaluate the antidiarrheal activity of Rhus tripartita root methanolic extract (RRE). The antidiarrheal activity of RRE oral doses (50, 100, 200 and 300mg/kg) was evaluated using the castor oil-induced diarrhea, the intestinal fluid emptying method and the normal intestinal transit test. The antibacterial activity was tested against four pathogenic bacteria using two methods. The RRE was also phytochemical studied. Diarrhea experiments showed a protective effect of the RRE which produced a significant (p<0.05) and dose-dependent reduction of all the diarrhea parameters. It delayed the onset of diarrhea, produced a significant decrease in the frequency of defecation and the diarrhea score severity and decreased the volume of intestinal fluid induced by castor oil as well as the propulsion intestinal transit. The effect of the extract at the highest dose (300mg/kg) was similar to that of loperamide, the standard anti-diarrheal drug (10mg/kg). The anti-bacterial activity test showed that RRE exhibited a great inhibition activity against four pathogenic bacteria strains (Esherichia coli, Salmonella typhimurium, Salmonella argenosa, Staphylococcus aureus). Oral administration of the extract up to 3g/kg did not produce any acute toxicity in rats. The preliminary phytochemical screening of the RRE revealed the presence of flavonoids, tannins, and polyphenols. Results showed that RRE at 300mg/kg possesses the highest anti-diarrheal activity possibly mediated by the inhibitory effects on gastrointestinal propulsion and intestinal fluid accumulation. Copyright © 2016 Elsevier Masson SAS. 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

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.

CPP-115, a Potent γ-Aminobutyric Acid Aminotransferase Inactivator for the Treatment of Cocaine Addiction

PubMed Central

Pan, Yue; Gerasimov, Madina R.; Kvist, Trine; Wellendorph, Petrine; Madsen, Karsten K.; Pera, Elena; Lee, Hyunbeom; Schousboe, Arne; Chebib, Mary; Bräuner-Osborne, Hans; Craft, Cheryl M.; Brodie, Jonathan D.; Schiffer, Wynne K.; Dewey, Stephen L.; Miller, Steven R.; Silverman, Richard B.

2011-01-01

Vigabatrin, a GABA aminotransferase (GABA-AT) inactivator, is used to treat infantile spasms and refractory complex partial seizures and is in clinical trials to treat addiction. We evaluated a novel GABA-AT inactivator (CPP-115) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. Using in vivo microdialysis techniques in freely moving rats and micro-PET imaging techniques, CPP-115 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at 1/300–1/600th the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose 1/300th that of vigabatrin. Electroretinographic (ERG) responses in rats treated with CPP-115, at doses 20–40 times higher than those needed to treat addiction in rats, exhibited reductions in ERG responses, which were less than the reductions observed in rats treated with vigabatrin at the same dose needed to treat addiction in rats. In conclusion, CPP-115 can be administered at significantly lower doses than vigabatrin, which suggests a potential new treatment for addiction with a significantly reduced risk of visual field defects. PMID:22128851

Dose and time dependent ototoxicity of aspartame in rats.

PubMed

Ozturan, Orhan; Dogan, Remzi; Tugrul, Selahattin; Gedik, Ozge; Sjostrand, Alev Pektas; Yildirim, Yavuz Selim

2017-04-01

Low-dose administration of Aspartame (Ap) did not produce a significant ototoxic effect at the end of the 6th month. However, duration of the ototoxic effect is shortened and severity of the effect is increased as dose and duration of Ap administration is increased. While Ap toxicity has been studied in short- and long-term studies, its effects on hearing have not been investigated. This study was conducted to evaluate the effects of long-term consumption of Ap administered in various doses on hearing status of rats. The study included 54 female Wistar Albino rats. Ap was given for 6 months to the rats. The groups were assigned according to levels of Ap dosage. DPOAE and ABR tests were utilized for serial hearing evaluations. Serial hearing measurement times were designed as baseline, 1st week, 2nd week, 1st, 2nd, 3rd, and 6th months. While audiological parameters deteriorated with 100 mg/kg/day dose after the 3rd month, ABR thresholds were elevated and DPOAE values were significantly decreased in 500 mg/kg/day and 1000 mg/kg/day applications after the 2nd month. In 2000 mg/kg/day and 4000 mg/kg/day applications, deteriorations in audiological parameters were detected as early as the first and second months; respectively.

Radiolysis products and sensory properties of electron-beam-irradiated high-barrier food-packaging films containing a buried layer of recycled low-density polyethylene.

PubMed

Chytiri, S D; Badeka, A V; Riganakos, K A; Kontominas, M G

2010-04-01

The aim was to study the effect of electron-beam irradiation on the production of radiolysis products and sensory changes in experimental high-barrier packaging films composed of polyamide (PA), ethylene-vinyl alcohol (EVOH) and low-density polyethylene (LDPE). Films contained a middle buried layer of recycled LDPE, while films containing 100% virgin LDPE as the middle buried layer were taken as controls. Irradiation doses ranged between zero and 60 kGy. Generally, a large number of radiolysis products were produced during electron-beam irradiation, even at the lower absorbed doses of 5 and 10 kGy (approved doses for food 'cold pasteurization'). The quantity of radiolysis products increased with irradiation dose. There were no significant differences in radiolysis products identified between samples containing a recycled layer of LDPE and those containing virgin LDPE (all absorbed doses), indicating the 'functional barrier' properties of external virgin polymer layers. Sensory properties (mainly taste) of potable water were affected after contact with irradiated as low as 5 kGy packaging films. This effect increased with increasing irradiation dose.

Experimental check of bremsstrahlung dosimetry predictions for 0.75 MeV electrons

NASA Astrophysics Data System (ADS)

Sanford, T. W. L.; Halbleib, J. A.; Beezhold, W.

Bremsstrahlung dose in CaF2 TLDs from the radiation produced by 0.75 MeV electrons incident on Ta/C targets is measured and compared with that calculated via the CYLTRAN Monte Carlo code. The comparison was made to validate the code, which is used to predict and analyze radiation environments of flash X-ray simulators measured by TLDs. Over a wide range of Ta target thicknesses and radiation angles the code is found to agree with the 5% measurements. For Ta thickness near those that optimize the radiation output, however, the code overestimates the radiation dose at small angles. Maximum overprediction is about 14 + or - 5%. The general agreement, nonetheless, gives confidence in using the code at this energy and in the TLD calibration procedure. For the bulk of the measurements, a standard TLD employing a 2.2 mm thick Al equilibrator was used. In this paper we also show that this thickness can significantly attenuate the free-field dose and introduces significant photon buildup in the equalibrator.

[The effect of aluminum adjuvant and immunization schedule on immunogenicity of Sabin inactivated poliovirus vaccine].

PubMed

Wang, Fang; Zhang, Ming; Xie, Bing-Feng; Cao, Han; Tong, Shao-Yong; Wang, Jun-Rong; Yu, Xiao-Ping; Tang, Yang; Yang, Jing-Ran; Sun, Ming-Bo

2013-04-01

To study the effect of aluminume adjuvant and immunization schedule on immunogenicity of Sabin inactivated poliovirus vaccine. Four batches of Sabin IPV were produced by different concentrations of type 1, 2, and 3 poliovirus and administrated on three-dose schedule at 0, 1, 2 months and 0, 2, 4 months on rats. Serum samples were collected one month after each dose and neutralizing antibody titers against three types poliovirus were determined by micro-neutralization assay. The GMTs of neutralizing antibodies against three types poliovirus increased significantly and the seropositivity rates were 100% in all groups after 3 doses. There was no significant difference between two immunization schedules, and the 0, 2, 4 month schedule could induce higher level neutralizing antibody compared to the 0, 1, 2 month schedule. The groups with aluminum adjuvant could induce higher level neutralizing antibody compared to the groups without adjuvant. Aluminum djuvant and immunization schedule could improve the immunogenicity of Sabin IPV.

Benchmarking the minimum Electron Beam (eBeam) dose required for the sterilization of space foods

NASA Astrophysics Data System (ADS)

Bhatia, Sohini S.; Wall, Kayley R.; Kerth, Chris R.; Pillai, Suresh D.

2018-02-01

As manned space missions extend in length, the safety, nutrition, acceptability, and shelf life of space foods are of paramount importance to NASA. Since food and mealtimes play a key role in reducing stress and boredom of prolonged missions, the quality of food in terms of appearance, flavor, texture, and aroma can have significant psychological ramifications on astronaut performance. The FDA, which oversees space foods, currently requires a minimum dose of 44 kGy for irradiated space foods. The underlying hypothesis was that commercial sterility of space foods could be achieved at a significantly lower dose, and this lowered dose would positively affect the shelf life of the product. Electron beam processed beef fajitas were used as an example NASA space food to benchmark the minimum eBeam dose required for sterility. A 15 kGy dose was able to achieve an approximately 10 log reduction in Shiga-toxin-producing Escherichia coli bacteria, and a 5 log reduction in Clostridium sporogenes spores. Furthermore, accelerated shelf life testing (ASLT) to determine sensory and quality characteristics under various conditions was conducted. Using Multidimensional gas-chromatography-olfactometry-mass spectrometry (MDGC-O-MS), numerous volatiles were shown to be dependent on the dose applied to the product. Furthermore, concentrations of off -flavor aroma compounds such as dimethyl sulfide were decreased at the reduced 15 kGy dose. The results suggest that the combination of conventional cooking combined with eBeam processing (15 kGy) can achieve the safety and shelf-life objectives needed for long duration space-foods.

Optimization of Monte Carlo dose calculations: The interface problem

NASA Astrophysics Data System (ADS)

Soudentas, Edward

1998-05-01

High energy photon beams are widely used for radiation treatment of deep-seated tumors. The human body contains many types of interfaces between dissimilar materials that affect dose distribution in radiation therapy. Experimentally, significant radiation dose perturbations has been observed at such interfaces. The EGS4 Monte Carlo code was used to calculate dose perturbations at boundaries between dissimilar materials (such as bone/water) for 60Co and 6 MeV linear accelerator beams using a UNIX workstation. A simple test of the reliability of a random number generator was also developed. A systematic study of the adjustable parameters in EGS4 was performed in order to minimize calculational artifacts at boundaries. Calculations of dose perturbations at boundaries between different materials showed that there is a 12% increase in dose at water/bone interface, and a 44% increase in dose at water/copper interface. with the increase mainly due to electrons produced in water and backscattered from the high atomic number material. The dependence of the dose increase on the atomic number was also investigated. The clinically important case of using two parallel opposed beams for radiation therapy was investigated where increased doses at boundaries has been observed. The Monte Carlo calculations can provide accurate dosimetry data under conditions of electronic non-equilibrium at tissue interfaces.

Interaction of different antidepressants with acute and chronic methadone in mice, and possible clinical implications.

PubMed

Schreiber, Shaul; Barak, Yonatan; Hostovsky, Avner; Baratz-Goldstein, Renana; Volis, Ina; Rubovitch, Vardit; Pick, Chaim G

2014-04-01

We studied the interaction of a single dose of different antidepressant medications with a single (acute) dose or implanted mini-pump (chronic) methadone administration in mice, using the hotplate assay. For the acute experiment, subthreshold doses of six antidepressant drugs were administered separately with a single dose of methadone. The addition of a subthreshold dose of desipramine or clomipramine to methadone produced significant augmentation of the methadone effect with each drug (p < 0.05). Fluvoxamine given at a fixed subthreshold dose induced a synergistic effect only with a low methadone dose. Escitalopram, reboxetine and venlafaxine given separately, each at a fixed subthreshold dose, induced no interaction. Possible clinical implications of these findings are that while escitalopram, reboxetine and venlafaxine do not affect methadone's antinociception in mice and are safe to be given together with methadone when indicated, fluvoxamine, clomipramine and desipramine considerably augment methadone-induced effects and should be avoided in this population due to the risk of inducing opiate overdose. For the chromic experiment, when a subthreshold dose of either escitalopram, desipramine or clomipramine was injected to mice following 2 weeks of methadone administration with the mini-pump, none of the antidepressant drugs strengthened methadone's analgesic effect. Further studies are needed before possible clinical implications can be drawn.

Sterility and Sexual Competitiveness of Tapachula-7 Anastrepha ludens Males Irradiated at Different Doses.

PubMed

Orozco-Dávila, Dina; Adriano-Anaya, Maria de Lourdes; Quintero-Fong, Luis; Salvador-Figueroa, Miguel

2015-01-01

A genetic sexing strain of Anastrepha ludens (Loew), Tapachula-7, was developed by the Mexican Program Against Fruit Flies to produce and release only males in programs where the sterile insect technique (SIT) is applied. Currently, breeding are found at a massive scale, and it is necessary to determine the optimum irradiation dose that releases sterile males with minimum damage to their sexual competitiveness. Under laboratory and field conditions, we evaluated the effects of gamma irradiation at doses of 0, 20, 40, 60 and 80 Gy on the sexual competitiveness of males, the induction of sterility in wild females and offspring survivorship. The results of the study indicate that irradiation doses have a significant effect on the sexual behavior of males. A reduction of mating capacity was inversely proportional to the irradiation dose of males. It is estimated that a dose of 60 Gy can induce more than 99% sterility in wild females. In all treatments, the degree of offspring fertility was correlated with the irradiation dose of the parents. In conclusion, the results of the study indicate that a dose of 60 Gy can be applied in sterile insect technique release programs. The application of this dose in the new genetic sexing strain of A. ludens is discussed.

Sterility and Sexual Competitiveness of Tapachula-7 Anastrepha ludens Males Irradiated at Different Doses

PubMed Central

Orozco-Dávila, Dina; Adriano-Anaya, Maria de Lourdes; Quintero-Fong, Luis; Salvador-Figueroa, Miguel

2015-01-01

A genetic sexing strain of Anastrepha ludens (Loew), Tapachula-7, was developed by the Mexican Program Against Fruit Flies to produce and release only males in programs where the sterile insect technique (SIT) is applied. Currently, breeding are found at a massive scale, and it is necessary to determine the optimum irradiation dose that releases sterile males with minimum damage to their sexual competitiveness. Under laboratory and field conditions, we evaluated the effects of gamma irradiation at doses of 0, 20, 40, 60 and 80 Gy on the sexual competitiveness of males, the induction of sterility in wild females and offspring survivorship. The results of the study indicate that irradiation doses have a significant effect on the sexual behavior of males. A reduction of mating capacity was inversely proportional to the irradiation dose of males. It is estimated that a dose of 60 Gy can induce more than 99% sterility in wild females. In all treatments, the degree of offspring fertility was correlated with the irradiation dose of the parents. In conclusion, the results of the study indicate that a dose of 60 Gy can be applied in sterile insect technique release programs. The application of this dose in the new genetic sexing strain of A. ludens is discussed. PMID:26274926

Chronic administration during early adulthood does not alter the hormonally-dependent disruptive effects of delta-9-tetrahydrocannabinol (Δ9-THC) on complex behavior in female rats.

PubMed

Winsauer, Peter J; Sutton, Jessie L

2014-02-01

This study examined whether chronic Δ(9)-THC during early adulthood would produce the same hormonally-dependent deficits in learning that are produced by chronic Δ(9)-THC during adolescence. To do this, either sham-operated (intact) or ovariectomized (OVX) female rats received daily saline or 5.6 mg/kg of Δ(9)-THC i.p. for 40 days during early adulthood. Following chronic administration, and a drug-free period to train both a learning and performance task, acute dose-effect curves for Δ(9)-THC (0.56-10 mg/kg) were established in each of the four groups (intact/saline, intact/THC, OVX/saline and OVX/THC). The dependent measures of responding under the learning and performance tasks were the overall response rate and the percentage of errors. Although the history of OVX and chronic Δ(9)-THC in early adulthood did not significantly affect non-drug or baseline behavior under the tasks, acute administration of Δ(9)-THC produced both rate-decreasing and error-increasing effects on learning and performance behavior, and these effects were dependent on their hormone condition. More specifically, both intact groups were more sensitive to the rate-decreasing and error-increasing effects of Δ(9)-THC than the OVX groups irrespective of chronic Δ(9)-THC administration, as there was no significant main effect of chronic treatment and no significant interaction between chronic treatment (saline or Δ(9)-THC) and the dose of Δ(9)-THC administered as an adult. Post mortem examination of 10 brain regions also indicated there were significant differences in agonist-stimulated GTPγS binding across brain regions, but no significant effects of chronic treatment and no significant interaction between the chronic treatment and cannabinoid signaling. Thus, acute Δ(9)-THC produced hormonally-dependent effects on learning and performance behavior, but a period of chronic administration during early adulthood did not alter these effects significantly, which is contrary to what we and others have shown for chronic administration during adolescence. Copyright © 2013 Elsevier Inc. All rights reserved.

Predicted Blood Glucose from Insulin Administration Based on Values from Miscoded Glucose Meters

PubMed Central

Raine, Charles H.; Pardo, Scott; Parkes, Joan Lee

2008-01-01

Objectives The proper use of many types of self-monitored blood glucose (SMBG) meters requires calibration to match strip code. Studies have demonstrated the occurrence and impact on insulin dose of coding errors with SMBG meters. This paper reflects additional analyses performed with data from Raine et al. (JDST, 2:205–210, 2007). It attempts to relate potential insulin dose errors to possible adverse blood glucose outcomes when glucose meters are miscoded. Methods Five sets of glucose meters were used. Two sets of meters were autocoded and therefore could not be miscoded, and three sets required manual coding. Two of each set of manually coded meters were deliberately miscoded, and one from each set was properly coded. Subjects (n = 116) had finger stick blood glucose obtained at fasting, as well as at 1 and 2 hours after a fixed meal (Boost®; Novartis Medical Nutrition U.S., Basel, Switzerland). Deviations of meter blood glucose results from the reference method (YSI) were used to predict insulin dose errors and resultant blood glucose outcomes based on these deviations. Results Using insulin sensitivity data, it was determined that, given an actual blood glucose of 150–400 mg/dl, an error greater than +40 mg/dl would be required to calculate an insulin dose sufficient to produce a blood glucose of less than 70 mg/dl. Conversely, an error less than or equal to -70 mg/dl would be required to derive an insulin dose insufficient to correct an elevated blood glucose to less than 180 mg/dl. For miscoded meters, the estimated probability to produce a blood glucose reduction to less than or equal to 70 mg/dl was 10.40%. The corresponding probabilities for autocoded and correctly coded manual meters were 2.52% (p < 0.0001) and 1.46% (p < 0.0001), respectively. Furthermore, the errors from miscoded meters were large enough to produce a calculated blood glucose outcome less than or equal to 50 mg/dl in 42 of 833 instances. Autocoded meters produced zero (0) outcomes less than or equal to 50 mg/dl out of 279 instances, and correctly coded manual meters produced 1 of 416. Conclusions Improperly coded blood glucose meters present the potential for insulin dose errors and resultant clinically significant hypoglycemia or hyperglycemia. Patients should be instructed and periodically reinstructed in the proper use of blood glucose meters, particularly for meters that require coding. PMID:19885229

Chlorozotocin

PubMed Central

Panasci, Lawrence C.; Green, Dianna; Schein, Philip S.

1979-01-01

Chlorozotocin is a chloroethyl nitrosourea with a glucose carrier that has curative activity for the murine L1210 leukemia, but is nonmyelosuppressive in mice. To determine the mechanism for this unique property of reduced bone marrow toxicity, comparative studies were conducted with chlorozotocin and CCNU, a myelotoxic chloroethyl nitrosourea. Suspensions of L1210 leukemia and murine bone marrow cells were incubated for 2 h with 0.1 mM [14C]-chloroethyl chlorozotocin or CCNU. Chlorozotocin demonstrated a fourfold increased covalent binding of the chloroethyl group to L1210 nuclei when compared to equimolar CCNU. Chlorozotocin alkylation of L1210 cells resulted in the binding of 57 pmol of [14C]ethyl group/mg of DNA, which represented a 2.3-fold increased alkylation when compared to CCNU. In marked contrast, the binding of the chloroethyl group to bone marrow nuclei was equivalent for both drugs. In addition, chlorozotocin alkylation of murine bone marrow DNA, 45 pmol of [14C]ethyl group/mg of DNA, was equivalent to that of CCNU. The ratio of L1210:bone marrow DNA alkylation was 1.3 for chlorozotocin compared to 0.6 for CCNU. The intracellular carbamoylation of L1210 and bone marrow protein by CCNU was 400- to 600-fold greater than that produced by chlorozotocin. After a 2-h exposure to 0.1, 0.05, or 0.01 mM drug, both chlorozotocin and CCNU produced a reduction in the cloning efficiency of L1210 cells that was dose dependent. However, chlorozotocin was significantly more cytotoxic than CCNU at all three molar concentrations (P < 0.01). Chlorozotocin, 0.1 mM, reduced L1210 DNA synthesis to 1% of control by 48 h, in contrast to 16% with equimolar CCNU (P < 0.01). In mice bearing 105 L1210 cells, chlorozotocin produced its optimal antitumor activity (332% increased life span [ILS]) at doses of 48-64 μmol/kg, with >50% indefinite survivors. In contrast, CCNU at the same molar doses resulted in only a 191% ILS; a CCNU dose of 128 μmol/kg was required for comparable optimal L1210 antitumor activity, 413% ILS. On a molar basis, the dose of chlorozotocin that produced optimal in vivo L1210 antitumor activity was one-third to one-half that of CCNU. Chlorozotocin, unlike CCNU, produced no murine bone marrow toxicity at its optimal therapeutic dose. This unique combination of antitumor activity without myelosuppression can be correlated with the advantageous ratio of L1210:bone marrow in vitro DNA alkylation by chlorozotocin (1.3) as compared to equimolar CCNU (0.6). PMID:158033

Are fish fed with cyanobacteria safe, nutritious and delicious? A laboratory study

NASA Astrophysics Data System (ADS)

Liang, Hualei; Zhou, Wenshan; Zhang, Yulei; Qiao, Qin; Zhang, Xuezhen

2015-10-01

Toxic cyanobacterial blooms, which produce cyclic heptapeptide toxins known as microcystins, are worldwide environmental problems. On the other hand, the cyanobacteria protein (30-50%) has been recommended as substitute protein for aquaculture. The present laboratory study verified the feasibility of cyanobacteria protein substitution and risk assessment. Goldfish were fed diets supplemented lyophilised cyanobacteria powder for 16 weeks with the various doses: 0% (control), 10%, 20%, 30% and 40%. Low doses (10% and 20%) promoted growth whereas high doses (30% and 40%) inhibited growth. In cyanobacteria treated fish, the proximate composition of ash, crude fat content and crude protein content decreased in 16 weeks; the saturated fatty acid (SFA) content significantly increased; the n-3 polyunsaturated fatty acid content, collagen content and muscle pH significantly decreased; cooking loss percents increased significantly. Muscle fiber diameter and myofibril length were negatively correlation. Additionally, flavour compounds (e.g., amino acids, nucleotides, organic acids and carnosine) changed significantly in the treated fish, and odour compounds geosmin and 2-methylisoborneol increased significantly. The estimated daily intake (EDI) of microcystins in muscle was close to or exceeded the World Health Organization (WHO) tolerable daily intake (TDI), representing a great health risk. Cyanobacterie is not feasible for protein sources use in aquaculture.

Are fish fed with cyanobacteria safe, nutritious and delicious? A laboratory study.

PubMed

Liang, Hualei; Zhou, Wenshan; Zhang, Yulei; Qiao, Qin; Zhang, Xuezhen

2015-10-16

Toxic cyanobacterial blooms, which produce cyclic heptapeptide toxins known as microcystins, are worldwide environmental problems. On the other hand, the cyanobacteria protein (30-50%) has been recommended as substitute protein for aquaculture. The present laboratory study verified the feasibility of cyanobacteria protein substitution and risk assessment. Goldfish were fed diets supplemented lyophilised cyanobacteria powder for 16 weeks with the various doses: 0% (control), 10%, 20%, 30% and 40%. Low doses (10% and 20%) promoted growth whereas high doses (30% and 40%) inhibited growth. In cyanobacteria treated fish, the proximate composition of ash, crude fat content and crude protein content decreased in 16 weeks; the saturated fatty acid (SFA) content significantly increased; the n-3 polyunsaturated fatty acid content, collagen content and muscle pH significantly decreased; cooking loss percents increased significantly. Muscle fiber diameter and myofibril length were negatively correlation. Additionally, flavour compounds (e.g., amino acids, nucleotides, organic acids and carnosine) changed significantly in the treated fish, and odour compounds geosmin and 2-methylisoborneol increased significantly. The estimated daily intake (EDI) of microcystins in muscle was close to or exceeded the World Health Organization (WHO) tolerable daily intake (TDI), representing a great health risk. Cyanobacterie is not feasible for protein sources use in aquaculture.

Are fish fed with cyanobacteria safe, nutritious and delicious? A laboratory study

PubMed Central

Liang, Hualei; Zhou, Wenshan; Zhang, Yulei; Qiao, Qin; Zhang, Xuezhen

2015-01-01

Toxic cyanobacterial blooms, which produce cyclic heptapeptide toxins known as microcystins, are worldwide environmental problems. On the other hand, the cyanobacteria protein (30–50%) has been recommended as substitute protein for aquaculture. The present laboratory study verified the feasibility of cyanobacteria protein substitution and risk assessment. Goldfish were fed diets supplemented lyophilised cyanobacteria powder for 16 weeks with the various doses: 0% (control), 10%, 20%, 30% and 40%. Low doses (10% and 20%) promoted growth whereas high doses (30% and 40%) inhibited growth. In cyanobacteria treated fish, the proximate composition of ash, crude fat content and crude protein content decreased in 16 weeks; the saturated fatty acid (SFA) content significantly increased; the n-3 polyunsaturated fatty acid content, collagen content and muscle pH significantly decreased; cooking loss percents increased significantly. Muscle fiber diameter and myofibril length were negatively correlation. Additionally, flavour compounds (e.g., amino acids, nucleotides, organic acids and carnosine) changed significantly in the treated fish, and odour compounds geosmin and 2-methylisoborneol increased significantly. The estimated daily intake (EDI) of microcystins in muscle was close to or exceeded the World Health Organization (WHO) tolerable daily intake (TDI), representing a great health risk. Cyanobacterie is not feasible for protein sources use in aquaculture. PMID:26470644

The effects of levetiracetam, sumatriptan, and caffeine in a rat model of trigeminal pain: interactions in 2-component combinations.

PubMed

Tomić, Maja A; Pecikoza, Uroš B; Micov, Ana M; Popović, Božidar V; Stepanović-Petrović, Radica M

2015-06-01

Levetiracetam is an antiepileptic drug with analgesic efficacy shown in pain models and small clinical trials. Sumatriptan is used in acute migraine treatment. Caffeine is widely consumed in some beverages/foods and is also an adjuvant in analgesic formulations. We examined the effects of systemic levetiracetam, sumatriptan, and caffeine and their interactions in 2-component combinations in the rat orofacial formalin test, a model of trigeminal pain. Rats received a subcutaneous injection of formalin solution into the perinasal area, and the total time spent in nociceptive behavior (face rubbing) was quantified. The antinociceptive effect of drugs/drug combinations was assessed 1 hour after per os administration. The type of interaction between levetiracetam/sumatriptan and caffeine was examined by comparing the effects of a fixed, effective dose of levetiracetam/sumatriptan alone with the effects of the same dose applied with increasing, subeffective doses of caffeine. The type of interaction between levetiracetam and sumatriptan was determined by isobolographic analysis. Levetiracetam (1-50 mg/kg) and sumatriptan (0.5-5 mg/kg) produced significant and dose-dependent antinociceptive effects in both phases of the orofacial formalin test (P ≤ 0.001). Caffeine (7.5-100 mg/kg) produced significant antinociception in the second phase of the test (P = 0.04). Caffeine (1-7.5 mg/kg) significantly reduced the antinociceptive effects of levetiracetam (25 mg/kg) (first phase P = 0.002, second phase P < 0.001) and sumatriptan (2.5 mg/kg) (first phase P = 0.014, second phase P = 0.027); dose-dependent inhibition was observed in the second phase. Levetiracetam and sumatriptan exerted an additive interaction in the second phase of the orofacial formalin test. Results indicate that levetiracetam may be useful for treatment of pain in the trigeminal region. Dietary caffeine might decrease the effects of levetiracetam and sumatriptan; this needs to be considered in clinical settings. A levetiracetam-sumatriptan combination could also be useful in trigeminal pain treatment. Its efficacy and adverse effects should be examined clinically.

Herbex-kid Inhibits Immediate Hypersensitivity Reactions in Mice and Rats

PubMed Central

Prasad, Rawal; Jogge, Nanjan Mulla; Bhojraj, Suresh; Emerson, Solomon F.; Prabakar, S.

2008-01-01

Herbex-kid (HK), a polyherbal formulation was evaluated in various experimental allergic models of Type I hypersensitivity reactions. Compound 48/80 (C 48/80) has been shown to induce rat mesentery mast cell degranulation and HK (1.07, 10.75 and 107.5 mg ml−1) inhibited the mast cell degranulation in a dose dependent manner. HK (1.07, 10.75 and 107.5 mg kg−1; p.o.) showed dose-dependent protection against C 48/80 induced systemic anaphylaxis in male Balb/C mice. In active anaphylaxis model, male Wistar rats orally administered with 10.75 and 107.5 mg kg−1 of HK showed significant (P < 0.01) protection against mast cell degranulation, while in passive anaphylaxis model, only at 107.5 mg kg−1 showed significant (P < 0.01) reduction in mast cell degranulation. HK at all dose levels was able to significantly decrease the time spent in nasal rubbing in Wistar rats sensitized to ovalbumin, while only at 107.5 mg kg−1 it showed significant (P < 0.01) reduction in number of sneezes. In C 48/80-induced skin itch model, all dose levels of HK significantly (P < 0.001) decreased the time spent in itching and the number of itches. HK did not produce any significant inhibition in histamine induced contraction in guinea pig ileum. From the above findings we conclude that the HK possesses antiallergic activity mediated by reducing of the release mediators from mast cells and also by 5-HT antagonism without the involvement of histamine (H1) receptors. PMID:18830458

Long-term effects of low-dose proton radiation on immunity in mice: shielded vs. unshielded

NASA Technical Reports Server (NTRS)

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

2003-01-01

BACKGROUND: Outside the protection of the terrestrial environment, astronauts on any long-term missions will unavoidably be exposed to fields of charged particle radiation dominated by protons. These fields and their biological risks are modified in complex ways by the presence of protective shielding. METHODS: To examine the long-term effects of space-like proton exposures on immune status, we treated female C57BL/6 mice with 3 or 4 Gy of 250 MeV monoenergetic protons or the complex space-like radiation field produced after 250 MeV protons are transported through 15 g x cm(-2) aluminum shielding. The animals were euthanized 122 d post-irradiation and lymphocyte phenotypes, hematological parameters, and lymphocyte blastogenesis were characterized. RESULTS: There were significant dose-dependent decreases in macrophage, CD3+/CD8+ T, NK, platelet, and red blood cell populations, as well as low hematocrit and hemoglobin levels. In contrast, dose-dependent increases in spontaneous, but not mitogen-induced, blastogenesis were noted. The differences in dose composition between pristine and shielded proton fields did not lead to significant effects in most measures, but did result in significant changes in monocyte and macrophage populations and spontaneous blastogenesis in the spleen. CONCLUSIONS: The data indicate that whole body exposure to proton radiation at doses of the order of large solar particle events or clinical treatment fractions may have long-term effects on immune system status.

Digital radiography can reduce scoliosis x-ray exposure

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

Kling, T.F. Jr.; Cohen, M.J.; Lindseth, R.E.

1990-09-01

Digital radiology is a new computerized system of acquiring x-rays in a digital (electronic) format. It possesses a greatly expanded dose response curve that allows a very broad range of x-ray dose to produce a diagnostic image. Potential advantages include significantly reduced radiation exposure without loss of image quality, acquisition of images of constant density irrespective of under or over exposure, and reduced repeat rates for unsatisfactory films. The authors prospectively studied 30 adolescents with scoliosis who had both conventional (full dose) and digital (full, one-half, or one-third dose) x-rays. They found digital made AP and lateral image with allmore » anatomic areas clearly depicted at full and one-half dose. Digital laterals were better at full dose and equal to conventional at one-half dose. Cobb angles were easily measured on all one-third dose AP and on 8 of 10 one-third dose digital laterals. Digital clearly depicted the Risser sign at one-half and one-third dose and the repeat rate was nil in this study, indicating digital compensates well for exposure errors. The study indicates that digital does allow radiation dose to be reduced by at least one-half in scoliosis patients and that it does have improved image quality with good contrast over a wide range of x-ray exposure.« less

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

Fourth ventricular thyrotropin induces satiety and increases body temperature in rats.

PubMed

Smedh, Ulrika; Scott, Karen A; Moran, Timothy H

2018-05-01

Besides its well-known action to stimulate thyroid hormone release, thyrotropin mRNA is expressed within the brain, and thyrotropin and its receptor have been shown to be present in brain areas that control feeding and gastrointestinal function. Here, the hypothesis that thyrotropin acts on receptors in the hindbrain to alter food intake and/or gastric function was tested. Fourth ventricular injections of thyrotropin (0.06, 0.60, and 6.00 µg) were given to rats with chronic intracerebroventricular cannulas aimed at the fourth ventricle. Thyrotropin produced an acute reduction of sucrose intake (30 min). The highest dose of thyrotropin caused inhibition of overnight solid food intake (22 h). In contrast, subcutaneous administration of corresponding thyrotropin doses had no effect on nutrient intake. The highest effective dose of fourth ventricular thyrotropin (6 µg) did not produce a conditioned flavor avoidance in a standardized two-bottle test, nor did it affect water intake or gastric emptying of glucose. Thyrotropin injected in the fourth ventricle produced a small but significant increase in rectal temperature and lowered plasma levels of tri-iodothyronin but did not affect plasma levels of thyroxine. In addition, there was a tendency toward a reduction in blood glucose 2 h after fourth ventricular thyrotropin injection ( P = 0.056). In conclusion, fourth ventricular thyrotropin specifically inhibits food intake, increases core temperature, and lowers plasma levels of tri-iodothyronin but does not affect gastromotor function.

Radiation-Induced Carcinogenesis: Mechanistically Based Differences between Gamma-Rays and Neutrons, and Interactions with DMBA

PubMed Central

Shuryak, Igor; Brenner, David J.; Ullrich, Robert L.

2011-01-01

Different types of ionizing radiation produce different dependences of cancer risk on radiation dose/dose rate. Sparsely ionizing radiation (e.g. γ-rays) generally produces linear or upwardly curving dose responses at low doses, and the risk decreases when the dose rate is reduced (direct dose rate effect). Densely ionizing radiation (e.g. neutrons) often produces downwardly curving dose responses, where the risk initially grows with dose, but eventually stabilizes or decreases. When the dose rate is reduced, the risk increases (inverse dose rate effect). These qualitative differences suggest qualitative differences in carcinogenesis mechanisms. We hypothesize that the dominant mechanism for induction of many solid cancers by sparsely ionizing radiation is initiation of stem cells to a pre-malignant state, but for densely ionizing radiation the dominant mechanism is radiation-bystander-effect mediated promotion of already pre-malignant cell clone growth. Here we present a mathematical model based on these assumptions and test it using data on the incidence of dysplastic growths and tumors in the mammary glands of mice exposed to high or low dose rates of γ-rays and neutrons, either with or without pre-treatment with the chemical carcinogen 7,12-dimethylbenz-alpha-anthracene (DMBA). The model provides a mechanistic and quantitative explanation which is consistent with the data and may provide useful insight into human carcinogenesis. PMID:22194850

In vivo adenylate cyclase activity in ultraviolet- and gamma-irradiated Escherichia coli.

PubMed

Chatterjee, A; Bhattacharya, A K

1988-06-01

The incorporation of [14C]adenine into the cyclic AMP fraction by whole cells of Escherichia coli B/r was taken as a measure of the in vivo adenylate cyclase activity. This activity was significantly inhibited by irradiation of the cells either with 60Co gamma-rays or with UV light from a germicidal lamp, suggesting inhibition of cyclic AMP synthesis. The incubation of cells after irradiation with lower doses (50-100 Gy) of gamma-rays produced a significant increase of in vivo adenylate cyclase activity, whereas there was no significant change after higher doses (150 Gy and above). Dark incubation of cells after irradiation with UV light (54 J m-2) led to recovery of enzyme activity to the level measured in unirradiated cells. Thus it appears that the catabolite repression of L-arabinose isomerase induced by UV light, as well as gamma-irradiation, is due to reduced cyclic AMP synthesis in irradiated cells.

Evaluation of Aqueous Leaf Extract of Cardiospermum halicacabum (L.) on Fertility of Male Rats.

