Sample records for dose 28-day oral

  1. Acute and repeated dose (28 days) oral safety studies of ALIBIRD in rats.

    PubMed

    Anadón, Arturo; Martínez, María A; Ares, Irma; Castellano, Victor; Martínez-Larrańaga, Maria R; Corzo, Nieves; Olano, Agustin; Montilla, Antonia; Recio, Isidra; Martínez-Maqueda, Daniel; Miralles, Beatriz; Fornari, Tiziana; García-Risco, Mónica R; Gonzalez, Monserrat; Reglero, Guillermo

    2013-07-01

    ALIBIRD, a test substance composed of oligosaccharides derived from lactulose, a hydrolysate of a whey protein concentrate, and a supercritical extract of rosemary (1:0.5:0.05), was prepared in the laboratory and evaluated for its safety as a multifunctional food additive. In oral toxicity studies (acute and 28 days repeated dose) using Wistar rats, ALIBIRD was administered in a single oral gavage dose of 2,000 mg/kg of body weight and resulted in no adverse events or mortality; a daily dose of 2,000 mg/kg of body weight for 28 days by gavage also resulted in no adverse effects or mortality. No abnormal clinical signs, behavioral changes, body weight changes, or changes in food and water consumption occurred in either study. There were no changes in hematological and serum chemistry values, organ weights, or gross or histological characteristics. Based on test results, it is concluded that ALIBIRD is well tolerated in rats at an acute and subchronic (28 days) dose of 2,000 mg/kg of body weight. PMID:23834798

  2. Repeated-dose (28 days) oral toxicity study in rats of an antiacne formula (BC-AF) derived from plants.

    PubMed

    Li, Shengli; Zou, Yingshu; Jiao, Kun; Qiao, Xin; Jiao, Ray; Wang, Ju

    2011-01-01

    To evaluate the safety of a formula (BC-AF) consisting of the extracts of danshen (Salvia miltiorrhiza), loquat leaf (Glycyrrhiza uralensis), and licorice (Eriobotrya japonica), a preliminary 28-day, repeated-dose oral toxicity study was performed in Sprague-Dawley rats. Eighty animals were divided into four groups, with each group comprising 10 male and 10 female rats. BC-AF was administered once-daily by oral gavage at doses of 0 (control), 2.5 (low), 5 (middle), and 10 (high) g/kg body weight successively for each group for 28 days, respectively. Rats in all groups were sacrificed on day 29, except half of the males and females in the high-dose group that were kept for an additional 2 weeks to observe any possible toxicity after drug withdrawal. In 4 weeks, there were no toxicity reactions or abnormal deaths in any animal groups. There was no significant difference, in comparison to the control group, in clinical signs, organ weights, hematological and serological parameters, or histopathologic findings. In conclusion, the 28-day repeated-dose oral toxicity study demonstrates that BC-AF produced no effects in either male or female rats following oral administration of up to 10?g/kg. PMID:20954811

  3. Evaluation of Genotoxicity and 28-day Oral Dose Toxicity on Freeze-dried Powder of Tenebrio molitor Larvae (Yellow Mealworm).

    PubMed

    Han, So-Ri; Yun, Eun-Young; Kim, Ji-Young; Hwang, Jae Sam; Jeong, Eun Ju; Moon, Kyoung-Sik

    2014-06-01

    The larval form of Tenebrio molitor (T. molitor) has been eaten in many countries and provides benefits as a new food source of protein for humans. However, no information exists regarding its safety for humans. The objective of the present study was to evaluate the genotoxicity and repeated dose oral toxicity of the freeze-dried powder of T. molitor larvae. The genotoxic potential was evaluated by a standard battery testing: bacterial reverse mutation test, in vitro chromosome aberration test, and in vivo micronucleus test. To assess the repeated dose toxicity, the powder was administered once daily by oral gavage to Sprague-Dawley (SD) rats at dose levels of 0, 300, 1000 and 3000 mg/kg/day for 28 days. The parameters which were applied to the study were mortality, clinical signs, body and organ weights, food consumption, ophthalmology, urinalysis, hematology, serum chemistry, gross findings and histopathologic examination. The freezedried powder of T. molitor larvae was not mutagenic or clastogenic based on results of in vitro and in vivo genotoxicity assays. Furthermore, no treatment-related changes or findings were observed in any parameters in rats after 28 days oral administration. In conclusion, the freeze-dried powder of T. molitor larvae was considered to be non-genotoxic and the NOAEL (No Observed Adverse Effect Level) was determined to be 3000 mg/kg/day in both sexes of SD rats under our experimental conditions. PMID:25071922

  4. Evaluation of Genotoxicity and 28-day Oral Dose Toxicity on Freeze-dried Powder of Tenebrio molitor Larvae (Yellow Mealworm)

    PubMed Central

    Han, So-Ri; Yun, Eun-Young; Kim, Ji-Young; Hwang, Jae Sam; Jeong, Eun Ju

    2014-01-01

    The larval form of Tenebrio molitor (T. molitor) has been eaten in many countries and provides benefits as a new food source of protein for humans. However, no information exists regarding its safety for humans. The objective of the present study was to evaluate the genotoxicity and repeated dose oral toxicity of the freeze-dried powder of T. molitor larvae. The genotoxic potential was evaluated by a standard battery testing: bacterial reverse mutation test, in vitro chromosome aberration test, and in vivo micronucleus test. To assess the repeated dose toxicity, the powder was administered once daily by oral gavage to Sprague-Dawley (SD) rats at dose levels of 0, 300, 1000 and 3000 mg/kg/day for 28 days. The parameters which were applied to the study were mortality, clinical signs, body and organ weights, food consumption, ophthalmology, urinalysis, hematology, serum chemistry, gross findings and histopathologic examination. The freezedried powder of T. molitor larvae was not mutagenic or clastogenic based on results of in vitro and in vivo genotoxicity assays. Furthermore, no treatment-related changes or findings were observed in any parameters in rats after 28 days oral administration. In conclusion, the freeze-dried powder of T. molitor larvae was considered to be non-genotoxic and the NOAEL (No Observed Adverse Effect Level) was determined to be 3000 mg/kg/day in both sexes of SD rats under our experimental conditions. PMID:25071922

  5. Acute and repeated doses (28 days) oral toxicity study of glycosides based standardized fenugreek seed extract in laboratory mice.

    PubMed

    Kandhare, Amit D; Bodhankar, Subhash L; Mohan, V; Thakurdesai, Prasad A

    2015-07-01

    The objective of the present work was to study acute and subacute (28-days repeated dose) oral toxicity effect of glycosides based standardized fenugreek seed extract (SFSE-G) in vivo. SFSE-G was prepared by resin-based chromatography and standardized to glycosides namely trigoneoside Ib (76%) and vicenin 1 (15%). The acute oral toxicity (AOT) and subacute toxicity studies were performed in Swiss albino mice (5 mice/sex/group) as per OECD 425 (up-and-down procedure) and OCED 407 guidelines respectively. Acute oral administration of 5000mg/kg of SFSE-G showed 40% mortality with no mortality in lower dosages. The subacute oral administration of SFSE-G did not show observational or toxicological effects on the body or organ weights, food consumption, ophthalmic effects, locomotor activity, hematology, blood biochemistry, urinalysis, or histopathology at dose 250mg/kg. However, SFSE-G (1000mg/kg) showed mortality and minor alterations to body weight, relative liver weights, hematology and blood chemistry parameters related to treatment but it was within normal laboratory ranges. In conclusion, SFSE-G showed median lethal dose (LD50) more than 4350mg/kg and no-observed adverse effect levels (NOAEL) of 250mg/kg for both sexes during AOT and sub-acute toxicity study, respectively. PMID:25979642

  6. Preliminary safety assessment of Yarrowia lipolytica extracellular lipase: results of acute and 28-day repeated dose oral toxicity studies in rats.

    PubMed

    Turki, Saoussen; Jabloun, Zeineb; Mrabet, Ghada; Marouani, Ammar; Thonart, Philippe; Diouani, Mohammed Fethi; Ben Abdallah, Fethi; Amara, Abdelkader; Rejeb, Ahmed; Kallel, Héla

    2010-01-01

    Interest in extracellular lipase sourced from the non conventional yeast Yarrowia lipolytica has increased over the last decade. The enzyme was recently suggested as a good candidate for pancreatic exocrine insufficiency treatment. However, there is still a lack of oral safety evaluation data. In this work, we conducted acute and 28-day repeated dose toxicity studies in rats. Both male and female rats were first orally treated with fungal lipase at either single or repeated doses. The results demonstrated that neither single dose nor chronic administration of lipase was associated with mortality or abnormalities in general conditions, behavior and growth. Except a decrease in urine pH and a dose-unrelated increase of triglycerides observed in males, chronic administration of lipase resulted in similar hematological, blood biochemical and urine parameters to those of untreated animals. Minor histopathological changes were observed in lungs and livers of treated and untreated animals but they were considered of no toxicological significance. This study provides, for the first time, safety data on Yarrowia lipolytica extracellular lipase that support its use as a pharmaceutical. PMID:20609427

  7. A repeated 28-day oral dose toxicity study of methoxychlor in rats, based on the 'enhanced OECD test guideline 407' for screening endocrine-disrupting chemicals.

    PubMed

    Okazaki, K; Okazaki, S; Nishimura, S; Nakamura, H; Kitamura, Y; Hatayama, K; Nakamura, A; Tsuda, T; Katsumata, T; Nishikawa, A; Hirose, M

    2001-11-01

    In association with the international validation project to establish an OECD Enhanced Test Guideline 407, we performed a 28-day repeated-dose toxicity study of methoxychlor, a chlorinated hydrocarbon pesticide with pro-estrogenic and anti-androgenic activities. Attention was paid to the sensitivity of certain additional parameters for detecting endocrine related effects of endocrine disrupting chemicals based on the existing TG 407. Seven-week-old Crj:CD(SD)IGS rats were allocated to one of four groups, each consisting often males and ten females, and methoxychlor was administered once daily by gavage at doses of 0 (control), 20, 100 or 500 mg/kg body weight per day. Male rats were killed on the day after the 28th administration. Female rats were killed on the day of the diestrus stage during 4 days after the 28th administration. Male rats receiving methoxychlor showed mainly atrophy of mammary acinus in the 20 mg/ kg and higher groups, together with decreases in prostate and seminal vesicle weights, and atrophy of epididymis, prostate, seminal vesicle and coagulating gland in the 100 and 500 mg/kg groups. In addition, decrease in serum testosterone level, increase in follicle-stimulating hormone level, decrease in testis and epididymis weights, atrophy of semiferous tubules and Leydig cells, decrease in the number of sperm in the caudal epididymis and their motility were observed in the 500 mg/kg group. Female rats receiving methoxychlor showed mainly abnormal estrous cycles, decrease in serum luteinizing hormone level, decrease in ovary weight, proliferation of mammary acinus, atrophy of ovary due to decrease in follicles and corpus luteum in histopathology, hypertrophy of endometrial epithelium of uterus and vagina epithelium in the 100 and 500 mg/kg groups. Among the parameters tested in the present experimental system, effects of methoxychlor on endocrine-related organs were detected with regard to serum hormone, organ weights, histopathological examination in both sexes, estrus cycle in females and sperm examination in males. Based on these results, a no-observed-adverse-effect level (NOAEL) in the present study was estimated to be below 20 mg/kg per day. In particular, the adverse effects were effectively detected in organ weights of accessory sex organs and histopathological examination. PMID:11760811

  8. Subacute (28-day) toxicity of furfural in Fischer 344 rats: a comparison of the oral and inhalation route

    Microsoft Academic Search

    Josje H. E. Arts; Hans Muijser; Marko J. Appel; C. Frieke Kuper; Jos G. M. Bessems; Ruud A. Woutersen

    2004-01-01

    The subacute oral and inhalation toxicity of furfural vapour was studied in Fischer 344 rats to investigate whether route-to-route extrapolation could be employed to derive the limit value for inhalation exposure from oral toxicity data. Groups of 5 rats per sex were treated by gavage daily for 28 days at dose levels of 6–192 mg\\/kg bw\\/day, or exposed by inhalation

  9. Acute and 28-day sub-acute oral toxicity evaluation of two dietary bamboo charcoal powders in Sprague-Dawley rats.

    PubMed

    Jia, Zhen-Chao; Luo, Sha; Zhong, Yu-Ting; Li, Xiao; Chen, Jin-Yao; Zhang, Li-Shi

    2015-04-01

    No data were available on the acute oral toxicity, short-term oral toxicity of vegetable carbon in animals. This study was designed to evaluate the safety of two commercially available dietary bamboo charcoal powders (BCP1 and BCP2). The size distribution of the two powders was determined by a Mastersizer 2000 laser particle size analyzer prior to the in vivo safety studies. For the acute toxicity study, a single dose of 11.24 g/kg body weight of BCP1 and BCP2 was given once orally to healthy Sprague-Dawley (SD) rats. Mortality and clinical symptoms were observed and recorded for the first 30 min after treatment, at 4 h post-administration, and then at least once daily for 14 days after administration. In the repeated dose 28-day oral toxicity study, BCP1 and BCP2 were administered orally at doses of 2.81, 5.62, and 11.24 g/kg body weight for 28 days to SD rats. Animals were sacrificed and organs and blood samples were analyzed. Results showed that both BCP1 and BCP2 were micro-sized and various in size. In the acute toxicity and the repeated dose 28-day oral toxicity studies, BCP caused neither mortality nor visible signs of toxicity in rats. No significant differences were found in the relative organ weights or in biochemical parameters in BCP treated groups compared to a control group. No treatment-related histological changes were observed in the organs of these animals. Based on these data, it is concluded that the median lethal dose (LD50) of BCP for both male and female rats is more than 11. 24 g/kg body weight and the no-observed-adverse-effect level (NOAEL) is >11.24 g/kg body weight for 28 days. PMID:25877351

  10. Immunotoxicity of silver nanoparticles in an intravenous 28-day repeated-dose toxicity study in rats

    PubMed Central

    2014-01-01

    Background Nanosilver is used in a variety of medical and consumer products because of its antibacterial activity. This wide application results in an increased human exposure. Knowledge on the systemic toxicity of nanosilver is, however, relatively scarce. In a previous study, the systemic toxicity of 20 nm silver nanoparticles (Ag-NP) was studied in a 28-day repeated-dose toxicity study in rats. Ag-NP were intravenously administered with a maximum dose of 6 mg/kg body weight (bw)/day. Several immune parameters were affected: reduced thymus weight, increased spleen weight and spleen cell number, a strongly reduced NK cell activity, and reduced IFN-? production were observed. Methods Prompted by these affected immune parameters, we wished to assess exposure effects on the functional immune system. Therefore, in the present study the T-cell dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) was measured in a similar 28-day intravenous repeated-dose toxicity study. In addition, a range of immunological parameters was measured. Data obtained using the benchmark dose (BMD) approach were analyzed by fitting dose-response models to the parameters measured. Results A reduction in KLH-specific IgG was seen, with a lowest 5% lower confidence bound of the BMD (BMDL) of 0.40 mg/kg bw/day. This suggests that Ag-NP induce suppression of the functional immune system. Other parameters sensitive to Ag-NP exposure were in line with our previous study: a reduced thymus weight with a BMDL of 0.76 mg/kg bw/day, and an increased spleen weight, spleen cell number, and spleen cell subsets, with BMDLs between 0.36 and 1.11 mg/kg bw/day. Because the effects on the spleen are not reflected by increased KLH-specific IgG, they, however, do not suggest immune stimulation. Conclusions Intravenous Ag-NP administration in a 28-day repeated-dose toxicity study induces suppression of the functional immune system. This finding underscores the importance to study the TDAR to evaluate immunotoxicity and not to rely solely on measuring immune cell subsets. PMID:24885556

  11. Uterotrophic assay, Hershberger assay, and repeated 28-day oral toxicity study of flumorph based on the Organization for Economic Co-operation and Development draft protocols

    Microsoft Academic Search

    Jian Zhao; Leiming Cai; Jie Wang; Yingliang Wu; Baoyu Yao; Le Zhang

    2011-01-01

    To evaluate the endocrine-mediated effects of flumorph, we performed the uterotrophic assay, the Hershberger assay, and the repeated 28-day oral toxicity study based on the OECD draft protocols. In the uterotrophic assay, female ovariectomized SD rats were subcutaneously injected with flumorph at doses of 0, 50, 150, and 500mg\\/kg on each of 3 days, and no changes were observed. In

  12. Oral 28-day and developmental toxicity studies of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate

    PubMed Central

    Clarke, Kieran; Tchabanenko, Kirill; Pawlosky, Robert; Carter, Emma; Knight, Nicholas S.; Murray, Andrew J.; Cochlin, Lowri E.; King, M. Todd; Wong, Andrea W.; Roberts, Ashley; Robertson, Jeremy; Veech, Richard L.

    2013-01-01

    (R)-3-Hydroxybutyl (R)-3-hydroxybutyrate (ketone monoester) has been developed as an oral source of ketones, which may be utilized for energy. In a 28-day toxicity study, Crl:WI (Wistar) rats received diets containing, as 30% of the calories, ketone monoester (12 and 15 g/kg body weight/day for male and female rats, respectively). Control groups received either carbohydrate- or fat-based diets. Rats in the test group consumed less feed and gained less weight than control animals; similar findings have been documented in studies of ketogenic diets. Between-group differences were noted in selected hematology, coagulation, and serum chemistry parameters; however, values were within normal physiological ranges and/or were not accompanied by other changes indicative of toxicity. Upon gross and microscopic evaluation, there were no findings associated with the ketone monoester. In a developmental toxicity study, pregnant Crl:WI (Han) rats were administered 2 g/kg body weight/day ketone monoester or water (control) via gavage on days 6 through 20 of gestation. No Caesarean-sectioning or litter parameters were affected by the test article. The overall incidence of fetal alterations was higher in the test group; however, there were no specific alterations attributable to the test substance. The results of these studies support the safety of ketone monoester. PMID:22504461

  13. Acute and 28-Day Subchronic Oral Toxicity of an Ethanol Extract of Zingiber zerumbet (L.) Smith in Rodents

    PubMed Central

    Chang, Chia Ju; Tzeng, Thing-Fong; Liou, Shorong-Shii; Chang, Yuan-Shiun; Liu, I-Min

    2012-01-01

    The objective of this study was to evaluate the acute and subacute toxicity (28 days) of the ethanol extract of Z. zerumbet rhizomes (EEZZ) via the oral route in Wistar rats of both sexes. In the acute toxicity study, Wistar rats were administered a single dose of 15?g?kg?1 of body weight by gavage, and were monitored for 14 days. EEZZ did not produce any toxic signs or deaths; the 50% lethal dose must be higher than 15?g?kg?1. In the subchronic toxicity study, EEZZ was administered by gavage at doses of 1000, 2000 and 3000?mg/kg daily for 4 weeks to Wistar rats. The subacute treatment with EEZZ did not alter either the body weight gain or the food and water consumption. The hematological and biochemical analysis did not show significant differences in any of the parameters examined in female or male groups. Necropsy and histopathological examination, did not reveal any remarkable and treatment related changes. A no-observed adverse-effect level for EEZZ is 3000?mg?kg?1 for rats under the conditions of this study. Hence, consumption of EEZZ for various medicinal purposes is safe. PMID:22536288

  14. Genotoxicity analysis of cerium oxide micro and nanoparticles in Wistar rats after 28 days of repeated oral administration.

    PubMed

    Kumari, Monika; Kumari, Srinivas Indu; Grover, Paramjit

    2014-11-01

    The applications of cerium oxide nanoparticles (CeO2 NPs; nanoceria) extend to polishing agents, diesel fuel additives and as a putative antioxidant in therapeutics. Therefore, understanding the long-term toxic effects of CeO2 NPs is of particular importance. This study investigated the 28 days of repeated toxicity of 30, 300 and 600 mg/kg body weight (bw)/day of nanoceria and CeO2 microparticles (MPs) in Wistar rats after oral exposure. Genotoxicity was analysed using comet, micronucleus (MN) and chromosomal aberration (CA) assays. The results demonstrated a significant increase in DNA damage in peripheral blood leukocytes and liver, MN and CA in bone marrow as well as MN in peripheral blood after exposure to CeO2 NPs at 300 and 600 mg/kg bw/day. Significant alterations were observed in alkaline phosphatase and lactate dehydrogenase activity in serum and reduced glutathione content in the liver, kidneys and brain at 300 and 600 mg/kg bw/day in a dose-dependent manner. Conversely, CeO2 MPs did not induce any significant toxicological changes. A much higher absorptivity and significant tissue distribution of CeO2 NPs was perceived in comparison to CeO2 MPs in a dose-dependent manner. A substantial fraction of CeO2 NPs was cleared by urine and faeces. Histopathological analysis revealed that CeO2 NPs caused alterations in liver, spleen and brain. Further, distinct difference in the data among genders was not obvious. In general, the results suggested that prolonged oral exposure to nanoceria has the potential to cause genetic damage, biochemical alterations and histological changes after retention in vital organs of rats at high concentrations. PMID:25209125

  15. An aqueous extract of Salacia oblonga root, a herb-derived peroxisome proliferator-activated receptor-alpha activator, by oral gavage over 28 days induces gender-dependent hepatic hypertrophy in rats

    Microsoft Academic Search

    Xianglu Rong; Moon Sun Kim; Ning Su; Suping Wen; Yukimi Matsuo; Johji Yamahara; Michael Murray; Yuhao Li

    2008-01-01

    Activation of peroxisome proliferator-activated receptor (PPAR)-alpha by natural and synthetic chemicals induces hepatic hypertrophy. An aqueous extract of Salacia oblonga root (SOW) is an Ayurvedic medicine with anti-diabetic and anti-obesity properties. In the present study, it was found that SOW (100, 300 and 900mg\\/kg, once daily by oral gavage over a 28 day period) elicited dose-related increases in liver weight

  16. A 28-day oral toxicity evaluation of small interfering RNAs and a long double-stranded RNA targeting vacuolar ATPase in mice.

    PubMed

    Petrick, Jay S; Moore, William M; Heydens, William F; Koch, Michael S; Sherman, James H; Lemke, Shawna L

    2015-02-01

    New biotechnology-derived crop traits have been developed utilizing the natural process of RNA interference (RNAi). However, plant-produced double stranded RNAs (dsRNAs) are not known to present a hazard to mammals because numerous biological barriers limit uptake and potential for activity. To evaluate this experimentally, dsRNA sequences matching the mouse vATPase gene (an established target for control of corn rootworms) were evaluated in a 28-day toxicity study with mice. Test groups were orally gavaged with escalating doses of either a pool of four 21-mer vATPase small interfering RNAs (siRNAs) or a 218-base pair vATPase dsRNA. There were no treatment-related effects on body weight, food consumption, clinical observations, clinical chemistry, hematology, gross pathology, or histopathology endpoints. The highest dose levels tested were considered to be the no observed adverse effect levels (NOAELs) for the 21-mer siRNAs (48 mg/kg/day) and the 218 bp dsRNA (64 mg/kg/day). As an additional exploratory endpoint, vATPase gene expression, was evaluated in selected gastrointestinal tract and systemic tissues. The results of this assay did not indicate treatment-related suppression of vATPase. The results of this study indicate that orally ingested dsRNAs, even those targeting a gene in the test species, do not produce adverse health effects in mammals. PMID:25445299

  17. Acute and sub-chronic (28days) oral toxicity evaluation of hydroethanolic extract of Bridelia ferruginea Benth root bark in male rodent animals.

    PubMed

    Bakoma, Batomayena; Berké, Bénédicte; Eklu-Gadegbeku, Kwashie; Agbonon, Amegnona; Aklikokou, Kodjo; Gbeassor, Messanvi; Creppy, Edmond E; Moore, Nicholas

    2013-02-01

    The present investigation was carried out to evaluate the safety of hydro-ethanol extract of Bridelia ferruginea Benth (Euphorbiaceae) root bark. For acute toxicity study, a single dose of 2000 and 5000 mg/kg of the B. ferruginea root bark extract was given orally to healthy male Wistar rats and Balb/c mice. The animals were observed for mortality and clinical signs for 3 h and then daily for 14 days. In the sub-chronic toxicity study, the extract was administered orally at doses of 250, 500 and 1000 mg/kg/day for 28 days to male Wistar rats. Animals were sacrificed to examine their organs, and urine and blood serum were analyzed. In the acute toxicity study, B. ferruginea root bark extract caused neither significant visible signs of toxicity, nor mortality in Wistar rats and Balb/c mice. In sub-chronic toxicity study, administration of the B. ferruginea root bark extract at 250, 500, and 1000 mg/kg for 28 consecutive days to Wistar rats did not produce mortality. No significant differences were found in relative organ weights, biochemical studied parameters in treated groups compared to control group. No obvious histological changes were observed in organs of B. ferruginea extract treated animals compared to controls. PMID:23201452

  18. Acute and 28-day repeated dose toxicology studies in mice with aryloxyalkanoate dioxygenase (AAD-1) protein expressed in 2,4-D tolerant DAS-40278-9 maize.

    PubMed

    Stagg, Nicola J; Thomas, Johnson; Herman, Rod A; Juberg, Daland R

    2012-03-01

    DAS-40278-9 maize (corn) plants have been genetically modified by the insertion of the aad-1 gene (aryloxyalkanoate dioxygenase), which confers tolerance to 2,4-dichlorophenoxyacetic acid (2,4-D) and aryloxyphenoxypropionate (AOPP) acetyl coenzyme A carboxylase (ACCase) inhibitors ("fop" herbicides) to enable the effective use of these herbicides on maize. The aad-1 gene, derived from Sphingobium herbicidovorans, encodes the aryloxyalkanoate dioxygenase (AAD-1) enzyme. As part of the safety assessment of the AAD-1 protein expressed in maize, acute and repeated dose mammalian toxicology studies were conducted. AAD-1 protein (heterologously produced) was orally administered to mice at a dose of 2000mg/kg, and no acute lethality or adverse effects were observed. Similarly, no adverse effects were observed in mice in a 28-day repeated-dose dietary toxicity study that incorporated the AAD-1 protein into diets at concentrations up to 1000-fold greater than the highest estimate of human exposure to maize. These results support the conclusion that the AAD-1 protein, as expressed in biotechnology derived DAS-40278-9 maize, represents a negligible risk to human health. PMID:22100718

  19. Evaluation of the toxicological safety of erinacine A-enriched Hericium erinaceus in a 28-day oral feeding study in Sprague-Dawley rats.

    PubMed

    Li, I-Chen; Chen, Yen-Lien; Lee, Li-Ya; Chen, Wan-Ping; Tsai, Yueh-Ting; Chen, Chin-Chu; Chen, Chin-Shuh

    2014-08-01

    Natural products have attained great importance as they are believed to be the new alternative medicines for conventional therapy. As numerous studies have proved the tremendous medicinal values of Hericium erinaceus, it is necessary to take into account its safety as well as its risk for the recipient. However, mushroom mycelium has an identity distinct from mushrooms, as two specific classes of compounds, hericenones and erinacines, can only be extracted from both the fruit body and the cultured mycelium, respectively. Therefore, this is the first report on the evaluation of the toxicity of H.erinaceus mycelium, enriched with 5mg/g erinacine A, by a 28-day repeated oral administration study in Sprague-Dawley rats. Three doses of 1 (Low), 2 (Mid) and 3 (High) g/kg body weight/day were selected for the study while distilled water served as control. All animals survived to the end of the study. No abnormal changes were observed in clinical signs. No adverse or test article-related differences were found in urinalysis, haematology and serum biochemistry parameters, between the treatment and control groups. No gross pathological findings and histopathological differences were seen. Therefore, the no-observed-adverse-effect level of erinacine A-enriched H.erinaceus is greater than 3g/kgbody weight/day. PMID:24810469

  20. Acute and subchronic (28 days) oral toxicity studies of Codonopsis lanceolata extract in Sprague-Dawley rats.

    PubMed

    Lee, Jong Seok; Kim, Young-Hyun; Kim, Dan-Bi; Shin, Gi-Hae; Lee, Jin-Ha; Cho, Ju-Hyun; Lee, Boo-Yong; Lee, Ok-Hwan

    2015-04-01

    Codonopsis lanceolata is a perennial plant that has been used as a food and in traditional medicine for the treatment of cough, bronchitis, and inflammation in East Asia including Korea, Japan, and China. However, information regarding its toxicity is limited. Therefore, we performed a safety evaluation of aqueous C. lanceolata root extract (CLE) in Sprague-Dawley rats. Assessment of acute toxicity revealed that CLE did not influence mortality, clinical appearance, body weight gain, or necropsy findings at a dose of 5000 mg/kg body weight. In the subchronic oral toxicity, data revealed that several significant alteration in food consumption, water consumption, protein excretion, WBCs levels, TGs, BUN levels, and the absolute and relative weights in the liver, spleen and lungs. However, these changes were transient and were not considered treatment related because they showed no apparent dose dependent. These results suggest that CLE (1250, 2500, and 5000 mg/kg body weight/day) administered orally does not cause acute or subchronic toxicity to male or female rats. The 50% lethal dose (LD50) of CLE was determined to be greater than 5000 mg/kg. PMID:25724632

  1. Systemic and immunotoxicity of silver nanoparticles in an intravenous 28 days repeated dose toxicity study in rats.

    PubMed

    De Jong, Wim H; Van Der Ven, Leo T M; Sleijffers, Annemarie; Park, Margriet V D Z; Jansen, Eugene H J M; Van Loveren, Henk; Vandebriel, Rob J

    2013-11-01

    Because of its antibacterial activity nanosilver is one of the most commonly used nanomaterials. It is increasingly used in a variety of both medical and consumer products resulting in an increase in human exposure. However, the knowledge on the systemic toxicity of nanosilver is relatively limited. To determine the potential systemic toxicity of silver nanoparticles (Ag-NP) with different sizes (20 nm and 100 nm) a 28-days repeated dose toxicity study was performed in rats using intravenous administration. The toxic effect of the 20 nm Ag-NP was performed using the bench mark dose (BMD) approach. Treatment with a maximum dose of 6 mg/kg body weight was well tolerated by the animals. However, both for 20 nm and 100 nm Ag-NP growth retardation was observed during the treatment. A severe increase in spleen size and weight was present which was due to an increased cell number. Both T and B cell populations showed an increase in absolute cell number, whereas the relative cell numbers remained constant. At histopathological evaluation brown and black pigment indicating Ag-NP accumulation was noted in spleen, liver, and lymph nodes. Ag-NP was also detected incidentally in other organs. Clinical chemistry indicated liver damage (increased alkaline phosphatase, alanine transaminase, and aspartate transaminase) that could not be confirmed by histopathology. Hematology showed a decrease in several red blood cell parameters. The most striking toxic effect was the almost complete suppression of the natural killer (NK) cell activity in the spleen at high doses. Other immune parameters affected were: decreased interferon-? and interleukin (IL)-10 production by concanavalin-A stimulated spleen cells, increased IL-1? and decreased IL-6, IL-10 and TNF-? production by lipopolysaccharide stimulated spleen cells, increase in serum IgM and IgE, and increase in blood neutrophilic granulocytes. For the spleen weight a critical effect dose of 0.37 mg/kg body weight (b.w.) could be established. The lowest critical effect dose (CED) for a 5% change compared to control animals was observed for thymus weight (CED05 0.01 mg/kg b.w.) and for functional immune parameters, i.e. decrease in NK cell activity (CED05 0.06 mg/kg b.w.) and LPS stimulation of spleen cells (CED05 0.04 mg/kg b.w.). These results show that for nanosilver the most sensitive parameters for potential adverse responses were effects on the immune system. PMID:23886731

  2. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...prior to blood sampling is recommended. 1 Investigations of plasma or serum shall include sodium, potassium, glucose, total...circumstances. 1 For a number of measurements in serum and plasma, most notably for glucose, overnight fasting would be...

  3. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...prior to blood sampling is recommended. 1 Investigations of plasma or serum shall include sodium, potassium, glucose, total...circumstances. 1 For a number of measurements in serum and plasma, most notably for glucose, overnight fasting would be...

  4. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...prior to blood sampling is recommended. 1 Investigations of plasma or serum shall include sodium, potassium, glucose, total...circumstances. 1 For a number of measurements in serum and plasma, most notably for glucose, overnight fasting would be...

  5. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...prior to blood sampling is recommended. 1 Investigations of plasma or serum shall include sodium, potassium, glucose, total...circumstances. 1 For a number of measurements in serum and plasma, most notably for glucose, overnight fasting would be...

  6. Evaluation of Immunotoxicity Induced by Pirimiphosmethyl in Male Balb\\/c Mice Following Exposure to for 28 Days

    Microsoft Academic Search

    Hyung Soo Kim; Juno H. Eom; Hye-young Cho; Young Joo Cho; Ji Young Kim; Jong Kwon Lee; Seung-Hee Kim; Kui Lea Park

    2007-01-01

    Pirimiphos-methyl (O-2-diethylamino-6-methylpyrimidin-4-yl O,O-dimethyl phosphorothioate: POM) is widely used organophosphorous(OP) insecticide as a grain protectant to control insects during storage. This study was carried out to assess the immunologic effects of POM in Balb\\/c mice after 28-day oral exposure. Three dose levels of POM (10, 60, or 120 mg\\/kg\\/day) were administered orally to mice for 4 weeks. At autopsy after 28-day

  7. An aqueous extract of Salacia oblonga root, a herb-derived peroxisome proliferator-activated receptor-alpha activator, by oral gavage over 28 days induces gender-dependent hepatic hypertrophy in rats.

    PubMed

    Rong, Xianglu; Kim, Moon Sun; Su, Ning; Wen, Suping; Matsuo, Yukimi; Yamahara, Johji; Murray, Michael; Li, Yuhao

    2008-06-01

    Activation of peroxisome proliferator-activated receptor (PPAR)-alpha by natural and synthetic chemicals induces hepatic hypertrophy. An aqueous extract of Salacia oblonga root (SOW) is an Ayurvedic medicine with anti-diabetic and anti-obesity properties. In the present study, it was found that SOW (100, 300 and 900mg/kg, once daily by oral gavage over a 28 day period) elicited dose-related increases in liver weight (LW) by 1.6%, 13.4% and 42.5%, respectively, and in the ratio of LW to body weight by 8.8%, 16.7% and 40.2%, respectively, in male rats. These effects were less pronounced in females. SOW selectively increased liver mass in male rats but Sudan red staining was not different, which indicates that hepatic lipid accumulation was similar in both genders. However, SOW even at the highest dosage did not influence serum ALT and AST activities in male or female rats. Moreover, SOW was found to activate PPAR-alpha in human hepatoma-derived HepG2 cells, as evidenced by the upregulation of PPAR-alpha and acyl-CoA oxidase mRNA expression. Thus, SOW-dependent PPAR-alpha activation may precede the development of the gender difference in hepatic hypertrophy; this process may be influenced by sex hormone status. PMID:18397819

  8. Phase I trial of low-dose oral Clofarabine in myelodysplastic syndromes patients who have failed frontline therapy.

    PubMed

    Rudrapatna, Venkatesh K; Morley, Kimberly; Boucher, Kenneth M; Pierson, Andrew S; Shull, Christian T; Kushner, James P; Shami, Paul J

    2015-08-01

    We investigated protracted low-dose oral Clofarabine for the treatment of myelodysplastic syndromes (MDS). Adults with an International Prognostic Scoring System (IPSS) score of INT-1 or higher who had failed first line therapy were eligible. INT-1 patients had to be transfusion-dependent. We started with oral Clofarabine at 5mg (fixed dose) daily for 10 consecutive days on a 28-day cycle. Toxicity prompted a modification to 1mg PO daily for 10 days and then 1mg PO daily for 7 days. Patients received treatment indefinitely until loss of response or unacceptable toxicity. Nine patients (5 women) were enrolled and evaluable (median age 65 years; range 55-81). A 10-day regimen of oral Clofarabine at 5mg/day induced Grade IV pancytopenia. A dose of 1mg/day for 7/28 days was very well tolerated without significant toxicity. Three patients had responses (2 with responses lasting up to 21 and 51 cycles) defined as stable disease in spite of no significant change on bone marrow evaluation. Low-dose oral Clofarabine (1mg daily for 7/28 days) proved both effective and safe for patients with MDS who had failed prior therapy. This patient population is particularly sensitive to more protracted Clofarabine treatment schedules. PMID:26038120

  9. Multinational, multicentre, randomised, open-label study evaluating the impact of a 91-day extended regimen combined oral contraceptive, compared with two 28-day traditional combined oral contraceptives, on haemostatic parameters in healthy women

    PubMed Central

    Paoletti, Anna Maria; Volpe, Annibale; Chiovato, Luca; Howard, Brandon; Weiss, Herman; Ricciotti, Nancy

    2014-01-01

    Objectives To evaluate the impact of a 91-day extended regimen combined oral contraceptive (150 ?g levonorgestrel [LNG]/30 ?g ethinylestradiol [EE] for 84 days, followed by 10 ?g EE for seven days [Treatment 1]) compared with two traditional 21/7 regimens (21 days 150 ?g LNG/30 ?g EE [Treatment 2] or 150 ?g desogestrel [DSG]/30 ?g EE [Treatment 3], both with seven days’ hormone free), on several coagulation factors and thrombin formation markers. Methods Randomised, open-label, parallel-group comparative study involving healthy women (18–40 years). The primary endpoint was change from baseline in prothrombin fragment 1 + 2 (F1 + 2) levels over six months. Results A total of 187 subjects were included in the primary analysis. In all groups, mean F1 + 2 values were elevated after six months of treatment. Changes were comparable between Treatments 1 and 2 (least squares mean change: 170 pmol/L and 158 pmol/L, respectively) but noticeably larger after Treatment 3 (least squares mean change: 592 pmol/L). The haemostatic effects of Treatment 1 were comparable to those of Treatment 2 and noninferior to those of Treatment 3 (lower limit of 95% confidence interval [? 18.3 pmol/L] > ? 130 pmol/L). Conclusions The LNG/EE regimens had similar effects on F1 + 2. Noninferiority was demonstrated between extended regimen LNG/EE and DSG/EE. PMID:24923685

  10. Flexibility of Oral Cholera Vaccine Dosing—A Randomized Controlled Trial Measuring Immune Responses Following Alternative Vaccination Schedules in a Cholera Hyper-Endemic Zone

    PubMed Central

    Kanungo, Suman; Desai, Sachin N.; Nandy, Ranjan Kumar; Bhattacharya, Mihir Kumar; Kim, Deok Ryun; Sinha, Anuradha; Mahapatra, Tanmay; Yang, Jae Seung; Lopez, Anna Lena; Manna, Byomkesh; Bannerjee, Barnali; Ali, Mohammad; Dhingra, Mandeep Singh; Chandra, Ananga Mohan; Clemens, John D.; Sur, Dipika; Wierzba, Thomas F.

    2015-01-01

    Background A bivalent killed whole cell oral cholera vaccine has been found to be safe and efficacious for five years in the cholera endemic setting of Kolkata, India, when given in a two dose schedule, two weeks apart. A randomized controlled trial revealed that the immune response was not significantly increased following the second dose compared to that after the first dose. We aimed to evaluate the impact of an extended four week dosing schedule on vibriocidal response. Methodology/Principal Findings In this double blind randomized controlled non-inferiority trial, 356 Indian, non-pregnant residents aged 1 year or older were randomized to receive two doses of oral cholera vaccine at 14 and 28 day intervals. We compared vibriocidal immune responses between these schedules. Among adults, no significant differences were noted when comparing the rates of seroconversion for V. cholerae O1 Inaba following two dose regimens administered at a 14 day interval (55%) vs the 28 day interval (58%). Similarly, no differences in seroconversion were demonstrated in children comparing the 14 (80%) and 28 day intervals (77%). Following 14 and 28 day dosing intervals, vibriocidal response rates against V. cholerae O1 Ogawa were 45% and 49% in adults and 73% and 72% in children respectively. Responses were lower for V. cholerae O139, but similar between dosing schedules for adults (20%, 20%) and children (28%, 20%). Conclusions/Significance Comparable immune responses and safety profiles between the two dosing schedules support the option for increased flexibility of current OCV dosing. Further operational research using a longer dosing regimen will provide answers to improve implementation and delivery of cholera vaccination in endemic and epidemic outbreak scenarios. PMID:25764513

  11. Alternative Method of Oral Dosing for Rats

    PubMed Central

    Atcha, Zeenat; Rourke, Claire; Neo, Aveline HP; Goh, Catherine WH; Lim, Jean SK; Aw, Chiu-Cheong; Browne, Edward R; Pemberton, Darrel J

    2010-01-01

    Oral administration of drugs to laboratory rodents typically is achieved by using the gavage technique. Although highly effective, this method occasionally can cause esophageal injury as well as restraint-associated distress, particularly with repeated use. The aim of this study was to assess an alternative oral dosing method that could reduce the distress and morbidity associated with standard gavage techniques. The palatability and pharmacokinetic profile of 2 medicines approved for the treatment of Alzheimer disease, donepezil and galantamine, were investigated in male Lister hooded rats by using a syringe-feeding method and compared with results from traditional gavage administration. In addition, the stimulant nicotine was tested by using the syringe-feeding method in a separate series of experiments. Animals reliably learned to drink voluntarily from the syringe, and latency to drink decreased rapidly. The addition of donepezil, galantamine, or nicotine to sucrose had no apparent effect on the palatability of the solution, although nicotine produced aversive effects that inhibited subsequent voluntary intake. Oral bioavailability was improved by using syringe feeding with donepezil but not galantamine. Both drugs improved cognitive performance in the novel object recognition test, with similar behavioral profiles between the 2 methods of administration. Our results suggest that the syringe-feeding technique is an effective alternative oral dosing method in rats. PMID:20587166

  12. A Phase I Study of an Oral Simulated FOLFOX with High Dose Capecitabine

    PubMed Central

    Mulkerin, D.; LoConte, N.K.; Holen, K.D.; Thomas, J.P.; Alberti, D.; Marnocha, R.; Kolesar, J.; Eickhoff, J.; Oliver, K.; Feierabend, C.; Wilding, G.

    2010-01-01

    Background A phase I study of high-dose capecitabine given over 2 days, along with oxaliplatin, bolus 5FU and leucovorin (LV), was designed to simulate FOLFOX6 without the need for infusional 5FU. Methods Schedule A included oxaliplatin 100 mg/m2, 5FU 400 mg/m2, and LV 20 mg/m2 (all given IV on days 1 and 15, 28 day cycle). Capecitabine was administered orally every 8 hours × 6 doses, days 1 and 15. Schedule B excluded 5FU and LV, maintaining oxaliplatin and capecitabine. Pharmacokinetics were performed for capecitabine for 6 patients on each schedule. Results 36 patients were treated. The dose-limiting toxicities seen included nausea, dehydration, fatigue, hypotension and confusion. Minimal palmar-plantar erythrodysesthesia was seen. Myelosuppression was common, but not a dose limiting toxicity. The pharmacokinetic parameters for capecitabine were unaltered. Conclusion Using capecitabine to mimic FOLFOX6 is feasible and well tolerated with a toxicity profile that differs from standard 14-day capecitabine dosing, with less palmar-plantar erythrodysesthesia. The phase II dose for capecitabine in combination with oxaliplatin, 5FU, and LV is 1500 mg/m2/dose or 2250 mg/m2/dose in the absence of bolus 5FU/LV. PMID:19129971

  13. High dose rate brachytherapy for oral cancer

    PubMed Central

    YamazakI, Hideya; Yoshida, Ken; Yoshioka, Yasuo; Shimizutani, Kimishige; Furukawa, Souhei; Koizumi, Masahiko; Ogawa, Kazuhiko

    2013-01-01

    Brachytherapy results in better dose distribution compared with other treatments because of steep dose reduction in the surrounding normal tissues. Excellent local control rates and acceptable side effects have been demonstrated with brachytherapy as a sole treatment modality, a postoperative method, and a method of reirradiation. Low-dose-rate (LDR) brachytherapy has been employed worldwide for its superior outcome. With the advent of technology, high-dose-rate (HDR) brachytherapy has enabled health care providers to avoid radiation exposure. This therapy has been used for treating many types of cancer such as gynecological cancer, breast cancer, and prostate cancer. However, LDR and pulsed-dose-rate interstitial brachytherapies have been mainstays for head and neck cancer. HDR brachytherapy has not become widely used in the radiotherapy community for treating head and neck cancer because of lack of experience and biological concerns. On the other hand, because HDR brachytherapy is less time-consuming, treatment can occasionally be administered on an outpatient basis. For the convenience and safety of patients and medical staff, HDR brachytherapy should be explored. To enhance the role of this therapy in treatment of head and neck lesions, we have reviewed its outcomes with oral cancer, including Phase I/II to Phase III studies, evaluating this technique in terms of safety and efficacy. In particular, our studies have shown that superficial tumors can be treated using a non-invasive mold technique on an outpatient basis without adverse reactions. The next generation of image-guided brachytherapy using HDR has been discussed. In conclusion, although concrete evidence is yet to be produced with a sophisticated study in a reproducible manner, HDR brachytherapy remains an important option for treatment of oral cancer. PMID:23179377

  14. Relative bioavailability and pharmacokinetics of two oral formulations of docosahexaenoic acid\\/eicosapentaenoic acid after multiple-dose administration in healthy volunteers

    Microsoft Academic Search

    Antonio Rusca; Andrea Francesco Daniele Di Stefano; Mira V. Doig; Claudia Scarsi; Emilio Perucca

    2009-01-01

    Objectives  To assess the comparative pharmacokinetic profile and bioavailability of docosahexaenoic acid (DHA)\\/eicosapentaenoic acid\\u000a (EPA) after multiple-dose administration of a new oral formulation (test formulation) and a commercially available reference\\u000a formulation in healthy subjects.\\u000a \\u000a \\u000a \\u000a Methods  Forty-eight healthy subjects received a 28-day oral treatment with DHA\\/EPA in the form of either the test or the reference\\u000a product according to an open-label, randomized, parallel-group

  15. Kinetics and disposition of orally dosed sodium chlorate in sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Experiments were conducted in sheep to determine excretory characteristics of sodium chlorate after a single oral dose. In Exp. 1 lambs (n = 16; age = 8.1 ± 1.7 d; BW = 8.2 ± 1.1 kg; mean ± SD) were dosed orally with 0, 30, 60, or 90 mg/kg BW of sodium chlorate. Twenty-four h after exposure chlorate...

  16. Pharmacokinetic profiles of ciprofloxacin after single intravenous and oral doses.

    PubMed Central

    Lettieri, J T; Rogge, M C; Kaiser, L; Echols, R M; Heller, A H

    1992-01-01

    Ciprofloxacin was administered to 12 healthy male volunteers at doses of 300 and 400 mg intravenously (i.v.) and 500 and 750 mg orally in a randomized, double-blind, single-dose, four-period crossover study. On each treatment day, each subject received both oral and i.v. formulations, one of which was a placebo. Blood and urine samples were obtained through 24 h postdose. By each dosing route, the pharmacokinetic profiles were dose proportional. The 400-mg i.v. dose was equivalent to the 500-mg oral dose with respect to the area under the concentration-time curve and was equivalent to the 750-mg oral dose with respect to the maximum concentration of ciprofloxacin in serum. The oral bioavailability was 78.0%. The steady-state volume of distribution averaged 178 liters, and the terminal half-life in serum after i.v. dosing was approximately 4.3 h. Renal clearance accounted for approximately 60% of total body clearance. No significant adverse events were associated with either route of administration. PMID:1510426

  17. Pharmacokinetics of ketoprofen following single oral, intramuscular and rectal doses and after repeated oral administration

    Microsoft Academic Search

    T. Ishizaki; T. Sasaki; T. Suganuma; Y. Horail; K. Chiba; M. Watanabe; W. Asuke; H. Hoshi

    1980-01-01

    The pharmacokinetics of ketoprofen was studied in the same healthy subjects after single oral, intramuscular and rectal doses, and after repeated oral administration. No significant difference in the mean t1\\/2 (1.13–1.27 h) was observed after the different modes of administration. The mean [AUC]08 after rectal administration of a suppository showed the minimum significant difference (p<0.05) from that after oral administration

  18. Pharmacokinetics of pioglitazone after multiple oral dose administration in horses.

    PubMed

    Wearn, J M G; Crisman, M V; Davis, J L; Geor, R J; Hodgson, D R; Suagee, J K; Ashraf-Khorassani, M; McCutcheon, L J

    2011-06-01

    Pioglitazone is a thiazolidinedione class of antidiabetic agent with proven efficacy in increasing insulin sensitivity in humans with noninsulin-dependent diabetes mellitus, a syndrome of insulin resistance sharing similarities with equine metabolic syndrome. The purpose of this study was to determine the pharmacokinetics of pioglitazone in adult horses following multiple oral dose administration. Pioglitazone hydrochloride (1 mg/kg) was administered orally for 11 doses at 24-h intervals, and plasma samples were collected. Initially, a pilot study was performed using one horse; and thereafter the drug was administered to six horses. Samples were analyzed by liquid chromatography with tandem mass spectrometry, and pharmacokinetic parameters were calculated using noncompartmental modeling. The maximum plasma concentration was 509.1 ± 413.5 ng/mL achieved at 1.88 ± 1.39 h following oral administration of the first dose, and 448.1 ± 303.5 ng/mL achieved at 2.83 ± 1.81 h (mean ± SD) following the eleventh dose. Apparent elimination half-life was 9.94 ± 4.57 and 9.63 ± 5.33 h after the first and eleventh dose, respectively. This study showed that in healthy horses, pioglitazone administered at a daily oral dose of 1 mg/kg results in plasma concentrations and total drug exposure approximating, but slightly below, those considered therapeutic in humans. PMID:21492190

  19. Effect of low dose oral contraceptives on exercise performance

    Microsoft Academic Search

    R W Bryner; R C Toffle; I H Ullrich; R A Yeater

    1996-01-01

    OBJECTIVE--to examine the effect of cycle phase or a low dose oral contraceptive on exercise performance in young women. METHODS--As controls, 15 men were tested twice by a maximal treadmill test (Vo2 max) and by an endurance run 14 d apart to determine performance variability from causes other than hormonal fluctuations. Ten women ages 18-30 were then tested for Vo2

  20. Oral surgery in anticoagulated patients without reducing the dose of oral anticoagulant: A prospective randomized study

    Microsoft Academic Search

    J. C Souto; A Oliver; I Zuazu-Jausoro; A Vives; J Fontcuberta

    1996-01-01

    Purpose:This study assessed the risk associated with several schedules of perioperative treatment with coumadin in anticoagulated patients who underwent oral surgery.Patients and Methods:A prospective, randomized study compared bleeding complications with six perioperative schedules in 92 patients chronically treated with acenocoumarol. In three of the perioperative schedules, the dose was reduced before surgery and calcium heparin was added. In the other

  1. Single dose oral aceclofenac for postoperative pain in adults

    PubMed Central

    Moore, R Andrew; Derry, Sheena; McQuay, Henry J

    2014-01-01

    Background Aceclofenac is the prodrug of the non-steroidal anti-inflammatory drug (NSAID) diclofenac, widely used to treat acute and chronic pain. There are no known systematic reviews of its analgesic efficacy in acute postoperative pain. This review sought to evaluate the efficacy and safety of oral aceclofenac in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish that drugs have analgesic properties. Objectives To assess the efficacy of single dose oral aceclofenac in acute postoperative pain, and any associated adverse events. Search methods We searched The Cochrane Library (Issue 1, 2009), MEDLINE via Ovid (1966 to March 2009); EMBASE via Ovid (1980 to March 2009); the Oxford Pain Relief Database (1950 to 1994); and reference lists of articles. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of oral aceclofenac for relief of acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. The area under the “pain relief versus time” curve was used to derive the proportion of participants with paracetamol plus codeine and placebo or paracetamol alone experiencing least 50% pain relief over 4 to 6 hours, using validated equations. The number needed to treat to benefit (NNT) was calculated using 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals was also collected. Main results Searches identified only one study (217 participants total), which used oral aceclofenac 150 mg in patients with established postoperative pain. Aceclofenac 150 mg could not be distinguished from placebo, though ibuprofen 400 mg was distinguished from placebo. Authors’ conclusions In the absence of evidence of efficacy for oral aceclofenac in acute postoperative pain (at least at 150 mg single dose), its use in this indication is not justified. Because trials clearly demonstrating analgesic efficacy in the most basic of acute pain studies are lacking, use in other indications should be evaluated carefully. Given the large number of effective drugs available in this and similar classes of analgesics, there is no urgent research agenda required to demonstrate the effective dose of aceclofenac in acute postoperative pain. PMID:19588436

  2. [Individualization of low-dose oral contraceptives. Pharmacological principles and practical indications for oral contraceptives].

    PubMed

    Cianci, A; De Leo, V

    2007-08-01

    The contraceptive pill has been a revolution of the last 40 years. In Italy, however, it is much less widely used than in other countries. Explanations for this phenomenon range from religious implications and customs to misinformation and word-of-mouth communication of negative experiences. The oral contraceptive pill is often used to correct menstrual disorders, leading to poor results and side-effects. Recent advances in oral contraception have led to a substantial reduction in doses and side-effects. Low-dose pills contain minimal doses of progesterones and estrogens and ensure good control of the menstrual cycle. Although reduction of ethinyl estradiol (EE) concentrations has reduced the incidence of negative systemic side effects such as water retention, edema and swollen breasts, the low estrogen dose may be associated with spotting and hypomenorrhea or amenorrhea in the long term, as well as dyspareunia due to reduced vaginal trophism, which may induce women to suspend use of the drug. It is also true that only one type of estrogen is used in the pill, albeit at different doses, whereas the progesterone may differ and in many cases is the cause of common side-effects. The choice of progesterone therefore involves not only its effect on the endometrium in synergy with estrogen, but also possible residual androgenic activity which may have negative metabolic repercussions. Indeed, addition of a progesterone, especially androgen-derived, attenuates the positive metabolic effects of estrogen. Two new monophasic oral contraceptives were recently released. They contain 30 microg (Yasmin) or 20 muicrog (Yasminelle) EE and a new progesterone, drospirenone, derived from spirolactone, which has antiandrogenic and antimineralcorticoid activity similar to endogenous progesterone. Like progesterone, the drospirenone molecule is an aldosterone antagonist and has a natriuretic effect that opposes the sodium retention effect of EE. It may, therefore, help to prevent the water retention, weight gain and arterial hypertension often associated with oral contraceptive use. Recent comparative studies recorded weight loss that stabilized after 6 months of treatment with drospirenone/EE. Overweight women may therefore benefit from the formulation with 20 microg EE, whereas the formulation with at least 30 microg EE should be more appropriate for underweight women. Women with slight to moderate acne, the formulation with 30 microg EE has been found to be as effective as 2 mg cyproterone acetate combined with 35 micrig EE (Diane). Menstrual cycle characteristics, however, remain the main factor determining the choice of formulation. Randomised control studies comparing the new formulation with others containing second or third generation progesterones have found similar efficacy in cycle control and incidence of spotting. From this point of view, it is not advisable to prescribe more than 30 microg EE (Yasmin or Yasminelle) for women with normal menstrual cycles, whereas in cases of hypomenorrhea and/or amenorrhea at least this dose of EE plus drospirenone may be used. Women with hypermenorrhea run the risk of spotting if an inappropriate drug is chosen. A solution is to use 30 microg EE/drospirenone from day 5 of the cycle. To control so-called minor side-effects, the dose of EE must be appropriate. In women with premenstrual tension a dose of at least 30 microg EE associated with drospirenone reduces or even prevents symptoms. On the other hand, in cases of chronic headache or headache as a side-effect of oral contraceptive use, a lower dose of estrogen is beneficial, and doses below 20 microg may be used. Although the progesterone component is not considered to affect headache, good results have been obtained with drospirenone, the antimineralcorticoid effects of which reduce blood pressure and improve symptoms. Formulations with 20 microg EE and drospirenone are particularly indicated in women with pre-existing mastodynia, fibrocystic breast manifestations or who develop mastodynia as a side-effect of oral contraceptive use. Since hi

  3. Coenzyme Q10 Abrogated the 28 Days Aluminium Chloride Induced Oxidative Changes in Rat Cerebral Cortex

    PubMed Central

    Majumdar, Anuradha S.; Nirwane, Abhijit; Kamble, Rahul

    2014-01-01

    Objective: The present study was designed to elucidate the impact of oral administration of aluminium chloride for 28 days with respect to oxidative stress in the cerebral cortex of female rats. Further, to investigate the potentials of Coenzyme (Co) Q10 (4, 8, and 12 mg/kg, i.p.) in mitigating the detrimental changes. Materials and Methods: Biochemical estimations of cerebral lipid peroxidation (LPO), reduced glutathione (GSH), vitamin E and activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) were carried out after 28 days of aluminium chloride (AlCl3) and Co Q10 exposures along with histopathological examination of cerebral cortex of the rats. Results: Subacute exposure to AlCl3(5 mg/kg) led to significant decrease in levels of GSH, vitamin E and activities of SOD, CAT, GPx, and an increase in LPO of cerebral cortex. These aberrations were restored by Co Q10 (12 mg/kg, i.p.). This protection offered was comparable to that of L-deprenyl (1 mg/kg, i.p.) which served as a reference standard. Histopathological evaluations confirmed that the normal cerebral morphology was maintained by Co Q10. Conclusion: Thus, AlCl3 exposure hampers the activities of various antioxidant enzymes and induces oxidative stress in cerebral cortex of female Wistar rats. Supplementation with intraperitoneal Co Q10 abrogated these deleterious effects of AlCl3. PMID:25253934

  4. Single dose oral piroxicam for acute postoperative pain

    PubMed Central

    Moore, R Andrew; Edwards, Jayne; Loke, Yoon; Derry, Sheena; McQuay, Henry J

    2014-01-01

    Background This is an updated version of the original Cochrane review published in Issue 2, 2000. Piroxicam is a non-steroidal anti-inflammatory drug (NSAID) with analgesic properties, and is used mainly for treating rheumatic disorders. Some drugs have been directly compared against each other within a trial setting to determine their relative efficacies, whereas other have not. It is possible, however, to compare analgesics indirectly by examining the effectiveness of each drug against placebo when used in similar clinical situations. Objectives To determine the analgesic efficacy and adverse effects of single-dose piroxicam compared with placebo in moderate to severe postoperative pain. To compare the effects of piroxicam with other analgesics. Search methods Published studies were identified from systematic searching of MEDLINE, Biological Abstracts, EMBASE, CENTRAL and the Oxford Pain Relief Database in December 2007. Additional studies were identified from the reference lists of retrieved reports. Selection criteria The following inclusion criteria were used: full journal publication, randomised placebo controlled trial, double-blind design, adult participants, postoperative pain of moderate to severe intensity at the baseline assessment, postoperative administration of oral or intramuscular piroxicam. Data collection and analysis Summed pain intensity and pain relief data were extracted and converted into dichotomous information to yield the number of participants obtaining at least 50% pain relief. This was used to calculate estimates of relative benefit and number-needed-to-treat-to-benefit (NNT) for one participant to obtain at least 50% pain relief. Information was collected on adverse effects and estimates of relative risk and number-needed-to-treat-to-harm (NNH) were calculated. Main results In this update no further studies were found. The original search identified three studies (141 participants) which compared oral piroxicam 20 mg with placebo and one (15 participants) compared oral piroxicam 40 mg with placebo. For single doses of piroxicam 20 mg and 40 mg the respective NNT for at least 50% pain relief were 2.7 (2.1 to 3.8) [95% confidence interval (CI)] and 1.9 (1.2 to 4.3) [95% CI] compared with placebo over four to six hours in moderate to severe postoperative pain. The reported incidence of adverse effects was no higher with piroxicam (20 mg or 40 mg) than with placebo. No further additional studies were found in the updated search. Authors’ conclusions Piroxicam appears to be of similar efficacy to other NSAIDs and intramuscular morphine 10 mg when used as a single oral dose in the treatment of moderate to severe postoperative pain. PMID:11034755

  5. Single dose oral paracetamol (acetaminophen) for postoperative pain in adults

    PubMed Central

    Toms, Laurence; McQuay, Henry J; Derry, Sheena; Moore, R Andrew

    2014-01-01

    Background This is an updated version of the original Cochrane review published in Issue 1, 2004 - this original review had been split from a previous title on ‘Single dose paracetamol (acetaminophen) with and without codeine for postoperative pain’. The last version of this review concluded that paracetamol is an effective analgesic for postoperative pain, but additional trials have since been published. This review sought to evaluate the efficacy and safety of paracetamol using current data, and to compare the findings with other analgesics evaluated in the same way. Objectives To assess the efficacy of single dose oral paracetamol for the treatment of acute postoperative pain. Search methods We searched The Cochrane Library, MEDLINE, EMBASE, the Oxford Pain Relief Database and reference lists of articles to update an existing version of the review in July 2008. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of paracetamol for acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Area under the “pain relief versus time” curve was used to derive the proportion of participants with paracetamol or placebo experiencing at least 50% pain relief over four to six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated, with 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use, were sought as measures of duration of analgesia. Information on adverse events and withdrawals was also collected. Main results Fifty-one studies, with 5762 participants, were included: 3277 participants were treated with a single oral dose of paracetamol and 2425 with placebo. About half of participants treated with paracetamol at standard doses achieved at least 50% pain relief over four to six hours, compared with about 20% treated with placebo. NNTs for at least 50% pain relief over four to six hours following a single dose of paracetamol were as follows: 500 mg NNT 3.5 (2.7 to 4.8); 600 to 650 mg NNT 4.6 (3.9 to 5.5); 975 to 1000 mg NNT 3.6 (3.4 to 4.0). There was no dose response. Sensitivity analysis showed no significant effect of trial size or quality on this outcome. About half of participants needed additional analgesia over four to six hours, compared with about 70% with placebo. Five people would need to be treated with 1000 mg paracetamol, the most commonly used dose, to prevent one needing rescue medication over four to six hours, who would have needed it with placebo. Adverse event reporting was inconsistent and often incomplete. Reported adverse events were mainly mild and transient, and occurred at similar rates with 1000 mg paracetamol and placebo. No serious adverse events were reported. Withdrawals due to adverse events were uncommon and occurred in both paracetamol and placebo treatment arms. Authors’ conclusions A single dose of paracetamol provides effective analgesia for about half of patients with acute postoperative pain, for a period of about four hours, and is associated with few, mainly mild, adverse events. PMID:18843665

  6. Effects of oral doses of fluoride on nestling European starlings

    USGS Publications Warehouse

    Fleming, W.J.; Grue, C.E.; Schuler, C.A.; Bunck, C.M.

    1987-01-01

    Nestling European starlings (Sturnus vulgaris), raised and fed by free-living adults, were given daily oral doses of either distilled water, 193 mg sodium as Na2CO3 per kg of body weight (sodium control group), or 6, 10, 13, 17,23, 30, 40, 80, 160 mg of the fluoride ion as NaF in distilled water per kg of body weight (mg/kg). Dosing began when nestlings were 24-48 hr old and continued for 16 days. The 24-hr LD50 of fluoride for day-old starlings was 50 mg/kg. The 16-day LD50 was 17 mg/kg. The sodium control group did not differ from the water control group with respect to any of the measured variables. Growth rates were significantly reduced in the 13 and 17 mg of fluoride/kg groups; weights of birds given higher dose levels were omitted from growth comparisons because of high, fluoride-induced mortality. Although pre-fledging weights for the 10, 13, and 17 mg of fluoride/kg groups averaged 3.6 to 8.6% less than controls at 17 days, this difference was not significant. Feather and bone growth of the fluoride and control groups were not different, except for keel length measured at 17 days of age which averaged less in the fluoride groups. Liver and spleen weights were not affected by fluoride treatments. No histological damage related to fluoride treatments was found in liver, spleen, or kidney. The logarithm of bone fluoride and magnesium concentration increased with the logarithm of increasing fluoride treatment levels and were significantly correlated with each other. Fluoride treatments had no effect on percent calcium or phosphorus in bone or plasma alkaline phosphatase activity. Oral doses of fluoride appear to be more toxic than equivalent dietary levels. Most birds probably acquire fluoride through their diet. Therefore, the results of the study may overestimate the potential effects of fluorides on songbirds living in fluoride-contaminated environments.