PubMed

Peiris, L Dinithi C; Dhanushka, M A T; Jayathilake, T A H D G

2015-01-01

Treatment with 100 mg/kg and 200 mg/kg body weight of aqueous leaf extract (ALE) of Cardiospermum halicacabum for 30 days produced a significant dose dependent increase in the sperm counts and sperm motility in both caput and cauda regions. Further, significant increase in serum testosterone level was evident at all applied doses. However, no significant changes in the weight of sex organs were observed. Aqueous leaf extract also increased the number of females impregnated, number of implantations, and number of viable fetuses while decreasing the total number of resorption sites in the pregnant females. However, the total cholesterol level in the serum remained unchanged and there were no records on renotoxicity; nevertheless ALE exhibited a hepatoprotective effect. It was concluded that aqueous leaf extract of Cardiospermum halicacabum enhanced sperm concentration, motility, and testosterone, leading to positive results in fertility.

Dose comparison between conventional and quasi-monochromatic systems for diagnostic radiology

NASA Astrophysics Data System (ADS)

Baldelli, P.; Taibi, A.; Tuffanelli, A.; Gambaccini, M.

2004-09-01

Several techniques have been introduced in the last year to reduce the dose to the patient by minimizing the risk of tumour induced by radiation. In this work the radiological potential of dose reduction in quasi-monochromatic spectra produced via mosaic crystal Bragg diffraction has been evaluated, and a comparison with conventional spectra has been performed for four standard examinations: head, chest, abdomen and lumbar sacral spine. We have simulated quasi-monochromatic x-rays with the Shadow code, and conventional spectra with the Spectrum Processor. By means of the PCXMC software, we have simulated four examinations according to parameters established by the European Guidelines, and calculated absorbed dose for principal organs and the effective dose. Simulations of quasi-monochromatic laminar beams have been performed without anti-scatter grid, because of their inherent scatter geometry, and compared with simulations with conventional beams with anti-scatter grids. Results have shown that the dose reduction due to the introduction of quasi-monochromatic x-rays depends on different parameters related to the quality of the beam, the organ composition and the anti-scatter grid. With parameters chosen in this study a significant dose reduction can be achieved for two out of four kinds of examination.

Treatment Planning for Accelerator-Based Boron Neutron Capture Therapy

NASA Astrophysics Data System (ADS)

Herrera, María S.; González, Sara J.; Minsky, Daniel M.; Kreiner, Andrés J.

2010-08-01

Glioblastoma multiforme and metastatic melanoma are frequent brain tumors in adults and presently still incurable diseases. Boron Neutron Capture Therapy (BNCT) is a promising alternative for this kind of pathologies. Accelerators have been proposed for BNCT as a way to circumvent the problem of siting reactors in hospitals and for their relative simplicity and lower cost among other advantages. Considerable effort is going into the development of accelerator-based BNCT neutron sources in Argentina. Epithermal neutron beams will be produced through appropriate proton-induced nuclear reactions and optimized beam shaping assemblies. Using these sources, computational dose distributions were evaluated in a real patient with diagnosed glioblastoma treated with BNCT. The simulated irradiation was delivered in order to optimize dose to the tumors within the normal tissue constraints. Using Monte Carlo radiation transport calculations, dose distributions were generated for brain, skin and tumor. Also, the dosimetry was studied by computing cumulative dose-volume histograms for volumes of interest. The results suggest acceptable skin average dose and a significant dose delivered to tumor with low average whole brain dose for irradiation times less than 60 minutes, indicating a good performance of an accelerator-based BNCT treatment.

Treatment Planning for Accelerator-Based Boron Neutron Capture Therapy

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

Herrera, Maria S.; Gonzalez, Sara J.; Minsky, Daniel M.

2010-08-04

Glioblastoma multiforme and metastatic melanoma are frequent brain tumors in adults and presently still incurable diseases. Boron Neutron Capture Therapy (BNCT) is a promising alternative for this kind of pathologies. Accelerators have been proposed for BNCT as a way to circumvent the problem of siting reactors in hospitals and for their relative simplicity and lower cost among other advantages. Considerable effort is going into the development of accelerator-based BNCT neutron sources in Argentina. Epithermal neutron beams will be produced through appropriate proton-induced nuclear reactions and optimized beam shaping assemblies. Using these sources, computational dose distributions were evaluated in a realmore » patient with diagnosed glioblastoma treated with BNCT. The simulated irradiation was delivered in order to optimize dose to the tumors within the normal tissue constraints. Using Monte Carlo radiation transport calculations, dose distributions were generated for brain, skin and tumor. Also, the dosimetry was studied by computing cumulative dose-volume histograms for volumes of interest. The results suggest acceptable skin average dose and a significant dose delivered to tumor with low average whole brain dose for irradiation times less than 60 minutes, indicating a good performance of an accelerator-based BNCT treatment.« less

Feeding blueberry diets to young rats dose-dependently inhibits bone resorption through suppression of rankl in stromal cells

USDA-ARS?s Scientific Manuscript database

Previous studies have demonstrated that weanling rats fed AIN-93G semi-purified diets supplemented with 10% whole blueberry (BB) powder for two weeks beginning on postnatal day 21 (PND21) significantly increased bone formation at PND35. However, the minimal level of dietary BB needed to produce thes...

X-ray emission reduction and photon dose lowering by energy loss of fast electrons induced by return current during the interaction of a short-pulse high-intensity laser on a metal solid target

NASA Astrophysics Data System (ADS)

Compant La Fontaine, A.

2018-04-01

During the interaction of a short-pulse high-intensity laser with the preplasma produced by the pulse's pedestal in front of a high-Z metal solid target, high-energy electrons are produced, which in turn create an X-ray source by interacting with the atoms of the converter target. The current brought by the hot electrons is almost completely neutralized by a return current j → driven by the background electrons of the conductive target, and the force exerted on the hot electrons by the electric field E → which induces Ohmic heating j → .E → , produced by the background electrons, reduces the energy of the hot electrons and thus lowers the X-ray emission and photon dose. This effect is analyzed here by means of a simple 1-D temperature model which contains the most significant terms of the relativistic Fokker-Planck equation with electron multiple scattering, and the energy equations of ions, hot, and cold electrons are then solved numerically. This Ohmic heating energy loss fraction τOh is introduced as a corrective term in an improved photon dose model. For instance, for a ps laser pulse with 10 μm spot size, the dose obtained with a tantalum target is reduced by less than about 10% to 40% by the Ohmic heating, depending upon the plasma scale length, target thickness, laser parameters, and in particular its spot size. The laser and plasma parameters may be optimized to limit the effect of Ohmic heating, for instance at a small plasma scale length or small laser spot size. Conversely, others regimes not suitable for dose production are identified. For instance, the resistive heating is enhanced in a foam target or at a long plasma scale length and high laser spot size and intensity, as the mean emission angle θ0 of the incident hot electron bunch given by the ponderomotive force is small; thus, the dose produced by a laser interacting in a gas jet may be inhibited under these circumstances. The resistive heating may also be maximized in order to reduce the X-ray emission to lower the radiation level for instance in a safety radiological goal.

The nature of alarm communication in Constrictotermes cyphergaster (Blattodea: Termitoidea: Termitidae): the integration of chemical and vibroacoustic signals

PubMed Central

Cristaldo, Paulo F.; Jandák, Vojtĕch; Kutalová, Kateřina; Rodrigues, Vinícius B.; Brothánek, Marek; Jiříček, Ondřej; DeSouza, Og; Šobotník, Jan

2015-01-01

ABSTRACT Alarm signalling is of paramount importance to communication in all social insects. In termites, vibroacoustic and chemical alarm signalling are bound to operate synergistically but have never been studied simultaneously in a single species. Here, we inspected the functional significance of both communication channels in Constrictotermes cyphergaster (Termitidae: Nasutitermitinae), confirming the hypothesis that these are not exclusive, but rather complementary processes. In natural situations, the alarm predominantly attracts soldiers, which actively search for the source of a disturbance. Laboratory testing revealed that the frontal gland of soldiers produces a rich mixture of terpenoid compounds including an alarm pheromone. Extensive testing led to identification of the alarm pheromone being composed of abundant monoterpene hydrocarbons (1S)-α-pinene and myrcene, along with a minor component, (E)-β-ocimene. The vibratory alarm signalling consists of vibratory movements evidenced as bursts; a series of beats produced predominantly by soldiers. Exposing termite groups to various mixtures containing the alarm pheromone (crushed soldier heads, frontal gland extracts, mixture of all monoterpenes, and the alarm pheromone mixture made of standards) resulted in significantly higher activity in the tested groups and also increased intensity of the vibratory alarm communication, with the responses clearly dose-dependent. Lower doses of the pheromone provoked higher numbers of vibratory signals compared to higher doses. Higher doses induced long-term running of all termites without stops necessary to perform vibratory behaviour. Surprisingly, even crushed worker heads led to low (but significant) increases in the alarm responses, suggesting that other unknown compound in the worker's head is perceived and answered by termites. Our results demonstrate the existence of different alarm levels in termites, with lower levels being communicated through vibratory signals, and higher levels causing general alarm or retreat being communicated through the alarm pheromone. PMID:26538635

Effects of 14-day treatment with the schedule III anorectic phendimetrazine on choice between cocaine and food in rhesus monkeys.

PubMed

Banks, Matthew L; Blough, Bruce E; Negus, S Stevens

2013-08-01

The clinical utility of monoamine releasers such as phenmetrazine or d-amphetamine as candidate agonist medications for cocaine dependence is hindered by their high abuse liability. Phendimetrazine is a clinically available schedule III anorectic that functions as a prodrug for phenmetrazine and thus may have lower abuse liability. This study determined the effects of continuous 14-day treatment with phendimetrazine on cocaine vs. food choice in rhesus monkeys (N=4). Responding was maintained under a concurrent schedule of food delivery (1-g pellets, fixed-ratio 100 schedule) and cocaine injections (0-0.1mg/kg/injection, fixed-ratio 10 schedule). Cocaine choice dose-effect curves were determined daily before and during 14-day periods of continuous intravenous treatment with saline or (+)-phendimetrazine (0.32-1.0mg/kg/h). Effects of 14-day treatment with (+)-phenmetrazine (0.1-0.32 mg/kg/h; N=5) and d-amphetamine (0.032-0.1mg/kg/h; N=6) were also examined for comparison. During saline treatment, food was primarily chosen during availability of low cocaine doses (0, 0.0032, and 0.01 mg/kg/injection), and cocaine was primarily chosen during availability of higher cocaine doses (0.032 and 0.1mg/kg/injection). Phendimetrazine initially decreased overall responding without significantly altering cocaine choice. Over the course of 14 days, tolerance developed to rate decreasing effects, and phendimetrazine dose-dependently decreased cocaine choice (significant at 0.032 mg/kg/injection cocaine). Phenmetrazine and d-amphetamine produced qualitatively similar effects. These results demonstrate that phendimetrazine can produce significant, though modest, reductions in cocaine choice in rhesus monkeys. Phendimetrazine may be especially suitable as a candidate medication for human studies because of its schedule III clinical availability. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Monte Carlo skin dose simulation in intraoperative radiotherapy of breast cancer using spherical applicators.

PubMed

Moradi, F; Ung, N M; Khandaker, M U; Mahdiraji, G A; Saad, M; Abdul Malik, R; Bustam, A Z; Zaili, Z; Bradley, D A

2017-07-28

The relatively new treatment modality electronic intraoperative radiotherapy (IORT) is gaining popularity, irradiation being obtained within a surgically produced cavity being delivered via a low-energy x-ray source and spherical applicators, primarily for early stage breast cancer. Due to the spatially dramatic dose-rate fall off with radial distance from the source and effects related to changes in the beam quality of the low keV photon spectra, dosimetric account of the Intrabeam system is rather complex. Skin dose monitoring in IORT is important due to the high dose prescription per treatment fraction. In this study, modeling of the x-ray source and related applicators were performed using the Monte Carlo N-Particle transport code. The dosimetric characteristics of the model were validated against measured data obtained using an ionization chamber and EBT3 film as dosimeters. By using a simulated breast phantom, absorbed doses to the skin for different combinations of applicator size (1.5-5 cm) and treatment depth (0.5-3 cm) were calculated. Simulation results showed overdosing of the skin (>30% of prescribed dose) at a treatment depth of 0.5 cm using applicator sizes larger than 1.5 cm. Skin doses were significantly increased with applicator size, insofar as delivering 12 Gy (60% of the prescribed dose) to skin for the largest sized applicator (5 cm diameter) and treatment depth of 0.5 cm. It is concluded that the recommended 0.5-1 cm distance between the skin and applicator surface does not guarantee skin safety and skin dose is generally more significant in cases with the larger applicators. • Intrabeam x-ray source and spherical applicators were simulated and skin dose was calculated. • Skin dose for constant skin to applicator distance strongly depends on applicator size. • Use of larger applicators generally results in higher skin dose. • The recommended 0.5-1 cm skin to applicator distance does not guarantee skin safety.

Cytotoxic effects and apoptosis induction of enrofloxacin in hepatic cell line of grass carp (Ctenopharyngodon idellus).

PubMed

Liu, Bo; Cui, Yanting; Brown, Paul B; Ge, Xianping; Xie, Jun; Xu, Pao

2015-12-01

We determined the effect of enrofloxacin on the lactate dehydrogenase (LDH) release, reactive oxygen species (ROS), superoxide dismutase (SOD), total antioxidant capacity (T-AOC), malondialdehyde (MDA), mitochondria membrane potential (ΔΨm) and apoptosis in the hepatic cell line of grass carp (Ctenopharyngodon idellus). Cultured cells were treated with different concentrations of enrofloxacin (12.5-200 ug/mL) for 24 h. We found that the cytotoxic effect of enrofloxacin was mediated by apoptosis, and that this apoptosis occurred in a dose-dependent manner. The doses of 50,100 and 200 μg/mL enrofloxacin increased the LDH release and MDA concentration, induced cell apoptosis and reduced the ΔΨm compared to the control. The highest dose of 200 ug/mL enrofloxacin also significantly induced apoptosis accompanied by ΔΨm disruption and ROS generation and significantly reduced T-AOC and increased MDA concentration compared to the control. Our results suggest that the dose of 200 ug/mL enrofloxacin exerts its cytotoxic effect and produced ROS via apoptosis by affecting the mitochondria of the hepatic cells of grass carp. Copyright © 2015 Elsevier Ltd. All rights reserved.

Inclusion of a universal tetanus toxoid CD4(+) T cell epitope P2 significantly enhanced the immunogenicity of recombinant rotavirus ΔVP8* subunit parenteral vaccines.

PubMed

Wen, Xiaobo; Wen, Ke; Cao, Dianjun; Li, Guohua; Jones, Ronald W; Li, Jianping; Szu, Shousun; Hoshino, Yasutaka; Yuan, Lijuan

2014-07-31

Currently available live oral rotavirus vaccines, Rotarix(®) and RotaTeq(®), are highly efficacious in developed countries. However, the immunogenicity and efficacy of such vaccines in some developing countries are low. We reported previously that bacterially-expressed rotavirus ΔVP8* subunit vaccine candidates with P[8], P[4] or P[6] specificity elicited high-titer virus neutralizing antibodies in animals immunized intramuscularly. Of note was the finding that antibodies induced with the P[8]ΔVP8* vaccine neutralized both homotypic P[8] and heterotypic P[4] rotavirus strains to high titer. To further improve its vaccine potential, a tetanus toxoid universal CD4(+) T cell epitope P2 was introduced into P[8] or P[6]ΔVP8* construct. The resulting recombinant fusion proteins expressed in Escherichia coli were of high solubility and were produced with high yield. Two doses (10 or 20 μg/dose) of the P2-P[8]ΔVP8* vaccine or P2-P[6]ΔVP8* vaccine with aluminum phosphate adjuvant elicited significantly higher geometric mean homologous neutralizing antibody titers than the vaccines without P2 in intramuscularly immunized guinea pigs. Interestingly, high levels of neutralizing antibody responses induced in guinea pigs with 3 doses of the P2-P[8]ΔVP8* vaccine persisted for at least 6 months. Furthermore, in the gnotobiotic piglet challenge study, three intramuscular doses (50 μg/dose) of the P2-P[8]ΔVP8* vaccine with aluminum phosphate adjuvant significantly delayed the onset of diarrhea and significantly reduced the duration of diarrhea and the cumulative diarrhea score after oral challenge with virulent human rotavirus Wa (G1P[8]) strain. The P2-P[8]ΔVP8* vaccine induced serum virus neutralizing antibody and VP4-specific IgG antibody production prechallenge, and primed the pigs for higher antibody and intestinal and systemic virus-specific IFN-γ producing CD4(+) T cell responses postchallenge. These two subunit vaccines could be used at a minimum singly or preferably in bivalent formulation to provide antigenic coverage of most of the G types of global importance. Copyright © 2014 Elsevier Ltd. All rights reserved.

Perinatal Exposure to Low Levels of the Environmental Antiandrogen Vinclozolin Alters Sex-Differentiated Social Play and Sexual Behaviors in the Rat

PubMed Central

Colbert, Nathan K.W.; Pelletier, Nicole C.; Cote, Joyce M.; Concannon, John B.; Jurdak, Nicole A.; Minott, Sara B.; Markowski, Vincent P.

2005-01-01

In this study we examined the effects of exposure to the antiandrogenic fungicide vinclozolin (Vz) on the development of two sex-differentiated behaviors that are organized by the perinatal actions of androgens. Pregnant Long-Evans rats were administered a daily oral dose of 0, 1.5, 3, 6, or 12 mg/kg Vz from the 14th day of gestation through postnatal day (PND)3. The social play behavior of juvenile offspring was examined on PND22 and again on PND34 during play sessions with a same-sex littermate. After they reached adulthood, the male offspring were examined with the ex copula penile reflex procedure to assess erectile function. Vz did not produce any gross maternal or neonatal toxicity, nor did it reduce the anogenital distance in male pups. We observed no effects of Vz on play behavior on PND22. However, the 12-mg/kg Vz dose significantly increased play behavior in the male offspring on PND34 compared with controls. The most dramatic increases were seen with the nape contact and pounce behavior components of play. The Vz effect was more pronounced in male than in female offspring. As adults, male offspring showed a significant reduction of erections at all dose levels during the ex copula penile reflex tests. The 12-mg/kg dose was also associated with an increase in seminal emissions. These effects demonstrate that perinatal Vz disrupts the development of androgen-mediated behavioral functions at exposure levels that do not produce obvious structural changes or weight reductions in androgen-sensitive reproductive organs. PMID:15929892

MicroPET/CT Imaging of an Orthotopic Model of Human Glioblastoma Multiforme and Evaluation of Pulsed Low-Dose Irradiation

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

Park, Sean S.; Chunta, John L.; Robertson, John M.

2011-07-01

Purpose: Glioblastoma multiforme (GBM) is an aggressive tumor that typically causes death due to local progression. To assess a novel low-dose radiotherapy regimen for treating GBM, we developed an orthotopic murine model of human GBM and evaluated in vivo treatment efficacy using micro-positron-emission tomography/computed tomography (microPET/CT) tumor imaging. Methods: Orthotopic GBM xenografts were established in nude mice and treated with standard 2-Gy fractionation or 10 0.2-Gy pulses with 3-min interpulse intervals, for 7 consecutive days, for a total dose of 14 Gy. Tumor growth was quantified weekly using the Flex Triumph (GE Healthcare/Gamma Medica-Ideas, Waukesha, WI) combined PET-single-photon emission CTmore » (SPECT)-CT imaging system and necropsy histopathology. Normal tissue damage was assessed by counting dead neural cells in tissue sections from irradiated fields. Results: Tumor engraftment efficiency for U87MG cells was 86%. Implanting 0.5 x 10{sup 6} cells produced a 50- to 70-mm{sup 3} tumor in 10 to 14 days. A significant correlation was seen between CT-derived tumor volume and histopathology-measured volume (p = 0.018). The low-dose 0.2-Gy pulsed regimen produced a significantly longer tumor growth delay than standard 2-Gy fractionation (p = 0.045). Less normal neuronal cell death was observed after the pulsed delivery method (p = 0.004). Conclusion: This study successfully demonstrated the feasibility of in vivo brain tumor imaging and longitudinal assessment of tumor growth and treatment response with microPET/CT. Pulsed radiation treatment was more efficacious than the standard fractionated treatment and was associated with less normal tissue damage.« less

MicroPET/CT imaging of an orthotopic model of human glioblastoma multiforme and evaluation of pulsed low-dose irradiation.

PubMed

Park, Sean S; Chunta, John L; Robertson, John M; Martinez, Alvaro A; Oliver Wong, Ching-Yee; Amin, Mitual; Wilson, George D; Marples, Brian

2011-07-01

Glioblastoma multiforme (GBM) is an aggressive tumor that typically causes death due to local progression. To assess a novel low-dose radiotherapy regimen for treating GBM, we developed an orthotopic murine model of human GBM and evaluated in vivo treatment efficacy using micro-positron-emission tomography/computed tomography (microPET/CT) tumor imaging. Orthotopic GBM xenografts were established in nude mice and treated with standard 2-Gy fractionation or 10 0.2-Gy pulses with 3-min interpulse intervals, for 7 consecutive days, for a total dose of 14 Gy. Tumor growth was quantified weekly using the Flex Triumph (GE Healthcare/Gamma Medica-Ideas, Waukesha, WI) combined PET-single-photon emission CT (SPECT)-CT imaging system and necropsy histopathology. Normal tissue damage was assessed by counting dead neural cells in tissue sections from irradiated fields. Tumor engraftment efficiency for U87MG cells was 86%. Implanting 0.5 × 10(6) cells produced a 50- to 70-mm(3) tumor in 10 to 14 days. A significant correlation was seen between CT-derived tumor volume and histopathology-measured volume (p = 0.018). The low-dose 0.2-Gy pulsed regimen produced a significantly longer tumor growth delay than standard 2-Gy fractionation (p = 0.045). Less normal neuronal cell death was observed after the pulsed delivery method (p = 0.004). This study successfully demonstrated the feasibility of in vivo brain tumor imaging and longitudinal assessment of tumor growth and treatment response with microPET/CT. Pulsed radiation treatment was more efficacious than the standard fractionated treatment and was associated with less normal tissue damage. Copyright © 2011 Elsevier Inc. All rights reserved.

Prospective Study of Adenosine on Atrioventricular Nodal Conduction in Pediatric and Young Adult Patients After Heart Transplantation.

PubMed

Flyer, Jonathan N; Zuckerman, Warren A; Richmond, Marc E; Anderson, Brett R; Mendelsberg, Tamar G; McAllister, Jennie M; Liberman, Leonardo; Addonizio, Linda J; Silver, Eric S

2017-06-20

Supraventricular tachycardia is common after heart transplantation. Adenosine, the standard therapy for treating supraventricular tachycardia in children and adults without transplantation, is relatively contraindicated after transplantation because of a presumed risk of prolonged atrioventricular block in denervated hearts. This study tested whether adenosine caused prolonged asystole after transplantation and if it was effective in blocking atrioventricular nodal conduction in these patients. This was a single-center prospective clinical study including healthy heart transplant recipients 6 months to 25 years of age presenting for routine cardiac catheterization during 2015 to 2016. After catheterization, a transvenous pacing catheter was placed and adenosine was given following a dose-escalation protocol until atrioventricular block was achieved. The incidence of clinically significant asystole (≥12 seconds after adenosine) was quantified. The effects of patient characteristics on adenosine dose required to produce atrioventricular block and duration of effect were also measured. Eighty patients completed adenosine testing. No patient (0%; 95% confidence interval, 0-3) required rescue ventricular pacing. Atrioventricular block was observed in 77 patients (96%; 95% confidence interval, 89-99). The median longest atrioventricular block was 1.9 seconds (interquartile range, 1.4-3.2 seconds), with a mean duration of adenosine effect of 4.3±2.0 seconds. No patient characteristic significantly predicted the adenosine dose to produce atrioventricular block or duration of effect. Results were similar across patient weight categories. Adenosine induces atrioventricular block in healthy pediatric and young adult heart transplant recipients with minimal risk when low initial doses are used (25 μg/kg; 1.5 mg if ≥60 kg) and therapy is gradually escalated. URL: http://www.clinicaltrials.gov. Unique identifier: NCT02462941. © 2017 American Heart Association, Inc.

In vivo radioprotection by alpha-TMG: preliminary studies.

PubMed

Satyamitra, M; Devi, P U; Murase, H; Kagiya, V T

2001-08-08

alpha-TMG is a novel water-soluble derivative of Vitamin E that has shown excellent antioxidant activity. The parent compound has demonstrated protection against radiation induced chromosomal damage in vivo. Hence, the preliminary experiments to determine the radioprotective activity of alpha-TMG were carried out in adult Swiss albino mice. Acute toxicity of the drug was studied taking 24h, 72 h and 30 day mortality after a single intraperitoneal injection of 500-2000 mg/kg body weight of the drug. The drug LD(50) for 24h and 72 h/30 day survival were found to be 1120 and 1000 mg/kg body weight, respectively. The optimum time of drug administration and drug dose-dependent effect on in vivo radiation protection of bone marrow chromosomes was studied in mice. Injection of 600 mg/kg of the drug 15 min before or within 5, 15 or 30min after 3Gy whole body gamma radiation resulted in a significant decrease in the aberrant metaphases percent at 24h post-irradiation; the maximum effect was seen when the drug was given immediately after irradiation. Injection of 200-800 mg/kg TMG within 5 min of irradiation with 3 Gy produced a significant dose-dependent reduction in the radiation induced percent aberrant metaphases and in the frequency of micronucleated erythrocytes at 24h after exposure, with a corresponding decrease in the different types of aberrations. The optimum dose for protection without drug toxicity was 600 mg/kg body weight. At this dose, TMG produced 70 and >60% reduction in the radiation induced percent aberrant metaphases and micronucleated erythrocytes, respectively. The high water solubility and effectiveness when administered post-irradiation favor TMG as a likely candidate for protection in case of accidental exposures.

Differential effects of presynaptic versus postsynaptic adenosine A2A receptor blockade on Δ9-tetrahydrocannabinol (THC) self-administration in squirrel monkeys.

PubMed

Justinová, Zuzana; Redhi, Godfrey H; Goldberg, Steven R; Ferré, Sergi

2014-05-07

Different doses of an adenosine A2A receptor antagonist MSX-3 [3,7-dihydro-8-[(1E)-2-(3-ethoxyphenyl)ethenyl]-7 methyl-3-[3-(phosphooxy)propyl-1-(2 propynil)-1H-purine-2,6-dione] were found previously to either decrease or increase self-administration of cannabinoids delta-9-tetrahydrocannabinol (THC) or anandamide in squirrel monkeys. It was hypothesized that the decrease observed with a relatively low dose of MSX-3 was related to blockade of striatal presynaptic A2A receptors that modulate glutamatergic neurotransmission, whereas the increase observed with a higher dose was related to blockade of postsynaptic A2A receptors localized in striatopallidal neurons. This hypothesis was confirmed in the present study by testing the effects of the preferential presynaptic and postsynaptic A2A receptor antagonists SCH-442416 [2-(2-furanyl)-7-[3-(4-methoxyphenyl)propyl]-7H-pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine] and KW-6002 [(E)-1, 3-diethyl-8-(3,4-dimethoxystyryl)-7-methyl-3,7-dihydro-1H-purine-2,6-dione], respectively, in squirrel monkeys trained to intravenously self-administer THC. SCH-442416 produced a significant shift to the right of the THC self-administration dose-response curves, consistent with antagonism of the reinforcing effects of THC. Conversely, KW-6002 produced a significant shift to the left, consistent with potentiation of the reinforcing effects of THC. These results show that selectively blocking presynaptic A2A receptors could provide a new pharmacological approach to the treatment of marijuana dependence and underscore corticostriatal glutamatergic neurotransmission as a possible main mechanism involved in the rewarding effects of THC.

Quantitating silver-stained neurodegeneration: the neurotoxicity of trimethlytin (TMT) in aged rats.

PubMed

Scallet, A C; Pothuluri, N; Rountree, R L; Matthews, J C

2000-05-15

This report describes the development of a histoanalytical procedure to measure the degree of neurodegeneration produced by the organometal toxicant trimethyltin (TMT). Based on a previous, non-quantitated experiment we hypothesized that the same dose of TMT would produce greater damage in animals of increasing age. Male rats aged 6, 12, 18, or 24 months at the time of dosing were given either 4.5 mg/kg TMT or saline (i.p.). One month after dosing, rats were perfused and their brains removed and processed to selectively silver-impregnate degenerating cell bodies as well as axon terminals and dendrites. Neurodegeneration was most prominent in the hippocampi (especially CA1 stratum radiatum) of TMT-treated rats, but not in the controls. Computer-assisted counting of the silver grains marking damage indicated greater neurotoxicity from the same dose of TMT when given to the older animals. Thus the grain density in the 6-month-old TMT-treated rats was not significantly elevated from the 6-month-old controls (P>0.10). The 12-month-old TMT-treated rats had significantly increased grain densities compared to their controls (P<0.05), but still larger increases of grain counts were observed in the 18- and 24-month-old rats (both P-values<0.01). Our findings with TMT are similar to previous, but nonquantitative, reports that the neurotoxic effects of kainic acid and methionine sulfoximine were also greater in older rats. An increased sensitivity to neurotoxicants might help explain the apparently spontaneous degeneration of cortical neurons in aging and in the neurological diseases of old age. The method we report here for quantitation of silver grains marking neurodegeneration should be adaptable to a wide range of histologically-based neurotoxicology investigations.

Sensitivity studies of beam directionality, beam size, and neutron spectrum for a fission converter-based epithermal neutron beam for boron neutron capture therapy.

PubMed

Sakamoto, S; Kiger, W S; Harling, O K

1999-09-01

Sensitivity studies of epithermal neutron beam performance in boron neutron capture therapy are presented for realistic neutron beams with varying filter/moderator and collimator/delimiter designs to examine the relative importance of neutron beam spectrum, directionality, and size. Figures of merit for in-air and in-phantom beam performance are calculated via the Monte Carlo technique for different well-optimized designs of a fission converter-based epithermal neutron beam with head phantoms as the irradiation target. It is shown that increasing J/phi, a measure of beam directionality, does not always lead to corresponding monotonic improvements in beam performance. Due to the relatively low significance, for most configurations, of its effect on in-phantom performance and the large intensity losses required to produce beams with very high J/phi, beam directionality should not be considered an important figure of merit in epithermal neutron beam design except in terms of its consequences on patient positioning and collateral dose. Hardening the epithermal beam spectrum, while maintaining the specific fast neutron dose well below the inherent hydrogen capture dose, improves beam penetration and advantage depth and, as a desirable by-product, significantly increases beam intensity. Beam figures of merit are shown to be strongly dependent on beam size relative to target size. Beam designs with J/phi approximately 0.65-0.7, specific fast neutron doses of 2-2.6x10(-13) Gy cm2/n and beam sizes equal to or larger than the size of the head target produced the deepest useful penetration, highest therapeutic ratios, and highest intensities.

Combined administration of buprenorphine and naltrexone produces antidepressant-like effects in mice

PubMed Central

Almatroudi, Abdulrahman; Husbands, Stephen M.; Bailey, Christopher P.; Bailey, Sarah J.

2016-01-01

Opiates have been used historically for the treatment of depression. Renewed interest in the use of opiates as antidepressants has focussed on the development of kappa opioid receptor (κ-receptor) antagonists. Buprenorphine acts as a partial μ-opioid receptor agonist and a κ-receptor antagonist. By combining buprenorphine with the opioid antagonist naltrexone, the activation of μ-opioid receptors would be reduced and the κ-antagonist properties enhanced. We have established that a combination dose of buprenorphine (1mg/kg) with naltrexone (1mg/kg) functions as a short-acting κ-antagonist in the mouse tail withdrawal test. Furthermore, this dose combination is neither rewarding nor aversive in the conditioned place preference paradigm and is without significant locomotor effects. We have shown for the first time that systemic co-administration of buprenorphine (1mg/kg) with naltrexone (1mg/kg) in CD-1 mice produced significant antidepressant-like responses in behaviours in both the forced swim test and novelty induced hypophagia task. Behaviours in the elevated plus maze and light dark box were not significantly altered by treatment with buprenorphine alone, or in combination with naltrexone. We propose that the combination of buprenorphine with naltrexone represents a novel, and potentially a readily translatable approach, to the treatment of depression. PMID:26045511

Moxonidine and cognitive function: interactions with moclobemide and lorazepam.

PubMed

Wesnes, K; Simpson, P M; Jansson, B; Grahnén, A; Weimann, H J; Küppers, H

1997-01-01

Moxonidine represents a new generation of centrally acting antihypertensive drugs. It binds to I1-imidazoline receptors and exerts its antihypertensive activity through a reduction in systemic vascular resistance, while cardiac output remains unchanged or even increases slightly. Moxonidine is prescribed for the treatment of mild to moderate hypertension. Typical doses are 0.4 to 2.0 mg given as one dose in the morning or as divided doses in the morning and evening. The effects of moxonidine 0.4 mg once daily in combination with moclobemide or lorazepam were investigated in two, double-blind, randomised, placebo-controlled, two-way crossover studies in a total of 48 healthy volunteers. Safety assessments were made in each study and included pre- and post-study measurement of blood pressure, heart rate, ECG, haematology, blood biochemistry, and urinalysis, and recording of adverse events. In the first study, moxonidine alone was found to produce small but statistically significant impairments of vigilance detection speed at 4 h and 6 h. Lowering of subjective alertness was also observed. Repeat dosing with moxonidine produced an impairment of memory scanning performance. These findings were not reproduced in the second study, in which moxonidine alone produced an improvement in immediate word recall at 4 h and 6 h. No interactions were observed when moxonidine was co-administered with moclobemide. Moxonidine, when co-administered with lorazepam, produced interactions with three tasks requiring high levels of attention: choice, simple reaction time and digit vigilance performance; memory tasks; immediate word recall, delayed word recall accuracy; and visual tracking. A total of 47 adverse events were reported in study 1. Moxonidine produced a slight decrease of systolic and diastolic blood pressure. In study 2, a total of 55 adverse events were reported. In both trials, the most frequently reported events were tiredness and dryness of mouth, the latter occurring only under the moxonidine treatment. There were no clinically relevant changes observed in blood pressure, pulse rate, and laboratory tests in either study, nor was there any evidence of any interaction between moxonidine and either moclobemide or lorazepam. Moxonidine was found to be safe and well tolerated in healthy volunteers. However, the impairments on attentional tasks were greater when moxonidine was co-administered with lorazepam 1 mg. These effects should be considered when moxonidine is codosed with lorazepam, although they were smaller than would have been produced by a single dose of lorazepam 2 mg.

Dose computation for therapeutic electron beams

NASA Astrophysics Data System (ADS)

Glegg, Martin Mackenzie

The accuracy of electron dose calculations performed by two commercially available treatment planning computers, Varian Cadplan and Helax TMS, has been assessed. Measured values of absorbed dose delivered by a Varian 2100C linear accelerator, under a wide variety of irradiation conditions, were compared with doses calculated by the treatment planning computers. Much of the motivation for this work was provided by a requirement to verify the accuracy of calculated electron dose distributions in situations encountered clinically at Glasgow's Beatson Oncology Centre. Calculated dose distributions are required in a significant minority of electron treatments, usually in cases involving treatment to the head and neck. Here, therapeutic electron beams are subject to factors which may cause non-uniformity in the distribution of dose, and which may complicate the calculation of dose. The beam shape is often irregular, the beam may enter the patient at an oblique angle or at an extended source to skin distance (SSD), tissue inhomogeneities can alter the dose distribution, and tissue equivalent material (such as wax) may be added to reduce dose to critical organs. Technological advances have allowed the current generation of treatment planning computers to implement dose calculation algorithms with the ability to model electron beams in these complex situations. These calculations have, however, yet to be verified by measurement. This work has assessed the accuracy of calculations in a number of specific instances. Chapter two contains a comparison of measured and calculated planar electron isodose distributions. Three situations were considered: oblique incidence, incidence on an irregular surface (such as that which would be arise from the use of wax to reduce dose to spinal cord), and incidence on a phantom containing a small air cavity. Calculations were compared with measurements made by thermoluminescent dosimetry (TLD) in a WTe electron solid water phantom. Chapter three assesses the planning computers' ability to model electron beam penumbra at extended SSD. Calculations were compared with diode measurements in a water phantom. Further measurements assessed doses in the junction region produced by abutting an extended SSD electron field with opposed photon fields. Chapter four describes an investigation of the size and shape of the region enclosed by the 90% isodose line when produced by limiting the electron beam with square and elliptical apertures. The 90% isodose line was chosen because clinical treatments are often prescribed such that a given volume receives at least 90% dose. Calculated and measured dose distributions were compared in a plane normal to the beam central axis. Measurements were made by film dosimetry. While chapters two to four examine relative doses, chapter five assesses the accuracy of absolute dose (or output) calculations performed by the planning computers. Output variation with SSD and field size was examined. Two further situations already assessed for the distribution of relative dose were also considered: an obliquely incident field, and a field incident on an irregular surface. The accuracy of calculations was assessed against criteria stipulated by the International Commission on Radiation Units and Measurement (ICRU). The Varian Cadplan and Helax TMS treatment planning systems produce acceptable accuracy in the calculation of relative dose from therapeutic electron beams in most commonly encountered situations. When interpreting clinical dose distributions, however, knowledge of the limitations of the calculation algorithm employed by each system is required in order to identify the minority of situations where results are not accurate. The calculation of absolute dose is too inaccurate to implement in a clinical environment. (Abstract shortened by ProQuest.).

Anticonvulsant properties of methanol leaf extract of Laggera Aurita Linn. F. (Asteraceae) in laboratory animals.

PubMed

Malami, S; Kyari, H; Danjuma, N M; Ya'u, J; Hussaini, I M

2016-09-15

Preparation of Laggera aurita Linn. (Asteraceae) is widely used in traditional medicine to treat various kinds of diseases such as epilepsy, malaria, fever, pain and asthma. Its efficacy is widely acclaimed among communities in Northern Nigeria. The present study is aimed at establishing the possible anticonvulsant effects of the methanol leaf extract of Laggera aurita using acute and chronic anticonvulsant models. Median lethal dose (LD50) was determined in mice and rats via oral and intraperitoneal routes. Anticonvulsant screening of the extract was performed using maximal electroshock-induced seizure test in day-old chicks; pentylenetetrazole-, strychnine- and picrotoxin- induced seizure models in mice. Similarly; its effects on pentylenetetrazole-induce kindling in rats as well as when co-administered with fluphenamic and cyproheptadine in mice, were evaluated. Median lethal dose (LD50) values were found to be >5000mg/kg, p.o. and 2154mg/kg, i.p., each for both rats and mice. The extract showed dose dependent protection against tonic hind limb extension (THLE) and significantly (p<0.05) decreased the mean recovery from seizure in the maximal electroshock-induced seizure. In the pentylenetetrazole-induced seizure model, the extract offered 50% protection at 600mg/kg and also increased the mean onset of seizure at all doses with significant (p<0.05) increase at the highest dose (600mg/kg). Similarly the extract produced significant (p<0.05) increase in the onset of seizures in both strychnine- and picrotoxin- induced seizure models, at all the doses except at 150mg/kg for the picrotoxin model. Co-administration of fluphenamic acid (FFA) (5mg/kg) and the extract (600mg/kg) showed an enhanced effect with percentage protection of 70% while co-administration of FFA (5mg/kg) and phenytoin (5mg/kg) as well phenytoin (5mg/kg) and the extract (600mg/kg) produced an additive effect. Administration of the extract (600mg/kg), phenytoin (20mg/kg) and cyproheptadine (4mg/kg) offered 40%, 100% and 0% protection against THLE, each respectively, while co-administration of cyproheptadine (4mg/kg) and the extract (600mg/kg) as well as co-administration of cyproheptadine (4mg/kg) and phenytoin (20mg/kg) offered reduced protection of 20% and 50% each respectively. The extract at all doses reduced the severity of seizure episodes induced by PTZ-induced kindling. The results suggest that the methanol leaf extract of Laggera aurita possesses anticonvulsant and antiepileptogenic properties. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Comparison of peripheral and central effects of single and repeated oral dose administrations of bilastine, a new H1 antihistamine: a dose-range study in healthy volunteers with hydroxyzine and placebo as control treatments.

PubMed

García-Gea, Consuelo; Martínez-Colomer, Joan; Antonijoan, Rosa M; Valiente, Román; Barbanoj, Manuel-José

2008-12-01

Peripheral anti-H1 and central nervous system (CNS) activities after single (day 1) and repeated (day 7) administrations of increasing doses of bilastine (BIL) were assessed in 20 healthy volunteers throughout a crossover, randomized, double-blind, placebo (PLA)-controlled study. Repeated doses of BIL 20, 40, or 80 mg and hydroxyzine 25 mg (HYD) as positive standard were administered on 7 consecutive days. Before and at several time points after drug intake, skin reactivity to the intradermal injection of histamine, objective tests of psychomotor performance, and subjective mood scales were evaluated. All active treatments led to a significant and similar reduction in the wheal reaction in relation to PLA after both the single (P < 0.001) and repeated administrations (P < 0.001). No delay was observed in the onset of its peripheral activity after the first dose of BIL as compared with HYD. No tolerance or sensitization was seen when comparing acute and repetitive assessments. Central nervous system effects showed that HYD induced the greatest psychomotor impairment (P < 0.05). Repeated HYD intake showed a lower number of significant alterations in comparison to acute administration. Bilastine 80 mg also showed some impairment (P < 0.05). Subjectively, the only active treatment that could not be differentiated from PLA was BIL 20 mg. Hydroxyzine 25 mg showed the greatest differentiation (P < 0.01). A clear dissociation between peripheral anti-H1 and CNS activity was found after BIL treatment. Significant and sustained peripheral H1-blocking effects were observed after both single and repeated administrations of the therapeutic dose of 20 mg BIL. The 40-mg dose of BIL produced subjective report of sedation, whereas unwanted objective CNS side effects were observed only with the 80-mg dose.

Involvement of glutamatergic N-methyl-d-aspartate receptors in the expression of increased head-dipping behaviors in the hole-board tests of olfactory bulbectomized mice.

PubMed

Hirose, Noritaka; Saitoh, Akiyoshi; Kamei, Junzo

2016-10-01

Olfactory bulbectomized (OB) mice produce agitated anxiety-like behaviors in the hole-board test, which was expressed by an increase in head-dipping counts and a decrease in head-dipping latencies. However, the associated mechanisms remain unclear. In the present study, MK-801 (10, 100μg/kg), a selective N-methyl-d-aspartate (NMDA) receptor antagonist, significantly and dose-dependently suppressed the increased head-dipping behaviors in OB mice, without affecting sham mice. Similar results were obtained with another selective NMDA receptor antagonist D-AP5 treatment in OB mice. On the other hand, muscimol, a selective aminobutyric acid type A (GABAA) receptor agonist produced no effects on these hyperemotional behaviors in OB mice at a dose (100μg/kg) that produced anxiolytic-like effects in sham mice. Interestingly, glutamine contents and glutamine/glutamate ratios were significantly increased in the amygdala and frontal cortex of OB mice compared to sham mice. Based on these results, we concluded that the glutamatergic NMDA receptors are involved in the expression of increased head-dipping behaviors in the hole-board tests of OB mice. Accordingly, the changes in glutamatergic transmission in frontal cortex and amygdala may play important roles in the expression of these abnormal behaviors in OB mice. Copyright © 2016. Published by Elsevier B.V.

Protracted ethanol withdrawal in rats: Tolerance to the anxiolytic effects of diazepam and pentobarbital but not phenobarbital

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

Lai, H.; Prather, P.L.

1990-02-26

Anxiety is a common symptom during ethanol withdrawal contributing to its continuous abuse and alcoholism. Ethanol withdrawal in rats produces an interoceptive discriminative stimulus (IDS) similar to that produced by the anxiogenic drug pentylenetetrazol (PTZ). This stimulus peaks at 12 hours after last dose of ethanol and thereafter the IDS is detected for several days (protracted withdrawal) by sensitization to a probe drug. previously, the authors have shown that during the protracted withdrawal, the IDS is enhanced by GABA receptor antagonists suggesting alteration of brain GABA systems. This report provides further evidence that chronic ethanol alters GABAergic systems. Rats weremore » trained to discriminate PTZ (20 mg/kg, ip) from saline. Diazepam, pentobarbital and phenobarbital blocked the PTZ-IDS dose dependently. Ethanol, 4.5% w/v, was then given in a nutritionally complete diet for a week. On termination of the ethanol diet, rats exhibited signs and symptoms of withdrawal which returned to baseline within 3 days. During the protracted withdrawal period, the authors then redetermined the blockade of the PTZ-IDS. Significant tolerance was observed to the effectiveness of diazepam and pentobarbital, but not to phenobarbital. Since diazepam and pentobarbital produce significantly more enhancement of GABAergic activity than does phenobarbital, these data further suggest alteration of brain GABAergic systems during protracted withdrawal from ethanol.« less

Adrenomedullin (ADM) in the human forearm vascular bed: effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH2-terminal 20 peptide (PAMP)

PubMed Central

Wilkinson, Ian B; McEniery, Carmel M; Bongaerts, Katherine H; MacCallum, Helen; Webb, David J; Cockcroft, John R

2001-01-01

Aims To compare the haemodynamic responses of proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (ADM) in the forearm vascular bed of healthy male volunteers, and to investigate the role of neutral endopeptidase (NEP) in the metabolism of ADM. Methods On two separate occasions, ADM (1–30 pmol min−1) and PAMP (100–3000 pmol min−1) were infused into the brachial artery of eight male subjects, and forearm blood flow (FBF) assessed using venous occlusion plethysmography. In a second study, eight male subjects received the same doses of ADM, co-infused with either the NEP inhibitor thiorphan (30 nmol min−1) or the control vasoconstrictor noradrenaline (120 pmol min−1), on separate occasions. Both studies were conducted in a double-blind, randomized manner. Results ADM and PAMP produced a dose-dependent increase in FBF (P ≤ 0.002). Based on the dose producing a 50% increase in FBF, ADM was ∼60 times more potent than PAMP. Thiorphan and noradrenaline produced similar reductions in FBF of 14 ± 4% (mean ± s.e. mean) and 22 ± 6%, respectively (P = 0.4). However, the area under the dose–response curve was significantly greater during co-infusion of ADM with thiorphan than with noradrenaline (P = 0.028), as was the maximum increase in FBF ratio (2.1 ± 1.0 vs 1.2 ± 0.2; P = 0.030). Conclusions ADM and PAMP both produce a local dose-related vasodilatation in the human forearm, but PAMP is ∼60 times less potent than ADM. In addition, NEP inhibition potentiates the haemodynamic effects of ADM. These findings suggest that PAMP may not play a role in the physiological regulation of blood flow. However, in pathophysiological conditions such as hypertension and heart failure, NEP inhibition may exert a beneficial effect by increasing the biological activity of ADM. PMID:11488772

GABAB-receptor activation alters the firing pattern of dopamine neurons in the rat substantia nigra.

PubMed

Engberg, G; Kling-Petersen, T; Nissbrandt, H

1993-11-01

Previous electrophysiological experiments have emphasized the importance of the firing pattern for the functioning of midbrain dopamine (DA) neurons. In this regard, excitatory amino acid receptors appear to constitute an important modulatory control mechanism. In the present study, extracellular recording techniques were used to investigate the significance of GABAB-receptor activation for the firing properties of DA neurons in the substantia nigra (SN) in the rat. Intravenous administration of the GABAB-receptor agonist baclofen (1-16 mg/kg) was associated with a dose-dependent regularization of the firing pattern, concomitant with a reduction in burst firing. At higher doses (16-32 mg/kg), the firing rate of the DA neurons was dose-dependently decreased. Also, microiontophoretic application of baclofen regularized the firing pattern of nigral DA neurons, including a reduction of burst firing. Both the regularization of the firing pattern and inhibition of firing rate produced by systemic baclofen administration was antagonized by the GABAB-receptor antagonist CGP 35348 (200 mg/kg, i.v.). The GABAA-receptor agonist muscimol produced effects on the firing properties of DA neurons that were opposite to those observed following baclofen, i.e., an increase in firing rate accompanied by a decreased regularity. The NMDA receptor antagonist MK 801 (0.4-3.2 mg/kg, i.v.) produced a moderate, dose-dependent increase in the firing rate of the nigral DA neurons as well as a slightly regularized firing pattern. Pretreatment with MK 801 (3.2 mg/kg, i.v., 3-10 min) did neither promote nor prevent the regularization of the firing pattern or inhibition of firing rate on the nigral DA neurons produced by baclofen. The present results clearly show that GABAB-receptors can alter the firing pattern of nigral DA neurons, hereby counterbalancing the previously described ability of glutamate to induce burst firing activity on these neurons.

Comparison of consolidation strategies in acute myeloid leukemia: high-dose cytarabine alone versus intermediate-dose cytarabine combined with anthracyclines.

PubMed

Kim, Dae Sik; Kang, Ka-Won; Lee, Se Ryeon; Park, Yong; Sung, Hwa Jung; Kim, Seok Jin; Choi, Chul Won; Kim, Byung Soo

2015-09-01

We compared the efficacy of high-dose cytarabine alone to that of intermediate-dose cytarabine combined with anthracyclines as consolidation therapy. Patients enrolled in the Korea University acute myeloid leukemia (AML) registry received remission induction chemotherapy with the same standard induction regimen (idarubicin and cytarabine 3 + 7). Postremission therapy was performed for three or four cycles according to one of the following regimens: high-dose cytarabine (3 g/m(2)) or combination of intermediate-dose cytarabine (1 g/m(2)) with anthracyclines (idarubicin or mitoxantrone). Among the 443 AML patients enrolled in the registry, 145 patients received consolidation chemotherapy. The median overall survival (OS) and relapse-free survival (RFS) in the high-dose cytarabine group were significantly longer than those in the anthracycline combination group (OS, not reached vs. 16.6 months, p = 0.045; RFS, 38.6 months vs. 11.0 months, p = 0.011). The median duration of neutropenia was longer in the anthracycline combination group than in the high-dose cytarabine group (8 vs. 10 days, p = 0.001). This study suggests that high-dose cytarabine consolidation may produce superior outcomes than combination treatment with intermediate-dose cytarabine and anthracyclines and that the addition of anthracyclines during AML consolidation has limited value as compared to cytarabine intensification.

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.

Antioxidant, analgesic and anti-inflammatory activities of the methanolic extract of Piper betle leaves.

PubMed

Alam, Badrul; Akter, Fahima; Parvin, Nahida; Sharmin Pia, Rashna; Akter, Sharmin; Chowdhury, Jesmin; Sifath-E-Jahan, Kazi; Haque, Ekramul

2013-01-01

The present study was designed to evaluate the antioxidant, analgesic, and anti-inflammatory activities of the methanolic extract of Piper betle leaves (MPBL). MPBL was evaluated for anti-inflammatory activity using carrageenan-induced hind paw edema model. Analgesic activity of MPBL was evaluated by hot plate, writhing, and formalin tests. Total phenolic and flavonoids content, total antioxidant activity, scavenging of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, peroxynitrate (ONOO) as well as inhibition of total ROS generation, and assessment of reducing power were used to evaluate antioxidant potential of MPBL. The extract of MPBL, at the dose of 100 and 200 mg/kg, produced a significant (p<0.05) increase in pain threshold in hot plate method whereas significantly (p<0.05) reduced the writhing caused by acetic acid and the number of licks induced by formalin in a dose-dependent manner. The same ranges of doses of MPBL caused significant (p<0.05) inhibition of carrageenan-induced paw edema after 4 h in a dose-dependent manner. In DPPH, ONOO(-), and total ROS scavenging method, MPBL showed good antioxidant potentiality with the IC50 value of 16.33±1.02, 25.16±0.61 , and 41.72±0.48 µg/ml, respectively with a significant (p<0.05) good reducing power. The findings of the study suggested that MPBL has strong analgesic, anti-inflammatory, and antioxidant effects, conforming the traditional use of this plant for inflammatory pain alleviation to its antioxidant potentiality.

CORK Study in Cystic Fibrosis: Sustained Improvements in Ultra-Low-Dose Chest CT Scores After CFTR Modulation With Ivacaftor.

PubMed

Ronan, Nicola J; Einarsson, Gisli G; Twomey, Maria; Mooney, Denver; Mullane, David; NiChroinin, Muireann; O'Callaghan, Grace; Shanahan, Fergus; Murphy, Desmond M; O'Connor, Owen J; Shortt, Cathy A; Tunney, Michael M; Eustace, Joseph A; Maher, Michael M; Elborn, J Stuart; Plant, Barry J

2018-02-01

Ivacaftor produces significant clinical benefit in patients with cystic fibrosis (CF) with the G551D mutation. Prevalence of this mutation at the Cork CF Centre is 23%. This study assessed the impact of cystic fibrosis transmembrane conductance regulator modulation on multiple modalities of patient assessment. Thirty-three patients with the G551D mutation were assessed at baseline and prospectively every 3 months for 1 year after initiation of ivacaftor. Change in ultra-low-dose chest CT scans, blood inflammatory mediators, and the sputum microbiome were assessed. Significant improvements in FEV 1 , BMI, and sweat chloride levels were observed post-ivacaftor treatment. Improvement in ultra-low-dose CT imaging scores were observed after treatment, with significant mean reductions in total Bhalla score (P < .01), peribronchial thickening (P = .035), and extent of mucous plugging (P < .001). Reductions in circulating inflammatory markers, including interleukin (IL)-1β, IL-6, and IL-8 were demonstrated. There was a 30% reduction in the relative abundance of Pseudomonas species and an increase in the relative abundance of bacteria associated with more stable community structures. Posttreatment community richness increased significantly (P = .03). Early and sustained improvements on ultra-low-dose CT scores suggest it may be a useful method of evaluating treatment response. It paralleled improvement in symptoms, circulating inflammatory markers, and changes in the lung microbiota. Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Antidepressant-like effect of aqueous extract of Channa striatus fillet in mice models of depression.

PubMed

Saleem, A M; Taufik Hidayat, M; Mat Jais, A M; Fakurazi, S; Moklas, Mohamad; Sulaiman, M R; Amom, Z

2011-07-01

Channa (C.) striatus (Malay-Haruan), is a fresh water snakehead fish, consumed as a rejuvenating diet in post-parturition period in local Malay population. The aqueous extract of C. striatus fillet (AECSF) was reported to act through serotonergic receptor system in a previous study. There is no scientific report on neuropharmacological effects of C. striatus. Based on these data, the antidepressant-like effect of C. striatus was evaluated in mice models of depression. AECSF was prepared by steaming the fillets as described previously. Antidepressant activity was studied in male ICR mice using forced swimming test (FST) and tail suspension test (TST). Open-field test was used to evaluate any psychomotor stimulant activity. AECSF was administered intraperitoneally at the concentrations of 30%, 40% and 50% w/v at the dosage of 10 ml/kg. Amitriptyline (10 mg/kg) was used as positive control. All the three concentrations of AECSF (30%, 40% and 50% w/v) significantly reduced the immobility time (p < 0.001) in FST and TST. All the three concentrations of AECSF (30%, 40% and 50% w/v) significantly (p < 0.001) reduced locomotor activity in a dose-dependent manner in open-field test. AECSF produced significant reduction of immobility time in both FST and TST. Amitriptyline produced a significant reduction of immobility time in both FST and TST similar to previous findings. The AECSF produced a dose-dependent decrease in locomotor activity in the open-field test. This hypolocomotion effect indicated the absence of any psychomotor stimulant activity thereby supporting the antidepressant-like effect of the AECSF. The pharmacological mechanisms of the observed antidepressant-like effect and hypolocomotion effect are not understood from our study. Hence, further studies are required.

Blocking GABA-A receptors in the Medial Septum Enhances Hippocampal Acetylcholine Release and Behavior in a Rat Model of Diencephalic Amnesia

PubMed Central

Roland, Jessica J.; Savage, Lisa M.

2009-01-01

Wernicke-Korsakoff syndrome (WKS), a form of diencephalic amnesia caused by thiamine deficiency, results in severe anterograde memory loss. Pyrithiamine-induced thiamine deficiency (PTD), an animal model of WKS, produces cholinergic abnormalities including decreased functional hippocampal acetylcholine (ACh) release and poor spatial memory. Increasing hippocampal ACh levels has increased performance in PTD animals. Intraseptal bicuculline (GABAA antagonist) augments hippocampal ACh release in normal animals and we found it (0.50μg/μl & 0.75μg/μl) also increased in-vivo hippocampal ACh release in PTD animals. However, the 0.75 μg/μl dose produced a greater change in hippocampal ACh release in control animals. The 0.50μg/μl dose of bicuculline was then selected to determine if it could enhance spontaneous alternation performance in PTD animals. This dose of bicuculline significantly increased hippocampal ACh levels above baseline in both PTD and control rats and resulted in complete behavioral recovery in PTD animals, without altering performance in control rats. This suggests that balancing ACh-GABA interactions in the septohippocampal circuit may be an effective therapeutic approach in certain amnestic syndromes. PMID:19463263

Thyroid abnormalities after therapeutic external radiation

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

Hancock, S.L.; McDougall, I.R.; Constine, L.S.

1995-03-30

The thyroid gland is the largest pure endocrine gland in the body and one of the organs most likely to produce clinically significant abnormalities after therapeutic external radiation. Radiation doses to the thyroid that exceed approximately 26 Gy frequently produce hypothyroidism, which may be clinically overt or subclinical, as manifested by increased serum thyrotropin and normal serum-free thyroxine concentrations. Pituitary or hypothalamic hypothyroidism may arise when the pituitary region receives doses exceeding 50 Gy with conventional, 1.8-2 Gy fractionation. Direct irradiation of the thyroid may increase the risk of Graves` disease or euthyroid Graves` ophthalmopathy. Silent thyroiditis, cystic degeneration, benignmore » adenoma, and thyroid cancer have been observed after therapeutically relevant doses of external radiation. Direct or incidental thyroid irradiation increases the risk for well-differentiated, papillary, and follicular thyroid cancer from 15- to 53-fold. Thyroid cancer risk is highest following radiation at a young age, decreases with increasing age at treatment, and increases with follow-up duration. The potentially prolonged latent period between radiation exposure and the development of thyroid dysfunction, thyroid nodularity, and thyroid cancer means that individuals who have received neck or pituitary irradiation require careful, periodic clinical and laboratory evaluation to avoid excess morbidity. 39 refs.« less

Characterization of adrenergic receptors of the cat iris and nictitating membrane.

PubMed

Koss, M C; Hey, J A; Gherezghiher, T

1990-01-01

Graded pupillary dilations and nictitating membrane (NM) contractions were elicited in anesthetized cats by electrical stimulation of the preganglionic sympathetic nerve or by i.a. administration of norepinephrine (NE) or phenylephrine into the carotid artery. Pupil and NM responses were measured simultaneously from the same side. Alpha-adrenoceptor antagonists were administered intravenously. All of the alpha 1-adrenoceptor blockers tested produced a dose-related reduction of NM responses to both neural and agonist activation; the potency rank order was prazosin greater than WB-4101 greater than phentolamine greater than phenoxybenzamine (PBZ). In contrast, responses of the iris dilator were antagonized only by WB-4101 and PBZ. The iris was almost totally refractory to doses of prazosin and phentolamine that blocked NM responses by more than 75% of control. Neither alpha 2- nor beta-adrenoceptor antagonism produced significant inhibition of neural or agonist activation of either organ (with the exception of high doses of yohimbine on the NM). These results suggest that the postjunctional adrenoceptors of the NM are exclusively of the alpha 1-adrenoceptor subtype. In contrast, those of the iris dilator muscle cannot be easily classified pharmacologically as either alpha 1 or alpha 2-adrenoceptors.

Aluminum exacerbates cyclosporin induced nephrotoxicity in rats.

PubMed

Tariq, M; Morais, C; Sujata, B; Sobki, S; al Sulaiman, M; al Khader, A

1999-01-01

Cyclosporin (CSA) has been universally used as an immunosuppressant for the management of allotransplantation and autoimmune diseases. However, nephrotoxicity of CSA limits its use to optimum level. Aluminum (Al) is an extensively distributed element in the environment and human exposure to this metal is unavoidable. Recent studies suggest that even a slight impairment of renal function may increase the Al body burden significantly, which may lead to neurotoxicity, nephrotoxicity, osteodystrophy or hypochromic anemia. In the present study, an attempt was made to study the effect of concomitant use of Al and CSA on structure and function of kidney in rats. This study was undertaken in two steps. In the first set of experiments, the effect of single dose of Al (1% Al2(SO4)3 18H2O) on the nephrotoxicity of multiple doses of CSA (12.5 mg/kg, 25 mg/kg and 50 mg/kg) was studied, where as in the second set of experiments the effect of multiple doses of Al (0.25%, 0.5% and 1%) on single dose of CSA (50 mg/kg) was undertaken. Male Sprague-Dawley rats (weighing 230 +/- 20 g) were used in this study. CSA was given once a day by gavage for seven days, where as Al was given in drinking water for the same period. Twenty four hours after the last dose of CSA, animals were sacrificed and blood and kidney were collected for biochemical and histopathological studies. The bio-chemical parameters included blood urea nitrogen (BUN), serum creatinine (SCr), CSA and Al levels. The kidney homogenates were assayed for malondialdehyde (MDA) and lipid hydroperoxides (LPH). Treatment of rats with CSA alone produced dose-dependent structural and functional changes in kidney. Although Al alone failed to produce any deleterious effect on renal function, it significantly increased the bioavailability and nephrotoxicity of CSA. Al also exacerbated CSA induced increase in oxidative stress (as evident by increased MDA and LPH). Thus, the exacerbation of CSA nephrotoxicity by Al may be attributed to increased bioavailability of CSA and excessive generation of free radicals following concomitant use of these drugs.

Aripiprazole effects on self-administration and pharmacodynamics of intravenous cocaine and cigarette smoking in humans

PubMed Central

Lofwall, M.R.; Nuzzo, P.A.; Campbell, C.; Walsh, S.L.

2014-01-01

Aripiprazole is a partial agonist at dopamine D2 and serotonin 5-HT1a receptors and antagonist at 5-HT2 receptors. Because both dopamine and serotonin systems are involved in the action of cocaine, this study aimed to determine if aripiprazole could diminish the reinforcing efficacy of cocaine. Secondary aims evaluated aripiprazole effects on ad lib cigarette smoking and a novel 40-hour cigarette smoking abstinence procedure. Healthy adults with regular cocaine and cigarette use completed this ~30-day inpatient double blind, randomized, placebo-controlled mixed-design study. An oral placebo lead-in period was followed by randomization to oral aripiprazole (0, 2 or 10 mg daily; n=7 completed/group). Three sets of test sessions, each consisting of three cocaine sample-choice (i.e., self-administration) sessions and one dose-response session, were conducted (during the lead-in period and after randomization before and after achieving aripiprazole steady state). Sample-choice sessions tested three cocaine doses (0, 20, and 40 mg/70 kg, i.v.) with one dose (random order) administered in each sample session; subjective, observer-rated and physiologic outcomes were collected repeatedly before and after cocaine administration. Later that day, participants chose between receiving the sample dose from that morning or descending amounts of money for seven trials ($19, 16, 13, 10, 7, 4, 1). Dose response sessions administered the three cocaine doses in ascending order for pharmacodynamic and potential pharmacokinetic assessment. A set of two cigarette smoking topography sessions were conducted during placebo lead-in and after randomization; one with and one without 40-hours of cigarette smoking abstinence. Number of ad lib cigarettes smoked during non-session days was also collected. Cocaine produced prototypic pharmacodynamic effects and self-administration; neither were significantly altered by aripiprazole. The 40-hour smoking abstinence procedure reliably produced nicotine withdrawal and craving and increased smoking modestly. Aripiprazole did not significantly alter smoking outcomes. These data do not support the further investigation of aripiprazole for the treatment of cocaine or tobacco use disorders. PMID:24467369

The anthelmintic effect of aqueous methanol extract of Combretum molle (R. Br. x. G. Don) (Combretaceae) in lambs experimentally infected with Haemonchus contortus.

PubMed

Simon, M K; Ajanusi, O J; Abubakar, M S; Idris, A L; Suleiman, M M

2012-06-08

The aqueous methanol extract from the stem-bark of Combretum molle was evaluated for anthelmintic activity in lambs infected with Haemonchus contortus using faecal egg count (FEC) reduction assay. The extract showed a dose-dependent reduction in FEC in infected animals. At doses of 500, 1000 and 2000 mg kg(-1), the extract caused FEC reduction of 63%, 69.25% and 96.23%, respectively. Similarly, the standard anthelmintic (albendazole) at a dose of 200 mg kg(-1) produced FEC reduction of 99.24%. FEC reduction produced by the extract at doses of 500 and 1000 mg kg(-1) is below the minimum standard of 90% FEC recommended by the World Association for the Advancement of Veterinary Parasitology (WAAVP). However, there was no significant (P>0.05) difference between the means of groups treated with 1000 mg kg(-1) and 2000 mg kg(-1) compared to that of albendazole. In this study, C. molle has shown a promising anthelmintic activity against experimental haemonchosis. Nonetheless, further studies to evaluate its detailed toxicity are required for the plant extract to be developed into a useful anthelmintic drug. There is also the need to evaluate other parts of the plant (root, leaves, fruits, etc.) for the same effect. Copyright © 2012 Elsevier B.V. All rights reserved.

Memantine elicits spinal blockades of motor function, proprioception, and nociception in rats.

PubMed

Chen, Yu-Wen; Chiu, Chong-Chi; Liu, Kuo-Sheng; Hung, Ching-Hsia; Wang, Jhi-Joung

2015-12-01

Although memantine blocks sodium currents and produces local skin anesthesia, spinal anesthesia with memantine is unknown. The purpose of the study was to evaluate the local anesthetic effect of memantine in spinal anesthesia and its comparison with a widely used local anesthetic lidocaine. After intrathecally injecting the rats with five doses of each drug, the dose-response curves of memantine and lidocaine were constructed. The potencies of the drugs and durations of spinal anesthetic effects on motor function, proprioception, and nociception were compared with those of lidocaine. We showed that memantine produced dose-dependent spinal blockades in motor function, proprioception, and nociception. On a 50% effective dose (ED50 ) basis, the rank of potency was lidocaine greater than memantine (P < 0.05 for the differences). At the equipotent doses (ED25 , ED50 , ED75 ), the block duration produced by memantine was longer than that produced by lidocaine (P < 0.05 for the differences). Memantine, but not lidocaine, displayed more sensory/nociceptive block than motor block. The preclinical data demonstrated that memantine is less potent than lidocaine, whereas memantine produces longer duration of spinal anesthesia than lidocaine. Memantine shows a more sensory-selective action over motor blockade. © 2015 Société Française de Pharmacologie et de Thérapeutique.

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

Impact of tumour motion compensation and delineation methods on FDG PET-based dose painting plan quality for NSCLC radiation therapy.

PubMed

Thomas, Hannah Mary; Kinahan, Paul E; Samuel, James Jebaseelan E; Bowen, Stephen R

2018-02-01

To quantitatively estimate the impact of different methods for both boost volume delineation and respiratory motion compensation of [18F] FDG PET/CT images on the fidelity of planned non-uniform 'dose painting' plans to the prescribed boost dose distribution. Six locally advanced non-small cell lung cancer (NSCLC) patients were retrospectively reviewed. To assess the impact of respiratory motion, time-averaged (3D AVG), respiratory phase-gated (4D GATED) and motion-encompassing (4D MIP) PET images were used. The boost volumes were defined using manual contour (MANUAL), fixed threshold (FIXED) and gradient search algorithm (GRADIENT). The dose painting prescription of 60 Gy base dose to the planning target volume and an integral dose of 14 Gy (total 74 Gy) was discretized into seven treatment planning substructures and linearly redistributed according to the relative SUV at every voxel in the boost volume. Fifty-four dose painting plan combinations were generated and conformity was evaluated using quality index VQ0.95-1.05, which represents the sum of planned dose voxels within 5% deviation from the prescribed dose. Trends in plan quality and magnitude of achievable dose escalation were recorded. Different segmentation techniques produced statistically significant variations in maximum planned dose (P < 0.02), as well as plan quality between segmentation methods for 4D GATED and 4D MIP PET images (P < 0.05). No statistically significant differences in plan quality and maximum dose were observed between motion-compensated PET-based plans (P > 0.75). Low variability in plan quality was observed for FIXED threshold plans, while MANUAL and GRADIENT plans achieved higher dose with lower plan quality indices. The dose painting plans were more sensitive to segmentation of boost volumes than PET motion compensation in this study sample. Careful consideration of boost target delineation and motion compensation strategies should guide the design of NSCLC dose painting trials. © 2017 The Royal Australian and New Zealand College of Radiologists.

Inhibition by spinal mu- and delta-opioid agonists of afferent-evoked substance P release.

PubMed

Kondo, Ichiro; Marvizon, Juan Carlos G; Song, Bingbing; Salgado, Frances; Codeluppi, Simone; Hua, Xiao-Ying; Yaksh, Tony L

2005-04-06

Opioid mu- and delta-receptors are present on the central terminals of primary afferents, where they are thought to inhibit neurotransmitter release. This mechanism may mediate analgesia produced by spinal opiates; however, when they used neurokinin 1 receptor (NK1R) internalization as an indicator of substance P release, Trafton et al. (1999) noted that this evoked internalization was altered only modestly by morphine delivered intrathecally at spinal cord segment S1-S2. We reexamined this issue by studying the effect of opiates on NK1R internalization in spinal cord slices and in vivo. In slices, NK1R internalization evoked by dorsal root stimulation at C-fiber intensity was abolished by the mu agonist [D-Ala2, N-Me-Phe4, Gly-ol5]-enkephalin (DAMGO) (1 microM) and decreased by the delta agonist [D-Phe2,5]-enkephalin (DPDPE) (1 microM). In vivo, hindpaw compression induced NK1R internalization in ipsilateral laminas I-II. This evoked internalization was significantly reduced by morphine (60 nmol), DAMGO (1 nmol), and DPDPE (100 nmol), but not by the kappa agonist trans-(1S,2S)-3,4-dichloro-N-mathyl-N-[2-(1-pyrrolidinyl)cyclohexyl]-benzeneacetamide hydrochloride (200 nmol), delivered at spinal cord segment L2 using intrathecal catheters. These doses of the mu and delta agonists were equi-analgesic as measured by a thermal escape test. Lower doses neither produced analgesia nor inhibited NK1R internalization. In contrast, morphine delivered by percutaneous injections at S1-S2 had only a modest effect on thermal escape, even at higher doses. Morphine decreased NK1R internalization after systemic delivery, but at a dose greater than that necessary to produce equivalent analgesia. All effects were reversed by naloxone. These results indicate that lumbar opiates inhibit noxious stimuli-induced neurotransmitter release from primary afferents at doses that are confirmed behaviorally as analgesic.

Complete Protection against Pneumonic and Bubonic Plague after a Single Oral Vaccination

PubMed Central

Derbise, Anne; Hanada, Yuri; Khalifé, Manal; Carniel, Elisabeth; Demeure, Christian E.

2015-01-01

Background No efficient vaccine against plague is currently available. We previously showed that a genetically attenuated Yersinia pseudotuberculosis producing the Yersinia pestis F1 antigen was an efficient live oral vaccine against pneumonic plague. This candidate vaccine however failed to confer full protection against bubonic plague and did not produce F1 stably. Methodology/Principal Findings The caf operon encoding F1 was inserted into the chromosome of a genetically attenuated Y. pseudotuberculosis, yielding the VTnF1 strain, which stably produced the F1 capsule. Given orally to mice, VTnF1 persisted two weeks in the mouse gut and induced a high humoral response targeting both F1 and other Y. pestis antigens. The strong cellular response elicited was directed mostly against targets other than F1, but also against F1. It involved cells with a Th1—Th17 effector profile, producing IFNγ, IL-17, and IL-10. A single oral dose (108 CFU) of VTnF1 conferred 100% protection against pneumonic plague using a high-dose challenge (3,300 LD50) caused by the fully virulent Y. pestis CO92. Moreover, vaccination protected 100% of mice from bubonic plague caused by a challenge with 100 LD50 Y. pestis and 93% against a high-dose infection (10,000 LD50). Protection involved fast-acting mechanisms controlling Y. pestis spread out of the injection site, and the protection provided was long-lasting, with 93% and 50% of mice surviving bubonic and pneumonic plague respectively, six months after vaccination. Vaccinated mice also survived bubonic and pneumonic plague caused by a high-dose of non-encapsulated (F1-) Y. pestis. Significance VTnF1 is an easy-to-produce, genetically stable plague vaccine candidate, providing a highly efficient and long-lasting protection against both bubonic and pneumonic plague caused by wild type or un-encapsulated (F1-negative) Y. pestis. To our knowledge, VTnF1 is the only plague vaccine ever reported that could provide high and durable protection against the two forms of plague after a single oral administration. PMID:26473734

Synergistic interactions between paracetamol and oxcarbazepine in somatic and visceral pain models in rodents.