  7. SODIUM BICARBONATE FACILITATES LOW-DOSE ORAL TOLERANCE TO PEANUT IN MICE

    EPA Science Inventory

    Rationale: Oral tolerance specifically inhibits production of allergic IgE antibody and is therefore a potential method for suppressing food allergy. We have previously demonstrated that a single oral dose of one mg is sufficient to induce oral tolerance to egg white but not pean...

  8. Effect of subacute oral doses of nivalenol on immune and metabolic defence systems in mice

    Microsoft Academic Search

    Marie-Estelle Gouze; Joëlle Laffitte; Philippe Pinton; Genevičve Dedieux; Anne Galinier; Jean-Paul Thouvenot; Nicolas Loiseau; Isabelle P. Oswald; Pierre Galtier

    2007-01-01

    Nivalenol (NIV) is a toxic Fusarium secondary trichothecene metabolite occurring naturally in cereal grains. In order to evaluate the no observed adverse effect level (NOAEL), we tested the effects of a large array of oral doses of this toxin for responses on plasma bio- chemistry, the immune system and hepatic drug metabolism in mice. C57Bl6 mice received oral doses of

  9. Single dose oral rofecoxib for acute postoperative pain in adults

    PubMed Central

    Bulley, Simon; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background Editor’s note: The anti-inflammatory drug rofecoxib (Vioxx) was withdrawn from the market at the end of September 2004 after it was shown that long-term use (greater than 18 months) could increase the risk of heart attack and stroke in a study of secondary prevention of adenoma recurrence. Further information is available at www.vioxx.com. Rofecoxib is a selective cyclooxygenase-2 (COX-2) inhibitor previously licensed for treating acute and chronic pain; it was associated with fewer gastrointestinal adverse events than conventional NSAIDs. An earlier Cochrane review (Barden 2005) showed that rofecoxib is at least as effective as conventional non-steroidal anti-inflammatory drugs (NSAIDs) for postoperative pain. Objectives To assess the analgesic efficacy and adverse effects of rofecoxib in single oral doses for moderate and severe postoperative pain. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to June 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered rofecoxib in adults with moderate to severe acute postoperative pain. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number needed to treat to benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results Twenty new studies and seven from the earlier review met the inclusion criteria. Twenty-four studies were in dental surgery and three in other types of surgery. In total, 2636 participants were treated with rofecoxib 50 mg, 20 with rofecoxib 500 mg, and 1251 with placebo. The NNT for at least 50% pain relief over 4 to 6 hours with rofecoxib 50 mg was 2.2 (2.0 to 2.3) in all studies combined, 1.9 (1.8 to 2.0) in dental studies, and 6.8 (4.6 to 13) in other types of surgery. The median time to use of rescue medication was 14 hours for rofecoxib 50 mg and 2 hours for placebo. Significantly fewer participants used rescue medication following rofecoxib 50 mg than with placebo. Adverse events did not differ from placebo. Authors’ conclusions Rofecoxib 50 mg (two to four times the standard daily dose for chronic pain) is an effective single dose oral analgesic for acute postoperative pain in adults, with a relatively long duration of action. PMID:19821329

  10. Single dose oral analgesics for acute postoperative pain in adults

    PubMed Central

    Moore, R Andrew; Derry, Sheena; McQuay, Henry J; Wiffen, Philip J

    2014-01-01

    Background Thirty-five Cochrane Reviews of randomised trials testing the analgesic efficacy of individual drug interventions in acute postoperative pain have been published. This overview brings together the results of all those reviews and assesses the reliability of available data. Objectives To summarise data from all Cochrane Reviews that have assessed the effects of pharmaceutical interventions for acute pain in adults with at least moderate pain following surgery, who have been given a single dose of oral analgesic taken alone. Methods We identified systematic reviews in The Cochrane Library through a simple search strategy. All reviews were overseen by a single Review Group, had a standard title, and had as their primary outcome numbers of participants with at least 50% pain relief over four to six hours compared with placebo. For individual reviews we extracted the number needed to treat (NNT) for this outcome for each drug/dose combination, and also the percentage of participants achieving at least 50% maximum pain relief, the mean of mean or median time to remedication, the percentage of participants remedicating by 6, 8, 12, or 24 hours, and results for participants experiencing at least one adverse event. Main results The overview included 35 separate Cochrane Reviews with 38 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 45,000 participants studied in approximately 350 individual studies. The individual reviews included only high-quality trials of standardised design and outcome reporting. The reviews used standardised methods and reporting for both efficacy and harm. Event rates with placebo were consistent in larger data sets. No statistical comparison was undertaken. There were reviews but no trial data were available for acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for dexibuprofen, dextropropoxyphene 130 mg, diflunisal 125 mg, etoricoxib 60 mg, fenbufen, and indometacin. Where there was adequate information for drug/dose combinations (at least 200 participants, in at least two studies), we defined the addition of four comparisons of typical size (400 participants in total) with zero effect as making the result potentially subject to publication bias and therefore unreliable. Reliable results were obtained for 46 drug/dose combinations in all painful postsurgical conditions; 45 in dental pain and 14 in other painful conditions. NNTs varied from about 1.5 to 20 for at least 50% maximum pain relief over four to six hours compared with placebo. The proportion of participants achieving this level of benefit varied from about 30% to over 70%, and the time to remedication varied from two hours (placebo) to over 20 hours in the same pain condition. Participants reporting at least one adverse event were few and generally no different between active drug and placebo, with a few exceptions, principally for aspirin and opioids. Drug/dose combinations with good (low) NNTs were ibuprofen 400 mg (2.5; 95% confidence interval (CI) 2.4 to 2.6), diclofenac 50 mg (2.7; 95% CI 2.4 to 3.0), etoricoxib 120 mg (1.9; 95% CI 1.7 to 2.1), codeine 60 mg + paracetamol 1000 mg (2.2; 95% CI 1.8 to 2.9), celecoxib 400 mg (2.5; 95% CI 2.2 to 2.9), and naproxen 500/550 mg (2.7; 95% CI 2.3 to 3.3). Long duration of action (8 hours) was found for etoricoxib 120 mg, diflunisal 500 mg, oxycodone 10 mg + paracetamol 650 mg, naproxen 500/550 mg, and celecoxib 400 mg. Not all participants had good pain relief and for many drug/dose combinations 50% or more did not achieve at last 50% maximum pain relief over four to six hours. Authors’ conclusions There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers. PMID:21901726

  11. Persistence of the Oral Probiotic Streptococcus salivarius M18 Is Dose Dependent and Megaplasmid Transfer Can Augment Their Bacteriocin Production and Adhesion Characteristics

    PubMed Central

    Burton, Jeremy P.; Wescombe, Philip A.; Macklaim, Jean M.; Chai, Melissa H. C.; MacDonald, Kyle; Hale, John D. F.; Tagg, John; Reid, Gregor; Gloor, Gregory B.; Cadieux, Peter A.

    2013-01-01

    Bacteriocin-producing probiotic Streptococcus salivarius M18 offers beneficial modulatory capabilities within the oral microbiome, apparently through potent inhibitory activity against potentially deleterious bacteria, such as Streptococcus pyogenes. The oral cavity persistence of S. salivarius M18 was investigated in 75 subjects receiving four different doses for 28 days. Sixty per cent of the subjects already had some inhibitor-producing S. salivarius in their saliva prior to probiotic intervention. Strain M18’s persistence was dependent upon the dose, but not the period of administration. Culture analysis indicated that in some individuals the introduced strain had almost entirely replaced the indigenous S. salivarius, though the total numbers of the species did not increase. Selected subjects showing either high or low probiotic persistence had their salivary populations profiled using Illumina sequencing of the V6 region of the 16S rRNA gene. Analysis indicated that while certain bacterial phenotypes were markedly modulated, the overall composition of the oral microbiome was not modified by the probiotic treatment. Megaplasmids encoding bacteriocins and adhesion factors were transferred in vitro to generate a transconjugant S. salivarius exhibiting enhanced antimicrobial production and binding capabilities to HEp-2 cells. Since no widespread perturbation of the existing indigenous microbiota was associated with oral instillation and given its antimicrobial activity against potentially pathogenic streptococci, it appears that application of probiotic strain M18 offers potential low impact alternative to classical antibiotic prophylaxis. For candidate probiotic strains having relatively poor antimicrobial or adhesive properties, unique derivatives displaying improved probiotic performance may be engineered in vitro by megaplasmid transfer. PMID:23785463

  12. Perturbation of cobalt 60 radiation doses by metal objects implanted during oral and maxillofacial surgery

    Microsoft Academic Search

    M. Tatcher; A. Kuten; J. Helman; D. Laufer

    1984-01-01

    The influence on cobalt 60 dose distributions of typical metal parts used in oral and maxillofacial surgery was studied. Relative doses were determined by exposing x-ray films in a polystyrene phantom set-up containing samples of vitallium, titanium, and stainless steel. Optical densities were converted to doses with the aid of sensitometric curves. The results show that for normal incidence there

  13. Continuous Low-Dose Oral Chemotherapy in Recurrent and Persistent Carcinoma of Cervix Following Chemoradiation: A Comparative Study Between Prolonged Oral Cyclophosphamide and Oral Etoposide

    PubMed Central

    Baruah, Upasana; Barmon, Debabrata; Hazarika, Munlima; Deka, Pankaj; Kataki, Amal Chandra; Shrivastava, Sushruta

    2014-01-01

    Aim: To compare the efficacy and toxicities of low-dose oral cyclophosphamide and oral etoposide in patients with persistent and recurrent cervical cancer with gross pelvic disease following full course of chemoradiation therapy. Materials and Methods: 30 patients with recurrent and persistent cervical cancer with gross pelvic disease were enrolled in this trial. The patients were randomly divided into two groups of 15 patients each with one group receiving low dose oral cyclophosphamide (100 mg/day) and the other group receiving low-dose oral etoposide (50 mg/day). Results were statistically analysed by IBM SPSS Statistics 19. Results: Oral etoposide was not well tolerated with grade 2 neutropenia occurring in 33.3% and grade 3 neutropenia in 6.6% and thrombocytopenia occurring in 13.3%. Oral cyclophosphamide group on the other hand was better tolerated with none of the patients having thrombocytopenia and 6.6% patients having grade 2 neutropenia. There were two complete response (15.38%) and one partial response at the end of study (7.6%) in the cyclophosphamide group whereas there was no complete response and two partial response (16.6%) in the oral etoposide group. Conclusion: Long-term, low-dose oral etoposide was found to be less tolerated without any significant effect with patients with persistent and recurrent cervical cancer with gross pelvic disease following full course of chemoradiation therapy in contrast to oral cyclophosphamide which was found to be effective and well-tolerated by the patients. PMID:25191008

  14. A phase 1, multicentre, open-label study to evaluate ovarian follicular activity and hormone levels with an extended-regimen combined oral contraceptive with low-dose ethinyl estradiol supplementation.

    PubMed

    Kroll, Robin; Seidman, Larry; Ricciotti, Nancy; Howard, Brandon; Weiss, Herman

    2015-08-01

    Objectives To evaluate the effect on ovarian follicular activity of the 91-day extended-regimen combined oral contraceptive (COC), consisting of 84 days of levonorgestrel (LNG)/ethinylestradiol (EE) 150 ?g/30 ?g tablets plus seven days of EE 10 ?g tablets in place of placebo. Methods This was a phase 1, open-label study. Ovarian follicular activity was classified via the Hoogland and Skouby method. Safety and tolerability as well as return to ovulation were assessed. Results Of the 35 subjects included in the efficacy analysis, luteinized, unruptured follicles, or ovulation were detected in 0 of 35 cycles during the first 28-day interval; 1 of 35 cycles (2.9%) in the second 28-day interval; and 2 of 35 cycles (5.7%) in the final 35-day interval. The ovarian activity rate over the entire 91-day treatment period was 2.9%. There was a low incidence of treatment-emergent adverse events. Ovulation returned in most subjects (77.1%, 27/35) within 32 days following the last dose of COC. Conclusions The 91-day extended-regimen COC with low-dose EE supplementation was found to be effective in suppressing ovarian activity and inhibiting ovulation and was well tolerated. Return to ovulation was rapid, occurring within approximately one month after discontinuation of COC. PMID:25522805

  15. Disposition of 2,4-dichlorophenoxyacetic acid dimethylamine by Fischer 344 rats dosed orally and dermally

    SciTech Connect

    Pelletier, O.; Ritter, L.; Caron, J.; Somers, D. (Environmental Health Centre, Ottawa, Ontario (Canada))

    1989-01-01

    The dimethylamine salt of 14C-ring-labeled 2,4-D was administered to Fischer 344 rats orally (1 and 0.4 mg/kg body weight) and dermally (10 mg/kg body weight). Absorption, distribution, and elimination were determined from 14C-labeled 2,4-D in blood, tissues, and excreta. Quantitatively, most of the orally administered dose (94-96%) became systemically available within 6 h. Following dermal administration 10% of the dose became systemically available over 72 h. However, peak concentrations in blood and kidneys were achieved within 30 min of dosing by either route. By 1.5 h after dosing, 2,4-D concentrations in blood, muscle, liver, and kidneys had decreased in both the orally dosed and dermally dosed animals. Between 2 and 8 h, the blood, muscle, liver and kidney concentrations in dermally dosed animals maintained a plateau while urinary excretion increased, presumably due to continued absorption of 2,4-D from the skin. The concentrations in orally dosed animals continued to decrease. Following 7 h of dermal exposure, skin cleansing removed about 63% of the applied dose; about 17% of the applied dose remained at the site of dermal dosing. At 8 h, 2,4-D concentrations in blood, muscle, liver, and kidneys of dermally dosed animals began to decrease, most likely a result of the removal of the reservoir on the skin. However, 2,4-D continued to be absorbed from skin site, resulting in a slower decline of the 2,4-D concentrations in these tissues over remainder of the 72-h study period. By comparison, in animals that had been orally dosed, the absorbed dose was almost completely excreted within 24 h.

  16. Home administration of high-dose oral busulfan in patients undergoing hematopoietic stem cell transplantation

    Microsoft Academic Search

    R H Matthews; M Emami; D G Connaghan; H K Holland; L E Morris

    2007-01-01

    We report our experience with oral busulfan (BU) in 159 consecutive patients to evaluate the safety of home administration. Patients received a myeloablative BU-containing regimen, including oral anticonvulsant and antiemetic prophylaxis, followed by hematopoietic stem cell transplantation. Comprehensive verbal and written education was provided. Pharmacokinetic monitoring was performed and dose adjustments were made to target an area under the plasma

  17. Occlusion-amblyopia following high dose oral levodopa combined with part time patching.

    PubMed

    Kothari, Mihir

    2014-12-01

    Part time occlusion therapy is not reported to cause occlusion (reverse) amblyopia. However, when combined with high dose oral levodopa, an increase in the plasticity of the visual cortex can lead to occlusion amblyopia. In this case report, we describe a six year old child who developed occlusion amblyopia following part time patching combined with oral levodopa. PMID:23571255

  18. Pharmacokinetics of cisapride in normal healthy cats and recommended oral dosing regimen 

    E-print Network

    LeGrange, Suzanne Nauman

    1996-01-01

    The purpose of this study was to determine the disposition of cisapride in cats following oral (PO) and intravenous (IV) administration of a single dose and the bioavailability (F) of the drug when administered as an oral capsule. 7 cats each were...

  19. Occlusion-amblyopia following high dose oral levodopa combined with part time patching

    PubMed Central

    Kothari, Mihir

    2014-01-01

    Part time occlusion therapy is not reported to cause occlusion (reverse) amblyopia. However, when combined with high dose oral levodopa, an increase in the plasticity of the visual cortex can lead to occlusion amblyopia. In this case report, we describe a six year old child who developed occlusion amblyopia following part time patching combined with oral levodopa. PMID:23571255

  20. Outpatient Treatment of Moderate Croup With Dexamethasone: Intramuscular Versus Oral Dosing

    Microsoft Academic Search

    Kristine K. Rittichier; Carol A. Ledwith

    ABSTRACT. Objective. Steroid use for the treatment of croup has been supported by several studies, although few have addressed the use of oral dexamethasone for outpatient management. The efficacy of oral (PO) versus intramuscular (IM) dosing of dexamethasone in the out- patient treatment of moderate croup are compared in this study. Methods. Patients between the ages of 3 months and

  1. High-Dose Oral Misoprostol for Mid-Trimester Pregnancy Interruption

    Microsoft Academic Search

    Kirk D. Ramin; Paul L. Ogburn; Diana R. Danilenko; Patrick S. Ramsey

    2002-01-01

    Objective: To evaluate the efficacy of high-dose oral misoprostol for mid-trimester pregnancy interruption. Methods: We reviewed our experience with high-dose oral misoprostol for mid-trimester pregnancy interruption from November 1995 to May 1999. Patients undergoing labor induction for intrauterine fetal demise or medically indicated pregnancy termination at 13–32 weeks of gestation with a non-dilated cervix were evaluated. Patients received 400 ?g

  2. Disposition of clorazepate in dogs after single- and multiple-dose oral administration 

    E-print Network

    Forrester, Sharon Dru

    1989-01-01

    DISPOSITION OF CLORAZEPATE IN DOGS AFTER SINGLE- AND MULTIPLE-DOSE ORAL ADMINISTRATION A Thesis by SHARON DRU FORRESTER Submitted to the Office of Graduate Studies of Texas ARM University in Partial fulfillment of the requirements... for the degree of MASTER OF SCIENCE May 1989 Major Subject: Veterinary Medicine and Surgery DISPOSITION OF CLORAZEPATE IN DOGS AFTER SINGLE- AND MULTIPLE-DOSE ORAL ADMINISTRATION A Thesis by SHARON DRU FORRESTER Approved as to sty1e and content by: Geo...

  3. Efficacy and tolerability of low-dose oral prolonged-release oxycodone/naloxone for chronic nononcological pain in older patients

    PubMed Central

    Guerriero, Fabio; Sgarlata, Carmelo; Marcassa, Claudio; Ricevuti, Giovanni; Rollone, Marco

    2015-01-01

    Purpose Chronic pain is highly prevalent in older adults. Increasing evidence indicates strong opioids as a valid option for chronic pain management in geriatrics. The aim of this study was to evaluate efficacy and safety of low-dose oral prolonged-release oxycodone–naloxone (OXN-PR) in patients aged ?70 years. Methods This open-label prospective study assessed older patients naďve to strong opioids presenting with moderate-to-severe chronic pain. Patients were prescribed OXN-PR at an initial dose of 10/5 mg/day for 28 days. In case of insufficient analgesia, the initial daily dose could be increased gradually. The primary efficacy measure was change in pain intensity from baseline, assessed by a ten-point Numeric Rating Scale (NRS) at day 28 (T28). Changes in cognitive state, daily functioning, quality of life, constipation, and other adverse events were assessed. Results Of 53 patients enrolled (mean 81.7±6.2 years [range 70–92 years]), 52 (98.1%) completed the 28-day observation. At T28, the primary end point (?30% reduction in mean pain from baseline in the absence of bowel function deterioration) was achieved in 38 patients (71.7%). OXN-PR significantly relieved pain (NRS score –3.26; P<0.0001), as well as daily need for rescue paracetamol (from 86.8% at baseline to 40.4% at T28; P<0.001), and reduced impact of pain on daily activities (Brief Pain Inventory Short Form from 6.2±1.5 to 3.4±2.1; P<0.0001). OXN-PR was also associated with significant improvement in daily functioning (Barthel Index from 53.3±14.1 to 61.3±14.3; P<0.01). No changes were observed in cognitive status and bowel function. OXN-PR was well tolerated; only one patient (1.9%) prematurely withdrew from treatment, due to drowsiness. Conclusion Findings from this open-label prospective study suggest that low-dose OXN-PR may be effective and well tolerated for treatment of moderate-to-severe chronic pain in older patients. Besides its effectiveness, these data indicate that low-dose OXN-PR may be considered a safe analgesic option in this fragile population and warrants further investigation in randomized controlled studies. PMID:25565782

  4. Yasminelle((R)): a new low-dose combined oral contraceptive containing drospirenone.

    PubMed

    Sillem, Martin

    2006-07-01

    Yasminelle((R)) is a newly developed combined oral contraceptive that contains ethinyl estradiol 20 microg and drospirenone 3 mg. Yasminelle is unlike other low-dose ethinyl estradiol combined oral contraceptives, since drospirenone produces antiandrogenic and antimineralocorticoid effects that offer various benefits including a reduced potential for estrogen-induced water retention. Pharmacological and pharmacokinetic data have been derived from clinical experience with ethinyl estradiol 30 microg and drospirenone 3 mg (Yasmin((R))). Clinical studies with Yasminelle have shown a high degree of contraceptive efficacy, similar to that of combined oral contraceptives that contain a low dose of ethinyl estradiol combined with other progestins. These studies have also demonstrated that Yasminelle produces excellent cycle control and has a good tolerability profile, similar to that of other low-dose ethinyl estradiol combined oral contraceptives. PMID:19803962

  5. Pharmacokinetics of diazepam following multiple-dose oral administration to healthy human subjects

    Microsoft Academic Search

    F. B. Eatman; W. A. Colburn; H. G. Boxenbaum; H. N. Posmanter; R. E. Weinfeld; R. Ronfeld; L. Weissman; J. D. Moore; M. Gibaldi; S. A. Kaplan

    1977-01-01

    Six healthy subjects between the ages of 21 and 31 years received diazepam tablets orally at a dose of 5 mg t.i.d. atO, 5, and 10hr on days 1–13. On day 14, the dose was 5 mg at 0 and 5 hr and 15 mg at 10 hr. Subsequently, the dose was 15 mg once daily on days 15–24. Numerous

  6. Pharmacokinetic overview of ethinyl estradiol dose and bioavailability using two transdermal contraceptive systems and a standard combined oral contraceptive

    PubMed Central

    Hofmann, Birte; Reinecke, Isabel; Schuett, Barbara; Merz, Martin; Zurth, Christian

    2014-01-01

    Objective: To determine the relative bioavailability of ethinyl estradiol (EE) and gestodene (GSD) after application of a novel transdermal contraceptive patch vs. a standard combined oral contraceptive (COC) pill (study 1), and to evaluate the pharmacokinetics (PK) of EE after application of the EE/GSD patch compared with an EE/norelgestromin (NGMN) patch (study 2). Materials: Participants were healthy, non-obese women aged 18 – 45 years (study 1) or 18 – 35 years (study 2). Compositions of study treatments were as follows: 0.55 mg EE/2.1 mg GSD (EE/GSD patch); 0.02 mg EE/0.075 mg GSD (standard COC); 0.6 mg EE/6 mg NGMN (EE/NGMN patch). Methods: In study 1, which consisted of 3 treatment periods (each followed by 7 patch- or pill-free days), treatments were administered in one of two randomized orders: either P–M–E (EE/GSD patch (P) every 7 days for 28 days ? COC (M) once-daily for 21 days ? two 7-day patch-wearing periods followed by one 10-day patch-wearing phase (E)), or the same treatments administered in sequence M–P–E. For study 2, participants received either the EE/GSD patch or EE/NGMN patch for seven treatment cycles (one patch per week for 3 weeks followed by a 7-day patch-free interval). Results: In study 1, average daily exposure to EE was similar for treatments P and M; the mean daily area under the concentration-time curve (AUC) ratio of treatment P vs. treatment M for EE was 1.06 (90% confidence interval (CI): 0.964 – 1.16), indicating average daily delivery similar to oral administration of 0.019 – 0.023 mg EE. For unbound GSD, average daily exposure was lower for treatment P vs. treatment M. The mean AUC ratio of treatment P vs. treatment M for unbound GSD was 0.820 (90% CI: 0.760 – 0.885), indicating average daily delivery from the patch of 0.057 – 0.066 mg GSD. Prolonged patch wearing did not result in a distinct decline in GSD and EE serum concentrations. In study 2, AUC at steady state (AUC0–168,ss), average steady-state serum concentration, and maximum steady-state serum concentration for EE was 2.0 – 2.7-fold higher for the EE/NGMN patch vs. the EE/GSD patch. The EE/GSD patch was well tolerated in both studies. Conclusions: Based on the 90% CI of the AUC ratio of oral treatment vs. patch application for unbound GSD and EE, the daily doses of GSD and EE released from the EE/GSD patch over the 7-day application period provided the same systemic exposure as those recorded after daily oral administration of a COC containing 0.02 mg EE and 0.06 mg GSD. The EE/GSD patch showed reduced EE exposure compared with the EE/NGMN patch. Together with its good tolerability, these properties support the EE/GSD patch as an effective and well-tolerated alternative to available transdermal and oral contraceptives. PMID:25295716

  7. IMMUNOTOXIC EFFECTS OF 2-BROMOPROPANE IN MALE SPRAGUE-DAWLEY RATS: A 28DAY EXPOSURE STUDY

    Microsoft Academic Search

    Tae Cheon Jeong; Eung-Seok Lee; Whigun Chae; Woo Suk Koh; Boo-Hyon Kang; Sang Seop Han

    2002-01-01

    Immunotoxic effects of 2-bromopropane were investigated in male Sprague-Dawley rats. The rats were treated orally daily with 2-bromopropane at 100, 330, or 1000 mg\\/kg for 28 consecutive days. Four days before necropsy, the rats were immunized intravenously with sheep red blood cells (SRBCs). The body and thymus weights were significantly reduced by treatment with 2-bromopropane at the highest dose. In

  8. Pharmacokinetics of single dose oral meloxicam in bottlenose dolphins (Tursiops truncatus).

    PubMed

    Simeone, Claire A; Nollens, Hendrik H; Meegan, Jenny M; Schmitt, Todd L; Jensen, Eric D; Papich, Mark G; Smith, Cynthia R

    2014-09-01

    The objective of this study was to investigate the pharmacokinetics of meloxicam in bottlenose dolphins (Tursiops truncatus). Ten adult bottlenose dolphins were used for the study. Each animal received a single oral dose of meloxicam at 0.1 mg/kg. Two to seven serial blood samples were collected per animal, at one of fourteen time points between T = 0 and T = 240 hr. Complete blood count and serum chemistry analysis were performed prior to drug administration, as well as at the final time point for each individual. Plasma drug concentrations were determined by high-pressure liquid chromatography. No adverse hematological, biochemical or clinical changes were noted during the study period. After oral administration, a peak plasma concentration of 1.03 microg/mL was achieved at approximately 11 hr. This suggests that a single oral dose of 0.1 mg/kg provides a peak plasma level similar to what is considered therapeutic in other species. However, the elimination of meloxicam in cetaceans was slower than in other species, with an elimination half-life of almost 70 hr, and detectable drug concentrations up to 7 days. A single oral dose of 0.1 mg/kg appears safe for use in this species, but caution in repeated dosing must be used, due to the prolonged elimination, until multi-dose pharmacokinetic studies are determined. PMID:25314827

  9. Comparison of high-dose intravenous methylprednisolone with low-dose oral prednisolone in acute renal allograft rejection in children

    Microsoft Academic Search

    N Orta-Sibu; C Chantler; M Bewick; G Haycock

    1982-01-01

    Two corticosteroid regimens were compared in a randomised, prospective study of 48 consecutive acute rejection episodes occurring at least one month after transplantation in 22 children who had received renal allografts. The higher dose schedule (intravenous methylprednisolone 600 mg\\/m2 daily for three days) was no more effective than the lower (oral prednisolone 3 mg\\/kg daily for three days) in reversing

  10. Pharmacokinetics and pharmacodynamics of oral diazepam: Effect of dose, plasma concentration, and time

    Microsoft Academic Search

    H Friedman; David J Greenblatt; Gary R Peters; Carl M Metzler; Melody D Charlton; Jerold S Harmatz; Edward J Antal; Elmer C Sanborn; Steven F Francom

    1992-01-01

    Eleven healthy subjects received single oral doses of placebo, 2 mg diazepam, 5 mg diazepam, and 10 mg diazepam in a randomized four-way crossover study. Plasma diazepam levels, the Digit Symbol Substitution Test (DSST), and fraction of total electroencephalographic (EEG) amplitude falling in the sigma plus beta (13 to 31 Hz) frequency range were determined during the 12 hours after

  11. Optimal dose of oral omeprazole for maximal 24 hour decrease of intragastric acidity

    Microsoft Academic Search

    B K Sharma; R P Walt; R E Pounder; M D Gomes; E C Wood; L H Logan

    1984-01-01

    In a series of 59 experiments in nine duodenal ulcer patients, 24 hour intragastric acidity was measured before, during, and after treatment with daily oral omeprazole. Omeprazole 10, 20, and 30 mg\\/day for one week caused a 37, 90, and 97% decrease of 24 hour intragastric acidity, respectively. No further decrease of acidity was observed when the dose of omeprazole

  12. Assessment of the oral administration of a high dose of retinol on vitamin E status of sheep

    E-print Network

    Paris-Sud XI, Université de

    Short note Assessment of the oral administration of a high dose of retinol on vitamin E status on vitamin E turnover in sheep's body was stud- ied. Five of 10 adult Canadian Arcott sheep were given daily for 30 d an oral dose of 250 mg vitamin A as retinol palmitate, while the remaining sheep were used

  13. Single- and multiple dose pharmacokinetics and multiple dose pharmacodynamics of oral ABT-116 (a TRPV1 antagonist) in dogs.

    PubMed

    Niyom, S; Mama, K R; Gustafson, D L; Rezende, M L

    2015-08-01

    Six dogs were used to determine single and multiple oral dose pharmacokinetics of ABT-116. Blood was collected for subsequent analysis prior to and at 15, 30 min and 1, 2, 4, 6, 12, 18, and 24 h after administration of a single 30 mg/kg dose of ABT-116. Results showed a half-life of 6.9 h, kel of 0.1/h, AUC of 56.5 ?g·h/mL, Tmax of 3.7 h, and Cmax of 3.8 ?g/mL. Based on data from this initial phase, a dose of 10 mg/kg of ABT-116 (no placebo control) was selected and administered to the same six dogs once daily for five consecutive days. Behavioral observations, heart rate, respiratory rate, temperature, thermal and mechanical (proximal and distal limb) nociceptive thresholds, and blood collection were performed prior to and 4, 8, and 16 h after drug administration each day. The majority of plasma concentrations were above the efficacious concentration (0.23 ?g/mL previously determined for rodents) for analgesia during the 24-h sampling period. Thermal and distal limb mechanical thresholds were increased at 4 and 8 h, and at 4, 8, and 16 h respectively, postdosing. Body temperature increased on the first day of dosing. Results suggest adequate exposure and antinociceptive effects of 10 mg/kg ABT-116 following oral delivery in dogs. PMID:25376244

  14. PULMONARY FUNCTION AND PATHOLOGY IN CATS EXPOSED 28 DAYS TO DIESEL EXHAUST

    EPA Science Inventory

    Young adult male cats were exposed 28 days, 20 hours per day, to a 1:14 dilution of diesel exhaust emissions. Following termination of exposure, the following pulmonary function measurements were carried out: lung volumes, maximum expiratory flow rates (MEF), MEF at 50%, 25% and ...

  15. Single intravenous and oral dose pharmacokinetics of florfenicol in the channel catfish (Ictalurus punctatus).

    PubMed

    Gaunt, P S; Langston, C; Wrzesinski, C; Gao, D; Adams, P; Crouch, L; Sweeney, D; Endris, R

    2012-10-01

    Plasma distribution and elimination of florfenicol in channel catfish were investigated after a single dose (10 mg/kg) of intravenous (i.v.) or oral administration in freshwater at a mean water temperature of 25.4 °C. Florfenicol concentrations in plasma were analyzed by means of liquid chromatography with MS/MS detection. After i.v. florfenicol injection, the terminal half-life (t(1/2)), volume of distribution at steady state (V(ss)), and central volume of distribution (V(c)) were 8.25 h, 0.9 and 0.381 L/kg, respectively. After oral administration of florfenicol, the terminal t(1/2), C(max), T(max), and oral bioavailability (F) were 9.11 h, 7.6 ?g/mL, 9.2 h, and 1.09, respectively. There was a lag absorption time of 1.67 h in oral dosing. Results from these studies support that 10 mg florfenicol/kg body weight in channel catfish is an efficacious dosage following oral administration. PMID:21929526

  16. PHARMACOKINETICS OF SINGLE-DOSE ORALLY ADMINISTERED CIPROFLOXACIN IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

    PubMed

    Barbosa, Lorraine; Johnson, Shawn P; Papich, Mark G; Gulland, Frances

    2015-06-01

    Ciprofloxacin is commonly selected for clinical use due to its broad-spectrum efficacy and is a frequently administered antibiotic at The Marine Mammal Center, a marine mammal rehabilitation facility. Ciprofloxacin is used for treatment of California sea lions ( Zalophus californianus ) suffering from a variety of bacterial infections at doses extrapolated from other mammalian species. However, as oral absorption is variable both within and across species, a more accurate determination of appropriate dosage is needed to ensure effective treatment and avoid emergence of drug-resistant bacterial strains. A pharmacokinetic study was performed to assess plasma concentrations of ciprofloxacin in California sea lions after a single oral dose. Twenty healthy California sea lions received a single 10-mg/kg oral dose of ciprofloxacin administered in a herring fish. Blood was then collected at two of the following times from each individual: 0.5, 0.75, 1, 2, 4, 8, 10, 12, 18, and 24 hr postingestion. Plasma ciprofloxacin concentration was assessed via high-performance liquid chromatography. A population pharmacokinetics model demonstrated that an oral ciprofloxacin dose of 10 mg/kg achieved an area under the concentration vs. time curve of 6.01 ?g hr/ml. Absorption was rapid, with ciprofloxacin detectable in plasma 0.54 hr after drug administration; absorption half-life was 0.09 hr. A maximum plasma concentration of 1.21 ?g/ml was observed at 1.01 hr, with an elimination half-life of 3.09 hr. Ciprofloxacin administered orally at 10 mg/kg produced therapeutic antibacterial exposure for only some of the most susceptible bacterial organisms commonly isolated from California sea lions. PMID:26056878

  17. Risk Factors and Dose-Effect Relationship for Mandibular Osteoradionecrosis in Oral and Oropharyngeal Cancer Patients

    SciTech Connect

    Lee, Ik Jae; Koom, Woong Sub [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Lee, Chang Geol, E-mail: cglee1023@yuhs.a [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Kim, Yong Bae; Yoo, Sei Whan; Keum, Ki Chang; Kim, Gwi Eon [Department of Radiation Oncology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Choi, Eun Chang [Department of Otolaryngology, Yonsei University College of Medicine, Seoul (Korea, Republic of); Cha, In Ho [Department of Oral and Maxillofacial Surgery, Yonsei University College of Dentistry, Seoul (Korea, Republic of)

    2009-11-15

    Purpose: To analyze risk factors and the dose-effect relationship for osteoradionecrosis (ORN) of the mandible after radiotherapy of oral and oropharyngeal cancers. Materials and Methods: One-hundred ninety-eight patients with oral (45%) and oropharyngeal cancer (55%) who had received external radiotherapy between 1990 and 2000 were retrospectively reviewed. All patients had a dental evaluation before radiotherapy. The median radiation dose was 60 Gy (range, 16-75 Gy), and the median biologically effective dose for late effects (BED{sub late}) in bone was 114 Gy{sub 2} (range, 30-167 Gy{sub 2}). Results: The frequency of ORN was 13 patients (6.6%). Among patients with mandibular surgery, eight had ORN at the surgical site. Among patients without mandibular surgery, five patients had ORN on the molar area of the mandible. The median time to ORN was 22 months (range, 1-69 months). Univariate analysis revealed that mandibular surgery and Co-60 were significant risk factors for ORN (p = 0.01 and 0.04, respectively). In multivariate analysis, mandibular surgery was the most important factor (p = 0.001). High radiation doses over BED 102.6 Gy{sub 2} (conventional dose of 54 Gy at 1.8 Gy/fraction) were also a significant factor for ORN (p = 0.008) and showed a positive dose-effect relationship in logistic regression (p = 0.04) for patients who had undergone mandibular surgery. Conclusions: Mandibular surgery was the most significant risk factor for ORN of mandible in oral and oropharyngeal cancers patients. A BED of 102.6 Gy{sub 2} or higher to the mandible also significantly increases the risk of ORN.

  18. Pulmonary function and pathology in cats exposed 28 days to diesel exhaust

    SciTech Connect

    Pepelko, W.E.; Mattox, J.K.; Yang, Y.Y.; Moore, W. Jr.

    1980-09-01

    Young adult male cats were exposed 28 days, 20 hrs per day, to a 1:14 dilution of diesel exhaust emissions. Following termination of exposure, the following pulmonary function measurements were carried out: lung volumes, maximum expiratory flow rates (MEF), MEF at 50%, 25% and 10% of vital capacity (VC): forced expiratory volume (FEV) after 0.2, 0.3 and 0.4 sec, dynamic compliance, resistance and helium washout at 25, 50, 75, and 100 breaths per min. The only significant functional change was a decrease in MEF at 10% of VC (P x .02). The lungs of the exposed cats appeared charcoal grey with frequent focal black spots visible on the pleural surface. Pathologic changes in the exposed cats included a predominantly peribronchiolar localization of black-pigmented macrophages within the alveoli producing a focal pneumonitis or alveolitis. In general, evidence of serious lung damage was not observed following the 28-day exposure period.

  19. Single dose intravenous methyl prednisolone versus oral prednisolone in Bell's palsy: A randomized controlled trial

    PubMed Central

    Giri, Prithvi; Garg, Ravindra Kumar; Singh, Maneesh Kumar; Verma, Rajesh; Malhotra, Hardeep Singh; Sharma, Praveen Kumar

    2015-01-01

    Objectives: Corticosteroids have been used in the treatment of Bell's palsy and several other postinfectious neurological conditions. We hypothesized that administration of a single dose of intravenous (IV) methylprednisolone might be an effective alternative to oral prednisolone. Materials and Methods: In this open label, randomized trial, patients with acute Bell's palsy were randomized into two groups. One group received single dose (500 mg) of IV methylprednisolone while the other group received 10 days of oral prednisone. Outcome was assessed at 1 and 3 months with House–Brackmann scale. Results: At 3 months, 93 (79.48%) patients had completely recovered. IV methylprednisolone and oral prednisolone groups had similar recovery rates (80% vs. 78.33%, P > 0.05). Patients with Grade 2 and 3 recovered completely. In patients with Grade 6, the recovery rate was 20%. A better outcome was observed if corticosteroids were administered within 3 days of onset of palsy. Conclusion: Intravenous methylprednisolone and oral prednisolone showed equivalent benefit in patients with acute Bell's palsy. PMID:25878371

  20. Effect of oral dosing vehicles on the subchronic hepatotoxicity of carbon tetrachloride in the rat

    Microsoft Academic Search

    K. P. Koporec; H. J. Kim; W. F. Mackenzie; J. V. Bruckner

    1995-01-01

    Previous studies in this laboratory have shown that corn oil delayed and prolonged the gastrointestinal absorption of carbon tetrachloride (CCI4) and reduced its acute hepatotoxicity in rats. The objective of the present study was to extend the duration of ingestion of CCI4 to assess vehicle effects on the subchronic oral toxicity of CCI4. Male Harlan Sprague?Dawley rats were given doses

  1. Single-Dose Pharmacokinetics of a Pleconaril (VP63843) Oral Solution in Children and Adolescents

    Microsoft Academic Search

    GREGORY L. KEARNS; SUSAN M. ABDEL-RAHMAN; LAURA P. JAMES; DOUGLAS L. BLOWEY; JAMES D. MARSHALL; THOMAS G. WELLS; RICHARD F. JACOBS; Pediatric Nephrology

    1999-01-01

    Pleconaril is an orally active, broad-spectrum antipicornaviral agent which demonstrates excellent pene- tration into the central nervous system, liver, and nasal epithelium. In view of the potential pediatric use of pleconaril, we conducted a single-dose, open-label study to characterize the pharmacokinetics of this antiviral agent in pediatric patients. Following an 8- to 10-h period of fasting, 18 children ranging in

  2. Telavancin for Hospital-Acquired Pneumonia: Clinical Response and 28-Day Survival

    PubMed Central

    Corey, G. Ralph; Kollef, Marin H.; Shorr, Andrew F.; Rubinstein, Ethan; Stryjewski, Martin E.; Hopkins, Alan

    2014-01-01

    U.S. Food and Drug Administration draft guidance for future antibiotic clinical trials of bacterial nosocomial pneumonia recommends the use of diagnostic criteria according to American Thoracic Society/Infectious Diseases Society of America (ATS/IDSA) guidelines and the use of a primary endpoint of 28-day all-cause mortality. The effect of applying these guidelines on outcomes of phase III nosocomial pneumonia studies of telavancin was evaluated in a post hoc analysis. ATS/IDSA criteria were applied in a blind fashion to the original all-treated (AT) group. Clinical cure rates at final follow-up were determined in the refined AT and clinically evaluable (CE) groups (ATS/IDSA-AT and ATS/IDSA-CE, respectively). The exploratory endpoint of 28-day survival was evaluated for the ATS/IDSA-AT group. Noninferiority of telavancin versus vancomycin was demonstrated, with similar cure rates in the ATS/IDSA-AT (59% versus 59%) and ATS/IDSA-CE (83% versus 80%) groups. Cure rates favored telavancin in ATS/IDSA-CE patients where Staphylococcus aureus was the sole pathogen (86% versus 75%). Overall, 28-day survival rates were similar in the telavancin (76%) and vancomycin (77%) groups but lower in telavancin-treated patients with preexisting moderate-to-severe renal impairment (creatinine clearance [CLCR] of <50 ml/min). Telavancin should be administered to patients with moderate-to-severe renal impairment only if treatment benefit outweighs the risk or if no suitable alternatives are available. PMID:24419353

  3. Evaluation of neuropathic pain occurring after high-dose-rate interstitial brachytherapy of oral tongue

    PubMed Central

    Sharma, Suresh C.; Kapoor, Rakesh; Ahuja, Chirag K.; Oinam, Arun S.; Ghoshal, Sushmita

    2015-01-01

    Purpose To recognize neuropathic pain as a complication of high-dose-rate (HDR) interstitial brachytherapy of oral tongue and to evaluate the possible causes of neuropathy. Material and methods Twenty one patients who underwent interstitial brachytherapy for early cancer of oral tongue were evaluated. The patients either underwent primary brachytherapy (42-48 Gy at 3-4 Gy/fraction) or a boost (18-24 Gy at 3 Gy/fraction) after external radiation to 40 Gy. Lingual nerve was the nerve concerned and the sublingual space (SLS) was contoured as its surrogate. Dosimetric parameters were correlated with onset of pain. Results Ten patients out of 21 (47.61%) developed painful neuropathy. Five patients of six (5/6) who underwent primary brachytherapy developed neuropathy. Five out of 15 (5/15) patients who underwent brachytherapy as a boost developed neuropathy. The patients who underwent primary brachytherapy were ten times more likely to develop neuropathy. Among the patients receiving boost treatment, the equivalent dose at 2 Gy/fraction (EQD2) to 2 cc of SLS was higher (39.25 Gy) in the patients who developed pain compared to those without pain (10.29 Gy). Conclusions This is the first report to recognize neuropathic pain as a complication of HDR brachytherapy of oral tongue. Patients undergoing primary brachytherapy were more likely to develop pain. Among other factors like dose to SLS, number of catheters, size of the primary tumor, and the dose rate, only dose to 2 cc of the SLS correlated with onset of pain. The SLS (containing the lingual nerve) may be considered an organ at risk to prevent the occurrence of this complication.

  4. Single, Escalating Dose Pharmacokinetics, Safety and Food Effects of a New Oral Androgen Dimethandrolone Undecanoate in Man: A prototype oral male hormonal contraceptive

    PubMed Central

    Swerdloff, Ronald S.; Nya-Ngatchou, Jean Jacques; Liu, Peter Y.; Amory, John K.; Leung, Andrew; Hull, Laura; Blithe, Diana L.; Woo, Jason; Bremner, William J.; Wang, Christina

    2014-01-01

    The novel androgen, dimethandrolone (DMA) has both androgenic and progestational activities, properties that may maximize gonadotropin suppression. We assessed the pharmacokinetics of dimethandrolone undecanoate (DMAU), an orally bioavailable, longer-acting ester of DMA, for male contraceptive development. Our objective was to examine the safety and pharmacokinetics of single, escalating doses of DMAU (powder in capsule formulation) administered orally with or without food in healthy men. We conducted a randomized, double-blind Phase 1 study. For each dose of DMAU (25 to 800 mg), ten male volunteers received DMAU and two received placebo at two academic medical centers. DMAU was administered both fasting and after a high fat meal (200–800 mg doses). Serial serum samples were collected over 24h following each dose. DMAU was well tolerated without significant effects on vital signs, safety laboratory tests or electrocardiograms. When administered while fasting, serum DMA (active compound) was detectable in only 4/10 participants after the 800mg dose. When administered with a 50% fat meal, serum DMA was detectable in all participants given 200mg DMAU and showed a dose-incremental increase up to 800mg, with peak levels 4 to 8h after taking the dose. Serum gonadotropins and sex hormone concentrations were significantly suppressed 12h after DMAU administration with food at doses above 200mg. This first-in-man study demonstrated that a single, oral dose of DMAU up to 800 mg is safe. A high-fat meal markedly improved DMAU/DMA pharmacokinetics. PMID:24789057

  5. Mass vaccination with a two-dose oral cholera vaccine in a refugee camp.

    PubMed Central

    Legros, D.; Paquet, C.; Perea, W.; Marty, I.; Mugisha, N. K.; Royer, H.; Neira, M.; Ivanoff, B.

    1999-01-01

    In refugee settings, the use of cholera vaccines is controversial since a mass vaccination campaign might disrupt other priority interventions. We therefore conducted a study to assess the feasibility of such a campaign using a two-dose oral cholera vaccine in a refugee camp. The campaign, using killed whole-cell/recombinant B-subunit cholera vaccine, was carried out in October 1997 among 44,000 south Sudanese refugees in Uganda. Outcome variables included the number of doses administered, the drop-out rate between the two rounds, the proportion of vaccine wasted, the speed of administration, the cost of the campaign, and the vaccine coverage. Overall, 63,220 doses of vaccine were administered. At best, 200 vaccine doses were administered per vaccination site and per hour. The direct cost of the campaign amounted to US$ 14,655, not including the vaccine itself. Vaccine coverage, based on vaccination cards, was 83.0% and 75.9% for the first and second rounds, respectively. Mass vaccination of a large refugee population with an oral cholera vaccine therefore proved to be feasible. A pre-emptive vaccination strategy could be considered in stable refugee settings and in urban slums in high-risk areas. However, the potential cost of the vaccine and the absence of quickly accessible stockpiles are major drawbacks for its large-scale use. PMID:10593032

  6. Dose-dependent pharmacokinetics and brain penetration of rufinamide following intravenous and oral administration to rats.

    PubMed

    Gáll, Zsolt; Vancea, Szende; Szilágyi, Tibor; Gáll, Orsolya; Kolcsár, Melinda

    2015-02-20

    Rufinamide is a third-generation antiepileptic drug, approved recently as an orphan drug for the treatment of Lennox-Gastaut syndrome. Although extensive research was conducted, its pharmacokinetics in rats was not described. This work addresses that area by describing in a rapid pharmacokinetic study the main pharmacokinetic properties of rufinamide at three different doses of 1 mg/kg body weight (bw), 5 mg/kg bw, and 20 mg/kg bw. Furthermore, total brain concentrations of the drug were determined in order to characterize its brain-to-plasma partition coefficient. Adult Wistar male rats, weighing 200-450 g, were administered rufinamide by intravenous and oral routes. Rufinamide concentrations from plasma samples and brain tissue homogenate were determined using a liquid chromatography-mass spectrometric method and pharmacokinetic parameters were calculated. The mean half-life was between 7 and 13 h, depending on route of administration--intravenously administered drug was eliminated faster than orally administered drug. Mean (S.E.M.) total plasma clearance was 84.01 ± 3.80 ml/h/kg for intravenous administration, while the apparent plasma clearance for oral administration was 95.52 ± 39.45 ml/h/kg. The mean (S.E.M.) maximum plasma concentration reached after oral administration of 1 mg/kg bw and 5 mg/kg bw was 0.89 ± 0.09 ?g/ml and 3.188 ± 0.71 ?g/ml, respectively. The median (range) time to reach maximum plasma concentration (t(max)) was 4 (2-8)h. Mean (S.E.M.) brain-to-plasma concentration ratio of rufinamide was 0.514 ± 0.036, consistent with the brain-to-plasma ratio calculated from the area under curves (AUC(0-t)) of 0.441 ± 0.047. No influence of dose, route of administration, or post-dosing time was observed on brain-to-plasma ratio. PMID:25530452

  7. Dose-dependent effects but not sensitization of DRL 45-s performance by oral d-amphetamine with cumulative- and repeated-dosing regimens.

    PubMed

    Lobarinas, E; Falk, J L

    1999-12-01

    The effects of d-amphetamine (AMPH) on a food-reinforced DRL 45-s schedule were evaluated using both cumulative- and repeated-dosing drug regimens. These two dosing regimens were designed to evaluate sensitization as a shift in the dose-response relationship, inasmuch as a range of doses was imposed within each dosing session. Daily 190-min sessions were composed of five 35-min subsessions separated by 3-min time-out periods. For selected sessions, five cumulative or repeated oral doses of AMPH were administered across the session, with a dose given during each of the time-out periods prior to the start of each subsession. Drug sessions were separated by intervals of 7-l0 days of non-drug sessions. Four cumulative dose-effect functions for AMPH were determined: for each dose-effect determination session, increasing doses (0.5, 1, 2, 4, 8 mg/kg gavage) were successively administered prior to each subsession. Four dose-effect functions were then determined in which a 0.5 mg/kg AMPH dose was repeated for each subsession (repetitive-dose regimen) rather than escalating subsession dose size. Then, four additional functions were determined using a larger repetitive dose of 1 mg/kg AMPH. Cumulative doses resulted in a leftward shift in the inter-response times (IRT) distribution accompanied by dose-dependent increases in subcriterion responses (< 45 s) and decreases in reinforced responses. The repeated doses of 0.5 or 1 mg/kg AMPH also resulted in progressive intrasession increases in subcriterion responses and decreases in reinforced responses. Although intrasession, accumulating dose effects were evident and statistically significant, there was no statistical significance or trend supporting sensitization of differential reinforcement of low-rate (DRL) responding with either cumulative- or repeated-dosing regimens across drugging sessions, unlike a previous, similar study in which oral cocaine resulted in robust sensitization. PMID:10780289

  8. Absorption, distribution, metabolism and excretion of daily oral doses of [ 14C]methyl parathion in hens

    Microsoft Academic Search

    Aqel W Abu-Qare; Ali A Abdel-Rahman; Husam Ahmad; Amal M Kishk; Mohamed B Abou-Donia

    2001-01-01

    Adult hens were given oral daily doses of 2 mg (2 ?Ci)\\/kg\\/day (14% of oral LD50 in male rats) of [14C]methyl parathion (O,O-dimethyl O-4-nitrophenyl phosphorothioate) for 10 consecutive days. Five treated hens were sacrificed at 1, 2, 4, 8, 12, 24, and 48 h after the last dose. Methyl parathion was absorbed from the gastrointestinal tract and distributed rapidly. Maximum

  9. Long-Term High-dose Oral Morphine in Phantom Limb Pain with No Addiction Risk

    PubMed Central

    Kumar, Vinod; Garg, Rakesh; Bharati, Sachidanand Jee; Gupta, Nishkarsh; Bhatanagar, Sushma; Mishra, Seema; Balhara, Yatan Pal Singh

    2015-01-01

    Chronic phantom limb pain (PLP) is a type of neuropathic pain, which is located in the missing/amputated limb. Phantom pain is difficult to treat as the exact basis of pain mechanism is still unknown. Various methods of treatment for PLP have been described, including pharmacological (NSAIDs, opioids, antiepileptic, antidepressants) and non-pharmacological (TENS, sympathectomy, deep brain stimulation and motor cortex stimulation). Opioids are used for the treatment of neuropathic pain and dose of opioid is determined based on its effect and thus there is no defined ceiling dose for opioids. We report a case where a patient receiving high-dose oral morphine for chronic cancer pain did not demonstrate signs of addiction. PMID:25709194

  10. Oral methylprednisolone acetate (Medrol Tablets) for seasonal rhinitis: examination of dose and symptom response.

    PubMed

    Brooks, C D; Karl, K J; Francom, S F

    1993-09-01

    The authors compared the effect of several doses an oral corticosteroid on symptom profile and severity in ragweed hay fever. Thirty-one patients were randomized to receive 0, 6, 12, or 24 mg methylprednisolone (Medrol Tablets [MP], Upjohn, Kalamazoo, MI). A baseline week in which no treatment was given preceded the treatment comparison. At the end of this week, symptom diaries showed that most of the subjects were experiencing moderate or severe symptoms. The corticoid produced dose-related reduction in all symptoms. The difference between placebo and 24 mg MP was significant for all the symptoms monitored, except itching, which benefited marginally. With 6 mg MP, congestion, drainage, and eye symptoms showed significant drug-placebo differences but itching, running/blowing, and sneezing did not. Not all rhinitis symptoms responded equally to corticoid treatment. Those that responded least could reflect histamine effect, which was not effectively suppressed by low-dose, short-term corticoid treatment. PMID:8227478

  11. Use of dose-dependent absorption into target tissues to more accurately predict cancer risk at low oral doses of hexavalent chromium.

    PubMed

    Haney, J

    2015-02-01

    The mouse dose at the lowest water concentration used in the National Toxicology Program hexavalent chromium (CrVI) drinking water study (NTP, 2008) is about 74,500 times higher than the approximate human dose corresponding to the 35-city geometric mean reported in EWG (2010) and over 1000 times higher than that based on the highest reported tap water concentration. With experimental and environmental doses differing greatly, it is a regulatory challenge to extrapolate high-dose results to environmental doses orders of magnitude lower in a meaningful and toxicologically predictive manner. This seems particularly true for the low-dose extrapolation of results for oral CrVI-induced carcinogenesis since dose-dependent differences in the dose fraction absorbed by mouse target tissues are apparent (Kirman et al., 2012). These data can be used for a straightforward adjustment of the USEPA (2010) draft oral slope factor (SFo) to be more predictive of risk at environmentally-relevant doses. More specifically, the evaluation of observed and modeled differences in the fraction of dose absorbed by target tissues at the point-of-departure for the draft SFo calculation versus lower doses suggests that the draft SFo be divided by a dose-specific adjustment factor of at least an order of magnitude to be less over-predictive of risk at more environmentally-relevant doses. PMID:25445295

  12. Adherence to oral bisphosphonates: 30 more minutes in dosing instructions matter.

    PubMed

    Vytrisalova, M; Touskova, T; Ladova, K; Fuksa, L; Palicka, V; Matoulkova, P; Horak, P; Stepan, J

    2015-08-01

    Objectives Low adherence to treatment with bisphosphonates significantly impedes its effectiveness. The objectives were: (1) to compare adherence to oral weekly and monthly bisphosphonates with emphasis on dosing instructions; and (2) to study associations between adherence and beliefs about the bisphosphonate treatment among women ? 55 years. Methods A multicenter survey was performed in secondary-care patients with osteoporosis. Osteoporosis Specific Morisky Medication Adherence Scale (OS-MMAS), questions on compliance with five dosing instructions and Beliefs about Medicines Questionnaire (BMQ) Specific were used. Results As many as 363 questionnaires (response rate 95%) were analyzed. Respondents (mean age 69 years) were treated with weekly bisphosphonates (37%) or monthly ibandronate (63%). Based on OS-MMAS, 67% of respondents showed high adherence with no differences between the subgroups. Only 44% of respondents were compliant with all dosing instructions. Compliance with dosing instructions concerning time interval (fasting and staying upright) was 71% in weekly and 52% in monthly subgroups, respectively (p < 0.001). Compliance with dosing instructions correlated positively with education (p = 0.009). The mean BMQ necessity score of 18.4 was greater than the mean BMQ concerns score of 13.3. OS-MMAS score correlated with necessity (p = 0.010). Persistence derived from OS-MMAS correlated with both necessity (p = 0.014) and concerns (p = 0.041). Conclusion Despite relatively high adherence to the treatment, most patients do not follow dosing instructions. Reduced bioavailability, particularly of monthly ibandronate, can be expected in clinical practice. Adherence-related outcomes are associated with beliefs about the oral treatment with bisphosphonates. PMID:25495333

  13. Effect of single oral dose of tramadol on gastric secretions pH

    PubMed Central

    Ullah, Khan Mueen; Aqil, Mansoor; Hussain, Altaf; Al Zahrani, Tariq; Hillis, Marwan

    2015-01-01

    Background: Tramadol is an atypical analgesic agent. It has been shown that intramuscular or intravenous injection tramadol is able to inhibit M3 muscarinic receptors. Tramadol is able to mediate smooth muscles contraction and glandular secretions. We have evaluated the effects of single oral dose of tramadol given preoperatively on gastric juices pH in patients electively scheduled for laparoscopic cholecystectomy. Materials and Methods: Sixty adult, American Society of Anesthesiologist I and II patients scheduled for laparoscopic cholecystectomy were included in the study. Patients were randomly assigned to receive either placebo (n = 30) or oral tramadol 50 mg (n = 30). General anesthesia was induced using propofol, fentanyl and cisatracurium. After induction of anesthesia 5 ml of gastric fluid was aspirated through orogastric tube. The gastric fluid pH was measured using pH meter. Result: There was no significant difference in the pH between the groups. Gastric pH of the placebo and tramadol groups was 1.97 versus 1.98 (P = 0.092) respectively. Conclusion: Preoperatively single oral dose of tramadol was unable to elevate the desired level of gastric acid secretions pH (>2.5). This may be due to pharmacokinetic disparity between the analgesic and pH elevating properties of tramadol. PMID:25558191

  14. Clinical outcome of high-dose-rate interstitial brachytherapy in patients with oral cavity cancer

    PubMed Central

    Lee, Sung Uk; Moon, Sung Ho; Choi, Sung Weon; Park, Joo Yong; Yun, Tak; Lee, Sang Hyun; Lim, Young Kyung; Jeong, Chi Young

    2014-01-01

    Purpose To evaluate the clinical outcome of high-dose-rate (HDR) interstitial brachytherapy (IBT) in patients with oral cavity cancer. Materials and Methods Sixteen patients with oral cavity cancer treated with HDR remote-control afterloading brachytherapy using 192Ir between 2001 and 2013 were analyzed retrospectively. Brachytherapy was administered in 11 patients as the primary treatment and in five patients as salvage treatment for recurrence after the initial surgery. In 12 patients, external beam radiotherapy (50-55 Gy/25 fractions) was combined with IBT of 21 Gy/7 fractions. In addition, IBT was administered as the sole treatment in three patients with a total dose of 50 Gy/10 fractions and as postoperative adjuvant treatment in one patient with a total of 35 Gy/7 fractions. Results The 5-year overall survival of the entire group was 70%. The actuarial local control rate after 3 years was 84%. All five recurrent cases after initial surgery were successfully salvaged using IBT ± external beam radiotherapy. Two patients developed local recurrence at 3 and 5 months, respectively, after IBT. The acute complications were acceptable (?grade 2). Three patients developed major late complications, such as radio-osteonecrosis, in which one patient was treated by conservative therapy and two required surgical intervention. Conclusion HDR IBT for oral cavity cancer was effective and acceptable in diverse clinical settings, such as in the cases of primary or salvage treatment. PMID:25568852

  15. The effect of cimetidine on the single dose pharmacokinetics of oral clobazam and N-desmethylclobazam.

    PubMed

    Pullar, T; Edwards, D; Haigh, J R; Peaker, S; Feely, M P

    1987-03-01

    The effect of cimetidine on the single dose pharmacokinetics of orally administered clobazam and N-desmethylclobazam (NDMC) was studied in volunteers. Cimetidine inhibited the elimination of both clobazam and NDMC and inhibited the rate of formation of NDMC from clobazam. The increase in the AUC for NDMC generated from clobazam was relatively greater than that for clobazam itself. This suggests that NDMC elimination is inhibited to a relatively greater extent than clobazam elimination. The increase in AUC for NDMC generated from clobazam was also relatively greater than that for NDMC administered orally. This would suggest that cimetidine either increases the bioavailability of clobazam or reduces that of NDMC. The increases in the AUC for NDMC and for clobazam in some individuals was of a magnitude which is likely to be clinically significant. PMID:3567046

  16. Metabolic effects of low-dose fluconazole in healthy female users and non-users of oral contraceptives.

    PubMed Central

    Devenport, M H; Crook, D; Wynn, V; Lees, L J

    1989-01-01

    1. Azole antifungal agents such as ketoconazole act by inhibiting cytochrome P-450 mediated sterol synthesis in the fungal cell membrane and thus have the potential to interfere with mammalian steroidogenesis. Fluconazole is a novel orally-effective antifungal triazole which has been reported to have more specific effects on the cytochrome P-450 enzymes involved in fungal sterol synthesis. 2. Due to the potential value of systemic antifungal agents in the treatment of infections commonly occurring in women, we assessed the effect of oral fluconazole on the metabolic profile of 18 healthy premenopausal women, 10 of whom were taking combined oral contraceptives (OC). Each woman acted as her own control, being studied both before and 21-28 days after fluconazole therapy (50 mg daily), in the luteal phase of consecutive menstrual cycles. 3. The endocrinological profile included measurement of serum oestradiol, progesterone, testosterone and sex hormone binding globulin (SHBG) concentrations, short tetracosactrin adrenal stimulation test and thyroid function tests. Carbohydrate metabolism was investigated by means of an oral glucose tolerance test with measurement of plasma glucose, insulin and C-peptide concentrations. Serum lipids, lipoproteins and apolipoproteins were analysed on samples taken after an overnight fast. 4. Minor biochemical changes associated with fluconazole treatment included increases in serum thyroxine and testosterone concentrations (but not in women taking OC as well as fluconazole) and in insulin and apolipoprotein B levels (but only in women taking OC as well as fluconazole). In general, these changes were small and of no clinical significance with the values remaining within the laboratory normal range. There were no adverse side-effects.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2547410

  17. Peripheral arterial disease in a female using high-dose combined oral contraceptive pills

    PubMed Central

    Pallavee, P.; Samal, Sunita; Samal, Rupal

    2013-01-01

    The association between oral contraceptive (OC) pills and vascular diseases is well-known, although, the present generation of pills is considered to be relatively safer in this regard. Hormonal treatment for severe abnormal uterine bleeding is usually considered after ruling out malignancy, when such bleeding is resistant to all other forms of treatment. We report a case of severe peripheral arterial disease in a female, who had been on high-dose OC pills for an extended period of time for severe uterine bleeding. PMID:23833381

  18. Vitamin D and its Major Metabolites: Serum Levels after Graded Oral Dosing in Healthy Men

    Microsoft Academic Search

    M. J. Barger-Lux; R. P. Heaney; S. Dowell; T. C. Chen; M. F. Holick

    1998-01-01

    :   We determined the quantitative relationships between graded oral dosing with vitamin D3, 25(OH)D3, and 1,25(OH)2D3 for short treatment periods and changes in circulating levels of these substances. The subjects were 116 healthy men (mean\\u000a age, 28 + 4 years, with usual milk consumption of 40.47 l\\/day and mean serum 25(OH)D of 67 + 25 nmol\\/l). They were distributed\\u000a among

  19. Preparation of Personalized-dose Salbutamol Sulphate Oral Films with Thermal Ink-Jet Printing

    Microsoft Academic Search

    Asma B. M. Buanz; Mark H. Saunders; Abdul W. Basit; Simon Gaisford

    Purpose  To evaluate the use of thermal ink-jetting as a method for dosing drugs onto oral films.\\u000a \\u000a \\u000a \\u000a Methods  A Hewlett-Packard printer cartridge was modified so that aqueous drug solutions replaced the ink. The performance of the printer\\u000a as a function of print solution viscosity and surface tension was determined; viscosities between 1.1 and 1.5 mm2 s-1 were found to be optimal, while surface

  20. Pharmacokinetics of marbofloxacin after a single oral dose to loggerhead sea turtles ( Caretta caretta)

    Microsoft Academic Search

    P. Marín; O. R. Lai; P. Laricchiuta; G. Marzano; A. Di Bello; C. M. Cárceles; G. Crescenzo

    2009-01-01

    The single-dose disposition kinetics of marbofloxacin (MBX) were determined in clinically healthy loggerhead sea turtles (n=5) after oral (PO) administration of 2mgkg?1 bodyweight. Marbofloxacin plasma concentrations were determined by DAD–HPLC (LOD\\/LOQ 0.015\\/0.05?gml?1). Data were subjected to non-compartmental analysis. Following PO administration, marbofloxacin achieved maximum plasma concentrations of 11.66±2.53mgL?1 at 15.00±3.00h. The absence of general adverse reactions in the turtles of

  1. Mineral and nitrogen balance study - Results of metabolic observations on Skylab II 28-day orbital mission

    NASA Technical Reports Server (NTRS)

    Whedon, G. D.; Lutwak, L.; Reid, J.; Rambaut, P.; Whittle, M.; Smith, M.; Leach, C.