PubMed

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

2010-04-01

Combination therapy is a valid approach in pain treatment, in which a reduction of doses could reduce side effects and still achieve optimal analgesia. We examined the effects of coadministered paracetamol, a widely used non-opioid analgesic, and oxcarbazepine, a relatively novel anticonvulsant with analgesic properties, in a rat model of paw inflammatory hyperalgesia and in a mice model of visceral pain and determined the type of interaction between components. The effects of paracetamol, oxcarbazepine, and their combinations were examined in carrageenan-induced (0.1 mL, 1%) paw inflammatory hyperalgesia in rats and in an acetic acid-induced (10 mg/kg, 0.75%) writhing test in mice. In both models, drugs were coadministered in fixed-dose fractions of the 50% effective dose (ED(50)), and type of interaction was determined by isobolographic analysis. Paracetamol (50-200 mg/kg peroral), oxcarbazepine (40-160 mg/kg peroral), and their combination (1/8, 1/4, 1/3, and 1/2 of a single drug ED(50)) produced a significant, dose-dependent antihyperalgesia in carrageenan-injected rats. In the writhing test in mice, paracetamol (60-180 mg/kg peroral), oxcarbazepine (20-80 mg/kg peroral), and their combination (1/16, 1/8, 1/4, and 1/2 of a single drug ED(50)) significantly and dose dependently reduced the number of writhes. In both models, isobolographic analysis revealed a significant synergistic interaction between paracetamol and oxcarbazepine, with a >4-fold reduction of doses of both drugs in combination, compared with single drugs ED(50). The synergistic interaction between paracetamol and oxcarbazepine provides new information about combination pain treatment and should be explored further in patients, especially with somatic and/or visceral pain.

Facilitatory effects of piracetam on excitability of motor nerve terminals and neuromuscular transmission.

PubMed

Hall, E D; Von Voigtlander, P F

1987-11-01

The possible in vivo facilitatory effects of the pyrrolidine acetamide no-otropic agent piracetam on neuromuscular transmission, were studied based upon reports of enhancement of central cholinergic function. Piracetam was shown to antagonize the lethal effects of the neuromuscular blocking agent hemicholinium-3 (HC-3), in female CF-1 mice when administered in a dose of 100 mg/kg (i.p.) simultaneously with HC-3. A 30 mg/kg (i.p.) dose of piracetam was ineffective by itself, although it potentiated the protective effects of choline (25 mg/kg i.p.). The analogs of piracetam, aniracetam, oxiracetam, pramiracetam and dupracetam also significantly antagonized the lethality of HC-3 at doses over a 30-300 mg/kg range. The acute facilitatory properties of piracetam on neuromuscular transmission were examined in more detail in vivo in the soleus nerve muscle preparation of the cat. A 100 mg/kg (i.v.) dose of piracetam, while having no effect on its own, significantly enhanced the ability of a 200 micrograms/kg (i.v.) dose of edrophonium to produce a potentiation of muscle contraction dependent on repetitive discharges in the soleus motor nerve terminals. In preparations in which the motor nerve terminals of the soleus were in a partially degenerated state as a result of section of the motor axons 48 hr earlier, piracetam acted to restore their sensitivity to edrophonium. Furthermore, in both normal and partially degenerated preparations, piracetam significantly decreased the neuromuscular blocking effects of a 150 micrograms/kg (i.v.) dose of d-tubocurarine. The mechanism of the neuromuscular facilitatory effects of piracetam on neuromuscular transmission is discussed in terms of an enhanced excitability of motor nerve terminals together with an action to increase the synthesis and/or release of acetylcholine.

Using 300 Pretreatment Shock Waves in a Voltage Ramping Protocol Can Significantly Reduce Tissue Injury During Extracorporeal Shock Wave Lithotripsy.

PubMed

Connors, Bret A; Evan, Andrew P; Handa, Rajash K; Blomgren, Philip M; Johnson, Cynthia D; Liu, Ziyue; Lingeman, James E

2016-09-01

Pretreating a pig kidney with 500 low-energy shock waves (SWs) before delivering a clinical dose of SWs (2000 SWs, 24 kV, 120 SWs/min) has been shown to significantly reduce the size of the hemorrhagic lesion produced in that treated kidney, compared with a protocol without pretreatment. However, since the time available for patient care is limited, we wanted to determine if fewer pretreatment SWs could be used in this protocol. As such, we tested if pretreating with 300 SWs can initiate the same reduction in renal lesion size as has been observed with 500 SWs. Fifteen female farm pigs were placed in an unmodified Dornier HM-3 lithotripter, where the left kidney of each animal was targeted for lithotripsy treatment. The kidneys received 300 SWs at 12 kV (120 SWs/min) followed immediately by 2000 SWs at 24 kV (120 SWs/min) focused on the lower pole. These kidneys were compared with kidneys given a clinical dose of SWs with 500 SW pretreatment, and without pretreatment. Renal function was measured both before and after SW exposure, and lesion size analysis was performed to assess the volume of hemorrhagic tissue injury (% functional renal volume, FRV) created by the 300 SW pretreatment regimen. Glomerular filtration rate fell significantly in the 300 SW pretreatment group by 1 hour after lithotripsy treatment. For most animals, low-energy pretreatment with 300 SWs significantly reduced the size of the hemorrhagic injury (to 0.8% ± 0.4%FRV) compared with the injury produced by a typical clinical dose of SWs. The results suggest that 300 pretreatment SWs in a voltage ramping treatment regimen can initiate a protective response in the majority of treated kidneys and significantly reduce tissue injury in our model of lithotripsy injury.

Aromatase inhibitors augment nociceptive behaviors in rats and enhance the excitability of sensory neurons

PubMed Central

Robarge, Jason D.; Duarte, Djane B.; Shariati, Behzad; Wang, Ruizhong; Flockhart, David A.; Vasko, Michael R.

2016-01-01

Although aromatase inhibitors (AIs) are commonly used therapies for breast cancer, their use is limited because they produce arthralgia in a large number of patients. To determine whether AIs produce hypersensitivity in animal models of pain, we examined the effects of the AI, letrozole, on mechanical, thermal, and chemical sensitivity in rats. In ovariectomized (OVX) rats, administering a single dose of 1 or 5 mg/kg letrozole significantly reduced mechanical paw withdrawal thresholds, without altering thermal sensitivity. Repeated injection of 5 mg/kg letrozole in male rats produced mechanical, but not thermal, hypersensitivity that extinguished when drug dosing was stopped. A single dose of 5 mg/kg letrozole or daily dosing of letrozole or exemestane in male rats also augmented flinching behavior induced by intraplantar injection of 1000 nmol of adenosine 5′-triphosphate (ATP). To determine whether sensitization of sensory neurons contributed to AI-induced hypersensitivity, we evaluated the excitability of neurons isolated from dorsal root ganglia of male rats chronically treated with letrozole. Both small and medium-diameter sensory neurons isolated from letrozole-treated rats were more excitable, as reflected by increased action potential firing in response to a ramp of depolarizing current, a lower resting membrane potential, and a lower rheobase. However, systemic letrozole treatment did not augment the stimulus-evoked release of the neuropeptide calcitonin gene-related peptide (CGRP) from spinal cord slices, suggesting that the enhanced nociceptive responses were not secondary to an increase in peptide release from sensory endings in the spinal cord. These results provide the first evidence that AIs modulate the excitability of sensory neurons, which may be a primary mechanism for the effect of these drugs to augment pain behaviors in rats. PMID:27072527

Effects of intravenous nonsteroidal antiinflammatory drugs on a C-fiber reflex elicited by a wide range of stimulus intensities in the rat.

PubMed

Bustamante, D; Paeile, C; Willer, J C; Le Bars, D

1996-03-01

A C-fiber reflex elicited by electrical stimulation within the territory of the sural nerve, was recorded from the ipsilateral biceps femoris muscle in anesthetized rats. The temporal evolution of the response was studied using a constant stimulus intensity (3 x threshold) and recruitment curves were built by varying stimulus intensity from 0 to 7 x threshold. The i.v. administration of aspirin, indomethacin, ketoprofen, paracetamol (= acetaminophen) and lysine clonixinate resulted in dose-dependent depressions of the C-fiber reflex by up to 30 to 40%. By contrast, saline was ineffective. High doses of the effective drugs that produced large disturbances in heart rate and/or acid-base equilibrium were not considered in the pharmacological analysis. When a constant level of stimulation was used, different dose-dependent profiles of drug action were observed. Aspirin induced a slow and gradual depression, although indomethacin, ketoprofen and paracetamol produced a peak effect within the first 10-min period and then reached a steady state phase for up to 30 min. The depressive effects of lysine clonixinate appeared more stable. When recruitment curves were built with a range of nociceptive stimulus intensities, all the drugs produced a dose-dependent decrease in the slopes and the areas under the recruitment curves without any major modification in the thresholds. The order of potency was the same for both stimulation paradigms, e.g., aspirin < paracetamol < lysine clonixinate = ketoprofen < indomethacin. It is concluded that NSAID elicit significant antinociceptive effects at a central level, which do not depend on the existence of a hyperalgesic or inflammatory state.

DARHT Axis-I Diode Simulations II: Geometrical Scaling

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

Ekdahl, Carl A. Jr.

2012-06-14

Flash radiography of large hydrodynamic experiments driven by high explosives is a venerable diagnostic technique in use at many laboratories. Many of the largest hydrodynamic experiments study mockups of nuclear weapons, and are often called hydrotests for short. The dual-axis radiography for hydrodynamic testing (DARHT) facility uses two electron linear-induction accelerators (LIA) to produce the radiographic source spots for perpendicular views of a hydrotest. The first of these LIAs produces a single pulse, with a fixed {approx}60-ns pulsewidth. The second axis LIA produces as many as four pulses within 1.6-{micro}s, with variable pulsewidths and separation. There are a wide varietymore » of hydrotest geometries, each with a unique radiographic requirement, so there is a need to adjust the radiographic dose for the best images. This can be accomplished on the second axis by simply adjusting the pulsewidths, but is more problematic on the first axis. Changing the beam energy or introducing radiation attenuation also changes the spectrum, which is undesirable. Moreover, using radiation attenuation introduces significant blur, increasing the effective spot size. The dose can also be adjusted by changing the beam kinetic energy. This is a very sensitive method, because the dose scales as the {approx}2.8 power of the energy, but it would require retuning the accelerator. This leaves manipulating the beam current as the best means for adjusting the dose, and one way to do this is to change the size of the cathode. This method has been proposed, and is being tested. This article describes simulations undertaken to develop scaling laws for use as design tools in changing the Axis-1 beam current by changing the cathode size.« less

Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects.

PubMed

Griffiths, Roland R; Johnson, Matthew W; Richards, William A; Richards, Brian D; McCann, Una; Jesse, Robert

2011-12-01

This dose-effect study extends previous observations showing that psilocybin can occasion mystical-type experiences having persisting positive effects on attitudes, mood, and behavior. This double-blind study evaluated psilocybin (0, 5, 10, 20, 30 mg/70 kg, p.o.) administered under supportive conditions. Participants were 18 adults (17 hallucinogen-naïve). Five 8-h sessions were conducted individually for each participant at 1-month intervals. Participants were randomized to receive the four active doses in either ascending or descending order (nine participants each). Placebo was scheduled quasi-randomly. During sessions, volunteers used eyeshades and were instructed to direct their attention inward. Volunteers completed questionnaires assessing effects immediately after and 1 month after each session, and at 14 months follow-up. Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained positive changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater positive effects. At 14 months, ratings were undiminished and were consistent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing function of dose, with the lowest dose showing significant effects. Under supportive conditions, 20 and 30 mg/70 kg psilocybin occasioned mystical-type experiences having persisting positive effects on attitudes, mood, and behavior. Implications for therapeutic trials are discussed.

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.

Effects of 17α-Methyltestosterone and Aromatase Inhibitor Letrozole on Sex Reversal, Gonadal Structure, and Growth in Yellow Catfish Pelteobagrus fulvidraco.

PubMed

Shen, Zhi-Gang; Fan, Qi-Xue; Yang, Wei; Zhang, Yun-Long; Wang, Han-Ping

2015-04-01

Monosex populations are in demand in many fish species with sexual dimorphism, e.g., better growth performance, higher gonad value, superior ornamental value. From the point of view of research, a monosex population is one of the best materials for investigating sex-determining mechanisms, sex differentiation, and sex-linked markers. Sex reversal of females (phenotypic reversal from XX female to XX male) is the first step in all-female production in species with an XX/XY system for sex determination. In the present study, masculinization of yellow catfish, a species with XX/XY sex determination, was investigated by oral administration of various doses of 17α-methyltestosterone (MT) or an aromatase inhibitor (AI) letrozole (LZ); effects on survival, growth performance, sex ratio, and changes in gonadal structure were evaluated. Three doses (20, 50, and 100 mg kg(-1) diet) of oral MT or LZ were administered to fry from 10 days post-hatching (DPH) to 59 DPH. Oral administration of MT at all doses did not significantly change the ratio of males (45.8%, 33.3%, and 50.0% respectively) compared to the control group (37.5%), while yielding intersex fish at all doses (4.2% to 8.3%). Oral administration of LZ produced a significantly higher proportion of males in all doses (75.5%, 83.3%, and 75.0%, respectively). Additionally, the lowest dose of LZ improved the growth of treated fish compared to the control, and all doses of LZ enhanced spermatogenesis in treated males. © 2015 Marine Biological Laboratory.

Comparison of buprenorphine and methadone effects on opiate self-administration in primates.

PubMed

Mello, N K; Bree, M P; Mendelson, J H

1983-05-01

The effects of ascending and descending doses of buprenorphine (0.014-0.789 mg/kg/day) and methadone (0.179-11.86 mg/kg/day) on opiate and food intake were studied in Macaque monkeys over 195 to 245 days. Food (1-g banana pellets) and i.v. drug self-administration (heroin 0.01 or 0.02 mg/kg/injection or Dilaudid 0.02 mg/kg/injection) were maintained on a second-order schedule of reinforcement [FR 4 (VR 16:S)]. Buprenorphine (0.282-0.789 mg/kg/day) produced a significant suppression of opiate self-administration at 2.5 to 7 times the dose shown to be effective in human opiate abusers (P less than .05-.001). Methadone (1.43-11.86 mg/kg/day) did not suppress opiate self-administration in four of five monkeys across a dose range equivalent to 100 to 800 mg/day in man. The distribution of opiate self-administration across drug sessions did not account for the absence of methadone suppression as monkeys took 43% of the total daily opiate injections during the first daily drug session, 2.5 hr after methadone administration. During buprenorphine maintenance, food intake remained stable or increased significantly above base-line levels. Methadone maintenance was associated with significant decrements in food intake in four of five monkeys. Buprenorphine appeared to be significantly more effective in suppressing opiate self-administration than methadone across the dose range studied. Buprenorphine had none of the toxic side effects (seizures, respiratory depression, profound psychomotor retardation) associated with high doses of methadone over 6 to 8 months of daily drug treatment. These data are consistent with clinical studies of buprenorphine effects on heroin self-administration in human opiate addicts.

A comparison of sequential and spiral scanning techniques in brain CT.

PubMed

Pace, Ivana; Zarb, Francis

2015-01-01

To evaluate and compare image quality and radiation dose of sequential computed tomography (CT) examinations of the brain and spiral CT examinations of the brain imaged on a GE HiSpeed NX/I Dual Slice 2CT scanner. A random sample of 40 patients referred for CT examination of the brain was selected and divided into 2 groups. Half of the patients were scanned using the sequential technique; the other half were scanned using the spiral technique. Radiation dose data—both the computed tomography dose index (CTDI) and the dose length product (DLP)—were recorded on a checklist at the end of each examination. Using the European Guidelines on Quality Criteria for Computed Tomography, 4 radiologists conducted a visual grading analysis and rated the level of visibility of 6 anatomical structures considered necessary to produce images of high quality. The mean CTDI(vol) and DLP values were statistically significantly higher (P <.05) with the sequential scans (CTDI(vol): 22.06 mGy; DLP: 304.60 mGy • cm) than with the spiral scans (CTDI(vol): 14.94 mGy; DLP: 229.10 mGy • cm). The mean image quality rating scores for all criteria of the sequential scanning technique were statistically significantly higher (P <.05) in the visual grading analysis than those of the spiral scanning technique. In this local study, the sequential technique was preferred over the spiral technique for both overall image quality and differentiation between gray and white matter in brain CT scans. Other similar studies counter this finding. The radiation dose seen with the sequential CT scanning technique was significantly higher than that seen with the spiral CT scanning technique. However, image quality with the sequential technique was statistically significantly superior (P <.05).

Asbestos-induced endothelial cell activation and injury. Demonstration of fiber phagocytosis and oxidant-dependent toxicity.

PubMed

Garcia, J G; Gray, L D; Dodson, R F; Callahan, K S

1988-10-01

Vascular endothelial cell injury is important in the development of a variety of chronic interstitial lung disorders. However, the involvement of such injury in the inflammatory response associated with the inhalation of asbestos fibers is unclear and the mechanism of asbestos fiber cytotoxicity remains unknown. In the present study, human umbilical vein endothelial cells were challenged with amosite asbestos and several parameters of cellular function were examined. Electron microscopic examination revealed that endothelial cell exposure to asbestos resulted in active phagocytosis of these particulates. Biochemical evidence of dose-dependent asbestos-mediated endothelial cell activation was indicated by increased metabolism of arachidonic acid. For example, amosite asbestos (500 micrograms/ml) produced a ninefold increase in prostacyclin (PGI2) levels over those levels in non-exposed cells. Incubation of human endothelial cells with asbestos fibers induced specific 51Cr release in both a dose- and time-dependent fashion indicative of cellular injury. Injury induced by amosite asbestos was not significantly attenuated by treatment of the endothelial cell monolayer with either the iron chelator deferoxamine, which prevents hydroxyl radical (.OH) formation, or by the superoxide anion (O2-) scavenger, superoxide dismutase. However, significant dose-dependent protection was observed with the hydrogen peroxide (H2O2) scavenger, catalase. Chelation of elemental iron present within amosite asbestos fibers by deferoxamine produced a 33% reduction in asbestos cytotoxicity, suggesting a potential role for hydroxyl radical-mediated injury via the iron-catalyzed Haber-Weiss reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

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

Effect of Chelator Conjugation Level and Injection Dose on Tumor and Organ Uptake of 111In Labeled MORAb-009, an Anti-mesothelin Antibody

PubMed Central

Shin, I. S.; Lee, S.-M.; Kim, H. S.; Yao, Z.; Regino, C.; Sato, N.; Cheng, K. T.; Hassan, R.; Campo, M. F.; Albone, E. F.; Choyke, P. L.; Pastan, I.; Paik, C. H.

2012-01-01

Introduction Radiolabeling of a monoclonal antibody (mAb) with a metallic radionuclide requires the conjugation of a bifunctional chelator to the mAb. The conjugation, however, can alter the physical and immunological properties of the mAb, consequently affecting its tumor targeting pharmacokinetics. In this study, we investigated the effect of the amount of 2-(p-isothiocyanatobenzyl)-cyclohexyl-diethylenetriamine-pentaacetic acid (CHX-A″) conjugated to MORAb-009, a mAb directed against mesothelin and the effect of MORAb dose on the biodistribution of 111In labeled MORAb-009. Methods We used nude mice bearing A431/K5 tumor as a mesothelin-positive tumor model and A431 tumor as a mesothelin-negative control. To find the optimal level of CHX-A″ conjugation, CHX-A″-MORAb-009 conjugates with 2.4, 3.5, and 5.5 CHX-A″ molecules were investigated. To investigate the effect of injected MORAb-009 dose on neutralizing the shed-mesothelin in the circulation, the biodistribution studies were performed after the i.v. co-injection of the 111In labeled MORAb-009 (2.4 CHX-A″/MORAb-009) with three different doses, 0.2, 2, and 30 μg of MORAb-009. Results The tumor uptake in A431/K5 tumor was 4 times higher than that in A431 tumor, indicating that the tumor uptake in A431/K5 was mesothelin-mediated. The conjugate with 5.5 CHX-A″ showed a lower isoelectric point (pI) and lower immunoreactivity (IR) than the 2.4 CHX-A″ conjugate. These differences were reflected in biodistribution of the 111In label. The 111In labeled MORAb-009 conjugated with 2.4 CHX-A″ produced higher tumor uptake, and lower liver and spleen uptakes than the 5.5 CHX-A″ conjugate. The biodistribution studies also revealed that the tumor uptake was significantly affected by the injected MORAb-009 dose and tumor size. The 30 μg dose produced higher tumor uptake than the 0.2 and 2 μg doses whereas the 30 μg dose produced lower liver and spleen uptakes than the 0.2 μg dose. Conclusion This study demonstrates that the number of chelate conjugation and the injected dose are two important parameters to achieve high tumor and low non-target organ uptake of 111In labeled MORAb-009. This study also suggests that the injected dose of mAb could be individualized based on the tumor size or the blood level of shed-antigen in a patient to achieve the ideal tumor-to-organ radioactivity ratios. PMID:21741258

Effect of chelator conjugation level and injection dose on tumor and organ uptake of 111In-labeled MORAb-009, an anti-mesothelin antibody.

PubMed

Shin, In Soo; Lee, Sang-Myung; Kim, Hyung Sub; Yao, Zhengsheng; Regino, Celeste; Sato, Noriko; Cheng, Kenneth T; Hassan, Raffit; Campo, Melissa F; Albone, Earl F; Choyke, Peter L; Pastan, Ira; Paik, Chang H

2011-11-01

Radiolabeling of a monoclonal antibody (mAb) with a metallic radionuclide requires the conjugation of a bifunctional chelator to the mAb. The conjugation, however, can alter the physical and immunological properties of the mAb, consequently affecting its tumor-targeting pharmacokinetics. In this study, we investigated the effect of the amount of 2-(p-isothiocyanatobenzyl)-cyclohexyl-diethylenetriamine-pentaacetic acid (CHX-A″) conjugated to MORAb-009, a mAb directed against mesothelin, and the effect of MORAb dose on the biodistribution of (111)In-labeled MORAb-009. We used nude mice bearing the A431/K5 tumor as a mesothelin-positive tumor model and the A431 tumor as a mesothelin-negative control. To find the optimal level of CHX-A″ conjugation, CHX-A″-MORAb-009 conjugates with 2.4, 3.5 and 5.5 CHX-A″ molecules were investigated. To investigate the effect of injected MORAb-009 dose on neutralizing the shed mesothelin in the circulation, biodistribution studies were performed after the intravenous co-injection of (111)In-labeled MORAb-009 (2.4 CHX-A″/MORAb-009) with three different doses: 0.2, 2 and 30 μg of MORAb-009. The tumor uptake in A431/K5 tumor was four times higher than that in A431 tumor, indicating that the tumor uptake in A431/K5 was mesothelin mediated. The conjugate with 5.5 CHX-A″ showed a lower isoelectric point (pI) and lower immunoreactivity (IR) than the 2.4 CHX-A″ conjugate. These differences were reflected in the biodistribution of the (111)In label. The (111)In-labeled MORAb-009 conjugated with 2.4 CHX-A″ produced higher tumor uptake and lower liver and spleen uptakes than the 5.5 CHX-A″ conjugate. The biodistribution studies also revealed that the tumor uptake was significantly affected by the injected MORAb-009 dose and tumor size. The 30-μg dose produced higher tumor uptake than the 0.2- and 2-μg doses, whereas the 30-μg dose produced lower liver and spleen uptakes than the 0.2-μg dose. This study demonstrates that the number of chelate conjugation and the injected dose are two important parameters to achieve high tumor and low non-target organ uptake of (111)In-labeled MORAb-009. This study also suggests that the injected dose of mAb could be individualized based on the tumor size or the blood level of shed antigen in a patient to achieve the ideal tumor-to-organ radioactivity ratios. Published by Elsevier Inc.

Antifeedant activity of plant extracts to an insect Helopeltis theivora.

PubMed

Dolui, A K; Debnath, M

2010-09-01

The different solvent extracts (viz Petroleum ether Ethyl acetate and Methanol) obtained from leaves and flowers of Heliotropium indicum and Spilanthes calva were screened for antifeedant activity against Helopeltis theivora. All the six different extracts showed antifeedant activity at four different concentrations. The methanolic extracts of leaves of Heliotropium indicum and Spilanthes calva exhibited significant activity at 4% concentration. The numbers of spots produced were only 18.67 and 22.67 respectively which are significantly less than the numberof spots produced in control (104.00 and 93.33 respectively). The treatment with methanolic extracts of flowers of both the plants significantly reduced the number of feeding spots to 22.33 and 23.67 respectively in comparison to the control values of 101.33. All the activities are dose dependent. The mean results with SEM (mean +/- SE) were statistically significant at 1% level (p<0.01) for three observations.

Evaluating the prophylactic potential of zafirlukast against the toxic effects of acetic acid on the rat colon.

PubMed

Mahgoub, Afaf A; El-Medany, Azza A; Hager, Hanan H; Mustafa, Ali A; El-Sabah, Doryia M

2003-11-01

The present work was conducted to assess the possible protective effects of zafirlukast against the toxic damage induced by acetic acid in rat colon. Zafirlukast is a potent and selective cysteinyl leukotriene receptor antagonist which is used mainly in the prophylaxis of bronchial asthma. Two doses of zafirlukast were used (40 and 80 mg/kg) dissolved in gum acacia and given either orally or rectally (0.5 ml/kg). Several parameters including, macroscopic score, histopathological and biochemical such as malondialdehyde (MDA), myeloperoxidase (MPO), catalase and reduced glutathione (GSH) levels were measured using standard assay procedures. The study showed that pretreatment with zafirlukast in a dose of 80 mg/kg orally produced a significant decrease in tissue malondialdehyde, myeloperoxidase, and an increase in both reduced glutathione and catalase levels, while there was no significant changes with the rectal route. The 40 mg/kg dose had no significant protective effects when given either orally or rectally. The available data indicate that the inhibition of leukotriene synthesis or action may have a role in inflammatory bowel disease (IBD) as they are considered as important mediators in this condition.

Fentanyl produces an anti-hyperalgesic effect through the suppression of sodium channels in mice with painful diabetic neuropathy.

PubMed

Tanaka, Ken-ichiro; Nakanishi, Yuki; Sekino, Shyota; Ikegami, Megumi; Ikeda, Hiroko; Kamei, Junzo

2014-06-15

Diabetic neuropathy is one of the most frequent complications of diabetes mellitus. Therefore, the present study was designed to investigate the anti-hyperalgesic mechanism of fentanyl in a mouse model of streptozotocin-induced diabetic neuropathy. The antinociceptive response was assessed by recording the latency in a tail-flick test. The tail-flick latency in diabetic mice was significantly shorter than that in non-diabetic mice. Fentanyl, at doses of 3 and 10 μg/kg, s.c., produced a dose-dependent increase in the tail-flick latencies in diabetic mice. While fentanyl (3 μg/kg, s.c.) did not produce a significant inhibition of the tail-flick response in non-diabetic mice, it significantly prolonged the tail-flick latency in diabetic mice to the same level as the baseline latency in non-diabetic mice. Although pretreatment with naloxone (3mg/kg, s.c.) completely antagonized fentanyl-induced antinociception in non-diabetic mice, it had no effect on the antinociceptive effect of fentanyl in diabetic mice. Pretreatment with either of the voltage-gated sodium channel openers fenvarelarte and veratridine practically abolished the antinociceptive effects of fentanyl in diabetic mice. However, neither fenvarelate nor veratridine affected the antinociceptive effect of fentanyl in non-diabetic mice. These results suggest that the anti-hyperalgesic effect of fentanyl is mediated through the blockade of sodium channels in diabetic mice, whereas opioid receptors mediate the antinociceptive effect of fentanyl in non-diabetic mice. Copyright © 2014 Elsevier B.V. All rights reserved.

Construction of new skin models and calculation of skin dose coefficients for electron exposures

NASA Astrophysics Data System (ADS)

Yeom, Yeon Soo; Kim, Chan Hyeong; Nguyen, Thang Tat; Choi, Chansoo; Han, Min Cheol; Jeong, Jong Hwi

2016-08-01

The voxel-type reference phantoms of the International Commission on Radiological Protection (ICRP), due to their limited voxel resolutions, cannot represent the 50- μm-thick radiosensitive target layer of the skin necessary for skin dose calculations. Alternatively, in ICRP Publication 116, the dose coefficients (DCs) for the skin were calculated approximately, averaging absorbed dose over the entire skin depth of the ICRP phantoms. This approximation is valid for highly-penetrating radiations such as photons and neutrons, but not for weakly penetrating radiations like electrons due to the high gradient in the dose distribution in the skin. To address the limitation, the present study introduces skin polygon-mesh (PM) models, which have been produced by converting the skin models of the ICRP voxel phantoms to a high-quality PM format and adding a 50- μm-thick radiosensitive target layer into the skin models. Then, the constructed skin PM models were implemented in the Geant4 Monte Carlo code to calculate the skin DCs for external exposures of electrons. The calculated values were then compared with the skin DCs of the ICRP Publication 116. The results of the present study show that for high-energy electrons (≥ 1 MeV), the ICRP-116 skin DCs are, indeed, in good agreement with the skin DCs calculated in the present study. For low-energy electrons (< 1 MeV), however, significant discrepancies were observed, and the ICRP-116 skin DCs underestimated the skin dose as much as 15 times for some energies. Besides, regardless of the small tissue weighting factor of the skin ( w T = 0.01), the discrepancies in the skin dose were found to result in significant discrepancies in the effective dose, demonstarting that the effective DCs in ICRP-116 are not reliable for external exposure to electrons.

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

Effects of topical combinations of clonidine and pentoxifylline on capsaicin-induced allodynia and postcapsaicin tourniquet-induced pain in healthy volunteers: a double-blind, randomized, controlled study.

PubMed

Ragavendran, J Vaigunda; Laferrière, André; Bennett, Gary J; Ware, Mark A; Gandhi, Wiebke; Bley, Keith; Schweinhardt, Petra; Coderre, Terence J

2016-10-01

This double-blind randomized controlled study was designed to evaluate the analgesic effects of topical treatments with clonidine (CLON) and pentoxifylline (PTX) tested alone or as low- and high-dose combinations in a human experimental model of pain. Of 69 healthy subjects aged 18 to 60 years, 23 each were randomly allocated to low-dose (0.04% + 2%) and high-dose (0.1% + 5%) CLON + PTX groups. Both of these groups also received their corresponding placebos in one of 2 treatment periods separated by at least 48 hours. Twenty-three additional subjects received either CLON (0.1%) or PTX (5%) as single drug treatments, in each of 2 treatment periods. Assessment of analgesic efficacy was based on allodynic effects of previous intraepidermal capsaicin injection, as well as postcapsaicin tourniquet-induced pain 50 minutes following capsaicin injection. Visual Analogue Scale (VAS) ratings of pain intensity and the area of dynamic mechanical allodynia were the primary outcome measures, whereas area of punctate mechanical allodynia (PMA) served as a secondary outcome measure. Topical treatments with high- or low-dose combinations significantly reduced VAS ratings compared with corresponding placebo treatments throughout the period of postcapsaicin tourniquet-induced pain. Importantly, the high-dose combination produced lower VAS ratings than CLON alone, which were lower than PTX alone. Results also revealed significant inhibition of postcapsaicin dynamic mechanical allodynia and PMA for the high-dose combination compared with placebo, and of PMA for CLON compared with the low-dose combination. Hence, the present data are supportive of further clinical investigation of the high-dose topical combination of CLON + PTX in complex regional pain syndrome and neuropathic pain patients, for which our preclinical data predict efficacy.

Anti-Inflammatory Activity of Polysaccharide Fraction of Curcuma longa (NR-INF-02).

PubMed

Illuri, Ramanaiah; Bethapudi, Bharathi; Anandhakumar, Senthilkumar; Murugan, Sasikumar; Joseph, Joshua Allan; Mundkinajeddu, Deepak; Agarwal, Amit; Velusami, Chandrasekaran Chinampudur

2015-04-07

The aim of the study was to investigate the safety and anti-inflammatory effects of polysaccharide fraction (F1) of Curcuma longa (NR-INF-02) in classical rodent models of inflammation. F1 was evaluated for its acute oral toxicity and found to be safe upto 5000 mg/kg body weight in rats. The anti-inflammatory activity of F1 was evaluated in acute (carrageenan - induced paw edema; xylene - induced ear edema) and chronic (cotton pellet - induced granuloma) models of inflammation. The results of the study demonstrated that F1 significantly (p ≤ 0.05) inhibited carrageenan-induced paw edema at 1 h and 3 h at doses of 11.25, 22.5 and 45 mg/kg body weight in rats. Also, F1 at doses of 15.75, 31.5 and 63 mg/kg significantly inhibited the xylene induced ear edema in mice. In a chronic model, F1 at 11.25, 22.5 and 45 mg/kg doses produced significant reduction of wet and dry weights of cotton pellets in rats. Overall results indicated that F1 of NR-INF-02 significantly attenuated acute and chronic inflammation in rodent models. This study emphasizes on the importance of Curcuma longa polysaccharide's role in acute and chronic inflammation.

Anti-Inflammatory Activity of Polysaccharide Fraction of Curcuma longa Extract (NR-INF-02).

PubMed

Illuri, Ramanaiah; Bethapudi, Bharathi; Anandakumar, Senthilkumar; Murugan, Sasikumar; Joseph, Joshua A; Mundkinajeddu, Deepak; Agarwal, Amit; Chandrasekaran, C V

2015-01-01

The aim of the study was to investigate the safety and anti-inflammatory effects of polysaccharide fraction (F1) of Curcuma longa extract (NR-INF-02) in classical rodent models of inflammation. F1 was evaluated for its acute oral toxicity and found to be safe upto 5000 mg/kg body weight in rats. The anti-inflammatory activity of F1 was evaluated in acute (carrageenan - induced paw edema; xylene - induced ear edema) and chronic (cotton pellet - induced granuloma) models of inflammation. The results of the study demonstrated that F1 significantly (p ≤ 0.05) inhibited carrageenan-induced paw edema at 1 h and 3 h at doses of 11.25, 22.5 and 45 mg/kg body weight in rats. Also, F1 at doses of 15.75, 31.5 and 63 mg/kg significantly inhibited the xylene induced ear edema in mice. In a chronic model, F1 at 11.25, 22.5 and 45 mg/kg doses produced significant reduction of wet and dry weights of cotton pellets in rats. Overall results indicated that F1 of NR-INF-02 significantly attenuated acute and chronic inflammation in rodent models. This study emphasizes on the importance of Curcuma longa polysaccharide's role in acute and chronic inflammation.

Technical Note: Enhancing the surface dose using a weak longitudinal magnetic field

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

Carlone, Marco, E-mail: marco.carlone@rmp.uhn.on.ca; Keller, Harald; Rezaee, Mohammad

2016-06-15

Purpose: The surface dose in radiotherapy is subject to the physical properties of the radiation beam and collimator. The purpose of this work is to investigate the manipulation of surface dose using magnetic fields produced with a resistive magnet. Better understanding of the feasibility and mechanisms of altered surface dose could have important clinical applications where the surface dose must be increased for therapeutic goals, or reduced to enhance the therapeutic benefit. Methods: A resistive magnet capable of generating a peak magnetic field up to 0.24 T was integrated with a cobalt treatment unit. The magnetic fringe field of themore » magnet was small due to the self-shielding built within the magnet. The magnetic field at the beam collimation jaws of the cobalt irradiator was less than 10 G. The surface dose and depth dose were measured for varying magnetic field strengths. Results: The resistive magnet was able to alter the dose in the buildup region of the {sup 60}Co depth dose significantly, and the magnitude of dose enhancement was directly related to the strength of the longitudinal magnetic field. Peak magnetic fields as low as 0.08 T were able to affect the surface dose. At a peak field of 0.24 T, the authors measured a surface dose enhancement of 2.8-fold. Conclusions: Surface dose enhancement using resistive magnets is feasible. Further experimental study is needed to understand the origin of the scattered electrons that contribute to the increase in surface dose.« less

Altered brain serotonergic neurotransmission following caffeine withdrawal produces behavioral deficits in rats.

PubMed

Khaliq, Saima; Haider, Saida; Naqvi, Faizan; Perveen, Tahira; Saleem, Sadia; Haleem, Darakhshan Jabeen

2012-01-01

Caffeine administration has been shown to enhance performance and memory in rodents and humans while its withdrawal on the other hand produces neurobehavioral deficits which are thought to be mediated by alterations in monoamines neurotransmission. A role of decreased brain 5-HT (5-hydroxytryptamine, serotonin) levels has been implicated in impaired cognitive performance and depression. Memory functions of rats were assessed by Water Maze (WM) and immobility time by Forced Swim Test (FST). The results of this study showed that repeated caffeine administration for 6 days at 30 mg/kg dose significantly increases brain 5-HT (p<0.05) and 5-HIAA (p<0.05) levels and its withdrawal significantly (p<0.05) decreased brain 5-HT levels. A significant decrease in latency time was exhibited by rats in the WM repeatedly injected with caffeine. Withdrawal of caffeine however produced memory deficits and significantly increases the immobility time of rats in FST. The results of this study are linked with caffeine induced alterations in serotonergic neurotransmission and its role in memory and depression.

Improved Pharmacokinetics of Sumatriptan With Breath Powered™ Nasal Delivery of Sumatriptan Powder

PubMed Central

Obaidi, Mohammad; Offman, Elliot; Messina, John; Carothers, Jennifer; Djupesland, Per G; Mahmoud, Ramy A

2013-01-01

Objectives.— The purpose of this study was to directly compare the pharmacokinetic (PK) profile of 22-mg sumatriptan powder delivered intranasally with a novel Breath Powered™ device (11 mg in each nostril) vs a 20-mg sumatriptan liquid nasal spray, a 100-mg oral tablet, and a 6-mg subcutaneous injection. Background.— A prior PK study found that low doses of sumatriptan powder delivered intranasally with a Breath Powered device were efficiently and rapidly absorbed. An early phase clinical trial with the same device and doses found excellent tolerability with high response rates and rapid onset of pain relief, approaching the benefits of injection despite significantly lower predicted drug levels. Methods.— An open-label, cross-over, comparative bioavailability study was conducted in 20 healthy subjects at a single center in the USA. Following randomization, fasted subjects received a single dose of each of the 4 treatments separated by a 7-day washout. Blood samples were taken pre-dose and serially over 14 hours post-dose for PK analysis. Results.— Quantitative measurement of residuals in used Breath Powered devices demonstrated that the devices delivered 8 ± 0.9 mg (mean ± standard deviation) of sumatriptan powder in each nostril (total dose 16 mg). Although the extent of systemic exposure over 14 hours was similar following Breath Powered delivery of 16-mg sumatriptan powder and 20-mg liquid nasal spray (area under the curve [AUC]0-∞ 64.9 ng*hour/mL vs 61.1 ng*hour/mL), sumatriptan powder, despite a 20% lower dose, produced 27% higher peak exposure (Cmax 20.8 ng/mL vs 16.4 ng/mL) and 61% higher exposure in the first 30 minutes compared with the nasal spray (AUC0-30 minutes 5.8 ng*hour/mL vs 3.6 ng*hour/mL). The magnitude of difference is larger on a per-milligram basis. The absorption profile following standard nasal spray demonstrated bimodal peaks, consistent with lower early followed by higher later absorptions. In contrast, the profile following Breath Powered delivery showed higher early and lower late absorptions. Relative to the 100-mg oral tablet (Cmax 70.2 ng/mL, AUC0-∞, 308.8 ng*hour/mL) and 6-mg injection (Cmax 111.6 ng/mL, AUC0-∞ 128.2 ng*hour/mL), the peak and overall exposure following Breath Powered intranasal delivery of sumatriptan powder was substantially lower. Conclusions.— Breath Powered intranasal delivery of sumatriptan powder is a more efficient form of drug delivery, producing a higher peak and earlier exposure with a lower delivered dose than nasal spray and faster absorption than either nasal spray or oral administration. It also produces a significantly lower peak and total systemic exposure than oral tablet or subcutaneous injection. PMID:23992438

A method to estimate the effect of deformable image registration uncertainties on daily dose mapping

PubMed Central

Murphy, Martin J.; Salguero, Francisco J.; Siebers, Jeffrey V.; Staub, David; Vaman, Constantin

2012-01-01

Purpose: To develop a statistical sampling procedure for spatially-correlated uncertainties in deformable image registration and then use it to demonstrate their effect on daily dose mapping. Methods: Sequential daily CT studies are acquired to map anatomical variations prior to fractionated external beam radiotherapy. The CTs are deformably registered to the planning CT to obtain displacement vector fields (DVFs). The DVFs are used to accumulate the dose delivered each day onto the planning CT. Each DVF has spatially-correlated uncertainties associated with it. Principal components analysis (PCA) is applied to measured DVF error maps to produce decorrelated principal component modes of the errors. The modes are sampled independently and reconstructed to produce synthetic registration error maps. The synthetic error maps are convolved with dose mapped via deformable registration to model the resulting uncertainty in the dose mapping. The results are compared to the dose mapping uncertainty that would result from uncorrelated DVF errors that vary randomly from voxel to voxel. Results: The error sampling method is shown to produce synthetic DVF error maps that are statistically indistinguishable from the observed error maps. Spatially-correlated DVF uncertainties modeled by our procedure produce patterns of dose mapping error that are different from that due to randomly distributed uncertainties. Conclusions: Deformable image registration uncertainties have complex spatial distributions. The authors have developed and tested a method to decorrelate the spatial uncertainties and make statistical samples of highly correlated error maps. The sample error maps can be used to investigate the effect of DVF uncertainties on daily dose mapping via deformable image registration. An initial demonstration of this methodology shows that dose mapping uncertainties can be sensitive to spatial patterns in the DVF uncertainties. PMID:22320766

Presence of Siloxanes in the Biogas of a Wastewater Treatment Plant Separation in Condensates and Influence of the Dose of Iron Chloride on its Elimination

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

Mariano, García; Daniel, Prats; Arturo, Trapote, E-mail: atj@ua.es

2015-12-21

The siloxanes present in the biogas produced during anaerobic digestion damage the mechanism of cogeneration equipment and, consequently, negatively affect the energy valorization process. For this reason, the detection and elimination of these silicon-derived chemical compounds are a priority in the management of cogeneration facilities. In this regard, the objectives of this paper are, firstly, to characterize the siloxanes in the biogas and, secondly, to qualitatively evaluate the influence of the dose of iron chloride on its elimination. The research was performed at the Rincón de León Wastewater Treatment Plant (Alicante, Spain). The outflow biogas of the digesters and ofmore » the pressurized gasometers was sampled and analyzed. The results obtained made it possible to demonstrate, firstly, the absence of linear siloxanes and that, of the cyclic siloxanes, the predominant type was decamethylcyclopentasiloxane, and, secondly, that the addition of iron chloride in the digesters significantly reduces the siloxane content in the biogas. Additionally, it was demonstrated that the process of compression of the biogas, with the elimination of condensates, also produces significant reductions in the concentration of siloxanes in the biogas.« less

Evaluation of the antinociceptive activity of extracts of Sonchus oleraceus L. in mice.

PubMed

Vilela, Fabiana Cardoso; de Mesquita Padilha, Marina; Dos Santos-E-Silva, Lucas; Alves-da-Silva, Geraldo; Giusti-Paiva, Alexandre

2009-07-15

Sonchus oleraceus L. has been used to relieve pain in Brazilian folk medicine. Sonchus oleraceus L. has been used to relieve pain in Brazilian folk medicine. This study was conducted to establish the antinociceptive properties of hydroethanolic and dichloromethane extracts from aerial parts of Sonchus oleraceus in mice using chemical and thermal models of nociception. The formalin, hot plate, and tail immersion tests as well as acetic acid-induced writhing were used to investigate the antinociceptive activity in mice. Given orally, the extracts at test doses of 30-300 mg/kg, produced significant inhibitions on chemical nociception induced by intraperitoneal acetic acid and subplantar formalin since decreased the number of writhing episodes and the time licking. Treatment with the extracts in the same doses produced a significant increase of the reaction time in tail immersion and in the hot plate test. The extracts administered at 300 mg/kg, p.o. had a stronger antinociceptive effect than indomethacin (5mg/kg, p.o.) and morphine (10mg/kg, p.o.). The extracts of Sonchus oleraceus markedly demonstrated antinociceptive action in mice, which supports previous claims of its traditional use.

Oral challenges with four apple cultivars result in significant differences in oral allergy symptoms.

PubMed

Nybom, Hilde; Cervin-Hoberg, Charlotte; Andersson, Morgan

2013-01-01

We analyzed the hypoallergenic potential of a recently bred apple selection with unusually low content of Mal d 1, using an oral challenge model with three additional apple cultivars for comparison. Sixty-six birch pollen-allergic individuals with a history of oral allergy syndrome after apple intake were subjected to a double-blind oral provocation with two apple cultivars (B:0654 and 'Discovery'). Thirteen also tested two other apple cultivars ('Ingrid Marie' and 'Gloster'). Three doses were given consecutively, 30 min apart: 10 g without peel, and 10 and 50 g with peel. A final assessment was conducted 30 min after the last intake. Oral symptoms were graded from 0 to 5. Total oral symptom score (TOS) included all scores for each cultivar at all time points. B:0654 induced significantly higher TOS than 'Discovery' when tested by 66 individuals, in spite of its lower Mal d 1 content. TOS values were higher in females and increased with increasing age of the individuals when challenged with 'Discovery'. Among the 13 individuals who tested all four cultivars, B:0654 produced a higher score after the second dose compared to 'Ingrid Marie'. This was also the case after the third dose compared to 'Ingrid Marie' and 'Gloster', and again 30 min after the last intake compared to each of the other three cultivars, as well as a higher TOS compared to each of the other three cultivars (all p < 0.01). Our test was safe and well tolerated, and produced significant differences among the apple cultivars. Contrary to expectations, B:0654 was less well tolerated than the other three cultivars. Copyright © 2013 S. Karger AG, Basel.

Transverse changes determined by rapid and slow maxillary expansion--a low-dose CT-based randomized controlled trial.

PubMed

Martina, R; Cioffi, I; Farella, M; Leone, P; Manzo, P; Matarese, G; Portelli, M; Nucera, R; Cordasco, G

2012-08-01

To compare transverse skeletal changes produced by rapid (RME) and slow (SME) maxillary expansion using low-dose computed tomography. The null hypothesis was that SME and RME are equally effective in producing skeletal maxillary expansion in patients with posterior crossbite. This study was carried out at the Department of Oral Sciences, University of Naples Federico II, Italy. Twelve patients (seven males, five females, mean age ± SD: 10.3 ± 2.5 years) were allocated to the SME group and 14 patients (six males, eight females, mean age ± SD: 9.7 ± 1.5 years) to the RME group. All patients received a two-band palatal expander and were randomly allocated to either RME or SME. Low-dose computed tomography was used to identify skeletal and dental landmarks and to measure transverse maxillary changes with treatment. A significant increase in skeletal transverse diameters was found in both SME and RME groups (anterior expansion = 2.2 ± 1.4 mm, posterior expansion = 2.2 ± 0.9 mm, pterygoid expansion = 0.9 ± 0.8 mm). No significant differences were found between groups at anterior (SME = 1.9 ± 1.3 mm; RME = 2.5 ± 1.5 mm) or posterior (SME = 1.9 ± 1.0 mm; RME = 2.4 ± 0.9 mm) locations, while a statistically significant difference was measured at the pterygoid processes (SME = 0.6 ± 0.6 mm; RME = 1.2 ± 0.9 mm, p = 0.04), which was not clinically relevant. Rapid maxillary expansion is not more effective than SME in expanding the maxilla in patients with posterior crossbite. © 2012 John Wiley & Sons A/S.

Anxiolytic, antidepressant, and antistress activities of the aqueous extract of Cinnamomum tamala Nees and Eberm in rats

PubMed Central

Upadhyay, Gayaprasad; Khoshla, Sarvesh; Kosuru, Ramoji; Singh, Sanjay

2016-01-01

Objective: The current study was designed to explore anxiolytic, antidepressant, and antistress actions of Cinnamomum tamala (CT) leaves (aqueous extract) in rats. Materials and Methods: Behavioral procedures of anxiety, depression, and stress were assessed in rats. CT (100, 200, and 400 mg/kg) was given once a daily for 7 days via oral route and the efficacy was matched by those elicited by lorazepam (1 mg/kg, p.o.), imipramine (10 mg/kg, p.o.), and Withania somnifera (100 mg/kg, p.o.) for anxiolytic, antidepressant, and antistress studies, respectively. Standard drugs were given 1 time, 30 min preceding the behavioral trials. Results: One-way analysis of variance followed by Newman–Keuls multiple comparison test was employed to analyze the results. P < 0.05 was considered statistically significant as compared to control. CT at 400 mg/kg produced an antianxiety effect equivalent to lorazepam, in the elevated plus maze, open field, and social interaction tests among selected doses of the CT. CT at 400 mg/kg also induced an antidepressant activity similar to imipramine, in the behavioral despair, learned helplessness test, and tail suspension among selected doses of the CT. Moreover, CT at 400 mg/kg produced a significant antistress effect comparable to W. somnifera in water immersion-restraint stress by decreasing ulcer index, adrenal gland weight, and by normalizing the plasma levels of corticosterone, glucose, cholesterol, and triglyceride levels when related to stress control. Conclusion: The study shows that among the different CT doses, CT at 400 mg/kg possesses significant anxiolytic, antidepressant, and anti-stress effects and has therapeutic beneficial for the management of psychological ailments. PMID:27721543

Protective effect of D-002, a mixture of beeswax alcohols, against indomethacin-induced gastric ulcers and mechanism of action.

PubMed

Pérez, Yohani; Oyárzabal, Ambar; Mas, Rosa; Molina, Vivian; Jiménez, Sonia

2013-01-01

D-002, a mixture of higher aliphatic beeswax alcohols, produces gastroprotective and antioxidant effects. To investigate the gastroprotective effect of D-002 against indomethacin-induced ulcers, oxidative variables and myeloperoxidase (MPO) activity in the rat gastric mucosa were examined. Rats were randomized into six groups: a negative vehicle control and five indomethacin (50 mg/kg) treated groups, comprising a positive control, three groups treated orally with D-002 (5, 25 and 100 mg/kg) and one group with omeprazole 20 mg/kg intraperitoneally (ip). The contents of malondialdehyde (MDA), protein carbonyl groups (PCG), hydroxyl radical generation and catalase (CAT), glutathione peroxidase (GSH-PX), superoxide dismutase (SOD) and MPO enzyme activities in the rat gastric mucosa were assessed. Indomethacin increased the content of MDA and PCG, the generation of *OH radical and MPO enzyme activity, while it decreased the CAT, GSH-PX and SOD activities as compared to the negative controls. D-002 (5-100 mg/kg) significantly and dose-dependently reduced indomethacin-induced ulceration to 75 %. Also, D-002 decreased the content of MDA and PCG, the generation of hydroxyl radicals and MPO activity as compared to the positive controls. The highest dose of D-002 (100 mg/kg) increased significantly GSH-PX and SOD activities, while all doses used increased CAT activities. Omeprazole 20 mg/kg, the reference drug, reduced significantly the ulcers (93 %), MDA and PCG, the generation of hydroxyl radicals and MPO activity, and increased the CAT, GSH-PX and SOD activities. D-002 treatment produced gastroprotective effects against indomethacin-induced gastric ulceration, which can be related to the reduction of hydroxyl radical generation, lipid peroxidation, protein oxidation and MPO activity, and to the increase of the antioxidant enzymes activities in the rat gastric mucosa.

Effect of cannabinoids on lithium-induced vomiting in the Suncus murinus (house musk shrew).

PubMed

Parker, Linda A; Kwiatkowska, Magdalena; Burton, Page; Mechoulam, Raphael

2004-01-01

Marijuana has been reported to interfere with nausea and vomiting in chemotherapy patients. The principal cannabinoids found in marijuana include the psychoactive compound Delta-9-tetrahydrocannabinol (THC) and the non-psychoactive compound cannabidiol (CBD). The experiments reported here evaluated the potential of THC and CBD to interfere with vomiting in the Suncus murinus (house musk shrew) produced by lithium chloride (LiCl), which is the most commonly employed unconditioned stimulus for taste avoidance. To evaluate the potential of the principal components of marijuana, THC and CBD, to suppress Li-induced vomiting in the house musk shrew. Shrews were injected with vehicle or one of two cannabinoids [Delta-9-THC (1-20 mg/kg), or CBD (2.5-40 mg/kg)] 10 min prior to an injection of LiCl (390 mg/kg of 0.15 M) and were then observed for 45 min. The frequency of vomiting episodes and the latency to the first episode were measured. The role of the CB1 receptor in these effects was also evaluated by pretreatment with SR-141716. Delta-9-THC produced a dose-dependent suppression of Li-induced vomiting, with higher doses producing greater suppression than lower doses. CBD produced a biphasic effect with lower doses producing suppression and higher doses producing enhancement of Li-induced vomiting. The suppression of Li-induced vomiting by THC, but not by CBD, was reversed by SR-141716. These results indicate that two major cannabinoid compounds found in marijuana, THC and CBD, are effective treatments for Li-induced vomiting; however, only THC acts by the CB1 receptor. The effects of THC and CBD on vomiting were dose dependent; with THC the effect was linear, but with CBD the effect was biphasic.

Pharmacological aspects of metaldehyde poisoning in mice.

PubMed

Homeida, A M; Cooke, R G

1982-03-01

Metaldehyde, when administered orally to mice at a dose of 1 g kg-1, produced convulsions and death within 2 h. Brain concentrations of noradrenaline (NA) 5-hydroxytryptamie (5-HT) and 5-hydroxyindoleacetic acid (5-HIAA) were significantly reduced in these animals relative to controls. Treatment with either intraperitoneal clonidine or diazepam 20 min after administration of metaldehyde reduced the mortality rate and in mice surviving for 5 h, the decrease in brain NA and 5-HT concentrations were significantly reduced.

UTILIZATION OF THE LEAST SHREW AS A RAPID AND SELECTIVE SCREENING MODEL FOR THE ANTIEMETIC POTENTIAL AND BRAIN PENETRATION OF SUBSTANCE P AND NK1 RECEPTOR ANTAGONISTS

PubMed Central

Darmani, Nissar A.; Wang, Yaozhi; Abad, Joseph; Ray, Andrew P.; Thrush, Gerald R.; Ramirez, Juan

2008-01-01

Substance P (SP) is thought to play a cardinal role in emesis via the activation of central tachykinin NK1 receptors during the delayed phase of vomiting produced by chemotherapeutics. Although the existing supportive evidence is significant, due to lack of an appropriate animal model, the evidence is indirect. As yet, no study has confirmed that emesis produced by SP or a selective NK1 receptor agonist is sensitive to brain penetrating antagonists of either NK1, NK2, or NK3 receptors. The goals of this investigation were to demonstrate: 1) whether intraperitoneal (i.p.) administration of either SP, a brain penetrating (GR73632) or non-penetrating (e.g. SarMet – SP) NK1 receptor agonist, an NK2 receptor agonist (GR64349), or an NK3 receptor agonist (Pro7-NKB), would induce vomiting and/or scratching in the least shrew (Cryptotis parva) in a dose-dependent manner; and whether these effects are sensitive to the above selective receptor antagonists; 2) whether an exogenous emetic dose of SP (50 mg/kg, i.p.) can penetrate into the shrew brain stem and frontal cortex; 3) whether GR73632 (2.5 mg/kg, i.p.)-induced activation of NK1 receptors increases Fos-measured neuronal activity in the neurons of both brain stem emetic nuclei and the enteric nervous system of the gut; and 4) whether selective ablation of peripheral NK1 receptors can affect emesis produced by GR73632. The results clearly demonstrated that while SP produced vomiting only, GR73632 caused both emesis and scratching behavior dose-dependently in shrews, and these effects were sensitive to NK1-, but not NK2- or NK3-receptor antagonists. Neither the selective, non-penetrating NK1 receptor agonists, nor the selective NK2- or NK3-receptor agonists, caused a significant dose-dependent behavioral effect. An emetic dose of SP selectively and rapidly penetrated the brain stem but not the frontal cortex. Systemic GR73632 increased Fos expression in the enteric nerve plexi, the medial subnucleus of nucleus tractus solitarius, and the dorsal motor nucleus of the vagus, but not the area postrema. Ablation of peripheral NK1 receptors attenuated the ability of GR73632 to induce a maximal frequency of emesis and shifted its percent animals vomiting dose-response curve to the right. The NK1-ablated shrews exhibited scratching behavior after systemic GR73632-injection. These results, for the first time, affirm a cardinal role for central NK1 receptors in SP-induced vomiting, and a facilitatory role for gastrointestinal NK1 receptors. In addition, these data support the validation of the least shrew as a specific and rapid behavioral animal model to screen concomitantly both the CNS penetration and the antiemetic potential of tachykinin NK1 receptor antagonists. PMID:18471804

Radiation preservation of meat and meat products: A review.

PubMed

Dempster, J F

1985-01-01

The World Health Organisation (WHO) in 1980 clarified the position regarding the medical acceptability of irradiated foods when it said'…no health hazard results from consuming any food irradiated up to a dose of one megarad (1 Mrad)'. This resulted in renewed interest in irradiation as a cost-effective alternative to traditional preservation methods such as canning and freezing. Thus, radurisation (the application of ionising radiation at a dose level which substantially reduces the microbial population) increases the shelf life of poultry, comminuted meat and meat dishes significantly. Low dose irradiation, or radicidation, eliminates parasites such as Trichinae and cysticerci in pork and, very importantly, salmonella organisms in poultry and red meat. Therefore, irradiation has an important rôle to play in public health protection. High dose irradiation, or radappertisation ('cold sterilisation'), uses doses in excess of 1 Mrad and is analogous to retorting as understood in the canning industry. However, it can adversely affect quality in producing 'free radicals' in high protein foods such as meat. To prevent this, special precautions are necessary, e.g. irradiation is conducted at very low temperatures and the product is usually vacuum packed. A further potential use of irradiation is its ability to reduce the quantity of nitrite necessary in cured meats. This may become of practical significance if legislation further reduces the amount of nitrite permitted in these products. Copyright © 1985. Published by Elsevier Ltd.

Effect of Reduced Tube Voltage on Diagnostic Accuracy of CT Colonography.

PubMed

Futamata, Yoshihiro; Koide, Tomoaki; Ihara, Riku

2017-01-01

The normal tube voltage in computed tomography colonography (CTC) is 120 kV. Some reports indicate that the use of a low tube voltage (lower than 120 kV) technique plays a significant role in reduction of radiation dose. However, to determine whether a lower tube voltage can reduce radiation dose without compromising diagnostic accuracy, an evaluation of images that are obtained while maintaining the volume CT dose index (CTDI vol ) is required. This study investigated the effect of reduced tube voltage in CTC, without modifying radiation dose (i.e. constant CTDI vol ), on image quality. Evaluation of image quality involved the shape of the noise power spectrum, surface profiling with volume rendering (VR), and receiver operating characteristic (ROC) analysis. The shape of the noise power spectrum obtained with a tube voltage of 80 kV and 100 kV was not similar to the one produced with a tube voltage of 120 kV. Moreover, a higher standard deviation was observed on volume-rendered images that were generated using the reduced tube voltages. In addition, ROC analysis revealed a statistically significant drop in diagnostic accuracy with reduced tube voltage, revealing that the modification of tube voltage affects volume-rendered images. The results of this study suggest that reduction of tube voltage in CTC, so as to reduce radiation dose, affects image quality and diagnostic accuracy.

(1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115), a potent γ-aminobutyric acid aminotransferase inactivator for the treatment of cocaine addiction.

PubMed

Pan, Yue; Gerasimov, Madina R; Kvist, Trine; Wellendorph, Petrine; Madsen, Karsten K; Pera, Elena; Lee, Hyunbeom; Schousboe, Arne; Chebib, Mary; Bräuner-Osborne, Hans; Craft, Cheryl M; Brodie, Jonathan D; Schiffer, Wynne K; Dewey, Stephen L; Miller, Steven R; Silverman, Richard B

2012-01-12

Vigabatrin, a GABA aminotransferase (GABA-AT) inactivator, is used to treat infantile spasms and refractory complex partial seizures and is in clinical trials to treat addiction. We evaluated a novel GABA-AT inactivator (1S, 3S)-3-amino-4-difluoromethylenyl-1-cyclopentanoic acid (CPP-115, compound 1) and observed that it does not exhibit other GABAergic or off-target activities and is rapidly and completely orally absorbed and eliminated. By use of in vivo microdialysis techniques in freely moving rats and microPET imaging techniques, 1 produced similar inhibition of cocaine-induced increases in extracellular dopamine and in synaptic dopamine in the nucleus accumbens at (1)/(300) to (1)/(600) the dose of vigabatrin. It also blocks expression of cocaine-induced conditioned place preference at a dose (1)/(300) that of vigabatrin. Electroretinographic (ERG) responses in rats treated with 1, at doses 20-40 times higher than those needed to treat addiction in rats, exhibited reductions in ERG responses, which were less than the reductions observed in rats treated with vigabatrin at the same dose needed to treat addiction in rats. In conclusion, 1 can be administered at significantly lower doses than vigabatrin, which suggests a potential new treatment for addiction with a significantly reduced risk of visual field defects.

Longitudinal trends of total white blood cell and differential white blood cell counts of atomic bomb survivors.

PubMed

Hsu, Wan-Ling; Tatsukawa, Yoshimi; Neriishi, Kazuo; Yamada, Michiko; Cologne, John; Fujiwara, Saeko

2010-01-01

In studying the late health effects of atomic-bomb (A-bomb) survivors, earlier findings were that white blood cell (WBC) count increased with radiation dose in cross-sectional studies. However, a persistent effect of radiation on WBC count and other risk factors has yet to be confirmed. The objectives of the present study were 1) to examine the longitudinal relationship between A-bomb radiation dose and WBC and differential WBC counts among A-bomb survivors and 2) to investigate the potential confounding risk factors (such as age at exposure and smoking status) as well as modification of the radiation dose-response. A total of 7,562 A-bomb survivors in Hiroshima and Nagasaki were included in this study from 1964-2004. A linear mixed model was applied using the repeated WBC measurements. During the study period, a secular downward trend of WBC count was observed. Radiation exposure was a significant risk factor for elevated WBC and differential WBC counts over time. A significant increase of WBC counts among survivors with high radiation dose (> 2 Gy) was detected in men exposed below the age of 20 and in women regardless of age at exposure. Effects on WBC of low dose radiation remain unclear, however. Cigarette smoking produced the most pronounced effect on WBC counts and its impact was much larger than that of radiation exposure.

The effect of irradiation in the quality of the avocado frozen pulp

NASA Astrophysics Data System (ADS)

Valdivia, Ma. Ángeles; Bustos, Ma. Emilia; Ruiz, Javier; Ruiz, Luisa F.

2002-03-01

The quality of frozen avocado pulp irradiated with 60Co gamma rays at doses of: 0.5, 1.0, 1.5, and 2.5 kGy, was studied. These are possible doses for reducing the content of bacteria Listeria monocytogenes by 1-4 log cycles. The study principally consisted of weekly evaluations of damages caused in lipids and chlorophyll pigment over a period of one year. No significant differences were found in either hydrolysis rancidity or in the oxidative rancidity for any of the doses. The concentrations of fatty acids and peroxides were below those established by Codex Alimentarius. This means that the quality of the oil in the frozen avocado pulp remains acceptable. The kinetic model for the oxidative rancidity is of first order and the shelf life of the product is of about 120 weeks. The concentrations of the fatty acids and of malondialdehyde were not high enough to produce off-flavors. It was also determined that the radiation doses did not influence the chemistry of the chlorophyll. The results were confirmed by the panelists, who accepted irradiated frozen pulp at the highest radiation dose.

Evaluating the potential of gold, silver, and silica nanoparticles to saturate mononuclear phagocytic system tissues under repeat dosing conditions.

PubMed

Weaver, James L; Tobin, Grainne A; Ingle, Taylor; Bancos, Simona; Stevens, David; Rouse, Rodney; Howard, Kristina E; Goodwin, David; Knapton, Alan; Li, Xiaohong; Shea, Katherine; Stewart, Sharron; Xu, Lin; Goering, Peter L; Zhang, Qin; Howard, Paul C; Collins, Jessie; Khan, Saeed; Sung, Kidon; Tyner, Katherine M

2017-07-17

As nanoparticles (NPs) become more prevalent in the pharmaceutical industry, questions have arisen from both industry and regulatory stakeholders about the long term effects of these materials. This study was designed to evaluate whether gold (10 nm), silver (50 nm), or silica (10 nm) nanoparticles administered intravenously to mice for up to 8 weeks at doses known to be sub-toxic (non-toxic at single acute or repeat dosing levels) and clinically relevant could produce significant bioaccumulation in liver and spleen macrophages. Repeated dosing with gold, silver, and silica nanoparticles did not saturate bioaccumulation in liver or spleen macrophages. While no toxicity was observed with gold and silver nanoparticles throughout the 8 week experiment, some effects including histopathological and serum chemistry changes were observed with silica nanoparticles starting at week 3. No major changes in the splenocyte population were observed during the study for any of the nanoparticles tested. The clinical impact of these changes is unclear but suggests that the mononuclear phagocytic system is able to handle repeated doses of nanoparticles.

Feasibility of the Utilization of BNCT in the Fast Neutron Therapy Beam at Fermilab

DOE R&D Accomplishments Database

Langen, Katja; Lennox, Arlene J.; Kroc, Thomas K.; DeLuca, Jr., Paul M.

2000-06-01

The Neutron Therapy Facility at Fermilab has treated cancer patients since 1976. Since then more than 2,300 patients have been treated and a wealth of clinical information accumulated. The therapeutic neutron beam at Fermilab is produced by bombarding a beryllium target with 66 MeV protons. The resulting continuous neutron spectrum ranges from thermal to 66 MeV in neutron energy. It is clear that this spectrum is not well suited for the treatment of tumors with boron neutron capture therapy (BNCT) only However, since this spectrum contains thermal and epithermal components the authors are investigating whether BNCT can be used in this beam to boost the tumor dose. There are clinical scenarios in which a selective tumor dose boost of 10 - 15% could be clinically significant. For these cases the principal treatment would still be fast neutron therapy but a tumor boost could be used either to deliver a higher dose to the tumor tissue or to reduce the dose to the normal healthy tissue while maintaining the absorbed dose level in the tumor tissue.

Subjective and physiological effects, and expired carbon monoxide concentrations in frequent and occasional cannabis smokers following smoked, vaporized, and oral cannabis administration.

PubMed

Newmeyer, Matthew N; Swortwood, Madeleine J; Abulseoud, Osama A; Huestis, Marilyn A

2017-06-01

Although smoking is the most common cannabis administration route, vaporization and consumption of cannabis edibles are common. Few studies directly compare cannabis' subjective and physiological effects following multiple administration routes. Subjective and physiological effects, and expired carbon monoxide (CO) were evaluated in frequent and occasional cannabis users following placebo (0.001% Δ 9 -tetrahydrocannabinol [THC]), smoked, vaporized, and oral cannabis (6.9% THC, ∼54mg). Participants' subjective ratings were significantly elevated compared to placebo after smoking and vaporization, while only occasional smokers' ratings were significantly elevated compared to placebo after oral dosing. Frequent smokers' maximum ratings were significantly different between inhaled and oral routes, while no differences in occasional smokers' maximum ratings between active routes were observed. Additionally, heart rate increases above baseline 0.5h after smoking (mean 12.2bpm) and vaporization (10.7bpm), and at 1.5h (13.0bpm) and 3h (10.2bpm) after oral dosing were significantly greater than changes after placebo, with no differences between frequent and occasional smokers. Finally, smoking produced significantly increased expired CO concentrations 0.25-6h post-dose compared to vaporization. All participants had significant elevations in subjective effects after smoking and vaporization, but only occasional smokers after oral cannabis, indicating partial tolerance to subjective effects with frequent exposure. There were no differences in occasional smokers' maximum subjective ratings across the three active administration routes. Vaporized cannabis is an attractive alternative for medicinal administrations over smoking or oral routes; effects occur quickly and doses can be titrated with minimal CO exposure. These results have strong implications for safety and abuse liability assessments. Published by Elsevier B.V.

A 90 day chronic toxicity study of Nigerian herbal preparation DAS-77 in rats

PubMed Central

2012-01-01

Background The herbal preparation DAS-77, used for the treatment of various ailments in Nigeria, contains the milled bark of Mangifera indica L. and root of Carica papaya L. Toxicological assessment of the preparation was carried out in this study. Methods In the acute toxicity study, DAS-77 was administered to mice p.o. up to 20 g/kg in divided doses and i.p. at 250–3000 mg/kg. Mortality within 24 h was recorded. In the chronic toxicity study, rats were treated p.o. for 90 days at doses of 80, 400 (therapeutic dose, TD) and 2000 mg/kg. By 90 days, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination, antioxidants and histopathological assessments. Results DAS-77 did not produce any lethality administered p.o. up to 20 g/kg in divided doses but the i.p. LD50 was 1122.0 mg/kg. At TD, DAS-77 produced significant (p < 0.05) reductions in body weight, food intake and K+, and increases in ovary weight, neutrophils and HDL, which were reversible. Histopathological presentations were generally normal. Effects at the other doses were comparable to those at TD except for reversible increases in antioxidants in the liver, kidney and testes, and sperm abnormality, and reductions in liver enzymes, sperm motility and count. Conclusions Findings in this study revealed that DAS-77 is relatively safe with the potential for enhancing in vivo antioxidant activity. However, possibly reversible side-effects include electrolyte imbalance and sterility in males. PMID:22892317

A 90 day chronic toxicity study of Nigerian herbal preparation DAS-77 in rats.

PubMed

Afolabi, Saheed O; Akindele, Abidemi J; Awodele, Olufunsho; Anunobi, Chidozie C; Adeyemi, Olufunmilayo O

2012-06-28

The herbal preparation DAS-77, used for the treatment of various ailments in Nigeria, contains the milled bark of Mangifera indica L. and root of Carica papaya L. Toxicological assessment of the preparation was carried out in this study. In the acute toxicity study, DAS-77 was administered to mice p.o. up to 20 g/kg in divided doses and i.p. at 250-3000 mg/kg. Mortality within 24 h was recorded. In the chronic toxicity study, rats were treated p.o. for 90 days at doses of 80, 400 (therapeutic dose, TD) and 2000 mg/kg. By 90 days, animals were sacrificed and blood samples collected for hematological and biochemical analysis. Organs were harvested for weight determination, antioxidants and histopathological assessments. DAS-77 did not produce any lethality administered p.o. up to 20 g/kg in divided doses but the i.p. LD50 was 1122.0 mg/kg. At TD, DAS-77 produced significant (p < 0.05) reductions in body weight, food intake and K+, and increases in ovary weight, neutrophils and HDL, which were reversible. Histopathological presentations were generally normal. Effects at the other doses were comparable to those at TD except for reversible increases in antioxidants in the liver, kidney and testes, and sperm abnormality, and reductions in liver enzymes, sperm motility and count. Findings in this study revealed that DAS-77 is relatively safe with the potential for enhancing in vivo antioxidant activity. However, possibly reversible side-effects include electrolyte imbalance and sterility in males.

Whole-brain hippocampal sparing radiation therapy: Volume-modulated arc therapy vs intensity-modulated radiation therapy case study

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

Lee, Katrina, E-mail: Trinabena23@gmail.com; Lenards, Nishele; Holson, Janice

The hippocampus is responsible for memory and cognitive function. An ongoing phase II clinical trial suggests that sparing dose to the hippocampus during whole-brain radiation therapy can help preserve a patient's neurocognitive function. Progressive research and advancements in treatment techniques have made treatment planning more sophisticated but beneficial for patients undergoing treatment. The aim of this study is to evaluate and compare hippocampal sparing whole-brain (HS-WB) radiation therapy treatment planning techniques using volume-modulated arc therapy (VMAT) and intensity-modulated radiation therapy (IMRT). We randomly selected 3 patients to compare different treatment techniques that could be used for reducing dose to themore » hippocampal region. We created 2 treatment plans, a VMAT and an IMRT, from each patient's data set and planned on the Eclipse 11.0 treatment planning system (TPS). A total of 6 plans (3 IMRT and 3 VMAT) were created and evaluated for this case study. The physician contoured the hippocampus as per the Radiation Therapy Oncology Group (RTOG) 0933 protocol atlas. The organs at risk (OR) were contoured and evaluated for the plan comparison, which included the spinal cord, optic chiasm, the right and left eyes, lenses, and optic nerves. Both treatment plans produced adequate coverage on the planning target volume (PTV) while significantly reducing dose to the hippocampal region. The VMAT treatment plans produced a more homogenous dose distribution throughout the PTV while decreasing the maximum point dose to the target. However, both treatment techniques demonstrated hippocampal sparing when irradiating the whole brain.« less

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

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

The effect of treatment strategy on stone comminution efficiency in shock wave lithotripsy.

PubMed

Zhou, Yufeng; Cocks, Franklin H; Preminger, Glenn M; Zhong, Pei

2004-07-01

The comminution of kidney stones in shock wave lithotripsy (SWL) is a dose dependent process caused primarily by the combination of 2 fundamental mechanisms, namely stress waves and cavitation. The effect of treatment strategy with emphasis on enhancing the effect of stress waves or cavitation on stone comminution in SWL was investigated. Because vascular injury in SWL is also dose dependent, optimization of the treatment strategy may produce improved stone comminution with decreased tissue injury in SWL. Using an in vitro experiment system that mimics stone fragmentation in the renal pelvis spherical BegoStone (Bego USA, Smithfield, Rhode Island) phantoms (diameter 10 mm) were exposed to 1,500 shocks at a pulse repetition rate of 1 Hz in an unmodified HM-3 lithotripter (Dornier Medical Systems, Kennesaw, Georgia). The 3 treatment strategies used were increasing output voltage from 18 to 20 and then to 22 kV every 500 shocks with emphasis on enhancing the effect of cavitation on medium fragments (2 to 4 mm) at the final treatment stage, decreasing output voltage from 22 to 20 and then to 18 kV every 500 shocks with emphasis on enhancing the effect of stress waves on large fragments (greater than 4 mm) at the initial treatment stage and maintaining a constant output voltage at 20 kV, as typically used in SWL procedures. Following shock wave exposure the size distribution of fragments was determined by the sequential sieving method. In addition, pressure waveforms at lithotripter focus (F2) produced at different output settings were measured using a fiber optic probe hydrophone. The rate of stone comminution in SWL varied significantly in a dose dependent manner depending on the treatment strategies used. Specifically the comminution efficiencies produced by the 3 strategies after the initial 500 shocks were 30.7%, 59% and 41.9%, respectively. After 1,000 shocks the corresponding comminution efficiencies became similar (60.2%, 68.1% and 66.4%, respectively) with no statistically significant differences (p = 0.08). After 1,500 shocks the final comminution efficiency produced by the first strategy was 88.7%, which was better than the corresponding values of 81.2% and 83.5%, respectively, for the other 2 strategies. The difference between the final comminution efficiency of the first and second strategies was statistically significant (p = 0.005). Progressive increase in lithotripter output voltage can produce the best overall stone comminution in vitro.