    1975-01-01

    The prediction that various stresses of flight, particularly weightlessness, would bring about significant derangements in the metabolism of the musculoskeletal system has been based on various balance-study observations of long-term immobilized or inactive bed rest. The three astronauts of Skylab II consumed a planned dietary intake of major metabolic elements in mixed foods and beverages and provided virtually complete collections of excreta for 31 days preflight, 28 days inflight, and 17 days postflight. Analyses showed that, in varying degree among the crewmen, urinary calcium increased gradually during flight in a pattern similar to that observed in bed-rest studies. Fecal calcium excretion did not change significantly, but calcium balance, owing to the urinary calcium rise, became either negative or less positive than in preflight measurement. Increased excretion and negative nitrogen and phosphorus balances inflight indicated appreciable loss of muscle tissue in all three crewmen. Significant losses also occurred inflight in potassium, sodium, and magnesium. Based on the similarity in pattern and degree between these observations of calcium, phosphorus, and nitrogen loss, musculoskeletal integrity would not be threatened in space flights of up to at least 3 months. However, if similar changes occur in the planed Skylab flights for considerably more than 28 days, concern for capable musculoskeletal function should be serious for flights of very many months' duration.

  2. Evaluation of spontaneous baroreflex response after 28 days head down tilt bedrest

    NASA Astrophysics Data System (ADS)

    Hughson, R. L.; Yamamoto, Y.; Butler, G. C.; Güell, A.; Gharib, C.

    The spontaneous baroreflex response was evaluated during supine rest and head up tilt (60°) before and immediately after a 28 day 6° HDT bedrest in 6 healthy adult men (age 30-42 years). Sequences of 3 or more beats where RR-interval and systolic blood pressure changed in the same direction were used to evaluate baroreflex response slope (BRS). Prior to bedrest, the mean BRS and RR-interval were 18.0 ± 3.9 ms/mm Hg and 926 ± 61 ms at rest and 10.5 ± 2.5 ms/mm Hg and 772 ± 63 ms during the first 10 min of 60° tilt. Following bedrest, these values changed to 15.6 ± 2.7 ms/mm Hg and 780 ± 53 ms at rest, and to 6.5 ± 1.2 ms/mm Hg and 636 ± 44 ms during tilt. Thus, (1) the spontaneous baroreflex can be evaluated in human subjects during experiments of orthostatic stress; (2) the baroreflex slope was reduced on going from supine to the head up tilt position; and (3) 28 days of bedrest reduced the spontaneous baroreflex slope.

  3. Single dose oral oxycodone and oxycodone plus paracetamol (acetaminophen) for acute postoperative pain in adults

    PubMed Central

    Gaskell, Helen; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background Oxycodone is a strong opioid agonist used to treat severe pain. It is commonly combined with milder analgesics such as paracetamol. This review updates a previous review that concluded, based on limited data, that all doses of oxycodone exceeding 5 mg, with or without paracetamol, provided analgesia in postoperative pain, but with increased incidence of adverse events compared with placebo. Additional new studies provide more reliable estimates of efficacy and harm. Objectives To assess efficacy, duration of action, and associated adverse events of single dose oral oxycodone, with or without paracetamol, in acute postoperative pain in adults. Search methods Cochrane CENTRAL, MEDLINE, EMBASE and Oxford Pain Relief Database, searched in May 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered oxycodone, with or without paracetamol, in adults with moderate to severe acute postoperative pain. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number-needed-to-treat-to-benefit (NNT) were calculated. Numbers of participants remedicating over specified time periods, and time-to-use of rescue medication, were sought as additional measures of efficacy. Adverse events and withdrawals information was collected. Main results This updated review includes 20 studies, with 2641 participants. For oxycodone 15 mg alone compared with placebo, the NNT for at least 50% pain relief was 4.6 (95% Confidence Interval 2.9 to 11). For oxycodone 10 mg plus paracetamol 650 mg, the NNT was 2.7 (2.4 to 3.1). A dose response was demonstrated for this outcome with combination therapy. Duration of effect was 10 hours with oxycodone 10 mg plus paracetamol 650 mg, and 4 hours with half that dose. Fewer participants needed rescue medication over 6 hours at the higher dose. Adverse events occurred more frequently with combination therapy than placebo, but were generally described as mild to moderate in severity and rarely led to withdrawal. Authors’ conclusions Single dose oxycodone is an effective analgesic in acute postoperative pain at doses over 5 mg; oxycodone is two to three times stronger than codeine. Efficacy increases when combined with paracetamol. Oxycodone 10 mg plus paracetamol 650 mg provides good analgesia to half of those treated, comparable to commonly used non-steroidal anti-inflammatory drugs, with the benefit of longer duration of action. PMID:19588335

  4. Comparative hazard identification of nano- and micro-sized cerium oxide particles based on 28-day inhalation studies in rats.

    PubMed

    Gosens, Ilse; Mathijssen, Liesbeth E A M; Bokkers, Bas G H; Muijser, Hans; Cassee, Flemming R

    2014-09-01

    There are many uncertainties regarding the hazard of nanosized particles compared to the bulk material of the parent chemical. Here, the authors assess the comparative hazard of two nanoscale (NM-211 and NM-212) and one microscale (NM-213) cerium oxide materials in 28-day inhalation toxicity studies in rats (according to Organisation for Economic Co-operation and Development technical guidelines). All three materials gave rise to a dose-dependent pulmonary inflammation and lung cell damage but without gross pathological changes immediately after exposure. Following NM-211 and NM-212 exposure, epithelial cell injury was observed in the recovery groups. There was no evidence of systemic inflammation or other haematological changes following exposure of any of the three particle types. The comparative hazard was quantified by application of the benchmark concentration approach. The relative toxicity was explored in terms of three exposure metrics. When exposure levels were expressed as mass concentration, nanosized NM-211 was the most potent material, whereas when expression levels were based on surface area concentration, micro-sized NM-213 material induced the greatest extent of pulmonary inflammation/damage. Particles were equipotent based on particle number concentrations. In conclusion, similar pulmonary toxicity profiles including inflammation are observed for all three materials with little quantitative differences. Systemic effects were virtually absent. There is little evidence for a dominant predicting exposure metric for the observed effects. PMID:23768316

  5. Pharmacokinetics of terbinafine after single oral dose administration in red-tailed hawks (Buteo jamaicensis).

    PubMed

    Bechert, Ursula; Christensen, J Mark; Poppenga, Robert; Fahmy, Sahar A; Redig, Patrick

    2010-06-01

    To determine pharmacokinetic parameters of orally administered terbinafine hydrochloride for potential treatment of aspergillosis in raptors, 10 adult red-tailed hawks (Buteo jamaicensis) were used in single dose trials by using 15, 30, and 60 mg/kg doses with a 2-week washout period between trials. After administration of 15 mg/kg terbinafine, mean (+/- SD) plasma concentration peaked in approximately 5 hours at 0.3 +/- 0.24 microg/mL, whereas a 30 mg/kg dose resulted in peak mean (+/- SD) plasma concentration of 1.2 +/- 0.40 microg/mL in 3 hours and a 60 mg/kg dose resulted in mean (+/- SD) concentration of 2.0 +/- 0.75 microg/mL in 5 hours. The volume of distribution decreased with increasing doses, averaging 76.8 +/- 38.06 mL/kg for the 15 mg/kg dose and falling to 55.2 +/- 17.4 mL/kg for the 30 mg/kg dose. This suggests that terbinafine accumulated in deep tissues, limiting further distribution at higher doses. The harmonic mean (+/- SD) half-life was biphasic, with initial values of 14.7 +/- 6.67 hours, 17.5 +/- 8.7 hours, and 13.3 +/- 5.03 hours for 15, 30, and 60 mg/kg doses, respectively. A rapid first-elimination phase was followed by a slower second phase, and final elimination was estimated to be 161 +/- 78.2 and 147 +/- 65.6 hours for 15 and 30 mg/kg doses, respectively. Linearity was demonstrated for the area under the curve but not for peak plasma concentrations for the 3 doses used. Calculations based on pharmacokinetic parameter values indicated that a dosage of 22 mg/kg terbinafine q24h would result in steady-state trough plasma concentrations above the minimum inhibitory concentration of terbinafine (0.8-1.6 microg/mL). This dosage is recommended as a potential treatment option for aspergillosis in raptors. However, additional research is required to determine both treatment efficacy and safety. PMID:20806657

  6. Single dose oral mefenamic acid for acute postoperative pain in adults

    PubMed Central

    Moll, Rachel; Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background Mefenamic acid is a non-steroidal anti-inflammatory drug (NSAID). It is most often used for treating pain of dysmenorrhoea in the short term (seven days or less), as well as mild to moderate pain including headache, dental pain, postoperative and postpartum pain. It is widely available in many countries worldwide. Objectives To assess the efficacy of single dose oral mefenamic acid in acute postoperative pain, and any associated adverse events. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to December 2010. Selection criteria Single oral dose, randomised, double-blind, placebo-controlled trials of mefenamic acid for relief of established moderate to severe postoperative pain in adults. Data collection and analysis Studies were assessed for methodological quality and the data extracted by two review authors independently. Summed total pain relief (TOTPAR) or pain intensity difference (SPID) over 4 to 6 hours was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over 4 to 6 hours. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results Four studies with 842 participants met the inclusion criteria; 126 participants were treated with mefenamic acid 500 mg, 67 with mefenamic acid 250 mg, 197 with placebo, and 452 with lignocaine, aspirin, zomepirac or nimesulide. Participants had pain following third molar extraction, episiotomy and orthopaedic surgery. The NNT for at least 50% pain relief over 6 hours with a single dose of mefenamic acid 500 mg compared to placebo was 4.0 (2.7 to 7.1), and the NNT to prevent use of rescue medication over 6 hours was 6.5 (3.6 to 29). There were insufficient data to analyse other doses or active comparators, or numbers of participants experiencing any adverse events. No serious adverse events or adverse event withdrawals were reported in these studies. Authors’ conclusions Oral mefenamic acid 500 mg was effective at treating moderate to severe acute postoperative pain, based on limited data. Efficacy of other doses, and safety and tolerability could not be assessed. PMID:21412904

  7. Pharmacokinetics, pharmacodynamics and food effect of LB30870, a novel direct thrombin inhibitor, after single oral doses in healthy men.

    PubMed

    Kim, John; Lee, Sung-Hack; Boyce, Malcolm; Warrington, Steve; Cho, Kwan Hyung; Yoon, Suk Kyoon; Park, Hee Dong; Kim, Aeri

    2015-08-01

    1.?The safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect of LB30870, a new selective thrombin inhibitor, were studied in 16 healthy men. 2.?A double-blind, placebo-controlled single ascending dose study was done at oral doses of 5, 15, 30, 60, 120, and 240?mg under fasting conditions. An open, randomized, balanced cross-over food effect study was done at 60?mg dose. Plasma and urinary concentrations were measured up to 48?h post-dose. Coagulation and thrombin activity markers were measured at selected time points. 3.?Cmax of LB30870 was at 1.3-3.0?h post-dose with a mean apparent terminal half-life (t1/2) of 2.8-4.1?h. AUC after doses above 15?mg appeared greater than dose-proportional. In fed state, AUC showed 80% reduction relative to fasting condition. 4.?At doses 60 and 120?mg, peak activated partial thromboplastin time (aPTT) increased by 1.5- and 2-fold, respectively, from baseline. The aPTT and international normalized ratio (INR) were concentration-dependent, with less within-individual variability than ecarin clotting time (ECT), prothrombin time (PT), or thrombin time (TT). 5.?Single oral doses of LB30870 up to 240?mg were well tolerated. The food effect must be overcome if LB30870 is to be used as an oral anti-coagulant. PMID:25673087

  8. High-dose oral N-acetylcysteine, a glutathione prodrug, modulates inflammation in cystic fibrosis

    PubMed Central

    Tirouvanziam, Rabindra; Conrad, Carol K.; Bottiglieri, Teodoro; Herzenberg, Leonore A.; Moss, Richard B.; Herzenberg, Leonard A.

    2006-01-01

    Neutrophilic airway inflammation is a hallmark of cystic fibrosis (CF). As high oxidant producers, airway neutrophils contribute largely to the systemic redox imbalance seen in CF. In turn, this chronic and profound imbalance can impact circulating neutrophils before their migration into airways. Indeed, in 18 CF patients with stable disease, blood neutrophils were readily deficient in the pivotal antioxidant glutathione (P = 0.003, compared with 9 healthy controls). In a phase 1 study, this deficiency was improved (P = 0.025) by the glutathione prodrug N-acetylcysteine, given orally in high doses (0.6 to 1.0 g three times daily, for 4 weeks). This treatment was safe and markedly decreased sputum elastase activity (P = 0.006), the strongest predictor of CF pulmonary function. Consistently, neutrophil burden in CF airways was decreased upon treatment (P = 0.003), as was the number of airway neutrophils actively releasing elastase-rich granules (P = 0.005), as measured by flow cytometry. Pulmonary function measures were not improved, as expected with short-term treatment. After excluding data from subjects without baseline airway inflammation, positive treatment effects were more pronounced and included decreased sputum IL-8 levels (P = 0.032). Thus, high-dose oral N-acetylcysteine has the potential to counter the intertwined redox and inflammatory imbalances in CF. PMID:16537378

  9. The effect of single oral doses of zopiclone on nocturnal melatonin secretion in healthy male volunteers.

    PubMed

    Norman, T R; Piccolo, J; Voudouris, N; Burrows, G D

    2001-05-01

    The effects of single oral doses of zopiclone and temazepam were investigated in eight healthy male volunteers using a single blind, placebo controlled cross over study. Doses of zopiclone were 7.5 and 15 mg while the dose of temazepam was 20 mg. Each dose was separated by at least a one-week washout period. For each subject the dim light melatonin onset (DLMO) was determined on a screening night and the drugs were administered at the time of the DLMO. Melatonin concentrations were determined by radioimmunoassay from plasma samples collected throughout the night. Both temazepam and zopiclone tended to reduce the amount of melatonin secreted, as determined by the area under the plasma concentration time curve. The differences from placebo were not statistically significant (F 3.31 = 1.07, P > 0.1). Similarly a repeated measures analysis of variance on the plasma concentration-time curves did not show any statistically significant differences between drugs and placebo (F 3.28 = 1.15, P > 0.1). There was no evidence from this study of a phase shifting effect of the drugs used. The reasons for the lack of effect on melatonin may be due to the differences in potency of the interaction of these drugs with the GABA-benzodiazepine-chloride ion channel. PMID:11383979

  10. Potassium toxicity and acid-base balance from large oral doses of potassium to young calves.

    PubMed

    Neathery, M W; Pugh, D G; Miller, W J; Whitlock, R H; Gentry, R P; Allen, J C

    1979-11-01

    Potassium chloride and sodium chloride were infused into the reticulorumen of male Holstein calves, approximately 6 mo of age and 260 kg, at .29, .58, 1.15, 1.73, 2.31, or 2.88 g potassium per kilogram body weight or 1.35, 2.12, or 2.16 g sodium per kilogram in equal volumes of water. Paired controls were infused with water. Calves were monitored for physiological changes for 6 h at 15, 30, or 60-min intervals. Potassium and total solids of plasma and packed cell volume were increased at potassium doses greater than .29 g of potassium per kilogram body weight within 1 h after dosing. At the higher doses of potassium, sodium content of plasma increased about 1 h after the increase in plasma potassium. Respiration rates within a potassium treatment varied with respect to time after dosing, but generally they increased, and associated variables of carbon dioxide pressure, pH, and bicarbonate in blood were decreased accordingly. Clinical toxicity signs, including excess salivation, muscular tremors of legs, and excitability were observed with potassium doses greater than .58 g of potassium per kilogram body weight. Three of five calves given 1.73 g of potassium per kilogram, three of four calves given 2.31 g of potassium per kilogram, and one calf given 2.88 g of potassium per kilogram body weight died. With a small number of calves, oral sodium infusions increased plasma sodium in proportion to the dose, but plasma potassium remained relatively constant. Sodium infusions of 2.12 and 2.16 g of sodium per kilogram body weight were fatal. PMID:536483

  11. Single dose oral indometacin for the treatment of acute postoperative pain

    PubMed Central

    Moore, R Andrew; Derry, Sheena; Mason, Lorna; McQuay, Henry J; Edwards, Jayne

    2014-01-01

    Background This is an updated version of the original Cochrane review published in Issue 4, 2004. Indometacin is a non-steroidal anti-inflammatory drug (NSAID) used most commonly for the treatment of inflammation and pain resulting from rheumatic disease (arthritis), and less commonly in postoperative pain management. When taken for chronic pain conditions, indometacin has been associated with a high incidence of adverse events. The benefits and harms of orally-administered indometacin for postoperative pain are not clear. Objectives To determine the efficacy of a single dose of oral indometacin compared with placebo in treating acute postoperative pain in adults, and to analyse information relating to adverse events. Search methods We searched the Cochrane CENTRAL Register of Controlled Trials in The Cochrane Library, MEDLINE, EMBASE and the Oxford Pain Relief Database for relevant studies in January 2002 and for the updated search in December 2007. Additional studies were sought from the reference lists of retrieved studies. Selection criteria Studies were included in the review if they were randomised, double blind, placebo-controlled clinical trials using a single oral dose of indometacin in adults with acute postoperative pain. Data collection and analysis Studies were assessed independently by two review authors. Pain relief or pain intensity data were extracted and converted into dichotomous information to give the number of participants with at least 50% pain relief over four to six hours. The relative benefit for at least 50% pain relief was calculated. Main results In the original review one study of 59 women with post-episiotomy pain met the inclusion criteria. The dose of indometacin assessed against placebo was 50 mg, and the results concluded that indometacin was not significantly better than placebo for relieving postoperative pain at four to six hours. There was insufficient information to conduct further efficacy analyses or assess adverse events. No further studies were identified in the update of this review. Authors’ conclusions Conclusions about the clinical efficacy of indometacin for postoperative pain cannot be made unless more studies are conducted for a variety of surgical procedures, and different doses of indometacin are assessed. Since the last version of this review no new relevant studies have been identified. PMID:15495100

  12. Single Oral Dose Toxicity Study of Prebrewed Armeniacae Semen in Rats

    PubMed Central

    Park, Ji-Ha; Seo, Bu-Il; Cho, Su-Yeon; Park, Kyu-Ryul; Choi, Seung-Hoon; Han, Chang-Kyun; Song, Chang-Hyun; Park, Soo-Jin; Ku, Sae-Kwang

    2013-01-01

    Armeniacae semen (AS) has been considered a toxic herb in the Korean medicine as it contains hydrogen cyanide and amygdalin, especially in its endocarp. Therefore, prebrewed AS that is devoid of endocarp has been traditionally used. In the present study, amygdalin content of the prebrewed AS was significantly lower (2.73 ± 0.32 ?g/ml; p < 0.01) than the content in the extract that contained the endocarps (28.50 ± 6.71 ?g/ml); amygdalin content corresponded to 10% of the extract in the present study. Because of single oral dose toxicity of prebrewed AS according to the recommendation of Korea Food and Drug Administration Guidelines (2009-116, 2009), which was based on single oral dose toxicity study of prebrewed AS, mortality due to toxic principles was significantly reduced. In this study, 2,000 mg/kg of prebrewed AS led to death of 1 female rat and 1 male rat at the end of 2 hr of administration. Based on these results, the 50% lethal dose in both male and female rats was determined to be 9279.5 mg/kg. Seizure, loss of locomotion, and increases in respiration and heart rate were observed as prebrewed AS treatment-related toxicological signs; these signs were restrictedly manifested in the prebrewed AS (2,000 mg/kg)-treated rats. In addition, no changes were observed in body weight, organ weight, gross features, and histopathological parameters with 2,000 mg/kg of AS in both male and female rats. These findings serve as direct evidence that amygdalin in AS is the toxic principle, which can be reduced by the traditional prebrewing method involving the exclusion of endocarp. PMID:24278634

  13. Oral High-Dose Multivitamins and Minerals or Post Myocardial Infarction Patients in TACT

    PubMed Central

    Lamas, Gervasio A.; Boineau, Robin; Goertz, Christine; Mark, Daniel B.; Rosenberg, Yves; Stylianou, Mario; Rozema, Theodore; Nahin, Richard L.; Lindblad, Lauren; Lewis, Eldrin F.; Drisko, Jeanne; Lee, Kerry L.

    2014-01-01

    Background Oral multivitamins and minerals are often used in conjunction with ethylenediamine tetra acetic acid infusions to treat atherosclerotic disease. Whether high-dose multivitamins are effective as secondary prevention of atherosclerotic disease, however, has not been established. Objective The vitamin component of the Trial to Assess Chelation Therapy assessed whether oral multivitamins reduced cardiovascular events, and were safe. Design The Trial to Assess Chelation Therapy was designed as a double-blind placebo-controlled 2×2 factorial multicenter randomized trial. Setting 134 US and Canadian academic and clinical sites participated. Patients 1708 patients, age ?50 years, ?6 weeks post myocardial infarction, with creatinine level ? 176.8 µmol/L (2.0 mg/dL). (ClinicalTrials.gov: NCT00044213). Intervention Patients were randomly assigned to an oral 28-component high-dose multivitamin and multimineral mixture or placebo. Measurements Study results were analyzed per randomized group. The primary endpoint was time to total mortality, recurrent myocardial infarction, stroke, coronary revascularization, or hospitalization for angina. Limited secondary endpoints and subgroup analyses were also pre-specified. Results The median age was 65 years, 18% female. The qualifying myocardial infarction had occurred 4.6 (1.6, 9.2) years prior to enrollment. The median duration of follow-up was 55 months (IQR 26, 60) overall. The median number of months during which patients took their vitamins was 31 (13, 59) in the active treatment group, and 35 (13, 60) in the placebo group (p=0.65). There were 645 (76%) vitamin patients and 646 (76%) placebo patients who completed at least 1 year of oral therapy (p=0.98); and 400 (46.9%) vitamin patients and 426 (49.8%) placebo patients who completed at least 3 years of oral therapy (p=0.23). There were 783 (46%) of patients who discontinued their vitamin regimen (390 (46%) in placebo, 394 (46%) in active; p=0.67), and 17% of patients withdrew from the study. The primary endpoint occurred in 230 (27%) patients in the active vitamin group and 253 (30%) in the placebo group (hazard ratio 0.89, 95% CI 0.75–1.07, p=0.21). There was no evidence suggesting harm from vitamin therapy in any category of adverse events Limitations The study had considerable non-compliance and drop-out. Thus, the ability to draw firm conclusions (particularly regarding safety) is limited. Conclusions High-dose oral multivitamins and multiminerals did not produce a statistically significant reduction in cardiovascular events in post-myocardial infarction patients on standard medications, but this conclusion has to be tempered by the non-compliance rate. Primary Funding Source National Institutes of Health. PMID:24490264

  14. Pharmacokinetics of single- and multiple-dose oral clarithromycin in soft tissues determined by microdialysis.

    PubMed

    Traunmüller, Friederike; Zeitlinger, Markus; Zeleny, Petra; Müller, Markus; Joukhadar, Christian

    2007-09-01

    The antimicrobial spectrum of clarithromycin renders this antibiotic a frequently used option in the treatment of skin and soft-tissue infections. In most cases, these infections are caused by extracellularly proliferating microorganisms. Thus, clarithromycin concentrations achieved in the interstitial space are considered particularly important for clinical efficacy. In the present study, clarithromycin concentrations in plasma and interstitial-space fluid of subcutaneous adipose tissue and skeletal muscle of six healthy male volunteers were assessed by means of the microdialysis technique after oral single-dose administration of 250 mg and multiple doses of 500 mg of clarithromycin twice a day (b.i.d.). The ratios of the area under the concentration-time curve of free clarithromycin from 0 to 24 h calculated for a single dose of 250 mg (fAUC(0-24)) in interstitial-space fluid to the fAUC(0-24) in plasma were 0.29 +/- 0.17 and 0.42 +/- 0.18 for subcutis and skeletal muscle, respectively. For 500 mg of clarithromycin at the steady state (3 to 5 days of intake twice daily), the fAUC(0-24(b.i.d.)) ratios at the steady state were 0.39 +/- 0.04 and 0.41 +/- 0.19 for subcutis and skeletal muscle, respectively. The half-life was around 2 h after a single dose but increased to approximately 4 h in plasma and tissues after repetitive clarithromycin administration. Based on subsequently performed pharmacokinetic-pharmacodynamic calculations, a dosing regimen of 500 mg b.i.d. may be ineffective in the treatment of soft-tissue infections caused by pathogens with a drug MIC higher than 0.125 mg/liter. PMID:17606673

  15. Pharmacokinetics of Single- and Multiple-Dose Oral Clarithromycin in Soft Tissues Determined by Microdialysis?

    PubMed Central

    Traunmüller, Friederike; Zeitlinger, Markus; Zeleny, Petra; Müller, Markus; Joukhadar, Christian

    2007-01-01

    The antimicrobial spectrum of clarithromycin renders this antibiotic a frequently used option in the treatment of skin and soft-tissue infections. In most cases, these infections are caused by extracellularly proliferating microorganisms. Thus, clarithromycin concentrations achieved in the interstitial space are considered particularly important for clinical efficacy. In the present study, clarithromycin concentrations in plasma and interstitial-space fluid of subcutaneous adipose tissue and skeletal muscle of six healthy male volunteers were assessed by means of the microdialysis technique after oral single-dose administration of 250 mg and multiple doses of 500 mg of clarithromycin twice a day (b.i.d.). The ratios of the area under the concentration-time curve of free clarithromycin from 0 to 24 h calculated for a single dose of 250 mg (fAUC0-24) in interstitial-space fluid to the fAUC0-24 in plasma were 0.29 ± 0.17 and 0.42 ± 0.18 for subcutis and skeletal muscle, respectively. For 500 mg of clarithromycin at the steady state (3 to 5 days of intake twice daily), the fAUC0-24(b.i.d.) ratios at the steady state were 0.39 ± 0.04 and 0.41 ± 0.19 for subcutis and skeletal muscle, respectively. The half-life was around 2 h after a single dose but increased to approximately 4 h in plasma and tissues after repetitive clarithromycin administration. Based on subsequently performed pharmacokinetic-pharmacodynamic calculations, a dosing regimen of 500 mg b.i.d. may be ineffective in the treatment of soft-tissue infections caused by pathogens with a drug MIC higher than 0.125 mg/liter. PMID:17606673

  16. Enantioselective disposition of hydroxychloroquine after a single oral dose of the racemate to healthy subjects.

    PubMed Central

    Ducharme, J; Fieger, H; Ducharme, M P; Khalil, S K; Wainer, I W

    1995-01-01

    1. Stereoselectivity in the disposition of hydroxychloroquine was investigated in 23 healthy males following a single oral dose of 200 mg racemic HCQ (rac-HCQ) sulphate. Total concentrations (R+S) and R/S ratios of HCQ and its metabolites were measured by stereoselective h.p.l.c. 2. HCQ was detected in whole blood and urine, up to 91 and 85 days after dosing, respectively. Metabolites could not be detected in whole blood while in urine detectable concentrations were still present after 85 days. The blood concentrations of HCQ enantiomers were measurable until 168 h post-dose. 3. R(-)-HCQ accounted for 62 +/- 3% (mean +/- s.d.) of the AUC of rac-HCQ AUC. The elimination half-life of S(+)-HCQ (457 +/- 122 h) was significantly shorter than that of R(-)-HCQ (526 +/- 140 h), partly due to its faster urinary excretion and hepatic metabolism. Its renal clearance was twice that of R(-)-HCQ (4.61 +/- 4.01 vs 1.79 +/- 1.30 1 h-1), and metabolites derived from the S-isomer represented 80-90% of the urinary recovery of the dose. 4. Over 85 days, 4.4 +/- 2.9 and 3.3 +/- 1.8% of the dose was recovered in urine as unchanged S(+)-HCQ and R(-)-HCQ, respectively. For the first 2 weeks, S(+)-HCQ excretion rate clearly surpassed that of R(-)-HCQ whereas afterwards the inverse was observed. However, since the first 2 weeks account for 95% of rac-HCQ renal excretion, the total urinary excretion of S(+)-HCQ clearly surpassed that of R(-)-HCQ.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8562294

  17. Single dose oral codeine, as a single agent, for acute postoperative pain in adults

    PubMed Central

    Derry, Sheena; Moore, R Andrew; McQuay, Henry J

    2014-01-01

    Background Codeine is an opioid metabolised to active analgesic compounds, including morphine. It is widely available by prescription, and combination drugs including low doses of codeine are commonly available without prescription. Objectives To assess the efficacy, the time to onset of analgesia, the time to use of rescue medication and any associated adverse events of single dose oral codeine in acute postoperative pain. Search methods We searched CENTRAL, MEDLINE, EMBASE and PubMed to November 2009. Selection criteria Single oral dose, randomised, double-blind, placebo-controlled trials of codeine for relief of established moderate to severe postoperative pain in adults. Data collection and analysis Studies were assessed for methodological quality and data independently extracted by two review authors. Summed total pain relief (TOTPAR) or pain intensity difference (SPID) over 4 to 6 hours were used to calculate the number of participants achieving at least 50% pain relief, which were used to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over 4 to 6 hours. Numbers using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Data on adverse events and withdrawals were collected. Main results Thirty-five studies were included (1223 participants received codeine 60 mg, 27 codeine 90 mg, and 1252 placebo). Combining all types of surgery (33 studies, 2411 participants), codeine 60 mg had an NNT of at least 50% pain relief over 4 to 6 hours of 12 (8.4 to 18) compared with placebo. At least 50% pain relief was achieved by 26% on codeine 60 mg and 17% on placebo. Following dental surgery the NNT was 21 (12 to 96) (15 studies, 1146 participants), and following other types of surgery the NNT was 6.8 (4.6 to 13) (18 studies, 1265 participants). The NNT to prevent use of rescue medication within 4 to 6 hours was 11 (6.3 to 50) (11 studies, 765 participants, mostly non-dental); the mean time to its use was 2.7 hours with codeine and 2.0 hours with placebo. More participants experienced adverse events with codeine 60 mg than placebo; the difference was not significant and none were serious. Two adverse event withdrawals occurred with placebo. Authors’ conclusions Single dose codeine 60 mg provides good analgesia to few individuals, and does not compare favourably with commonly used alternatives such as paracetamol, NSAIDs and their combinations with codeine, especially after dental surgery; the large difference between dental and other surgery was unexpected. Higher doses were not evaluated. PMID:20393966

  18. Shock Index and Prediction of Traumatic Hemorrhagic Shock 28-Day Mortality: Data from the DCLHb Resuscitation Clinical Trials

    PubMed Central

    Sloan, Edward P.; Koenigsberg, Max; Clark, James M.; Weir, William B.; Philbin, Nora

    2014-01-01

    Introduction To assess the ability of the shock index (SI) to predict 28-day mortality in traumatic hemorrhagic shock patients treated in the diaspirin cross-linked hemoglobin (DCLHb) resuscitation clinical trials. Methods We used data from two parallel DCLHb traumatic hemorrhagic shock efficacy trials, one in U.S. emergency departments, and one in the European Union prehospital setting to assess the relationship between SI values and 28-day mortality. Results In the 219 patients, the mean age was 37 years, 64% sustained a blunt injury, 48% received DCLHb, 36% died, and 88% had an SI?1.0 at study entry. The percentage of patients with an SI?1.0 dropped by 57% (88 to 38%) from the time of study entry to 120 minutes after study resuscitation (p<0.001). Patients with a SI?1.0, 1.4, and 1.8 at any time point were 2.3, 2.7, and 3.1 times, respectively, more likely to die by 28 days than were patients with SI values below these cutoffs (p<0.001). Similarly, after 120 minutes of resuscitation, patients with a SI?1.0 were 3.9× times more likely to die by 28 days (40 vs. 15%, p<0.001). Although the distribution of SI values differed based on treatment group, the receiver operator characeristics data showed no difference in SI predictive ability for 28-day mortality in patients treated with DCLHb. Conclusion In these traumatic hemorrhagic shock patients, the shock index correlates with 28-day mortality, with higher SI values indicating greater mortality risk. Although DCLHb treatment did alter the distribution of SI values, it did not influence the ability of the SI to predict 28-day mortality. PMID:25493120

  19. Attenuation of interleukin 2-induced pulmonary vascular leak syndrome by low doses of oral methotrexate.

    PubMed

    DeJoy, S Q; Jeyaseelan, R; Torley, L W; Schow, S R; Wick, M M; Kerwar, S S

    1995-11-01

    Pulmonary vascular leak induced in mice by interleukin 2 (IL-2) was attenuated by pretreatment with single or multiple doses of oral methotrexate. Methotrexate also attenuated pulmonary vascular leak when either larger doses of IL-2 or when lymphokine-activated killer (LAK) cells or LAK cells plus IL-2 were administered. Lymphoid infiltrates in the lungs of mice treated with IL-2 and methotrexate were significantly lower. The number of mice surviving treatment with high doses of IL-2 was also significantly increased when these mice were treated with methotrexate. Methotrexate prevented the IL-2-induced increase in the number of splenocytes that were asialo GM1+ but had no effect on Lyt 2+ or L3T4+ cell content. A marginal but significant inhibition in the generation of effector splenocytes that were cytolytic to either YAC or MCA-205 tumor targets was observed in mice treated with methotrexate and IL-2. In vivo studies indicated that methotrexate did not compromise the anti-tumor efficacy of treatment regimens that contained IL-2, LAK cells, or IL-2 and LAK cells. These results demonstrate the potential clinical utility of methotrexate in attenuating pulmonary vascular leak induced by IL-2 without compromising its efficacy. One potential mechanism of action of methotrexate is related to its ability to stimulate the release of adenosine followed by the inhibition of the adhesion of leukocytes to the IL-2-activated endothelium. PMID:7585532

  20. Distribution, elimination, and renal effects of single oral doses of europium in rats.

    PubMed

    Ohnishi, Keiko; Usuda, Kan; Nakayama, Shin; Sugiura, Yumiko; Kitamura, Yasuhiro; Kurita, Akihiro; Tsuda, Yuko; Kimura, Motoshi; Kono, Koichi

    2011-11-01

    Single doses of europium (III) chloride hexahydrate were orally administered to several groups of rats. Cumulative urine samples were taken at 0-24 h, and blood samples were drawn after 24-h administration. The europium concentration was determined in these samples by inductively coupled plasma atomic emission spectroscopy. The volume, creatinine, ß-2-microglobulin, and N-acetyl-ß-D-glucosaminidase were measured in the urine samples to evaluate possible europium-induced renal effects. The blood samples showed low europium distribution, with an average of 77.5 ?g/L for all groups. Although the urinary concentration and excretion showed dose-dependent increases, the percentage of europium excreted showed a dose-dependent decrease, with an average of 0.31% in all groups. The administration of europium resulted in a significant decrease of creatinine and a significant increase of urinary volume, N-acetyl-ß-D-glucosaminidase, and ß-2-microglobulin. Rare earth elements, including europium, are believed to form colloidal conjugates that deposit in the reticuloendothelial system and glomeruli. This specific reaction may contribute to low europium bioavailability and renal function disturbances. Despite low bioavailability, the high performance of the analytical method for determination of europium makes the blood and urine sampling suitable tools for monitoring of exposure to this element. The results presented in this study will be of great importance in future studies on the health impacts of rare earth elements. PMID:21221839

  1. Oral low-dose dexamethasone for androgen-independent prostate cancer patients

    PubMed Central

    KOMIYA, AKIRA; SHIMBO, MASAKI; SUZUKI, HIROYOSHI; IMAMOTO, TAKASHI; KATO, TOMONORI; FUKASAWA, SATOSHI; KAMIYA, NAOTO; NAYA, YUKIO; MORI, IKUO; ICHIKAWA, TOMOHIKO

    2010-01-01

    We retrospectively evaluated the outcome of oral low-dose dexamethasone (DXM) therapy for androgen-independent prostate cancer (AIPC). Between January 1999 and April 2006, 99 consecutive patients with AIPC were enrolled in this study. The median patient age was 70 years (range 46–86), and the median pretreatment prostate-specific antigen (PSA) level was 243 ng/ml (range 8.2–29600). Median follow-up was 41.9 months (range 11.4–170.4). Upon biochemical failure, patients were treated with oral low-dose DXM. A total of 40 of the 99 cases (40.4%) showed a ?50% decrease in serum PSA levels (PSA responders). Twenty-five cases (25.2%) showed a <50% decrease in PSA, and the remaining 34 cases (34.3%) had increased PSA levels (PSA non-responders). The median PSA progression-free survival was 3.0 (range 0–27) and 8.0 months (range 2–27) for the entire cohort and PSA responders, respectively. The PSA responders had a significantly increased survival (median 30.1 months) compared to the non-responders (median 8.8 months, P<0.001). Of the 34 patients who were under pain control for bone metastases before the administration of DXM, 23 (67.6%) were able to discontinue the regular use of analgesics. The PSA responders also showed an increase in hemoglobin levels. The change in serum interleukin-6 levels was significantly associated with a response to DXM (P=0.0065). Severe adverse events of DXM were rare. Clinicopathological factors predicting the PSA response to DXM were age, time from initial androgen deprivation therapy to DXM and PSA velocity prior to DXM. In conclusion, oral low-dose DXM led to an acceptable PSA response in patients with AIPC. Thus, this therapy may be an effective and safe alternative for the treatment of AIPC, particularly for patients who are not favourable candidates for chemotherapy. PMID:22966259

  2. Plasma appearance and disappearance of an oral dose of 25-hydroxyvitamin D2 in healthy adults.

    PubMed

    Jones, Kerry S; Schoenmakers, Inez; Bluck, Les J C; Ding, Shujing; Prentice, Ann

    2012-04-01

    25-Hydroxyvitamin D (25(OH)D) half-life is a potential biomarker for investigating vitamin D metabolism and requirements. We performed a pilot study to assess the approach and practical feasibility of measuring 25(OH)D half-life after an oral dose. A total of twelve healthy Gambian men aged 18-23 years were divided into two groups to investigate the rate and timing of (1) absorption and (2) plasma disappearance after an 80 nmol oral dose of 25(OH)D2. Fasting blood samples were collected at baseline and, in the first group, every 2 h post-dose for 12 h, at 24 h, 48 h and on day 15. In the second group, fasting blood samples were collected on days 3, 4, 5, 6, 9, 12, 15, 18 and 21. Urine was collected for 2 h after the first morning void at baseline and on day 15. 25(OH)D2 plasma concentration was measured by ultra-performance liquid chromatography-tandem MS/MS and corrected for baseline. Biomarkers of vitamin D, Ca and P metabolism were measured at baseline and on day 15. The peak plasma concentration of 25(OH)D2 was 9·6 (sd 0·9) nmol/l at 4·4 (sd 1·8) h. The terminal slope of 25(OH)D2 disappearance was identified to commence from day 6. The terminal half-life of plasma 25(OH)D2 was 13·4 (sd 2·7) d. There were no significant differences in plasma 25(OH)D3, total 1,25(OH)2D, parathyroid hormone, P, Ca and ionised Ca and urinary Ca and P between baseline and day 15 and between the two groups. The present study provides data on the plasma response to oral 25(OH)D2 that will underpin and contribute to the further development of studies to investigate 25(OH)D half-life. PMID:21896243

  3. Phase I clinical trial to determine maximum tolerated dose of oral albendazole in patients with advanced cancer

    Microsoft Academic Search

    Mohammad H. Pourgholami; Michael Szwajcer; Melvin Chin; Winston Liauw; Jonathan Seef; Peter Galettis; David L. Morris; Matthew Links

    2010-01-01

    Purpose  Albendazole is a potential anticancer agent that is currently under development for the treatment of cancer. We carried out\\u000a a dose-finding phase I study of oral albendazole in patients with advanced malignancies.\\u000a \\u000a \\u000a \\u000a Patients and methods  Thirty-six patients with refractory solid tumors were enrolled. Albendazole was given orally on a day 1–14 of a 3 weekly cycle,\\u000a starting at 400 mg BD with dose

  4. Prospective Evaluation to Establish a Dose Response for Clinical Oral Mucositis in Patients Undergoing Head-and-Neck Conformal Radiotherapy

    SciTech Connect

    Narayan, Samir [Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA (United States)], E-mail: narayans@trinity-health.org; Lehmann, Joerg [Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA (United States); Coleman, Matthew A. [Lawrence Livermore National Laboratory, Livermore, CA (United States); Vaughan, Andrew; Yang, Claus Chunli [Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA (United States); Enepekides, Danny; Farwell, Gregory [Department of Otolaryngology, University of California Davis Medical Center, Sacramento, CA (United States); Purdy, James A.; Laredo, Grace [Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA (United States); Nolan, Kerry A.S.; Pearson, Francesca S. [Lawrence Livermore National Laboratory, Livermore, CA (United States); Vijayakumar, Srinivasan [Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA (United States)

    2008-11-01

    Purpose: We conducted a clinical study to correlate oral cavity dose with clinical mucositis, perform in vivo dosimetry, and determine the feasibility of obtaining buccal mucosal cell samples in patients undergoing head-and-neck radiation therapy. The main objective is to establish a quantitative dose response for clinical oral mucositis. Methods and Materials: Twelve patients undergoing radiation therapy for head-and-neck cancer were prospectively studied. Four points were chosen in separate quadrants of the oral cavity. Calculated dose distributions were generated by using AcQPlan and Eclipse treatment planning systems. MOSFET dosimeters were used to measure dose at each sampled point. Each patient underwent buccal sampling for future RNA analysis before and after the first radiation treatment at the four selected points. Clinical and functional mucositis were assessed weekly according to National Cancer Institute Common Toxicity Criteria, Version 3. Results: Maximum and average doses for sampled sites ranged from 7.4-62.3 and 3.0-54.3 Gy, respectively. A cumulative point dose of 39.1 Gy resulted in mucositis for 3 weeks or longer. Mild severity (Grade {<=} 1) and short duration ({<=}1 week) of mucositis were found at cumulative point doses less than 32 Gy. Polymerase chain reaction consistently was able to detect basal levels of two known radiation responsive genes. Conclusions: In our sample, cumulative doses to the oral cavity of less than 32 Gy were associated with minimal acute mucositis. A dose greater than 39 Gy was associated with longer duration of mucositis. Our technique for sampling buccal mucosa yielded sufficient cells for RNA analysis using polymerase chain reaction.

  5. Pharmacokinetics of Eicosapentaenoic Acid in Plasma and Red Blood Cells After Multiple Oral Dosing With Icosapent Ethyl in Healthy Subjects

    PubMed Central

    Braeckman, Rene A; Stirtan, William G; Soni, Paresh N

    2014-01-01

    Objective Icosapent ethyl (IPE) is a prescription form of eicosapentaenoic acid (EPA) ethyl ester. This randomized, open-label study characterized EPA pharmacokinetics. Methods Four healthy subject groups received IPE for 28 days: three received 2 g/day (1 × 1,000 mg BID, 2 × 1,000 mg QD, or 2 × 500 mg BID); one received 4 g/day (2 × 1,000 mg BID) administered with meals. Blood sampling was before the morning dose on days 1, 14, 26, 28, and at specified intervals during an 18-day pharmacokinetic period. EPA was measured in plasma (total and unesterified) and red blood cells (RBCs) by liquid chromatography/tandem mass spectrometry. Results Mean plasma total EPA increased from 19 µg/mL to a peak (Cmax) of 366 µg/mL at 5 hours postdosing 4 g/day IPE on Day 28. Mean RBC EPA Cmax after 4 g/day was 89 µg/mL (baseline, 12 µg/mL). Mean steady state (SD) for half-life, clearance, and volume of distribution of total EPA were 79 (47) hours, 757 (283) mL/h, and 82 (56) L, respectively. Steady state for total and unesterified plasma EPA was reached by Day 28, whereas RBC levels were still increasing. Conclusions EPA pharmacokinetic profile demonstrated a slowly cleared, extensively distributed molecule with dose linearity and comparable exposures with BID and QD regimens.

  6. The effect of pycnogenol on patients with dysmenorrhea using low-dose oral contraceptives

    PubMed Central

    Maia, Hugo; Haddad, Clarice; Casoy, Julio

    2014-01-01

    Objective Menstrual symptoms such as dysmenorrhea usually occur during the hormone-free interval in oral contraceptive users. Progestin withdrawal activates NF-?B transcription factor, which upregulates both vascular endothelial growth factor (VEGF) and Cox-2 expression in the endometrium. The use of natural NF-?B inhibitors such as pycnogenol may block this response, improving dysmenorrhea. Patients and methods Twenty-four patients with severe dysmenorrhea were allocated to one of two treatment groups. In Group A (n=13), women were treated with an oral contraceptive containing 15 ?g of ethinyl estradiol and 60 mg of gestodene (Adoless®) in a 24/4 regimen for three consecutive cycles. Women in Group B (n=11) used the same contraceptive regimen together with 100 mg of pycnogenol (Flebon®) continuously for 3 months. Pain scores were graded using a visual analog scale (VAS) before and during the hormone-free interval at the end of the third treatment cycle. Results Before treatment, VAS pain scores for dysmenorrhea were 8 and 9 in Groups A and B, respectively. However, by the end of the third treatment cycle, pain scores had decreased significantly (P<0.05) both in groups A and B. The final pain scores were 6 in Group A and 2 in Group B, a difference that was statistically significant (P<0.0001). In Group B, 27% of the patients became pain-free, while in Group A, none of the women reported complete disappearance of this symptom. The number of bleeding days was also lower in Group B. Discussion Pycnogenol effectively decreased pain scores and the number of bleeding days when administered concomitantly with a low-dose 24/4 oral contraceptive containing gestodene. PMID:25525393

  7. Quality of Life of Oral Cancer Patients After Low-Dose-Rate Interstitial Brachytherapy

    SciTech Connect

    Yoshimura, Ryo-ichi [Division of Radiation Oncology, National Cancer Center Hospital, Tokyo (Japan); Department of Radiology, Tokyo Medical and Dental University, Tokyo (Japan)], E-mail: ryoshimu@ncc.go.jp; Shibuya, Hitoshi; Miura, Masahiko; Watanabe, Hiroshi; Ayukawa, Fumio; Hayashi, Keiji; Toda, Kazuma [Department of Radiology, Tokyo Medical and Dental University, Tokyo (Japan)

    2009-03-01

    Purpose: To assess the quality of life (QOL) of oral cancer patients treated with low-dose-rate interstitial brachytherapy (LDR-BT) alone. Methods and Materials: Between June 2005 and July 2006, a total of 56 patients with oral cancer were enrolled in this prospective study. QOL was assessed by means of the core questionnaire and head and neck questionnaire module of the European Organization for Research and Treatment of Cancer (EORTC Quality of Life Questionnaire-Core 30 [QLQ-C30] and QLQ Head and Neck 35 [H and N35]). The questionnaires were distributed to the patients before the start of treatment and 3 months, 6 months, and 12 months after the start of LDR-BT. Results: It was possible to analyze the results for 20 of the initial 56 patients because they did not experience metastasis or recurrence during this study. No functions or symptoms asked about in the QLQ-C30 deteriorated during the first year. The emotional function score steadily and significantly increased. No symptoms in the QLQ-H and N35 significantly deteriorated. The scores for pain, trouble with social eating, and weight loss on the QLQ-H and N35 steadily and significantly decreased. Age, gender, and LDR-BT source had no effect on the change in QOL during the first year, but T-stage significantly affected the change in global health status, tumor site affected the changes in swallowing, sensory problems, sticky saliva, and complications affected the changes in pain, swallowing, and mouth opening. Conclusions: QOL of oral cancer patients treated with LDR-BT is high. However, tumor stage, tumor site, and complications affected the changes in a few functions and symptoms during the first year.

  8. Pharmacokinetics of enrofloxacin after single dose oral and intravenous administration in the African penguin (Spheniscus demersus).

    PubMed

    Wack, Allison N; KuKanich, Butch; Bronson, Ellen; Denver, Mary

    2012-06-01

    The pharmacokinetics of a single dose of enrofloxacin administered orally, both pilled and in fish, and i.v. to African penguins (Spheniscus demersus) at 15 mg/kg were determined. Plasma concentrations of enrofloxacin and its metabolite ciprofloxacin were measured via high-pressure liquid chromatography with mass spectrometry. An i.v. administration of enrofloxacin resulted in an extrapolated mean plasma concentration of 7.86 microg/ml at time zero. Plasma volume of distribution for i.v. administration was 3.00 L/kg, with a mean elimination half-life of 13.67 hr and a mean total body clearance rate of 3.03 ml/min/kg. Oral administration of enrofloxacin achieved a mean maximum plasma concentration of4.38 microg/ml at 4.8 hr after administration when pilled, whereas mean maximum plasma concentration was 4.77 microg/ml at 1.59 hr after administration when given in fish. Mean terminal elimination half-life was 13.79 hr pilled and 11.93 hr when given in fish. Low concentrations of ciprofloxacin were detected after both oral and i.v. enrofloxacin administration. Enrofloxacin administered to African penguins at 15 mg/kg p.o.q. 24 hr, whether in fish or pilled, is expected to achieve the surrogate markers of efficacy for bacteria with a minimum inhibitory concentration of 0.5 microg/ml or less; however, clinical studies are needed to determine efficacy. PMID:22779234

  9. Porcine focal symmetrical poliomyelomalacia: experimental reproduction with oral doses of encapsulated sodium selenite.

    PubMed Central

    Wilson, T M; Hammerstedt, R H; Palmer, I S; deLahunta, A

    1988-01-01

    Sodium selenite (encapsulated as doses of 1.4 mg, 2.6 mg and 4.2 mg per kilogram of body weight) was given orally on a daily basis to male weaner pigs, and features of these animals were compared to a control group. Porcine focal symmetrical poliomyelomalacia was produced in all experimental groups between 3 and 20 days after initiation of the treatment. Analysis of blood and several tissues revealed an elevated selenium content for all pigs. Histological lesions in the brain and the cervical lumbar/sacral spinal cord enlargements included endothelial proliferation, neuronal degeneration, microcavitation and glial cell reaction. Images Fig. 1. Fig. 2. Fig. 3. Fig. 4. Fig. 5. PMID:3349404

  10. Oral dosing of rats with polychlorinated biphenyls increases urinary homovanillic acid production

    SciTech Connect

    Seegal, R.F.; Brosch, K.O.; Bush, B.

    1985-01-01

    The effect of a single oral gavage with a mixture of Aroclors 1254 and 1260 on 24-h production of urinary homovanillic acid was determined in the laboratory rat. Adult male Wistar-derived rats were exposed to a single dose of corn oil, either alone or containing equal amounts of Aroclors 1254 and 1260 at a dosage of 500 or 1000 mg/kg. Urinary homovanillic acid concentrations were determined by high-performance liquid chromatography with electrochemical detection. The 500-mg/kg group showed a transient increase in homovanillic acid production, while the 1000-mg/kg group showed a biphasic response - an initial decrease (due to decreased food consumption) followed by a prolonged elevation. Only transient changes in body weight, food and water consumption, and urine output were observed. The results demonstrate that peripheral measurement of a dopamine metabolite may provide a means of monitoring changes in an important neurotransmitter system after exposure to a putative neurotoxin.

  11. The serum concentrations of lupine alkaloids in orally-dosed Holstein cattle.

    PubMed

    Green, Benedict T; Lee, Stephen T; Welch, Kevin D; Gardner, Dale R; Stegelmeier, Bryan L; Davis, T Zane

    2015-06-01

    Teratogenic alkaloid-containing Lupinus spp. cause congenital defects known as crooked calf disease that is periodically economically devastating for the cattle industry. Previous research indicates that cattle breeds may eliminate plant toxins differently, potentially altering their susceptibility. The objective of this study was to describe the toxicokinetics in Holsteins of anagyrine, the teratogenic lupine alkaloid that produces crooked calf disease. Other alkaloids including lupanine, an unidentified alkaloid and 5,6-dehydrolupanine were also evaluated. Dried ground Lupinus leucophyllus was orally dosed to four Holstein steers and blood samples were collected for 96?h, analyzed for serum alkaloid concentrations and toxicokinetic parameters calculated. The serum elimination of anagyrine in Holstein steers was faster than those reported for beef breeds. This suggests that Holsteins may be less susceptible to lupine-induced crooked calf disease. Additional work is needed to confirm these findings and to verify if there is a breed difference in disease incidence or severity. PMID:25912242

  12. Ingesting a preworkout supplement containing caffeine, creatine, ?-alanine, amino acids, and B vitamins for 28 days is both safe and efficacious in recreationally active men.

    PubMed

    Kendall, Kristina L; Moon, Jordan R; Fairman, Ciaran M; Spradley, Brandon D; Tai, Chih-Yin; Falcone, Paul H; Carson, Laura R; Mosman, Matt M; Joy, Jordan M; Kim, Michael P; Serrano, Eric R; Esposito, Enrico N

    2014-05-01

    The purpose of this study was to determine the safety and efficacy of consuming a preworkout supplement (SUP) containing caffeine, creatine, ?-alanine, amino acids, and B vitamins for 28 days. We hypothesized that little to no changes in kidney and liver clinical blood markers or resting heart rate and blood pressure (BP) would be observed. In addition, we hypothesized that body composition and performance would improve in recreationally active males after 28 days of supplementation. In a double-blind, placebo-controlled study, participants were randomly assigned to ingest one scoop of either the SUP or placebo every day for 28 days, either 20 minutes before exercise or ad libitum on nonexercise days. Resting heart rate and BP, body composition, and fasting blood samples were collected before and after supplementation. Aerobic capacity as well as muscular strength and endurance were also measured. Significant (P < .05) main effects for time were observed for resting heart rate (presupplementation, 67.59 ± 7.90 beats per minute; postsupplementation, 66.18 ± 7.63 beats per minute), systolic BP (presupplementation, 122.41 ± 11.25 mm Hg; postsupplementation, 118.35 ± 11.58 mm Hg), blood urea nitrogen (presupplementation, 13.12 ± 2.55 mg/dL; postsupplementation, 15.24 ± 4.47 mg/dL), aspartate aminotransferase (presupplementation, 34.29 ± 16.48 IU/L; postsupplementation, 24.76 ± 4.71 IU/L), and alanine aminotransferase (presupplementation, 32.76 ± 19.72 IU/L; postsupplementation, 24.88 ± 9.68 IU/L). Significant main effects for time were observed for body fat percentage (presupplementation, 15.55% ± 5.79%; postsupplementation, 14.21% ± 5.38%; P = .004) and fat-free mass (presupplementation, 70.80 ± 9.21 kg; postsupplementation, 71.98 ± 9.27 kg; P = .006). A significant decrease in maximal oxygen consumption (presupplementation, 47.28 ± 2.69 mL/kg per minute; postsupplementation, 45.60 ± 2.81 mL/kg per minute) and a significant increase in percentage of oxygen consumption per unit time at which ventilatory threshold occurred (presupplementation, 64.38% ± 6.63%; postsupplementation, 70.63% ± 6.39%) and leg press one-repetition maximum (presupplementation, 218.75 ± 38.43 kg; postsupplementation, 228.75 ± 44.79 kg) were observed in the SUP only. No adverse effects were noted for renal and hepatic clinical blood markers, resting heart rate, or BP. Supplements containing similar ingredients and doses should be safe for ingestion periods lasting up to 28 days in healthy, recreationally trained, college-aged men. PMID:24916558

  13. Single Oral Dose Toxicity Test of Blue Honeysuckle Concentrate in Mice

    PubMed Central

    Park, Sang-In; Choi, Seung-Hoon; Song, Chang-Hyun; Park, Soo-Jin; Shin, Yong-Kook; Han, Chang-Hyun; Lee, Young Joon; Ku, Sae-Kwang

    2015-01-01

    The objective of this study was to obtain single oral dose toxicity information for concentrated and lyophilized powder of blue honeysuckle (Lonicera caerulea L., Caprifoliaceae; BHcL) in female and male ICR mice to aid in the process of developing natural origin medicinal ingredients or foods following proximate analysis and phytochemical profile measurement. The proximate analysis revealed that BHcL had an energy value of 3.80 kcal/g and contained 0.93 g/g of carbohydrate, 0.41 g/g of sugar, 0.02 g/g of protein, and 0.20 mg/g of sodium. BHcL did not contain lipids, including saturated lipids, trans fats, or cholesterols. Further, BHcL contained 4.54% of betaine, 210.63 mg/g of total phenols, 159.30 mg/g of total flavonoids, and 133.57 mg/g of total anthocyanins. Following administration of a single oral BHcL treatment, there were no treatment-related mortalities, changes in body weight (bw) or organ weight, clinical signs, necropsy or histopathological findings up to 2,000 mg/kg bw, the limited dosage for rodents of both sexes. We concluded that BHcL is a practically non-toxic material in toxicity potency. PMID:25874034

  14. Ability of Saudi mothers to appropriately and accurately use dosing devices to administer oral liquid medications to their children

    PubMed Central

    Almazrou, Saja; Alsahly, Hind; Alwattar, Huda; Alturki, Lamya; Alamri, Mona

    2015-01-01

    Background Most liquid medications are packaged with administration devices, which may be used inappropriately or inaccurately, and sometimes are not used at all. Because of the importance of their proper use for children’s health, this study was designed to assess Saudi mothers’ experiences with measuring cups, syringes, and droppers for oral liquid medications; to compare accuracy of dosing across these devices; and to determine the effects of mothers’ education statuses and pharmacist counseling on dosing accuracy. Methods This was a cross-sectional study in which mothers were observed as they used a set of commonly available dosing devices which are a dosing cup, syringe, and dropper. Interviews were conducted in the outpatient pharmacy waiting area in several tertiary hospitals and primary clinics in Riyadh, Saudi Arabia between March and April 2013. Saudi women who were mothers of children aged 12 years old or younger and who gave their consent were eligible. Caregivers other than mothers and subjects with vision problems or cognitive/physical disabilities were excluded. We gathered demographic information such as age, number of children, and education status. Subjects were asked if they had had counseling on how to use measuring devices and which device they preferred. Then, the mothers were required to demonstrate how to measure 5 mL of paracetamol (acetaminophen) syrup using a cup and a syringe and 1 mL of paracetamol syrup using a dropper. Dosing errors were evaluated visually as overdosing, underdosing, or no error (if the dose was accurate). The data were entered into Microsoft Excel and evaluated using Stata 11.1. Logistic regression was employed to determine relationships. Results The results revealed that 58% of participants measured an accurate dose of paracetamol using the oral dosing syringe versus 50% of participants using the dropper and 51% using the dosing cup. In general, participants measured more than the intended dose with the dosing cup and less than the intended dose with the dropper. Furthermore, we found that dosing accuracy for each type of instrument was significantly influenced by the mothers’ education status. Among the study participants, 77% had not had previous counseling on the use of liquid medication measuring devices. However, dosing errors were not affected by previous counseling. Conclusion Among mothers using measuring devices, the most accurate doses were found to be measured with the use of the oral syringe, whereas the most errors were made with the use of the dropper. Moreover, education status had a significant effect on dosing errors. The use of a pictographic diagram could improve the mothers’ dosing abilities and, thus, reduce dosing errors. PMID:25565895

  15. Oral exposure to low-dose of nonylphenol impairs memory performance in Sprague-Dawley rats.

    PubMed

    Kawaguchi, Shinichiro; Kuwahara, Rika; Kohara, Yumi; Uchida, Yutaro; Oku, Yushi; Yamashita, Kimihiro

    2015-02-01

    Nonylphenol ethoxylate (NPE) is a non-ionic surfactant, that is degraded to short-chain NPE and 4-nonylphenol (NP) by bacteria in the environment. NP, one of the most common environmental endocrine disruptors, exhibits weak estrogen-like activity. In this study, we investigated whether oral administration of NP (at 0.5 and 5 mg/kg doses) affects spatial learning and memory, general activity, emotionality, and fear-motivated learning and memory in male and female Sprague-Dawley (SD) rats. SD rats of both sexes were evaluated using a battery of behavioral tests, including an appetite-motivated maze test (MAZE test) that was used to assess spatial learning and memory. In the MAZE test, the time required to reach the reward in male rats treated with 0.5 mg/kg NP group and female rats administered 5 mg/kg NP was significantly longer than that for control animals of the corresponding sex. In other behavioral tests, no significant differences were observed between the control group and either of the NP-treated groups of male rats. In female rats, inner and ambulation values for animals administered 0.5 mg/kg NP were significantly higher than those measured in control animals in open-field test, while the latency in the group treated with 5 mg/kg NP was significantly shorter compared to the control group in step-through passive avoidance test. This study indicates that oral administration of a low-dose of NP slightly impairs spatial learning and memory performance in male and female rats, and alters emotionality and fear-motivated learning and memory in female rats only. PMID:25560395

  16. Alteration of the Systemic and Microcirculation by a Single Oral Dose of Flavan-3-Ols

    PubMed Central

    Ingawa, Kodai; Aruga, Nozomi; Matsumura, Yusuke; Shibata, Masahiro; Osakabe, Naomi

    2014-01-01

    Several systematic reviews have reported that flow mediated dilatation (FMD) was significantly increased in subjects after ingestion of chocolate that contains flavan-3-ols; however, the mechanisms responsible for this effect are not clear. In this study, we evaluated the effects of a single oral dose of flavan-3-ols on the systemic circulation and microcirculation in the cremaster muscle using intravital video microscopy in vivo. The cremaster muscle in rats was spread over a plastic chamber and a gastric tube was placed into the stomach. Blood flow in the cremasteric artery was determined using a laser Doppler flowmeter, while blood pressure and heart rate were measured by the tail-cuff method. Red blood cell velocity in arterioles and blood flow in the artery were significantly increased 5 min after the administration of 10 mg/kg flavan-3-ols compared with distilled water treatment. The number of capillaries recruited in the cremaster muscle was also significantly increased 15 min after treatment. Microscopic observation confirmed that increased shear stress on endothelial cells was maintained during the measurement period. The mean arterial blood pressure and heart rate were also significantly elevated soon after administration and returned to baseline before the end of the observation period. Plasma nitrate and nitrite levels, and NO phosphorylation of aortic tissue were significantly increased at 60 min after administration of flavan-3-ols. According to these results, a single oral dose of flavan-3-ols elevates blood pressure and flow transiently, and these effects induce NO production through increased shear stress on endothelial cells. PMID:24740211

  17. A chronic oral reference dose for hexavalent chromium-induced intestinal cancer.

    PubMed

    Thompson, Chad M; Kirman, Christopher R; Proctor, Deborah M; Haws, Laurie C; Suh, Mina; Hays, Sean M; Hixon, J Gregory; Harris, Mark A

    2014-05-01

    High concentrations of hexavalent chromium [Cr(VI)] in drinking water induce villous cytotoxicity and compensatory crypt hyperplasia in the small intestines of mice (but not rats). Lifetime exposure to such cytotoxic concentrations increases intestinal neoplasms in mice, suggesting that the mode of action for Cr(VI)-induced intestinal tumors involves chronic wounding and compensatory cell proliferation of the intestine. Therefore, we developed a chronic oral reference dose (RfD) designed to be protective of intestinal damage and thus intestinal cancer. A physiologically based pharmacokinetic model for chromium in mice was used to estimate the amount of Cr(VI) entering each intestinal tissue section (duodenum, jejunum and ileum) from the lumen per day (normalized to intestinal tissue weight). These internal dose metrics, together with corresponding incidences for diffuse hyperplasia, were used to derive points of departure using benchmark dose modeling and constrained nonlinear regression. Both modeling techniques resulted in similar points of departure, which were subsequently converted to human equivalent doses using a human physiologically based pharmacokinetic model. Applying appropriate uncertainty factors, an RfD of 0.006 mg kg(-1) day(-1) was derived for diffuse hyperplasia-an effect that precedes tumor formation. This RfD is protective of both noncancer and cancer effects in the small intestine and corresponds to a safe drinking water equivalent level of 210 µg l(-1). This concentration is higher than the current federal maximum contaminant level for total Cr (100 µg l(-1)) and well above levels of Cr(VI) in US drinking water supplies (typically ? 5 µg l(-1)). PMID:23943231

  18. Effect of rare earth filtration on patient exposure, dose reduction, and image quality in oral panoramic radiology

    Microsoft Academic Search

    Donald A. Tyndall; David B. Washburn

    1987-01-01

    Rare earth intensifying screen material (Gd2O2S:Tb) was added to the standard Al filtration of an oral panoramic x-ray unit, resulting in a beam capable of achieving reductions in patient dose without a loss of image quality. The added rare earth filtration technique resulted in patient dose reductions of 21-56%, depending on anatomic sites, when compared to the conventional Al filtration

  19. Single dose oral dexibuprofen [S(+)-ibuprofen] for acute postoperative pain in adults

    PubMed Central

    Moore, R Andrew; Derry, Sheena; McQuay, Henry J

    2014-01-01

    Background Dexibuprofen (S(+)-ibuprofen) is a non-steroidal anti-inflammatory drug (NSAID) licensed for use in rheumatic disease and other musculoskeletal disorders in the UK, and widely available in other countries worldwide. It is an active isomer of ibuprofen. This review sought to evaluate the efficacy and safety of oral dexibuprofen in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish that drugs have analgesic properties. Objectives To assess efficacy, duration of action, and associated adverse events of single dose oral dexibuprofen in acute postoperative pain in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to May 2009. Selection criteria Randomised, double blind, placebo-controlled clinical trials of oral dexibuprofen for relief of acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number needed to treat to benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Main results In the single included study, both S(+)-ibuprofen (dexibuprofen, an active isomer of ibuprofen) 200 mg and 400 mg gave high levels of response, with 31/51 (61%) and 35/50 (70%) respectively having at least 50% pain relief over 4 to 6 hours, compared with 2/25 (8%) with placebo. The median time to additional analgesic use was 5.8 hours, 6.1 hours, and 1.8 hours respectively. The numbers of participants was too small to calculate NNTs with any meaning. Authors’ conclusions The information from the single trial in acute postoperative pain suggests it to be a useful analgesic, but at doses not very different from racemic ibuprofen. PMID:19588434

  20. A pig tonsil cell culture model for evaluating oral, low-dose IFN-? treatments.

    PubMed

    Razzuoli, Elisabetta; Villa, Riccardo; Ferrari, Angelo; Amadori, Massimo

    2014-08-15

    Oral, low-dose IFN-? treatments proved effective in several models of viral infections and immunopathological conditions. Also, they do not give rise to the serious side effects observed after parenteral inoculation of high doses (10(5)U/kg b.w. and higher). There is convincing evidence that such treatments work through an early, effective interaction with oral lymphoid tissues before the IFN-? molecules are rapidly destroyed by gut enzymes. Yet, the paucity of detailed information about these crucial interactions and the lack of recognized in vitro models hamper the development of proper administration protocols. On the basis of a previous study, we developed an in vitro model of interaction between different types of human and porcine IFNs-? at low/moderate concentrations and pig tonsil cells. The IFNs-? under study showed different properties with respect to three fundamental control actions: (1) IgA release in culture, (2) release of natural antimicrobial compounds, and (3) homeostatic regulation of the inflammatory response. This was checked in pig intestinal epithelial cells (IPEC-J2 cell line) treated with supernatants of control and IFN ?-treated tonsil cell cultures, respectively, in terms of inflammatory cytokine and chemokine responses. Some IFNs-? caused a significant inhibition of IL-8 (protein release and gene expression) and beta-defensin 1 (gene expression) probably through second messengers released by IFN ?-treated tonsil cells. Interestingly, a human lymphoblastoid IFN-? under study caused the decrease of polyclonal IgA release by pig tonsil cells and significantly stimulated the in vitro recall antibody response of swine PBMC to Foot-and-Mouth Disease virus. The modulation of IgA and antibacterial compounds was accompanied by an anti-inflammatory control action at the same, low to moderate IFN-? concentrations (1-100 U/ml). This highlights the very foundation of the homeostatic control actions performed by Type I IFNs: to promote an effective host response to infectious and non-infectious stressors and to turn off noxious inflammatory responses associated with tissue damage and waste of metabolic energy. The described tonsil cell model in vitro can be conducive to a further development of oral cytokine treatments in humans and animals in the "one health" conceptual framework. PMID:24951265

  1. ANALYTICAL RESULTS OF MOX COLEMANITE CONCRETE SAMPLE POURED JULY 25, 2012 - CURED 28 DAYS

    SciTech Connect

    Cozzi, A. D.; Best, D. R.; Reigel, M. M.

    2012-09-18

    The Mixed Oxide Fuel Fabrication Facility (MFFF) will use Colemanite bearing concrete neutron absorber panels credited with attenuating neutron flux in the criticality design analyses and shielding operators from radiation. The Savannah River National Laboratory is tasked with measuring the total density, partial hydrogen density, and partial boron density of the colemanite concrete. Samples 8.1.2, 8.2.2, 8.3.2, and 8.4.2 were received on 8/1/2012 and analyzed after curing for 28 days. The average total density measured by the ASTM method C 642 was 2.09 g/cm{sup 3}, within the lower bound of 1.88 g/cm{sup 3}. The average partial hydrogen density was 7.48E-02 g/cm{sup 3} as measured using method ASTM E 1311 and met the lower bound of 6.04E-02 g/cm{sup 3}. The average measured partial boron density was 1.71E-01 g/cm{sup 3} which met the lower bound of 1.65E-01 g/cm{sup 3} measured by the ASTM C 1301 method.

  2. Effect of single oral dose of sodium benzoate on ureagenesis in healthy men and two patients with late onset citrullinaemia

    Microsoft Academic Search

    K. Kubota; T. Ishizaki

    1993-01-01

    Although sodium benzoate therapy is beneficial in patients with inborn error of urea cycle, it has been suggested that an accumulation of benzoyl-CoA would inhibit ureagenesis. In this study, we examined several aspects of ureagenesis after the single oral dosing of sodium benzoate in six healthy subjects who participated in the study previously reported and in two patients with citrullinaemia.

  3. Novel and Distinct Metabolites Identified Following a Single Oral Dose of Alpha- or Gamma-Hexabromocyclododecane in Mice

    EPA Science Inventory

    The metabolism of alpha- and gamma-hexabromocyclododecane (HBCD) was investigated in adult C57BL/6 female mice. Alpha- or gamma-[14C]HBCD (3 mg/kg bw) was orally administered with subsequent urine and feces collection for 4 consecutive days; a separate group of mice were dosed a...

  4. Pulse steroid therapy in rheumatoid arthritis: can equivalent doses of oral prednisolone give similar clinical results to intravenous methylprednisolone?

    Microsoft Academic Search

    M D Smith; M J Ahern; P J Roberts-Thomson

    1988-01-01

    Pulse methylprednisolone therapy has dramatic effects on clinical and immunological parameters of disease activity in patients with rheumatoid arthritis. Previous studies of this treatment have all used the intravenous route and methylprednisolone succinate. This study addresses the question of whether oral prednisolone in equivalent doses can substitute for intravenous methylprednisolone in pulse therapy in a double blind parallel study. It

  5. Survival patterns in white-tailed and mule deer after oral inoculation with a standardized, conspecific prion dose.

    PubMed

    Miller, Michael W; Wolfe, Lisa L; Sirochman, Tracey M; Sirochman, Michael A; Jewell, Jean E; Williams, Elizabeth S

    2012-04-01

    We orally inoculated white-tailed deer (Odocoileus virginianus) and mule deer (Odocoileus hemionus) with a standardized, conspecific prion dose and collected biologic samples throughout the disease course. Mule deer (PRNP genotype 225SS) and PRNP genotype 96GG white-tailed deer succumbed along similar trajectories, but 96GS- and 96SS-genotype individuals tended to survive longer. PMID:22493138

  6. Evaluating human variability in chemical risk assessment: hazard identification and dose-response assessment for noncancer oral toxicity of trichloroethylene

    Microsoft Academic Search

    H. A. Barton; C. D. Flemming; J. C. Lipscomb

    1996-01-01

    Human variability can be addressed during each stage in the risk assessment of chemicals causing noncancer toxicities. Noncancer toxicities arising from oral exposure to trichloroethylene (TCE) are used in this paper as a case study for exploring strategies for identifying and incorporating information about human variability in the chemical specific hazard identification and dose-response assessment steps. Toxicity testing in laboratory

  7. [Effect of low doses of oral pamidronate (APD) on the calcemia of osteopenic or osteoporotic patients].

    PubMed

    Roldan, E J; Kerzberg, E M; Castelli, G; Lloret, A P

    1996-01-01

    Oral pamidronate (APD) at high doses (400-900 mg/day) is employed as antiresorptive agent for the treatment of Paget's disease. In some occasions hypocalcemia may occur, and is interpreted as a relative overdosage. To avoid this complication and the consequent PTH release, supplementation with calcium salts is recommended. In osteoporotic syndromes, APD is prescribed at a lower dosage (200 mg/day) and currently calcium or vitamin D are also systematically added. But at this low dose the antiresorptive activity is partial and transient. In order to observe the effects on calcemia of multiple therapy, data from 129 postmenopausal women with the diagnosis of osteopenia or osteoporosis treated with 200 mg/day of APD soft capsules during 6-10 months, were gathered retrospectively. The first group (n: 13) received APD alone; the second group was supplemented with 1 g/day calcium salts (n: 61); the third group received 0.015-0.025 mg/day vitamina D (n: 10); and the fourth received both calcium plus vitamin D (n: 45). In samples of 24 h, urine, calcium, creatinine, hydroxyproline, and serum total calcium were measured before and after therapy. No hypocalcemia was detected. All groups, except the one treated with APD alone, showed a significant trend to increase their calcemia values between normal ranges (Table 1, 2). Only in one patient treated with APD + Ca + vitamin D, hypercalcemia was detected. Measuring HOP/Cr and Ca/Cr in urine as resorption markers, showed that 27% of the APD + Ca group and 33% of the APD + Ca + vitamin D group showed scant or any repercussion on mentioned resorption indexes, meaning that the response to APD could be hindered in those cases. In conclusion, while using low doses of oral APD, calcium salts should not be systematically recommended. There is no trend to hypocalcemia. Furthermore, calcium salts may favor drug interactions and so induce digestive side effects or poor responses. Calcium supplementation should be prescribed only on the basis of low calcium diet and not to prevent APD collateral effects on calcemia. PMID:8935564

  8. A chewable low-dose oral contraceptive: a new birth control option?

    PubMed

    Weisberg, Edith

    2012-01-01

    A new chewable combined oral contraceptive pill containing ethinyl estradiol (EE) 0.025 mg and norethindrone (NE) 0.8 mg in a 24/4 regimen was approved for marketing in December 2010. Each of the four inactive tablets contains 75 mg ferrous fumarate, which has no therapeutic benefit. The tablet can be taken with food but not water as this affects the absorption of EE. The Pearl index based on intention to treat women aged 18-35 years has been reported at 2.01 (confidence interval [CI] 1.21, 3.14) and for the whole population 1.65 (CI 1.01, 2.55). The effect of a body mass index of >35 was not studied. Regular withdrawal bleeding occurred for 78.6% of women in Cycle 1, but by Cycle 13 almost half the women failed to have a withdrawal bleed. This new formulation provides an intermediate dose of an EE/NE combination that will be useful for women experiencing breakthrough bleeding on the lower-dose EE/NE pill. The convenience of a low-dose pill, which can be chewed without the need for water, will be useful to enable women who have forgotten a pill to take one whenever they remember, provided they carry it with them. The advantage of a 24/4 regimen is better suppression of follicular development in the pill-free interval and may be beneficial for women who experience menstrual cycle-related problems, such as heavy bleeding or dysmenorrhea. PMID:22573934

  9. Development of an oral solid dispersion formulation for use in low-dose metronomic chemotherapy of paclitaxel.

    PubMed

    Moes, Johannes; Koolen, Stijn; Huitema, Alwin; Schellens, Jan; Beijnen, Jos; Nuijen, Bastiaan

    2013-01-01

    For the clinical development of low-dose metronomic (LDM) chemotherapy of paclitaxel, oral administration is vital. However, the development of an oral formulation is difficult due to paclitaxel's low oral bioavailability, caused by its low permeability and low solubility. We increased the oral bioavailability of paclitaxel by combining a pharmacokinetic booster, ritonavir, with a new oral solid dispersion formulation of paclitaxel. The combined use of Hansen solubility parameters and dissolution experiments resulted in the development of a solid dispersion formulation containing 1/11 w/w paclitaxel, 9/11 w/w polyvinylpyrrolidone (PVP) K30, and 1/11 w/w sodium lauryl sulfate (SLS). Analysis of the solid dispersion formulation by X-ray diffraction, Fourier transform infrared (FT-IR) spectroscopy, and modulated differential scanning calorimetry (mDSC) confirmed the amorphous nature of paclitaxel and the fine dispersion of paclitaxel in the matrix of PVP-K30 and SLS. Furthermore, in vitro tests showed a major increase in the apparent solubility and dissolution rate of paclitaxel. To test the clinical significance of these findings, the solid dispersion formulation of paclitaxel (ModraPac001 10mg capsule) was compared to the paclitaxel premix solution in four patients with advanced cancer. Although the mean systemic exposure to paclitaxel after oral administration of the solid dispersion formulation was slightly lower compared to the paclitaxel premix solution (190±63.1ng/mLh for vs. 247±100ng/mLh), the systemic exposure to paclitaxel is clinically relevant [1,2]. In addition to this, the favorable pharmaceutical characteristics, for example, neutral taste, dosing accuracy, and the 2-year ambient shelf life, make the ModraPac001 10mg capsule an attractive candidate for oral paclitaxel chemotherapy. Currently, the ModraPac001 formulation is applied in the first clinical trial with oral LDM chemotherapy of paclitaxel. PMID:23085332

  10. Toxicity evaluation of zinc aluminium levodopa nanocomposite via oral route in repeated dose study.

    PubMed

    Kura, Aminu Umar; Cheah, Pike-See; Hussein, Mohd Zobir; Hassan, Zurina; Tengku Azmi, Tengku Ibrahim; Hussein, Nor Fuzina; Fakurazi, Sharida

    2014-01-01

    Nanotechnology, through nanomedicine, allowed drugs to be manipulated into nanoscale sizes for delivery to the different parts of the body, at the same time, retaining the valuable pharmacological properties of the drugs. However, efficient drug delivery and excellent release potential of these delivery systems may be hindered by possible untoward side effects. In this study, the sub-acute toxicity of oral zinc aluminium nanocomposite with and without levodopa was assessed using the Organization for Economic Co-operation and Development guidelines. No sign or symptom of toxicity was observed in orally treated rats with the nanocomposite at 5 and 500 mg/kg concentrations. Body weight gain, feeding, water intake, general survival and organosomatic index were not significantly different between control and treatment groups. Aspartate aminotransferase (AST) in 500 mg/kg levodopa nanocomposite (169?±?30 U/L), 5 mg/kg levodopa nanocomposite (172?±?49 U/L), and 500 mg/kg layered double hydroxides (LDH) nanocomposite (175?±?25 U/L) were notably elevated compared to controls (143?±?05 U/L); but the difference were not significant (p?>?0.05). However, the differences in aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio of 500 mg/kg levodopa nanocomposite (0.32?±?0.12) and 500 mg/kg LDH nanocomposite (0.34?±?0.12) were statistically significant (p?orally administered levodopa intercalated nanocomposite; it is also dose-dependent that needs further assessment. PMID:24948886

  11. Polaprezinc prevents oral mucositis in patients treated with high-dose chemotherapy followed by hematopoietic stem cell transplantation.

    PubMed

    Hayashi, Hiroko; Kobayashi, Ryo; Suzuki, Akio; Ishihara, Masashi; Nakamura, Nobuhiko; Kitagawa, Junichi; Kanemura, Nobuhiro; Kasahara, Senji; Kitaichi, Kiyoyuki; Hara, Takeshi; Tsurumi, Hisashi; Moriwaki, Hisataka; Itoh, Yoshinori

    2014-12-01

    We have previously reported that polaprezinc in sodium alginate suspension (P-AG) inhibited the incidence of oral mucositis induced by radiochemotherapy in patients with head and neck cancer. The present study was designed to investigate whether P-AG prevents oral mucositis in all patients (36 patients) with hematological malignancy receiving high-dose chemotherapy and radiotherapy followed by hematopoietic stem cell transplantation (HSCT). P-AG dramatically reduced the incidence of moderate-to-severe oral mucositis as compared to the control group treated with azulene gargle (20% versus 82% for grade ? 2, p<0.01; 0% versus 45% for grade ? 3, p<0.01). Pain associated with oral mucositis was also significantly (p=0.004) relieved by P-AG, resulting in a reduction in the use of analgesic agents (28% versus 73%, p=0.025). The incidence of xerostomia and taste disturbance tended to be lowered but not significantly by P-AG. On the other hand, P-AG had no influence on the incidence of other adverse events, tumor remission rate or the survival rate. Therefore, P-AG was found to be highly effective in preventing oral mucositis induced not only by radiochemotherapy for head and neck cancer but also by high-dose chemotherapy and radiotherapy followed by HSCT. PMID:25503160

  12. Dietary Lysine Responses of Male Broilers From 14 to 28 Days of Age Subjected to Different Environmental Conditions

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dietary amino acid requirements are influenced by environmental conditions. Two experiments examined growth responses of Ross × Ross TP 16 male broilers fed diets varying in digestible (dig) Lys concentrations from 14 to 28 days of age under different environmental conditions. Experiment 1 was condu...

  13. FV-162 is a novel, orally bioavailable, irreversible proteasome inhibitor with improved pharmacokinetics displaying preclinical efficacy with continuous daily dosing.

    PubMed

    Wang, Z; Dove, P; Wang, X; Shamas-Din, A; Li, Z; Nachman, A; Oh, Y J; Hurren, R; Ruschak, A; Climie, S; Press, B; Griffin, C; Undzys, E; Aman, A; Al-Awar, R; Kay, L E; O'Neill, D; Trudel, S; Slassi, M; Schimmer, A D

    2015-01-01

    Approved proteasome inhibitors have advanced the treatment of multiple myeloma but are associated with serious toxicities, poor pharmacokinetics, and most with the inconvenience of intravenous administration. We therefore sought to identify novel orally bioavailable proteasome inhibitors with a continuous daily dosing schedule and improved therapeutic window using a unique drug discovery platform. We employed a fluorine-based medicinal chemistry technology to synthesize 14 novel analogs of epoxyketone-based proteasome inhibitors and screened them for their stability, ability to inhibit the chymotrypsin-like proteasome, and antimyeloma activity in vitro. The tolerability, pharmacokinetics, pharmacodynamic activity, and antimyeloma efficacy of our lead candidate were examined in NOD/SCID mice. We identified a tripeptide epoxyketone, FV-162, as a metabolically stable, potent proteasome inhibitor cytotoxic to human myeloma cell lines and primary myeloma cells. FV-162 had limited toxicity and was well tolerated on a continuous daily dosing schedule. Compared with the benchmark oral irreversible proteasome inhibitor, ONX-0192, FV-162 had a lower peak plasma concentration and longer half-life, resulting in a larger area under the curve (AUC). Oral FV-162 treatment induced rapid, irreversible inhibition of chymotrypsin-like proteasome activity in murine red blood cells and inhibited tumor growth in a myeloma xenograft model. Our data suggest that oral FV-162 with continuous daily dosing schedule displays a favorable safety, efficacy, and pharmacokinetic profile in vivo, identifying it as a promising lead for clinical evaluation in myeloma therapy. PMID:26158521

  14. Randomized Study Comparing Two Regimens of Oral Sodium Phosphates Solution Versus Low-Dose Polyethylene Glycol and Bisacodyl

    Microsoft Academic Search

    Pramod Malik; David H. Balaban; William O. Thompson; Deborah J. B. Galt

    2009-01-01

    Purpose Low-volume bowel preparation regimens for colonoscopy are reported to improve patient acceptance and compliance. We sought\\u000a to compare the bowel cleansing efficacy, tolerability, and acceptability of three low-volume regimens: an oral sodium phosphates\\u000a solution 45\\/45 ml (NaP-45\\/45), a reduced-dose oral sodium phosphates solution 45\\/30 ml (NaP-45\\/30), and polyethylene glycol\\u000a plus bisacodyl (PEG-2L). Results A total of 121 patients were

  15. Acute oral administration of low doses of methylphenidate targets calretinin neurons in the rat septal area.

    PubMed

    García-Avilés, Álvaro; Albert-Gascó, Héctor; Arnal-Vicente, Isabel; Elhajj, Ebtisam; Sanjuan-Arias, Julio; Sanchez-Perez, Ana María; Olucha-Bordonau, Francisco

    2015-01-01

    Methylphenidate (MPD) is a commonly administered drug to treat children suffering from attention deficit hyperactivity disorder (ADHD). Alterations in septal driven hippocampal theta rhythm may underlie attention deficits observed in these patients. Amongst others, the septo-hippocampal connections have long been acknowledged to be important in preserving hippocampal function. Thus, we wanted to ascertain if MPD administration, which improves attention in patients, could affect septal areas connecting with hippocampus. We used low and orally administered MPD doses (1.3, 2.7 and 5 mg/Kg) to rats what mimics the dosage range in humans. In our model, we observed no effect when using 1.3 mg/Kg MPD; whereas 2.7 and 5 mg/Kg induced a significant increase in c-fos expression specifically in the medial septum (MS), an area intimately connected to the hippocampus. We analyzed dopaminergic areas such as nucleus accumbens and striatum, and found that only 5 mg/Kg induced c-fos levels increase. In these areas tyrosine hydroxylase correlated well with c-fos staining, whereas in the MS the sparse tyrosine hydroxylase fibers did not overlap with c-fos positive neurons. Double immunofluorescence of c-fos with neuronal markers in the septal area revealed that co-localization with choline acethyl transferase, parvalbumin, and calbindin with c-fos did not change with MPD treatment; whereas, calretinin and c-fos double labeled neurons increased after MPD administration. Altogether, these results suggest that low and acute doses of methylphenidate primary target specific populations of caltretinin medial septal neurons. PMID:25852493

  16. Chemoprophylaxis with oral amoxycillin against bacterial endocarditis: when should second doses be administered after dentistry?

    PubMed Central

    Kumana, C R; Chau, K K; Chau, P Y; Kou, M; Lauder, I

    1986-01-01

    The adequacy of serum bactericidal activity after oral amoxycillin given as prophylaxis against infective endocarditis was studied using a double blind randomised protocol in healthy volunteers having dentistry. One hour before their procedure 38 patients received 3 g amoxycillin syrup and 12 received matching placebo. Venous blood samples were drawn before and one and nine hours after dosing and serum amoxycillin concentrations determined using a standard bioassay. Samples containing amoxycillin had inhibitory titres measured against two reference isolates of viridans streptococci known to have caused infective endocarditis. The susceptibility to amoxycillin of one strain was high and the other low, respective minimal bactericidal and inhibitory concentrations being 0.08 and 0.04 mumol/l (0.03 and 0.015 microgram/ml) and 2.74 and 1.37 mumol/l (1 and 0.5 microgram/ml). Amoxycillin was detected in only post-treatment samples of patients given the active drug. There were no significant correlations between one or nine hour drug concentrations and age or physical characteristics, nor was there any relation to preceding food consumption. Correlations between drug concentrations at one and nine hours were weak (r = 0.34; p less than 0.05), but between corresponding drug concentrations and serum inhibitory titres there were consistent correlations (r = 0.46-0.48; p less than 0.005). Against the low susceptibility reference isolate bactericidal amoxycillin concentrations were encountered in only 20 of the 38 nine hour samples (95% confidence limits 34% and 66%). When repeat doses of amoxycillin are indicated after dentistry they should be given about four hours later, not eight hours later as commonly practised. PMID:3099944

  17. Chemoprophylaxis with oral amoxycillin against bacterial endocarditis: when should second doses be administered after dentistry?

    PubMed

    Kumana, C R; Chau, K K; Chau, P Y; Kou, M; Lauder, I

    1986-12-13

    The adequacy of serum bactericidal activity after oral amoxycillin given as prophylaxis against infective endocarditis was studied using a double blind randomised protocol in healthy volunteers having dentistry. One hour before their procedure 38 patients received 3 g amoxycillin syrup and 12 received matching placebo. Venous blood samples were drawn before and one and nine hours after dosing and serum amoxycillin concentrations determined using a standard bioassay. Samples containing amoxycillin had inhibitory titres measured against two reference isolates of viridans streptococci known to have caused infective endocarditis. The susceptibility to amoxycillin of one strain was high and the other low, respective minimal bactericidal and inhibitory concentrations being 0.08 and 0.04 mumol/l (0.03 and 0.015 microgram/ml) and 2.74 and 1.37 mumol/l (1 and 0.5 microgram/ml). Amoxycillin was detected in only post-treatment samples of patients given the active drug. There were no significant correlations between one or nine hour drug concentrations and age or physical characteristics, nor was there any relation to preceding food consumption. Correlations between drug concentrations at one and nine hours were weak (r = 0.34; p less than 0.05), but between corresponding drug concentrations and serum inhibitory titres there were consistent correlations (r = 0.46-0.48; p less than 0.005). Against the low susceptibility reference isolate bactericidal amoxycillin concentrations were encountered in only 20 of the 38 nine hour samples (95% confidence limits 34% and 66%). When repeat doses of amoxycillin are indicated after dentistry they should be given about four hours later, not eight hours later as commonly practised. PMID:3099944

  18. A novel method for delineation of oral mucosa for radiotherapy dose-response studies.

    PubMed

    Dean, Jamie A; Welsh, Liam C; Gulliford, Sarah L; Harrington, Kevin J; Nutting, Christopher M

    2015-04-01

    There is currently no standard method for delineating the oral mucosa and most attempts are oversimplified. A new method to obtain anatomically accurate contours of the oral mucosa surfaces was developed and applied to 11 patients. This is expected to represent an opportunity for improved toxicity modelling of oral mucositis. PMID:25779721

  19. Concentrations of gemifloxacin at the target site in healthy volunteers after a single oral dose.

    PubMed

    Islinger, Florian; Bouw, Rene; Stahl, Mathias; Lackner, Edith; Zeleny, Petra; Brunner, Martin; Müller, Markus; Eichler, Hans Georg; Joukhadar, Christian

    2004-11-01

    Free gemifloxacin concentrations in the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue were measured by means of in vivo microdialysis to characterize the ability of gemifloxacin to penetrate human soft tissues. Twelve healthy volunteers received a single oral dose of 320 mg of gemifloxacin. The mean areas under the concentration-time curves from 0 to 10 h (AUC(0-10)) were significantly higher for soft tissue than for unbound gemifloxacin in plasma (P < 0.05). The ratios of the mean AUC(0-10) for tissue to the AUC(0-10) for free gemifloxacin in plasma were 1.7 +/- 0.7 (mean +/- standard deviation) for skeletal muscle and 2.4 +/- 1.0 for adipose tissue. The AUC(0-24) ratios for free gemifloxacin in tissues to the MIC at which 90% of frequently isolated bacteria are inhibited were close to or higher than 100 h. Therefore, based on pharmacokinetic and pharmacodynamic calculations, we conclude that gemifloxacin might be a useful therapeutic option for the treatment of soft tissue infections. PMID:15504848

  20. Concentrations of Gemifloxacin at the Target Site in Healthy Volunteers after a Single Oral Dose

    PubMed Central

    Islinger, Florian; Bouw, Rene; Stahl, Mathias; Lackner, Edith; Zeleny, Petra; Brunner, Martin; Müller, Markus; Eichler, Hans Georg; Joukhadar, Christian

    2004-01-01

    Free gemifloxacin concentrations in the interstitial space fluid of skeletal muscle and subcutaneous adipose tissue were measured by means of in vivo microdialysis to characterize the ability of gemifloxacin to penetrate human soft tissues. Twelve healthy volunteers received a single oral dose of 320 mg of gemifloxacin. The mean areas under the concentration-time curves from 0 to 10 h (AUC0-10) were significantly higher for soft tissue than for unbound gemifloxacin in plasma (P < 0.05). The ratios of the mean AUC0-10 for tissue to the AUC0-10 for free gemifloxacin in plasma were 1.7 ± 0.7 (mean ± standard deviation) for skeletal muscle and 2.4 ± 1.0 for adipose tissue. The AUC0-24 ratios for free gemifloxacin in tissues to the MIC at which 90% of frequently isolated bacteria are inhibited were close to or higher than 100 h. Therefore, based on pharmacokinetic and pharmacodynamic calculations, we conclude that gemifloxacin might be a useful therapeutic option for the treatment of soft tissue infections. PMID:15504848

  1. The reproductive effects in rats after chronic oral exposure to low-dose depleted uranium.

    PubMed

    Hao, Yuhui; Li, Rong; Leng, Yanbing; Ren, Jiong; Liu, Jing; Ai, Guoping; Xu, Hui; Su, Yongping; Cheng, Tianmin

    2012-01-01

    This two-generation study evaluated the effects of depleted uranium (DU) on reproduction in rats. Across two generations, Wistar rats (30/sex/group) were maintained on feed containing DU at dose levels of 0 (control group), 4 (DU? group), or 40 (DU?? group) mg kg?ą day?ą for 4 months prior to mating. After 4 months of exposure, the pregnancy rate, normal labour rate, and survival rate of offspring produced by F? rats were all significantly decreased as compared to the control group, and especially in the DU?? group, these parameters fell by half to two-thirds, while no adverse effects were evident in F? rats. The uranium content in the testes and ovaries of F? rats in the DU? and DU?? groups was significantly higher than that found in F? rats. The levels of sex hormone in the serum were disorder in both generations. The enzymes related to spermiogenesis were also significantly different between generations, and the damage was more severe in F? rats. In conclusion, the reproductive effects in F? rats were slight after chronic oral exposure to DU, while the effects were obvious in F? rats. PMID:22739007

  2. Quantitative oral dosing of water soluble and lipophilic contaminants in the Japanese medaka (Oryzias latipes)

    SciTech Connect

    Schultz, Irv; Reed, Stacey M.; Pratt, Amanda V.; Skillman, Ann D.

    2007-02-01

    Quantitative oral dosing in fish can be challenging, particularly with water soluble contaminants, which can leach into the aquarium water prior to ingestion. We applied a method of bioencapsulation using newly hatched brine shrimp (Artemia franciscana) nauplii to study the toxicokinetics of five chlorinated and brominated halogenated acetic acids (HAAs), which are drinking water disinfection by-products. These results are compared to those obtained in a previous study using a polybrominated diphenyl ether (PBDE-47), a highly lipophilic chemical. The HAAs and PBDE-47 were bioencapsulated using freshly hatched A. franciscana nauplii after incubation in concentrated solutions of the study chemicals for 18 h. Aliquots of the brine shrimp were quantitatively removed for chemical analysis and fed to individual fish that were able to consume 400–500 nauplii in less than 5min. At select times after feeding, fish were euthanized and the HAA or PBDE-47 content determined. The absorption of HAAs was quantitatively similar to previous studies in rodents: rapid absorptionwith peak body levels occurringwithin 1–2 h, then rapidly declining with elimination half-life of 0.3–3 h depending on HAA. PBDE-47 was more slowly absorbed with peak levels occurring by 18 h and very slowly eliminated with an elimination half-life of 281 h.

  3. Pharmacokinetics of a single oral dose of clobazam in patients with liver disease.

    PubMed

    Monjanel-Mouterde, S; Antoni, M; Bun, H; Botta-Frindlund, D; Gauthier, A; Durand, A; Cano, J P

    1994-06-01

    The pharmacokinetic effect of a single oral in dose of 20 mg clobazam was studied in 15 patients with liver disease and in 6 healthy volunteers. Plasma concentrations of clobazam and its main metabolite, norclobazam, were measured by gas liquid chromatography. Clobazam was rapidly absorbed. Peak plasma concentrations were 350 +/- 63 ng/ml at 1.7 +/- 0.8 hr in healthy volunteers, 239 +/- 70 ng/ml at 3 +/- 1.9 hr in patients with viral hepatitis and 240 +/- 113 ng/ml at 2.5 +/- 1.5 hr in patients with cirrhosis. Total distribution volume was 173 +/- 88 l and 168 +/- 71 l in patients with viral hepatitis and cirrhosis respectively, and 81 +/- 20 l in volunteers. Corresponding half-life values were 47 +/- 18 hr and 51 +/- 21 hr in patients and 22 +/- 6.3 hr in volunteers. The difference between patients was not significant, whereas the difference between patients and volunteers was significant. PMID:7937568

  4. Stimulation of colonic motility by oral PEG electrolyte bowel preparation assessed by MRI: comparison of split vs single dose

    PubMed Central

    Marciani, L; Garsed, K C; Hoad, C L; Fields, A; Fordham, I; Pritchard, S E; Placidi, E; Murray, K; Chaddock, G; Costigan, C; Lam, C; Jalanka-Tuovinen, J; De Vos, W M; Gowland, P A; Spiller, R C

    2014-01-01

    Background Most methods of assessing colonic motility are poorly acceptable to patients. Magnetic resonance imaging (MRI) can monitor gastrointestinal motility and fluid distributions. We predicted that a dose of oral polyethylene glycol (PEG) and electrolyte solution would increase ileo-colonic inflow and stimulate colonic motility. We aimed to investigate the colonic response to distension by oral PEG electrolyte in healthy volunteers (HVs) and to evaluate the effect of single 2 L vs split (2 × 1 L) dosing. Methods Twelve HVs received a split dose (1 L the evening before and 1 L on the study day) and another 12 HVs a single dose (2 L on the main study day) of PEG electrolyte. They underwent MRI scans, completed symptom questionnaires, and provided stool samples. Outcomes included small bowel water content, ascending colon motility index, and regional colonic volumes. Key Results Small bowel water content increased fourfold from baseline after ingesting both split (p = 0.0010) and single dose (p = 0.0005). The total colonic volume increase from baseline was smaller for the split dose at 35 ± 8% than for the single dose at 102 ± 27%, p = 0.0332. The ascending colon motility index after treatment was twofold higher for the single dose group (p = 0.0103). Conclusions & Inferences Ingestion of 1 and 2 L PEG electrolyte solution caused a rapid increase in the small bowel and colonic volumes and a robust rise in colonic motility. The increase in both volumes and motility was dose dependent. Such a challenge, being well-tolerated, could be a useful way of assessing colonic motility in future studies. PMID:25060551

  5. Application of physiologically-based toxicokinetic modelling in oral-to-dermal extrapolation of threshold doses of cosmetic ingredients.

    PubMed

    Gajewska, M; Worth, A; Urani, C; Briesen, H; Schramm, K-W

    2014-06-16

    The application of physiologically based toxicokinetic (PBTK) modelling in route-to-route (RtR) extrapolation of three cosmetic ingredients: coumarin, hydroquinone and caffeine is shown in this study. In particular, the oral no-observed-adverse-effect-level (NOAEL) doses of these chemicals are extrapolated to their corresponding dermal values by comparing the internal concentrations resulting from oral and dermal exposure scenarios. The PBTK model structure has been constructed to give a good simulation performance of biochemical processes within the human body. The model parameters are calibrated based on oral and dermal experimental data for the Caucasian population available in the literature. Particular attention is given to modelling the absorption stage (skin and gastrointestinal tract) in the form of several sub-compartments. This gives better model prediction results when compared to those of a PBTK model with a simpler structure of the absorption barrier. In addition, the role of quantitative structure-property relationships (QSPRs) in predicting skin penetration is evaluated for the three substances with a view to incorporating QSPR-predicted penetration parameters in the PBTK model when experimental values are lacking. Finally, PBTK modelling is used, first to extrapolate oral NOAEL doses derived from rat studies to humans, and then to simulate internal systemic/liver concentrations - Area Under Curve (AUC) and peak concentration - resulting from specified dermal and oral exposure conditions. Based on these simulations, AUC-based dermal thresholds for the three case study compounds are derived and compared with the experimentally obtained oral threshold (NOAEL) values. PMID:24731971

  6. Effect of rare earth filtration on patient exposure, dose reduction, and image quality in oral panoramic radiology

    SciTech Connect

    Tyndall, D.A.; Washburn, D.B.

    1987-01-01

    Rare earth intensifying screen material (Gd2O2S:Tb) was added to the standard Al filtration of an oral panoramic x-ray unit, resulting in a beam capable of achieving reductions in patient dose without a loss of image quality. The added rare earth filtration technique resulted in patient dose reductions of 21-56%, depending on anatomic sites, when compared to the conventional Al filtration technique. Films generated from both techniques were measured densitometrically and evaluated by a panel of practicing clinicians. Diagnostically significant differences were minimal. The results indicate that use of rare earth filters in oral panoramic radiography is an effective means of reducing exposures of dental patients to ionizing radiation.

  7. An integrated assessment of the clinical safety of artemether-lumefantrine: a new oral fixed-dose combination antimalarial drug

    Microsoft Academic Search

    R. Bakshi; I. Hermeling-Fritz; I. Gathmann; E. Alteri

    2000-01-01

    Artemether-lumefantrine (A-L), a new fixed-dose oral antimalarial drug, combines the fast onset of action of artemether (an artemisinin derivative) in terms of parasite clearance with the high cure rate of lumefantrine in the treatment of acute uncomplicated Plasmodium falciparum malaria. The extensive clinical trial database of A-L has allowed a comprehensive evaluation of its tolerability and safety in a total

  8. The pharmacokinetics of C-glycosyl flavones of Hawthorn leaf flavonoids in rat after single dose oral administration

    Microsoft Academic Search

    L. Y. Ma; R. H. Liu; X. D. Xu; M. Q. Yu; Q. Zhang; H. L. Liu

    2010-01-01

    Hawthorn leaf flavonoids (HLF) are used in the treatment of cardiovascular diseases. Various potential pharmacodynamic effects have been observed for vitexin-4?-O-glucoside (VOG) and vitexin-2?-O-rhamnoside (VOR) which are the main constituents of HLF. The aim of this study was to investigate the pharmacokinetics of VOG and VOR when a single dose of HLF was administrated orally. The levels of VOG and

  9. A single oral dose of thalidomide enhances the capacity of lymphocytes to secrete gamma interferon in healthy humans

    Microsoft Academic Search

    ANNELIES VERBON; NICOLE P. JUFFERMANS; PETER SPEELMAN; Deventer van S. J. H; Berge ten R. J. M; HENK-JAN GUCHELAAR; TOM VAN DER POLL

    2000-01-01

    Thalidomide is increasingly being used as adjuvant therapy for patients with mycobacterial and human immunodeficiency virus (HIV) infections. The T-helper (Th)1 cytokine-Th2 cytokine balance critically deter- mines the outcomes of these diseases. To obtain insight into the effect of thalidomide on the capacity of lymphocytes to produce Th1 and Th2 cytokines, six healthy volunteers received an oral dose (400 mg)

  10. Toxicokinetics and toxicological effects of single oral dose of fumonisin B1 containing Fusarium verticillioides culture material in weaned piglets

    Microsoft Academic Search

    P. Dilkin; G. Direito; M. M. S. Simas; C. A. Mallmann; B. Corręa

    2010-01-01

    Toxicokinetics and the toxicological effects of culture material containing fumonisin B1 (FB1) were studied in male weaned piglets by clinical, pathological, biochemical and sphingolipid analyses. The animals received a single oral dose of 5mgFB1\\/kg of body weight, obtained from Fusarium verticillioides culture material. FB1 was detected by HPLC in plasma collected at 1-h intervals up to 6h and at 12-h

  11. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects

    PubMed Central

    Frost, Charles; Wang, Jessie; Nepal, Sunil; Schuster, Alan; Barrett, Yu Chen; Mosqueda-Garcia, Rogelio; Reeves, Richard A; LaCreta, Frank

    2013-01-01

    Aims To evaluate apixaban single dose safety, tolerability, pharmacokinetics and pharmacodynamics and assess the effect of food on apixaban pharmacokinetics. Methods A double-blind, placebo-controlled, single ascending-dose, first-in-human study assessed apixaban safety, pharmacokinetics and pharmacodynamics in healthy subjects randomized to oral apixaban (n = 43; 0.5–2.5 mg as solution or 5–50 mg as tablets) or placebo (n = 14) under fasted conditions. An open label, randomized, two treatment crossover study investigated apixaban pharmacokinetics/pharmacodynamics in healthy subjects (n = 21) administered apixaban 10 mg in fasted and fed states. Both studies measured apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and prothrombin time (PT) or a modified PT (mPT). Results In the single ascending-dose study increases in apixaban exposure appeared dose-proportional. Median tmax occurred 1.5–3.3 h following oral administration. Mean terminal half-life ranged between 3.6 and 6.8 h following administration of solution doses ?2.5 mg and between 11.1 and 26.8 h for tablet doses ?5 mg. Concentration-related changes in pharmacodynamic assessments were observed. After a 50 mg dose, peak aPTT, INR and mPT increased by 1.2-, 1.6- and 2.9-fold, respectively, from baseline. In the food effect study: 90% confidence intervals of geometric mean ratios of apixaban Cmax and AUC in a fed vs. fasted state were within the predefined no effect (80–125%) range. Apixaban half-life was approximately 11.5 h. The effect of apixaban on INR, PT and aPTT was comparable following fed and fasted administration. Conclusions Single doses of apixaban were well tolerated with a predictable pharmacokinetic/pharmacodynamic profile and a half-life of approximately 12 h. Apixaban can be administered with or without food. PMID:22759198

  12. Acute and repeated dose toxicity studies of different ?-cyclodextrin-based nanosponge formulations.

    PubMed

    Shende, Pravin; Kulkarni, Yogesh A; Gaud, R S; Deshmukh, Kiran; Cavalli, Roberta; Trotta, Francesco; Caldera, Fabrizio

    2015-05-01

    Nanosponges (NS) show promising results in different fields such as medicine, agriculture, water purification, fire engineering and so on. The present study was designed to evaluate toxicity of different NS formulations (namely, S1-S6) synthesized with different cross-linking agents such as carbonyl diimidazole, pyromellitic dianhydride and hexamethylene diisocynate; and preparation methods in experimental animals. Acute and repeated dose toxicity studies of formulations were carried out as per OECD guidelines 423 and 407, respectively. For acute toxicity study, formulations were administered to female rats at doses of 300 and 2000 mg/kg orally. The general behaviour of the rats was continuously monitored for 1 h after dosing, periodically during the first 24 h and daily thereafter for a total of 14 days. On day 14, animals were fasted overnight, weighed, and sacrificed. After sacrification, animals were subjected to necropsy. For repeated dose toxicity study, rats of either sex were orally administered with formulations at the dose of 300 mg/kg per day for a period of 28 days. The maximally tolerated dose of all formulations was found to be 2000 mg/kg. Repeated administration of formulations for 28 days did not show any significant changes in haematological and biochemical parameters in experimental animals. These results indicate that the formulations are safe, when tested in experimental animals. PMID:25754724

  13. Adjuvant potential of low dose all-trans retinoic acid during oral typhoid vaccination in Zambian men.

    PubMed

    Lisulo, M M; Kapulu, M C; Banda, R; Sinkala, E; Kayamba, V; Sianongo, S; Kelly, P

    2014-03-01

    There is an urgent need to identify ways of enhancing the mucosal immune response to oral vaccines. Rotavirus vaccine protection is much lower in Africa and Asia than in industrialized countries, and no oral vaccine has efficacy approaching the best systemic vaccines. All-trans retinoic acid (ATRA) up-regulates expression of ?4?7 integrin and CCR9 on lymphocytes in laboratory animals, increasing their gut tropism. The aim of this study was to establish the feasibility of using ATRA as an oral adjuvant for oral typhoid vaccination. In order to establish that standard doses of oral ATRA can achieve serum concentrations greater than 10?nmol/l, we measured ATRA, 9-cis and 13-cis retinoic acid in serum of 14 male volunteers before and 3?h after 10?mg ATRA. We then evaluated the effect of 10?mg ATRA given 1?h before, and for 7 days following, oral typhoid vaccine in eight men, and in 24 men given various control interventions. We measured immunoglobulin (Ig)A directed against lipopolysaccharide (LPS)and protein preparations of vaccine antigens in whole gut lavage fluid (WGLF) and both IgA and IgG in serum, 1 day prior to vaccination and on day 14. Median [interquartile range (IQR)] C(max) was 26·2 (11·7-39·5) nmol/l, with no evidence of cumulation over 8 days. No adverse events were observed. Specific IgA responses to LPS (P?=?0·02) and protein (P?=?0·04) were enhanced in WGLF, but no effect was seen on IgA or IgG in serum. ATRA was well absorbed, well tolerated and may be a promising candidate oral adjuvant. PMID:24237035

  14. Assessing Sediment Toxicity from Navigational Pools of the Upper Mississippi River Using a 28Day Hyalella azteca Test

    Microsoft Academic Search

    N. E. Kemble; E. L. Brunson; T. J. Canfield; F. J. Dwyer; C. G. Ingersoll

    1998-01-01

    .   To assess the extent of sediment contamination in the Upper Mississippi River (UMR) system after the flood of 1993, sediment\\u000a samples were collected from 24 of the 26 navigational pools in the river and from one site in the Saint Croix River in the\\u000a summer of 1994. Whole-sediment tests were conducted with the amphipod Hyalella azteca for 28 days

  15. Oral pregabalin premedication for attenuation of haemodynamic pressor response of airway instrumentation during general anaesthesia: A dose response study

    PubMed Central

    Rastogi, Bhawna; Gupta, Kumkum; Gupta, Prashant K; Agarwal, Salony; Jain, Manish; Chauhan, Himanshu

    2012-01-01

    Background: The airway instrumentation of direct laryngoscopy and tracheal intubation are powerful noxious stimuli that should be attenuated by appropriate premedication, smooth induction and rapid intubation. The present study evaluated the safe and clinically effective dose of oral pregabalin premedication for attenuation of haemodynamic pressor response of airway instrumentation. Methods: A total of 90 normotensive adult consented patients aged 24–56 years, ASA grade I and II, of both gender were randomized into three treatment groups of 30 patients each. Group I received oral placebo, Group II oral pregabalin 75 mg and Group III oral pregabalin 150 mg 1 h prior to induction. Anaesthetic technique was standardized and all groups were assessed for pre-operative sedation, haemodynamic changes after the premedication, before and after induction, after laryngoscopy and intubation, along with intraoperative haemodynamic stability and post-operative side-effects. Results: Pre-operative sedation levels were higher with pregabalin premedication. Significant increase in heart rate and mean arterial pressure was observed in Groups I and II after airway instrumentation, while statistically significant attenuation of mean arterial pressure was seen in Group III. No significant decrease in heart rate was observed in any group. None of the patient has suffered from any post-operative side-effects, and no significant differences in the parameters of recovery and awakening time were observed. Conclusion: Oral pregabalin premedication has adequately sedated the patients. The haemodynamic pressor response of airway instrumentation was attenuated in a dose-related fashion. The premedicated patients were haemodynamically stable perioperatively without prolongation of recovery time and side-effects. PMID:22529420

  16. The In Vivo Fate of Hydroxytyrosol and Tyrosol, Antioxidant Phenolic Constituents of Olive Oil, after Intravenous and Oral Dosing of Labeled Compounds to Rats

    Microsoft Academic Search

    Kellie L. Tuck; Matthew P. Freeman; Peter J. Hayball; Graham L. Stretch; Ieva Stupans

    In vitro studies have shown phenolics in olive oil to be strong radical scavengers. The absorption and elimination of two radiolabeled phenolic constituents of olive oil, hydroxytyrosol and tyrosol were studied in vivo using rats. Compounds were administered intravenously (in saline) and orally (in oil- and water-based solutions). For both compounds, the intravenously and orally administered oil-based dosings resulted in

  17. Safety of one 52-mumol (50,000 IU) oral dose of vitamin A administered to neonates.

    PubMed

    Agoestina, T; Humphrey, J H; Taylor, G A; Usman, A; Subardja, D; Hidayat, S; Nurachim, M; Wu, L; Friedman, D S; West, K P

    1994-01-01

    A placebo-controlled trial was carried out among 2067 Indonesian neonates to assess the safety of administering one oral 52-mumol (50,000 IU) dose of vitamin A. Infants were assessed for potential acute side-effects before and throughout 48 hours after the dose. The first 965 infants were examined by cranial ultrasound before and at 24 hours after dosing to rule out intracranial haemorrhage and determine the resistive index (RI) of the anterior cerebral artery using duplex Doppler. Groups were comparable at the baseline. A bulging fontanelle occurred in the control and vitamin A groups, respectively, among 2.7% and 4.6% of the infants at 24 hours, and 2.4% and 4.5% of the infants at 48 hours. The groups did not differ in any other sign or symptom assessed. No infant developed intracranial haemorrhage. Mean RI values were normal and not different between groups at baseline or at 24 hours. Mean RI fell during the 24 hours, as normally occurs; the mean decrease was nearly identical in the two groups. A bulging fontanelle was not associated with increased rates of any sign or symptom or with an increase in RI. The 52-mumol dose of oral vitamin A may cause a small increase in intracranial volume in a small proportion of infants, but no increase in intracranial pressure. Acute side-effects following this intervention were rare and mild. PMID:7867131

  18. Single-dose bioavailability of levetiracetam intravenous infusion relative to oral tablets and multiple-dose pharmacokinetics and tolerability of levetiracetam intravenous infusion compared with placebo in healthy subjects

    Microsoft Academic Search

    Steven Ramael; Florence De Smedt; Nathalie Toublanc; Christian Otoul; Pierre Boulanger; Jean-Michel Riethuisen; Armel Stockis

    2006-01-01

    Background: Antiepileptic drugs are usually administere dorally, but alternative routes of drug delivery may be required when oral administration is not feasible.Objective: The purpose of this study was to evaluate the single-dose bioavailability of an IV formulation of levetiracetam relative to oral tablets and the multiple-dose tolerability and pharmacokinetics of this formulation compared with placebo in healthy subjects.Methods: This study

  19. Oral challenge with increasing doses of LPS modulated the patterns of plasma metabolites and minerals in periparturient dairy cows.

    PubMed

    Zebeli, Qendrim; Mansmann, Dominik; Sivaraman, Shanti; Dunn, Suzanna M; Ametaj, Burim N

    2013-06-01

    We showed recently that repeated oral exposure to LPS stimulated humoral immune responses in periparturient dairy cows. Here, metabolic and mineral responses to repeated oral administration of LPS were investigated. Sixteen clinically healthy, pregnant Holstein cows were orally administered 3?ml of saline solution (control) or 3?ml of saline solution containing 3 increasing doses of LPS, at 07:00?h, as follows: (i) 0.01?µg/kg body mass (BM) on d -14 and -10, (ii) 0.05?µg/kg BM on d?-7 and -3, and (iii) 0.1?µg/kg BM on d?3 and 7 relative to parturition. Blood samples were measured shortly before, and at 8 different time-points after (up to 6?h), the first challenge of each LPS dosage to evaluate the post-challenge plasma profile, as well as weekly up to 4 wk postpartum. Results showed that oral administration of LPS lowered concentrations of non-esterified fatty acids (P?oral LPS challenge, treatment tended to increase plasma glucose. Plasma calcium did not change, but concentrations of insulin (P?oral administration of LPS around parturition to modulate the profile of plasma metabolites and minerals postpartum. PMID:23109506

  20. Voriconazole Disposition After Single and Multiple, Oral Doses in Healthy, Adult Red-tailed Hawks ( Buteo jamaicensis ).

    PubMed

    Gentry, Jordan; Montgerard, Christy; Crandall, Elizabeth; Cruz-Espindola, Crisanta; Boothe, Dawn; Bellah, Jamie

    2014-09-01

    Voriconazole is effective for treatment of aspergillosis, a common disease in captive red-tailed hawks ( Buteo jamaicensis ). To determine the disposition and safety of voriconazole after single and multiple, oral doses, 12 adult red-tailed hawks were studied in 2 phases. In phase 1, each bird received a single dose of voriconazole solution (10 mg/kg) by gavage. Blood samples were collected at 0, 0.5, 1, 3, 6, 9, 12, 16, 24, and 36 hours after treatment. In phase 2, each of 8 birds received voriconazole oral solution at 10 mg/kg PO q12h for 14 days. Plasma samples were collected on days 0, 5, and 10 and after the final dose and were processed as in phase 1. Plasma samples were submitted for analysis of voriconazole levels by high-performance liquid chromatography and ultraviolet spectrophotometry and for measurement of selected plasma biochemical parameters. After single dosing, voriconazole concentrations reached a (mean ± SD) peak (Cmax) of 4.7 ± 1.3 ?g/mL at 2.0 ± 1.2 hours. The disappearance half-life (t1/2) was 2.8 ± 0.7 hours, and the mean residence time (MRT) was 4.6 ± 0.9 hours. After the last dose at 14 days, the mean Cmax of voriconazole was 4.5 ± 2.7 ?g/mL at 2.4 ± 1.1 hours. The t1/2 was 2.1 ± 0.8 hours, and the MRT was 3.5 ± 1.1 hours. Although concentrations of several plasma biochemical parameters were significantly different at study end compared with prestudy concentrations, only plasma creatine kinase activity was outside the reference range. No adverse reactions were observed in any of the birds. After both single and multiple dosing at 10 mg/kg, voriconazole concentrations exceeded the minimum inhibitory concentration to inhibit 90% (MIC90) of Aspergillus species (1 ?g/mL) by at least fourfold and remained above the MIC90 for 8.8 ± 1.1 hours after single dosing versus 6.5 ± 1.5 hours after multiple dosing (P = .003). This difference suggests that more frequent dosing (eg, up to q8h) may be necessary to maintain target concentrations during prolonged therapy. PMID:25843319

  1. Phase 1 study of weekly dosing with the investigational oral proteasome inhibitor ixazomib in relapsed/refractory multiple myeloma.

    PubMed

    Kumar, Shaji K; Bensinger, William I; Zimmerman, Todd M; Reeder, Craig B; Berenson, James R; Berg, Deborah; Hui, Ai-Min; Gupta, Neeraj; Di Bacco, Alessandra; Yu, Jiang; Shou, Yaping; Niesvizky, Ruben

    2014-08-14

    Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m(2). Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820. PMID:24904120

  2. Head-to-head, randomised, crossover study of oral versus subcutaneous methotrexate in patients with rheumatoid arthritis: drug-exposure limitations of oral methotrexate at doses ?15?mg may be overcome with subcutaneous administration

    PubMed Central

    Schiff, Michael H; Jaffe, Jonathan S; Freundlich, Bruce

    2014-01-01

    Objective To compare the relative bioavailability, safety and tolerability of oral methotrexate (MTX) and subcutaneous (SC) MTX administered via an auto-injector (MTXAI) in patients with rheumatoid arthritis (RA). Methods In this randomised, multicenter, open-label, three-way crossover study, patients ?18?years with adult RA undergoing treatment with MTX for ?3?months were assigned to receive MTX 10, 15, 20 and 25?mg weekly in a random sequence of three treatments: oral, SC into the abdomen and SC into the thigh. For 24?h after administration of each treatment, blood samples were collected for pharmacokinetic analysis and injection sites were assessed. Results Forty-seven patients completed the study. Systemic exposure of oral MTX plateaued at doses ?15?mg/week. In contrast, SC MTX demonstrated a linear increase in systemic exposure that was greater than oral MTX at each dose. No unexpected AEs were noted for either formulation. Conclusions Unlike oral MTX, the systemic exposure of SC MTX did not plateau over the doses studied, particularly at doses ?15?mg/week. In this study, higher systemic MTX exposure was not associated with increases in AEs. Patients with an inadequate clinical response to oral MTX may benefit from higher drug exposure by switching to SC MTX. Trial registration number NCT01618968. PMID:24728329

  3. A double-blind, single-dose comparison of the analgesic efficacy of tramadol\\/acetaminophen combination tablets, hydrocodone\\/acetaminophen combination tablets, and placebo after oral surgery

    Microsoft Academic Search

    James R. Fricke; Rezaul Karim; Donna Jordan; Norman Rosenthal

    2002-01-01

    Background: Improved clinical outcomes have been documented with combinations of oral analgesic agents, particularly those with complementary activities. However, because not all combinations or dose ratios lead to enhanced analgesia or reduced adverse events (AEs), each combination and dose ratio must be evaluated individually in carefully designed preclinical and clinical trials.Objective: The goal of the study was to compare the

  4. Prolongation of rat tail bleeding time caused by oral doses of a thromboxane synthetase inhibitor which have little effect on platelet aggregation.

    PubMed

    Butler, K D; Maguire, E D; Smith, J R; Turnbull, A A; Wallis, R B; White, A M

    1982-02-26

    N (7-carboxyheptyl) imidazole is an inhibitor of platelet thromboxane synthetase that has no effect on the cyclooxygenase activity. An oral dose of the substance to rats (10 mg/kg) prolonged tail bleeding time from 170 +/- 13 sec to 284 +/- 22 sec. This oral dose also inhibited platelet thromboxane B2 production induced by collagen ex vivo but had little effect on the aggregation dose response curve. There was no effect on thrombin-induced aggregation. Neither the thrombocytopenia induced by the Arthus reaction nor thrombus formation on an implanted cotton thread were inhibited by oral doses of carboxyheptylimidazole up to 30 mg/kg. Similarly neither the prothrombin nor activated partial thromboplastin time were affected. It is postulated that this thromboxane synthetase inhibitor prolongs bleeding time nor by inhibiting platelet aggregation or blood coagulation but rather by preventing the vasoconstriction which would normally be caused by thromboxane A2. PMID:6461944

  5. Effects of low-dose oral contraceptives on female whole saliva.

    PubMed

    Laine, M; Pienihäkkinen, K; Ojanotko-Harri, A; Tenovuo, J

    1991-01-01

    The composition and flow rate of paraffin-stimulated whole saliva were analysed in 22 women, of whom 11 used oral contraceptives and 11 did not. Ten men served as the controls. The salivary samples were collected during one month (oral contraceptive users and men), or during one menstrual cycle (non-users). The saliva analyses included flow rate, pH, buffer effect, sialic acid, thiocyanate, peroxidase, lysozyme, amylase, immunoglobulins A, G and M, total protein, mutans streptococci, lactobacilli, yeasts and total numbers of aerobic bacteria. The salivary buffer effect of oral contraceptive users was significantly (p less than 0.005) higher than that of non-users. All the other constituents showed intra- and interindividual variation in all groups, but with no apparent hormone-dependency. PMID:1837983

  6. Pharmacokinetics of Licarbazepine in Healthy Volunteers: Single and Multiple Oral Doses and Effect of Food

    Microsoft Academic Search

    Claire Souppart; Chem Eng; Anne Gardin; Gerard Greig; Sebastien Balez; Yannick Batard; Axel Krebs-Brown; Silke Appel-Dingemanse

    2008-01-01

    Two studies characterized single- and multiple-dose pharmacokinetics of licarbazepine immediate-release tablets and food effects on single-dose pharmacokinetics. In 1 study, 12 volunteers received 500 mg licarbazepine on day 1, 500 mg bid on days 3 to 6, and 500 mg on day 7. In the second study, 12 subjects received one 500-mg licarbazepine dose under fasted and fed conditions. After

  7. Optimization of Hyalella azteca IQ Toxicity Test{trademark} for prediction of 28-day sediment toxicity tests

    SciTech Connect

    Novotny, A.N.; Ezzard, C.L.; Douglas, W.S.; Home, M.T. [Aqua Survey, Inc., Flemington, NJ (United States)

    1995-12-31

    The IQ Toxicity Test, which is a rapid screening toxicity test consisting of the observation of in-vivo inhibition of an enzymatic process using a fluorescent substrate, has proven successful for the determination of 24 and 48-hour EC50`s of D. magna, C. dubia, D. pulex and M. bahia. The application of this concept to utilize the freshwater amphipod Hyalella azteca may be an excellent way in which to reduce the standard 28-day chronic sediment toxicity test to possibly one hour`s time. This study incorporates an additive experimental design to explore the effects of and interactions between five specific variables: size of the amphipod, exposure time to the toxicant, concentration of substrate, exposure time to the substrate, and length of time starved prior to testing. The results of the IQ toxicity test were compared to those of a 28-day chronic sediment toxicity test. Preliminary data indicate that there is an optimal combination of these variables which results in a concise, reproducible toxicity test for use with Hyalella azteca, and would potentially be applicable to other freshwater amphipods in the future.

  8. Inhibition of prolactin with bromocriptine for 28days increases blood-brain barrier permeability in the rat.

    PubMed

    Rosas-Hernandez, H; Ramirez, M; Ramirez-Lee, M A; Ali, S F; Gonzalez, C

    2015-08-20

    The blood-brain barrier (BBB) is necessary for the proper function of the brain. Its maintenance is regulated by endogenous factors. Recent evidences suggest prolactin (PRL) regulates the BBB properties in vitro, nevertheless no evidence of these effects have been reported in vivo. The aim of this study was to evaluate the role of PRL in the maintenance of the BBB in the rat. Male Wistar rats were treated with Bromocriptine (Bromo) to inhibit PRL production for 28days in the absence or presence of lipopolysaccharide (LPS). BBB permeability was evaluated through the Evans Blue dye and fluorescein-dextran extravasation as well as through edema formation. The expression of claudin-5, occludin, glial fibrillary acidic protein (GFAP) and the PRL receptor (PRLR) was evaluated through western blot. Bromo reduced the physiological levels of PRL at 28days. At the same time, Bromo increased BBB permeability and edema formation associated with a decrement in claudin-5 and occludin and potentiated the increase in BBB permeability induced by LPS. However, no neuroinflammation was detected, since the expression of GFAP was unchanged, as well as the expression of the PRLR. These data provide the first evidence that inhibition of PRL with Bromo affects the maintenance of the BBB through modulating the expression of tight junction proteins in vivo. PMID:26047726

  9. Specific accumulation of orally administered redox nanotherapeutics in the inflamed colon reducing inflammation with dose-response efficacy.