Energy deposition at the bone-tissue interface from nuclear fragments produced by high-energy nucleons

NASA Technical Reports Server (NTRS)

Cucinotta, Francis A.; Hajnal, Ferenc; Wilson, John W.

1990-01-01

The transport of nuclear fragmentation recoils produced by high-energy nucleons in the region of the bone-tissue interface is considered. Results for the different flux and absorbed dose for recoils produced by 1 GeV protons are presented in a bidirectional transport model. The energy deposition in marrow cavities is seen to be enhanced by recoils produced in bone. Approximate analytic formulae for absorbed dose near the interface region are also presented for a simplified range-energy model.

Effects of sibutramine alone and with alcohol on cognitive function in healthy volunteers

PubMed Central

Wesnes, K A; Garratt, C; Wickens, M; Gudgeon, A; Oliver, S

2000-01-01

Aims To investigate the effects of sibutramine in combination with alcohol in a double-blind, randomised, placebo-controlled, four-way crossover study in 20 healthy volunteers. Methods On each study day each volunteer received either: sibutramine 20 mg+0.5 g kg−1 alcohol; sibutramine 20 mg+placebo alcohol; placebo capsules+0.5 g kg−1 alcohol; or placebo capsules+placebo alcohol. Alcohol was administered 2 h following ingestion of the study capsules. During each study day, assessments of cognitive performance were made prior to dosing, and at 3, 4.5, 6 and 10 h post dosing. Blood alcohol concentration was estimated using a breath alcometer immediately prior to each cognitive performance test session. Each study day was followed by a minimum 7 day washout period. Results Alcohol was found to produce statistically significant impairments in tests of attention (maximum impairment to speed of digit vigilance=49 ms) and episodic memory (maximum impairment to speed of word recognition=74 ms). Alcohol also increased body sway (maximum increase 17.4 units) and lowered self rated alertness (maximum decrease 13.6 mm). These effects were produced by an inferred blood alcohol level of 53.2 mg dl−1.Sibutramine was not found to potentiate any of the effects of alcohol. There was a small, yet statistically significant, interaction effect observed on the sensitivity index of the picture recognition task. In this test, the combined effects of sibutramine and alcohol were smaller than the impairments produced by alcohol alone. Sibutramine, when dosed alone, was associated with improved performance on several tasks. Sibutramine improved attention (mean speed of digit vigilance improved by 21 ms), picture recognition speed (improvement at 3=81) and motor control (tracking error at 3 h reduced by 1.58 mm). Also sibutramine improved postural stability (reducing body sway at 3 h by 14.2 units). Adverse events reported were unremarkable and consistent with the known pharmacology of sibutramine and alcohol. Conclusions There was little evidence of a clinically relevant interaction of sibutramine with the impairment of cognitive function produced by alcohol in healthy volunteers. The single statistically significant interaction indicated a reduction, rather than a worsening, of alcohol-induced impairment when sibutramine is taken concomitantly. Sibutramine when administered alone is associated with improved performance on several tasks. PMID:10671904

Comparison of the Efficacy and Safety of 2 Acetaminophen Dosing Regimens in Febrile Infants and Children: A Report on 3 Legacy Studies.

PubMed

Temple, Anthony R; Zimmerman, Brenda; Gelotte, Cathy; Kuffner, Edwin K

2017-01-01

Compare efficacy and safety of 10 to 15 mg/kg with 20 to 30 mg/kg acetaminophen in febrile children 6 months to ≤ 11 years from 3 double-blind, randomized, single or multiple dose studies. Doses were compared on sum of the temperature differences (SUMDIFF), maximum temperature difference (MAXDIFF), temperature differences at each time point, and dose by time interactions. Alanine aminotransferase (ALT) was evaluated in the 72-hour duration study. A single dose of acetaminophen 20 to 30 mg/kg produced a greater effect on temperature decrement and duration of antipyretic effect over 8 hours than a single dose of 10 to 15 mg/kg. When equivalent total doses (i.e., 2 doses of 10 to 15 mg/kg given at 4-hour intervals and 1 dose of 20 to 30 mg/kg) were given over the initial 8-hour period, there were no significant temperature differences. Over a 72-hour period, 10 to 15 mg/kg acetaminophen administered every 4 hours maintained a more consistent temperature decrement than 20 to 30 mg/kg acetaminophen administered every 8 hours. Following doses of 60 to 90 mg/kg/day for up to 72 hours, no child had a clinically important increase in ALT from baseline. The number of children with reported adverse events was similar between doses. Data demonstrate the antipyretic effect of acetaminophen is dependent on total dose over a given time interval. These 3 studies provide clinical evidence that the recommended standard acetaminophen dose of 10 to 15 mg/kg is a safe and effective dose for treating fever in pediatric patients when administered as a single dose or as multiple doses for up to 72 hours.

Effect of DA-9701 on Colorectal Distension-Induced Visceral Hypersensitivity in a Rat Model

PubMed Central

Kim, Eun Ran; Min, Byung-Hoon; Lee, Tae Ho; Son, Miwon; Rhee, Poong-Lyul

2014-01-01

Background/Aims DA-9701 is a newly developed drug made from the vegetal extracts of Pharbitidis semen and Co-rydalis tuber. The aim of this study was to evaluate the effect of DA-9701 on colorectal distension (CRD)-induced visceral hypersensitivity in a rat model. Methods Male Sprague-Dawley rats were subjected to neonatal colon irritation (CI) using CRD at 1 week after birth (CI group). At 6 weeks after birth, CRD was applied to these rats with a pressure of 20 to 90 mm Hg, and changes in the mean arterial pressure (MAP) were measured at baseline (i.e., without any drug administration) and after the administration of different doses of DA-9701. Results In the absence of DA-9701, the MAP changes after CRD were significantly higher in the CI group than in the control group at all applied pressures. In the control group, MAP changes after CRD were not significantly affected by the administration of DA-9701. In the CI group, however, the administration of DA-9701 resulted in a significant decrease in MAP changes after CRD. The administration of DA-9701 at a dose of 1.0 mg/kg produced a more significant decrease in MAP changes than the 0.3 mg/kg dose. Conclusions The administration of DA-9701 resulted in a significant increase in pain threshold in rats with CRD-induced visceral hypersensitivity. PMID:25071903

Effect of DA-9701 on colorectal distension-induced visceral hypersensitivity in a rat model.

PubMed

Kim, Eun Ran; Min, Byung-Hoon; Lee, Tae Ho; Son, Miwon; Rhee, Poong-Lyul

2014-07-01

DA-9701 is a newly developed drug made from the vegetal extracts of Pharbitidis semen and Co-rydalis tuber. The aim of this study was to evaluate the effect of DA-9701 on colorectal distension (CRD)-induced visceral hypersensitivity in a rat model. Male Sprague-Dawley rats were subjected to neonatal colon irritation (CI) using CRD at 1 week after birth (CI group). At 6 weeks after birth, CRD was applied to these rats with a pressure of 20 to 90 mm Hg, and changes in the mean arterial pressure (MAP) were measured at baseline (i.e., without any drug administration) and after the administration of different doses of DA-9701. In the absence of DA-9701, the MAP changes after CRD were significantly higher in the CI group than in the control group at all applied pressures. In the control group, MAP changes after CRD were not significantly affected by the administration of DA-9701. In the CI group, however, the administration of DA-9701 resulted in a significant decrease in MAP changes after CRD. The administration of DA-9701 at a dose of 1.0 mg/kg produced a more significant decrease in MAP changes than the 0.3 mg/kg dose. The administration of DA-9701 resulted in a significant increase in pain threshold in rats with CRD-induced visceral hypersensitivity.

Evaluation of film and thermoluminescent dosimetry of high-energy electron beams in heterogeneous phantoms.

PubMed

el-Khatib, E; Antolak, J; Scrimger, J

1992-01-01

Film and thermoluminescent dosimetry (TLD) are investigated in heterogeneous phantoms irradiated by high-energy electron beams. Both film and TLD are practical dosimeters for multiple and moving beam radiotherapy. The accuracy and precision of these dosimeters for radiation dose measurements in homogeneous water-equivalent phantoms has been discussed in the literature. However, film and TLD are often used for dose measurements in heterogeneous phantoms. In those situations perturbations are produced which are related to the density and atomic number of the phantom material and the physical size and orientation of the dosimeter. In our experiments the relative dose measurements in homogeneous phantoms were the same regardless of dosimeter or dosimeter orientation. However, significant differences were observed between the dose measurements within the inhomogeneity. These differences were influenced by the type and orientation of the dosimeter in addition to the properties of the heterogeneity. These differences could be reproduced with Monte Carlo calculations and modeling of the experimental conditions.

Development of a pharmacogenetic-guided warfarin dosing algorithm for Puerto Rican patients

PubMed Central

Ramos, Alga S; Seip, Richard L; Rivera-Miranda, Giselle; Felici-Giovanini, Marcos E; Garcia-Berdecia, Rafael; Alejandro-Cowan, Yirelia; Kocherla, Mohan; Cruz, Iadelisse; Feliu, Juan F; Cadilla, Carmen L; Renta, Jessica Y; Gorowski, Krystyna; Vergara, Cunegundo; Ruaño, Gualberto; Duconge, Jorge

2012-01-01

Aim This study was aimed at developing a pharmacogenetic-driven warfarin-dosing algorithm in 163 admixed Puerto Rican patients on stable warfarin therapy. Patients & methods A multiple linear-regression analysis was performed using log-transformed effective warfarin dose as the dependent variable, and combining CYP2C9 and VKORC1 genotyping with other relevant nongenetic clinical and demographic factors as independent predictors. Results The model explained more than two-thirds of the observed variance in the warfarin dose among Puerto Ricans, and also produced significantly better ‘ideal dose’ estimates than two pharmacogenetic models and clinical algorithms published previously, with the greatest benefit seen in patients ultimately requiring <7 mg/day. We also assessed the clinical validity of the model using an independent validation cohort of 55 Puerto Rican patients from Hartford, CT, USA (R2 = 51%). Conclusion Our findings provide the basis for planning prospective pharmacogenetic studies to demonstrate the clinical utility of genotyping warfarin-treated Puerto Rican patients. PMID:23215886

Effect of gamma irradiation on lipoxygenases, trypsin inhibitor, raffinose family oligosaccharides and nutritional factors of different seed coat colored soybean (Glycine max L.)

NASA Astrophysics Data System (ADS)

Kumar Dixit, Amit; Kumar, Vineet; Rani, Anita; Manjaya, J. G.; Bhatnagar, Deepak

2011-04-01

Three soybean genotypes Kalitur, Hara soya and NRC37 with black, green and yellow seed coat color, respectively, were gamma irradiated at 0.5, 2.0 and 5.0 kGy and tested for antinutritional and nutritional factors. Gamma irradiation at all doses reduced the level of lipoxygenase isomers, trypsin inhibitor (TI) and ascorbic acid in all the 3 soybean genotypes as compared to the unirradiated control. However, irradiation dose of 5.0 kGy increased the sucrose content of the soybean genotypes. No significant change was observed in oil, protein fatty acids and total tocopherol content of the 3 genotypes at any irradiation dose. It is suggested that inhibition of lipoxygenase, reduction in TI and ascorbic acid may be due to the breakage or oxidation of protein structure by the gamma irradiation. Similarly, gamma irradiation at higher doses may break glycosidic linkages in oligosaccharides to produce more sucrose and decrease the content of flatulence causing oligosaccharides.

Reduction of soil pollution by usingwaste of the limestone in the cement industry

NASA Astrophysics Data System (ADS)

Muñoz, M. Cecilia Soto; Robles Castillo, Marcelo; Blanco Fernandez, David; Diaz Gonzalez, Marcos; Naranjo Lamilla, Pedro; Moore Undurraga, Fernando; Pardo Fabregat, Francisco; Vidal, Manuel Miguel Jordan; Bech, Jaume; Roca, Nuria

2016-04-01

In the cement manufacturing process (wet) a residue is generated in the flotation process. This builds up causing contamination of soil, groundwater and agricultural land unusable type. In this study to reduce soil and water pollution 10% of the dose of cement was replaced by waste of origin limestone. Concretes were produced with 3 doses of cement and mechanical strengths of each type of concrete to 7, 28 and 90 days were determined. the results indicate that the characteristics of calcareous residue can replace up to 10% of the dose of cement without significant decreases in strength occurs. It is noted that use of the residue reduces the initial resistance, so that the dose of cement should not be less than 200 kg of cement per m3. The results allow recommends the use of limestone waste since it has been observed decrease in soil and water contamination without prejudice construction material Keywords: Soil contamination; Limestone residue; Adding concrete

Critical dose and toxicity index of organs at risk in radiotherapy: Analyzing the calculated effects of modified dose fractionation in non–small cell lung cancer

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

Pedicini, Piernicola, E-mail: ppiern@libero.it; Strigari, Lidia; Benassi, Marcello

2014-04-01

To increase the efficacy of radiotherapy for non–small cell lung cancer (NSCLC), many schemes of dose fractionation were assessed by a new “toxicity index” (I), which allows one to choose the fractionation schedules that produce less toxic treatments. Thirty-two patients affected by non resectable NSCLC were treated by standard 3-dimensional conformal radiotherapy (3DCRT) with a strategy of limited treated volume. Computed tomography datasets were employed to re plan by simultaneous integrated boost intensity-modulated radiotherapy (IMRT). The dose distributions from plans were used to test various schemes of dose fractionation, in 3DCRT as well as in IMRT, by transforming the dose-volumemore » histogram (DVH) into a biological equivalent DVH (BDVH) and by varying the overall treatment time. The BDVHs were obtained through the toxicity index, which was defined for each of the organs at risk (OAR) by a linear quadratic model keeping an equivalent radiobiological effect on the target volume. The less toxic fractionation consisted in a severe/moderate hyper fractionation for the volume including the primary tumor and lymph nodes, followed by a hypofractionation for the reduced volume of the primary tumor. The 3DCRT and IMRT resulted, respectively, in 4.7% and 4.3% of dose sparing for the spinal cord, without significant changes for the combined-lungs toxicity (p < 0.001). Schedules with reduced overall treatment time (accelerated fractionations) led to a 12.5% dose sparing for the spinal cord (7.5% in IMRT), 8.3% dose sparing for V{sub 20} in the combined lungs (5.5% in IMRT), and also significant dose sparing for all the other OARs (p < 0.001). The toxicity index allows to choose fractionation schedules with reduced toxicity for all the OARs and equivalent radiobiological effect for the tumor in 3DCRT, as well as in IMRT, treatments of NSCLC.« less

Dual actions of lysergic acid diethylamide tartrate (LSD), 2-bromo-D-lysergic acid diethylamide bitartrate (BOL) and methysergide on dorsal root potentials evoked by stimulation of raphe nuclei.

PubMed

Larson, A A; Chinn, C; Proudfit, H K; Anderson, E G

1981-04-01

A variety of drugs reported to antagonize serotonin were found to affect spinal cord potentials evoked by electrical stimulation of the caudal raphe nuclei of the cat. These brain stem-evoked dorsal root potentials (DRPs) consisted of a short latency depolarization (DRP-1), which was evoked by stimulation of a wide variety of sites in the medial brain stem and a long latency potential (DRP-2), which was elicited only when stimuli were applied near the raphe. The ability of serotonergic antagonists to increase or decrease these DRPs was dependent on the dose of the drug administered. High doses of lysergic acid diethylamide tartrate (LSD), 2-bromo-D-lysergic acid diethylamide bitartrate (BOL), methysergide and cinanserin each produced an immediate inhibition of DRP-2 and a simultaneous enhancement of DRP-1, both of which recovered by approximately 30 min. Each of the drugs produced a dose-related inhibition of DRP-2 at high doses, with LSD being the most potent and cinanserin the least potent. In contrast, low doses of LSD, BOL and methysergide elicited little or no immediate change in either DRP-2 or DRP-1, but produced an enhancement of DRP-2 which developed slowly over a period of 60 to 90 min. This increase in DRP-2 was most dramatic after administration of LSD and was not accompanied by changes in DRP-1. The inhibition of DRP-2 by high doses of LSD, BOL, methysergide and cinanserin may result primarily from inhibition of postsynaptic serotonergic receptors located on the primary afferent terminals. The increase in DRP-2 produced by low doses of LSD, BOL and methysergide is postulated to result from an interaction with receptors distinct from those which produced the inhibition of DRP-2 at higher doses.

Effects of oxotremorine and physostigmine on the inhibitory avoidance impairment produced by amitriptyline in male and female mice.

PubMed

Monleón, Santiago; Urquiza, Adoración; Vinader-Caerols, Concepción; Parra, Andrés

2009-12-28

We have previously observed that amitriptyline and other antidepressants produce impairing effects on inhibitory avoidance (also called passive avoidance) in mice of both sexes. In the present study we investigated the involvement of the cholinergic system in the inhibitory avoidance impairment produced by acute amitriptyline in male and female CD1 mice. For this purpose, the effects on said task of acute i.p. administration of several doses of amitriptyline, either alone or in combination with the cholinergic agonists oxotremorine and physostigmine, were evaluated. Pre-training administration of 5, 7.5, 10 or 15 mg/kg of amitriptyline produced a significant impairment of inhibitory avoidance in both males and females. When oxotremorine (0.05 or 0.1 mg/kg) was co-administered with amitriptyline, the antidepressant's impairing effect was partially counteracted, although inhibitory avoidance learning was not significant. Physostigmine (0.15, 0.3 or 0.6 mg/kg) counteracted the impairment produced by amitriptyline, as mice treated with both drugs exhibited inhibitory avoidance learning. These results show that the inhibitory avoidance impairment produced by amitriptyline in male and female mice is mediated, at least partially, by the cholinergic system.

Low-, medium- and high-dose steroids with or without aminocaproic acid in adult hematopoietic SCT patients with diffuse alveolar hemorrhage.

PubMed

Rathi, N K; Tanner, A R; Dinh, A; Dong, W; Feng, L; Ensor, J; Wallace, S K; Haque, S A; Rondon, G; Price, K J; Popat, U; Nates, J L

2015-03-01

Diffuse alveolar hemorrhage (DAH) is a poorly understood complication of transplantation carrying a high mortality. Patients commonly deteriorate and require intensive care unit (ICU) admission. Treatment with high-dose steroids and aminocaproic acid (ACA) has been suggested. The current study examined 119 critically ill adult hematopoietic transplant patients treated for DAH. Patients were subdivided into low-, medium- and high-dose steroid groups with or without ACA. All groups had similar baseline characteristics and severity of illness scores. Primary objectives were 30, 60, 100 day, ICU and hospital mortality. Overall mortality (n=119) on day 100 was high at 85%. In the steroids and ACA cohort (n=82), there were no significant differences in 30, 60, 100, day, ICU and hospital mortality between the dosing groups. In the steroids only cohort (n=37), the low-dose steroid group had a lower ICU and hospital mortality (P=0.02). Adjunctive treatment with ACA did not produce differences in outcomes. In the multivariate analysis, medium- and high-dose steroids were associated with a higher ICU mortality (P=0.01) as compared with the low-dose group. Our data suggest that treatment strategies may need to be reanalyzed to avoid potentially unnecessary and potentially harmful therapies.

SU-F-J-133: Adaptive Radiation Therapy with a Four-Dimensional Dose Calculation Algorithm That Optimizes Dose Distribution Considering Breathing Motion

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

Ali, I; Algan, O; Ahmad, S

Purpose: To model patient motion and produce four-dimensional (4D) optimized dose distributions that consider motion-artifacts in the dose calculation during the treatment planning process. Methods: An algorithm for dose calculation is developed where patient motion is considered in dose calculation at the stage of the treatment planning. First, optimal dose distributions are calculated for the stationary target volume where the dose distributions are optimized considering intensity-modulated radiation therapy (IMRT). Second, a convolution-kernel is produced from the best-fitting curve which matches the motion trajectory of the patient. Third, the motion kernel is deconvolved with the initial dose distribution optimized for themore » stationary target to produce a dose distribution that is optimized in four-dimensions. This algorithm is tested with measured doses using a mobile phantom that moves with controlled motion patterns. Results: A motion-optimized dose distribution is obtained from the initial dose distribution of the stationary target by deconvolution with the motion-kernel of the mobile target. This motion-optimized dose distribution is equivalent to that optimized for the stationary target using IMRT. The motion-optimized and measured dose distributions are tested with the gamma index with a passing rate of >95% considering 3% dose-difference and 3mm distance-to-agreement. If the dose delivery per beam takes place over several respiratory cycles, then the spread-out of the dose distributions is only dependent on the motion amplitude and not affected by motion frequency and phase. This algorithm is limited to motion amplitudes that are smaller than the length of the target along the direction of motion. Conclusion: An algorithm is developed to optimize dose in 4D. Besides IMRT that provides optimal dose coverage for a stationary target, it extends dose optimization to 4D considering target motion. This algorithm provides alternative to motion management techniques such as beam-gating or breath-holding and has potential applications in adaptive radiation therapy.« less

Pulmonary Bovine-Type Tuberculosis in Rabbits: Bacillary Virulence, Inhaled Dose Effects, Tuberculin Sensitivity, and Mycobacterium vaccae Immunotherapy

PubMed Central

Converse, P. J.; Dannenberg, A. M.; Shigenaga, T.; McMurray, D. N.; Phalen, S. W.; Stanford, J. L.; Rook, G. A. W.; Koru-Sengul, T.; Abbey, Helen; Estep, J. E.; Pitt, M. L. M.

1998-01-01

This report elucidates four aspects of the immunology of pulmonary tuberculosis produced in rabbits: (i) the virulence of bovine-type tubercle bacilli, strain Ravenel S, (ii) systemic factors influencing the generation of visible primary pulmonary tubercles, (iii) differences in tuberculin sensitivity of rabbits and humans, and (iv) the effect of Mycobacterium vaccae immunotherapy on cavitary tuberculosis. Laboratory strain Ravenel S (ATCC 35720) was not fully virulent. Fully virulent strains produce one visible primary pulmonary tubercle for each three bacillary units inhaled. Strain ATCC 35720 produced one such tubercle for each 18 to 107 bacillary units inhaled, indicating that its virulence was reduced by 6- to 36-fold. When a low dose of this Ravenel S strain was inhaled, the host resistance (measured by the number of inhaled bacilli needed to generate one visible primary pulmonary tubercle) was increased at least 3.5-fold compared to the host resistance when a high dose was inhaled. Rabbits and humans differ in the degree and in the maintenance of their dermal sensitivities to tuberculin. Compared to rabbits, humans are 100 times more sensitive to tuberculin. Also, at 33 weeks rabbits with well-controlled cavitary tuberculosis usually showed a decrease in their tuberculin reactions of about 50% from peak values, whereas humans with such well-controlled tuberculosis are thought to maintain strong reactions for many years. These species differences may be due to desensitization to group II mycobacterial antigens in the rabbits because they have a different diet and a different type of digestive tract. M. vaccae immunotherapy of rabbits with cavitary tuberculosis produced no statistically significant effects. Experiments with many more rabbits would be required to prove whether or not such immunotherapy is beneficial. PMID:9801350

The PDE10A inhibitor MP-10 and haloperidol produce distinct gene expression profiles in the striatum and influence cataleptic behavior in rodents.

PubMed

Gentzel, Renee C; Toolan, Dawn; Roberts, Rhonda; Koser, Amy Jo; Kandebo, Monika; Hershey, James; Renger, John J; Uslaner, Jason; Smith, Sean M

2015-12-01

Phosphodiesterase 10A (PDE10A) has garnered attention as a potential therapeutic target for schizophrenia due to its prominent striatal expression and ability to modulate striatal signaling. The present study used the selective PDE10A inhibitor MP-10 and the dopamine D2 antagonist haloperidol to compare effects of PDE10A inhibition and dopamine D2 blockade on striatopallidal (D2) and striatonigral (D1) pathway activation. Our studies confirmed that administration of MP-10 significantly elevates expression of the immediate early genes (IEG) c-fos, egr-1, and arc in rat striatum. Furthermore, we demonstrated that MP-10 induced egr-1 expression was distributed evenly between enkephalin-containing D2-neurons and substance P-containing D1-neurons. In contrast, haloperidol (3 mg/kg) selectively activated egr-1 expression in enkephalin neurons. Co-administration of MP-10 and haloperidol (0.5 mg/kg) increased IEG expression to a greater extent than either compound alone. Similarly, in a rat catalepsy assay, administration of haloperidol (0.5 mg/kg) or MP-10 (3-30 mg/kg) did not produce cataleptic behavior when dosed alone, but co-administration of haloperidol with MP-10 (3 and 10 mg/kg) induced cataleptic behaviors. Interestingly, co-administration of haloperidol with a high dose of MP-10 (30 mg/kg) failed to produce cataleptic behavior. These findings are important for understanding the neural circuits involved in catalepsy and suggest that the behavioral effects produced by PDE10A inhibitors may be influenced by concomitant medication and the level of PDE10A inhibition achieved by the dose of the inhibitor. Copyright © 2015. Published by Elsevier Ltd.

Effect of gamma irradiation on microbial load, physicochemical and sensory characteristics of soybeans (Glycine max L. Merrill)

NASA Astrophysics Data System (ADS)

Yun, Juan; Li, Xihong; Fan, Xuetong; Tang, Yao; Xiao, Yao; Wan, Sen

2012-08-01

Gamma irradiation is highly effective in inactivating microorganisms in various foods and offers a safe alternative method of food decontamination. In the present study, soybeans (Glycine max L. Merrill) were treated with 0, 1.0, 3.0, 5.0 and 10.0 KGy of gamma irradiation. Microbial populations on soybeans, isoflavone, tocopherol contents, raffinose family oligosaccharides, color and sensory properties were evaluated as a function of irradiation dose. The results indicated that gamma irradiation reduced aerobic bacterial and fungal load. Irradiation at the doses applied did not cause any significant change (p>0.05) in the contents of isoflavone of soybeans, but decreased tocopherol contents. The content of key flatulence-producing raffinose family oligosaccharides in irradiated soybeans (10.0 kGy) decreased by 82.1% compared to the control. Sensory analysis showed that the odor of the soybeans was organoleptically acceptable at doses up to 5.0 kGy and no significant differences were observed between irradiated and nonirradiated samples in flavor, texture and color after irradiation.

[Effect of sodium valproate on aggressive behavior of male mice with various aggression experience].

PubMed

Smagin, D A; Bondar', N P; Kudriavtseva, N N

2010-01-01

Sector of Social Behavior Neurogenetics, Institute of Cytology and Genetics, Siberian Branch, Effects of sodium valproate on the aggressive behavior of male mice with 2- and 20-day positive fighting experience have been studied. It is established that valproate administered in a singe dose of 100 mg/kg has no effect on the behavior of male mice with a 2-day experience of aggression. The treatment of mice with 300 mg/kg of valproate significantly decreased the level of aggressive motivation and the percentage of animals demonstrating attacks and threats. In male mice with a 20-day experience of aggression, valproate decreased the time of hostile behavior in a dose-dependent manner. Valproate in a single dose of 300 mg/kg significantly decreased the level of aggressive motivation, but also produced a toxic effect, whereby 73% of aggressive males demonstrated long-term immobility and 45% exhibited movement abnormalities (falls) upon the treatment. It is suggested that changes in the brain neurochemical activity, which are caused by a prolonged experience of aggression, modify the effects of sodium valproate.

Influence of injected interstitials on the void swelling in two structural variants of 304L stainless steel induced by self-ion irradiation at 500 °C

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

Sun, C.; Garner, F. A.; Shao, L.

The two variants of AISI 304L stainless steel (SS) with different grain size distributions were ion irradiated at 500 °C to a peak dose of ~60 dpa. In the coarse-grained annealed variant, a peak swelling of ~12% was observed closer to the specimen surface rather than at the depth of peak displacement damage. The forward shift in depth between peak swelling and peak dose is proposed to be a consequence of suppression of void nucleation by injected interstitials. The swelling behavior in the front portion of the ion range mirrors that of neutron-induced swelling in this steel, exhibiting significant curvaturemore » with increasing dose as the swelling rate approaches the terminal swelling rate of 1%/dpa. Furthermore, an ultrafine grain variant of this steel produced by severely plastic deformation exhibits a similar suppression of void nucleation in the injected interstitial region, but also shows a significantly extended transient regime, not reaching the terminal swelling rate by 60 dpa.« less

Differential epileptogenic potentials of selective mu and delta opiate receptor agonists.

PubMed

Haffmans, J; Dzoljic, M R

1983-01-01

By using electroencephalographic (EEG) and electromyographic recordings in anaesthetized and free-moving rats, two opioid peptides, known as selective agonists for mu and delta opiate receptors, respectively, were examined for their epileptogenic properties. The delta receptor peptide (DSTLE, 4.6-18.6 nmol, intraventricularly, ivt), a putative delta opiate agonist, produced a dose-related increase of myoclonic contractions (MC) with epileptic discharges in anaesthetized rats and severe wet dog shakes, with occasionally falling down, in free-moving animals. Morphiceptin, a specific mu opiate agonist, used in equimolar doses and under the same experimental conditions, had a significantly less pronounced effect on the number of MC and epileptiform EEG phenomena. Similarly, DSTLE (18.6 nmol) injected in the CA2 area of the hippocampus, a region with a nearly equal distribution of mu and delta opiate receptors, induced epileptic discharges in anaesthetized and free-moving rats, while an equimolar dose of morphiceptin had no significant effect. It is suggested that the epileptiform activity of opioid peptides is mainly due to an activation of delta opiate receptors in the central nervous system.

Influence of injected interstitials on the void swelling in two structural variants of 304L stainless steel induced by self-ion irradiation at 500 °C

DOE PAGES

Sun, C.; Garner, F. A.; Shao, L.; ...

2017-03-28

The two variants of AISI 304L stainless steel (SS) with different grain size distributions were ion irradiated at 500 °C to a peak dose of ~60 dpa. In the coarse-grained annealed variant, a peak swelling of ~12% was observed closer to the specimen surface rather than at the depth of peak displacement damage. The forward shift in depth between peak swelling and peak dose is proposed to be a consequence of suppression of void nucleation by injected interstitials. The swelling behavior in the front portion of the ion range mirrors that of neutron-induced swelling in this steel, exhibiting significant curvaturemore » with increasing dose as the swelling rate approaches the terminal swelling rate of 1%/dpa. Furthermore, an ultrafine grain variant of this steel produced by severely plastic deformation exhibits a similar suppression of void nucleation in the injected interstitial region, but also shows a significantly extended transient regime, not reaching the terminal swelling rate by 60 dpa.« less

Sedative and Hypnotic Activities of the Methanolic and Aqueous Extracts of Lavandula officinalis from Morocco

PubMed Central

Alnamer, Rachad; Alaoui, Katim; Bouidida, El Houcine; Benjouad, Abdelaziz; Cherrah, Yahia

2012-01-01

We evaluate the sedative and hypnotic activities of the methanolic and aqueous extract of Lavandula officinalis L. on central nervous system (CNS). In this study, the effect of the methanolic and aqueous extracts of this plant was investigated in a battery of behavioural models in mice. Stems and flowers of Lavandula officinalis L. have several therapeutic applications in folk medicine in curing or managing a wide range of diseases, including insomnia. The methanolic extract produced significant sedative effect at the doses of 200, 400, and 600 mg/kg (by oral route), compared to reference substance diazepam (DZP), and an hypnotic effect at the doses of 800 and 1000 mg/kg while the treatment of mice with the aqueous extract at the doses of 200 and 400 mg/kg via oral pathway significantly reduced in both the reestablishment time and number of head dips during the traction and hole-board tests. In conclusion, these results suggest that the methanolic and aqueous extracts of Lavandula officinalis possess potent sedative and hypnotic activities, which supported its therapeutic use for insomnia. PMID:22162677

Effect on White Grape Must of Multiflora Bee Pollen Addition during the Alcoholic Fermentation Process.

PubMed

Amores-Arrocha, Antonio; Roldán, Ana; Jiménez-Cantizano, Ana; Caro, Ildefonso; Palacios, Víctor

2018-05-31

The aim of the present study was to compare and analyze the impact of using bee pollen doses (0.1, 0.25, 1, 5, 10 and 20 g/L) as activator in the alcoholic fermentation process of Palomino fino and Riesling wines. In this regard, its influence on the musts composition, the fermentative kinetics, the evolution of the populations of Saccharomyces cerevisiae , the evolution of yeast-assimilable nitrogen and physico-chemical characteristics of final wines has been analyzed. Bee pollen addition produces significant increases in yeast-assimilable nitrogen and maximum yeasts population and exponential velocity reached during alcoholic fermentation. Bee pollen showed an important effect on yeast survival during the death phase. Final wines showed significantly increase in volatile acidity above doses higher than 10 g/L and Comisión Internacional de L'Eclairage parameters (CIELab), color intensity and Abs 420 nm, from 1 g/L. Therefore, pollen could be used as fermentative activator for the alcoholic fermentation of white wines applying doses below of 1 g/L.

Effect of Isoprinosine Against Influenza and Some Other Viruses Causing Respiratory Diseases

PubMed Central

Muldoon, Robert L.; Mezny, Linda; Jackson, George G.

1972-01-01

The antiviral activity of isoprinosine was tested in tissue cultures and mice. In tissue cultures, concentrations of 25 to 100 μg/ml inhibited the infectivity of influenza and herpes hominis viruses but not parainfluenza virus, rhinovirus, or adenovirus. Among different strains of influenza A, there was considerable variability in the inhibitory concentration of isoprinosine. For influenza B, a zone effect was observed in the inhibitory drug concentration. Oral prophylactic administration of isoprinosine beginning 24 hr before infection with an intermediate challenge dose of influenza A and continued as treatment for 5 days produced a significant reduction in mortality. No protection was provided against a high dose challenge. Oral or intraperitoneal treatment of mice beginning 24 hr after infection with influenza A or B viruses significantly delayed or prevented death when the drug was administered for 10 days, but not when treatment was limited to 4 days. An increased fatality rate which occurred in treated mice given a virus dose of low lethality could not be attributed to drug toxicity. PMID:4790561

Changes of the immune reactivities of antibodies produced against gamma-irradiated antigen

NASA Astrophysics Data System (ADS)

Byun, Myung-Woo; Lee, Ju-Woon; Seo, Ji-Hyun; Kim, Jae-Hun; Jo, Cheorun; Kim, Dong-Ho; Chung, Hyung-Wook

2004-09-01

To observe the changes of immunogenicity and antigenicity of gamma-irradiated ovalbumin (OVA), an antigen (Ag) solution (2.0 mg/ml) was prepared and irradiated with the absorbed doses of 3 and 10 kGy. Immunoglobulin G (IgG) was produced for each Ag. 0, 3 and 10 kGy-IgG were individually reacted against 3 Ags in an ELISA cross reactivity test. Cross reactivity of each IgG was significantly different for each Ag. Especially the 10 kGy-irradiated OVA lost most antigenicity compared to the 0 kGy-IgG.

Characterization of a gamma-ray source based on a laser-plasma accelerator with applications to radiography

NASA Astrophysics Data System (ADS)

Edwards, R. D.; Sinclair, M. A.; Goldsack, T. J.; Krushelnick, K.; Beg, F. N.; Clark, E. L.; Dangor, A. E.; Najmudin, Z.; Tatarakis, M.; Walton, B.; Zepf, M.; Ledingham, K. W. D.; Spencer, I.; Norreys, P. A.; Clarke, R. J.; Kodama, R.; Toyama, Y.; Tampo, M.

2002-03-01

The application of high intensity laser-produced gamma rays is discussed with regard to picosecond resolution deep-penetration radiography. The spectrum and angular distribution of these gamma rays is measured using an array of thermoluminescent detectors for both an underdense (gas) target and an overdense (solid) target. It is found that the use of an underdense target in a laser plasma accelerator configuration produces a much more intense and directional source. The peak dose is also increased significantly. Radiography is demonstrated in these experiments and the source size is also estimated.