    PubMed

    Vong, Long Binh; Mo, John; Abrahamsson, Bertil; Nagasaki, Yukio

    2015-07-28

    Although current medications for ulcerative colitis (UC) are effective to some extent, there are still some limitation of their use due to the non-specific distribution, drug metabolism in the gastrointestinal tract, and severe adverse effects. In our previous studies, we developed oral redox nanoparticles (RNP(O)) that specifically accumulated and scavenged overproduced reactive oxygen species (ROS) in an inflamed colon. However, the mechanism leading to specific accumulation of RNP(O) in an inflamed colon is still unclear. In this study, we investigated the cellular uptake of RNP(O) into ROS-treated epithelial colonic cells in vitro, and compared to the untreated cells, found a significantly increased uptake in ROS-treated cells. In vivo, we discovered that orally administered RNP(O) were not internalized into the cells of a normal colon. A significant amount of disintegrated RNP(O) was detected in the cells of an inflamed colon of dextran sodium sulfate (DSS)-induced colitis mice, resulting in scavenging of ROS and suppression of inflammation with low adverse effects. Furthermore, we confirmed a significant reduction of disease activity and a robust dose response efficacy following RNP(O) treatment in acute DSS-induced colitis mice, outperforming the positive control 5-aminosalicylic acid. Oral administration of RNP(O) is a promising approach to develop a new therapy for UC disease. PMID:25998050

  10. Relative toxicity of bifenthrin to Hyalella azteca in 10 day versus 28 day exposures.

    PubMed

    Anderson, Brian S; Phillips, Bryn M; Voorhees, Jennifer P; Petersen, Megan A; Jennings, Lydia L; Fojut, Tessa L; Vasquez, Martice E; Siegler, Catherine; Tjeerdema, Ronald S

    2015-04-01

    Many watersheds in the Central Valley region of California are listed as impaired due to pyrethroid-associated sediment toxicity. The Central Valley Regional Water Quality Control Board is developing numeric sediment quality criteria for pyrethroids, beginning with bifenthrin. Criteria are being developed using existing data, along with data from 10?d and 28?d toxicity tests with Hyalella azteca conducted as part of the current study. A single range-finder and 2 definitive tests were conducted for each test duration. Median lethal concentrations (LC50s), as well as LC20s and inhibition concentrations (IC20s) were calculated based on measured whole sediment bifenthrin concentrations and interstitial water concentrations. Sediment LC50s were also corrected for organic C content. Average LC50s were not significantly different in 10?d versus 28?d tests with H. azteca: 9.1 and 9.6?ng/g bifenthrin for 10?d and 28?d tests, respectively. Average LC20 values were also similar with concentrations at 7.1 and 7.0 for 10?d and 28?d tests, respectively. Bifenthrin inhibition concentrations (IC20s) based on amphipod growth were variable, particularly in the 28?d tests, where a clear dose-response relationship was observed in only 1 of the definitive experiments. Average amphipod growth IC20s were 3.9 and 9.0?ng/g for 10?d and 28?d tests, respectively. Amphipod growth calculated as biomass resulted in IC20s of 4.1 and 6.3?ng/g for the 10?d and 28?d tests, respectively. Lack of a clear growth effect in the longer term test may be related to the lack of food adjustment to account for amphipod mortality in whole sediment exposures. The average C-corrected LC50s were 1.03 and 1.09??g/g OC for the 10?d and 28?d tests, respectively. Interstitial water LC50s were determined as the measured dissolved concentration of bifenthrin relative to interstitial water dissolved organic carbon. The average LC50s for dissolved interstitial water bifenthrin were 4.23 and 4.28?ng/L for the 10?d and 28?d tests, respectively. In addition, a set of 10?d and 28?d tests were conducted at 15?°C to assess the relative toxicity of bifenthrin at a lower temperature than the standard 23?°C test temperature. These results showed that bifenthrin was more toxic at the lower temperature, with LC50s of 5.1 and 3.4?ng/g bifenthrin in 10?d and 28?d tests, respectively. Amphipod growth at 15?°C after a 28?d exposure resulted in the lowest effect concentration of all experiments conducted (IC20?=?0.61?ng/g). This article discusses how bifenthrin dose-response data from 10?d and 28?d exposures inform development of sediment quality criteria for this pesticide for California Central Valley watersheds. PMID:25564769

  11. Oral Versus High-Dose Pulse Corticosteroids for Problematic Infantile Hemangiomas: A Randomized, Controlled Trial

    Microsoft Academic Search

    Elena Pope; Bernice R. Krafchik; Colin Macarthur; Diana Stempak; Derek Stephens; Miriam Weinstein; Nhung Ho; Sylvain Baruchel

    2010-01-01

    OBJECTIVES.Oral systemic corticosteroids are the mainstay of treatment for problem- atic hemangiomas; however, current information is based on anecdotal experience and retrospective studies. We aimed to determine whether systemic steroids are efficacious in proliferating hemangioma and to compare the efficacy and safety of 2 corticosteroid treatment modalities. PATIENTS AND METHODS.Twenty patients with problematic hemangiomas of infancy were randomly assigned to

  12. Dose finding study of oral PSC 833 combined with weekly intravenous etoposide in children with relapsed or refractory solid tumours.

    PubMed

    Pein, F; Pinkerton, R; Berthaud, P; Pritchard-Jones, K; Dick, G; Vassal, G

    2007-09-01

    PSC 833 is an effective MDR1 reversal agent in vitro, including studies with paediatric cancer cell lines such as neuroblastoma and rhabdomyosarcoma. This study was performed to determine the safety profile, dose limiting toxicity (DLT) and maximum tolerated dose (MTD) in children with solid tumours and to determine the influence of PSC 833 on the pharmacokinetics of co-administered etoposide. Each patient received one cycle of intravenous etoposide (100 mg/m2 daily for 3 days on three consecutive weeks) to document baseline pharmacokinetics, and subsequently the same schedule using a dose of 50 mg/m2 was given combined with PSC 833 given orally every 6h at a starting dose of 4 mg/kg. Thirty two eligible patients (23 male, median age 8.3 years) were enrolled. Neuroblastoma and rhabdomyosarcoma were the common disease types. Brain tumours were excluded. DLT was defined as any non-haematological grade 3-4 toxicity (common toxicity criteria) and using a specific toxicity scale for cerebellar toxicity. The MDT was defined as the first dose below which 2 or more patients per dose level experienced DLT. Grade 1-2 ataxia occurred in cohorts 2 and 3 (4 and 5 mg/kg, respectively). Three patients developed grade 3 neurotoxicity in the 6 mg/kg cohort and this defined the MTD. Six responses were observed (2 CR, 4 PR). Pharmacokinetic studies indicated that the clearance of etoposide was reduced by approximately 50% when combined with PSC 833. It is concluded that the toxicity profile and MDT is similar in both children and adults, as is the effect on etoposide metabolism. The study demonstrated the feasibility and safety of carrying out a paediatric phase 1 trial across European boundaries and acts as a model for future cooperative studies in rare cancers among children. PMID:17716890

  13. Pharmacokinetics of Levetiracetam in Healthy Hispaniolan Amazon Parrots ( Amazona ventralis ) After Oral Administration of a Single Dose.

    PubMed

    Schnellbacher, Rodney; Beaufrčre, Hugues; Vet, Dr Med; Arnold, Robert D; Tully, Thomas N; Mayer, Joerg; Divers, Stephen J

    2014-09-01

    Long-term anticonvulsive treatments have been poorly described in birds, and few pharmacokinetic studies have been performed, with mixed results. Levetiracetam, a new anticonvulsive drug, has shown good efficacy for monotherapy or adjunctive treatment of seizures in both human and veterinary medicine. To determine pharmacokinetics of levetiracetam in Hispaniolan Amazon parrots ( Amazona ventralis ), 20 healthy birds were randomly divided into 2 groups and administered either a 50 mg/kg (n = 10) or a 100 mg/kg (n = 10) oral dose of levetiracetam with no observable adverse effects. Blood samples were collected at baseline and at 12 time intervals (6 per group) for 16 hours. The concentration-time profiles resembled characteristic absorption, with maximum plasma concentrations of 61.0 ?g/mL and 95.1 ?g/mL at 60 minutes; terminal half-lives at 2.38 and 2.37 hours; volumes of distribution of 0.807 and 0.773 L/kg, with an area under the curve at 14?100 and 28?820 mg × min/L; and clearance rates of 3.65 and 3.60 mL/min per kg, respectively. Plasma concentrations were greater than 5.5 mg/L for up to 9.4 and 12 hours, suggesting an 8- and 12-hour oral dosing at 50 and 100 mg/kg, respectively, would be sufficient to maintain targeted values. Clinically, doses and frequencies may need escalation based on differences in species and individuals, and drug levels should be monitored. PMID:25843318

  14. Toxicokinetics of 14C-endosulfan in male Sprague-Dawley rats following oral administration of single or repeated doses.

    PubMed

    Chan, Melissa P L; Morisawa, Shinsuke; Nakayama, Aki; Kawamoto, Yuko; Sugimoto, Miki; Yoneda, Minoru

    2005-10-01

    Endosulfan (ES), an organochlorine (OC) insecticide that belongs to the cyclodiene group, is one of the most commonly used pesticides to control pests in vegetables, cotton, and fruits. The toxicokinetics of 14C-endosulfan following oral administration of a single dose of 5 mg/kg body weight was investigated in male Sprague-Dawley rats. Three rats were sacrificed 30 min, 1 h, 2 h, 4 h, and 8 h after dosing. 14C-endosulfan radioactivity was detected in all tissues at each time point. In a separate experiment urine and feces were collected for 96 h. The total radioactivity recovered in the excreta for 4 days was 106.8% +/- 26.2%, with fecal elimination the major route of elimination route (94.4% +/- 21.4%). The cumulative excretion in the urine for 4 days was 12.4% +/- 4.8%. Radioactivity 8 h after administration was highest in gastrointestinal (GI) tract tissue (20.28 +/- 16.35 mg ES eq./L) and lowest in muscle (0.18 +/- 0.06 mg ES eq./L). The toxicokinetic parameters obtained from 14C-endosulfan-derived radioactivity in blood were distribution half-life (T1/2 x) = 31 min and terminal elimination half-life (T1/2 y) = 193 h. Blood concentration reached its maximum (Cmax) of 0.36 +/- 0.08 mg ES eq./L 2 h after the oral dose. Endosulfan was rapidly absorbed into the GI tract in rats, with an absorption rate constant (ka) of 3.07 h(-1). PMID:16161119

  15. Absorption, distribution, metabolism and excretion of daily oral doses of [14C]methyl parathion in hens.

    PubMed

    Abu-Qare, A W; Abdel-Rahman, A A; Ahmad, H; Kishk, A M; Abou-Donia, M B

    2001-12-15

    Adult hens were given oral daily doses of 2 mg (2 microC(i))/kg/day (14% of oral LD(50) in male rats) of [14C]methyl parathion (O,O-dimethyl O-4-nitrophenyl phosphorothioate) for 10 consecutive days. Five treated hens were sacrificed at 1, 2, 4, 8, 12, 24, and 48 h after the last dose. Methyl parathion was absorbed from the gastrointestinal tract and distributed rapidly. Maximum radioactivity was detected in tissues within 8 h of dosing, (ng methyl parathion equivalent/g fresh tissue or ml plasma): Plasma (189.2), liver (94.7), kidney (146.2), brain (61.4), gastrointestinal tissues (106.7). Methyl parathion was detected in the plasma, kidney and liver, while methyl parathion metabolite p-nitrophenol was detected in the liver and in the kidney. Elimination of methyl parathion from plasma was monophasic with a terminal half-life of 17.5 h, corresponding to an elimination rate constant of 0.039 ng/hr. Most of the absorbed radioactivity was excreted in the combined fecal-urine excreta (98%). Analysis of the metabolites in the excreta revealed that non-conjugated metabolites accounted for 13% of the total excretion. Conjugated metabolites accounted for 87% of the total excretion; of that, 6% as p-nitrophenyl-glucoronide conjugate, 7% as p-nitrophenyl-sulfate conjugate, 23% as bound hot sulfuric acid hydrolyzable residues, and 51% as water soluble metabolites. The presence of majority of radioactivity in the excreta as conjugated metabolites indicates that determining only unbound p-nitrophenol as a biological marker for methyl parathion exposure underestimates total fecal-urine excretion of p-nitrophenol. The slow elimination rate of methyl parathion is significant, since hens are more comparable to humans with respect to their cytochrome P450 activities. PMID:11701217

  16. Randomized, Controlled Human Challenge Study of the Safety, Immunogenicity, and Protective Efficacy of a Single Dose of Peru15, a Live Attenuated Oral Cholera Vaccine

    Microsoft Academic Search

    Mitchell B. Cohen; Ralph A. Giannella; Judy Bean; David N. Taylor; Susan Parker; Amy Hoeper; Stephen Wowk; Jennifer Hawkins; Sims K. Kochi; Gilbert Schiff; Kevin P. Killeen; Walter Reed

    2002-01-01

    Peru-15 is a live attenuated oral vaccine derived from a Vibrio cholerae O1 El Tor Inaba strain by a series of deletions and modifications, including deletion of the entire CT genetic element. Peru-15 is also a stable, motility-defective strain and is unable to recombine with homologous DNA. We wished to determine whether a single oral dose of Peru-15 was safe

  17. Ethyl glucuronide concentrations in oral fluid, blood, and urine after volunteers drank 0.5 and 1.0 g/kg doses of ethanol.

    PubMed

    Hřiseth, Gudrun; Yttredal, Borghild; Karinen, Ritva; Gjerde, Hallvard; Mřrland, Jřrg; Christophersen, Asbjřrg

    2010-01-01

    The aim of this study was to investigate the concentrations of ethyl glucuronide (EtG) in oral fluid, blood, and urine after healthy volunteers drank two doses of ethanol, 0.5 (n = 11) and 1.0 g/kg (n = 10), after an overnight fast. Samples of oral fluid, blood, and urine were collected before drinking started and at 1.5, 3.5, 5.5, 8.5, 11.5, and 24 h post-dosing. Following ingestion of low dose of ethanol, the Cmax for EtG was 0.36 mg/L (range 0.28-0.41 mg/L) in blood and 69.8 mg/L (range 47.1-96.5 mg/L) in urine. In oral fluid, the concentrations were < 1% of those in blood, and only three subjects exceeded the limit of quantification for EtG in oral fluid. After ingestion of the high dose of ethanol, the Cmax for EtG was 1.06 mg/L (range 0.8-1.22 mg/L) in blood, 159.9 mg/L (range 97.2-225.5 mg/L) in urine, and 0.032 mg/L (range 0.013-0.059 mg/L) in oral fluid. The median oral fluid/blood ratio was 0.029 (range 0.012-0.054) for EtG. The detection time for EtG was median 11.5 h (range 3.5-11.5 h) in oral fluid. According to this, the detection time for EtG in oral fluid is therefore only a few hours longer than for ethanol itself and represents limited additional value. PMID:20663284

  18. Using oral ziprasidone effectively: the food effect and dose-response

    Microsoft Academic Search

    Leslie Citrome

    2009-01-01

    Ziprasidone is a newer “atypical” or “secondgeneration” antipsychotic. Oral ziprasidone (zipras idone hydrochlor ide) has\\u000a been approved by the US Food and Drug Administration (FDA) for the treatment of schizophrenia, and acute manic or mixed episodes\\u000a associated with bipolar disorder (with or without psychotic features). Comparisons with other second-generation antipsychotics\\u000a in meta-analyses reveal similar efficacy to that observed for quetiapine

  19. A 15-day oral dose toxicity study of aspirin eugenol ester in Wistar rats.

    PubMed

    Li, Jianyong; Yu, Yuanguang; Yang, Yajun; Liu, Xiwang; Zhang, Jiyu; Li, Bing; Zhou, Xuzheng; Niu, Jianrong; Wei, Xiaojuan; Liu, Zhiqi

    2012-06-01

    The subchronic toxicity of aspirin eugenol ester (AEE) was evaluated after 15-day intragastrically administration in rats at daily doses of 50, 1000, and 2000 mg/kg. AEE at low-dose showed no toxicity to the tested rats. Following repeated exposure to medium- or high-dose of AEE, apparent changes were observed in the levels of blood glucose, AST, ALP, ALT and TB in both male and female rats, and appeared to be dose-independent. There were no significant gender differences in most indexes of subchronic toxicity throughout the experimental period with the exception of food consumption and body weight. The no-observed-adverse-effect level (NOAEL) of AEE was considered to be 50 mg/kg/day under the present study conditions. PMID:22516304

  20. A new solid oral tablet formulation of posaconazole: a randomized clinical trial to investigate rising single- and multiple-dose pharmacokinetics and safety in healthy volunteers

    PubMed Central

    Krishna, G.; Ma, L.; Martinho, M.; Preston, R. A.; O'Mara, E.

    2012-01-01

    Objectives Posaconazole is an extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis. The marketed oral suspension should be taken with food to maximize systemic absorption. A new solid oral tablet has been developed with improved bioavailability that can be administered without regard to food. The aim of this study was to evaluate rising single- and multiple-dose pharmacokinetics, safety and tolerability of the new tablet. Methods This was a single-centre, randomized, placebo-controlled, Phase I, rising single- and multiple-dose study of healthy subjects aged 18–65 years who received a posaconazole tablet as 200 mg once daily, 200 mg twice daily or 400 mg once daily. The 24 subjects were studied in two cohorts of 12 subjects each (9 active and 3 placebo). Results After single or multiple oral dose administration of posaconazole tablets (200 and 400 mg), exposure increased in a dose-related manner. Peak posaconazole concentrations were attained at a median Tmax of 4–5 h. Mean half-life was similar for 200 and 400 mg posaconazole doses (25 and 26 h). The accumulation ratio upon multiple doses over 8 days was ?3 for 200 and 400 mg once daily and ?5 for 200 mg twice daily. Cavg values exceeded 1300 ng/mL. The posaconazole oral tablet was safe and well tolerated, although mild, transient elevations in liver function were reported in some patients. Conclusions Posaconazole exposure increased in a dose-related manner. The pharmacokinetics of this new solid oral tablet of posaconazole supports the clinical evaluation of once-daily dosing regimens for fungal infections. PMID:22833639

  1. Comparative Single-Dose Pharmacokinetics of Clonazepam following Intravenous, Intramuscular and Oral Administration to Healthy Volunteers

    Microsoft Academic Search

    C. Crevoisier; M. C. Delisle; I. Joseph; G. Foletti

    2003-01-01

    The objective was to assess the single-dose pharmacokinetics of clonazepam following i.m., p.o. and i.v. administration. In an open-label, three-way crossover study, 12 healthy volunteers were randomized to receive a single dose of 2 mg clonazepam either by the i.m., p.o. or i.v. route. Serial blood samples were collected up to 120 h after drug administration. Plasma concentrations of clonazepam

  2. The bioavailability and pharmacokinetics of oral and depot intramuscular haloperidol in schizophrenic patients.

    PubMed

    Nayak, R K; Doose, D R; Nair, N P

    1987-02-01

    In a four-segment long-term (greater than or equal to 6 mo) study, patients with schizophrenia received oral haloperidol in single daily doses and subsequently depot intramuscular (IM) haloperidol decanoate q28d. For each route of administration, a period of stabilization was followed by a maintenance period. Dosages for both oral haloperidol and IM haloperidol decanoate were determined on the basis of the patient's past psychiatric history and clinical response during the stabilization period. To characterize the concentration-time profile of the two routes of administration, blood samples were obtained on two separate occasions at steady state during maintenance dosing for each route of administration. Examination of values for cumulative area under the plasma concentration-time curves (AUC) to each sampling time indicated a sustained release of haloperidol from the intramuscularly administered haloperidol decanoate. Dose ranges during maintenance periods were 5-35 mg/d for oral haloperidol (mean, 17 mg/d), and 75-500 mg/28 d for IM haloperidol decanoate (mean, haloperidol decanoate was 243 mg equivalents of haloperidol/28 d). The ratio of long-acting to daily oral doses during maintenance therapy ranged from 9.4:1.0 to 15.0:1.0 (mean, 14.1:1.0). At these ratios, plasma concentration data showed that haloperidol decanoate gave lower values than did oral haloperidol for peak plasma, minimum plasma, and mean steady-state plasma concentrations. The absolute concentration swing was significantly less for decanoate than for the oral drug. Dose-normalized AUC values were compared determine the IM dose of haloperidol decanoate that would have yielded haloperidol plasma concentrations equivalent to those resulting from daily oral administration of haloperidol for 28 days.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3680566

  3. Extended-Cycle Levonorgestrel/Ethinylestradiol and Low-Dose Ethinylestradiol (Seasonique(®)): A Review of Its Use as an Oral Contraceptive.

    PubMed

    Burness, Celeste B

    2015-06-01

    A 91-day extended-cycle oral contraceptive (OC) consisting of levonorgestrel/ethinylestradiol 150/30 µg for 84 days and ethinylestradiol 10 µg for 7 days (Seasonique(®)) has recently been approved for the prevention of pregnancy in adult women in the EU. This regimen allows for a reduction in the number of withdrawal bleeding episodes to four per year, compared with 13 episodes per year with conventional 28-day regimens. Seasonique(®) was effective in preventing pregnancy in a large (n = 1006), noncomparative trial of healthy, sexually active women. In this trial, the overall Pearl index (pregnancies per 100 woman-years of use) in women aged 18-35 years (n = 621) was 0.76 and the Pearl index for method-failure (compliant use) was 0.26. Scheduled (withdrawal) bleeding and/or spotting remained fairly constant over time, with a mean of 2 days of bleeding and 1 day of spotting per each 91-day cycle. Unscheduled bleeding and unscheduled spotting was highest during the first few cycles of use and decreased thereafter. Seasonique(®) was generally well tolerated, with a tolerability profile in line with that expected for OCs. Seasonique(®) extends the contraceptive options currently available to women, particularly in those who desire fewer withdrawal bleeding episodes. PMID:26017303

  4. Evaluation of sphingolipids in Wistar rats treated to prolonged and single oral doses of fumonisin b?.

    PubMed

    Direito, Glória M; Almeida, Adriana P; Aquino, Simone; dos Reis, Tatiana Alves; Pozzi, Claudia Rodrigues; Corręa, Benedito

    2009-01-01

    The objective of the present study was to evaluate sphingolipid levels (sphingosine-So and sphinganine-Sa) and to compare the Sa/So ratio in liver, serum and urine of Wistar rats after prolonged administration (21 days) of fumonisin B(1) (FB(1)). In parallel, the kinetics of sphingolipid elimination in urine was studied in animals receiving a single dose of FB(1). Prolonged exposure to FB(1) caused an increase in Sa levels in urine, serum and liver. The most marked effect on sphingolipid biosynthesis was observed in animals treated with the highest dose of FB(1). Animals receiving a single dose of FB(1) presented variations in Sa and So levels and in the Sa/So ratio. PMID:19333435

  5. A Phase Two Randomised Controlled Double Blind Trial of High Dose Intravenous Methylprednisolone and Oral Prednisolone versus Intravenous Normal Saline and Oral Prednisolone in Individuals with Leprosy Type 1 Reactions and\\/or Nerve Function Impairment

    Microsoft Academic Search

    Stephen L. Walker; Peter G. Nicholls; Sushmita Dhakal; Rachel A. Hawksworth; Murdo Macdonald; Kishori Mahat; Shudan Ruchal; Sushma Hamal; Deanna A. Hagge; Kapil D. Neupane; Diana N. J. Lockwood

    2011-01-01

    BackgroundLeprosy Type 1 reactions are a major cause of nerve damage and the preventable disability that results. Type 1 reactions are treated with oral corticosteroids and there are few data to support the optimal dose and duration of treatment. Type 1 reactions have a Th1 immune profile: cells in cutaneous and neural lesions expressing interferon-? and interleukin-12. Methylprednisolone has been

  6. Formulation design, challenges, and development considerations for fixed dose combination (FDC) of oral solid dosage forms.

    PubMed

    Desai, Divyakant; Wang, Jennifer; Wen, Hong; Li, Xuhong; Timmins, Peter

    2013-01-01

    Fixed dose combination (FDC) products are common in the treatment of hypertension, diabetes, human immunodeficiency virus, and tuberculosis. They make it possible to combine two or more drug molecules with different modes of pharmacological actions in a single dosing unit and optimize the treatment. From a patient perspective, they offer convenience, reduced dosing unit burden, and cost savings. From a clinical perspective, aging population in developed countries will need multiple medications to treat age related diseases and co-morbidities. FDC products simplify dosing regimen and enhance patient compliance. As outlined in the article, the number of FDC products has grown over the years and the trend is likely to continue. This review article gives an overview to pharmaceutical scientists about recent trends in the formulation development of the FDC products and provides decision trees to select most optimum formulation development strategy. While some formulation technologies such as multi-layer tablets, multiparticulate systems, active film coating, and hot-melt granulation are discussed in more detail, a few specialized technologies are also introduced briefly to the readers. PMID:22339230

  7. Skin and soft tissue concentrations of tedizolid (formerly torezolid), a novel oxazolidinone, following a single oral dose in healthy volunteers

    PubMed Central

    Sahre, Martina; Sabarinath, Sreedharan; Grant, Maria; Seubert, Christoph; DeAnda, Carisa; Prokocimer, Philippe

    2013-01-01

    Plasma concentrations of antimicrobial drugs have long been used to correlate exposure with effect, yet one cannot always assume that unbound plasma and tissue concentrations are similar. Knowledge about unbound tissue concentrations is important in the development of antimicrobial drugs, since most infections are localised in tissues. Therefore, a clinical microdialysis study was conducted to evaluate the distribution of tedizolid (TR-700), the active moiety of the antimicrobial prodrug tedizolid phosphate (TR-701), into interstitial fluid (ISF) of subcutaneous adipose and skeletal muscle tissues following a single oral 600 mg dose of tedizolid phosphate in fasting conditions. Twelve healthy adult subjects were enrolled. Two microdialysis probes were implanted into the thigh of each subject, one into the vastus medialis muscle and one into subcutaneous adipose tissue. Probes were calibrated using retrodialysis. Dialysate samples were collected every 20 min for 12 h following a single oral dose of 600 mg tedizolid phosphate, and blood samples were drawn over 24 h. Unbound tedizolid levels in plasma were similar to those in muscle and adipose tissue. The ratios of unbound (free) AUC in tissues over unbound AUC in plasma (fAUCtissue/fAUCplasma) were 1.1 ± 0.2 and 1.2 ± 0.2 for adipose and muscle tissue, respectively. The median half-life was 8.1, 9.2 and 9.6 h for plasma, adipose tissue and muscle tissue, respectively. Mean protein binding was 87.2 ± 1.8%. The study drug was very well tolerated. The results of this study show that tedizolid distributes well into ISF of adipose and muscle tissues. Unbound levels of tedizolid in plasma, adipose tissue and muscle tissue were well correlated. Free plasma levels are indicative of unbound levels in the ISF of muscle and adipose tissues. PMID:22584101

  8. Skin and soft tissue concentrations of tedizolid (formerly torezolid), a novel oxazolidinone, following a single oral dose in healthy volunteers.

    PubMed

    Sahre, Martina; Sabarinath, Sreedharan; Grant, Maria; Seubert, Christoph; Deanda, Carisa; Prokocimer, Philippe; Derendorf, Hartmut

    2012-07-01

    Plasma concentrations of antimicrobial drugs have long been used to correlate exposure with effect, yet one cannot always assume that unbound plasma and tissue concentrations are similar. Knowledge about unbound tissue concentrations is important in the development of antimicrobial drugs, since most infections are localised in tissues. Therefore, a clinical microdialysis study was conducted to evaluate the distribution of tedizolid (TR-700), the active moiety of the antimicrobial prodrug tedizolid phosphate (TR-701), into interstitial fluid (ISF) of subcutaneous adipose and skeletal muscle tissues following a single oral 600 mg dose of tedizolid phosphate in fasting conditions. Twelve healthy adult subjects were enrolled. Two microdialysis probes were implanted into the thigh of each subject, one into the vastus medialis muscle and one into subcutaneous adipose tissue. Probes were calibrated using retrodialysis. Dialysate samples were collected every 20 min for 12h following a single oral dose of 600 mg tedizolid phosphate, and blood samples were drawn over 24h. Unbound tedizolid levels in plasma were similar to those in muscle and adipose tissue. The ratios of unbound (free) AUC in tissues over unbound AUC in plasma (fAUC(tissue)/fAUC(plasma)) were 1.1 ± 0.2 and 1.2 ± 0.2 for adipose and muscle tissue, respectively. The median half-life was 8.1, 9.2 and 9.6h for plasma, adipose tissue and muscle tissue, respectively. Mean protein binding was 87.2 ± 1.8%. The study drug was very well tolerated. The results of this study show that tedizolid distributes well into ISF of adipose and muscle tissues. Unbound levels of tedizolid in plasma, adipose tissue and muscle tissue were well correlated. Free plasma levels are indicative of unbound levels in the ISF of muscle and adipose tissues. PMID:22584101

  9. Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

    PubMed

    Heuberger, Jules A A C; Guan, Zheng; Oyetayo, Olubukayo-Opeyemi; Klumpers, Linda; Morrison, Paul D; Beumer, Tim L; van Gerven, Joop M A; Cohen, Adam F; Freijer, Jan

    2015-02-01

    ?(9)-Tetrahydrocannobinol (THC), the main psychoactive compound of Cannabis, is known to have a long terminal half-life. However, this characteristic is often ignored in pharmacokinetic (PK) studies of THC, which may affect the accuracy of predictions in different pharmacologic areas. For therapeutic use for example, it is important to accurately describe the terminal phase of THC to describe accumulation of the drug. In early clinical research, the THC challenge test can be optimized through more accurate predictions of the dosing sequence and the wash-out between occasions in a crossover setting, which is mainly determined by the terminal half-life of the compound. The purpose of this study is to better quantify the long-term pharmacokinetics of THC. A population-based PK model for THC was developed describing the profile up to 48 h after an oral, intravenous, and pulmonary dose of THC in humans. In contrast to earlier models, the current model integrates all three major administration routes and covers the long terminal phase of THC. Results show that THC has a fast initial and intermediate half-life, while the apparent terminal half-life is long (21.5 h), with a clearance of 38.8 L/h. Because the current model characterizes the long-term pharmacokinetics, it can be used to assess the accumulation of THC in a multiple-dose setting and to forecast concentration profiles of the drug under many different dosing regimens or administration routes. Additionally, this model could provide helpful insights into the THC challenge test used for the development of (novel) compounds targeting the cannabinoid system for different therapeutic applications and could improve decision making in future clinical trials. PMID:25316574

  10. Effect of ethane-1-hydroxy-1,1-bisphosphonate (EHBP) on endochondral ossification lesions induced by a lethal oral dose of uranyl nitrate.

    PubMed

    Bozal, C B; Martinez, A B; Cabrini, R L; Ubios, A M

    2005-08-01

    A 350 mg/kg body weight (b.w.) oral dose of uranyl nitrate (UN) caused 100% mortality in mice three days after administration, due to resulting kidney lesions. Mortality decreased 50% after an oral (o) or subcutaneous (sc) dose of bisodic etidronate (EHBP). Given that bone is also a target organ for uranium (U) in acute intoxication, the aim of this work was to study the effect of exposure to a lethal oral dose of UN on endochondral ossification, and the latter's response to EHBP treatment. One hundred male Balb/c mice weighing 25 g were assigned to one of ten groups. Group I served as control. Group II received a lethal 350 mg/kg b.w. oral dose of UN by gavage. Groups III, IV, VII, and VIII received an equal dose of UN immediately followed by a single 500 mg/kg oral dose of EHBP in groups III and VII and a single 50 mg/kg subcutaneous dose of EHBP in groups IV and VIII. Groups V and IX only received a single 500 mg/kg oral dose of EHBP, and groups VI and X received a single 50 mg/kg subcutaneous dose of EHBP. The animals in groups II, III, IV, V, and VI were sacrificed 48 h after the onset of the experiment, whereas those in groups VII, VIII, IX, and X were killed at 14 days. Histologic and histomorphometric studies were performed on the femurs to determine growth cartilage width, bone volume, and metaphyseal bone activity. Our results showed that all growth cartilage and metaphyseal bone histomorphometric parameters were significantly lower in animals exposed to UN at 48 h than in controls. EHPB administration was found to prevent this condition at 48 h reaching similar values to those of controls. Although histomorphometric values did not reach control values at 14 days, they were higher than those of animals exposed to UN at 48 h not treated with EHBP. It is noteworthy that these values also decreased in animals only receiving EHBP at 14 days. Our results show that EHBP effectively ameliorates the adverse effects of a lethal dose of UN on endochondral ossification. PMID:15798912

  11. Effect on blood, liver, and kidney variables of age and of dosing rats with lead acetate orally or via the drinking water

    Microsoft Academic Search

    Gary O. Korsrud; J. Blair Meldrum

    1988-01-01

    Levels of lead in the livers and kidneys of rats increased in proportion to the dose of lead acetate that the rats were given\\u000a orally or in the drinking water. The activities of delta-aminolevulinic acid dehydratase (DALAD) in blood and liver decreased\\u000a when the rats were dosed with lead, whereas glutathione levels in the blood increased. The decrease in the

  12. Lack of efficacy of low dose oral interferon alfa in symptomatic HIV1 infection: a randomised, double blind, placebo controlled trial

    Microsoft Academic Search

    E. T. Katabira; N. K. Sewankambo; R. D. Mugerwa; E. M. Belsey; F. X. Mubiru; C. Othieno; P. Kataaha; M. Karam; M. Youle; J. H. Perriens; J. M. A. Lange

    1998-01-01

    BACKGROUND: Interferon alfa (IFN-alpha) exhibits dose related in vitro activity against human immunodeficiency virus (HIV), with complete inhibition of HIV replication at IFN-alpha concentrations > or = 256 IU\\/ml. In mid-1990, Kenyan investigators reported that oral administration of an extremely low dose (150 IU\\/day) of natural human (nHu) IFN-alpha resulted in complete alleviation of AIDS related complex and AIDS symptoms

  13. Effect of Mesalamine and Prednisolone on TNBS Experimental Colitis, following Various Doses of Orally Administered Iron

    PubMed Central

    Triantafillidis, John K.; Douvi, Georgia; Agrogiannis, George; Patsouris, Efstratios; Gikas, Aristofanis; Papalois, Apostolos E.

    2014-01-01

    Background. Experimental data suggest that oral iron (I.) supplementation can worsen colitis in animals. Aim. To investigate the influence of various concentrations of orally administered I. in normal gut mucosa and mucosa of animals with TNBS colitis, as well as the influence of Mesalamine (M.) and Prednisolone (P.) on the severity of TNBS colitis following orally administered I. Methods and Materials. 156 Wistar rats were allocated into 10 groups. Colitis was induced by TNBS. On the 8th day, all animals were euthanatized. Activity of colitis and extent of tissue damage were assessed histologically. The levels of tissue tumor necrosis factor-? (t-TNF-?) and tissue malondialdehyde (t-MDA) were estimated in all animal groups. Results. Moderate and high I. supplementation induced inflammation in the healthy colon and increased the activity of the experimentally induced TNBS colitis. Administration of M. on TNBS colitis following moderate iron supplementation (0.3?g/Kg diet) resulted in a significant improvement in the overall histological score as well as in two individual histological parameters. M. administration, however, did not significantly reduce the t-TNF-? levels (17.67 ± 4.92 versus 14.58 ± 5.71, P = 0.102), although it significantly reduced the t-MDA levels (5.79 ± 1.55 versus 3.67 ± 1.39, P = 0.000). Administration of M. on TNBS colitis following high iron supplementation (3.0?g/Kg diet) did not improve the overall histological score and the individual histological parameters, neither reduced the levels of t-TNF-? (16.57? ± 5.61 versus 14.65 ± 3.88, P = 0.296). However, M. significantly reduced the t-MDA levels (5.99 ± 1.37 versus 4.04 ± 1.41, P = 0.000). Administration of P. on TNBS colitis after moderate iron supplementation resulted in a significant improvement in the overall histological score as well as in three individual histological parameters. P. also resulted in a significant reduction in the t-TNF-? levels (17.67 ± 4.92 versus 12.64 ± 3.97, P = 0.003) and the t-MDA levels (5.79 ± 1.54 versus 3.47 ± 1.21, P = 0.001). Administration of P on TNBS colitis after high I. supplementation resulted in a significant improvement of the overall histological score and three individual histological parameters and significantly reduced the levels of t-TNF-? (16.6 ± 5.6 versus 11.85 ± 1.3, P = 0.001). Conclusion. I. can induce colonic inflammation and aggravate TNBS colitis. M. and P. can significantly improve the inflammatory process in the colonic mucosa in TNBS colitis aggravated by orally administered I. P. has a stable anti-TNF-? effect. These findings suggest that the harmful. PMID:24895596

  14. Duration-dependent effects of clinically relevant oral alendronate doses on cortical bone toughness in beagle dogs.

    PubMed

    Burr, David B; Liu, Ziyue; Allen, Matthew R

    2015-02-01

    Bisphosphonates (BPs) have been shown to significantly reduce bone toughness in vertebrae within one year when given at clinical doses to dogs. Although BPs also reduce toughness in the cortical bone when given at high doses, their effect on cortical bone material properties when given at clinical doses is less clear. In part, this may be due to the use of small sample sizes that were powered to demonstrate differences in bone mineral density rather than the bone's material properties. Our lab has conducted several studies in which dogs were treated with alendronate at a clinically relevant dose. The goal of this study was to examine these published and unpublished data collectively to determine whether there is a significant time-dependent effect of alendronate on toughness of the cortical bone. This analysis seemed particularly relevant given the recent occurrence of atypical femoral fractures in humans. Differences in the toughness of ribs taken from dogs derived from five separate experiments were measured. The dogs were orally administered saline (CON, 1ml/kg/day) or alendronate (ALN) at a clinical dose (0.2mg/kg/day). Treatment duration ranged from 3months to 3years. Groups were compared using ANOVA, and time trends analyzed with linear regression analysis. Linear regressions of the percent difference in toughness between CON and ALN at each time point revealed a significant reduction in toughness with longer exposure to ALN. The downward trend was primarily driven by a downward trend in post-yield toughness, whereas toughness in the pre-yield region was not changed relative to CON. These data suggest that a longer duration of treatment with clinical doses of ALN results in deterioration of cortical bone toughness in a time-dependent manner. As the duration of treatment is lengthened, the cortical bone exhibits increasingly brittle behavior. This may be important in assessing the role that long-term BP treatments play in the risk of atypical fractures of the femoral cortical bone in humans. PMID:25445446

  15. Single oral dose of azithromycin for therapy of susceptible sexually transmitted diseases: a multicenter open evaluation.

    PubMed

    Odugbemi, T; Oyewole, F; Isichei, C S; Onwukeme, K E; Adeyemi-Doro, F A

    1993-01-01

    In three randomised, multicentre studies, azithromycin treatment (1g) as a single dose was administered to patients with uncomplicated gonococcal and non-gonococcal urethritis attending STD Research Laboratories in Lagos, Jos and Ibadan; between January 1989 and December, 1990. One hundred and eighty three patients, comprising 106 males and 77 females who had infections were evaluable at the end of the treatment. Of these 71% of the N. gonorrhoeae isolates were penicillinase producers (PPNG), while 39% were non-PPNG. One hundred and fourteen (95%) of 120 patients with gonococcal urethritis including 104 cases due to penicillinase producing Neiserria gonorrhoeae (PPNG) were clinically and bacteriologically cured with a single 1g dose of azithromycin. Fifty-four (90%) out of 60 patients with non-gonococcal urethritis were cured whilst administered the same dose of azithromycin. The side effects reported for azithromycin were mainly mild and moderate gastro-intestinal complaints and there were no major abnormalities in laboratory parameters. It is concluded that azithromycin was efficacious and safe for the treatment of uncomplicated gonococcal and non-gonococcal infections and may improve patient compliance. PMID:8312208

  16. A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles

    PubMed Central

    Kurosawa, Yuko; Nirengi, Shinsuke; Homma, Toshiyuki; Esaki, Kazuki; Ohta, Mitsuhiro; Clark, Joseph F.; Hamaoka, Takafumi

    2015-01-01

    Our aim was to determine the quantitative effects of a single-dose of Nattokinase (NK) administration on coagulation/fibrinolysis parameters comprehensively in healthy male subjects. A double-blind, placebo-controlled cross-over NK intervention study was carried out in 12 healthy young males. Following the baseline blood draw, each subject was randomized to receive either a single-dose of 2,000 FU NK (NSK-SD, Japan Bio Science Laboratory Co., Ltd) or placebo with subsequent cross-over of the groups. Subjects donated blood samples at 2, 4, 6 and 8?hours following administration for analysis of coagulation/fibrinolysis parameters. As a result, D-dimer concentrations at 6, and 8?hours, and blood fibrin/fibrinogen degradation products at 4?hours after NK administration elevated significantly (p?dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously. PMID:26109079

  17. Tissue distribution of inhaled micro- and nano-sized cerium oxide particles in rats: results from a 28-day exposure study.

    PubMed

    Geraets, Liesbeth; Oomen, Agnes G; Schroeter, Jeffry D; Coleman, Victoria A; Cassee, Flemming R

    2012-06-01

    In order to obtain more insight into the tissue distribution, accumulation, and elimination of cerium oxide nanoparticles after inhalation exposure, blood and tissue kinetics were investigated during and after a 28-day inhalation study in rats with micro- and nanocerium oxide particles (nominal primary particle size: < 5000, 40, and 5-10 nm). Powder aerosolization resulted in comparable mass median aerodynamic diameter (1.40, 1.17, and 1.02 ?m). After single exposure, approximately 10% of the inhaled dose was measured in lung tissue, as was also estimated by a multiple path particle dosimetry model (MPPD). Though small differences in pulmonary deposition efficiencies of cerium oxide were observed, no consistent differences in pulmonary deposition between the micro- and nanoparticles were observed. Each cerium oxide sample was also distributed to tissues other than lung after a single 6-h exposure, such as liver, kidney, and spleen and also brain, testis, and epididymis. No clear particle size-dependent effect on extrapulmonary tissue distribution was observed. Repeated exposure to cerium oxide resulted in significant accumulation of the particles in the (extra)pulmonary tissues. In addition, tissue clearance was shown to be slow, and, overall, insignificant amounts of cerium oxide were eliminated from the body at 48- to 72-h post-exposure. In conclusion, no clear effect of the primary particle size or surface area on pulmonary deposition and extrapulmonary tissue distribution could be demonstrated. This is most likely explained by similar aerodynamic diameter of the cerium oxide particles in air because of the formation of aggregates and irrespective possible differences in surface characteristics. The implications of the accumulation of cerium oxide particles for systemic toxicological effects after repeated chronic exposure via ambient air are significant and require further exploration. PMID:22430073

  18. A Prospective Randomized Trial Comparing Low-Dose Oral Sodium Phosphate Plus Stimulant Laxatives with Large Volume Polyethylene Glycol Solution for Colon Cleansing

    Microsoft Academic Search

    Lawrence C Hookey; William T Depew; Stephen J Vanner

    2004-01-01

    This study examined whether the combination of a single dose (45 ml) oral sodium phosphate (NaP), four bisacodyl tablets (5 mg), and one bisacodyl enema (10 mg) preparation, Fleet Prep Kit 3 (FPK #3), was better tolerated and more efficacious than 4 L polyethylene glycol solution (PEG) for colonic cleansing prior to colonoscopy. One hundred and seventy-one patients were enrolled

  19. An open-label, multicenter study to evaluate Yasmin, a low-dose combination oral contraceptive containing drospirenone, a new progestogen

    Microsoft Academic Search

    Kelly S Parsey; Annpey Pong

    2000-01-01

    This open-label, multicenter study evaluated the efficacy, safety, and cycle control of Yasmin, a new low-dose, monophasic oral contraceptive containing the unique progestogen drospirenone (DRSP) 3 mg and ethinyl estradiol (EE) 30 ?g. DRSP is a synthetic progestogen that has antiandrogenic and antimineralocorticoid effects. In this study, 326 women were evaluated and 220 (67%) completed all 13 treatment cycles. The

  20. Safety, tolerability, and pharmacokinetics of 6-month daily dosing of an oral formulation of cyclosporine (ATOPICA for cats®) in cats

    PubMed Central

    Roberts, E S; VanLare, K A; Strehlau, G; Peyrou, M; Roycroft, L M; King, S

    2014-01-01

    Cyclosporine was proven efficacious in the treatment of feline hypersensitivity dermatitis. This target animal study was conducted to evaluate the safety, tolerability, and pharmacokinetics of ATOPICA for Cats® (cyclosporine oral solution, USP) MODIFIED following 6-month daily dosing in cats. Forty healthy cats (four cats/sex/group) received 0, 8 (1×), 16 (2×), 24 (3×), or 40 (5×) mg/kg cyclosporine once daily for 6 months (183 days). Body weight, food consumption, ophthalmoscopic, physical examinations including neurological assessments, blood pressure, electrocardiography, clinical pathology (hematology, coagulation, clinical chemistry, urinalysis), organ weights, and macroscopic and microscopic examinations were performed and assessed. In addition, blood concentrations of cyclosporine were measured at the pretreatment trough on Days 1, 2, 7, 14, 31, 91, 154, and 182, and post-treatment on Days 1, 31, and 182. Adverse effects possibly related to treatment included prolonged APTT and one report each of bone marrow hypocellularity and lymphoma; all occurred in cats treated with doses more than 16 mg/kg. There was no significant accumulation of cyclosporine beyond the first week of treatment. Results confirm that ATOPICA for Cats is safe and well tolerated in cats without unexpected accumulation beyond the first week of treatment when administered as directed. PMID:24134659

  1. Short-term dose-response relationships for the relative systemic effects of oral prednisolone and inhaled fluticasone in asthmatic adults

    PubMed Central

    Wilson, A M; Lipworth, B J

    1999-01-01

    Aims To determine the systemic dose–response relationships with oral prednisolone and inhaled fluticasone propionate administered in a putative 11:1 mg equivalent basis, in terms of effects on adrenal, bone and haematological markers. Methods Twelve asthmatic patients mean (s.e.) age, 28.8 [3.3] years, FEV1 94.7 [3.6]% predicted, FEF25–75 65.5 [6.1]% predicted were studied in a double-blind, double dummy randomised crossover design comparing placebo, inhaled fluticasone propionate via volumatic spacer given twice a day (ex actuator dose 0.44 mg day?1, 0.88 mg day?1, 1.76 mg day?1) and oral prednisolone given once daily (5 mg day?1, 10 mg day?1, 20 mg day?1). All treatments were for 4 days at each dose level with a 7-day washout at crossover. Measurements were made at 08.00 h after the last dose of each dose level for plasma cortisol, serum osteocalcin and blood eosinophil count. Results There were significant dose-related effects for suppression of all three endpoints with both prednisolone and fluticasone propionate. Parallel slope analysis revealed a calculated dose ratio for relative potency of 8.5:1 mg (95% CI 5.7–11.2) comparing Pred with FP for morning cortisol. The magnitude of suppression with FP was less for osteocalcin and eosinophils than for cortisol. Conclusions Systemic tissues exhibit different dose–response relationships for the effects of inhaled and oral corticosteroids with suppression of cortisol being greater than osteocalcin or eosinophils. For cortisol suppression we observed an 8.5:1 mg relative potency ratio comparing prednisolone with fluticasone propionate. Patients taking high dose inhaled fluticasone propionate should therefore be screened for evidence of impaired adrenal reserve. PMID:10583029

  2. Osteonecrosis following short-term, low-dose oral corticosteroids: a population-based study of 24 million patients.

    PubMed

    Dilisio, Matthew F

    2014-07-01

    Although the association between chronic, high-dose corticosteroid use and osteonecrosis is well known, the incidence of osteonecrosis following short-term, low-dose steroid taper packs has never been reported across a large population. The goal of this study was to report the incidence and risk of osteonecrosis after methylprednisolone taper pack (MTP) prescriptions in a multicenter electronic medical records database. A commercially available software platform was used to evaluate the records of 24,533,880 patients to determine the incidence of osteonecrosis in patients who had received single or multiple MTP over a 12-year period. This was compared with the incidence of osteonecrosis in patients who had never been prescribed an MTP. Patients with a history of osteonecrosis or prior corticosteroid use were excluded from the study. A total of 98,390 patients were identified who had received a single MTP. One hundred thirty (0.132%; 95% confidence interval [CI], 0.176%-0.283%) of these patients were subsequently diagnosed with osteonecrosis. The incidence of osteonecrosis in patients who had been prescribed 2 or more MTPs was 0.230% (95% CI, 0.176%-0.283%). Compared with the 0.083% incidence of osteonecrosis in the control group that had never been prescribed an MTP, the relative risk of osteonecrosis after the prescription of a single MTP or multiple MTPs was 1.591 and 2.763, respectively, with a statistically significant difference between cohorts (P<.001). Short-term, low-dose oral corticosteroid administration may be associated with a low but statistically significant increased incidence of osteonecrosis when compared with patients who have never been prescribed a steroid product. PMID:24992058

  3. Assessing sediment toxicity from navigational pools of the Upper Mississippi River using a 28-day Hyalella azteca test

    USGS Publications Warehouse

    Kemble, N.E.; Brunson, E.L.; Canfield, T.J.; Dwyer, F.J.; Ingersoll, C.G.

    1998-01-01

    To assess the extent of sediment contamination in the Upper Mississippi River (UMR) system after the flood of 1993, sediment samples were collected from 24 of the 26 navigational pools in the river and from one site in the Saint Croix River in the summer of 1994. Whole-sediment tests were conducted with the amphipod Hyalella azteca for 28 days measuring the effects on survival, growth, and sexual maturation. Amphipod survival was significantly reduced in only one sediment (13B) relative to the control and reference sediments. Body length of amphipods was significantly reduced relative to the control and reference sediments in only one sample (26C). Sexual maturation was not significantly reduced in any treatment when compared to the control and reference sediments. No significant correlations were observed between survival, growth, and maturation to either the physical or chemical characteristics of the sediment samples from the river. When highly reliable effect range medians (ERMs) were used to evaluate sediment chemistry, 47 of 49 (96%) of the samples were correctly classified as nontoxic. These results indicate that sediment samples from the Upper Mississippi River are relatively uncontaminated compared to other areas of known contamination in the United States.

  4. Admission Cell Free DNA Levels Predict 28-Day Mortality in Patients with Severe Sepsis in Intensive Care

    PubMed Central

    Almog, Yaniv; Perl, Yael; Novack, Victor; Galante, Ori; Klein, Moti; Pencina, Michael J.; Douvdevani, Amos

    2014-01-01

    Aim The aim of the current study is to assess the mortality prediction accuracy of circulating cell-free DNA (CFD) level at admission measured by a new simplified method. Materials and Methods CFD levels were measured by a direct fluorescence assay in severe sepsis patients on intensive care unit (ICU) admission. In-hospital and/or twenty eight day all-cause mortality was the primary outcome. Results Out of 108 patients with median APACHE II of 20, 32.4% have died in hospital/or at 28-day. CFD levels were higher in decedents: median 3469.0 vs. 1659 ng/ml, p<0.001. In multivariable model APACHE II score and CFD (quartiles) were significantly associated with the mortality: odds ratio of 1.05, p?=?0.049 and 2.57, p<0.001 per quartile respectively. C-statistics for the models was 0.79 for CFD and 0.68 for APACHE II. Integrated discrimination improvement (IDI) analyses showed that CFD and CFD+APACHE II score models had better discriminatory ability than APACHE II score alone. Conclusions CFD level assessed by a new, simple fluorometric-assay is an accurate predictor of acute mortality among ICU patients with severe sepsis. Comparison of CFD to APACHE II score and Procalcitonin (PCT), suggests that CFD has the potential to improve clinical decision making. PMID:24955978

  5. Efficacy and safety of low dose oral prednisolone as compared to pulse intravenous methylprednisolone in managing moderate severe Graves’ orbitopathy: A randomized controlled trial

    PubMed Central

    Roy, Ajitesh; Dutta, Deep; Ghosh, Sujoy; Mukhopadhyay, Pradip; Mukhopadhyay, Satinath; Chowdhury, Subhankar

    2015-01-01

    Background: High dose oral prednisolone (100 mg/day) in Graves’ orbitopathy (GO) is limited by lesser response, and greater side-effects compared to intravenous (iv) methylprednisolone. Low dose oral prednisolone has not been evaluated in GO. This study aimed to evaluate the safety and efficacy of low dose oral prednisolone in GO. Materials and Methods: A total of 114 consecutive GO patients were screened of which 65 patients with previously untreated moderate-severe GO, clinical activity score (CAS) >2, without co-morbid states were randomized into treatment Group-A (iv methylprednisolone 0.5 g for 3 days/month for 4 months) and Group-B (oral prednisolone 1 mg/kg/day for 6 weeks then tapered stopped), and followed-up. Thirty-one patients in each group with at least 1-year follow-up were analyzed. Responders were defined as improvement in ? 1 major response criteria or ? 2 minor response criteria. The trial is registered at ctri.nic.in (CTRI/2013/12/004264). Results: At 1-year, 27/31 (87.10%) patients were responders in Group-A compared to 17/31 (54.84%) in Group-B (P = 0.005). There was a greater improvement in CAS score in patients of Group-A as compared to Group-B (P < 0.001). Responders (n = 44) had significantly higher baseline intra-ocular pressures and left eye proptosis as compared to nonresponders. Cox-regression revealed baseline T4 levels, diplopia, and smoking history were predictive of remission. Low dose prednisolone was well tolerated, and the occurrence of adverse events were comparable in both groups. Conclusions: Low dose oral prednisolone is inferior to iv pulse methylprednisolone in managing GO, having a comparable side-effect profile. It can be a safe second line alternative in patients intolerant to pulse iv methylprednisolone. PMID:25932389

  6. Oral Repeated Dose Toxicity Studies of Coenzyme Q10 in Beagle Dogs

    PubMed Central

    Yerramilli-Rao, Padmaja; Beal, M. Flint; Watanabe, Dai; Kieburtz, Karl; de Blieck, Elisabeth A.; Kitano, Mitsuaki; Hosoe, Kazunori; Funahashi, Iwao; Cudkowicz, Merit E.

    2011-01-01

    To support phase III testing of Coenzyme Q10 (CoQ10) in humans, we conducted pharmacokinetic and toxicology studies in beagle dogs. Following single gavage administration of CoQ10 at 600, 1200, 1800 or 2400mg/kg/day no obvious dose response was observed in maximum concentration (Cmax) or area under the concentration versus time curve (AUC) at the three highest dosages. In a repeated dose study of CoQ10 at 600, 1200, 1800 or 2400mg/kg/day for four weeks, CoQ10 reached steady state in plasma by two weeks at all dosages. Cmax and AUC increased with increasing dosage of CoQ10. The highest plasma levels were recorded at 1800mg/kg/day. In a 39-week chronic toxicity study of CoQ10 at 1200, 1800mg/kg/day or placebo, CoQ10 reached steady state in plasma by 13 weeks. Behaviors, blood chemistries and detailed histopathology were normal. No deaths occurred. These results support the use of a 2400mg/day dosage of CoQ10 in human clinical trials. PMID:22267890

  7. Vaginal impact of the oral administration of total freeze-dried culture of LCR 35 in healthy women.

    PubMed

    Bohbot, J M; Cardot, J M

    2012-01-01

    The use of probiotics in the prevention or treatment of some vaginal infections has been the subject of numerous studies. To assess the presence of Lactobacillus casei rhamnosus (LCR35) in the vagina after an oral administration, an open randomised pilot study was conducted on 20 healthy women of child-bearing age. Materials and Methods. 2 groups of 10 women were given a 28-day oral course, that is, at least 108?CFU/day (group 1) or 2 × 108?CFU/day (group 2) of LCR35. Nugent score and vaginal screening for LCR35 were undertaken before and after 28 days of treatment. Results. The mean Nugent score decreased in group 1 (-0,2) as well as in group 2 (-0,3). 10% of women in group 1 versus 40% of women in group 2 were carrying LCR35 at the end of the trial. Conclusion. LCR35, at the minimal dose of 2 × 108?CFU/day, can return the Nugent score to normal in healthy women of child-bearing age, by means of a well-tolerated vaginal temporary presence. Phase III clinical trials will specify the preventive or curative impact of this orally administered strain on a range of vaginal disorders such as bacterial vaginosis or vulvovaginal candidiasis. PMID:22701297

  8. Effect on Adherence to Nicotine Replacement Therapy of Informing Smokers Their Dose Is Determined by Their Genotype: A Randomised Controlled Trial

    PubMed Central

    Marteau, Theresa M.; Aveyard, Paul; Munafň, Marcus R.; Prevost, A. Toby; Hollands, Gareth J.; Armstrong, David; Sutton, Stephen; Hill, Chloe; Johnstone, Elaine; Kinmonth, Ann Louise

    2012-01-01

    Background The behavioural impact of pharmacogenomics is untested. We tested two hypotheses concerning the behavioural impact of informing smokers their oral dose of NRT is tailored to analysis of DNA. Methods and Findings We conducted an RCT with smokers in smoking cessation clinics (N?=?633). In combination with NRT patch, participants were informed that their doses of oral NRT were based either on their mu-opioid receptor (OPRM1) genotype, or their nicotine dependence questionnaire score (phenotype). The proportion of prescribed NRT consumed in the first 28 days following quitting was not significantly different between groups: (68.5% of prescribed NRT consumed in genotype vs 63.6%, phenotype group, difference ?=? 5.0%, 95% CI ?0.9,10.8, p ?=? 0.098). Motivation to make another quit attempt among those (n ?=? 331) not abstinent at six months was not significantly different between groups (p ?=? 0.23). Abstinence at 28 days was not different between groups (p?=?0.67); at six months was greater in genotype than phenotype group (13.7% vs 7.9%, difference ?=? 5.8%, 95% CI 1.0,10.7, p ?=? 0.018). Conclusions Informing smokers their oral dose of NRT was tailored to genotype not phenotype had a small, statistically non-significant effect on 28-day adherence to NRT. Among those still smoking at six months, there was no evidence that saying NRT was tailored to genotype adversely affected motivation to make another quit attempt. Higher abstinence rate at six months in the genotype arm requires investigation. Trial registration Controlled-Trials.com ISRCTN14352545. PMID:22509402

  9. Pharmacokinetics of single oral dose of pimobendan in Hispaniolan Amazon parrots (Amazona ventralis).

    PubMed

    Guzman, David Sanchez-Migallon; Beaufrčre, Hugues; KuKanich, Butch; Barker, Steven A; Brandăo, Joăo; Paul-Murphy, Joanne; Tully, Thomas N

    2014-06-01

    Pimobendan is a phosphodiesterase (PDE) inhibitor and calcium sensitizer with inotropic, lusitropic, and rasodilator properties used in the treatment of congestive heart failure. The mechanism of action is by inhibition of PDE III and V and by increasing intracellular calcium sensitivity in the cardiac myocardium. Pharmacokinetic and pharmacodynamic studies have been published in humans, dogs, and cats, but there are no studies in avian species. Pimobendan has been used in birds at the empirical dosage of 0.25 mg/kg q12h. To determine the pharmacokinetic parameters of pimobendan in Hispaniolan Amazon parrots (Amazona ventralis), 3 pilot studies with 2 birds, each receiving 1, 3, and 10 mg/kg PO, provided the basis for the pivotal trials with 6 birds, each receiving 10 mg/kg PO using 2 different suspensions. Blood samples were obtained at 0, 0.5, 1, 1.5, 2, 3, 4, 8, 12, and 18 hours after drug administration. Plasma concentrations were determined by liquid chromatography-tandem mass spectrometry (HPLC/MS) by use of electrospray ionization. Because of the erratic and low concentrations of pimobendan, pharmacokinetic parameters were calculated using naive averaged analysis. Plasma concentrations after commercial pimobendan tablet suspension at 10 mg/kg reached a Cmax of 8.26 ng/mL at 3 hours with a terminal half-life of 2.1 hours, while concentrations after the bulk chemical suspension reached a Cmax of 1.28 ng/mL at 12 hours and had a terminal half-life of 2.3 hours. Further studies evaluating the effect of oral pimobendan in parrots are needed. PMID:25115037

  10. Efficacy of short period, low dose oral prednisolone for the prevention of stricture after circumferential endoscopic submucosal dissection (ESD) for esophageal cancer

    PubMed Central

    Kataoka, Mikinori; Anzai, Sho; Shirasaki, Tomoaki; Ikemiyagi, Hidekazu; Fujii, Takashi; Mabuchi, Kazuhisa; Suzuki, Shinji; Yoshida, Masashi; Kawai, Takashi; Kitajima, Masaki

    2015-01-01

    Background and aims: Endoscopic submucosal dissection (ESD) was developed in Japan and has been performed on many patients with early stage esophageal cancer; however quality of life in patients with postoperative stricture is drastically decreased and repeat, periodic endoscopic balloon dilatation (EBD) is usually required over long periods. In this study, we evaluate the efficacy of short period, low dose oral prednisolone in controlling post-procedural esophageal stricture. Patients and methods: In total, 33 patients who underwent semicircular or complete circular ESD for esophageal superficial squamous cell carcinoma were included in this study. They were divided into two groups: those who underwent large-circumference ESD with no preventative treatment for stricture (ESD alone group) and those who received systemic steroid treatment for stricture (oral prednisolone group). We compared the two groups in terms of stricture rate and total number of EBD sessions. The ESD alone group underwent no preventative treatment. The oral prednisolone group started with 30?mg/day prednisolone on the second day post-ESD, and continued with a gradually tapering prednisolone dose, finally discontinuing systemic steroid administration 3 weeks later. Results: The stricture rate after ESD was significantly lower in the oral prednisolone group (3 of 17 patients; 17.6?%) than in the ESD alone group (11 of 16 patients; 68.7?%) (P?oral prednisolone group than in the ESD alone group (median 4.6, range 2?–?10 vs. median 8.1, range 1?–?18; P?dose oral prednisolone showed promising results for the prevention of stricture after ESD for early stage esophageal cancers.

  11. Enhancement of Energy Expenditure following a Single Oral Dose of Flavan-3-Ols Associated with an Increase in Catecholamine Secretion

    PubMed Central

    Matsumura, Yusuke; Nakagawa, Yuta; Mikome, Katsuyuki; Yamamoto, Hiroki; Osakabe, Naomi

    2014-01-01

    Numerous clinical studies have reported that ingestion of chocolate reduces the risk of metabolic syndrome. However, the mechanisms by which this occurs remain unclear. In this murine study, the metabolic-enhancing activity of a 10 mg/kg mixture of flavan-3-ol fraction derived from cocoa (FL) was compared with the same single dose of (-)-epicatechin (EC). Resting energy expenditure (REE) was significantly increased in mice treated with the FL versus the group administered the distilled water vehicle (Cont) during periods of ad libitum feeding and fasting. Mice were euthanized under the effect of anesthesia 2, 5, and 20 hr after treatment with FL or Cont while subsequently fasting. The mRNA levels of the uncoupling protein-1 (UCP-1) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1?) in brown adipose tissue (BAT) were significantly increased 2 hr after administration of FL. UCP-3 and PGC-1? in the gastrocnemius were significantly increased 2 and 5 hr after administration of the FL. The concentrations of phosphorylated AMP-activated protein kinase (AMPK) 1? were found to be significant in the gastrocnemius of mice 2 and 5 hr after ingesting FL. However, these changes were not observed following treatment with EC. Plasma was collected for measurement of catecholamine levels in other animals euthanized by decapitation 2 and 4 hr after their respective group treatment. Plasma adrenaline level was significantly elevated 2 hr after treatment with FL; however, this change was not observed following the administration of EC alone. The present results indicated that FL significantly enhanced systemic energy expenditure, as evidenced by an accompanying increase in the type of gene expression responsible for thermogenesis and lipolysis, whereas EC exhibited this less robustly or effectively. It was suggested the possible interaction between thermogenic and lipolytic effects and the increase in plasma catecholamine concentrations after administration of a single oral dose of FL. PMID:25375880

  12. In vivo effect of single oral dose of artemether against early juvenile stages of Schistosoma mansoni Egyptian strain.

    PubMed

    El-Beshbishi, Samar N; Taman, Amira; El-Malky, Mohamed; Azab, Manar S; El-Hawary, Amira K; El-Tantawy, Dina A

    2013-10-01

    The current treatment and control of schistosomiasis, rely on a single drug, praziquantel, although, it has minor activity against juvenile stages of the parasite. Studies have shown that artemether (ART) exhibits effects against juveniles of Schistosoma mansoni Liberian and Puerto Rican strains, Schistosoma japonicum and Schistosoma haematobium. Aiming to assess the in vivo activity of single oral dose of ART against early juvenile stages of S. mansoni Egyptian strain, this study was established. Mice were treated with ART (400 mg/kg) at two time points evenly spaced over the period of larval development (7 and 21 days post-infection; pi), and a third treatment point (day 49 pi) was included to elucidate when susceptibility decreases. Administration of ART on day 7 pi reduced the total worm burden by 85.94%. The greatest reductions were seen when treatment was given on day 21 pi, with total and female worm burden reductions of 91.52% and 90.57%, respectively, and cessation of oviposition. Similar dose given on day 49 pi reduced total worm burden by 55.17% and female worm burden by 66.51%. Moreover, it induced significant reduction in the tissue egg load and significant alterations in the oogram pattern with decreased immature eggs and increased dead eggs. Antipathological activities were evident in significant reductions in granulomata count and diameter. In conclusion, ART exhibits major in vivo schistosomicidal effects against the early larval migratory stages of S. mansoni Egyptian strain, mainly the 21-day old schistosomula, hence preventing disease progression and morbidity. PMID:23876575

  13. Pharmacokinetics and serum bactericidal titers of ciprofloxacin and ofloxacin following multiple oral doses in healthy volunteers.

    PubMed Central

    Israel, D; Gillum, J G; Turik, M; Harvey, K; Ford, J; Dalton, H; Towle, M; Echols, R; Heller, A H; Polk, R

    1993-01-01

    Fourteen adult males participated in a randomized three-way crossover study to compare the pharmacokinetics and serum bactericidal titers (SBTs) of 500 mg of ciprofloxacin (regimen A), 750 mg of ciprofloxacin (regimen B), and 400 mg of ofloxacin (regimen C) administered every 12 h for seven doses. Mean steady-state peak concentrations in serum for regimens A, B, and C were 3.0, 4.4, and 6.5 micrograms/ml, respectively (P < 0.01, all comparisons) and mean half-lives were 4.5, 4.3, and 6.5 h, respectively (P < 0.05, C versus A and B). Mean steady-state areas under the concentration-time curve were 14.1, 21.1, and 48.1 micrograms/h/ml for regimens A, B, and C, respectively (P < 0.05, all comparisons). SBTs were determined at different times postdose for three isolates each of Streptococcus pneumoniae, Staphylococcus aureus, Escherichia coli, Enterobacter cloacae, and Pseudomonas aeruginosa. Mean steady-state peak SBTs for regimens A, B, and C, respectively, were as follows: S. pneumoniae, < 1:2, 1:8, 1:8, S. aureus, 1:16, 1:16, 1:16; E. coli, 1: > or = 128, 1: > or = 128, 1:64; E. cloacae, 1: > or = 128, 1: > or = 128, 1:64; P. aeruginosa, 1:8, 1:8, 1:2. These differences in SBTs within each genus were statistically significant. The majority of predicted SBTs were within one dilution of measured SBTs. Areas under the serum bactericidal time curves for E. coli, E. cloacae, and P. aeruginosa were significantly higher for ciprofloxacin; areas under the serum bactericidal time curves for S. pneumoniae and S. aureus were significantly greater for ofloxacin. Ofloxacin achieved higher concentrations in serum than ciprofloxacin, but differences in in vitro activity were a more important determinant of SBTs. PMID:8257144

  14. Comparison of orally dissolving carbidopa/levodopa (Parcopa) to conventional oral carbidopa/levodopa: A single dose, double-blind, double-dummy, placebo-controlled, cross-over trial

    E-print Network

    Lichtarge, Olivier

    /levodopa: A single dose, double-blind, double-dummy, placebo-controlled, cross-over trial William G. Ondo, MD,* Lina the active drug and the placebo. They first swallowed the oral C/L then placed the OD C/L in their mouth. At the same time on the second day the active and placebo drugs were reversed and subjects underwent identical

  15. Oral integrity and salivary profile in myeloma patients undergoing high-dose therapy followed by autologous SCT.

    PubMed

    Avivi, I; Avraham, S; Koren-Michowitz, M; Zuckerman, T; Aviv, A; Ofran, Y; Benyamini, N; Nagler, A; Rowe, J M; Nagler, R M

    2009-05-01

    The underlying mechanism of high-dose therapy (HDT)-related oral mucositis (OM) may be partly mediated by alterations in the normal salivary composition. This study evaluated salivary antioxidant and immunological capacities observed in myeloma patients suffering from HDT-related OM, and assessed potential contribution of these factors to OM development. Twenty-five consecutive myeloma patients treated with melphalan 200 mg/m(2) followed by autologous SCT were enrolled. Patients underwent a daily assessment for OM, and salivary samples were collected on days -3 and +7 of transplantation and analyzed for secretory IgA and antioxidant capacity. The degree of mucosal damage was assessed by measuring the salivary carbonyl and albumin (Alb) levels. OM, reported in 96% of patients, appeared to be most severe on 8 day after transplantation (range: +2 to +14). Clinical mucositis was associated with significant reduction in salivary secretory IgA (54%; P=0.05), and antioxidant activity, measured by total antioxidant status (40%; P=0.0004), antioxidant capacity (ImAnOx) (23%; P=0.002) and uric acid level (51%; P=0.006). The increase found in salivary Alb (119%; P=0.024) and carbonyl (28%; P=0.047) levels, indicates mucosal and oxidative damage, respectively. These salivary changes might enhance mucositis development and symptoms. Therapeutic interventions, enhancing antioxidative and immunological activities need to be investigated. PMID:19029961

  16. Effect of single-dose oral artemether and tribendimidine on the tegument of adult Clonorchis sinensis in rats.

    PubMed

    Xiao, Shu-Hua; Keiser, Jennifer; Xue, Jian; Tanner, Marcel; Morson, Gianni; Utzinger, Jürg

    2009-02-01

    The tegument of trematodes plays a key role in nutrient absorption, exerts secretory functions, protects the parasite against the immune system of the host, and is a target for anti-trematocidal drugs. We performed a temporal examination of tegumental changes following artemether and tribendimidine administration on adult Clonorchis sinensis in rats using scanning electron microscopy. Rats infected with C. sinensis for 6 weeks were treated orally with a single dose of artemether (150 mg/kg) or tribendimidine (300 mg/kg). Worms were collected between 8 h and 7 days (artemether) and between 4 h and 2 days post-treatment (tribendimidine). Worms recovered from untreated rats served as controls. Eight hours after artemether administration, the tegument of C. sinensis was extensively disrupted, including severe swelling, fusion and vacuolization, and the suckers were damaged. Four hours after administration of tribendimidine, C. sinensis worms showed extensive tegumental alterations, characterized by massive sloughing, and the suckers were damaged. Interestingly, the severity of tegumental changes did not progress further with time. Our results show that both artemether and tribendimidine rapidly disrupt the tegument and damage the suckers of adult C. sinensis. The subtle differences in tegumental changes induced by artemether and tribendimidine might indicate different mechanisms of action of these drugs against C. sinensis. PMID:18975004

  17. Residue depletion of nitrofuran drugs and their tissue-bound metabolites in channel catfish (Ictalurus punctatus) after oral dosing.

    PubMed

    Chu, Pak-Sin; Lopez, Mayda I; Abraham, Ann; El Said, Kathleen R; Plakas, Steven M

    2008-09-10

    The depletion of the nitrofuran drugs furazolidone, nitrofurazone, furaltadone, and nitrofurantoin and their tissue-bound metabolites [3-amino-2-oxazolidinone (AOZ), semicarbazide (SC), 3-amino-5-morpholinomethyl-2-oxazolidinone (AMOZ), and 1-aminohydantoin (AH), respectively] were examined in the muscle of channel catfish following oral dosing (1 mg/kg body weight). Parent drugs were measurable in muscle within 2 h. Peak levels were found at 4 h for furazolidone (30.4 ng/g) and at 12 h for nitrofurazone, furaltadone, and nitrofurantoin (104, 35.2, and 9.8 ng/g respectively). Parent drugs were rapidly eliminated from muscle, and tissue concentrations fell below the limit of detection (1 ng/g) at 96 h. Peak levels of tissue-bound AMOZ and AOZ (46.8 and 33.7 ng/g respectively) were measured at 12 h, and of SC and AH (31.1 and 9.1 ng/g, respectively) at 24 h. Tissue-bound metabolites were measurable for up to 56 days postdose. These results support the use of tissue-bound metabolites as target analytes for monitoring nitrofuran drugs in channel catfish. PMID:18698789

  18. A Double-Blind, Placebo-Controlled Evaluation of the Effect of Oral Doses of Rizatriptan 10 mg on Oral Contraceptive Pharmacokinetics in Healthy Female Volunteers

    Microsoft Academic Search

    Craig R. Shadle; Guanghan Liu; Michael R. Goldberg

    2000-01-01

    Rizatriptan (MAXALTTM), a potent, oral 5-HT,1B\\/1D agonist with a rapid onset of action, is available now for the acute treatment of migraine. This study examined the pharnacokinetic and clinical interaction between rizatriptan 10 mg and the components (ethinyl estradiol [EE] 35 &mgr;g and norethindrone [NET] 1.0 mg) of a well-established oral contraceptive combination product, ORTHO-NOVUM 1\\/35. Levels of sex hormone

  19. Assessment of oral toxicity and safety of pentamethylchromanol (PMCol), a potential chemopreventative agent, in rats and dogs.

    PubMed

    Lindeblad, Matthew; Kapetanovic, Izet M; Kabirov, Kasim K; Detrisac, Carol J; Dinger, Nancy; Mankovskaya, Irina; Zakharov, Alexander; Lyubimov, Alexander V

    2010-06-29

    2,2,5,7,8-Pentamethyl-6-chromanol (PMCol) was administered by gavage in rats for 28 days at dose levels of 0, 100, 500, and 2000mg/kg/day. PMCol administration induced decreases in body weight gains and food consumption, hepatotoxicity (increased TBILI, ALB, ALT, TP; increased relative liver weights; increased T4 and TSH), nephrotoxicity (increased BUN and BUN/CREAT, histopathology lesions), effect on lipid metabolism (increased CHOL), anemia, increase in WBC counts (total and differential), coagulation (FBGN upward arrow and PT downward arrow) and hyperkeratosis of the nonglandular stomach in the 2000mg/kg/day dose group (in one or both sexes). In the 500mg/kg/day dose group, toxicity was seen to a lesser extent. In the 100mg/kg/day dose group, only increased CHOL (females) was observed. To assess the toxicity of PMCol in male dogs it was administered orally by capsule administration for 28 days at dose levels of 0, 50, 200 and 800mg/kg/day (four male dogs/dose group). PMCol treatment at 800mg/kg/day resulted in pronounced toxicity to the male dogs. Target organs of toxicity were liver and thymus. Treatment at 200mg/kg/day resulted in toxicity consistent with slight adverse effect on the liver only. The results of the safety pharmacology study indicate that doses of 0, 50, 200 and 800mg/kg administered orally did not have an effect on the QT interval, blood pressures and body temperatures following dosing over a 24-h recording period. Under the conditions of this study, the no-observed-adverse effect level (NOAEL) for daily oral administration of PMCol by gavage for 28 days to male rats was 100mg/kg/day and 50mg/kg in male dogs. In female rats, the NOAEL was not established due to statistically significant and biologically meaningful increases in CHOL level seen in the 100mg/kg/day dose group. The results of these studies indicated that administration of PMCol at higher dose levels resulted in severe toxicity in dogs and moderate toxicity in rats, however, administration at lower levels is considered to be less likely to result in toxicity following 28 days of exposure. Sex-related differences were seen in rats. Male rats appeared to have greater sensitivity to nephrotoxicity, while female animals had a greater incidence of hepatoxicity and changes in hematological parameters evaluated, especially at a dose of 500mg/kg/day, which correlated to the higher plasma drug levels in female rats. It appeared that dogs were generally more sensitive than rats to oral administration of PMCol. Further examination of the potential toxic effects of PMCol in longer term studies is required prior to understanding the full risks of PMCol administration as a chemopreventative agent. PMID:20430063

  20. Assessment of Oral Toxicity and Safety of Pentamethylchromanol (PMCol), A Potential Chemopreventative Agent, in Rats and Dogs

    PubMed Central

    Lindeblad, Matthew; Kapetanovic, Izet M.; Kabirov, Kasim K.; Detrisac, Carol J.; Dinger, Nancy; Mankovskaya, Irina; Zakharov, Alexander; Lyubimov, Alexander V.

    2010-01-01

    2,2,5,7,8-pentamethyl-6-chromanol (PMCol) was administered by gavage in rats for 28 days at dose levels of 0, 100, 500, and 2000 mg/kg/day. PMCol administration induced decreases in body weight gains and food consumption, hepatotoxicity (increased TBILI, ALB, ALT, TP; increased relative liver weights; increased T4 and TSH), nephrotoxicity (increased BUN and BUN/CREAT, histopathology lesions), effect on lipid metabolism (increased CHOL), anemia, increase in WBC counts (total and differential), coagulation (FBGN?and PT?) and hyperkeratosis of the nonglandular stomach in the 2000 mg/kg/day dose group (in one or both sexes). In the 500 mg/kg/day dose group, toxicity was seen to a lesser extent. In the 100 mg/kg/day dose group, only increased CHOL (females) was observed. To assess the toxicity of PMCol in male dogs it was administered orally by capsule administration for 28 days at dose levels of 0, 50, 200 and 800 mg/kg/day (4 male dogs/dose group). PMCol treatment at 800 mg/kg/day resulted in pronounced toxicity to the male dogs. Target organs of toxicity were liver and thymus. Treatment at 200 mg/kg/day resulted in toxicity consistent with slight adverse effect on the liver only. The results of the safety pharmacology study indicate that doses of 0, 50, 200 and 800 mg/kg administered orally did not have an effect on the QT interval, blood pressures and body temperatures following dosing over a 24-hour recording period. Under the conditions of this study, the no-observed-adverse effect level (NOAEL) for daily oral administration of PMCol by gavage for 28 days to male rats was 100 mg/kg/day and 50 mg/kg in male dogs. In female rats, the NOAEL was not established due to statistically significant and biologically meaningful increases in CHOL level seen in the 100 mg/kg/day dose group. The results of these studies indicated that administration of PMCol at higher dose levels resulted in severe toxicity in dogs and moderate toxicity in rats, however, administration at lower levels is considered to be less likely to result in toxicity following 28 days of exposure. Sex-related differences were seen in rats. Male rats appeared to have greater sensitivity to nephrotoxicity, while female animals had a greater incidence of hepatoxicity and changes in hematological parameters evaluated, especially at a dose of 500 mg/kg/day, which correlated to the higher plasma drug levels in female rats. It appeared that dogs were generally more sensitive than rats to oral administration of PMCol. Further examination of the potential toxic effects of PMCol in longer term studies is required prior to understanding the full risks of PMCol administration as a chemopreventative agent. PMID:20430063

  1. An oral DNA vaccine against infectious haematopoietic necrosis virus (IHNV) encapsulated in alginate microspheres induces dose-dependent immune responses and significant protection in rainbow trout (Oncorrhynchus mykiss).

    PubMed

    Ballesteros, Natalia A; Alonso, Marta; Saint-Jean, Sylvia Rodríguez; Perez-Prieto, Sara I

    2015-08-01

    Administered by intramuscular injection, a DNA vaccine (pIRF1A-G) containing the promoter regions upstream of the rainbow trout interferon regulatory factor 1A gene (IRF1A) driven the expression of the infectious hematopoietic necrosis virus (IHNV) glycoprotein (G) elicited protective immune responses in rainbow trout (Oncorhynchus mykiss). However, less laborious and cost-effective routes of DNA vaccine delivery are required to vaccinate large numbers of susceptible farmed fish. In this study, the pIRF1A-G vaccine was encapsulated into alginate microspheres and orally administered to rainbow trout. At 1, 3, 5, and 7 d post-vaccination, IHNV G transcripts were detected by quantitative real-time PCR in gills, spleen, kidney and intestinal tissues of vaccinated fish. This result suggested that the encapsulation of pIRF1A-G in alginate microparticles protected the DNA vaccine from degradation in the fish stomach and ensured vaccine early delivery to the hindgut, vaccine passage through the intestinal mucosa and its distribution thought internal and external organs of vaccinated fish. We also observed that the oral route required approximately 20-fold more plasmid DNA than the injection route to induce the expression of significant levels of IHNV G transcripts in kidney and spleen of vaccinated fish. Despite this limitation, increased IFN-1, TLR-7 and IgM gene expression was detected by qRT-PCR in kidney of vaccinated fish when a 10 ?g dose of the oral pIRF1A-G vaccine was administered. In contrast, significant Mx-1, Vig-1, Vig-2, TLR-3 and TLR-8 gene expression was only detected when higher doses of pIRF1A-G (50 and 100 ?g) were orally administered. The pIRF1A-G vaccine also induced the expression of several markers of the adaptive immune response (CD4, CD8, IgM and IgT) in kidney and spleen of immunized fish in a dose-dependent manner. When vaccinated fish were challenged by immersion with live IHNV, evidence of a dose-response effect of the oral vaccine could also be observed. Although the protective effects of the oral pIRF1A-G vaccine after a challenge with IHNV were partial, significant differences in cumulative percent mortalities among the orally vaccinated fish and the unvaccinated or empty-plasmid vaccinated fish were observed. Similar levels of protection were obtained after the intramuscular administration of 5 ?g of pIRF1A-G or after the oral administration of a high dose of pIRF1A-G vaccine (100 ?g); with 70 and 56 relative percent survival values, respectively. When fish were vaccinated with alginate microspheres containing high doses of the pIRF1A-G vaccine (50 or 100 ?g), a significant increase in the production of anti-IHNV antibodies was detected in serum samples of the vaccinated fish compared with that in unvaccinated fish. At 10 days post-challenge, IHNV N gene expression was nearly undetectable in kidney and spleen of orally vaccinated fish which suggested that the vaccine effectively reduced the amount of virus in tissues of vaccinated fish that survived the challenge. In conclusion, our results demonstrated a significant increase in fish immune responses and resistance to an IHNV infection after the oral administration of increasing concentrations of a DNA vaccine against IHNV encapsulated into alginate microspheres. PMID:26054788

  2. CYP4F2 1347 G>A & GGCX 12970 C>G polymorphisms: frequency in north Indians & their effect on dosing of acenocoumarol oral anticoagulant

    PubMed Central

    Rathore, Saurabh Singh; Agarwal, Surendra Kumar; Pande, Shantanu; Singh, Sushil Kumar; Mittal, Tulika; Mittal, Balraj

    2014-01-01

    Background & objectives: CYP4F2 and ?-glutamyl carboxylase (GGCX) have small but significant roles in the maintenance dose of coumarinic oral anticoagulants (COAs). CYP4F2 1347 G>A and GGCX 12970 C>G polymorphisms have been used in the pharmacogenetic dosing algorithms of warfarin for Caucasians and Chinese populations. India has a large population with multiple ethnic groups but there are no reports about the frequencies of these polymorphisms in north Indians. In the present study, we aimed to find out the allelic frequencies of CYP4F2 1347 G>A and GGCX 12970 C>G polymorphisms in a north Indian population and relate these to daily maintenance drug dose requirements of COA. Methods: CYP4F2 1347 G>A and GGCX 12970 C>G polymorphisms were genotyped by polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP) protocols and Taqman SNP discrimination assays in healthy volunteers (n=102) and patients (n=225) receiving acenocoumarol, an oral anticoagulant, after cardiac valve replacement surgery. Results: In healthy volunteers, the allele frequencies for CYP4F2 1347 G>A and GGCX 12970 C>G were 43.14 and 1.43 per cent, respectively. No significant differences in mean weight normalized doses of acenocoumarol were found for these CYP4F2 and GGCX genotypes. Binary logistic regression analysis revealed no significant association of any of the genotypes or alleles with the dosing phenotypes for both the SNPs. Interpretation & conclusions: We report distinct frequencies of CYP4F2 1347 G>A and GGCX 12970 C>G polymorphisms in north Indians but these polymorphisms did not have significant bearing on maintenance dose of acenocoumarol oral anticoagulant in cardiac valve replacement patients. PMID:24927344

  3. Nomegestrol acetate/estradiol: in oral contraception.

    PubMed

    Yang, Lily P H; Plosker, Greg L

    2012-10-01

    Nomegestrol acetate/estradiol is a combined oral contraceptive with approval in many countries. This fixed-dose combination tablet contains nomegestrol acetate, a highly selective progestogen, and estradiol, a natural estrogen. It is the first monophasic combined oral contraceptive to contain estradiol, and is taken in 28-day cycles, consisting of 24 active therapy days with 4 placebo days (i.e. 24/4-day cycles). In two large, 1-year, randomized, open-label, multicentre, phase III trials in healthy adult women (aged 18-50 years), nomegestrol acetate/estradiol was at least as effective as drospirenone/ethinylestradiol as contraceptive therapy, as the pregnancy rates in women aged 18-35 years (primary efficacy population) in terms of the Pearl Index (primary endpoint) were numerically lower with nomegestrol acetate/estradiol, although the between-group difference was not statistically significant. In both trials, nomegestrol acetate/estradiol was given in a 24/4-day cycle, and drospirenone/ethinylestradiol was given in a 21/7-day cycle. The criteria for using condoms in case of forgotten doses were less stringent in the nomegestrol acetate/estradiol group than in the drospirenone/ethinylestradiol group. Nomegestrol acetate/estradiol therapy for up to 1 year was generally well tolerated in healthy adult women, with an acceptable tolerability profile in line with that expected for a combined oral contraceptive. The most commonly reported adverse events were acne and abnormal withdrawal bleeding (most often shorter, lighter or absent periods). Overall, compared with drospirenone/ethinylestradiol, nomegestrol acetate/estradiol appeared to be associated with less favourable acne-related outcomes, and shorter, lighter or absent periods. PMID:22950535

  4. [A fifty two-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T) in dogs].

    PubMed

    Aoki, M; Ohtaki, T; Seki, T; Kojima, K; Yoshimura, S; Ikeda, H; Kawaguchi, H; Katsumura, H; Yamaguchi, K; Inada, H

    1992-05-01

    A 52-week oral repeated dose toxicity study of suplatast tosilate (IPD-1151T), a newly developed anti-allergic agent, was carried out in beagles by oral administration of 30, 90, 270 and 810 mg/kg/day for 52 weeks. The recovery study was carried out by the withdrawal for 5 weeks using control and the 810 mg/kg groups. The results are as follows: 1. Observation of general conditions revealed soft feces, mucous feces, and diarrhea in both sexes of the 270 and 810 mg/kg groups during the administration period, and these findings disappeared during the withdrawal period. One female of the 810 mg/kg group exhibited tremors in the legs and neck, staggering, a decrease of spontaneous motor activity, and clonic convulsions in Week 17 of administration and died on Day 118. One male of the same group exhibited whole body tremors and staggering from Week 32 to Week 52. 2. Body weight gain tended to be inhibited in males of the 810 mg/kg group during the administration period. The body weight of the female that died decreased rapidly after the appearance of neurological symptoms. The body weight of the male that exhibited neurological symptoms decreased after their appearance but later increased. 3. There were no abnormal changes in food consumption in all of the sacrificed dogs. The female that died did not eat at all after the appearance of neurological symptoms. The male that exhibited neurological symptoms did not eat at all for 1 week after their appearance, but the food consumption returned to normal thereafter. 4. Prothrombin times were prolonged in males of the 270 and 810 mg/kg groups at Week 26, and activated partial thromboplastin times were prolonged in males of the 810 mg/kg group at Week 52. 5. Plasma levels of alkaline phosphatase, GPT and LDH were elevated in some males and females of the 810 mg/kg groups. 6. No abnormalities due to IPD-1151T administration were found in urinalysis, opthalmological examination, electrocardiography, and fecal occult blood examination, or organ weights. 7. Autopsies including histopathological and electron microscopic examinations on the sacrificed dogs revealed no abnormalities. Subserosal hemorrhage in the base of the heart, congestion in the lungs, congestion and vacuolation in the liver and slight cell infiltration around vessels of the brain were found in the female that died.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:1321256

  5. Repeated dose liver and gastrointestinal tract micronucleus assays using N-methyl-N'-nitro-N-nitrosoguanidine in young adult rats.

    PubMed

    Takayanagi, Tomomi; Wako, Yumi; Kawasako, Kazufumi; Hori, Hisako; Fujii, Wataru; Ohyama, Wakako

    2015-03-01

    N-Methyl-N'-nitro-N-nitrosoguanidine (MNNG) is a direct-acting mutagen that induces tumors in the glandular stomach, but not in the liver or colon, of rats after oral administration. To evaluate the performance of repeated dose liver and gastrointestinal tract micronucleus (MN) assays in young adult rats, MNNG was administered by oral gavage to male CD (SD) rats aged 6 weeks at doses of 0 (vehicle; 2.5% DMSO aqueous solution), 3.125, 6.25, 12.5, and 25mg/kg/day once daily for 14 and 28 days, and the MN frequencies were examined in the hepatocytes, glandular stomach cells, and colonic cells. The MN induction in immature erythrocytes in the bone marrow of these animals was also simultaneously evaluated. The frequencies of micronucleated (MNed) glandular stomach cells were significantly increased in all MNNG treatment groups in a dose-dependent manner in both repeated dose studies. In contrast, the frequencies of MNed hepatocytes and colonic cells were not significantly increased compared to the vehicle control. In the bone marrow, a small but significant increase in the frequency of MNed immature erythrocytes was observed only at the highest dose in the 28-day study. Since a clear positive result in the glandular stomach agrees with the tissue specificity of tumor induction by this chemical, the MN assay with the glandular stomach, which is a direct contact site with high concentrations of test substances administered by oral gavage, may be useful for detecting genotoxic compounds that are short-lived in vivo, such as MNNG. PMID:25892628

  6. Toxicity of weekly oral topotecan in relation to dosage for gynecologic malignancies: a phase I study

    PubMed Central

    von Gruenigen, Vivian E.; Frasure, Heidi E.; Smith, Deborah A.; Fusco, Nancy L.; Eaton, Susan M.; DeBernardo, Robert L.; Heugeland, Anne M.; Waggoner, Steven E.

    2015-01-01

    The aim of this study was to determine the dose of weekly oral topotecan that allows safe administration and to evaluate the pharmacokinetics of this dose in patients with recurrent gynecologic malignancies. The first cohort of patients received oral topotecan 6 mg/week administered orally on days 1, 8, and 15 of a 28-day regimen. A standard 3 + 3 dose-escalating phase design was used for dose levels II–V (8, 10, 12 and 14 mg/week). Toxicity was scored according to the Common Terminology Criteria for Adverse Events. Cumulative toxicity was summarized in the 6–12 mg/week combined cohort and 14 mg/week cohort separately. Pharmacokinetic samples were obtained for day 1, cycle 1 only in the expansion cohort (dose level V). Twenty-five patients received a total of 88 cycles of therapy. Hematologic toxicities of grade 3 (6–12 mg dose) were neutropenia (25%) and anemia (8.3%). Gastrointestinal toxicities of grade 3 were diarrhea (16.7%) and obstruction (8.3%, disease-related). Grade 3 or 4 (14 mg/week) hematologic toxicities consisted of neutropenia (38.5%), platelets (15.4%), anemia (15.4%), infection with neutropenia (7.7%), and thrombosis (7.7%). Gastrointestinal toxicities of grade 3 were diarrhea (7.7%), obstruction (7.7%), and vomiting (7.7%). One patient died secondary to neutropenic sepsis. One patient (4%; 95% confidence interval: 2.1, 22.3) showed a partial response and five patients (20%; 95% confidence interval: 7.6, 41.3) had stable disease. An oral topotecan dose of 14 mg/week for 3 consecutive weeks out of 4 is mostly associated with acceptable toxicities and may be considered for use in future single-agent phase II trials. PMID:22555194

  7. New metabolites of di(2-ethylhexyl)phthalate (DEHP) in human urine and serum after single oral doses of deuterium-labelled DEHP

    Microsoft Academic Search

    Holger M. Koch; Hermann M. Bolt; Ralf Preuss; Jürgen Angerer

    2005-01-01

    The metabolism of di(2-ethylhexyl)phthalate (DEHP) in humans was studied after three doses of 0.35 mg (4.7 ?g\\/kg), 2.15 mg (28.7 ?g\\/kg) and 48.5 mg (650 ?g\\/kg) of D4-ring-labelled DEHP were administered orally to a male volunteer. Two new metabolites, mono(2-ethyl-5-carboxypentyl)phthalate (5cx-MEPP) and mono[2-(carboxymethyl)hexyl]phthalate (2cx-MMHP) were monitored for 44 h in urine and for 8 h in serum for the high-dose case, in addition to the three metabolites previously

  8. Di(2-ethylhexyl)phthalate (DEHP) metabolites in human urine and serum after a single oral dose of deuterium-labelled DEHP

    Microsoft Academic Search

    Holger M. Koch; Hermann M. Bolt; Jürgen Angerer

    2004-01-01

    Human metabolism of di(2-ethylhexyl)phthalate (DEHP) was studied after a single oral dose of 48.1 mg to a male volunteer. To avoid interference by background exposure the D4-ring-labelled DEHP analogue was dosed. Excretion of three metabolites, mono(2-ethyl-5-hydroxyhexyl)phthalate (5OH-MEHP), mono(2-ethyl-5-oxohexyl)phthalate (5oxo-MEHP) and mono(2-ethylhexyl)phthalate (MEHP), was monitored for 44 h in urine and for 8 h in serum. Peak concentrations of all metabolites were found in

  9. Pharmacokinetics and tolerance of a new film-coated tablet of sodium fusidate administered as a single oral dose to healthy volunteers.

    PubMed

    MacGowan, A P; Greig, M A; Andrews, J M; Reeves, D S; Wise, R

    1989-03-01

    Single oral doses of 250, 500, 750 and 1000 mg of sodium fusidate as one, two, three and four film-coated 250 mg tablets were compared in a cross over design trial with a solution dose of 500 mg in 12 healthy male volunteers. The effect of food on absorption of two-film coated tablets was also studied. Compared with the dose given as a solution, tablets gave complete oral absorption, the area under the curve (AUC) for blood concentration being virtually identical. After administration of 250, 500, 750 and 1000 mg the mean of the maximum serum concentrations (Cmax) was 11.6 +/- 1.1, 30.6 +/- 2.2, 48.1 +/- 3.0 and 65.2 +/- 4.2 mg/l, respectively, indicating a greater than expected increase in Cmax with increasing dose. This was also apparent with AUC, while there was a significant trend for beta, the terminal slope of the serum/concentration time curve, to decrease. Food significantly reduced Cmax and delayed Tmax but did not affect AUC or beta. Dosage had no effect on parameters of renal, hepatic or haemopoietic function but 25% of the volunteers complained of upper gastro-intestinal symptoms mainly at the highest dose studied. PMID:2732122

  10. Differential Cytokine mRNA Expression in Mice after Oral Exposure to the Trichothecene Vomitoxin (Deoxynivalenol): Dose Response and Time Course

    Microsoft Academic Search

    Hui-Ren Zhou; Ding Yan; James J. Pestka

    1997-01-01

    Acute oral exposure of B6C3F1 mice to vomitoxin (VT) has been previously shown to induce expression of mRNAs for cytokines that are characteristically produced in lymphoid tissues by macrophage and T cells. The purpose of this study was to evaluate the effects of VT dose on the expression of mRNAs for a cytokine profile consisting of TNF-?, IL-1?, IL-6, IL-12,

  11. Efficacy trial of single-dose live oral cholera vaccine CVD 103-HgR in North Jakarta, Indonesia, a cholera-endemic area

    Microsoft Academic Search

    Emily Richie; Narain H Punjabi; Yuwono Sidharta; Kenny Peetosutan; Melanie Sukandar; Steven S Wasserman; Murad Lesmana; Ferry Wangsasaputra; Sri Pandam; Myron M Levine; Peter O’Hanley; Cyrus H Simanjuntak

    2000-01-01

    A randomized, double-blind, placebo-controlled efficacy trial of one dose of CVD 103-HgR live oral cholera vaccine was performed in Indonesia from 1993 to 1997. 67,508 persons aged 2–41 years ingested vaccine or placebo and were followed for four years, detecting cholera cases using hospital-based surveillance. A nested reactogenicity study (538 vaccinees, 535 controls) revealed no vaccine-attributable side effects. A nested

  12. A comparative study between the efficacy of oral cimetidine and low-dose systemic meglumine antimoniate (MA) with a standard dose of systemic MA in the treatment of cutaneous leishmaniasis.

    PubMed

    Shanehsaz, Siavash M; Ishkhanian, Silva

    2015-07-01

    Cutaneous leishmaniasis (CL) is a major world health problem, which is increasing in incidence. Pentavalent antimonials have been considered as standard treatment for leishmaniasis. Many studies are performed to find an effective and safe treatment for patients with CL. The aim of this study was to compare the effect of oral cimetidine and low-dose systemic meglumine antimoniate (MA) with standard dose of systemic MA in the treatment of CL. This study was, to our knowledge, the first to show the effect of combination therapy oral cimetidine and MA in the treatment of CL all over the world. In this randomized double-blind placebo-controlled clinical trial, 120 patients with suspected CL were referred to the Aleppo University Hospital Clinic; 90 of these patients with the clinical and parasitological diagnosis of CL were recruited and were randomly divided into three treatment groups of 30 subjects each. Group A was treated with MA 60 mg/kg/d IM and oral placebo. Groups B and C received MA 30 mg/kg/d IM and oral cimetidine 1200 mg/d, MA 30 mg/kg/d IM and oral placebo, respectively. The duration of treatment was three weeks for all groups. The effectiveness of the treatment was classified in three levels as complete response, partial response, and no response. Data were analyzed by SPSS 19 using KI square, Mann-Whitney, Kaplan-Mayer, and ANOVA tests. At the end of the study (12 weeks), the rate of complete response was 91.11% in the first group, and 84.66% and 78.33% in groups B and C, respectively (P < 0.05). The highest response rate was for the group treated with a standard dose of systemic MA and placebo. Our results showed that although oral cimetidine and low-dose systemic MA had less efficacy in comparison to a standard dose of systemic MA in the treatment of CL, it still can be considered as a replacement therapy in high-risk patients (such as patients with heart, kidney, and/or liver disease) under close supervision of physicians. PMID:26108265

  13. Effects of high-dose major components in oral disinfectants on the cell cycle and apoptosis in primary human gingival fibroblasts in vitro.

    PubMed

    Nomura, Yuji; Bhawal, Ujjal Kumar; Nishikiori, Ryo; Sawajiri, Masahiko; Maeda, Takeshi; Okazaki, Masayuki

    2010-01-01

    We evaluated the effects of high-dose major components in oral disinfectants on oral cells from the standpoints of the cell cycle and apoptosis. We examined the viability and cell cycle of human gingival fibroblasts (HGFs) treated with the components of dental disinfectants, benzethonium chloride (BEC), benzalkonium chloride (BAC), and povidone iodine (PVD-I) using a cell counting kit and flow cytometry. The IC(50) inhibitory concentration value in HGF cultures at 24 hours was 1.3x10(-2) mM BEC, 6.0x10(-3) mM BAC, and 2.6x10(-1) mM PVD-I. In the cell cycle analysis, propidium iodide-stained HGFs were arrested in G(0)/G(1) of the cell cycle by all three disinfectants, and in the apoptosis assay, annexin V-FITC/PI-stained HGFs that became apoptotic at 5.0x10(-2) and 1.0x10(-1) mM BEC and 5.0x10(-2) and 1.0x10(-1) mM BAC, but not in PVD-I at concentrations as high as 5.0x10(-1) mM. Our findings describe the effects of high-dose oral disinfectants, rather than clinical concentrations. Nevertheless, appreciating the effects of high-dose disinfectants absorbed into the human body is important, where they may accumulate in specific tissues and cells. PMID:20379016

  14. Fixed-Dose Combination Gel of Adapalene and Benzoyl Peroxide plus Doxycycline 100 mg versus Oral Isotretinoin for the Treatment of Severe Acne: Efficacy and Cost Analysis

    PubMed Central

    Penna, Pete; Meckfessel, Matthew H.; Preston, Norman

    2014-01-01

    Background Acne vulgaris is a chronic skin disease with a high prevalence. Left untreated or inadequately treated, acne vulgaris can lead to psychological and physical scarring, as well as to unnecessary medical expenses. Oral isotretinoin is an effective treatment for severe resistant nodular and conglobate acne vulgaris. A regimen consisting of a fixed-dose combination of adapalene and benzoyl peroxide gel, 0.1%/2.5% (A-BPO) with oral doxycycline 100 mg (A-BPO/D) has been demonstrated to be efficacious and well tolerated in patients with severe acne and may be an alternative to oral isotretinoin for some patients with severe acne. Objective The objective of this analysis was to compare the relative efficacy and associated costs of A-BPO/D versus oral isotretinoin. Methods In this analysis, comparisons of relative efficacy were made using previously published studies involving similar patient populations with severe acne that warrant the use of oral isotretinoin. The pricing for oral doxycycline and oral isotretinoin was estimated based on the maximum allowable cost from 9 states, and the pricing for A-BPO was calculated as the range between the average wholesale price and the wholesale acquisition cost. For this analysis, 2 treatment models were generated to compare costs: (1) a basic treatment model that examined the costs of an initial regimen of either A-BPO/D or oral isotretinoin without considering probable outcomes, and (2) a long-term model that factored in likely treatment outcomes and subsequent treatments into associated costs. The basic treatment model assumed that patients would be prescribed a single regimen of A-BPO/D for 12 weeks or oral isotretinoin for 20 weeks. The long-term model considered the probability of each treatment successfully managing patients' acne, as well as likely additional regimens of A-BPO monotherapy or an additional regimen of oral isotretinoin. As a result of different treatment durations, the costs for each treatment were normalized to weekly cost of treatment. Results Based on evidence from the published literature, patients treated with A-BPO/D would be expected to have an initial 72% reduction in inflammatory lesions, and patients treated with oral isotretinoin would have an 80% to 90% reduction of these lesions. The median weekly cost for the basic treatment model was $44 for A-BPO/D and $62 for oral isotretinoin. The weekly median costs for the long-term model were $44 for patients initially receiving a regimen of A-BPO/D followed by a maintenance regimen of A-BPO monotherapy and $50 for patients receiving an initial regimen of A-BPO/D who required a subsequent regimen of oral isotretinoin. The weekly cost for oral isotretinoin in the long-term model was $62. Conclusions The comparison of these 2 treatments demonstrated that they are both effective in treating severe acne, and that A-BPO/D was less expensive weekly than oral isotretinoin. These models show that A-BPO/D is safer than and is a more cost-effective alternative to oral isotretinoin for treating patients with severe acne vulgaris. PMID:24991389

  15. Toxicokinetics and toxicological effects of single oral dose of fumonisin B1 containing Fusarium verticillioides culture material in weaned piglets.

    PubMed

    Dilkin, P; Direito, G; Simas, M M S; Mallmann, C A; Corręa, B

    2010-05-14

    Toxicokinetics and the toxicological effects of culture material containing fumonisin B(1) (FB(1)) were studied in male weaned piglets by clinical, pathological, biochemical and sphingolipid analyses. The animals received a single oral dose of 5 mg FB(1)/kg of body weight, obtained from Fusarium verticillioides culture material. FB(1) was detected by HPLC in plasma collected at 1-h intervals up to 6h and at 12-h intervals up to 96 h. FB(1) eliminated in feces and urine was quantified over a 96-h period and in liver samples collected 96 h post-intoxication. Blood samples were obtained at the beginning and end of the experiment to determine serum enzyme activity, total bilirubin, cholesterol, sphinganine (Sa), sphingosine (So) and the Sa/So ratio. FB(1) was detected in plasma between 30 min and 36 h after administration. The highest concentration of FB(1) was observed after 2 h, with a mean concentration of 282 microg/ml. Only 0.93% of the total FB(1) was detected in urine between 75 min and 41 h after administration, the highest mean concentration (561 microg/ml) was observed during the interval after 8 at 24 h. Approximately 76.5% of FB(1) was detected in feces eliminated between 8 and 84 h after administration, with the highest levels observed between 8 and 24 h. Considering the biochemical parameters, a significant increase only occurred in cholesterol, alkaline phosphatase and aspartate aminotransferase activities. In plasma and urine, the highest Sa and Sa/So ratios were obtained at 12 and 48 h, respectively. PMID:20338158

  16. Pharmacokinetics of a single dose of intravenous and oral meloxicam in red-tailed hawks (Buteo jamaicensis) and great horned owls (Bubo virginianus).

    PubMed

    Lacasse, Claude; Gamble, Kathryn C; Boothe, Dawn M

    2013-09-01

    Pharmacokinetic data were determined after a single dose of meloxicam in red-tailed hawks (RTH; Buteo jamaicensis) and great horned owls (GHO; Bubo virginianus). In a nonrandomized crossover design, individual birds of each species received 1 dose of intravenous meloxicam (0.5 mg/kg i.v.; n = 7 for each species) followed by a 2-week washout period, and then each received 1 dose of oral meloxicam (0.5 mg/kg PO; n = 5 for each species). Blood samples were collected intermittently after administration, and meloxicam was detected in plasma by high-performance liquid chromatography. Time versus plasma concentration data were subjected to noncompartmental analysis. Red-tailed hawks were determined to have the shortest elimination half-life for meloxicam (0.49 +/- 0.5 hours) of any species documented. Great horned owls also eliminated meloxicam very rapidly (0.78 +/- 0.52 hours). Great horned owls achieved higher plasma concentrations (368 +/- 87 ng/mL) of meloxicam than RTH (182 +/- 167 ng/mL) after oral administration, although RTH had a markedly higher volume of distribution (832 +/- 711 mL/kg) than GHO (137.6 +/- 62.7 mL/kg). The differences in meloxicam pharmacokinetics between these 2 raptor species supports the need for species-dependent studies and underlines the challenges of extrapolating drug dosages between species. Results of this study suggest that the current recommended once-daily dosing interval of oral meloxicam is unlikely to maintain plasma concentrations anticipated to be therapeutic in either RTH or GHO, and practical dosing options are questionable for this nonsteriodal anti-inflammatory drug in these raptor species. PMID:24344511

  17. Evaluation of D-ribose pharmacokinetics, dose proportionality, food effect, and pharmacodynamics after oral solution administration in healthy male and female subjects.

    PubMed

    Thompson, Jeff; Neutel, Joel; Homer, Ken; Tempero, Ken; Shah, Ajit; Khankari, Raj

    2014-05-01

    This was a double blind, randomized, crossover study of three periods evaluating pharmacokinetics and pharmacodynamics in 12 healthy, adult subjects after administration of D-ribose powder for oral solution, 2.5, 5.0, and 10.0?g, under fasting conditions followed by an open label, randomized, fourth period assessing the effect of food on the pharmacokinetics of D- ribose (10.0?g) under fed conditions with either a high fat (HF, N?=?6) or high carbohydrate (HC, N?=?6) meal. D-ribose was absorbed rapidly with mean Tmax ranging between 18 and 30?minutes. Cmax and AUC increased more than proportionally with dose indicating increased absorption and saturation of metabolism. When D-ribose was administered with meals, Tmax was unchanged; however, Cmax and AUC decreased by 42.6% and 40.8%, respectively with HF and 69.1% and 64.9%, respectively with HC. The amount of D-ribose in urine ranged from 4.15% to 7.20% of the administered dose. Dose-related decreases in serum glucose up to 26.3?mg/dL (30.3% of baseline) occurred in the first 60?minutes post dose and insulin response attained a dose-related peak 15?minutes post dose. D-ribose was generally safe and well tolerated in the dose range studied. PMID:24272966

  18. Implications of dose-dependent target tissue absorption for linear and non-linear/threshold approaches in development of a cancer-based oral toxicity factor for hexavalent chromium.

    PubMed

    Haney, J

    2015-07-01

    Dose-dependent changes in target tissue absorption have important implications for determining the most defensible approach for developing a cancer-based oral toxicity factor for hexavalent chromium (CrVI). For example, mouse target tissue absorption per unit dose is an estimated 10-fold lower at the CrVI dose corresponding to the federal maximum contaminant level (MCL) than at the USEPA draft oral slope factor (SFo) point of departure dose. This decreasing target tissue absorption as doses decrease to lower, more environmentally-relevant doses is inconsistent with linear low-dose extrapolation. The shape of the dose-response curve accounting for this toxicokinetic phenomenon would clearly be non-linear. Furthermore, these dose-dependent differences in absorption indicate that the magnitude of risk overestimation by a linear low-dose extrapolation approach (e.g., SFo) increases and is likely to span one or perhaps more orders of magnitude as it is used to predict risk at progressively lower, more environmentally-relevant doses. An additional apparent implication is that no single SFo can reliably predict risk across potential environmental doses (e.g., doses corresponding to water concentrations?the federal MCL). A non-linear approach, consistent with available mode of action data, is most scientifically defensible for derivation of an oral toxicity factor for CrVI-induced carcinogenesis. PMID:25910675

  19. Studies on combined effects of organophosphates and heavy metals in birds. I. Plasma and brain cholinesterase in Coturnix quail fed methyl mercury and orally dosed with parathion

    USGS Publications Warehouse

    Dieter, M.P.; Ludke, J.L.

    1975-01-01

    We found that mercury potentiated the toxicity and biochemical effects of parathion. Male Coturnix quail (Coturnix coturnix japonica) were fed a sublethal concentration of morsodren (4 ppm as methyl mercury) for 18 weeks. This resulted in an accumulation of 21.0 ppm of mercury in the liver and 8.4 ppm in the carcass. Birds fed clean feed and those fed morsodren-treated feed were orally dosed with 2, 4, 6, 8,and 10 mg/kg parathion, and their 48-h survival times compared. The computed LD50 was 5.86mg/kg in birds not fed morsodren and 4.24 in those fed the heavy metal. When challenged with a sublethal, oral dose of parathion (1.0 mg/kg), morsodren-fed birds exhibited significantly greater inhibition of plasma and brain cholinesterase activity than controls dosed with parathion. Brain cholinesterase activity was inhibited 41% in morsodren-fed birds and 26in clean-fed birds dosed with parathion, which suggested that the increase in parathion toxicity in the presence of morsodren was directly related to the inhibitation of brain cholinesterase.

  20. Continuous, low-dose oral exposure to sodium chlorate reduces fecal generic in sheep feces without inducing clinical chlorate toxicosis.

    PubMed

    Taylor, J B; Smith, D J

    2015-04-01

    Our objectives were to determine an effective, yet safe, daily dose of sodium chlorate for reducing fecal shedding of generic in mature ewes. In a completely randomized experimental design, 25 Targhee ewes (age ?18 mo; BW = 62.5 ± 7.3 kg, mean ± SD) were assigned randomly to 1 of 5 sodium chlorate treatments, which were administered in the drinking water for 5 consecutive days. Treatments were control group (no sodium chlorate) and 4 targeted levels of daily sodium chlorate intake: 30, 60, 90, and 120 mg·kg BW·d for 5 d. Individual ewe ad libitum intake of water (with treatments) was measured daily, and BW was measured at the beginning of and 15 and 51 d after the 5-d treatment period. Serum chlorate, whole blood methemoglobin and packed-cell volume (PCV), and fecal generic and general Enterobacteriaceae coliforms were measured from corresponding samples collected at the end of the 5-d treatment period. Average daily intakes of sodium chlorate from drinking water treatments were 95%, 91%, 90%, and 83% of the target treatment intakes of 30, 60, 90, and 120 mg·kg BW·d, respectively. Daily sodium chlorate intake remained constant for all treatment groups except for ewes offered 120 mg NaClO·kg BW·d, which decreased (quadratic; = 0.04) over the course of the 5-d treatment period. This decrease in sodium chlorate intake indicated that the 120-mg NaClO level may have induced either toxicity and/or an aversion to the drinking water treatment. Serum chlorate concentrations increased (quadratic; < 0.001) with increasing sodium chlorate intake. At the end of the 5-d treatment period, mean (least squares ± SEM) serum chlorate concentrations for ewes offered 30, 60, 90, and 120 mg NaClO·kg BW·d were 15.6 ± 14.1, 32.8 ± 15.8, 52.9 ± 14.1, and 90.3 ± 14.1 ?g/mL, respectively. Whole blood methemoglobin and PCV were similar ( = 0.31 to 0.81) among the control group and ewes offered sodium chlorate. Likewise, BW was not affected by sodium chlorate ( > 0.27). Ewes consuming approximately 55 mg NaClO·kg BW·d or more (i.e., ewes offered 60, 90, and 120 mg) had a >1.4 log unit reduction in fecal and Enterobacteriaceae coliforms compared with control ewes. We suggest that for a short-term, 5-d dosing strategy, 55 to 81 mg NaClO·kg BW·d is an effective, yet safe, daily oral dose range for mature ewes to achieve a 97% to 99% reduction in fecal shedding of generic . PMID:26020217

  1. Oral Steroids for Dermatitis.

    PubMed

    Fisher, Andrew D; Clarke, Jesse; Williams, Timothy K

    2015-01-01

    Contact/allergic dermatitis is frequently treated inappropriately with lower-than-recommended doses or inadequate duration of treatment with oral and intramuscular glucocorticoids. This article highlights a case of dermatitis in a Ranger Assessment and Selection Program student who was improperly treated over 2 weeks with oral steroids after being bit by Cimex lectularius, commonly known as bed bugs. The article also highlights the pitfalls of improper oral steroid dosing and provides reasoning for longer-duration oral steroid treatment. PMID:26125159

  2. Safety and pharmacokinetics of the anti-orthopoxvirus compound ST-246 following a single daily oral dose for 14 days in human volunteers.

    PubMed

    Chinsangaram, Jarasvech; Honeychurch, Kady M; Tyavanagimatt, Shanthakumar R; Leeds, Janet M; Bolken, Tove' C; Jones, Kevin F; Jordan, Robert; Marbury, Thomas; Ruckle, Jon; Mee-Lee, Denis; Ross, Eric; Lichtenstein, Israel; Pickens, Margaret; Corrado, Michael; Clarke, Jean M; Frimm, Annie M; Hruby, Dennis E

    2012-09-01

    ST-246 is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. To this end, a phase 2, double-blind, randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was safe and well tolerated, with no deaths or serious adverse events reported during the study. There was a low incidence of treatment-emergent adverse events (TEAEs), the most common of which were mild nausea and headache. There were no clinically significant results from laboratory assessments, vital sign measurements, physical examinations, or electrocardiograms. The PK and dose proportionality of ST-246 were determined. The PK analysis showed that steady state was achieved by day 5 for the ST-246 400-mg treatment group and by day 6 for the 600-mg group. The dose proportionality analysis showed that the 400- and 600-mg ratio of dose-normalized peak drug concentration in plasma (C(max)) and relative exposure for each dosing interval (AUC(?)) ranged from 80% to 85%. However, the 90% confidence intervals did not include 1.0, so dose proportionality could not be concluded. Overall, ST-246 was shown to be safe, and the PK was predictable. These results support further testing of ST-246 in a multicenter pivotal clinical safety study for licensure application. PMID:22777041

  3. Safety and Pharmacokinetics of the Anti-Orthopoxvirus Compound ST-246 following a Single Daily Oral Dose for 14 Days in Human Volunteers

    PubMed Central

    Chinsangaram, Jarasvech; Honeychurch, Kady M.; Tyavanagimatt, Shanthakumar R.; Leeds, Janet M.; Bolken, Tove' C.; Jones, Kevin F.; Jordan, Robert; Marbury, Thomas; Ruckle, Jon; Mee-Lee, Denis; Ross, Eric; Lichtenstein, Israel; Pickens, Margaret; Corrado, Michael; Clarke, Jean M.; Frimm, Annie M.

    2012-01-01

    ST-246 is being evaluated as a treatment for pathogenic orthopoxvirus infections in humans. To this end, a phase 2, double-blind, randomized, placebo-controlled, multicenter trial was conducted to assess the safety, tolerability, and pharmacokinetics (PK) of ST-246 when administered as a single daily oral dose (400 mg or 600 mg) for 14 days in fed adult volunteers. ST-246 was safe and well tolerated, with no deaths or serious adverse events reported during the study. There was a low incidence of treatment-emergent adverse events (TEAEs), the most common of which were mild nausea and headache. There were no clinically significant results from laboratory assessments, vital sign measurements, physical examinations, or electrocardiograms. The PK and dose proportionality of ST-246 were determined. The PK analysis showed that steady state was achieved by day 5 for the ST-246 400-mg treatment group and by day 6 for the 600-mg group. The dose proportionality analysis showed that the 400- and 600-mg ratio of dose-normalized peak drug concentration in plasma (Cmax) and relative exposure for each dosing interval (AUC?) ranged from 80% to 85%. However, the 90% confidence intervals did not include 1.0, so dose proportionality could not be concluded. Overall, ST-246 was shown to be safe, and the PK was predictable. These results support further testing of ST-246 in a multicenter pivotal clinical safety study for licensure application. PMID:22777041

  4. Titrating Optimal Dose of Osmotic-Controlled Release Oral Delivery (OROS)-Methylphenidate and Its Efficacy and Safety in Korean Children with ADHD: A Multisite Open Labeled Study

    PubMed Central

    Song, Dong-Ho; Choi, Soul; Joung, Yoo Sook; Ha, Eun Hye; Kim, Boong-Nyun; Shin, Yee-Jin; Shin, Dongwon; Yoo, Hee Jeong

    2012-01-01

    Objective This study was aimed to determine effectiveness and tolerability of Osmotic-controlled Release Oral delivery (OROS) methylphenidate (MPH) and its optimal dose administered openly over a period of up to 12 weeks in drug naďve Korean children with ADHD. Methods Subjects (n=143), ages 6 to 18-years, with a clinical diagnosis of any subtype of ADHD were recruited from 7 medical centers in Korea. An individualized dose of OROS-MPH was determined for each subject depending on the response criteria. The subjects were assessed with several symptom rating scales in week 1, 3, 6, 9 and 12. Results 77 of 116 subjects (66.4%) achieved the criteria for response and the average of optimal daily dose for response was to 30.05±12.52 mg per day (0.90±0.31 mg/kg/d) at the end of the study. Optimal dose was not significantly different between ADHD subtypes, whereas, significant higher dose was needed in older aged groups than younger groups. The average of optimal daily dose for response for the subjects aged above 12 years old was 46.38±15.52 per day (0.81±0.28 mg/kg/d) compared to younger groups (p<0.01). No serious adverse effects were reported and the dose did not have a significant effect on adverse effects. Conclusion Optimal mean dose of OROS-MPH was significantly different by age groups. Higher dose was needed in older aged groups than younger groups. Effectiveness and tolerability of OROS-MPH in symptoms of ADHD is sustained for up to 12 weeks. PMID:22993525

  5. A double-blind randomized controlled study to evaluate the efficacy of low-dose oral interferon-alpha in preventing hepatitis C relapse.

    PubMed

    Lee, Chuan-Mo; Chen, Chi-Yi; Chien, Rong-Nan; Tseng, Kuo-Chih; Peng, Cheng-Yuan; Tung, Shui-Yi; Fang, Yi-Jen; Huang, Yi-Hsiang; Lu, Sheng-Nan; Hung, Chao-Hung; Tsai, Tsung-Jang; Fang, Chien-Chung; Hsu, Chao-Wei; Yeh, Chau-Ting

    2014-03-01

    Low-dose oral interferon could exert immune-modulating effects in human. We conducted a clinical trial to investigate the efficacy of oral interferon-alpha in preventing hepatitis C relapse. Totally 169 genotype 1b chronic hepatitis C patients having achieved end-of-therapy virological clearance were randomized to receive interferon-alpha lozenge 500?IU/day (n=59), 1,500?IU/day (n=53), or placebo (n=57) for 24 weeks. Overall, no significant differences were found for the relapse rates in the 3 groups (P>0.05). However, in patients with fibroindex 1.4-1.7, relapse occurred in 1/12 (8.3%) 500?IU-group patients versus 9/21 (42.9%) patients of the other groups (P=0.05). In 158 patients receiving at least 4 weeks of oral interferon, significantly higher platelet count was found at the end of trial in the 500?IU group (P=0.003). In thrombocytopenic patients, a significantly expedited recovery of platelet count was found in the 500?IU group (P=0.002). No drug-related severe adverse events were reported. In conclusion, at 500?IU/day, oral interferon exerted a borderline suppression effect of virological relapse in chronic hepatitis C patients with mild liver fibrosis. Additionally, it significantly expedited platelet count recovery after the end of peginterferon therapy. PMID:24237300

  6. A Double-Blind Randomized Controlled Study to Evaluate the Efficacy of Low-Dose Oral Interferon-Alpha in Preventing Hepatitis C Relapse

    PubMed Central

    Lee, Chuan-Mo; Chen, Chi-Yi; Chien, Rong-Nan; Tseng, Kuo-Chih; Peng, Cheng-Yuan; Tung, Shui-Yi; Fang, Yi-Jen; Huang, Yi-Hsiang; Lu, Sheng-Nan; Hung, Chao-Hung; Tsai, Tsung-Jang; Fang, Chien-Chung; Hsu, Chao-Wei

    2014-01-01

    Low-dose oral interferon could exert immune-modulating effects in human. We conducted a clinical trial to investigate the efficacy of oral interferon-alpha in preventing hepatitis C relapse. Totally 169 genotype 1b chronic hepatitis C patients having achieved end-of-therapy virological clearance were randomized to receive interferon-alpha lozenge 500?IU/day (n=59), 1,500?IU/day (n=53), or placebo (n=57) for 24 weeks. Overall, no significant differences were found for the relapse rates in the 3 groups (P>0.05). However, in patients with fibroindex 1.4–1.7, relapse occurred in 1/12 (8.3%) 500?IU-group patients versus 9/21 (42.9%) patients of the other groups (P=0.05). In 158 patients receiving at least 4 weeks of oral interferon, significantly higher platelet count was found at the end of trial in the 500?IU group (P=0.003). In thrombocytopenic patients, a significantly expedited recovery of platelet count was found in the 500?IU group (P=0.002). No drug-related severe adverse events were reported. In conclusion, at 500?IU/day, oral interferon exerted a borderline suppression effect of virological relapse in chronic hepatitis C patients with mild liver fibrosis. Additionally, it significantly expedited platelet count recovery after the end of peginterferon therapy. PMID:24237300

  7. Biodistribution of PLGA and PLGA/chitosan nanoparticles after repeat-dose oral delivery in F344 rats for 7 days

    PubMed Central

    Navarro, Sara M; Darensbourg, Caleb; Cross, Linda; Stout, Rhett; Coulon, Diana; Astete, Carlos E; Morgan, Timothy; Sabliov, Cristina M

    2015-01-01

    Aim To quantify in vivo the biodistribution of poly(lactic-co-glycolic) acid (PLGA) and PLGA/chitosan nanoparticles (PLGA/Chi NPs) and assess if the positive charge of chitosan significantly enhances nanoparticle absorption in the GI tract. Material & methods PLGA and PLGA/Chi NPs covalently linked to tetramethylrhodamine-5-isothiocyanate (TRITC) were orally administered to F344 rats for 7 days, and the biodistribution of fluorescent NPs was analyzed in different organs. Results The highest amount of particles (% total dose/g) was detected for both treatments in the spleen, followed by intestine and kidney, and then by liver, lung, heart and brain, with no significant difference between PLGA and PLGA/Chi NPs. Conclusion Only a small percentage of orally delivered NPs was detected in the analyzed organs. The positive charge conferred by chitosan was not sufficient to improve the absorption of the PLGA/Chi NPs over that of PLGA NPs. PMID:25491670

  8. Oral toxicity evaluation of kefir-isolated Lactobacillus kefiranofaciens M1 in Sprague-Dawley rats.

    PubMed

    Owaga, E E; Chen, M J; Chen, W Y; Chen, C W; Hsieh, R H

    2014-08-01

    Lactobacilli kefiranofaciens M1 has shown novel immunomodulation and anti-allergy probiotic attributes in cell and animal models. An acute oral toxicity assessment of L. kefiranofaciens M1 was evaluated in Sprague-Dawley rats. The rats were randomly assigned to four groups (12 rats/sex/group): the low dose group was orally gavaged with L. kefiranofaciens M1 at 3.0×10(8)cfu/kg bw while the medium dose and high dose groups received 9.0×10(9)cfu/kg bw and 1.8×10(10)cfu/kg bw, respectively, for 28days. The control group received phosphate buffer saline. The body weights were measured weekly while blood samples were collected for haematology and serum biochemistry tests. Histopathology of the organs (heart, liver, kidney, adrenal glands, spleen, ovary, testis), and urinalysis were conducted on study termination. The body weight gain of the L. kefiranofaciens M1 and control groups were comparable during the administration period. Overall, L. kefiranofaciens M1 did not induce adverse effects on haematology, serum biochemistry, and urinalysis parameters. Gross and microscopic histopathology of the organs revealed no toxicity effect of L. kefiranofaciens M1. In conclusion, 1.8×10(10)cfu/kg bw of L. kefiranofaciens M1 was considered as the no-observed-adverse-effect-level (NOAEL), which was the highest dose tested in the present study. PMID:24842838

  9. Oxidative stress and hepatocellular injury induced by oral administration of cr(3+) in chicken.

    PubMed

    Fan, Wen-Tao; Zhao, Xiao-Na; Cheng, Jia; Liu, Yan-Han; Liu, Jian-Zhu

    2015-06-01

    This study aims to investigate the oxidative stress and hepatocellular injury induced by Cr(3+) in chicken. Different doses of CrCl3 solutions (50% LD50 , 25% LD50 , and 12.5% LD50 ) and equivalent water were orally administered to chicken. Chicken liver samples were measured for the activities of antioxidant enzymes, the contents of glutathione, total antioxidant capacity (T-AOC), malondialdehyde (MDA), and hydrogen peroxide to indirectly evaluate the oxidative stress in chicken liver. Results indicated that the oral administration of Cr(3+) at high dose significantly increased (P < 0.05) the MDA levels after 28 days of exposure, with decreased T-AOC, glutathione, and antioxidant enzymes activities. Low and medium doses groups show that T-AOC, glutathione, and antioxidant enzymes activities increased after 14 days, then decreased gradually, but low and medium groups higher than control group, only high group lower than control group finally. These statistics and histopathological analysis suggest that high dose and long-term exposure of Cr(3+) induce oxidative stress and hepatocellular injury. PMID:25800437

  10. Evaluation of repeated dose micronucleus assays of the liver using N-nitrosopyrrolidine: a report of the collaborative study by CSGMT/JEMS.MMS.

    PubMed

    Ogawa, Izumi; Hagioa, Soichiro; Furukawa, Satoshi; Abe, Masayoshi; Kuroda, Yusuke; Hayashi, Seigo; Wako, Yumi; Kawasako, Kazufumi

    2015-03-01

    The repeated dose liver micronucleus (RDLMN) assay has the potential to detect liver carcinogens, and can be integrated into a general toxicological study. To assess the performance of the assay, N-nitrosopyrrolidine (NPYR), a genotoxic hepatocarcinogen, was tested in 14- or 28-day RDLMN assays. NPYR was orally administered to rats at a daily dose of 25, 50 or 100 mg/kg. One day after the last administration, a portion of the liver was removed and hepatocyte micronucleus (MN) specimens were prepared by the new method recently established by Narumi et al. In addition, a bone marrow MN assay and a histopathological examination of the liver were conducted. The detection of Phospho-Histone H3 was performed by immunohistochemistry to evaluate the proliferation rate of hepatocytes. The results showed significant increase in the number of micronucleated hepatocytes and Phospho-Histone H3-positive cells from the lowest dose in both 14- and 28-day RDLMN assays. On the other hand, the bone marrow MN assay yielded a negative result, which was in accordance with the existing report of the bone marrow MN assay using mice. Upon histopathological examination, inflammatory lesions and hypertrophy were noted, which may explain the increase in the hepatocyte proliferation and the enhancement of MN induction by NPYR. Our findings indicate that the RDLMN assay could be a useful tool for comprehensive risk assessment of carcinogenicity by providing information on both genotoxicity and histopathology when integrated into a general repeat dosing toxicity assay. PMID:26065307

  11. Evaluation of Oral and IntravenousRoute Pharmacokinetics, Plasma Protein Binding and Uterine Tissue Dose Metrics of Bisphenol A: A Physiologically Based Pharmacokinetic Approach

    SciTech Connect

    Teeguarden, Justin G.; Waechter, John M.; Clewell, III, H. J.; Covington, Tammie R.; Barton, H. A.