Failure to produce conditioning with low-dose trimethylthiazoline or cat feces as unconditioned stimuli.

PubMed

Blanchard, D Caroline; Markham, Chris; Yang, Mu; Hubbard, David; Madarang, Eric; Blanchard, Robert J

2003-04-01

Trimethylthiazoline (TMT), a derivative of fox feces, has been reported to fail to produce aversive conditioning as an unconditioned stimulus (UCS) when presented in large amounts (I. S. McGregor, L. Schrama, P. Ambermoon, & R. A. Dielenberg, 2002). Experiment I evaluated very low TMT levels that nonetheless produced defensive behaviors in rats during exposure. Although each level (0.01, 0.05, and 0.10 microl TMT) produced significant change in defensiveness, none resulted in significant changes the following day in the absence of TMT. Experiment 2 evaluated cat urine, cat feces, and cat fur/skin odor against a no-odor control. Urine produced no significant changes, but feces and fur/skin odors elicited virtually identical changes in defensive behaviors during exposure. When tested the next day in the absence of odor, the fur/skin odor-exposed group showed significant differences on the same behaviors as during exposure, but the feces-exposed group showed no differences on any measure. Results suggest that lack of conditioning to TMT may relate to the type of predator odor rather than the amount, predator species, or possible lack of odor components in TMT that are present in natural feces. Predator feces may also be less effective as a UCS because they are poorly predictive of the actual presence of the predator, suggesting the need for a reevaluation of UCS functions in aversive conditioning.

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

Welsh, James, E-mail: jwelsh@mdanderson.org; Amini, Arya; UC Irvine School of Medicine, Irvine, CA

Stereotactic body radiotherapy (SBRT) can produce excellent local control of several types of solid tumor; however, toxicity to nearby critical structures is a concern. We found previously that in SBRT for lung cancer, the chest wall (CW) volume receiving 20, 30, or 40 Gy (V{sub 20}, V{sub 30}, or V{sub 40}) was linked with the development of neuropathy. Here we sought to determine whether the dosimetric advantages of protons could produce lower CW doses than traditional photon-based SBRT. We searched an institutional database to identify patients treated with photon SBRT for lung cancer with tumors within < 2.5 cm ofmore » the CW. We found 260 cases; of these, chronic grade ≥ 2 CW pain was identified in 23 patients. We then selected 10 representative patients from this group and generated proton SBRT treatment plans, using the identical dose of 50 Gy in 4 fractions, and assessed potential differences in CW dose between the 2 plans. The proton SBRT plans reduced the CW doses at all dose levels measured. The median CW V{sub 20} was 364.0 cm{sup 3} and 160.0 cm{sup 3} (p < 0.0001), V{sub 30} was 144.6 cm{sup 3}vs 77.0 cm{sup 3} (p = 0.0012), V{sub 35} was 93.9 cm{sup 3}vs 57.9 cm{sup 3} (p = 0.005), V{sub 40} was 66.5 cm{sup 3}vs 45.4 cm{sup 3} (p = 0.0112), and mean lung dose was 5.9 Gy vs 3.8 Gy (p = 0.0001) for photons and protons, respectively. Coverage of the planning target volume (PTV) was comparable between the 2 sets of plans (96.4% for photons and 97% for protons). From a dosimetric standpoint, proton SBRT can achieve the same coverage of the PTV while significantly reducing the dose to the CW and lung relative to photon SBRT and therefore may be beneficial for the treatment of lesions closer to critical structures.« less

SU-E-T-495: Neutron Induced Electronics Failure Rate Analysis for a Single Room Proton Accelerator

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

Knutson, N; DeWees, T; Klein, E

2014-06-01

Purpose: To determine the failure rate as a function of neutron dose of the range modulator's servo motor controller system (SMCS) while shielded with Borated Polyethylene (BPE) and unshielded in a single room proton accelerator. Methods: Two experimental setups were constructed using two servo motor controllers and two motors. Each SMCS was then placed 30 cm from the end of the plugged proton accelerator applicator. The motor was then turned on and observed from outside of the vault while being irradiated to known neutron doses determined from bubble detector measurements. Anytime the motor deviated from the programmed motion a failuremore » was recorded along with the delivered dose. The experiment was repeated using 9 cm of BPE shielding surrounding the SMCS. Results: Ten SMCS failures were recorded in each experiment. The dose per monitor unit for the unshielded SMCS was 0.0211 mSv/MU and 0.0144 mSv/MU for the shielded SMCS. The mean dose to produce a failure for the unshielded SMCS was 63.5 ± 58.3 mSv versus 17.0 ±12.2 mSv for the shielded. The mean number of MUs between failures were 2297 ± 1891 MU for the unshielded SMCS and 2122 ± 1523 MU for the shielded. A Wilcoxon Signed Ranked test showed the dose between failures were significantly different (P value = 0.044) while the number of MUs between failures were not (P value = 1.000). Statistical analysis determined a SMCS neutron dose of 5.3 mSv produces a 5% chance of failure. Depending on the workload and location of the SMCS, this failure rate could impede clinical workflow. Conclusion: BPE shielding was shown to not reduce the average failure of the SMCS and relocation of the system outside of the accelerator vault was required to lower the failure rate enough to avoid impeding clinical work flow.« less

Radiation dose enhancement of gold nanoparticle on different polymer gel dosimeters

NASA Astrophysics Data System (ADS)

Jabaseelan Samuel, E. James; Srinivasan, K.; Poopathi, V.

2017-05-01

In this work, we evaluated the dose enhancement produced by gold nanoparticle on ten different polymer gel dosimeters with a concentration of 7mgAu /g over a wide photon energy range of 15KeV to 20MeV and the results were compared with Soft tissue ICRU-44 produced. Our result showed that maximum DEF was observed at 40KeV, while it was almost negligible at higher energy range. Dose enhancement produced by AuNP on the gel dosimeter medium was varied compared to the reference ICRU-44 tissue, it was ± <1% for PAGAT, NIPAM, nPAG and ± <5% for PABIG, VIPAR, HEAG, BANG1, nMAG & ± <10% for MAGIC, ABAGIC gel dosimeters. Hence, we conclude that choosing the proper gel dosimeter is essential in dose enhancement study.

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

Subtle changes in brain functions produced by single doses of mevinphos (Phosdrin).

DOT National Transportation Integrated Search

1973-02-01

Mevinphos (Phosdrin) was found to inhibit the amplitude of hippocampal evoked potentials in unanesthetized squirrel monkeys with chronically indwelling electrodes. The threshold dose was 0.050 mg/kg and the maximal dose studied was 0.200 mg/kg. Doses...

Comparison of neurotoxic effects and potential risks from oral administration or ingestion of tricresyl phosphate and jet engine oil containing tricresyl phosphate.

PubMed

Mackerer, C R; Barth, M L; Krueger, A J; Chawla, B; Roy, T A

1999-07-09

Neurotoxicity of tricresyl phosphates (TCPs) and jet engine oil (JEO) containing TCPs were evaluated in studies conducted in both rat and hen. Results for currently produced samples ("conventional" and "low-toxicity") were compared with published findings on older samples to identify compositional changes and relate those changes to neurotoxic potential. Finally, a human risk assessment for exposure by oral ingestion of currently produced TCPs in JEO at 3% (JEO + 3%) was conducted. TCPs and certain other triaryl phosphates administered as single doses inhibited brain neuropathy target esterase (B-NTE; neurotoxic esterase) in the rat and the hen (hen 3.25 times as sensitive), and both species were deemed acceptable for initial screening purposes. Neither rat nor hen was sensitive enough to detect statistically significant inhibition of B-NTE after single doses of IEO + 3% "conventional" TCP. Subacute administration of 2 g/kg/d of JEO + 3% "conventional" TCP to the hen produced B-NTE inhibition (32%), which did not result in organophosphorus-induced delayed neurotoxicity (OPIDN). Subchronic administration of JEO + 3% TCP but not JEO + 1% TCP at 2 g/kg/d produced OPIDN. Thus, the threshold for OPIDN was between 20 and 60 mg "conventional" TCP/kg/d in JEO for 10 wk. The current "conventional" TCPs used in JEO and new "low-toxicity" TCPs now used in some JEO are synthesized from phenolic mixtures having reduced levels of ortho-cresol and ortho-xylenols resulting in TCPs of very high content of meta- and para-substituted phenyl moieties; this change in composition results in lower toxicity. The "conventional" TCPs still retain enough inhibitory activity to produce OPIDN, largely because of the presence of ortho-xylyl moieties; the "low-toxicity" TCPs are largely devoid of ortho substituents and have extremely low potential to cause OPIDN. The TCPs produced in the 1940s and 1950s were more than 400 times as toxic as the "low-toxicity" TCPs produced today. Analysis of the doses required to produce OPIDN in a subchronic hen study suggests that the minimum toxic dose of "conventional" TCP for producing OPIDN in a 70-kg person would be 280 mg/d, and for JEO containing 3% TCP, 9.4 g/d. Food products could be inadvertently contaminated with neat "conventional" TCP but it is unlikely that food such as cooking oil would be contaminated with enough JEO + 3% TCP to cause toxicity. Further, at the dosage required for neurotoxicity, it would be virtually impossible for a person to receive enough JEO + 3% TCP in the normal workplace (or in an aircraft) to cause such toxicity. There is no record of a JEO formulated with the modern "conventional" TCP causing human neurotoxicity.

Experimental verification of the Acuros XB and AAA dose calculation adjacent to heterogeneous media for IMRT and RapidArc of nasopharygeal carcinoma.

PubMed

Kan, Monica W K; Leung, Lucullus H T; So, Ronald W K; Yu, Peter K N

2013-03-01

To compare the doses calculated by the Acuros XB (AXB) algorithm and analytical anisotropic algorithm (AAA) with experimentally measured data adjacent to and within heterogeneous medium using intensity modulated radiation therapy (IMRT) and RapidArc(®) (RA) volumetric arc therapy plans for nasopharygeal carcinoma (NPC). Two-dimensional dose distribution immediately adjacent to both air and bone inserts of a rectangular tissue equivalent phantom irradiated using IMRT and RA plans for NPC cases were measured with GafChromic(®) EBT3 films. Doses near and within the nasopharygeal (NP) region of an anthropomorphic phantom containing heterogeneous medium were also measured with thermoluminescent dosimeters (TLD) and EBT3 films. The measured data were then compared with the data calculated by AAA and AXB. For AXB, dose calculations were performed using both dose-to-medium (AXB_Dm) and dose-to-water (AXB_Dw) options. Furthermore, target dose differences between AAA and AXB were analyzed for the corresponding real patients. The comparison of real patient plans was performed by stratifying the targets into components of different densities, including tissue, bone, and air. For the verification of planar dose distribution adjacent to air and bone using the rectangular phantom, the percentages of pixels that passed the gamma analysis with the ± 3%/3mm criteria were 98.7%, 99.5%, and 97.7% on the axial plane for AAA, AXB_Dm, and AXB_Dw, respectively, averaged over all IMRT and RA plans, while they were 97.6%, 98.2%, and 97.7%, respectively, on the coronal plane. For the verification of planar dose distribution within the NP region of the anthropomorphic phantom, the percentages of pixels that passed the gamma analysis with the ± 3%/3mm criteria were 95.1%, 91.3%, and 99.0% for AAA, AXB_Dm, and AXB_Dw, respectively, averaged over all IMRT and RA plans. Within the NP region where air and bone were present, the film measurements represented the dose close to unit density water in a heterogeneous medium, produced the best agreement with the AXB_Dw. For the verification of point doses within the target using TLD in the anthropomorphic phantom, the absolute percentage deviations between the calculated and measured data when averaged over all IMRT and RA plans were 1.8%, 1.7%, and 1.8% for AAA, AXB_Dm and AXB_Dw, respectively. From all the verification results, no significant difference was found between the IMRT and RA plans. The target dose analysis of the real patient plans showed that the discrepancies in mean doses to the PTV component in tissue among the three dose calculation options were within 2%, but up to about 4% in the bone content, with AXB_Dm giving the lowest values and AXB_Dw giving the highest values. In general, the verification measurements demonstrated that both algorithms produced acceptable accuracy when compared to the measured data. GafChromic(®) film results indicated that AXB produced slightly better accuracy compared to AAA for dose calculation adjacent to and within the heterogeneous media. Users should be aware of the differences in calculated target doses between options AXB_Dm and AXB_Dw, especially in bone, for IMRT and RA in NPC cases.

Genetic variants associated with warfarin dose in African-American individuals: a genome-wide association study.

PubMed

Perera, Minoli A; Cavallari, Larisa H; Limdi, Nita A; Gamazon, Eric R; Konkashbaev, Anuar; Daneshjou, Roxana; Pluzhnikov, Anna; Crawford, Dana C; Wang, Jelai; Liu, Nianjun; Tatonetti, Nicholas; Bourgeois, Stephane; Takahashi, Harumi; Bradford, Yukiko; Burkley, Benjamin M; Desnick, Robert J; Halperin, Jonathan L; Khalifa, Sherief I; Langaee, Taimour Y; Lubitz, Steven A; Nutescu, Edith A; Oetjens, Matthew; Shahin, Mohamed H; Patel, Shitalben R; Sagreiya, Hersh; Tector, Matthew; Weck, Karen E; Rieder, Mark J; Scott, Stuart A; Wu, Alan H B; Burmester, James K; Wadelius, Mia; Deloukas, Panos; Wagner, Michael J; Mushiroda, Taisei; Kubo, Michiaki; Roden, Dan M; Cox, Nancy J; Altman, Russ B; Klein, Teri E; Nakamura, Yusuke; Johnson, Julie A

2013-08-31

VKORC1 and CYP2C9 are important contributors to warfarin dose variability, but explain less variability for individuals of African descent than for those of European or Asian descent. We aimed to identify additional variants contributing to warfarin dose requirements in African Americans. We did a genome-wide association study of discovery and replication cohorts. Samples from African-American adults (aged ≥18 years) who were taking a stable maintenance dose of warfarin were obtained at International Warfarin Pharmacogenetics Consortium (IWPC) sites and the University of Alabama at Birmingham (Birmingham, AL, USA). Patients enrolled at IWPC sites but who were not used for discovery made up the independent replication cohort. All participants were genotyped. We did a stepwise conditional analysis, conditioning first for VKORC1 -1639G→A, followed by the composite genotype of CYP2C9*2 and CYP2C9*3. We prespecified a genome-wide significance threshold of p<5×10(-8) in the discovery cohort and p<0·0038 in the replication cohort. The discovery cohort contained 533 participants and the replication cohort 432 participants. After the prespecified conditioning in the discovery cohort, we identified an association between a novel single nucleotide polymorphism in the CYP2C cluster on chromosome 10 (rs12777823) and warfarin dose requirement that reached genome-wide significance (p=1·51×10(-8)). This association was confirmed in the replication cohort (p=5·04×10(-5)); analysis of the two cohorts together produced a p value of 4·5×10(-12). Individuals heterozygous for the rs12777823 A allele need a dose reduction of 6·92 mg/week and those homozygous 9·34 mg/week. Regression analysis showed that the inclusion of rs12777823 significantly improves warfarin dose variability explained by the IWPC dosing algorithm (21% relative improvement). A novel CYP2C single nucleotide polymorphism exerts a clinically relevant effect on warfarin dose in African Americans, independent of CYP2C9*2 and CYP2C9*3. Incorporation of this variant into pharmacogenetic dosing algorithms could improve warfarin dose prediction in this population. National Institutes of Health, American Heart Association, Howard Hughes Medical Institute, Wisconsin Network for Health Research, and the Wellcome Trust. Copyright © 2013 Elsevier Ltd. All rights reserved.

SU-F-T-87: Comparison of Advanced Radiotherapy Techniques for Post- Mastectomy Breast Cancer Patients

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

Heins, D; Zhang, R; Hogstrom, K

2016-06-15

Purpose: To determine if bolus electron conformal therapy (Bolus-ECT) combined with intensity modulated x-ray therapy (IMXT) and flattening filter free volumetric modulated arc therapy (FFF-VMAT (6x and 10x)) can maintain equal or better dose coverage than standard volumetric modulated arc therapy (Std-VMAT) while reducing doses to organs at risk (OARs). Methods: Bolus-ECT with IMXT, FFF-VMAT, and Std-VMAT treatment plans were produced for ten post-mastectomy radiotherapy (PMRT) patients previously treated at our clinic. The treatment plans were created on commercially available treatment planning system (TPS) and all completed treatment plans were reviewed and approved by a radiation oncologist. The plans weremore » evaluated based on planning target volume (PTV) coverage, tumor control probability (TCP), dose homogeneity index (DHI), conformity index (CI), and dose to organs at risk (OAR). Results: All techniques produced clinically acceptable PMRT plans. Overall, Bolus-ECT with IMXT exhibited higher maximum dose compared to all VMAT techniques. Bolus-ECT with IMXT and FFF-VMAT10x had slightly improved TCP over FFF-VMAT6x and Std-VMAT. However, all VMAT techniques showed improved CI and DHI over Bolus-ECT with IMXT. All techniques showed very similar mean lung dose. Bolus-ECT with IMXT exhibited a reduced mean heart dose over Std-VMAT. Both FFF-VMAT techniques had higher mean heart dose compared to Std-VMAT. In addition, Bolus-ECT with IMXT was able to reduce mean dose to the contralateral breast compared to Std-VMAT and both FFF-VMAT techniques had comparable but slightly reduced dose compared to Std-VMAT. Conclusion: This work has shown that Bolus-ECT with IMXT produces clinically acceptable plans while reducing OAR doses. Both FFF-VMAT techniques are comparable to Std-VMAT with slight improvements. Even though all VMAT techniques produce more homogenous and conformal dose distributions, Bolus-ECT with IMXT is a viable option for treating post-mastectomy patients possibly leading to reduced risks of normal tissue complications.« less

Clonal analysis of T-cell responses to herpes simplex virus: isolation, characterization and antiviral properties of an antigen-specific helper T-cell clone.

PubMed

Leung, K N; Nash, A A; Sia, D Y; Wildy, P

1984-12-01

A herpes simplex virus (HSV)-specific long-term T-cell clone has been established from the draining lymph node cells of BALB/c mice; the cells required repeated in vitro restimulation with UV-irradiated virus. The established T-cell clone expresses the Thy-1 and Lyt-1+2,3- surface antigens. For optimal proliferation of the cloned cells, both the presence of specific antigen and an exogenous source of T-cell growth factor are required. The proliferative response of the cloned T cells was found to be virus-specific but it did not distinguish between HSV-1 and HSV-2. Adoptive cell transfer of the cloned T cells helped primed B cells to produce anti-herpes antibodies: the response was antigen-specific and cell dose-dependent. The clone failed to produce a significant DTH reaction in vivo, but did produce high levels of macrophage-activating factor. Furthermore, the T-cell clone could protect from HSV infection, as measured by a reduction in local virus growth, and by enhanced survival following the challenge of mice with a lethal dose of virus. The mechanism(s) whereby this clone protects in vivo is discussed.

[Hydroxymethyluracil in the correction of adverse effects caused by chemotherapy of malignant neoplasms].

PubMed

Sakaeva, D D

2004-01-01

Hydroxymethyluracil (HMU) in a dose of 1.5-3 g/day produces a stimulant effect upon leukopoiesis and granulocytopoiesis in cases of toxic neutropenia caused by chemotherapy. In the same dose range, HMU produces immunostimulant action in patients with immune deficit caused by oncopathology and chemotherapy.

Activity of crude cold-water extract of the culinary-medicinal oyster mushroom, Pleurotus ostreatus (Jacq.:Fr.) P.Kumm. (higher Basidiomycetes), and timolol maleate on induced ocular hypertension.

PubMed

Ebigwai, Joseph Kayefor; Edu, Esther Aja; Itam, Edisua Hogan; Mofunanya, Ann Jerry

2012-01-01

Aqueous crude cold-water extract from the fruiting body of the culinary-medicinal oyster mushroom Pleurotus ostreatus was assessed for activity against increased intra-ocular pressure (IOP) in mice. A 0.1% dexamethasone instillation was used to raise the intra-ocular pressure in the animals above the 21-mmHg threshold limit. The extract has intrinsic anti-hypertensive properties that are dose dependent. A comparison analysis indicated that 150 mg/mL of the crude extract produced 57.69% reduction in the intra-ocular pressure, while doses of 100 mg/ mL and 200 mg/mL produced 44.78% and 70.03% IOP reduction, respectively, compared with timolol maleate with 57.69%. The results were significant at 0.05 confidence limit (p < 0.05) when compared to a placebo and therefore support its use for the treatment of increased intra-ocular pressure.

Modulators of Bufo arenarum ovulation.

PubMed

Ramos, Inés; Cisint, Susana B; Crespo, Claudia A; Medina, Marcela F; Fernández, Silvia N

2008-02-01

In this study we investigated ovulation in vitro using ovary samples from Bufo arenarum with respect to their response to stimulation with homologous pituitary homogenate (HPH) or with progesterone and prostaglandins (PGF2alpha and PGE1) as intermediates of pituitary action. Ovary samples were obtained from animals captured during the breeding period. Our results demonstrate that the ovulatory response to all different inducers was dose dependent, the highest percentage of ovulated oocytes being obtained with HPH treatment. An important increase in the ovulatory response was obtained by the association of PGF2alpha with either HPH or progesterone at suboptimal doses, indicating that this prostaglandin induced a synergistic potentiating effect. Incubation with cyclooxygenase inhibitors (indomethacin or diclofenac sodium) produced a significant decrease in the ovulation induced by HPH, demonstrating that prostaglandins are involved in the action of the pituitary gland in this process. According to our results, PGE1 not only had no participation in the ovulatory process, but also produced an inhibitory effect on ovulation induced by HPH treatment.

CORRECTIONS ASSOCIATED WITH ON-PHANTOM CALIBRATIONS OF NEUTRON PERSONAL DOSEMETERS.

PubMed

Hawkes, N P; Thomas, D J; Taylor, G C

2016-09-01

The response of neutron personal dosemeters as a function of neutron energy and angle of incidence is typically measured by mounting the dosemeters on a slab phantom and exposing them to neutrons from an accelerator-based or radionuclide source. The phantom is placed close to the source (75 cm) so that the effect of scattered neutrons is negligible. It is usual to mount several dosemeters on the phantom together. Because the source is close, the source distance and the neutron incidence angle vary significantly over the phantom face, and each dosemeter may receive a different dose equivalent. This is particularly important when the phantom is angled away from normal incidence. With accelerator-produced neutrons, the neutron energy and fluence vary with emission angle relative to the charged particle beam that produces the neutrons, contributing further to differences in dose equivalent, particularly when the phantom is located at other than the straight-ahead position (0° to the beam). Corrections for these effects are quantified and discussed in this article. © Crown copyright 2015.

Genistein modulation of streptozotocin diabetes in male B6C3F1 mice can be induced by diet

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

Guo, Tai L., E-mail: tlguo1@uga.edu; Wang, Yunbiao; Key Laboratory of Wetland Ecology and Environment, Northeast Institute of Geography and Agroecology, Chinese Academy of Sciences, Changchun 130102

Diet and phytoestrogens affect the development and progression of diabetes. The objective of the present study was to determine if oral exposure to phytoestrogen genistein (GE) by gavage changed blood glucose levels (BGL) through immunomodulation in streptozotocin (STZ)-induced diabetic male B6C3F1 mice fed with three different diets. These three diets were: NTP-2000 diet (NTP), soy- and alfalfa-free 5K96 diet (SOF) and high fat diet (HFD) with 60% of kcal from fat, primarily rendered fat of swine. The dosing regimen for STZ consisted of three 100 mg/kg doses (i.p.): the first dose was administered at approximately 2 weeks following the initiationmore » of daily GE (20 mg/kg) gavage, and the second dose was on day 19 following the first dose, and the third dose was on day 57 following the first dose. In mice on the NTP diet, GE treatment decreased BGL with statistical significances observed on days 33 and 82 following the first STZ injection. In mice fed the HFD diet, GE treatment produced a significant decrease and a significant increase in BGL on days 15 and 89 following the first STZ injection, respectively. In mice fed the SOF diet, GE treatment had no significant effects on BGL. Although GE treatment affected phenotypic distributions of both splenocytes (T cells, B cells, natural killer cells and neutrophils) and thymocytes (CD4/CD8 and CD44/CD25), and their mitochondrial transmembrane potential and generation of reactive oxygen species, indicators of cell death (possibly apoptosis), GE modulation of neutrophils was more consistent with its diabetogenic or anti-diabetic potentials. The differential effects of GE on BGL in male B6C3F1 mice fed with three different diets with varied phytoestrogen contents suggest that the estrogenic properties of this compound may contribute to its modulation of diabetes. - Highlights: • Diets affected streptozotocin-induced diabetes in male B6C3F1 mice. • Genistein modulation of streptozotocin diabetes can be induced by diet. • Genistein modulation of neutrophils is associated with blood glucose levels.« less

SU-E-T-79: Comparison of Doses Received by the Hippocampus in Patients Treated with Single Vs Multiple Isocenter Based Stereotactic Radiation Therapy to the Brain for Multiple Brain Metastases

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

Algan, O; Giem, J; Young, J

Purpose: To investigate the doses received by the hippocampus and normal brain tissue during a course of stereotactic radiotherapy utilizing a single isocenter (SI) versus multiple isocenter (MI) in patients with multiple intracranial metastases. Methods: Seven patients imaged with MRI including SPGR sequence and diagnosed with 2–3 brain metastases were included in this retrospective study. Two sets of stereotactic IMRT treatment plans, (MI vs SI), were generated. The hippocampus was contoured on SPGR sequences and doses received by the hippocampus and whole brain were calculated. The prescribed dose was 25Gy in 5 fractions. The two groups were compared using t-testmore » analysis. Results: There were 17 lesions in 7 patients. The median tumor, right hippocampus, left hippocampus and brain volumes were: 3.37cc, 2.56cc, 3.28cc, and 1417cc respectively. In comparing the two treatment plans, there was no difference in the PTV coverage except in the tail of the DVH curve. All tumors had V95 > 99.5%. The only statistically significant parameter was the V100 (72% vs 45%, p=0.002, favoring MI). All other evaluated parameters including the V95 and V98 did not reveal any statistically significant differences. None of the evaluated dosimetric parameters for the hippocampus (V100, V80, V60, V40, V20, V10, D100, D90, D70, D50, D30, D10) revealed any statistically significant differences (all p-values > 0.31) between MI and SI plans. The total brain dose was slightly higher in the SI plans, especially in the lower dose regions, although this difference was not statistically significant. Utilizing brain-sub-PTV volumes did not change these results. Conclusion: The use of SI treatment planning for patients with up to 3 brain metastases produces similar PTV coverage and similar normal tissue doses to the hippocampus and the brain compared to MI plans. SI treatment planning should be considered in patients with multiple brain metastases undergoing stereotactic treatment.« less

Epibatidine, an alkaloid from the poison frog Epipedobates tricolor, is a powerful ganglionic depolarizing agent.

PubMed

Fisher, M; Huangfu, D; Shen, T Y; Guyenet, P G

1994-08-01

Epibatidine, a newly discovered alkaloid from the skin of Dendrobatidae frogs, has structural similarities to nicotine. We examined the effects of epibatidine on cardiorespiratory function and ganglionic synaptic transmission. Superior cervical or splanchnic sympathetic nerve discharge (sSND) and phrenic nerve discharge (PND) were recorded along with arterial pressure (AP) in urethane-anesthetized, paralyzed and artificially ventilated rats. Epibatidine administered i.v. at low doses (0.5-2 micrograms/kg) produced a transient increase in AP and sSND, followed by a decrease and return to baseline; this low dose of epibatidine also produced a dose-dependent increase in PND. At high doses (cumulative dose of 8-16 micrograms/kg), epibatidine produced bradycardia, a profound depression in sSND and a transient elimination of PND. After i.v. administration of the ganglionic blocker chlorisondamine (5 mg/kg), AP was still increased by 1 microgram/kg epibatidine (+39 +/- 11 mm Hg). This pressor effect was not altered by pretreatment with the alpha-1 adrenergic antagonist phentolamine (+40 +/- 10 mm Hg); however, it was blocked by additional pretreatment with the vasopressin antagonist [beta-mercapto-beta,beta-cyclopentamethylenepropiony1, O-ET-Tyr2,Val4,Arg8]vasopressin (50 micrograms/kg i.v.; +2 +/- 0.4 mm Hg). Low doses of epibatidine (0.5-2 micrograms/kg) produced firing of postganglionic neurons in a decentralized ganglion preparation and potentiated synaptic transmission; at high doses (cumulative dose of 8-16 micrograms/kg), the alkaloid blocked ganglionic synaptic transmission. These results suggest that epibatidine is a potent agonist of ganglionic nicotinic receptors and that the alkaloid elicits cardiorespiratory effects similar to those of nicotine.

Involvement of adenosine A1 and A2A receptors in the adenosinergic modulation of the discriminative-stimulus effects of cocaine and methamphetamine in rats.

PubMed

Justinova, Zuzana; Ferre, Sergi; Segal, Pavan N; Antoniou, Katerina; Solinas, Marcello; Pappas, Lara A; Highkin, Jena L; Hockemeyer, Jorg; Munzar, Patrik; Goldberg, Steven R

2003-12-01

Adenosine, by acting on adenosine A1 and A2A receptors, is known to antagonistically modulate dopaminergic neurotransmission. We have recently reported that nonselective adenosine receptor antagonists (caffeine and 3,7-dimethyl-1-propargylxanthine) can partially substitute for the discriminative-stimulus effects of methamphetamine. In the present study, by using more selective compounds, we investigated the involvement of A1 and A2A receptors in the adenosinergic modulation of the discriminative-stimulus effects of both cocaine and methamphetamine. The effects of the A1 receptor agonist N6-cyclopentyladenosine (CPA; 0.01-0.1 mg/kg) and antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 1.3-23.7 mg/kg) and the A2A receptor agonist 2-p-(2-carboxyethyl)phenethylamino-5'-N-ethylcarboxamidoadenosine hydrochloride (CGS 21680; 0.03-0.18 mg/kg) and antagonist 3-(3-hydroxypropyl)-8-(3-methoxystyryl)-7-methyl-1-propargylxanthin phosphate disodium salt (MSX-3; 1-56 mg/kg) were evaluated in rats trained to discriminate either 1 mg/kg methamphetamine or 10 mg/kg cocaine from saline under a fixed-ratio 10 schedule of food presentation. The A1 and A2A receptor antagonists (CPT and MSX-3) both produced high levels of drug-lever selection when substituted for either methamphetamine or cocaine and significantly shifted dose-response curves of both psychostimulants to the left. Unexpectedly, the A2A receptor agonist CGS 21680 also produced drug-appropriate responding (although at lower levels) when substituted for the cocaine-training stimulus, and both CGS 21680 and the A1 receptor agonist CPA significantly shifted the cocaine dose-response curve to the left. In contrast, both agonists did not produce significant levels of drug-lever selection when substituted for the methamphetamine-training stimulus and failed to shift the methamphetamine dose-response curve. Therefore, adenosine A1 and A2A receptors appear to play important but differential roles in the modulation of the discriminative-stimulus effects of methamphetamine and cocaine.

Bowel cleansing before colonoscopy: Balancing efficacy, safety, cost and patient tolerance

PubMed Central

Harrison, Nicole M; Hjelkrem, Michael C

2016-01-01

Effective colorectal cancer screening relies on reliable colonoscopy findings which are themselves dependent on adequate bowel cleansing. Research has consistently demonstrated that inadequate bowel preparation adversely affects the adenoma detection rate and leads gastroenterologists to recommend earlier follow up than is consistent with published guidelines. Poor preparation affects as many as 30% of colonoscopies and contributes to an increased cost of colonoscopies. Patient tolerability is strongly affected by the preparation chosen and manner in which it is administered. Poor tolerability is, in turn, associated with lower quality bowel preparations. Recently, several new developments in both agents being used for bowel preparation and in the timing of administration have brought endoscopists closer to achieving the goal of effective, reliable, safe, and tolerable regimens. Historically, large volume preparations given in a single dose were administered to patients in order to achieve adequate bowel cleansing. These were poorly tolerated, and the unpleasant taste of and significant side effects produced by these large volume regimens contributed significantly to patients’ inability to reliably complete the preparation and to a reluctance to repeat the procedure. Smaller volumes, including preparations that are administered as tablets to be consumed with water, given as split doses have significantly improved both the patient experience and efficacy, and an appreciation of the importance of the preparation to colonoscopy interval have produced additional cleansing. PMID:26788258

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

Antioxidant, analgesic and anti-inflammatory activities of the methanolic extract of Piper betle leaves

PubMed Central

Alam, Badrul; Akter, Fahima; Parvin, Nahida; Sharmin Pia, Rashna; Akter, Sharmin; Chowdhury, Jesmin; Sifath-E-Jahan, Kazi; Haque, Ekramul

2013-01-01

Objective: The present study was designed to evaluate the antioxidant, analgesic, and anti-inflammatory activities of the methanolic extract of Piper betle leaves (MPBL). Materials and Methods: MPBL was evaluated for anti-inflammatory activity using carrageenan-induced hind paw edema model. Analgesic activity of MPBL was evaluated by hot plate, writhing, and formalin tests. Total phenolic and flavonoids content, total antioxidant activity, scavenging of 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, peroxynitrate (ONOO) as well as inhibition of total ROS generation, and assessment of reducing power were used to evaluate antioxidant potential of MPBL. Results: The extract of MPBL, at the dose of 100 and 200 mg/kg, produced a significant (p<0.05) increase in pain threshold in hot plate method whereas significantly (p<0.05) reduced the writhing caused by acetic acid and the number of licks induced by formalin in a dose-dependent manner. The same ranges of doses of MPBL caused significant (p<0.05) inhibition of carrageenan-induced paw edema after 4 h in a dose-dependent manner. In DPPH, ONOO-, and total ROS scavenging method, MPBL showed good antioxidant potentiality with the IC50 value of 16.33±1.02, 25.16±0.61 , and 41.72±0.48 µg/ml, respectively with a significant (p<0.05) good reducing power. Conclusion: The findings of the study suggested that MPBL has strong analgesic, anti-inflammatory, and antioxidant effects, conforming the traditional use of this plant for inflammatory pain alleviation to its antioxidant potentiality. PMID:25050265

Effect of Dose of Behavioral Treatment for Obesity on Binge Eating Severity

PubMed Central

Ariel, Aviva H.; Perri, Michael G.

2016-01-01

Objectives We evaluated the effects of three doses of a behavioral intervention for obesity (High dose = 24 sessions, Moderate = 16 sessions, Low = 8 sessions) compared with a nutrition education control group (Control) on binge eating. We also examined whether participants with clinically significant improvements in binge eating had better treatment adherence and weight-loss outcomes than those who did not experience clinically significant improvements in binge eating. Finally, we examined the relation of pretreatment binge eating severity to changes at six months. Methods Participants included 572 adults (female = 78.7%; baseline mean ±SD: age = 52.7 ±11.2 years, BMI = 36.4 ±3.9 kg/m2) who provided binge eating data at baseline. We evaluated binge eating severity (assessed via the Binge Eating Scale) and weight status at baseline and six months, as well as treatment adherence over six months. Results At six months, participants in the Moderate and High treatment conditions reported greater reductions in binge eating severity than participants in the Low and Control conditions, ps < .02. Participants who demonstrated improvements in binge eating severity reported greater dietary self-monitoring adherence and attained larger weight losses than those who did not experience clinically significant reductions, ps < .001. Pretreatment binge eating severity predicted less improvement in binge eating severity over six months and fewer days with dietary self-monitoring records completed, ps ≤ .002. Conclusion A moderate or high dose of behavioral weight-loss treatment may be required to produce clinically significant reductions in binge eating severity in adults with obesity. PMID:27086049

Differential dose- and time-dependent effects of molindone on dopamine neurons of rat brain: mediation by irreversible inhibition of monoamine oxidase.

PubMed

Meller, E; Friedman, E

1982-03-01

The effects of molindone (2.5, 10 and 40 mg/kg) on striatal tyrosine hydroxylase activity and dopamine (DA), 3,4-dihydroxyphenylacetic acid and homovanillic acid levels were measured as a function of time (0-72 hr). Whereas a dose of 2.5 mg/kg produced effects typical of DA receptor blockade (activation of synaptosomal tyrosine hydroxylase, increased DA metabolite levels and unchanged DA levels), a dose of 40 mg/kg produced opposite effects (decreased tyrosine hydroxylase activity and metabolite concentrations and elevated DA levels). A dose of 10 mg/kg elicited intermediate effects. The atypical effects of both higher doses were long-lasting (less than 72 hr). Molindone at doses of 10 or 40 mg/kg, but nor 2.5 mg/kg, selectively, irreversibly and dose-dependently inhibited type A monoamine oxidase. This inhibition appeared to be due to a metabolite, inasmuch as the drug itself inhibited monoamine oxidase (reversibly) only at high concentrations (less than or equal to 10(-4) M). The heretofore unsuspected inhibition of monoamine oxidase by molindone provided a consistent mechanistic interpretation of the differential dose- and time-dependent effects of the drug on dopaminergic neuronal activity. This mechanism may also serve to explain the reported efficacy of molindone in animal tests for antidepressant activity as well as its inability to produce increased DA receptor binding after chronic treatment.

Psilocybin occasioned mystical-type experiences: Immediate and persisting dose-related effects

PubMed Central

Griffiths, R. R.; Johnson, M.W.; Richards, W. A.; Richards, B.D.; McCann, U.; Jesse, R.

2012-01-01

Rationale This dose-effect study extends previous observations showing that psilocybin can occasion mystical-type experiences having persisting positive effects on attitudes, mood, and behavior. Objectives This double-blind study evaluated psilocybin (0, 5, 10, 20, 30 mg/70 kg, p.o.) administered under supportive conditions. Methods Participants were 18 adults (17 hallucinogen-naïve). Five 8-hour sessions were conducted individually for each participant at 1-month intervals. Participants were randomized to receive the four active doses in either ascending or descending order (9 participants each). Placebo was scheduled quasi-randomly. During sessions volunteers used eyeshades and were instructed to direct their attention inward. Volunteers completed questionnaires assessing effects immediately after and 1 month after each session, and at 14 months follow-up. Results Psilocybin produced acute perceptual and subjective effects including, at 20 and/or 30 mg/70 kg, extreme anxiety/fear (39% of volunteers) and/or mystical-type experience (72% of volunteers). One month after sessions at the two highest doses, volunteers rated the psilocybin experience as having substantial personal and spiritual significance, and attributed to the experience sustained positive changes in attitudes, mood, and behavior, with the ascending dose sequence showing greater positive effects. At 14 months, ratings were undiminished and were consistent with changes rated by community observers. Both the acute and persisting effects of psilocybin were generally a monotonically increasing function of dose, with the lowest dose showing significant effects. Conclusions Under supportive conditions, 20 and 30 mg/70 kg psilocybin occasioned mystical-type experiences having persisting positive effects on attitudes, mood and behavior. Implications for therapeutic trials are discussed. PMID:21674151

Injectable, sustained-release naltrexone for the treatment of opioid dependence: a randomized, placebo-controlled trial

PubMed Central

Comer, Sandra D.; Sullivan, Maria A.; Yu, Elmer; Rothenberg, Jami L.; Kleber, Herbert D.; Kampman, Kyle; Dackis, Charles; O'Brien, Charles P.; Chiang, C. Nora; Hawks, Richard L.

2013-01-01

Context Naltrexone is a medication available in oral form that can completely block the effects produced by opioid agonists, such as heroin. However, poor medication compliance with naltrexone has been a major obstacle to the effective treatment of opioid dependence. Objective To evaluate the safety and efficacy of a sustained-release depot formulation of naltrexone in treating opioid dependence. Design, Setting, and Participants Randomized, double-blind, placebo-controlled, 8-week multi-center trial of male and female heroin-dependent patients who participated in the study between September 2000 and November 2003. Participants were stratified by years of heroin use (≥5, <4.9) and gender, and then randomized to receive one of three doses: placebo, 192 mg, or 384 mg depot naltrexone. Doses were administered at the beginning of Week 1 and then again four weeks later at the beginning of Week 5. All participants received twice-weekly relapse prevention therapy, provided observed urine samples, and completed other assessments at each visit. Main Outcome Measures Primary outcome measures were retention in treatment and percentage of opioid-negative urine samples. Results A total of 60 patients were randomized at two centers. Retention in treatment was dose related with 39%, 60%, and 68% of the patients in the placebo, naltrexone 192 mg, and naltrexone 384 mg groups, respectively, remaining in treatment at the end of the two-month treatment period. Analysis of the time to dropout revealed a significant main effect of dose with mean time to dropout of 27, 36, and 48 days, respectively, for the placebo, naltrexone 192 mg, and naltrexone 384 mg groups. The percentage of urine samples negative for opioids varied significantly as a function of dose, as did the percentage of urine samples negative for methadone, cocaine, benzodiazepines, and amphetamine. The percentage of urine samples negative for cannabinoids was not significantly different across groups. When the data were recalculated without the assumption that missing urine samples were positive, however, a main effect of group was not found for any of the drugs tested with the exception of cocaine, where the percentage of cocaine-negative urines was lower in the placebo group. Adverse events were minimal and generally mild in severity. This sustained-release formulation of naltrexone was well tolerated and produced a robust and dose-related increase in treatment retention. Conclusion The present data provide exciting new evidence for the feasibility, efficacy, and tolerability of long-lasting antagonist treatments for opioid dependence. PMID:16461865

Systemic Effects of Intracoronary Nitroglycerin during Coronary Angiography in Children after Heart Transplantation

PubMed Central

Lara, Diego A.; Olive, Mary K.; George, James F.; Brown, Robert N.; Carlo, Waldemar F.; Colvin, Edward V.; Steenwyck, Brad L.

2014-01-01

Coronary spasm during coronary angiography for vasculopathy in children can be prevented by the intracoronary administration of nitroglycerin. We reviewed the anesthesia and catheterization reports and charts for pediatric transplant recipients who underwent angiography from 2005 through 2010. Correlation analysis was used to study the relation of post-injection systolic blood pressure (SBP) to nitroglycerin dose. Forty-one angiographic evaluations were performed on 25 patients (13 male and 12 female). Mean age was 9.9 ± 3.2 years (range, 3.3–16.1 yr). The mean total dose of nitroglycerin was 2.93 ± 1.60 µg/kg (range, 1–8 µg/kg). There was a significant drop between the baseline SBP (mean, 106 ± 21.6 mmHg) and the lowest mean SBP before nitroglycerin administration (78 ± 13.2, P <0.0001, paired t test). There was no significant additional change in SBP (mean after nitroglycerin administration, 80.7 ± 13.1 mmHg; P = 0.2). There was a significant drop in lowest heart rate between baseline (109 ± 16.5 beats/min) and before nitroglycerin administration (89 ± 14.3 beats/min; P <0.0001, paired t test). There was no significant additional change in heart rate (mean heart rate after nitroglycerin, 84 ± 17.7 beats/min; P = 0.09). There were 2 interventions for SBP before nitroglycerin and 2 after nitroglycerin. One child experienced a transient ST-T–segment change during angiography after nitroglycerin. In the highest dose range, the additional decrease in SBP was 7.2 mmHg (P=0.03). Routine intracoronary nitroglycerin administration in this dose range produced no significant changes in SBP or heart rate in children. PMID:24512395

Systemic effects of intracoronary nitroglycerin during coronary angiography in children after heart transplantation.

PubMed

Lara, Diego A; Olive, Mary K; George, James F; Brown, Robert N; Carlo, Waldemar F; Colvin, Edward V; Steenwyck, Brad L; Pearce, F Bennett

2014-02-01

Coronary spasm during coronary angiography for vasculopathy in children can be prevented by the intracoronary administration of nitroglycerin. We reviewed the anesthesia and catheterization reports and charts for pediatric transplant recipients who underwent angiography from 2005 through 2010. Correlation analysis was used to study the relation of post-injection systolic blood pressure (SBP) to nitroglycerin dose. Forty-one angiographic evaluations were performed on 25 patients (13 male and 12 female). Mean age was 9.9 ± 3.2 years (range, 3.3-16.1 yr). The mean total dose of nitroglycerin was 2.93 ± 1.60 µg/kg (range, 1-8 µg/kg). There was a significant drop between the baseline SBP (mean, 106 ± 21.6 mmHg) and the lowest mean SBP before nitroglycerin administration (78 ± 13.2, P <0.0001, paired t test). There was no significant additional change in SBP (mean after nitroglycerin administration, 80.7 ± 13.1 mmHg; P = 0.2). There was a significant drop in lowest heart rate between baseline (109 ± 16.5 beats/min) and before nitroglycerin administration (89 ± 14.3 beats/min; P <0.0001, paired t test). There was no significant additional change in heart rate (mean heart rate after nitroglycerin, 84 ± 17.7 beats/min; P = 0.09). There were 2 interventions for SBP before nitroglycerin and 2 after nitroglycerin. One child experienced a transient ST-T-segment change during angiography after nitroglycerin. In the highest dose range, the additional decrease in SBP was 7.2 mmHg (P=0.03). Routine intracoronary nitroglycerin administration in this dose range produced no significant changes in SBP or heart rate in children.

Cardiovascular effects of medetomidine, detomidine and xylazine in horses.

PubMed

Yamashita, K; Tsubakishita, S; Futaok, S; Ueda, I; Hamaguchi, H; Seno, T; Katoh, S; Izumisawa, Y; Kotani, T; Muir, W W

2000-10-01

The cardiovascular effects of medetomidine, detomidine, and xylazine in horses were studied. Fifteen horses, whose right carotid arteries had previously been surgically raised to a subcutaneous position during general anesthesia were used. Five horses each were given the following 8 treatments: an intravenous injection of 4 doses of medetomidine (3, 5, 7.5, and 10 microg/kg), 3 doses of detomidine (10, 20, and 40 microg/kg), and one dose of xylazine (1 mg/kg). Heart rate decreased, but not statistically significant. Atrio-ventricular block was observed following all treatments and prolonged with detomidine. Cardiac index (CI) and stroke volume (SV) were decreased with all treatments. The CI decreased to about 50% of baseline values for 5 min after 7.5 and 10 microg/kg medetomidine and 1 mg/kg xylazine, for 20 min after 20 microg/kg detomidine, and for 50 min after 40 microg/kg detomidine. All treatments produced an initial hypertension within 2 min of drug administration followed by a significant decrease in arterial blood pressure (ABP) in horses administered 3 to 7.5 microg/kg medetomidine and 1 mg/kg xylazine. Hypertension was significantly prolonged in 20 and 40 microg/kg detomidine. The hypotensive phase was not observed in 10 microg/kg medetomidine or detomidine. The changes in ABP were associated with an increase in peripheral vascular resistance. Respiratory rate was decreased for 40 to 120 min in 5, 7.5, and 10 microg/kg medetomidine and detomidine. The partial pressure of arterial oxygen decreased significantly in 10 microg/kg medetomidine and detomidine, while the partial pressure of arterial carbon dioxide did not change significantly. Medetomidine induced dose-dependent cardiovascular depression similar to detomidine. The cardiovascular effects of medetomidine and xylazine were not as prolonged as that of detomidine.

Effect of a high-fructose diet on glucose tolerance, plasma lipid and hemorheological parameters during oral contraceptive administration in female rats.

PubMed

Olatunji, Lawrence Aderemi; Oyeyipo, Ibukun Peter; Usman, Taofeek Oluwamayowa

2013-01-01

Oral contraceptive (OC) use and increased fructose feeding have been associated with altered cardiometabolic effects. The effect of increased dietary fructose during OC use on cardiometabolic parameters is unknown. We investigated the effects of a high-fructose diet on body weight gain, fasting blood glucose, glucose tolerance, plasma lipid and hemorheological parameters in female rats treated with a combination of OC steroids (norgestrel/ethinyl estradiol; NEE). Rats were given (p.o.) vehicle, high-dose NEE (10.0 μg norgestrel/1.0 μg ethinyl estradiol) or low-dose NEE (1.0 μg norgestrel/0.1 μg ethinyl estradiol) with or without high dietary fructose daily for 6 weeks. Results demonstrated that high-dose NEE but not low-dose NEE treatment led to significant increases in hematocrit, blood viscosity, and decreases in body weight gain, glucose tolerance, and plasma HDL-cholesterol level. Both NEE treatments resulted in significant increases in plasma viscosity and triglyceride. Increased dietary fructose without NEE treatment produced significant increases in fasting blood glucose, hematocrit, blood and plasma viscosities, while increased dietary fructose significantly potentiated the effects on blood and plasma viscosities observed during NEE treatment. Conversely, the effects of NEE treatment on body weight gain, glucose tolerance, plasma triglyceride and HDL-cholesterol were significantly attenuated. In conclusion, the results indicate that increase in dietary fructose may worsen abnormal blood rheology. The results also demonstrate that increased dietary fructose may not impact negatively on glucose and lipid metabolisms during OC use. The findings imply that fructose-enriched diet might be an important consideration during OC use regarding blood rheological properties.

Monte Carlo skin dose simulation in intraoperative radiotherapy of breast cancer using spherical applicators

NASA Astrophysics Data System (ADS)

Moradi, F.; Ung, N. M.; Khandaker, M. U.; Mahdiraji, G. A.; Saad, M.; Malik, R. Abdul; Bustam, A. Z.; Zaili, Z.; Bradley, D. A.

2017-08-01

The relatively new treatment modality electronic intraoperative radiotherapy (IORT) is gaining popularity, irradiation being obtained within a surgically produced cavity being delivered via a low-energy x-ray source and spherical applicators, primarily for early stage breast cancer. Due to the spatially dramatic dose-rate fall off with radial distance from the source and effects related to changes in the beam quality of the low keV photon spectra, dosimetric account of the Intrabeam system is rather complex. Skin dose monitoring in IORT is important due to the high dose prescription per treatment fraction. In this study, modeling of the x-ray source and related applicators were performed using the Monte Carlo N-Particle transport code. The dosimetric characteristics of the model were validated against measured data obtained using an ionization chamber and EBT3 film as dosimeters. By using a simulated breast phantom, absorbed doses to the skin for different combinations of applicator size (1.5-5 cm) and treatment depth (0.5-3 cm) were calculated. Simulation results showed overdosing of the skin (>30% of prescribed dose) at a treatment depth of 0.5 cm using applicator sizes larger than 1.5 cm. Skin doses were significantly increased with applicator size, insofar as delivering 12 Gy (60% of the prescribed dose) to skin for the largest sized applicator (5 cm diameter) and treatment depth of 0.5 cm. It is concluded that the recommended 0.5-1 cm distance between the skin and applicator surface does not guarantee skin safety and skin dose is generally more significant in cases with the larger applicators. Highlights: • Intrabeam x-ray source and spherical applicators were simulated and skin dose was calculated. • Skin dose for constant skin to applicator distance strongly depends on applicator size. • Use of larger applicators generally results in higher skin dose. • The recommended 0.5-1 cm skin to applicator distance does not guarantee skin safety.

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

SU-E-T-491: Importance of Energy Dependent Protons Per MU Calibration Factors in IMPT Dose Calculations Using Monte Carlo Technique

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

Randeniya, S; Mirkovic, D; Titt, U

2014-06-01

Purpose: In intensity modulated proton therapy (IMPT), energy dependent, protons per monitor unit (MU) calibration factors are important parameters that determine absolute dose values from energy deposition data obtained from Monte Carlo (MC) simulations. Purpose of this study was to assess the sensitivity of MC-computed absolute dose distributions to the protons/MU calibration factors in IMPT. Methods: A “verification plan” (i.e., treatment beams applied individually to water phantom) of a head and neck patient plan was calculated using MC technique. The patient plan had three beams; one posterior-anterior (PA); two anterior oblique. Dose prescription was 66 Gy in 30 fractions. Ofmore » the total MUs, 58% was delivered in PA beam, 25% and 17% in other two. Energy deposition data obtained from the MC simulation were converted to Gy using energy dependent protons/MU calibrations factors obtained from two methods. First method is based on experimental measurements and MC simulations. Second is based on hand calculations, based on how many ion pairs were produced per proton in the dose monitor and how many ion pairs is equal to 1 MU (vendor recommended method). Dose distributions obtained from method one was compared with those from method two. Results: Average difference of 8% in protons/MU calibration factors between method one and two converted into 27 % difference in absolute dose values for PA beam; although dose distributions preserved the shape of 3D dose distribution qualitatively, they were different quantitatively. For two oblique beams, significant difference in absolute dose was not observed. Conclusion: Results demonstrate that protons/MU calibration factors can have a significant impact on absolute dose values in IMPT depending on the fraction of MUs delivered. When number of MUs increases the effect due to the calibration factors amplify. In determining protons/MU calibration factors, experimental method should be preferred in MC dose calculations. Research supported by National Cancer Institute grant P01CA021239.« less

Analgesic effects of β-phenylethylamine and various methylated derivatives in mice.

PubMed

Mosnaim, Aron D; Hudzik, Thomas; Wolf, Marion E

2014-09-01

Administration of β-phenylethylamine (PEA), the simplest endogenous neuroamine, and various methylated PEA derivatives including α-methyl PEA (amphetamine, AMP) elicits analgesia in mice. Five or 20 min after intraperitoneal PEA injection of as little as 6 mg/kg resulted in an increased latency response time (from 2.4 ± 0.4 to 8.5 ± 2.3 or 7.0 ± 3.0 s, respectively) to the thermal stimulus (hot-plate test), which reached statistical significance at the 15 mg/kg (20 min; 13.1 ± 0.4 s) or 25 mg/kg dose (5 min; 15.3 ± 4.1 s). This PEA effect, was dose-dependent (albeit non-linear: 6, 12, 15, 25, 50 and 100 mg/kg), reached the cut-off time of 45 s at the upper PEA dose (5 min), and it was consistently enhanced by pretreatment with the monoamine oxidase inhibitor pargyline (P). Methylated PEA derivatives (15 and 100 mg/kg dose) produced various degrees of analgesia (in decreasing order p-Me PEA > PEA > N,N-diMe PEA > N-Me PEA) which, likewise to PEA itself, were consistently increased by P and declined over time (mice tested 5, 20 and 60 min after amine injection); small but statistically significant o- and β-Me PEA antinociceptive effects (5 min) were observed only at the higher dose (in the presence of P for β-Me PEA). A small analgesic effect was observed after the administration of AMP (5 or 10 mg/kg) which failed, even after P, to reach statistically significance. Independent of the amine and concentration tested, individual compound's antinociceptive properties were reliably increased by P (exception of AMP), decreased by reserpine (R) or haloperidol (H), and remained essentially unchanged after naloxone (N) administration suggesting the involvement of catecholamines, but not opioid peptides, in their observed analgesic effects. Injection of P + N produced results similar to those seen after P alone. Under the experimental conditions described neither P, R, H or N had any effects by themselves. These findings suggest additional understanding of the mechanism of action responsible for the analgesic effects of these amines would be of interest, leading further to controlled studies on their alleged usefulness as weight reducing agents and sport performance enhancers.

Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids.

PubMed

Bateman, Eric D; Guerreros, Alfredo G; Brockhaus, Florian; Holzhauer, Björn; Pethe, Abhijit; Kay, Richard A; Townley, Robert G

2017-08-01

Dose-related efficacy and safety of fevipiprant (QAW039), an oral DP 2 (CRTh2) receptor antagonist, was assessed in patients with allergic asthma uncontrolled by low-dose inhaled corticosteroids (ICS).Adult patients were randomised to 12 weeks' treatment with once-daily (1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d ) or twice-daily (2, 25, 75 or 150 mg b.i.d ) fevipiprant (n=782), montelukast 10 mg q.d (n=139) or placebo (n=137). All patients received inhaled budesonide 200 μg b.i.d Fevipiprant produced a statistically significant improvement in the primary end-point of change in pre-dose forced expiratory volume in 1 s at week 12 (p=0.0035) with a maximum model-averaged difference to placebo of 0.112 L. The most favourable pairwise comparisons to placebo were for the fevipiprant 150 mg q.d and 75 mg b.i.d groups, with no clinically meaningful differences between q.d and b.i.d Montelukast also demonstrated a significant improvement in this end-point. No impact on other efficacy end-points was observed. Adverse events were generally mild/moderate in severity, and were evenly distributed across doses and treatments.Fevipiprant appears to be efficacious and well-tolerated in this patient population, with an optimum total daily dose of 150 mg. Further investigations into the clinical role of fevipiprant in suitably designed phase III clinical trials are warranted. Copyright ©ERS 2017.

Fevipiprant, an oral prostaglandin DP2 receptor (CRTh2) antagonist, in allergic asthma uncontrolled on low-dose inhaled corticosteroids

PubMed Central

Guerreros, Alfredo G.; Brockhaus, Florian; Pethe, Abhijit; Kay, Richard A.; Townley, Robert G.

2017-01-01

Dose-related efficacy and safety of fevipiprant (QAW039), an oral DP2 (CRTh2) receptor antagonist, was assessed in patients with allergic asthma uncontrolled by low-dose inhaled corticosteroids (ICS). Adult patients were randomised to 12 weeks' treatment with once-daily (1, 3, 10, 30, 50, 75, 150, 300 or 450 mg q.d.) or twice-daily (2, 25, 75 or 150 mg b.i.d.) fevipiprant (n=782), montelukast 10 mg q.d. (n=139) or placebo (n=137). All patients received inhaled budesonide 200 μg b.i.d. Fevipiprant produced a statistically significant improvement in the primary end-point of change in pre-dose forced expiratory volume in 1 s at week 12 (p=0.0035) with a maximum model-averaged difference to placebo of 0.112 L. The most favourable pairwise comparisons to placebo were for the fevipiprant 150 mg q.d. and 75 mg b.i.d. groups, with no clinically meaningful differences between q.d. and b.i.d. Montelukast also demonstrated a significant improvement in this end-point. No impact on other efficacy end-points was observed. Adverse events were generally mild/moderate in severity, and were evenly distributed across doses and treatments. Fevipiprant appears to be efficacious and well-tolerated in this patient population, with an optimum total daily dose of 150 mg. Further investigations into the clinical role of fevipiprant in suitably designed phase III clinical trials are warranted. PMID:28838980

Immunomodulatory activity of methanolic leaf extract of Moringa oleifera in animals.

PubMed

Sudha, P; Asdaq, Syed Mohammed Basheeruddin; Dhamingi, Sunil S; Chandrakala, Gowda Kallenahalli

2010-01-01

The aim of the present study was to investigate the immunomodulatory action of methanolic extract of Moringa oleifera (MEMO) in an experimental model of immunity. The cellular immunity was evaluated using neutrophil adhesion test, cyclophosphamide induced neutropenia and carbon clearance assay, whereas, humoral immunity was tested by mice lethality test, serum immunoglobulin estimation and indirect haemagglutination assay in animals. Administration of MEMO (250 and 750 mg/kg, po) and Ocimum sanctum (100 mg/kg, po) significantly increased the levels of serum immunoglobulins and also prevented the mortality induced by bovine Pasteurella multocida in mice. They also increased significantly the circulating antibody titre in indirect haemagglunation test. Moreover, MEMO produced significant increase in adhesion of neutrophils, attenuation of cyclophosphamide-induced neutropenia and an increase in phagocytic index in carbon clearance assay. From the above results, it can be concluded that MEMO stimulate both cellular and humoral immune response. However, low dose of MEMO was found to be more effective than the high dose.

Histotripsy of the Prostate for the Treatment of BPH: Chronic Results From a Canine Model

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

Hall, Timothy L.; Hempel, Chris R.; Lake, Alison M.

2009-04-14

Histotripsy was evaluated as a non-invasive BPH treatment. The prostates of 21 canine subjects were targeted with one of three histotripsy doses. Prostates were harvested immediately, 7 days, or 28 days after treatment and assessed for changes. Lower treatment doses were found to produced scattered cellular disruption and hemorrhage that was sometimes reversible. Higher doses perforated the urethra and produced cavities in the glandular prostate that healed to leave an enlarged urinary channel.

Histotripsy of the Prostate for the Treatment of BPH: Chronic Results From a Canine Model

NASA Astrophysics Data System (ADS)

Hall, Timothy L.; Hempel, Chris R.; Lake, Alison M.; Kieran, Kathy; Ives, Kim; Fowlkes, J. Brian; Cain, Charles A.; Roberts, William W.

2009-04-01

Histotripsy was evaluated as a non-invasive BPH treatment. The prostates of 21 canine subjects were targeted with one of three histotripsy doses. Prostates were harvested immediately, 7 days, or 28 days after treatment and assessed for changes. Lower treatment doses were found to produced scattered cellular disruption and hemorrhage that was sometimes reversible. Higher doses perforated the urethra and produced cavities in the glandular prostate that healed to leave an enlarged urinary channel.

Development of a Chlorine Dosing Strategy for Fresh Produce Washing Process to Maintain Microbial Food Safety and Minimize Residual Chlorine.

PubMed

Chen, Xi; Hung, Yen-Con

2018-06-01

The residual free chlorine level in fresh produce wash solution is closely correlated to the chemical and microbial safety of produce. Excess amount of free chlorine can quickly react with organic matters to form hazardous disinfection by-products (DBPs) above EPA-permitted levels, whereas deficiency of residual chlorine in produce wash solution may result in incompletely removing pathogens on produce. The purpose of this study was to develop a chlorine dosing strategy to optimize the chlorine dosage during produce washing process without impacting the microbial safety of fresh produce. Prediction equations were developed to estimate free chlorine needed to reach targeted residual chlorine at various sanitizer pH and organic loads, and then validated using fresh-cut iceberg lettuce and whole strawberries in an automated produce washer. Validation results showed that equations successfully predicted the initial chlorine concentration needed to achieve residual chlorine at 10, 30, 60, and 90 mg/L for both lettuce and strawberry washing processes, with the root mean squared error at 4.45 mg/L. The Escherichia coli O157:H7 reductions only slightly increased on iceberg lettuce and strawberries with residual chlorine increasing from 10 to 90 mg/L, indicating that lowering residual chlorine to 10 mg/L would not compromise the antimicrobial efficacy of chlorine-based sanitizer. Based on the prediction equations and E. coli O157:H7 reduction results, a chlorine dosing strategy was developed to help the produce industry to maintain microbial inactivation efficacy without adding excess amount of free chlorine. The chlorine dosing strategy can be used for fresh produce washing process to enhance the microbial food safety and minimize the DBPs formation potential. © 2018 Institute of Food Technologists®.

A comparison of the fragmentation thresholds and inertial cavitation doses of different ultrasound contrast agents

NASA Astrophysics Data System (ADS)

Chen, Wen-Shiang; Matula, Thomas J.; Brayman, Andrew A.; Crum, Lawrence A.

2003-01-01

Contrast bubble destruction is important in several new diagnostic and therapeutic applications. The pressure threshold of destruction is determined by the shell material, while the propensity for of the bubbles to undergo inertial cavitation (IC) depends both on the gas and shell properties of the ultrasound contrast agent (UCA). The ultrasonic fragmentation thresholds of three specific UCAs (Optison, Sonazoid, and biSpheres), each with different shell and gas properties, were determined under various acoustic conditions. The acoustic emissions generated by the agents, or their derivatives, characteristic of IC after fragmentation, was also compared, using cumulated broadband-noise emissions (IC ``dose''). Albumin-shelled Optison and surfactant-shelled Sonazoid had low fragmentation thresholds (mean=0.13 and 0.15 MPa at 1.1 MHz, 0.48 and 0.58 MPa at 3.5 MHz, respectively), while polymer-shelled biSpheres had a significant higher threshold (mean=0.19 and 0.23 MPa at 1.1 MHz, 0.73 and 0.96 MPa for thin- and thick-shell biSpheres at 3.5 MHz, respectively, p<0.01). At comparable initial concentrations, surfactant-shelled Sonazoid produced a much larger IC dose after shell destruction than did either biSpheres or Optison (p<0.01). Thick-shelled biSpheres had the highest fragmentation threshold and produced the lowest IC dose. More than two and five acoustic cycles, respectively, were necessary for the thin- and thick-shell biSpheres to reach a steady-state fragmentation threshold.

SU-F-T-360: Dosimetric Impacts On the Mucosa and Bone in Radiotherapy with Unflattened Photon Beams

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

Chow, J; Owrangi, A

Purpose: This study investigated the dosimetric impacts on the mucosa and bone when using the unflattened photon beams in radiotherapy. Dose calculations were carried out by Monte Carlo simulation. Methods: Heterogeneous phantoms containing water (soft tissue and mucosa), air and bone, with mucosa thicknesses varying from 0.5 – 3 mm were irradiated by the 6 MV unflattened and flattened photon beams (field size = 10 × 10 cm{sup 2}), produced by a Varian TrueBEAM linear accelerator. The photon energy spectra of the beams, mean bone and mucosal doses with different mucosa thicknesses were calculated using the EGSnrc Monte Carlo code.more » Results: It is found that the flattened photon beams had higher mean bone doses (1.3% and 2% for upper and lower bone regarding the phantom geometry, respectively) than the unflattened beams, and the mean bone doses of both beams did not vary significantly with the mucosa thickness. Similarly, flattened photon beams had higher mucosal dose (0.9% and 1.6% for upper and lower mucosa, respectively) than the unflattened beams. This is due to the larger slope of the depth dose for the unflattened photon beams compared to the flattened. The mucosal doses of both beams were found increased with the mucosa thickness. Moreover, the mucosal dose differences between the unflattened and flattened beams increased with the mucosa thickness. For photon energy spectra on the mucosal layers, it is found that the unflattened photon beams contained a larger portion of lowenergy photons than the flattened beams. The photon energy spectra did not change significantly with the mucosa thickness. Conclusion: It is concluded that the mucosal and bone dose for the unflattened photon beams were not more than 2% lower than the flattened beams, though the flattening filter free beams contained larger portion of low-energy photons than the flattened beams.« less

[Pharmacological correction of central nervous system function in exposure to Coriolis acceleration].

PubMed

Karkishchenko, N N; Dimitriadi, N A; Molchanovskiĭ, V V

1986-01-01

Healthy volunteers with a low vestibular tolerance were exposed to Coriolis acceleration. Potassium orotate, pyracetame and riboxine were used as prophylactic measures against disorders in the function of the vestibular apparatus and higher compartments of the higher nervous system. The central nervous function was assessed with respect to the spectral power of electroencephalograms, short-term memory and mental performance. Potassium orotate given at a dose of 40 mg/kg body weight/day during 12-14 days as well as pyracetame given at a dose of 30 mg/kg body weight/day during 3 or 7 days increased significantly statokinetic tolerance and produced a protective effect on the central nervous function against Coriolis acceleration.

[Morphological study of the adrenals of rats exposed on the Kosmos-690 satellite].

PubMed

Savina, E A; Alekseev, E I

1979-01-01

Adrenals of 12 rats flown aboard the biosatellite Cosmos-690 and 30 rats used in the ground-based experiments Control-1 and Control-2 were studied morphologically. The animals were sacrificed on the 2nd and 27th days after completion of the experiments (i. e., on the 12 and 37th days after irradiation at a total dose of 800 rad). A comparative study of morphological changes in the adrenals of flight and control rats did not show any distinct differences. It is therefore concluded that space flight factors did not produce a significant effect on the adrenal response to irradiation at a dose of 800 rad.

Anti-inflammatory activities of ethanolic extract of Carica papaya leaves.

PubMed

Owoyele, Bamidele V; Adebukola, Olubori M; Funmilayo, Adeoye A; Soladoye, Ayodele O

2008-08-01

The anti-inflammatory activity of an ethanolic extract of Carica papaya leaves was investigated in rats using carrageenan induced paw oedema, cotton pellet granuloma and formaldehyde induced arthritis models. Experimental animals received 25-200 mg/Kg (orally) of the extracts or saline (control group) and the reference group received 5 mg/ Kg of indomethacin. The ulcerogenic activity of the extract was also investigated. The results show that the extracts significantly (p <0.05) reduced paw oedema in the carrageenan test. Likewise the extract produced significant reduction in the amount of granuloma formed from 0.58 +/-0.07 to 0.22 +/-0.03 g. In the formaldehyde arthritis model, the extracts significantly reduced the persistent oedema from the 4th day to the 10th day of the investigation. The extracts also produced slight mucosal irritation at high doses. The study establishes the anti-inflammatory activity of Carica papaya leaves.

Aspirin administered to women at 100 mg every other day produces less platelet inhibition than aspirin administered at 81 mg per day: implications for interpreting the women's health study.

PubMed

Swaim, Lisa; Hillman, Robert S

2009-07-01

We aimed to determine the relative level of platelet inhibition achieved with low-dose aspirin (81 mg daily) compared with a very low-dose (100 mg every other day). The Womens Health Study (WHS) found that a dose of 100 mg every other day of aspirin provided protection against stroke as primary prophylaxis, but not myocardial infarction. In the United States, the most commonly prescribed dose of aspirin for primary prophylaxis is 81 mg per day. As a result, it is important to know whether these doses are equivalent before extrapolating the results of the WHS to women in the U.S. To achieve this goal, we have studied the effects of these two dosing regimens on platelet function in healthy women meeting the WHS inclusion criteria using a randomized design. We enrolled 49 healthy female volunteers and used a sequential, crossover design to compare the two regimens. The participants received a 17-day course of each aspirin-dosing regimen separated by a 7-day washout period. The degree of platelet inhibition was measured on days 14-17 of each dosing regimen using a point-of-care platelet function assay utilizing arachidonic acid to activate platelets (VerifyNow-Aspirin). Participants platelet response, expressed as Aspirin Response Unit (ARU) attained a significantly greater level of platelet inhibition on days 14-17 while taking aspirin 81 mg daily compared to aspirin 100 mg every other day (31.3% vs. 12.7%, P < 0.0001) with mean +/- SD ARU values of 445 +/- 50 and 570 +/- 68, P < 0.0001. Significantly more daily readings in participants were >or=550 ARU, a value correlated with clinical outcomes in several studies, with the 100 mg every other day regimen (72.0% vs. 6.4% with 81 mg daily, P < 0.0001), and this alternate-day regimen also resulted in more day-to-day variability in platelet function (P = 0.0002). We found significantly less inhibition of platelet function with the dose used in the WHS than the usual U.S. dose. We observed that the degree of platelet inhibition was significantly less with aspirin 100 mg every other day compared with aspirin 81 mg daily, suggesting that results of the Women's Health Study may have underestimated both the efficacy and toxicity of aspirin as it is commonly administered. These data need to be considered when developing recommendations about the use of aspirin in the primary prevention of cardiovascular disease in women.

Modulation of some quantitative and qualitative characteristics in rice ( Oryza sativa L.) and mung ( Phaseolus mungo L.) by ionizing radiation

NASA Astrophysics Data System (ADS)

Maity, J. P.; Mishra, D.; Chakraborty, A.; Saha, A.; Santra, S. C.; Chanda, S.

2005-12-01

The present work describes radiation-induced effects on some morphological characters of a cereal and a pulse-producing crop in India. 60Co gamma source is used for irradiating (from 50 to 350 Gy) the rice ( Oryza sativa L., Cv-2233) and mung ( Phaseolus mungo L.). Irradiation at lower doses of gamma rays effectively influences improving the morphological traits like seedling/plant height, tiller number, panicle number, panicle length, seed per panicle, seed per pod, pod length, pod number, while exposure at higher doses results in depletion of such parameters. Effective stimulatory dose for Oryza sativa L. Cv-2233 is 50 Gy and that for Phaseolus mungo L. is 200 Gy. Significance of such stimulation correlated with yielding ability of the plant concerned is discussed in the light of newer aspects in agricultural research.

Stability of nanosized oxides in ferrite under extremely high dose self ion irradiations

DOE PAGES

Aydogan, E.; Almirall, N.; Odette, G. R.; ...

2017-01-10

We produced a nanostructured ferritic alloy (NFA), 14YWT, in the form of thin walled tubing. The stability of the nano-oxides (NOs) was determined under 3.5 MeV Fe +2 irradiations up to a dose of ~585 dpa at 450 °C. Transmission electron microscopy (TEM) and atom probe tomography (APT) show that severe ion irradiation results in a ~25% reduction in size between the unirradiated and irradiated case at 270 dpa while no further reduction within the experimental error was seen at higher doses. Conversely, number density increased by ~30% after irradiation. Moreover, this ‘inverse coarsening’ can be rationalized by the competitionmore » between radiation driven ballistic dissolution and diffusional NO reformation. There were no significant changes in the composition of the matrix or NOs observed after irradiation. Modeling the experimental results also indicated a dissolution of the particles.« less

Effects of gamma radiation on development, sterility, fecundity, and sex ratio of Dermanyssus gallinae (DeGeer) (Acari: Dermanyssidae)

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

Entrekin, D.L.; Oliver, J.H. Jr.; Pound, J.M.

1987-06-01

Protonymphal Dermanyssus gallinae were irradiated with 0.50, 0.75, 1.0, 3.0, and 6.0 krad of gamma radiation and subsequently monitored regarding their developmental, feeding, and mating success. Also, sex ratios of adults treated as protonymphs were recorded as were sex ratios of embryos and F1 adults produced by these adults. Doses up to 1.0 krad did not prevent development of treated protonymphs to the adult stage or stop mating. Three krad reduced the number of treated protonymphs attaining adulthood and 6.0-krad treatment prevented all mites from developing to the adult stage. Egg (embryo) production was normal for mites treated with 0.50more » krad, but significantly curtailed by doses of 0.75 krad and greater. Radiation doses used in this study did not appear to affect the normal variable sex ratios observed in untreated mites.« less