    2005-06-01

    Bisphenol A (BPA) is a weakly estrogenic monomer used in the production of polycarbonate plastic and epoxy resins, both of which are used in food contact and other applications. A physiologically based pharmacokinetic (PBPK) model of BPA pharmacokinetics in rats and humans was developed to provide a physiological context in which the processes controlling BPA pharmacokinetics (e.g. plasma protein binding, enterohepatic recirculation of the glucuronide (BPAG)) could be incorporated. A uterine tissue compartment was included to allow the correlation of simulated ER binding of BPA with increases in uterine wet weight (UWW) in rats. Intravenous and oral-route blood kinetics of BPA in rats and oral-route plasma and urinary elimination kinetics in humans were well described by the model. Simulations of rat oral-route BPAG pharmacokinetics were less exact, most likely the result of oversimplification of the GI tract compartment. Comparison of metabolic clearance rates derived from fitting rat i.v. and oral-route data implied that intestinal glucuronidation of BPA is significant. In rats but not humans, terminal elimination rates were strongly influenced by enterohepatic recirculation. In the absence of BPA binding to plasma proteins, simulations showed high ER occupancy at doses without uterine effects. Restricting free BPA to the measured unbound amount demonstrated the importance of including plasma binding in BPA kinetic models: the modeled relationship between ER occupancy and UWW increases was consistent with expectations for a receptor mediated response with low ER occupancy at doses with no response and increasing occupancy with larger increases in UWW.

  12. Protection of mice against gastric colonization by Helicobacter pylori by single oral dose immunization with attenuated Salmonella typhimurium producing urease subunits A and B.

    PubMed

    Gómez-Duarte, O G; Lucas, B; Yan, Z X; Panthel, K; Haas, R; Meyer, T F

    1998-03-01

    Helicobacter pylori is a Gram-negative bacterial pathogen associated with gastritis, peptic ulceration, and gastric carcinoma. The bacteria express a strong urease activity which is known to be essential for colonization of gnotobiotic pigs and nude mice. UreA and UreB, two structural subunits of the active enzyme, were expressed in the attenuated Salmonella typhimurium live vaccine SL3261 strain. Evaluation of protection against H. pylori was performed in Balb/c mice by oral immunization with a single dose of the vaccine strain. Five weeks after immunization, mice were challenged orally three times with a mouse-adapted H. pylori wild type strain and, six weeks later, mice were sacrificed to determine H. pylori infection by detection of urease activity from the antral region of the mouse stomachs. In several independent experiments, we observed 100% infection with H. pylori in the non-immunized mice and no infection (100% protection) in the mice immunized with S. typhimurium expressing recombinant UreA and UreB. Specific humoral and mucosal antibody responses against UreA and UreB were observed in mice immunized as indicated by western blots and ELISA assays. These data shows that oral immunization of mice with urease subunits delivered by an attenuated Salmonella strain induced a specific immune response and protected mice against H. pylori colonization. Single oral dose immunization with UreA and UreB delivered by a live Salmonella vaccine vector appears to be an attractive candidate for human vaccination against H. pylori infection. In addition, this model will aid to elucidate the effective protection mechanisms against H. pylori in the gastric mucosa. PMID:9491500

  13. Distribution after repeated oral administration of different dose levels of risperidone and 9-hydroxy-risperidone in the brain and other tissues of rat

    Microsoft Academic Search

    M. Aravagiri; Arthur Yuwiler; Stephen R. Marder

    1998-01-01

    Rats were treated with daily oral doses of 1, 4, and 6?mg\\/kg risperidone (RSP) and its metabolite, 9-hydroxy-risperidone\\u000a (9-OH-RSP), for 15 consecutive days. Concentrations of RSP and 9-OH-RSP were measured in plasma, brain, liver, kidney, lungs\\u000a and fat tissue by high-performance liquid chromatography with electrochemical detection. Non-specific distribution of RSP\\u000a and 9-OH-RSP in various brain regions was also studied after

  14. Interchangeability of low-dose oral contraceptives. Are current bioequivalent testing measures adequate to ensure therapeutic equivalency?

    PubMed

    Ansbacher, R

    1991-02-01

    Current Food and Drug Administration guidelines for assessing the differences in bioavailability between generic oral contraceptives and brand-name products are inadequate to ensure therapeutic equivalence. The guidelines do not take into account those women who may have blood levels of active ingredients well outside the range of acceptability. Due to the narrow therapeutic range of steroids, these women may become pregnant or experience an increased incidence of breakthrough bleeding. Furthermore, oral contraceptive packaging is unique to each manufacturer, and any change in brands (and therefore packaging) can easily negate the sequential administration of the appropriate tablet. These are among the reasons proposed for placing oral contraceptives in the critical drug category, in which generic substitution and interchangeability of products should not be allowed. PMID:2040168

  15. A comparison of regularly dosed oral morphine and on-demand intramuscular morphine in the treatment of postsurgical pain

    Microsoft Academic Search

    James P. McCormack; C. Brian Warriner; Marc Levine; Ned Glick

    1993-01-01

    A randomized, placebo-controlled, double-blind clinical trial was conducted to compare the use of regularly dosed po morphine\\u000a and on-demand im morphine in 47 patients undergoing total hip arthroplasty. Patients were randomized to receive either 20\\u000a mg (initial dose) of regularly dosed morphine (every four hours po) plus breakthrough pain medication on-demand consisting\\u000a of both 10 mg morphine po and placebo

  16. Pharmacokinetics and safety of resveratrol derivatives in humans after oral administration of melinjo (Gnetum gnemon L.) seed extract powder.

    PubMed

    Tani, Hiroko; Hikami, Susumu; Iizuna, Sanae; Yoshimatsu, Maiko; Asama, Takashi; Ota, Hidetaka; Kimura, Yuka; Tatefuji, Tomoki; Hashimoto, Ken; Higaki, Kazutaka

    2014-02-26

    Fruits and seeds of melinjo (Gnetum gnemon L.) are resveratrol derivative-rich materials. Pharmacokinetics of resveratrol derivatives in healthy volunteers after oral administration of 1000 mg of melinjo seed extract (MSE) powder were assessed and compared with those after oral dosing of trans-resveratrol (tRV) powder containing 4.8 mg of tRV only, equivalent to the content in 1000 mg MSE powder. Plasma tRV concentrations with enzymatic hydrolysis were maintained over 24 h, with a tmax of 12 h and a mean residence time (MRT) of 14 h, 5 and 2 times higher than those for tRV powder intake, respectively. Gnetin C, a resveratrol dimer, with hydrolysis was maintained in plasma for >96 h with a 36 h MRT. With repeated doses once daily for 28 days, plasma tRV and gnetin C concentrations with hydrolysis were in good agreement with the theoretical curves. MSE powder was well tolerated up to the oral dosing of 5000 mg with no serious adverse events. PMID:24495149

  17. Pharmacokinetics of Tedizolid Following Oral Administration: Single and Multiple Dose, Effect of Food, and Comparison of Two Solid Forms of the Prodrug

    PubMed Central

    Flanagan, Shawn D; Bien, Paul A; Muńoz, Kelly A; Minassian, Sonia L; Prokocimer, Philippe G

    2013-01-01

    Objectives The single- and multiple-dose pharmacokinetics (PK) of tedizolid were examined after oral administration of tedizolid phosphate disodium (TPD), including the effect of food on PK. The relative bioavailability of TPD to the free acid tedizolid phosphate was determined to bridge the results of these and other studies to the solid form of the prodrug selected for further development. Design Randomized placebo-controlled, double-blind single- and multiple-ascending dose studies and randomized open-label, crossover food effect and relative bioavailability studies. Setting Clinical Research Units. Participants Healthy subjects. Intervention Study TR701-101 enrolled 40 subjects in single-ascending dose (200–1200 mg TPD or placebo) and 40 subjects in 21-day multiple-ascending dose (200, 300, or 400 mg TPD once/day; 600 mg linezolid twice/day; or placebo) arms. Study TR701-103 was a food-effect study in 12 subjects administered 600 mg TPD. Study TR701-108 was a relative bioavailability study in 12 subjects administered 150-mg tedizolid equivalents as TPD or tedizolid phosphate. Measurements and Main Results Plasma concentrations of the prodrug tedizolid phosphate, its active moiety tedizolid, and/or linezolid were collected. After administration of 200 to 600 mg TPD, tedizolid values increased approximately dose proportionally in area under the concentration-time curve (AUC) and maximum plasma concentration (Cmax). Tedizolid half-life values were approximately 2-fold greater compared with linezolid. TPD administration with food delayed tedizolid absorption and reduced Cmax relative to the fasted state but did not alter AUC. Minimal accumulation was predicted and observed for tedizolid, whereas observed accumulation of linezolid exceeded predictions based on single-dose PK. Comparable PK of tedizolid was observed following oral administration of either TPD or tedizolid phosphate. In the multiple-ascending dose study, 3 of 24 tedizolid subjects were withdrawn under prespecified stopping rules (one each of elevated alanine aminotransferase, low reticulocyte count, or low white blood cell count), as was 1 of 8 linezolid subjects (low reticulocyte count). Conclusions Overall, tedizolid has a favorable PK profile, a half-life that supports once daily administration, and no nonlinearities at steady state. Tedizolid phosphate can be administered without regard to food. PMID:23926058

  18. Oral transmucosal fentanyl citrate (OTFC) for the treatment of breakthrough pain in cancer patients: a controlled dose titration study

    Microsoft Academic Search

    Russell K Portenoy; Richard Payne; Paul Coluzzi; James W Raschko; Alan Lyss; Michael A Busch; Vicki Frigerio; Jane Ingham; Diane B Loseth; Earl Nordbrock; Michelle Rhiner

    1999-01-01

    Oral transmucosal fentanyl citrate (OTFC) is a novel opioid formulation in which the potent synthetic ?-agonist fentanyl is embedded in a sweetened matrix that is dissolved in the mouth. It is undergoing investigation as a treatment for cancer-related breakthrough pain, a prevalent phenomenon defined as a transitory flare of moderate to severe pain that interrupts otherwise controlled persistent pain. There

  19. Pharmacokinetics of mirtazapine and its main metabolites after single intravenous and oral administrations in rats at two dose rates

    PubMed Central

    2014-01-01

    Background Mirtazapine (MRZ) is a human antidepressant drug metabolized to 8-OH mirtazapine (8-OH) and dimethylmirtazapine (DMR) metabolites. Recently, this drug has been proposed as a potential analgesic for use in a multidrug analgesic regime in the context of veterinary medicine. The aim of this study was to assess the pharmacokinetics of MRZ and its metabolites DMR and 8-OH in rats. Findings Eighteen fasted, healthy male rats were randomly divided into 3 groups (n?=?6). Animals in these groups were respectively administered MRZ at 2 and 10 mg/kg orally and 2 mg/kg intravenously. Plasma MRZ and metabolite concentrations were evaluated by HPLC-FL detection method. After intravenous administration, MRZ was detected in all subjects, while DMR was only detected in three. 8-OH was not detected. After oral administration, MRZ was detected in 3 out of 6 rats treated with 2 mg/kg, it was detected in 6 out of 6 animals in the 10 mg/kg group. DMR was only detectable in the latter group, while 8-OH was not detected in either group. The oral bioavailability was about 7% in both groups. Conclusions The plasma concentration of the MRZ metabolite 8-OH was undetectable, and the oral bioavailability of the parental drug was very low. PMID:24397986

  20. Single and multiple daily dose toxicokinetics of fluoride after oral administration of sodium fluoride along with aluminum sulfate in goats

    Microsoft Academic Search

    Vinay Kant; A. K. Srivastava; P. K. Verma; Rajinder Raina

    2010-01-01

    Our previous study suggested that toxicokinetic parameters of fluoride were significantly changed on the 30th day as compared with 1st day, after repeated oral administration of sodium fluoride alone for 30 days in goats. The purpose of this study was to investigate whether aluminum sulfate has ameliorative effect on the toxicokinetics of fluoride. For this, sodium fluoride (20 mg kg

  1. The pharmacokinetics of a single oral dose of mycophenolate mofetil in patients with varying degrees of renal function

    Microsoft Academic Search

    Heather J. Johnson; Suzanne K. Swan; Karen L. Heim-Duthoy; Andrew J. Nicholls; Irene Tsina; Thomas Tarnowski

    1998-01-01

    Background: The purpose of this study was to determine the effect of renal function on the elimination and disposition of mycophenolic acid and its glucuronide metabolite (MPAG) after oral administration of the pro-drug mycophenolate mofetil. In addition, this study sought to examine hemodialysis removal of mycophenolic acid and its MPAG.Methods: Subjects were stratified into five groups on the basis of

  2. Estimation by a 24-hour study of the daily dose of intra-oral mercury vapor inhaled after release from dental amalgam

    SciTech Connect

    Berglund, A. (Univ. of Umea (Sweden))

    1990-10-01

    The difficulties associated with estimations of daily doses of inhaled mercury vapor released from dental amalgam are considerable. Existing data are often unreliable, especially if they are based on a single or a small series of samples of intra-oral concentrations of mercury vapor before, during, and after chewing stimulation. In the present paper, the aim was to obtain a more representative estimation of the daily dose of mercury vapor inhaled from amalgam fillings by measurement of amounts of mercury vapor released in the oral cavity during 24 h, under conditions that were as normal as possible. A series of measurements was carried out on each of 15 subjects, with at least nine occlusal surfaces restored with dental amalgam, and on five subjects without any amalgam restorations. The subjects had to follow a standardized schedule for 24 h, whereby they ate, drank, and brushed their teeth at pre-determined time periods. The amount of mercury vapor released per time unit was measured at intervals of 30-45 min by means of a measuring system based on atomic absorption spectrophotometry. None of the subjects was professionally exposed to mercury, and all of their amalgam fillings were more than one year old. Study casts were made for each subject, and the area of the amalgam surfaces was measured. Samples of urine and saliva were analyzed so that values for the mercury concentrations and the rate of release of mercury into saliva could be obtained. The average frequency of fish meals per month was noted.

  3. Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment.

    PubMed

    Dourson, Michael; Reichard, John; Nance, Patricia; Burleigh-Flayer, Heather; Parker, Ann; Vincent, Melissa; McConnell, Ernest E

    2014-04-01

    1,4-Dioxane is found in consumer products and is used as a solvent in manufacturing. Studies in rodents show liver tumors to be consistently reported after chronic oral exposure. However, there were differences in the reporting of non-neoplastic lesions in the livers of rats and mice. In order to clarify these differences, a reread of mouse liver slides from the 1978 NCI bioassay on 1,4-dioxane in drinking water was conducted. This reread clearly identified dose-related non-neoplastic changes in the liver; specifically, a dose-related increase in the hypertrophic response of hepatocytes, followed by necrosis, inflammation and hyperplastic hepatocellular foci. 1,4-Dioxane does not cause point mutations, DNA repair, or initiation. However, it appears to promote tumors and stimulate DNA synthesis. Using EPA Guidelines (2005), the weight of the evidence suggests that 1,4-dioxane causes liver tumors in rats and mice through cytotoxicity followed by regenerative hyperplasia. Specific key events in this mode of action are identified. A Reference Dose (RfD) of 0.05mg/kgday is proposed to protect against regenerative liver hyperplasia based on a benchmark dose (BMD) approach. Based on this RfD, a maximum contaminant level goal of 350?g/L is proposed using a default relative source contribution for water of 20%. PMID:24491968

  4. Induction therapy with low-dose intravenous cyclophosphamide, oral mizoribine, and steroids for severe lupus nephritis in children

    Microsoft Academic Search

    Shuichiro Fujinaga; Kazunari Kaneko; Yoshiyuki Ohtomo; Hitohiko Murakami; Masaru Takada; Shunji Akashi; Mayako Hira; Yuichiro Yamashiro

    2005-01-01

    Although immunosuppressive regimens of corticosteroids combined with high-dose intravenous cyclophosphamide (IVCY) have been reported to suppress the activity of lupus nephritis, there is controversy regarding its application for children and adolescents, because of its potential toxicity including gonadal dysfunction. On the basis of the recent finding that a low-dose IVCY regimen for induction therapy in adult lupus nephritis effectively achieves

  5. Memory B cell and other immune responses in children receiving two doses of an oral killed cholera vaccine compared to responses following natural cholera infection in Bangladesh.

    PubMed

    Leung, Daniel T; Rahman, Mohammad Arif; Mohasin, M; Patel, Sweta M; Aktar, Amena; Khanam, Farhana; Uddin, Taher; Riyadh, M Asrafuzzaman; Saha, Amit; Alam, Mohammad Murshid; Chowdhury, Fahima; Khan, Ashraful Islam; Charles, Richelle; LaRocque, Regina; Harris, Jason B; Calderwood, Stephen B; Qadri, Firdausi; Ryan, Edward T

    2012-05-01

    Current oral cholera vaccines induce lower protective efficacy and shorter duration of protection against cholera than wild-type infection provides, and this difference is most pronounced in young children. Despite this, there are limited data comparing immune responses in children following wild-type disease versus vaccination, especially with regard to memory responses associated with long-term immunity. Here, we report a comparison of immune responses in young children (2 to 5 years of age; n = 20) and older children (6 to 17 years of age; n = 20) given two doses of an oral killed cholera vaccine containing recombinant cholera toxin B subunit (CtxB) 14 days apart and compare these responses to those induced in similarly aged children recovering from infection with Vibrio cholerae O1 Ogawa in Bangladesh. We found that the two vaccine groups had comparable vibriocidal and lipopolysaccharide (LPS)-specific plasma antibody responses. Vaccinees developed lower levels of IgG memory B cell (MBC) responses against CtxB but no significant MBC responses against LPS. In contrast, children recovering from natural cholera infection developed prominent LPS IgG and IgA MBC responses, as well as CtxB IgG MBC responses. Plasma LPS IgG, IgA, and IgM responses, as well as vibriocidal responses, were also significantly higher in children following disease than after vaccination. Our findings suggest that acute and memory immune responses following oral cholera vaccination in children are significantly lower than those observed following wild-type disease, especially responses targeting LPS. These findings may explain, in part, the lower efficacy of oral cholera vaccination in children. PMID:22441386

  6. Memory B Cell and Other Immune Responses in Children Receiving Two Doses of an Oral Killed Cholera Vaccine Compared to Responses following Natural Cholera Infection in Bangladesh

    PubMed Central

    Rahman, Mohammad Arif; Mohasin, M.; Patel, Sweta M.; Aktar, Amena; Khanam, Farhana; Uddin, Taher; Riyadh, M. Asrafuzzaman; Saha, Amit; Alam, Mohammad Murshid; Chowdhury, Fahima; Khan, Ashraful Islam; Charles, Richelle; LaRocque, Regina; Harris, Jason B.; Calderwood, Stephen B.; Qadri, Firdausi; Ryan, Edward T.

    2012-01-01

    Current oral cholera vaccines induce lower protective efficacy and shorter duration of protection against cholera than wild-type infection provides, and this difference is most pronounced in young children. Despite this, there are limited data comparing immune responses in children following wild-type disease versus vaccination, especially with regard to memory responses associated with long-term immunity. Here, we report a comparison of immune responses in young children (2 to 5 years of age; n = 20) and older children (6 to 17 years of age; n = 20) given two doses of an oral killed cholera vaccine containing recombinant cholera toxin B subunit (CtxB) 14 days apart and compare these responses to those induced in similarly aged children recovering from infection with Vibrio cholerae O1 Ogawa in Bangladesh. We found that the two vaccine groups had comparable vibriocidal and lipopolysaccharide (LPS)-specific plasma antibody responses. Vaccinees developed lower levels of IgG memory B cell (MBC) responses against CtxB but no significant MBC responses against LPS. In contrast, children recovering from natural cholera infection developed prominent LPS IgG and IgA MBC responses, as well as CtxB IgG MBC responses. Plasma LPS IgG, IgA, and IgM responses, as well as vibriocidal responses, were also significantly higher in children following disease than after vaccination. Our findings suggest that acute and memory immune responses following oral cholera vaccination in children are significantly lower than those observed following wild-type disease, especially responses targeting LPS. These findings may explain, in part, the lower efficacy of oral cholera vaccination in children. PMID:22441386

  7. Single-Dose Phase I Study To Evaluate the Pharmacokinetics of Posaconazole in New Tablet and Capsule Formulations Relative to Oral Suspension

    PubMed Central

    Ma, Lei; Martinho, Monika; O'Mara, Edward

    2012-01-01

    Posaconazole oral suspension, a marketed extended-spectrum triazole with proven efficacy as antifungal treatment and prophylaxis, should be taken with food to maximize absorption. New tablet and capsule formulations have been developed in an attempt to optimize absorption and bioavailability. The aims of this exploratory open-label, partially randomized, 2-part, 4-way, single-dose crossover study in 16 healthy adults were to characterize pharmacokinetics for posaconazole tablet and capsule formulations relative to those for posaconazole oral suspension under fasted and fed conditions and to assess safety and tolerability. Under fasted conditions, posaconazole exposures (area under the curve [AUC]) for the tablet and capsule formulations were similar (mean AUC from time zero to infinity [AUC0–?], tablet A, 11,700 ng · h/ml [coefficient of variation {CV}, 26%]; tablet B, 11,300 ng · h/ml [CV, 22%]; capsule, 11,000 ng · h/ml [CV, 25%]) and were substantially higher than the exposure for the oral suspension (mean AUC0–?, 3,420 ng · h/ml [CV, 44%]). Tablets and capsule showed less variability in exposure than the oral suspension. In fed subjects, tablets and capsule resulted in similar AUC values (mean AUC0–?, tablet A, 11,900 ng · h/ml [23%]; tablet B, 12,400 ng · h/ml [CV, 25%]; capsule, 12,300 ng · h/ml [CV, 28%]) and slightly higher exposure than the oral suspension (mean AUC0–?, 8,750 [CV, 24%]). Median times to the maximum concentration of drug in plasma were 4 to 5 h (fasted conditions) and 6 to 8 h (fed conditions). Mean half-lives values were similar for all formulations under fed and fasted conditions (23.1 to 29.2 h). Consistent with previous data, exposure for the oral suspension increased 2.5- to 3-fold when it was given with a high-fat meal. Conversely, exposures for tablets and capsule were not markedly affected by food. All formulations of posaconazole at 100 mg were safe and well tolerated. PMID:22615291

  8. Metabolism of tryptophan and niacin in oral contraceptive users receiving controlled intakes of vitamin B61'2

    Microsoft Academic Search

    J. E. Lekiem; R. R. Brown; D. P. Rose; R. A. Arend

    ABSTRAO Tryptophan and niacin metabolism, after a 2-g tryptophan load, were studied in 10 female controls and 15 females taking estrogen-containing oral contraceptives while they were fed a low vitamin B6 diet for 28 days. Subgroups were supplemented with 0.8. 2.0. or 20 mg pyridoxine hydrochloride (pyridoxine-HCI) for the next 28 days and restudied. During the deficiency, those females taking

  9. A pharmacokinetic study comparing single and repeated oral doses of 20 mg and 40 mg omeprazole and its two optical isomers, S omeprazole (esomeprazole) and R omeprazole, in healthy subjects

    Microsoft Academic Search

    M. Hassan-Alin; T. Andersson; M. Niazi; K. Röhss

    2005-01-01

    Objective To investigate the pharmacokinetics of S-omeprazole (esomeprazole), R-omeprazole and racemic omeprazole following single and repeated oral doses of 20 mg and 40 mg of each compound in healthy male and female subjects. Methods In an open, randomised, three-way, cross-over study, 12 subjects received 20 mg and another 12 subjects received 40 mg S-omeprazole, R-omeprazole and racemic omeprazole as oral solutions once daily for

  10. Food effect on the oral bioavailability of Manidipine: single dose, randomized, crossover study in healthy male subjects

    Microsoft Academic Search

    D. ROSILLONl; A. STOCKISl; G. Poli; D. Acerbi; R. Lins; B. Jeanbaptiste

    1998-01-01

    Summary  The effect of food on the oral bioavailability of a manidipine 20 mg tablet was studied after a single administration in 12\\u000a male healthy subjects. The clinical trial was conducted as an open, randomised, crossover study. In two different administration\\u000a sessions, the subjects received a 20 mg manidipine tablet either in the fasting state or after a standardized breakfast. Plasma

  11. Dose-related Endocrine Effects and Pharmacokinetics of Oral and Intramuscular 4Hydroxyandrostenedione in Postmenopausal Breast Cancer Patients1

    Microsoft Academic Search

    M. Dowsett; D. C. Cunningham; R. C. Stein; S. Evans; L. Dehennin; A. Hedley; R. C. Coombes

    Hydroxyandrostenedione (CGP32349; 4-OHA) is a clinically effec tive treatment for advanced postmenopausal breast cancer by both the parenteral and p.o. routes, as a result of its inhibition of ¡immutasi- and consequent suppression of plasma estrogen levels. Thirty patients were randomized to treatment with 250 mg 4-OHA orally once, twice, and 4 times daily for 2 weeks and 29 of these

  12. Disposition of 2-(2-quinolyl)-1,3-indandione (D. C. yellow #11) in rats dosed orally or intravenously.

    PubMed

    el Dareer, S M; Kalin, J R; Tillery, K F; Hill, D L

    1988-01-01

    The disposition of 2-(2-quinolyl)-1,3-indandione (D. C. yellow #11, DCY) in male Fischer rats dosed intravenously or by feeding was determined. For rats given [14C]DCY in the feed (0.00044-0.41% of the diet), recovery of radioactivity during the 24-h dosing period and the 72-h period thereafter ranged from 89.1 to 93.9% for feces and from 4.98 to 6.25 for urine. Tissues contained only trace amounts. Following intravenous dosing with [14C]DCY (0.93 mg/kg), radioactivity distributed readily into most tissues; maximum amounts were present at 5 min, the earliest time of assay. Maximum amounts of radioactivity in fat, skin, and gut tissue, however, were present at 30 min after dosing. These three tissues also had relatively long alpha phases for the elimination of radioactivity. In 24 h after intravenous dosing, rats excreted 81.1% of the dose in the feces and 16.0% of the dose in the urine. For rats fitted with biliary cannulas, 54.5% of the dose, all of which was metabolites of [14C]DCY, was recovered in the bile in 4 h. Associated with the rapid and extensive biliary excretion of metabolites of intravenously administered [14C]DCY was the appearance of large amounts of radioactivity in the feces and also, at intermediate time points, in the liver, gut contents, and gut tissue. In conclusion, rats rapidly distribute, metabolize, and excrete [14C]DCY. PMID:3351983

  13. Subchronic oral toxicity study of Decitabine (DAC) in Combination with Tetrahydrouridine (THU) in CD-1 Mice

    PubMed Central

    Terse, Pramod; Engelke, Kory; Chan, Kenneth; Ling, Yonghua; Sharpnack, Douglas; Saunthararajah, Yogen; Covey, Joe

    2014-01-01

    Decitabine (5-aza-2’-deoxycytidine; DAC) in combination with tetrahydrouridine (THU) is a potential oral therapy for sickle cell disease and ?-thalassemia. A study was conducted in mice to assess safety of this combination therapy using oral gavage of DAC and THU administered 1 hour prior to DAC on two consecutive days/week for up to 9-weeks followed by a 28-day recovery to support its clinical trials upto 9 week duration. THU, a competitive inhibitor of cytidine deaminase, was used in the combination to improve oral bioavailability of DAC. Doses were 167 mg/kg THU followed by 0, 0.2, 0.4, or 1.0 mg/kg DAC; or THU vehicle followed by 1.0 mg/kg DAC; or vehicle alone. Endpoints evaluated were clinical observations, body weights, food consumption, clinical pathology, gross/histopathology, bone marrow micronuclei, and toxicokinetics. There were no treatment-related effects noticed on body weight, food consumption, serum chemistry or urinalysis parameters. Dose- and gender- dependent changes in plasma DAC levels were observed with a Cmax within 1 hr. At the 1mg/kg dose tested, THU increased DAC plasma concentration (~10-fold) as compared to DAC alone. Severe toxicity occurred in females receiving high dose 1mg/kg DAC + THU, requiring treatment discontinuation at week 5. Severity and incidence of microscopic findings increased in a dose-dependent fashion; findings included bone marrow hypocellularity (with corresponding hematologic changes; decreases in white blood cells, red blood cells, hemoglobin, hematocrit, reticulocytes, neutrophils and lymphocytes), thymic/lymphoid depletion, intestinal epithelial apoptosis and testicular degeneration. Bone marrow micronucleus analysis confirmed bone marrow cytotoxicity, suppression of erythropoeisis, and genotoxicity. Following the recovery period, a complete or trend towards resolution of these effects was observed. In conclusion, the combination therapy resulted in an increased sensitivity to DAC toxicity correlating with DAC plasma levels, and females are more sensitive compared to their male counterparts. PMID:24639139

  14. Collaborative work to evaluate toxicity on male reproductive organs by repeated dose studies in rats 23). A comparative 2- and 4-week repeated oral dose testicular toxicity study of boric acid in rats.

    PubMed

    Kudo, S; Tanase, H; Yamasaki, M; Nakao, M; Miyata, Y; Tsuru, K; Imai, S

    2000-10-01

    To assess the validity and limitations of 2-week repeated daily dosing to detect toxic effects on male reproductive organs in rodents, a comparative 2- and 4-week oral repeated dosing study of boric acid, a known testicular toxicant, was given to 6- or 8-week-old Crj:Wistar rats at daily levels of 0, 125, 250 and 500 mg/kg. The ages of the rats were selected so that they were all sacrificed at 10 weeks of age. The testes and epididymides were weighed at necropsy; histopathological specimens were prepared in a routine manner and stained with H&E or PAS-H. In addition, the sperm number and motility rates were evaluated. There were no boric acid-induced effects on reproductive organ weights and on gross behavior/appearance in any groups in either the 2- or 4-week studies. The sperm number and motility rate were not decreased in any group after 2 weeks, while both decreased in the 250 and 500 mg/kg groups after 4 weeks. Histopathologically, as evidence of toxicity at the early stage of boric acid exposure, retention of step 19 spermatids of stages IX-XI was observed in the testes of almost all rats treated with 500 mg/kg after both 2 weeks and 4 weeks. Degenerative/necrotic germ cells and multinucleated giant cell formation were observed in 2 weeks, though to a lesser extent than in 4 weeks. On stage analysis of germinal cells in 2 weeks, spermatogonia and spermatids of stage VII were found to be decreased, and pachytene spermatocytes of stage X were increased. In conclusion, the results indicate that if the selection of doses is appropriate, testicular toxicity of boric acid can be detected even after only 2 weeks of repeated daily oral treatment. PMID:11349447

  15. Phase 1 dose escalation trial of ilorasertib, a dual Aurora/VEGF receptor kinase inhibitor, in patients with hematologic malignancies.

    PubMed

    Garcia-Manero, Guillermo; Tibes, Raoul; Kadia, Tapan; Kantarjian, Hagop; Arellano, Martha; Knight, Emily A; Xiong, Hao; Qin, Qin; Munasinghe, Wijith; Roberts-Rapp, Lisa; Ansell, Peter; Albert, Daniel H; Oliver, Brian; McKee, Mark D; Ricker, Justin L; Khoury, Hanna Jean

    2015-08-01

    Background Ilorasertib (ABT-348) is a novel inhibitor of Aurora kinase, vascular endothelial growth factor (VEGF) and platelet-derived growth factor receptors, and the Src families of tyrosine kinases. Ilorasertib alone or in combination with azacitidine demonstrated activity in preclinical models in various hematological malignancies, indicating that pan-Aurora kinase and multiple kinase inhibition may have preferential antileukemic activity. This phase 1 trial determined the safety, pharmacokinetics, and preliminary antitumor activity of ilorasertib alone or combined with azacitidine in advanced hematologic malignancies. Patients and methods Fifty-two patients (median age, 67 years; 35 % with >4 prior regimens) with acute myelogenous leukaemia (AML; n?=?38), myelodysplastic syndrome (n?=?12), or chronic myelomonocytic leukaemia (n?=?2) received 3 or 6 doses of ilorasertib per 28-day cycle and were assigned to arm A (once-weekly oral), B (twice-weekly oral), C (once-weekly oral plus azacitidine), or D (once-weekly intravenous) treatment. Results Maximum tolerated doses were not determined; the recommended phase 2 oral monotherapy doses were 540 mg once weekly and 480 mg twice weekly. The most common grade 3/4 adverse events were hypertension (28.8 %), hypokalemia (15.4 %), anemia (13.5 %), and hypophosphatemia (11.5 %). Oral ilorasertib pharmacokinetics appeared dose proportional, with a 15-hour half-life and no interaction with azacitidine. Ilorasertib inhibited biomarkers for Aurora kinase and VEGF receptors, and demonstrated clinical responses in 3 AML patients. Conclusions Ilorasertib exhibited acceptable safety and pharmacokinetics at or below the recommended phase 2 dose, displayed evidence of dual Aurora kinase and VEGF receptor kinase inhibition, and activity in AML. PMID:25933833

  16. Pharmacokinetic comparison of sustained- and immediate-release formulations of cilostazol after multiple oral doses in fed healthy male Korean volunteers

    PubMed Central

    Kim, Yo Han; Ghim, Jong-Lyul; Jung, Jin Ah; Cho, Sang-Heon; Choe, Sangmin; Choi, Hee Youn; Bae, Kyun-Seop; Lim, Hyeong-Seok

    2015-01-01

    Background A new extended-release form of cilostazol has recently been developed. This study was conducted to compare the pharmacokinetic characteristics of sustained-release (SR) and immediate-release (IR) formulations of cilostazol after multiple oral doses in healthy male Korean volunteers. Methods This was an open-label, randomized, multiple-dose, crossover study conducted in 30 healthy Korean subjects. In each treatment period, subjects received oral doses of 200 mg SR formulation every 24 hours or 100 mg IR formulation every 12 hours for 5 consecutive days in a fed state, with a washout period of 9 days. The plasma concentrations of cilostazol and its metabolites were determined using a validated liquid chromatography-tandem mass spectrometry method. The area under the plasma concentration–time curve within a dosing interval (AUCT), the measured peak plasma concentration at steady state (Cmax,ss), and the time to reach Cmax,ss (tmax,ss) were analyzed using a noncompartmental method. Results A total of 24 healthy male subjects completed the study. The mean (standard deviation [SD]) AUCT (96–120 hours) values for SR and IR were 27,378.0 (10,301.6) ng·h/mL and 27,860.3 (7,152.3) ng·h/mL, respectively. The mean (SD) Cmax,ss values were 2,741.4 (836.0) ng/mL and 2,051.0 (433.2) ng/mL, respectively. The median tmax,ss values were 8.0 hours and 4.0 hours, respectively. The geometric mean ratios (90% confidence intervals) of the SR to IR formulations were 0.937 (0.863–1.017), 0.960 (0.883–1.043), and 0.935 (0.859–1.017) for AUCT and 0.644 (0.590–0.703), 0.586 (0.536–0.642), and 0.636 (0.577–0.702) for dose-normalized Cmax,ss of cilostazol, OPC-13015 (3,4-dehydro-cilostazol), and OPC-13213 (4?-trans-hydroxyl-cilostazol), respectively. All formulations were well tolerated. Conclusion At steady state, the AUCT of cilostazol SR 200 mg is comparable to that of cilostazol IR 100 mg twice a day in healthy male Korean subjects. Both formulations are well tolerated. PMID:26185423

  17. A comparison of the pharmacokinetic profile of an ascending-dose, extended-regimen combined oral contraceptive to those of other extended regimens.

    PubMed

    Darwish, Mona; Bond, Mary; Ricciotti, Nancy; Hsieh, Jennifer; Fiedler-Kelly, Jill; Grasela, Thaddeus

    2014-11-01

    Quartette (levonorgestrel [LNG]/ethinyl estradiol [EE] and EE) is an ascending-dose, extended-regimen combined oral contraceptive (COC) that consists of a constant dose of LNG 150 µg on days 1 to 84 with EE 20 µg on days 1 to 42, 25 µg on days 43 to 63, 30 µg on days 64 to 84, and 10 µg of EE monotherapy on days 85 to 91. A population pharmacokinetic (PK) model for EE was developed using nonlinear mixed-effects modeling to characterize the PK profile of EE administered in Quartette and other extended-regimen LNG/EE COCs. Model-predicted plasma concentration-time profiles demonstrated a stepwise increase in systemic exposure to EE during the first 84 days of the cycle following each EE dose change. Lower concentrations of EE were noted during the final 7-day period of EE 10 µg. Gradual increases in EE seen with Quartette may decrease the incidence of unscheduled bleeding frequently observed during early cycles of extended-regimen COCs. PMID:24647707

  18. Evaluation of Sphingolipids in Wistar Rats Treated to Prolonged and Single Oral Doses of Fumonisin B1

    PubMed Central

    Direito, Glória M.; Almeida, Adriana P.; Aquino, Simone; dos Reis, Tatiana Alves; Pozzi, Claudia Rodrigues; Corręa, Benedito

    2009-01-01

    The objective of the present study was to evaluate sphingolipid levels (sphingosine-So and sphinganine-Sa) and to compare the Sa/So ratio in liver, serum and urine of Wistar rats after prolonged administration (21 days) of fumonisin B1 (FB1). In parallel, the kinetics of sphingolipid elimination in urine was studied in animals receiving a single dose of FB1. Prolonged exposure to FB1 caused an increase in Sa levels in urine, serum and liver. The most marked effect on sphingolipid biosynthesis was observed in animals treated with the highest dose of FB1. Animals receiving a single dose of FB1 presented variations in Sa and So levels and in the Sa/So ratio. PMID:19333435

  19. Adverse reaction to ceftriaxone in a 28-day-old infant undergoing urgent craniotomy due to epidural hematoma: review of neonatal biliary pseudolithiasis

    PubMed Central

    Bartkowska-?niatkowska, Alicja; Jo?czyk-Potoczna, Katarzyna; Zieli?ska, Marzena; Rosada-Kurasi?ska, Jowita

    2015-01-01

    The debate as to whether to administer ceftriaxone to neonates is likely to continue. Ceftriaxone has numerous advantages for critically ill pediatric patients. However, it is also known to contribute substantially to the development of biliary pseudolithiasis. Although pediatric patients rarely develop gallbladder disorders, this complication may lead to adverse events in high-risk patients with predisposing factors, particularly in neonates and infants treated with ceftriaxone. In this paper we present an interesting case report of a 28-day-old neonate with spontaneous severe epidural hematoma who developed biliary pseudolithiasis related to the use of ceftriaxone. We also discuss the efficacy of ceftriaxone in neonates and infants. Neonatologists and pediatric intensivists should be aware of the higher risk of co-existence of hyperbilirubinemia and gallbladder disorders while using ceftriaxone in pediatric settings. PMID:26170682

  20. A single-dose, randomized, open-label, two-period crossover bioequivalence study of a fixed-dose pediatric combination of lamivudine 40-mg, nevirapine 70-mg, and stavudine 10-mg tablet for oral suspension with individual liquid formulations in healthy adult male volunteers

    Microsoft Academic Search

    Tausif Monif; Nageshwar Rao Thudi; Sudhakar Koundinya Tippabhotla; Arshad Khuroo; Amit Marwah; Vikesh Kumar Shrivastav; Monika Tandon; Rajeev Raghuvanshi; Shibadas Biswal

    2007-01-01

    Background: Because of the lack of suitable pediatric antiretroviral (ARV) agents, adult fixed-dose ARVs are commonly used in children. This practice poses concerns about dose inaccuracy, which may lead to resistance or toxicity.Objective: The objective of the present study was to evaluate the bioequivalence of a new pediatric fixed-dose combination (FDC) ARV tablet for oral suspension as compared with individual

  1. Renal Hemodynamic and Morphological Changes after 7 and 28 Days of Leptin Treatment: The Participation of Angiotensin II via the AT1 Receptor

    PubMed Central

    Thieme, Karina; Oliveira-Souza, Maria

    2015-01-01

    The role of hyperleptinemia in cardiovascular diseases is well known; however, in the renal tissue, the exact site of leptin’s action has not been established. This study was conducted to assess the effect of leptin treatment for 7 and 28 days on renal function and morphology and the participation of angiotensin II (Ang II), through its AT1 receptor. Rats were divided into four groups: sham, losartan (10 mg/kg/day, s.c.), leptin (0.5 mg/kg/day for the 7 days group and 0.25 mg/kg/day for the 28 days group) and leptin plus losartan. Plasma leptin, Ang II and endothelin 1 (ET-1) levels were measured using an enzymatic immuno assay. The systolic blood pressure (SBP) was evaluated using the tail-cuff method. The renal plasma flow (RPF) and the glomerular filtration rate (GFR) were determined by p-aminohippuric acid and inulin clearance, respectively. Urinary Na+ and K+ levels were also analyzed. Renal morphological analyses, desmin and ED-1 immunostaining were performed. Proteinuria was analyzed by silver staining. mRNA expression of renin-angiotensin system (RAS) components, TNF-? and collagen type III was analyzed by quantitative PCR. Our results showed that leptin treatment increased Ang II plasma levels and progressively increased the SBP, achieving a pre-hypertension state. Rats treated with leptin 7 days showed a normal RPF and GFR, but increased filtration fraction (FF) and natriuresis. However, rats treated with leptin for 28 showed a decrease in the RPF, an increase in the FF and no changes in the GFR or tubular function. Leptin treatment-induced renal injury was demonstrated by: glomerular hypertrophy, increased desmin staining, macrophage infiltration in the renal tissue, TNF-? and collagen type III mRNA expression and proteinuria. In conclusion, our study demonstrated the progressive renal morphological changes in experimental hyperleptinemia and the interaction between leptin and the RAS on these effects. PMID:25793389

  2. Toxicology and humoral immunity assessment of octamethylcyclotetrasiloxane (D4) following a 28-day whole body vapor inhalation exposure in Fischer 344 rats.

    PubMed

    Klykken, P C; Galbraith, T W; Kolesar, G B; Jean, P A; Woolhiser, M R; Elwell, M R; Burns-Naas, L A; Mast, R W; McCay, J A; White, K L; Munson, A E

    1999-11-01

    Octamethylcyclotetrasiloxane, D4, is a low viscosity, silicone fluid consisting of four dimethyl-siloxy units ((CH3)2SiO)4 in a cyclic structure. It is primarily used as a building block in the industrial synthesis of long chain silicone polymers. The combination of D4 with decamethylcyclopentasiloxane (D5) is commonly referred to as cyclomethicone which has a wide range of applications as a formulation aid in personal care products. To extend the existing database regarding the biological activities of D4, a 28 day whole body vapor inhalation study was conducted using Fischer 344 rats at 0 (room air), 7, 20, 60, 180 and 540 ppm for 6 hours/day, 5 days/week. Parameters measured included body weights, organ weights, gross pathology, histopathology, serum chemistries, and urinalysis. In addition to these standard toxicological endpoints, the ability of D4 exposed animals to mount an IgM antibody response was evaluated by a splenic antibody forming cell (AFC) assay and a serum enzyme-linked immunosorbant assay (ELISA). The results of this 28-day inhalation study indicate that D4 exposure caused no adverse effects on body weight, food consumption, or urinalysis parameters. In addition, there were no exposure related histopathological alterations at any site for any exposure group. A statistically significant increase in liver weight and the liver to body weight ratio was observed in both male (180-540 ppm) and female (20-540 ppm) rats, which was not observed in the 14-day recovery group animals. There were no other significant organ weight changes. Although statistically significant changes were observed in several hematological and serum chemistry parameters in both the terminal and 14-day recovery animals, the changes were marginal and within the normal range of values for the rat. Under these experimental conditions, there were no alterations noted in immune system function at any of the D4 exposure levels. PMID:10536755

  3. Review of oral fixed-dose combination netupitant and palonosetron (NEPA) for the treatment of chemotherapy-induced nausea and vomiting.

    PubMed

    Lorusso, Vito; Karthaus, Meinolf; Aapro, Matti

    2015-02-01

    Current guidelines recommend the combination of a neurokinin-1 (NK1) receptor antagonist (RA) and a 5-hydroxytryptamine-3 (5-HT3) RA, together with corticosteroids, in order to prevent chemotherapy-induced nausea and vomiting with anthracycline-cyclophosphamide and highly emetogenic chemotherapy, and it is to be considered with moderately emetogenic chemotherapy. Netupitant and palonosetron (NEPA) is a fixed-dose combination of netupitant, a novel, highly selective NK1 RA, and palonosetron, a new-generation 5-HT3 RA, targeting two major emetic pathways in a single oral capsule. In clinical trials, NEPA administered on day 1 together with dexamethasone was highly effective and well tolerated in the prevention of chemotherapy-induced nausea and vomiting in patients with solid tumors undergoing moderately emetogenic chemotherapy or highly emetogenic chemotherapy. NEPA offers maximal convenience, and as a simple guideline-based regimen, has the potential to improve adherence to guidelines. PMID:25360998

  4. Effects of short-term oral dosing of polychlorotrifluoroethylene (polyCTFE) on the rhesus monkey. (Reannouncement with new availability information). Final report, March 1989-March 1990

    SciTech Connect

    Jones, C.E.; Ballinger, M.B.; Seckel, C.; Vinegar, A.; Mattie, D.R.

    1991-12-31

    Polychlorotrifluoroethylene (polyCTFE-primarily oligomers with 3-4 monomer units), a nonflammable hydraulic fluid for aircraft, was given daily for 15 days by oral gavage to four Rhesus monkeys at a concentration of 0.725 g kg-1. The administered dose was at a level that had caused toxicity in rats. Steady-state blood and liver concentrations reached were the same in both species. In monkeys, polyCTFE did not cause the electrolyte, serum protein, liver enzyme and anemic disturbances previously seen in rats. Liver sections taken at 15 days, analyzed for palmitoyl Co-A beta-oxidation rates or by electron microscopy, showed no significant indication of peroxisomal proliferation. An increased blood urea nitrogen (BUN) at 15 days was the only clinical pathological abnormality seen in both monkeys and rats. Previously unobserved effects were increased triglycerides and glycogen depletion. polyGTFE; aircraft hydraulic fluid; toxicity; peroxisome proliferation.

  5. Seroprevalence of poliovirus antibodies among 7-month-old infants after 4 doses of oral polio vaccine in Sistan-va-Baluchestan, Islamic Republic of Iran.

    PubMed

    Izadi, S; Shahmahmoodi, S; Zahraei, S M; Dorostkar, F; Majdzadeh, S-R

    2015-02-01

    Despite high coverage rates of polio vaccine in the Islamic Republic of Iran, the seroconversion rates of infants may be inadequate. This study measured seroprevalence of antibodies against poliovirus serotypes 1 to 3 (PV1, PV2 and PV3) in 7-month-old infants who had received at least 4 doses of trivalent oral polio vaccine. A serosurvey was conducted in 2010 in rural areas of Chabahar, Sistan-va-Baluchestan province. Using cluster sampling, 72 eligible infants were tested for antibody against the 3 poliovirus serotypes according to WHO guidelines. Antibody titres ? 1:10 were considered positive. The seropositive rates for antibody against PV1, PV2 and PV3 were 84.7%, 95.8% and 70.8% respectively. Only 63.9% of participants were seropositive for antibodies against all 3 poliovirus serotypes. Except for PV2, the seroprevalence of antibody against the other 2 poliovirus serotypes, especially PV3, was unsatisfactory. PMID:25876819

  6. Determination of roxithromycin by liquid chromatography/mass spectrometry after multiple-dose oral administration in broilers.

    PubMed

    Lim, Jong-hwan; Park, Byung-kwon; Yun, Hyo-in

    2003-04-01

    A highly sensitive and specific method for the determination of roxithromycin in broiler tissues by LC/MS was developed and validated. A dichloromethane extract of the sample was separated on C18 reversed-phase column with acetonitrile-50 mM ammonium acetate (80:20, v/v) as the mobile phase and analyzed by LC/MS via atmospheric pressure ionization/electrospray ionization interface. The limit of detection and limit of quantitation were 1 ng/g and 5 ng/g. The method has been successfully applied to determine for roxithromycin in various tissues of broilers. Residue concentrations were associated with administered dose. At the termination of treatment, roxithromycin was found in all collected samples for both dose groups. Liver was detected to have the highest residual concentration of roxithromycin. Residue concentrations of roxithromycin were lower than its LOQ in all tissues from both dose groups 10 days after the treatment of roxithromycin mixed with drinking water at a dose rate of 15 mg/L or 60 mg/L to each broiler for 7 days. PMID:12819363

  7. Single and multiple dose pharmacokinetics of maritime pine bark extract (Pycnogenol) after oral administration to healthy volunteers

    Microsoft Academic Search

    Tanja Grimm; Roswitha Skrabala; Zuzana Chovanová; Jana Muchová; Katarína Sumegová; Anna Liptáková; Zde?ka ?ura?ková; Petra Högger

    2006-01-01

    BACKGROUND: Since plant extracts are increasingly used as phytotherapeutics or dietary supplements information on bioavailability, bioefficacy and safety are warranted. We elucidated the plasma kinetics of genuine extract components and metabolites after single and multiple ingestion of the standardized maritime pine bark extract Pycnogenol (USP quality) by human volunteers. METHODS: Eleven volunteers received a single dose of 300 mg pine

  8. Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors

    ClinicalTrials.gov

    2015-06-23

    Dose Escalation; Safety; Preliminary Efficacy; Advanced Solid Tumors; Metastatic Breast Cancer; Advanced Pancreatic Adenocarcinoma; Metastatic Colorectal Cancer; Recurrent Glioblastoma Multiforme; Gastric Cancer; Gastroesophageal Junction Cancer; Triple Negative Metastatic Breast Cancer; Hormone Receptor Positive (ER+/PR+, and Her2-) Metastatic Breast Cancer

  9. Phase III Randomized, Double-Blind Study Comparing Single-Dose Intravenous Peramivir with Oral Oseltamivir in Patients with Seasonal Influenza Virus Infection ? †

    PubMed Central

    Kohno, Shigeru; Yen, Muh-Yong; Cheong, Hee-Jin; Hirotsu, Nobuo; Ishida, Tadashi; Kadota, Jun-ichi; Mizuguchi, Masashi; Kida, Hiroshi; Shimada, Jingoro

    2011-01-01

    Antiviral medications with activity against influenza viruses are important in controlling influenza. We compared intravenous peramivir, a potent neuraminidase inhibitor, with oseltamivir in patients with seasonal influenza virus infection. In a multinational, multicenter, double-blind, double-dummy randomized controlled study, patients aged ?20 years with influenza A or B virus infection were randomly assigned to receive either a single intravenous infusion of peramivir (300 or 600 mg) or oral administration of oseltamivir (75 mg twice a day [b.i.d.] for 5 days). To demonstrate the noninferiority of peramivir in reducing the time to alleviation of influenza symptoms with hazard model analysis and a noninferiority margin of 0.170, we planned to recruit 1,050 patients in South Korea, Japan, and Taiwan. A total of 1,091 patients (364 receiving 300 mg and 362 receiving 600 mg of peramivir; 365 receiving oseltamivir) were included in the intent-to-treat infected population. The median durations of influenza symptoms were 78.0, 81.0, and 81.8 h in the groups treated with 300 mg of peramivir, 600 mg of peramivir, and oseltamivir, respectively. The hazard ratios of the 300- and 600-mg-peramivir groups compared to the oseltamivir group were 0.946 (97.5% confidence interval [CI], 0.793, 1.129) and 0.970 (97.5% CI, 0.814, 1.157), respectively. Both peramivir groups were noninferior to the oseltamivir group (97.5% CI, <1.170). The overall incidence of adverse drug reactions was significantly lower in the 300-mg-peramivir group, but the incidence of severe reactions in either peramivir group was not different from that in the oseltamivir group. Thus, a single intravenous dose of peramivir may be an alternative to a 5-day oral dose of oseltamivir for patients with seasonal influenza virus infection. PMID:21825298

  10. Pharmacokinetics of a single oral dose of vitamin D3 (70,000 IU) in pregnant and non-pregnant women

    PubMed Central

    2012-01-01

    Background Improvements in antenatal vitamin D status may have maternal-infant health benefits. To inform the design of prenatal vitamin D3 trials, we conducted a pharmacokinetic study of single-dose vitamin D3 supplementation in women of reproductive age. Methods A single oral vitamin D3 dose (70,000 IU) was administered to 34 non-pregnant and 27 pregnant women (27 to 30 weeks gestation) enrolled in Dhaka, Bangladesh (23°N). The primary pharmacokinetic outcome measure was the change in serum 25-hydroxyvitamin D concentration over time, estimated using model-independent pharmacokinetic parameters. Results Baseline mean serum 25-hydroxyvitamin D concentration was 54 nmol/L (95% CI 47, 62) in non-pregnant participants and 39 nmol/L (95% CI 34, 45) in pregnant women. Mean peak rise in serum 25-hydroxyvitamin D concentration above baseline was similar in non-pregnant and pregnant women (28 nmol/L and 32 nmol/L, respectively). However, the rate of rise was slightly slower in pregnant women (i.e., lower 25-hydroxyvitamin D on day 2 and higher 25-hydroxyvitamin D on day 21 versus non-pregnant participants). Overall, average 25-hydroxyvitamin D concentration was 19 nmol/L above baseline during the first month. Supplementation did not induce hypercalcemia, and there were no supplement-related adverse events. Conclusions The response to a single 70,000 IU dose of vitamin D3 was similar in pregnant and non-pregnant women in Dhaka and consistent with previous studies in non-pregnant adults. These preliminary data support the further investigation of antenatal vitamin D3 regimens involving doses of ?70,000 IU in regions where maternal-infant vitamin D deficiency is common. Trial registration ClinicalTrials.gov (NCT00938600) PMID:23268736

  11. Orally administrated pterostilbene attenuates acute cerebral ischemia-reperfusion injury in a dose- and time-dependent manner in mice.

    PubMed

    Zhou, Yu; Zhang, Xue-Mei; Ma, Ang; Zhang, Ya-Li; Chen, Yan-Yi; Zhou, Hao; Li, Wen-Jun; Jin, Xin

    2015-08-01

    Pterostilbene (3,5-dimethoxy-4-hydroxystilbene) is a component of blueberry. It has been reported that long-term treatment with blueberry has a neuroprotective effect. However, it has not been reported whether pterostilbene is effective in attenuating cerebral ischemia/reperfusion (I/R) injury. In the present study, focal cerebral ischemia was induced by middle cerebral artery occlusion for 90min followed by reperfusion. To observe the dose-dependent effect, pterostilbene (2.5-80mg/kg, ig) was administered for 3days before ischemia. To determine the time-dependent effect, pterostilbene (10mg/kg, ig) was administered as a single dose at 0, 1, or 3h after reperfusion. Twenty-four hours after I/R, pterostilbene dose-dependently improved neurological function, reduced brain infarct volume, and alleviated brain edema. The most effective dose was 10mg/kg; the therapeutic time window was within 1h after I/R and treatment immediately after reperfusion showed the best protective effect. The protective effect is further confirmed by the results that post-ischemic treatment with pterostilbene (10mg/kg) significantly improved motor function, alleviated blood brain barrier disruption, increased neurons survival and reduced cell apoptosis in cortical penumbra after cerebral I/R. We also found that pterostilbene (10mg/kg) significantly reversed the increased content of malondialdehyde and the decreased activity of superoxide dismutase in the ipsilateral hemisphere. Furthermore, pterostilbene decreased the oxidative stress markers 4-hydroxynonenal and 8-hydroxyguanosine positive cells in the cortical penumbra. All these findings indicate that pterostilbene dose- and time-dependently exerts a neuroprotective effect against acute cerebral I/R injury. This neuroprotective effect of pterostilbene may be associated with its inhibition of oxidative stress and subsequent neuronal apoptosis in the cortical penumbra. PMID:26086685

  12. Absorption and elimination of an oral dose of sup 3 H-deoxynivalenol in colostomized and intact chickens

    SciTech Connect

    Lun, A.K.; Moran, E.T. Jr.; Young, L.G.; McMillan, E.G. (Univ. of Guelph, Ontario (Canada))

    1989-06-01

    Deoxynivalenol (DON or 3, 7, 15-trihydroxy-12, 13-epoxy-trichothec-9-en-8-one) is a mycotoxin produced by Fusarium graminearum that can contaminate grain. Domestic fowl are particularly tolerant to DON ingestion. Prelusky et al. orally administered {sup 14}C-DON to chickens and observed high radioactivity in the liver and bile with over 90% of the original label accruing in the excreta before 48 h. DON cannot be detected in portal blood concurrent to its disappearance from the gastrointestinal tract. Presumably, DON was structurally modified upon absorption then hepatically retrieved and excreted in bile. In the present experimentation, {sup 3}H-DON was intubated into colostomized and intact hens. The objective was to measure the progressive changes in distribution of radioactivity along the gastrointestinal tract, among body tissues and between urine and feces.

  13. Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models

    PubMed Central

    TANAKA, NOZOMU; SAKAMOTO, KAZUKI; OKABE, HIROYUKI; FUJIOKA, AKIO; YAMAMURA, KEISUKE; NAKAGAWA, FUMIO; NAGASE, HIDEKI; YOKOGAWA, TATSUSHI; OGUCHI, KEI; ISHIDA, KEIJI; OSADA, AKIKO; KAZUNO, HIROMI; YAMADA, YUKARI; MATSUO, KENICHI

    2014-01-01

    TAS-102 is a novel oral nucleoside antitumor agent containing trifluridine (FTD) and tipiracil hydrochloride (TPI). The compound improves overall survival of colorectal cancer (CRC) patients who are insensitive to standard chemotherapies. FTD possesses direct antitumor activity since it inhibits thymidylate synthase (TS) and is itself incorporated into DNA. However, the precise mechanisms underlying the incorporation into DNA and the inhibition of TS remain unclear. We found that FTD-dependent inhibition of TS was similar to that elicited by fluorodeoxyuridine (FdUrd), another clinically used nucleoside analog. However, washout experiments revealed that FTD-dependent inhibition of TS declined rapidly, whereas FdUrd activity persisted. The incorporation of FTD into DNA was significantly higher than that of other antitumor nucleosides. Additionally, orally administered FTD had increased antitumor activity and was incorporated into DNA more effectively than continuously infused FTD. When TAS-102 was administered, FTD gradually accumulated in tumor cell DNA, in a TPI-independent manner, and significantly delayed tumor growth and prolonged survival, compared to treatment with 5-FU derivatives. TAS-102 reduced the Ki-67-positive cell fraction, and swollen nuclei were observed in treated tumor tissue. The amount of FTD incorporation in DNA and the antitumor activity of TAS-102 in xenograft models were positively and significantly correlated. These results suggest that TAS-102 exerts its antitumor activity predominantly due to its DNA incorporation, rather than as a result of TS inhibition. The persistence of FTD in the DNA of tumor cells treated with TAS-102 may underlie its ability to prolong survival in cancer patients. PMID:25230742

  14. Oral sedation.

    PubMed

    Dionne, R

    1998-09-01

    "I fear a trip to the dentist more than I fear death" is the response one person gave in a national survey recently cited in USA Today. While clearly representing an extreme, the results of many surveys suggest that fear of dentistry is still prevalent and is a measure of the failure of current therapeutic approaches to reduce pain and anxiety sufficiently to enable people, especially those with special needs, to visit the dentist. Patients who are fearful would likely seek oral health care more regularly if anesthesia and sedation were more readily available. Taking into consideration that the safety of anxiolytic drugs is highly dependent on the drug, dose, and route of administration used, oral premedication should be the sedative technique used by most dentists because it is efficacious, requires little monitoring when appropriate doses are used, and is unlikely to result in serious morbidity. PMID:9852800

  15. Safety and Efficacy of Dose-Intensive Oral Vitamin A in Subjects with Sun-Damaged Skin

    Microsoft Academic Search

    David Alberts; James Ranger-Moore; Janine Einspahr; Kathylynn Saboda; Paul Bozzo; Yun Liu; Xiao-chun Xu; Reuben Lotan; James Warneke; Stuart Salasche; Suzanne Stratton; Norman Levine; Rayna Goldman; Marcy Islas; Laura Duckett; Deborah Thompson; Peter Bartels

    2004-01-01

    Purpose: Previously, we reported the results of a Phase III, placebo-controlled trial in 2,297 randomized participants with moderately severe actinic keratoses wherein 25,000 IU\\/ day vitamin A caused a 32% risk reduction in squamous cell skin cancers. We hypothesized that dose escalation of vitamin A to 50,000 or 75,000 IU\\/day would be both safe and more efficacious in skin cancer

  16. Chemoimmunotherapy with oral low-dose fludarabine, cyclophosphamide and rituximab (old-FCR) as treatment for elderly patients with chronic lymphocytic leukaemia.

    PubMed

    Gozzetti, Alessandro; Candi, Veronica; Fabbri, Alberto; Schiattone, Luana; Cencini, Emanuele; Lauria, Francesco; Frasconi, Adele; Crupi, Rosaria; Raspadori, Donatella; Papini, Giulia; Defina, Marzia; Bartalucci, Giulia; Bocchia, Monica

    2014-08-01

    Median age at diagnosis for chronic lymphocytic leukaemia (CLL) patients is now 72 years, thus a consistent number of patients may not tolerate standard doses i.v. of fludarabine, cyclophosphamide and rituximab (FCR), the best available therapy, due to unacceptable myelotoxicity and risk of severe infections. We studied safety and efficacy of the addition of rituximab to the oral low-dose FC regimen (old-FCR) in a selected population of 30 elderly (median age 75, 15 untreated, 15 treated with 1 prior therapy) CLL patients. Complete remission (CR) rate was 80% in the untreated patients (overall response rate, ORR 93%), and 30% in pretreated patients (ORR 74%). Progression free survivals (PFS) were 45 months and 30 months in the untreated and treated patients, respectively. In patients achieving CR, old-FCR led to PFS of 67 months. Moreover, haematological toxicity was mild (grade 3-4: 15%) and patients were treated mostly in outpatient clinic. Old-FCR could be a good therapy option for elderly CLL patients outside clinical trials, larger studies are needed to confirm our findings. PMID:24934847

  17. Chronic toxicity and oncogenic dose-response effects of lifetime oral acrylonitrile exposure to Fischer 344 rats.

    PubMed

    Johannsen, Frederick R; Levinskas, George J

    2002-06-24

    Acrylonitrile (AN) was administered in the drinking water for approximately 2 years to groups of 100 male and 100 female Fischer 344 rats at nominal concentrations of 1, 3, 10, 30, and 100 ppm. Two groups, each of 100 males and 100 females, were used as untreated controls. Average daily intake was 0.1, 0.3, 0.8, 2.5 or 8.4 mg AN per kg body weight per day, respectively, for treated male rats and 0.1, 0.4, 1.3, 3.7, or 10.9 mg AN per kg per body weight per day, respectively, for dosed females. Clinical biochemistry, interim necropsies, organ weights and microscopic evaluation of tissues and organs were performed on groups of ten rats per sex per group at months 6, 12, and 18 and at study termination. Females were sacrificed in the 24th month and males were terminated after 26 months of dosing. A consistent decrease in survival, lower body weight and reduced water intake, as well as small reductions in hematological parameters, were observed in both sexes of the 100 ppm group. Elevated numbers of early deaths were observed in groups of males receiving 10 ppm AN and females receiving 30 ppm AN. Organ:body weight ratios at various study intervals were consistently elevated in the high dose group and likely were related to lower body weights. At these same intervals, mean absolute weights were either comparable to controls or only slightly elevated and few changes in weight ratios were seen when organ weights were compared with brain weights. No biochemical changes suggested a treatment-related effect. An increase in urine specific gravity in 100 ppm male rats was reflective of a decrease in liquid intake at this level. The only significant non-neoplastic finding observed histologically was a dose-related increase in hyperplasia/hyperkeratosis in squamous cells of the forestomach in male and female rats given 3 ppm and higher AN. This observation correlated with the induction of treatment-related squamous cell tumors (papillomas and carcinomas) of the forestomach seen primarily in rats at 3 ppm AN and higher. Mammary gland carcinomas were observed only in female groups. Both sexes given 10 ppm AN or more in their drinking water for their lifetime had astrocytomas of the brain/spinal cord and adenomas/carcinomas of the Zymbal's gland. PMID:12044705

  18. Lack of male-female differences in disposition and esterase hydrolysis of ramipril to ramiprilat in healthy volunteers after a single oral dose.

    PubMed

    Vree, Tom B; Dammers, Erik; Ulc, Ivan; Horkovics-Kovats, Stefan; Ryska, Miroslav; Merkx; Ijsbrand

    2003-12-11

    The objective of this study was to identify differences in disposition and esterase hydrolysis of ramipril between male and female volunteers. Plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) data of ramipril and its active metabolite ramiprilat (-diacid) were obtained from a randomised, cross-over bioequivalence study in 36 subjects (18 females and 18 males). Participants received a single 5-mg oral dose of two different formulations of ramipril (Formulation I and II). Plasma ramipril and ramiprilat concentrations were determined according to validated methods involving liquid chromatography-mass spectrometry. A total number of 2 x 34 available plasma concentration-time curves of both the parent drug and the metabolite could be analysed, and variations (50-100% coefficient of variation [CV]) in plasma concentrations of both parent drug and metabolite were found. With both the formulations, the mean plasma concentrations-time curves of males and females were identical. The groups of female and male volunteers showed similar yields (AUCt = microg x h/L) of the metabolite ramiprilat (p = 0.37); however, females showed a higher AUCt/kg than males (p = 0.046). This difference was solely attributed to the difference in body weight between males and females (p = 0.00049). In both male and female groups, a subject-dependent yield of active metabolite ramiprilat was demonstrated, which was independent of the formulation. There is a large variation in the ramiprilat t1/2beta (50-60% CV). There is a group of subjects who showed a t1/2beta of approximately 80 h (15% CV), and two apparent groups with a longer t1/2beta for each formulation (124 h, 22.5% CV; 166 h, 21.6% CV, respectively, p = 0.0013). This variation in the terminal half-life of ramiprilat is not sex related. In all three groups of half-lives, the corresponding Cmax values (mean +/- SD) of ramiprilat in males and females were identical. Thus, with identical Cmax and half-lives, the difference found in the AUCt/kg of ramiprilat must be due to the difference in dose, as the consequence of the difference in body weight, following a standard dose of 5 mg in both males and females. This study showed clearly that despite subject-dependent hydrolysis of ramipril to the active metabolite ramiprilat, the variability in the rate of hydrolysis between males and females is similar. With a fixed dose (5 mg), females received a higher dose/kg than males and consequently showed a higher AUCt/kg of the active metabolite ramiprilat. PMID:14755115

  19. Added benefits and user satisfaction with a low-dose oral contraceptive containing drospirenone: results of three multicentre trials.

    PubMed

    Bitzer, Johannes; Paoletti, Anna M

    2009-01-01

    The ethinylestradiol 20 microg/drospirenone 3 mg combined oral contraceptive (COC), administered in cycles of 21 days continuous use followed by a 7-day hormone-free interval (21/7) [Yasminelle], has been proven to be an effective and well tolerated contraceptive with an acceptable bleeding pattern and good safety profile. In addition, the ethinylestradiol 20 microg/drospirenone 3 mg 21/7 COC prevents water-retention-related weight gain, and improves physical and emotional well-being, consistent with other drospirenone-containing COCs. In clinical studies, >85% of those who received the ethinylestradiol 20 microg/drospirenone 3 mg 21/7 COC were satisfied or very satisfied with this contraceptive. The positive attributes of the ethinylestradiol 20 microg/drospirenone 3 mg 21/7 COC beyond contraceptive protection may have important implications for improving treatment compliance and reducing treatment discontinuation. Physical well-being stayed the same or improved during use of this COC in 56% and 34% of women, respectively. Emotional well-being stayed the same or improved in 71% and 20% of women, respectively. PMID:19133702

  20. Influence of Exercise on the Metabolic Profile Caused by 28 days of Bed Rest with Energy Deficit and Amino Acid Supplementation in Healthy Men

    PubMed Central

    Brooks, Naomi E.; Cadena, Samuel M.; Cloutier, Gregory; Vega-López, Sonia; Roubenoff, Ronenn; Castaneda-Sceppa, Carmen

    2014-01-01

    Objective Muscle loss and metabolic changes occur with disuse [i.e. bed rest (BR)]. We hypothesized that BR would lead to a metabolically unhealthy profile defined by: increased circulating tumor necrosis factor (TNF)-?, decreased circulating insulin-like-growth-factor (IGF)-1, decreased HDL-cholesterol, and decreased muscle density (MD; measured by mid-thigh computerized tomography). Methods We investigated the metabolic profile after 28 days of BR with 8±6% energy deficit in male individuals (30-55 years) randomized to resistance exercise with amino acid supplementation (RT, n=24) or amino acid supplementation alone (EAA, n=7). Upper and lower body exercises were performed in the horizontal position. Blood samples were taken at baseline, after 28 days of BR and 14 days of recovery. Results We found a shift toward a metabolically unfavourable profile after BR [compared to baseline (BLN)] in both groups as shown by decreased HDL-cholesterol levels (EAA: BLN: 39±4 vs. BR: 32±2 mg/dL, RT: BLN: 39±1 vs. BR: 32±1 mg/dL; p<0.001) and Low MD (EAA: BLN: 27±4 vs. BR: 22±3 cm2, RT: BLN: 28±2 vs. BR: 23±2 cm2; p<0.001). A healthier metabolic profile was maintained with exercise, including NormalMD (EAA: BLN: 124±6 vs. BR: 110±5 cm2, RT: BLN: 132±3 vs. BR: 131±4 cm2; p<0.001, time-by-group); although, exercise did not completely alleviate the unfavourable metabolic changes seen with BR. Interestingly, both groups had increased plasma IGF-1 levels (EAA: BLN:168±22 vs. BR 213±20 ng/mL, RT: BLN:180±10 vs. BR: 219±13 ng/mL; p<0.001) and neither group showed TNF? changes (p>0.05). Conclusions We conclude that RT can be incorporated to potentially offset the metabolic complications of BR. PMID:25317071

  1. A Comparative Efficacy of Low-Dose Combined Oral Contraceptives Containing Desogestrel and Drospirenone in Premenstrual Symptoms

    PubMed Central

    Wichianpitaya, Jirath; Taneepanichskul, Surasak

    2013-01-01

    Objective. To compare the efficacy of low-dose COC containing desogestrel (DSG) with drospirenone (DRSP) in the changes of premenstrual symptoms. Methods. In an open-label randomized controlled trial, 90 women with premenstrual syndrome who required COC were randomly recruited and allocated equally to receive either 6 cycles of 20 micrograms ethinyl estradiol (EE)/150 micrograms DSG (DSG group) or 20 micrograms EE/3?mg DRSP (DRSP group) in 24/4 extended regimen. Analysis of covariance and repeated analysis of variance were used to determine the difference of mean Women's Health Assessment Questionnaire (WHAQ) scores changes between groups, within group, and in premenstrual, menstrual, and postmenstrual phases. Results. Baseline characteristics and WHAQ scores were comparable. At the ends of the 3rd and the 6th cycles, mean WHAQ scores of all the 3 phases in DRSP group showed significant reduction and were significantly lower than those in DSG group. DSG group showed significant reduction in both premenstrual and menstrual phases after the 6th cycle. Adverse effects were comparable in both groups. In conclusion, low-dose COC containing either DSG or DRSP reduced premenstrual symptoms, but the latter showed greater efficacy and earlier reduction. PMID:23577032

  2. Evaluation of the repeated-dose liver micronucleus assay using 2,4-dinitrotoluene: a report of a collaborative study by CSGMT/JEMS.MMS.

    PubMed

    Maeda, Akihisa; Tsuchiyama, Hiromi; Asaoka, Yoshiji; Hirakata, Mikito; Miyoshi, Tomoya; Oshida, Keiyu; Miyamoto, Yohei

    2015-03-01

    The liver micronucleus assay using young adult rats has the potential to detect liver carcinogens by repeated dosing, and could be expected to be integrated into repeated-dose toxicity studies using a hepatocyte isolation method without the traditional in situ collagenase perfusion. In this study, to assess the performance of the repeated-dose liver micronucleus assay, 2,4-dinitrotoluene (DNT), which is a rodent liver carcinogen, was administered orally to male rats at doses of 50, 100 and 200 mg/kg/day once daily for 14 or 28 consecutive days, and the frequencies of micronucleated hepatocytes (MNHEPs) and micronucleated immature erythrocytes (MNIMEs) were examined. Significant increases in the MNHEPs were observed at 50 mg/kg/day or more in the 14-day treatment, and 50 and 100 mg/kg/day in the 28-day treatment. These increases were dependent on both the dose and the number of administrations, which indicates the possibility that the MNHEPs accumulate as a result of repeated dosing. In contrast, no increase in the MNIMEs was observed. In conclusion, the repeated-dose liver micronucleus assay using young adult rats is sufficiently sensitive to detect the genotoxicity of 2,4-DNT at a low dose. PMID:26065309

  3. A Phase I, dose-finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors.

    PubMed

    Yamamoto, Noboru; Nokihara, Hiroshi; Yamada, Yasuhide; Goto, Yasushi; Tanioka, Maki; Shibata, Takashi; Yamada, Kazuhiko; Asahina, Hajime; Kawata, Toshio; Shi, Xiaojin; Tamura, Tomohide

    2012-03-01

    Olaparib (AZD2281) is an orally active Poly(ADP-ribose) polymerase (PARP) inhibitor with favorable antitumor activity in advanced ovarian and breast cancers with BRCA1/2 mutations in Western (USA and European) studies. This Phase I dose-finding study evaluated the tolerability, pharmacokinetics, PARP inhibitory activity, and antitumor activity of olaparib in Japanese patients with solid tumors. Olaparib was administered as a single-dose on day 1, followed by twice-daily dosing for 28 days from 48 h after a single dose. Doses were escalated from 100 mg b.i.d. in successive cohorts, up to a maximum of 400 mg b.i.d. The present study enrolled 12 patients (n = 3, 3, and 6 in 100, 200 and 400-mg b.i.d. levels, respectively). The most common adverse events were nausea, increased blood creatinine, decreased hematocrit, leukopenia and lymphopenia; dose-limiting toxicities were not observed up to and including the 400-mg b.i.d. dose level. Following twice-daily dosing, olaparib showed no marked increase in exposure at steady state over that expected from the single-dose pharmacokinetics. PARP-1 inhibition was observed from the 100-mg b.i.d. dose level in peripheral blood mononuclear cells from 6 h post-dose on day 1 during the multiple-dosing period. A patient with metastatic breast cancer (100 mg b.i.d.) had a partial response for 13 months and four patients (two each in the 200 and 400-mg b.i.d. levels) had stable disease >8 weeks. Olaparib was well tolerated up to the 400-mg b.i.d. dose in Japanese patients with solid tumors. Preliminary evidence of antitumor activity was observed. PMID:22145984

  4. A phase I/II study of oral clofarabine plus low-dose cytarabine in previously treated acute myeloid leukaemia and high-risk myelodysplastic syndrome patients at least 60 years of age.

    PubMed

    Buckley, Sarah A; Mawad, Raya; Gooley, Ted A; Becker, Pamela S; Sandhu, Vicky; Hendrie, Paul; Scott, Bart L; Wood, Brent L; Walter, Roland B; Smith, Kelly; Dean, Carol; Estey, Elihu H; Pagel, John M

    2015-08-01

    Outcomes for older adults with acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS) are generally poor, and new effective therapies are needed. We investigated oral clofarabine combined with low-dose cytarabine (LDAC) in patients aged 60 years and above with relapsed or refractory AML or high-risk MDS in a phase I/II trial. A 3 + 3 dose escalation of oral clofarabine was followed by a phase II expansion with the aim of obtaining a complete response (CR) rate ?30%. We identified 20 mg/d for 5 d as the maximum tolerated dose (MTD) of oral clofarabine. A total of 35 patients, with a median age of 72 years, were treated. Of 26 patients enrolled at the MTD, 4 had treatment-related grade 3-4 non-haematological toxicities, but none died within 28 d. The observed CR rate and median survival were 34% [95% confidence interval (CI), 18-50%] and 6·8 months overall and 38% [95% CI, 19-57%] and 7·2 months at the MTD. The median disease-free survival was 7·4 months. Fifty-two percent (23/44) of cycles administered at the MTD were done without hospital admission. This combination of oral clofarabine and LDAC demonstrated efficacy with a CR rate of >30% and acceptable toxicity in older patients. PMID:25854284

  5. Immunohistochemical localization of thyroid stimulating hormone induced by a low oral dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin in female Sprague-Dawley rats.

    PubMed

    Nishimura, Noriko; Miyabara, Yuichi; Sato, Mikio; Yonemoto, Junzo; Tohyama, Chiharu

    2002-02-28

    We have investigated how a low dose of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) affects thyroid hormone regulation, especially in relation to the localization of thyroid stimulating hormone (TSH) in the pituitary and that of thyroxin (T4) of the thyroid in the rat. Female Sprague-Dawley rats were given a single oral administration of TCDD ranging from 1.0 to 4.0 microg/kg body weight (bw), and then tissue specimens were removed on day 7 post-administration. Thyroid hormone concentrations were measured in serum, and the expression of the TCDD-responsive genes, UDP-glucuronosyltransferase-1 (UGT1) and cytochrome P4501A1 (CYP1A1) were examined in the liver. TCDD administration resulted in an increase in both immunostaining intensity and the number of TSH-positive cells in the anterior pituitary. T4 was found to localize only in the follicular lumen of the thyroid in vehicle-treated control rats, while TCDD administration caused a foamy change in the colloid of some follicles, an indication of accelerating the biosynthesis of T4 in the thyroid. By morphometrical analysis, the ratio of parenchymal/lumenal area of the thyroid was found to increase in response to TCDD. TCDD treatment as low as 2.0 microg TCDD/kg bw induced a significant decrease in both serum total T4 (TT4) and free T4 (FT4) concentrations in the rats, with a significant increase in serum TSH levels in the 4.0 microg TCDD/kg bw rats. Serum total triiodothyronine (TT3) level was unchanged in all groups. The UGT1 gene was significantly induced at a TCDD dose as low as 1.0 microg/kg bw in a dose-dependent manner. TCDD concentrations in the serum, liver and adipose tissues were detected in a dose-related fashion. The present immunohistochemical results clearly support the earlier biochemical findings on the perturbation of the thyroid-pituitary axis by TCDD and suggest that UGT1 is an immediate target of a low TCDD exposure that triggers the perturbation. PMID:11836014

  6. Comparison of efficacy, cycle control, and tolerability of two low-dose oral contraceptives in a multicenter clinical study.

    PubMed

    Endrikat, J; Düsterberg, B; Ruebig, A; Gerlinger, C; Strowitzki, T

    1999-11-01

    This study compares the contraceptive reliability, cycle control, and tolerability of two oral contraceptive preparations containing 20 micrograms of ethinyl estradiol combined with either 75 micrograms of gestodene (EE/GSD) or 150 micrograms of desogestrel (EE/DSG). Women received the trial preparations daily for 21 days, followed by a 7-day pill-free interval. Contraceptive efficacy, cycle control, and tolerability were evaluated over a period of 12 cycles. Efficacy data of 14,700 treatment cycles (EE/GSD: 7299; EE/DSG: 7401) were obtained from 1476 women (EE/GSD, n = 740; EE/DSG, n = 736). Both preparations provided effective contraception and good cycle control with a similarly low incidence of both spotting and breakthrough bleeding. The spotting rates in both treatment groups decreased from 35.1% (EE/GSD) and 37.5% (EE/DSG) in the first treatment cycle to approximately 10% in the fourth treatment cycle. The spotting incidence as percent of the total number of cycles was 12.7% for EE/GSD and 14.3% for EE/DSG. The breakthrough bleeding incidence was 5.2% of all cycles for EE/GSD and 6.0% of all cycles for EE/DSG. For 84.7% of the cycles in the gestodene group and for 82.5% of the cycles in the desogestrel group, neither spotting nor breakthrough bleeding were recorded. Overall, the spotting and breakthrough bleeding incidence tended to be lower with EE/GSD than with EE/DSG. However, the difference was not statistically significant. Amenorrhea was recorded in 2.7% of the cycles with EE/GSD and in 2.9% with EE/DSG. Both preparations were well tolerated and showed a similar pattern of adverse events. More than 83% of the women in both groups either did not gain weight or lost more than 2 kg. Both preparations had a beneficial effect on dysmenorrhea. Both regimens provided reliable contraception and good cycle control. The incidence of adverse events was relatively low and both preparations were well tolerated. PMID:10717778

  7. Scoring oral mucositis

    Microsoft Academic Search

    W Parulekar; R Mackenzie; G Bjarnason; R. C. K Jordan

    1998-01-01

    Oral mucositis is a common, dose limiting and potentially serious complication of both radiation and chemotherapy. Both these therapies are non-specific, interfering with the cellular homeostasis of both malignant and normal host cells. An important effect is the loss of the rapidly proliferating epithelial cells in the oral cavity, gut and in the bone marrow. Within the mouth, the loss

  8. Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study

    PubMed Central

    Hesketh, P. J.; Rossi, G.; Rizzi, G.; Palmas, M.; Alyasova, A.; Bondarenko, I.; Lisyanskaya, A.; Gralla, R. J.

    2014-01-01

    Background NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK1) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-hydroxytryptamine type 3 (5-HT3) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program. Patients and methods This randomized, double-blind, parallel group study in 694 chemotherapy naďve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300 mg) + PALO 0.50 mg with oral PALO 0.50 mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1–4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0–120 h) phase. Results All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA100, NEPA200, and NEPA300, respectively versus 76.5% PALO; P < 0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0–24 h), delayed (25–120 h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable. Conclusions Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND. PMID:24608196

  9. Factors affecting the infectivity of tissues from pigs with classical swine fever: thermal inactivation rates and oral infectious dose.

    PubMed

    Cowan, Lucie; Haines, Felicity J; Everett, Helen E; Crudgington, Bentley; Johns, Helen L; Clifford, Derek; Drew, Trevor W; Crooke, Helen R

    2015-03-23

    Outbreaks of classical swine fever are often associated with ingestion of pig meat or products derived from infected pigs. Assessment of the disease risks associated with material of porcine origin requires knowledge on the likely amount of virus in the original material, how long the virus may remain viable within the resulting product and how much of that product would need to be ingested to result in infection. Using material from pigs infected with CSFV, we determined the viable virus concentrations in tissues that comprise the majority of pork products. Decimal reduction values (D values), the time required to reduce the viable virus load by 90% (or 1 log10), were determined at temperatures of relevance for chilling, cooking, composting and ambient storage. The rate of CSFV inactivation varied in different tissues. At lower temperatures, virus remained viable for substantially longer in muscle and serum compared to lymphoid and fat tissues. To enable estimation of the temperature dependence of inactivation, the temperature change required to change the D values by 90% (Z values) were determined as 13 °C, 14 °C, 12 °C and 10 °C for lymph node, fat, muscle and serum, respectively. The amount of virus required to infect 50% of pigs by ingestion was determined by feeding groups of animals with moderately and highly virulent CSFV. Interestingly, the virulent virus did not initiate infection at a lower dose than the moderately virulent strain. Although higher than for intranasal inoculation, the amount of virus required for infection via ingestion is present in only a few grams of tissue from infected animals. PMID:25592758

  10. Risk of polio reintroduction to border regions of Islamic Republic of Iran: seroprevalence study of children with at least 5 doses of oral polio vaccine.

    PubMed

    Izadi, S; Shahmahmoodi, S; Zahraei, S M; Dorostkar, F; Majdzadeh, R

    2014-05-01

    Movements of populations from countries where polio has not been eradicated is a concern in the Islamic Republic of Iran. A cross-sectional, community-based study was implemented in 2010 in 2 districts in Sistan-va-Baluchestan Province near the south-east border. The aim was to determine the seroprevalence of antibodies in children aged 20 (± 2) months who had received at least 5 doses of trivalent oral polio vaccine. Using cluster sampling, 365 children were enrolled for serological testing. Antibody titres ? 1:10 were considered positive. Seropositive rates for antibody against poliovirus serotypes 1, 2 and 3 were 94.1%, 96.7% and 78.3% respectively. The lowest seropositive rate was for antibody against polio serotype 3 (PV3) among boys (58.3%). Exclusive breastfeeding showed a direct relationship with antibody response to PV3 (OR = 2.0; 95% CI: 1.1-3.6). Improving community protection against PV3 is an urgent programme priority. PMID:24952285

  11. The acute effects of single-dose orally administered doramectin, eprinomectin and selamectin on natural infections of Syphacia muris in rats.

    PubMed

    Sevimli, Feride Kircali; Kozan, Esma; Sevimli, Alper; Do?an, Nurhan; Bülbül, Aziz

    2009-07-01

    This study was designed to determine the acute effects of a single-dose of orally administered doramectin, eprinomectin and selamectin on Syphacia muris infection in rats. Rats, naturally infected with S. muris, were divided into four groups: three different treatment groups (n=7) and one positive control (n=7). Cellophane tape preparations were obtained from the treated rats on day 0 pre-treatment and on days 2, 4 and 6 post-treatment. Syphacia sp. eggs were counted. Eprinomectin was found to be 100% effective in eliminating eggs on two post-treatment. However when egg counts on day 6 post-treatment were compared with pre-treatment egg counts, doramectin and selamectin were found to be 99.32 and 98.77% effective in eliminating eggs, respectively. On day 7 post-treatment, blood samples were obtained from all groups, and then the rats were necropsied. Doramectin, eprinomectin and selamectin were found to be 100% effective in eliminating adult S. muris, when compared with the positive control group. PMID:19318096

  12. Dose-dependent improvements in learning and memory deficits in APPPS1-21 transgenic mice treated with the orally active A? toxicity inhibitor SEN1500.

    PubMed

    Lo, Adrian C; Tesseur, Ina; Scopes, David I C; Nerou, Edmund; Callaerts-Vegh, Zsuzsanna; Vermaercke, Ben; Treherne, J Mark; De Strooper, Bart; D'Hooge, Rudi

    2013-12-01

    In the Alzheimer's disease (AD) brain, accumulation of A?1-42 peptides is suggested to initiate a cascade of pathological events. To date, no treatments are available that can reverse or delay AD-related symptoms in patients. In the current study, we introduce a new A? toxicity inhibitor, SEN1500, which in addition to its block effect on A?1-42 toxicity in synaptophysin assays, can be administered orally and cross the blood-brain barrier without adverse effects in mice. In a different set of animals, APPPS1-21 mice were fed with three different doses of SEN1500 (1 mg/kg, 5 mg/kg and 20 mg/kg) for a period of 5 months. Cognition was assessed in a variety of behavioral tests (Morris water maze, social recognition, conditioned taste aversion and passive avoidance). Results suggest a positive effect on cognition with 20 mg/kg SEN1500 compared to control APPPS1-21 mice. However, no changes in soluble or insoluble A?1-40 and A?1-42 were detected in the brains of SEN1500-fed mice. SEN1500 also attenuated the effect of A?1-42 on synaptophysin levels in mouse cortical neurons, which indicated that the compound blocked the synaptic toxicity of A?1-42. In vitro and in vivo effects presented here suggest that SEN1500 could be an interesting AD therapeutic. PMID:24035915

  13. Immunomodulatory screening test of corn oil administered orally to female mice: effect of timing of dosing within 24 hours.

    PubMed

    Ratajczak, H V; Sothern, R B; Dozier, M M; Gaworski, C L

    1999-03-01

    The effect of varying the dose-delivery time within a 24 h period (12:12 light-dark cycle) on the immunomodulatory properties of corn oil administered by gavage to 120 B6C3F1 female mice was investigated. Mice, housed in six separate boxes equipped with timers to regulate light onset and offset (staggered by 4 h increments), were treated for 5 consecutive days by intragastric (i.g.), administration of 5 mL/kg corn oil. Negative and positive control mice were given sham injections (needle inserted, but no injection). Sheep red blood cells (SRBCs) were injected intraperitoneally (i.p.) on the fifth day. Three days later, positive control mice were given cyclophosphamide intraperitoneally (80 mg/kg). Four days after SRBC injection, mice were weighed and killed, and spleens and thymuses were removed and weighed. Spleens were brought to single-cell suspensions and tested for an antibody response to the SRBC. Plaque-forming cells (PFCs), as measured per spleen, per 10(6) viable spleen cells or per 10(6) total spleen cells, exhibited significant circadian rhythms for mice given corn oil, but not for sham-gavage- and cyclophosphamide-treated mice. The peak response (acrophase, phi) occurred at 21 h, 22 h, and 23 h after lights on (HALO), respectively, with PFC values significantly different between the different time points. Corn oil and sham gavage affected the circadian pattern of antibody production; there was a high-amplitude (21-27%) rhythm observed when mice were treated with corn oil and no rhythm when mice received the sham-gavage treatment. In addition to testing mice near the end of the daily dark span and/or early light span to obtain a maximum immune response, this finding points to the importance of including as controls a group of animals that are not treated at all and a group given vehicle alone, rather than only sham-treated animals, for comparison with experimentally treated animals. PMID:10219490

  14. Soluble receptor for advanced glycation end products in critically ill patients and its associations with other clinical markers and 28-day mortality

    PubMed Central

    Cheng, Yanzi; Zhong, Jiwen; Xiang, Yang; Zeng, Fan; Cai, Dehong; Zhao, Ling

    2014-01-01

    Purpose To investigate the possible associations between serum levels of soluble receptor for advanced glycation end products (sRAGE) and specific clinical markers and prognosis in critically ill patients diagnosed with stress hyperglycemia. Patients and methods A total of 70 critically ill patients and 25 normal controls were recruited for this study. Serum levels of sRAGE and advanced glycation end products (AGEs) were determined using enzyme-linked immunosorbent assay. Additional data on other clinical markers were obtained from patient records in the intensive care unit. Comparisons of sRAGE and AGEs levels between groups were assessed by t-test. The relationships between sRAGE and other clinical markers were assessed by Pearson’s correlation analyses and multiple linear regression analyses. Risk factors for prognosis, such as 28-day mortality were analyzed using logistic regression analysis. Results Serum sRAGE and AGEs levels were significantly higher in critically ill patients, compared to normal controls (P<0.05). The increase in serum sRAGE levels was significantly correlated with AGEs levels, interleukin-6 levels, and the sequential organ failure assessment score (P<0.01). Using multiple linear regression analysis, the association between AGEs and sRAGE remained significant after adjustment of other clinical factors. However, there were no significant correlations between sRAGE levels and patient outcome in these critically ill patients. Conclusion Serum sRAGE levels were significantly elevated in critically ill patients and positively correlated with higher AGEs levels, but sRAGE levels were not associated with increased mortality, suggesting sRAGE levels are not a predictor of prognosis in critically ill patients. PMID:25429209

  15. Single dose and multiple dose studies of itraconazole nanoparticles

    Microsoft Academic Search

    Jason M. Vaughn; Jason T. McConville; David Burgess; Jay I. Peters; Keith P. Johnston; Robert L. Talbert; Robert O. Williams

    2006-01-01

    The objective of this study was to determine and compare the lung and serum concentrations in mice following oral and pulmonary dosing of amorphous nanoparticulate itraconazole (ITZ) compositions as well as the Sporanox® oral solution (itraconazole\\/Janssen). Second, the steady state partitioning of ITZ in lung tissue and circulatory compartments following repeated oral and pulmonary dosing was determined. The pulmonary formulation

  16. Chemotherapy of second stage human African trypanosomiasis: comparison between the parenteral diamidine DB829 and its oral prodrug DB868 in vervet monkeys.

    PubMed

    Thuita, John K; Wolf, Kristina K; Murilla, Grace A; Bridges, Arlene S; Boykin, David W; Mutuku, James N; Liu, Qiang; Jones, Susan K; Gem, Charles O; Ching, Shelley; Tidwell, Richard R; Wang, Michael Z; Paine, Mary F; Brun, Reto

    2015-02-01

    Human African trypanosomiasis (HAT, sleeping sickness) ranks among the most neglected tropical diseases based on limited availability of drugs that are safe and efficacious, particularly against the second stage (central nervous system [CNS]) of infection. In response to this largely unmet need for new treatments, the Consortium for Parasitic Drug Development developed novel parenteral diamidines and corresponding oral prodrugs that have shown cure of a murine model of second stage HAT. As a rationale for selection of one of these compounds for further development, the pharmacokinetics and efficacy of intramuscular (IM) active diamidine 2,5-bis(5-amidino-2-pyridyl)furan (DB829; CPD-0802) and oral prodrug2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868) were compared in the vervet monkey model of second stage HAT. Treatment was initiated 28 days post-infection of monkeys with T. b. rhodesiense KETRI 2537. Results showed that IM DB829 at 5 mg/kg/day for 5 consecutive days, 5 mg/kg/day every other day for 5 doses, or 2.5 mg/kg/day for 5 consecutive days cured all monkeys (5/5). Oral DB868 was less successful, with no cures (0/2) at 3 mg/kg/day for 10 days and cure rates of 1/4 at 10 mg/kg/day for 10 days and 20 mg/kg/day for 10 days; in total, only 2/10 monkeys were cured with DB868 dose regimens. The geometric mean plasma Cmax of IM DB829 at 5 mg/kg following the last of 5 doses was 25-fold greater than that after 10 daily oral doses of DB868 at 20 mg/kg. These data suggest that the active diamidine DB829, administered IM, should be considered for further development as a potential new treatment for second stage HAT. PMID:25654243

  17. Chemotherapy of Second Stage Human African Trypanosomiasis: Comparison between the Parenteral Diamidine DB829 and Its Oral Prodrug DB868 in Vervet Monkeys

    PubMed Central

    Thuita, John K.; Wolf, Kristina K.; Murilla, Grace A.; Bridges, Arlene S.; Boykin, David W.; Mutuku, James N.; Liu, Qiang; Jones, Susan K.; Gem, Charles O.; Ching, Shelley; Tidwell, Richard R.; Wang, Michael Z.; Paine, Mary F.; Brun, Reto

    2015-01-01

    Human African trypanosomiasis (HAT, sleeping sickness) ranks among the most neglected tropical diseases based on limited availability of drugs that are safe and efficacious, particularly against the second stage (central nervous system [CNS]) of infection. In response to this largely unmet need for new treatments, the Consortium for Parasitic Drug Development developed novel parenteral diamidines and corresponding oral prodrugs that have shown cure of a murine model of second stage HAT. As a rationale for selection of one of these compounds for further development, the pharmacokinetics and efficacy of intramuscular (IM) active diamidine 2,5-bis(5-amidino-2-pyridyl)furan (DB829; CPD-0802) and oral prodrug2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868) were compared in the vervet monkey model of second stage HAT. Treatment was initiated 28 days post-infection of monkeys with T. b. rhodesiense KETRI 2537. Results showed that IM DB829 at 5 mg/kg/day for 5 consecutive days, 5 mg/kg/day every other day for 5 doses, or 2.5 mg/kg/day for 5 consecutive days cured all monkeys (5/5). Oral DB868 was less successful, with no cures (0/2) at 3 mg/kg/day for 10 days and cure rates of 1/4 at 10 mg/kg/day for 10 days and 20 mg/kg/day for 10 days; in total, only 2/10 monkeys were cured with DB868 dose regimens. The geometric mean plasma Cmax of IM DB829 at 5 mg/kg following the last of 5 doses was 25-fold greater than that after 10 daily oral doses of DB868 at 20 mg/kg. These data suggest that the active diamidine DB829, administered IM, should be considered for further development as a potential new treatment for second stage HAT. PMID:25654243

  18. Pharmacokinetic Profile of Rizatriptan 10-mg Tablet and 10-mg Orally Disintegrating Tablet Administered With or Without Water in Healthy Subjects: An Open-Label, Randomized, Single-Dose, 3Period Crossover Study

    Microsoft Academic Search

    Suzanne K. Swan; Harry Alcorn; Anthony Rodgers; Carolyn M. Hustad; Karen E. Ramsey; Susan Woll; Franck Skobieranda

    2006-01-01

    This open-label, 3-period crossover study compared the plasma concentration profiles of rizatriptan tablet, orally disintegrating tablet with water (ODTc), and ODT without water (ODTs) in 24 healthy volunteers aged 18 to 45 years. At each period, subjects received a single dose of either 10-mg rizatriptan tablet, 10-mg rizatriptan ODTs, or 10-mg rizatriptan ODTc. The authors hypothesized that ODTc has a

  19. Acute and sub-chronic oral toxicity profiles of lipopeptides from Bacillus mojavensis A21 and evaluation of their in vitro anticoagulant activity.

    PubMed

    Ben Ayed, Hanen; Nasri, Rim; Jemil, Nawel; Ben Amor, Ikram; Gargouri, Jalel; Hmidet, Noomen; Nasri, Moncef

    2015-07-01

    The aim of the present study was to evaluate the acute and sub-chronic toxicity of lipopeptides mixture produced by Bacillus mojavensis A21 as well as their in vitro anticoagulant activity. A21 lipopeptides was given to mice at single dose from 75mg to 1000mg/kg body weight (bw). The median lethal dose (LD50) of A21 lipopeptides was about 550mg/kgbw. Sub-chronic toxicity study for 28days was done by daily oral administration of A21 lipopeptides at doses of 40 and 400mg/kgbw in rats. Results showed that A21 lipopeptides did not cause any change in body weights and they did not produce any marked alterations in the hematological blood parameters including hematocrit concentration, hemoglobin level, white and red cells count. However, the platelets level decreased significantly compared to control value. Moreover, no significant differences in the serum biochemical characteristics were observed for rats treated by the lowest dose. In contrast, a little enhancement of alanine-aminotransferase (ALT) activity and decrease in total cholesterol were observed with the highest dose. A21 lipopeptides were also found to cause a prolongation of the thrombin time (TT), the prothrombin time (PT) and the activated partial thromboplastin time (APTT). Overall, A21 lipopeptides may be very promising compounds for therapeutic purposes. PMID:25912554

  20. Tissue distribution of tungsten in mice following oral exposure to sodium tungstate.

    PubMed

    Guandalini, Gustavo S; Zhang, Lingsu; Fornero, Elisa; Centeno, Jose A; Mokashi, Vishwesh P; Ortiz, Pedro A; Stockelman, Michael D; Osterburg, Andrew R; Chapman, Gail G

    2011-04-18

    Heavy metal tungsten alloys have replaced lead and depleted uranium in many munitions applications, due to public perception of these elements as environmentally unsafe. Tungsten materials left in the environment may become bioaccessible as tungstate, which might lead to population exposure through water and soil contamination. Although tungsten had been considered a relatively inert and toxicologically safe material, recent research findings have raised concerns about possible deleterious health effects after acute and chronic exposure to this metal. This investigation describes tissue distribution of tungsten in mice following oral exposure to sodium tungstate. Twenty-four 6-9 weeks-old C57BL/6 laboratory mice were exposed to different oral doses of sodium tungstate (0, 62.5, 125, and 200 mg/kg/d) for 28 days, and after one day, six organs were harvested for trace element analysis with inductively coupled plasma mass spectrometry (ICP-MS). Kidney, liver, colon, bone, brain, and spleen were analyzed by sector-field high-resolution ICP-MS. The results showed increasing tungsten levels in all organs with increased dose of exposure, with the highest concentration found in the bones and the lowest concentration found in brain tissue. Gender differences were noticed only in the spleen (higher concentration of tungsten in female animals), and increasing tungsten levels in this organ were correlated with increased iron levels, something that was not observed for any other organ or either of the two other metals analyzed (nickel and cobalt). These findings confirmed most of what has been published on tungsten tissue distribution; they also showed that the brain is relatively protected from oral exposure. Further studies are necessary to clarify the findings in splenic tissue, focusing on possible immunological effects of tungsten exposure. PMID:21375269

  1. Determination of gemifloxacin in different tissues of rat after oral dosing of gemifloxacin mesylate by LC-MS/MS and its application in drug tissue distribution study.

    PubMed

    Roy, Bikash; Das, Ayan; Bhaumik, Uttam; Sarkar, Amlan Kanti; Bose, Anirbandeep; Mukharjee, Jayanti; Chakrabarty, Uday Sankar; Das, Anjan Kumar; Pal, Tapan Kumar

    2010-06-01

    A simple, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to evaluate the accumulation of gemifloxacin in different tissues of Wister albino rat. The analytical method consists of the homogenization of tissues followed by simple liquid-liquid extraction and determination of gemifloxacin by an LC-MS/MS. The analyte was separated on a Peerless basic C(18) column (33 mm x 4.6 mm, 3 microm) with an isocratic mobile phase of methanol-water containing formic acid (1.0%, v/v) (9:1, v/v) at a flow rate of 0.6 ml/min. The MS/MS detection was carried out by monitoring the fragmentation of m/z 390.100-->372.100 for gemifloxacin and m/z 332.100-->314.200 for ciprofloxacin (internal standard; IS) on a triple quadrupole mass spectrometer. The validated method was accurate, precise and rugged with good linearity in all tissue homogenates. The accuracy and precision value obtained from six different sets of quality control samples of all tissues and serum analyzed in separate occasions within 91.833-102.283% and 0.897-5.291%, respectively. The method has been successfully applied to tissue distribution studies of gemifloxacin. The present study demonstrates that the highest tissue concentration of gemifloxacin was obtained in lung (11.891 ng/g), followed by liver (10.110 ng/g), kidney (10.095 ng/g), heart (4.251 ng/g), testis (3.750 ng/g), stomach (3.182 ng/g), adipose tissue (1.116 ng/g) and brain (0.982 ng/ml) in 3h after multiple oral dosing of 200mg gemifloxacin mesylate for 7 days. This method may also be used for gemifloxacin tissue distribution modeling study in rat tissues and antibiotic residue analyses in other animal tissues. PMID:20092976

  2. Low-Dose Oral Sirolimus and the Risk of Menstrual-Cycle Disturbances and Ovarian Cysts: Analysis of the Randomized Controlled SUISSE ADPKD Trial

    PubMed Central

    Braun, Matthias; Young, James; Reiner, Cäcilia S.; Poster, Diane; Krauer, Fabienne; Kistler, Andreas D.; Kristanto, Paulus; Wang, Xueqi; Liu, Yang; Loffing, Johannes; Andreisek, Gustav; von Eckardstein, Arnold; Senn, Oliver; Wüthrich, Rudolf P.; Serra, Andreas L.

    2012-01-01

    Sirolimus has been approved for clinical use in non proliferative and proliferative disorders. It inhibits the mammalian target of rapamycin (mTOR) signaling pathway which is also known to regulate ovarian morphology and function. Preliminary observational data suggest the potential for ovarian toxicity but this issue has not been studied in randomized controlled trials. We reviewed the self-reported occurrence of menstrual cycle disturbances and the appearance of ovarian cysts post hoc in an open label randomized controlled phase II trial conducted at the University Hospital Zürich between March 2006 and March 2010. Adult females with autosomal dominant polycystic kidney disease, an inherited kidney disease not known to affect ovarian morphology and function, were treated with 1.3 to 1.5 mg sirolimus per day for a median of 19 months (N?=?21) or standard care (N?=?18). Sirolimus increased the risk of both oligoamenorrhea (hazard ratio [HR] 4.3, 95% confidence interval [CI] 1.1 to 29) and ovarian cysts (HR 4.4, CI 1.1 to 26); one patient was cystectomized five months after starting treatment with sirolimus. We also studied mechanisms of sirolimus-associated ovarian toxicity in rats. Sirolimus amplified signaling in rat ovarian follicles through the pro-proliferative phosphatidylinositol 3-kinase pathway. Low dose oral sirolimus increases the risk of menstrual cycle disturbances and ovarian cysts and monitoring of sirolimus-associated ovarian toxicity is warranted and might guide clinical practice with mammalian target of rapamycin inhibitors. Trial Registration ClinicalTrials.gov NCT00346918 PMID:23071528

  3. Reversed phase-high performance liquid chromatographic method for simultaneous estimation of tolperisone hydrochloride and etodolac in a combined fixed dose oral formulations

    PubMed Central

    Patel, Mit J.; Badmanaban, R.; Patel, C. N.

    2011-01-01

    A reversed-phase liquid chromatographic (RP-HPLC) method was developed for the simultaneous determination of tolperisone hydrochloride (TOLP) and etodolac (ETD) in a combined fixed dose oral formulation. The analysis was carried out using a phenomenax C-18, pre-packed column. A mobile phase containing a phosphate buffer (pH 5.5) : Methanol : Acetonitrile : Tri-ethylamine (40 : 40 : 20 : 1.5), with the pH adjusted to orthophosphoric acid, was pumped at a flow rate of 1.0 ml min1 with a UV-detector and PDA detection at 257 nm. Retention time was 3.91 minutes and 6.89 minutes for TOLP and ETD, respectively. The method was validated for linearity, accuracy, precision, sensitivity, and specificity. The method showed good linearity in the range of 3 – 21 ?g ml for TOLP ?g / ml and 8 – 56 ?g / ml for ETD. The detection limit of the proposed method was 0.16 ?g / ml and 0.58 ?g / ml for TOLP and ETD, respectively. The quantification limit of the proposed method was 0.51 ?g / ml and 1.7 ?g / ml for TOLP and ETD, respectively. The % recovery was within the range of 99.42 – 101.15 for TOLP and 98.63 – 100.94 for ETD. The percentage RSD for precision of the method was found to be less than 2%. The method was validated as per the International Conference on Harmonization (ICH) guidelines. The developed method could be applied for routine analysis of TOLP and ETD in tablet dosage form. PMID:23781442

  4. Changes in the concentrations of vitamin D and its metabolites in the plasma of healthy subjects orally given physiological doses of vitamin D2 by multivitamin or vitamin D preparations.

    PubMed

    Matsuoka, M; Otsuka, H; Masuda, S; Okano, T; Kobayashi, T; Takeuchi, T; Itokawa, Y

    1989-08-01

    Changes in the concentrations of vitamin D and its metabolites in plasma of healthy subjects orally given physiological doses of vitamin D2 by multivitamin or vitamin D liquid preparations were determined and the bioavailability of vitamin D was studied. Separative assay on the D2 and D3 compounds of vitamin D, 25-hydroxyvitamin D (25-OH-D), 24R,25-dihydroxyvitamin D [24,25(OH)2D], and 1 alpha,25-dihydroxyvitamin D [1,25(OH)2D] was performed in plasma of eight healthy male volunteers. When the concentrations of vitamin D and its metabolites in plasma of volunteers were assayed after daily oral administration of 400 IU of vitamin D2 in a form of multivitamin tablet for 1 week, the variations of vitamin D3 and its metabolites in plasma levels were very small. In contrast, the concentrations of 25-OH-D2 and 1,25(OH)2D2 slightly increased after the administration, while neither vitamin D2 nor 24,25(OH)2D2 was detected. A single dose of 4,000 IU of vitamin D2 was orally given to the volunteers in a form of a vitamin D liquid preparation and the hourly variations were observed during 24 h. These concentrations of vitamin D2, 25-OH-D2, and 1,25(OH)2D2 were slightly higher than those of the repeated doses. The result suggests that even the high dose of 4,000 IU has little effect on the plasma levels of vitamin D2 and its metabolites by a single dose, indicating a low risk for hypervitaminosis D. PMID:2585147

  5. Effects of orally administered Bdellovibrio bacteriovorus on the well-being and Salmonella colonization of young chicks.

    PubMed

    Atterbury, Robert J; Hobley, Laura; Till, Robert; Lambert, Carey; Capeness, Michael J; Lerner, Thomas R; Fenton, Andrew K; Barrow, Paul; Sockett, R Elizabeth

    2011-08-15

    Bdellovibrio bacteriovorus is a bacterium which preys upon and kills Gram-negative bacteria, including the zoonotic pathogens Escherichia coli and Salmonella. Bdellovibrio has potential as a biocontrol agent, but no reports of it being tested in living animals have been published, and no data on whether Bdellovibrio might spread between animals are available. In this study, we tried to fill this knowledge gap, using B. bacteriovorus HD100 doses in poultry with a normal gut microbiota or predosed with a colonizing Salmonella strain. In both cases, Bdellovibrio was dosed orally along with antacids. After dosing non-Salmonella-infected birds with Bdellovibrio, we measured the health and well-being of the birds and any changes in their gut pathology and culturable microbiota, finding that although a Bdellovibrio dose at 2 days of age altered the overall diversity of the natural gut microbiota in 28-day-old birds, there were no adverse effects on their growth and well-being. Drinking water and fecal matter from the pens in which the birds were housed as groups showed no contamination by Bdellovibrio after dosing. Predatory Bdellovibrio orally administered to birds that had been predosed with a gut-colonizing Salmonella enterica serovar Enteritidis phage type 4 strain (an important zoonotic pathogen) significantly reduced Salmonella numbers in bird gut cecal contents and reduced abnormal cecal morphology, indicating reduced cecal inflammation, compared to the ceca of the untreated controls or a nonpredatory ?pilA strain, suggesting that these effects were due to predatory action. This work is a first step to applying Bdellovibrio therapeutically for other animal, and possibly human, infections. PMID:21705523

  6. [Twenty-eight days repeated dose toxicity test of N-(fluorodichloromethylthio)phthalimide in rats].

    PubMed

    Matsushima, Y; Tsuda, M; Naito, K; Saitoh, M; Isama, K; Ikarashi, Y; Kawasaki, Y; Momma, J; Kitajima, S; Kaniwa, M

    1995-01-01

    N-(Fluorodichloromethylthio)phthalimide (Fluor-folpet) has been widely used as an anti-mold and anti-bacterial agent. In this study, 28 days repeated-dose oral toxicity study of fluor-folpet was carried out in Slc:Wistar rats. An oral toxicity study for fluor-folpet, the twenty-eight days test, repeated-dose, oral administration, was performed as follows: Five week-old rats, male and female, 10 rats, each/group, were treated with intragastric administration of fluor-folpet with a dose of 0 (1% Sodium CMC, control), 20, 80 and 320 mg/kg, body weight. Recovery test, for 14 days after the last treatment, was examined for the control and the 320 mg/kg groups. The 320 mg/kg groups, both males and females, showed significantly reduced their body-weight gain compared with the control group. In the 320 mg/kg group, five out of 20 male rats and four out of 20 female rats died from dyspnea during the treatment period. In the female rats in the 320 mg/kg group, serum ChE level was decreased to 50% of control level and gamma-GT was increased in a dose-dependent manner, but these serum levels recovered after 14 days non-treatment period. No histopathological change, relating to the treatment, in liver was observed. Increased weight of the kidney and vacuolation in renal tubules were found in both sexes of 320 mg/kg group. Hyperkeratosis and hyperplasia of the stomach epithelium were observed at the dose more than 80 mg/kg in male, and more than 20 mg/kg in female. A supplemental study, repeated-dose, oral administration in rats carried out to examine the dyspnea revealed that severe acute toxic damages in epithelium of nasal cavity and meatus nasopharyngeus were induced by intragastric administration of fluor-folpet. Fluor-folpet is shown to be cytotoxic. In conclusion, the no-observed-effect level (NOEL) for fluor-folpet was not found under the experimental conditions employed in this repeated-dose toxicity study. PMID:8717224

  7. Effects of a short course of oral phosphate treatment on serum parathyroid hormone (1–84) and biochemical markers of bone turnover: A dose-response study

    Microsoft Academic Search

    Kiln Brixen; Henning K. Nielsen; Peder Charles; Leif Mosekilde

    1992-01-01

    To investigate the possible use of oral phosphate as an activator of bone remodeling in coherence treatment of osteoporosis, 82 postmenopausal females, aged 50–75 years, were randomized to treatment with oral phosphate (750, 1500, or 2550 mg\\/day) or placebo for 7 days and followed for 4 months thereafter. All patients had sustained at least one previous fracture of the distal

  8. Dose-related neurocognitive effects of marijuana use

    Microsoft Academic Search

    K. I. Bolla; K. Brown; D. Eldreth; K. Tate; J. L. Cadet

    2006-01-01

    Abstract—Background: Although about 7 million people in the US population use marijuana at least weekly, there is a paucity,of scientific data,on persistent,neurocognitive,effects of marijuana,use. Objective: To determine,if neurocognitive deficits persist,in 28-day abstinent,heavy,marijuana,users,and,if these,deficits are,dose-related,to the,number,of marijuana,joints smoked,per,week.,Methods: A battery,of neurocognitive,tests was,given,to 28-day abstinent,heavy marijuana abusers. Results: As joints smoked per week increased, performance decreased on tests measuring memory, executive functioning,

  9. Dietary administration of high doses of pterostilbene and quercetin to mice is not toxic.

    PubMed

    Ruiz, M J; Fernández, M; Picó, Y; Mańes, J; Asensi, M; Carda, C; Asensio, G; Estrela, J M

    2009-04-22

    The aim of this study is to evaluate possible harmful effects of high doses of t-pterostilbene (t-PTER) and quercetin (QUER) in Swiss mice. Mice were fed during 28 days at doses of 0, 30, 300, and 3000 mg/kg body weight/day of t-PTER, QUER, or a mixture of both, t-PTER + QUER, which are equivalent to 5, 50, and 500 times, respectively, the estimated mean human intake of these polyphenols (25 mg/day). Daily oral administration of QUER, t-PTER, or a mixture of both of them did not cause mortality during the experimental period. There were no differences in food and water consumption on sex. No significant body weight gain in the male or female groups was observed. Red blood cell number and the hematocrit increased after polyphenols administration compared to control groups. Biochemical parameters were not affected. Histopathological examination revealed no alterations in clinical signs or organ weight at any dose. PMID:19292443

  10. Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial

    PubMed Central

    2012-01-01

    Background Hemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR) has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE) in patients with venous thromboembolism (VTE). Methods and design This is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1) will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1) Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2) Time from the start of oral anticoagulant treatment to achievement of a stable INR within the therapeutic range; 3) Number of INR determinations within the therapeutic range in the first six weeks of treatment. Discussion To date, there are no clinical trials comparing pharmacogenetic acenocoumarol dosing algorithm versus routine clinical practice in VTE. Implementation of this pharmacogenetic algorithm in the clinical practice routine could reduce side effects and improve patient safety. Trial registration Eudra CT. Identifier: 2009-016643-18. PMID:23237631

  11. Sub-chronic toxicity study in rats orally exposed to nanostructured silica

    PubMed Central

    2014-01-01

    Background Synthetic Amorphous Silica (SAS) is commonly used in food and drugs. Recently, a consumer intake of silica from food was estimated at 9.4 mg/kg bw/day, of which 1.8 mg/kg bw/day was estimated to be in the nano-size range. Food products containing SAS have been shown to contain silica in the nanometer size range (i.e. 5 – 200 nm) up to 43% of the total silica content. Concerns have been raised about the possible adverse effects of chronic exposure to nanostructured silica. Methods Rats were orally exposed to 100, 1000 or 2500 mg/kg bw/day of SAS, or to 100, 500 or 1000 mg/kg bw/day of NM-202 (a representative nanostructured silica for OECD testing) for 28 days, or to the highest dose of SAS or NM-202 for 84 days. Results SAS and NM-202 were extensively characterized as pristine materials, but also in the feed matrix and gut content of the animals, and after in vitro digestion. The latter indicated that the intestinal content of the mid/high-dose groups had stronger gel-like properties than the low-dose groups, implying low gelation and high bioaccessibility of silica in the human intestine at realistic consumer exposure levels. Exposure to SAS or NM-202 did not result in clearly elevated tissue silica levels after 28-days of exposure. However, after 84-days of exposure to SAS, but not to NM-202, silica accumulated in the spleen. Biochemical and immunological markers in blood and isolated cells did not indicate toxicity, but histopathological analysis, showed an increased incidence of liver fibrosis after 84-days of exposure, which only reached significance in the NM-202 treated animals. This observation was accompanied by a moderate, but significant increase in the expression of fibrosis-related genes in liver samples. Conclusions Although only few adverse effects were observed, additional studies are warranted to further evaluate the biological relevance of observed fibrosis in liver and possible accumulation of silica in the spleen in the NM-202 and SAS exposed animals respectively. In these studies, dose-effect relations should be studied at lower dosages, more representative of the current exposure of consumers, since only the highest dosages were used for the present 84-day exposure study. PMID:24507464

  12. Phase I trial of split-dose induction docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1)

    PubMed Central

    2012-01-01

    Background Induction chemotherapy (ICT) with docetaxel, cisplatin and fluorouracil (TPF) followed by radiotherapy is an effective treatment option for unresectable locally advanced head and neck cancer. This phase I study was designed to investigate the safety and tolerability of a split-dose TPF ICT regimen prior to surgery for locally advanced resectable oral and oropharyngeal cancer. Methods Patients received TPF split on two dosages on day 1 and 8 per cycle for one or three 3-week cycles prior to surgery and postoperative radiotherapy or radiochemotherapy. Docetaxel was escalated in two dose levels, 40 mg/m2 (DL 0) and 30 mg/m2 (DL ?1), plus 40 mg/m2 cisplatin and 2000 mg/m2 fluorouracil per week using a 3 +3 dose escalation algorithm. Results Eighteen patients were enrolled and were eligible for toxicity and response. A maximum tolerated dose of 30 mg/m2 docetaxel per week was reached. The most common grade 3+ adverse event was neutropenia during ICT in 10 patients. Surgery reached R0 resection in all cases. Nine patients (50%) showed complete pathologic regression. Conclusions A split-dose regime of TPF prior to surgery is feasible, tolerated and merits additional investigation in a phase II study with a dose of 30 mg/m docetaxel per week. Trial registration number NCT01108042 (ClinicalTrials.gov Identifier) PMID:23083061

  13. Dose-escalation study of rivaroxaban (BAY 59-7939) – an oral, direct Factor Xa inhibitor – for the prevention of venous thromboembolism in patients undergoing total hip replacement

    Microsoft Academic Search

    Bengt I. Eriksson; Lars C. Borris; Ola E. Dahl; Sylvia Haas; Menno V. Huisman; Ajay K. Kakkar; Frank Misselwitz; Eva Muehlhofer; Peter Kälebo

    2007-01-01

    IntroductionRivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention of thromboembolic disorders. The aim of this study was to demonstrate proof-of-principle for rivaroxaban.

  14. Safety Evaluation of Multiple Strains of Lactobacillus plantarum and Pediococcus pentosaceus in Wistar Rats Based on the Ames Test and a 28-Day Feeding Study

    PubMed Central

    Leu, Sew-Fen; Huang, Quan-Rong; Chou, Lan-Chun; Huang, Chun-Chih

    2014-01-01

    Three lactic acid bacterial strains, Lactobacillus plantarum, HK006, and HK109, and Pediococcus pentosaceus PP31 exhibit probiotic potential as antiallergy agents, both in vitro and in vivo. However, the safety of these new strains requires evaluation when isolated from infant faeces or pickled cabbage. Multiple strains (HK006, HK109, and PP31) were subject to a bacterial reverse mutation assay and a short-term oral toxicity study. The powder product exhibited mutagenic potential in Salmonella Typhimurium strains TA98 and TA1535 (with or without metabolic activation). In the short-term oral toxicity study, rats received a normal dosage of 390?mg/kg/d (approximately 9 × 109?CFU/kg/d) or a high dosage of 1950?mg/kg/d (approximately 4.5 × 1010?CFU/kg/d) for 28?d. No adverse effects were observed regarding the general condition, behaviour, growth, feed and water consumption, haematology, clinical chemistry indices, organ weights, or histopathologic analysis of the rats. These studies have demonstrated that the consumption of multiple bacterial strains is not associated with any signs of mutagenicity of S. Typhimurium or toxicity in Wistar rats, even after consuming large quantities of bacteria. PMID:25379552

  15. Safety evaluation of multiple strains of Lactobacillus plantarum and Pediococcus pentosaceus in Wistar rats based on the Ames test and a 28-day feeding study.

    PubMed

    Tsai, Cheng-Chih; Leu, Sew-Fen; Huang, Quan-Rong; Chou, Lan-Chun; Huang, Chun-Chih

    2014-01-01

    Three lactic acid bacterial strains, Lactobacillus plantarum, HK006, and HK109, and Pediococcus pentosaceus PP31 exhibit probiotic potential as antiallergy agents, both in vitro and in vivo. However, the safety of these new strains requires evaluation when isolated from infant faeces or pickled cabbage. Multiple strains (HK006, HK109, and PP31) were subject to a bacterial reverse mutation assay and a short-term oral toxicity study. The powder product exhibited mutagenic potential in Salmonella Typhimurium strains TA98 and TA1535 (with or without metabolic activation). In the short-term oral toxicity study, rats received a normal dosage of 390 mg/kg/d (approximately 9 × 10(9) CFU/kg/d) or a high dosage of 1950 mg/kg/d (approximately 4.5 × 10(10) CFU/kg/d) for 28 d. No adverse effects were observed regarding the general condition, behaviour, growth, feed and water consumption, haematology, clinical chemistry indices, organ weights, or histopathologic analysis of the rats. These studies have demonstrated that the consumption of multiple bacterial strains is not associated with any signs of mutagenicity of S. Typhimurium or toxicity in Wistar rats, even after consuming large quantities of bacteria. PMID:25379552

  16. Oral myiasis.

    PubMed

    Saravanan, Thalaimalai; Mohan, Mathan A; Thinakaran, Meera; Ahammed, Saneem

    2015-01-01

    Myiasis is a pathologic condition in humans occurring because of parasitic infestation. Parasites causing myiasis belong to the order Diptera. Oral myiasis is seen secondary to oral wounds, suppurative lesions, and extraction wounds, especially in individuals with neurological deficit. In such cases, neglected oral hygiene and halitosis attracts the flies to lay eggs in oral wounds resulting in oral myiasis. We present a case of oral myiasis in 40-year-old male patient with mental disability and history of epilepsy. PMID:25709196

  17. Evaluation of Octamethylcyclotetrasiloxane (D 4) as an Inducer of Rat Hepatic Microsomal Cytochrome P450, UDP-Glucuronosyltransferase, and Epoxide Hydrolase: A 28Day Inhalation Study

    Microsoft Academic Search

    James M. McKim; Paul C. Wilga; Gary B. Kolesar; Supratim Choudhuri; Ajay Madan; Leland W. Dochterman; John G. Breen; Andrew Parkinson; Richard W. Mast; Robert G. Meeks

    1998-01-01

    Repeated inhalation exposure to octamethylcyclotetrasiloxane (D4) produces a reversible and dose-related hepatomegaly and proliferation of hepatic endoplasmic reticulum in rats. However, the effects of D4on the expression of cytochrome P450 enzymes have not been evaluated. In the present study, the time course for changes in hepatic microsomal cytochrome P450 enzyme expression following repeated inhalation exposure to D4vapors was determined in

  18. Phase II Study of Oral S-1 and Concurrent Radiotherapy in Patients With Unresectable Locally Advanced Pancreatic Cancer

    SciTech Connect

    Sudo, Kentaro, E-mail: kentarosudo9@yahoo.co.j [Department of Gastroenterology, Chiba Cancer Center, Chiba (Japan); Yamaguchi, Taketo [Department of Gastroenterology, Chiba Cancer Center, Chiba (Japan); Ishihara, Takeshi [Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba (Japan); Nakamura, Kazuyoshi; Hara, Taro; Denda, Tadamichi; Tawada, Katsunobu [Department of Gastroenterology, Chiba Cancer Center, Chiba (Japan); Imagumbai, Toshiyuki; Araki, Hitoshi; Sakai, Mitsuhiro; Hatano, Kazuo [Department of Radiation Oncology, Chiba Cancer Center, Chiba (Japan); Kawakami, Hiroyuki; Uno, Takashi; Ito, Hisao [Department of Radiation Oncology, Graduate School of Medicine, Chiba University, Chiba (Japan); Yokosuka, Osamu [Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba (Japan)

    2011-05-01

    Purpose: S-1 is an oral fluoropyrimidine derivative that has demonstrated favorable antitumor activity in patients with metastatic pancreatic cancer. The aim of this study was to evaluate safety and efficacy of S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Methods and Materials: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day at a dose of 80 mg/m{sup 2}/day from day 1 to 14 and 22 to 35. Two weeks after the completion of chemoradiotherapy, maintenance chemotherapy with S-1 was administered for 28 days every 6 weeks until progression. Results: Thirty-four patients were enrolled in this study. The most common Grade 3 toxicities during chemoradiotherapy were anorexia (24%) and nausea (12%). The overall response rate was 41% (95% confidence interval, 25%-58%) and overall disease control rate (partial response plus stable disease) was 97%. More than 50% decrease in serum CA 19-9 was seen in 27 of 29 evaluable patients (93%). The median progression-free survival was 8.7 months. The median overall survival and 1-year survival rate were 16.8 months and 70.6%, respectively. Conclusions: Oral S-1 and concurrent radiotherapy exerted a promising antitumor activity with acceptable toxicity in patients with locally advanced pancreatic cancer. This combination therapy seems to be an attractive alternative to conventional chemoradiotherapy using 5-fluorouracil infusion.

  19. Phase I and pharmacokinetic study of BIBX 1382 BS, an epidermal growth factor receptor (EGFR) inhibitor, given in a continuous daily oral administration.

    PubMed

    Dittrich, Ch; Greim, G; Borner, M; Weigang-Köhler, K; Huisman, H; Amelsberg, A; Ehret, A; Wanders, J; Hanauske, A; Fumoleau, P

    2002-05-01

    The pyrimido-pyrimidine BIBX 1382 BS inhibits the intracellular tyrosine kinase domain of the epidermal growth factor receptor (EGFR), thus specifically reverting the aberrant enzymatic activity from overexpressed and constitutively activated EGFR. A phase I and pharmacokinetic study of this new specific molecule was carried out. After initially performing an accelerated titration design from the first toxicities onwards, a modified Fibonacci scheme was used to escalate the daily oral dose. The following dosages and cycles (defined as treatment during 28 days) were applied: 25 mg: 6; 50 mg: 3; 100 mg: 6; 200 mg: 7; 150 mg: 3. Over a 10 months accrual phase, 11 patients (pts) (7 females, 4 males) with a median age of 63 years (range 50-73 years), World Health Organization Performance Status (WHO PS) 0:5 pts, 1:6 pts and miscellaneous solid tumours were entered. The median number of cycles applied per pt was 2 (range 1-7). Reversible, dose-dependent increase of liver enzymes (maximal Common Toxicity Criteria (CTC) grades: gamma-glutamyl transferase (GGT): 4, aspartate aminotransferase (GOT): 3, alanine aminotransferase (GPT): 3, alkaline phosphatase (AP): 3, bilirubin: 3) occurred. Oral medication yielded plasma levels far below those expected to be efficacious. In conclusion, target plasma levels could not be reached via the oral route at a reasonable dosage. Meanwhile, a preclinically unknown metabolite was identified from the urine of one patient. Subsequently, this metabolite was found to be abundant in patient plasma. The metabolite was demonstrated to be pharmacologically inactive. Due to a dose-limiting increase of liver enzymes, low bioavailability of BIBX 1382 BS and the detection of a pharmacologically inactive metabolite, this trial was discontinued. PMID:12008195

  20. A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor Rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis. The EINSTEIN-DVT Dose-Ranging Study

    Microsoft Academic Search

    Harry R. Buller; Anthonie W. A. Lensing; Martin H. Prins; Giancarlo Agnelli; Alexander Cohen; Alexander S. Gallus; Frank Misselwitz; Gary Raskob; Sebastian Schellong; Annelise Segers

    We performed a randomized dose- ranging study, double-blind for rivaroxa- ban doses and open-label for the comparator (low-molecular-weight hepa- rin followed by vitamin K antagonists) to assess the optimal dose of rivaroxaban for the treatment of deep vein thrombo- sis. A total of 543 patients with acute deep-venous thrombosis received rivar- oxaban 20, 30, or 40 mg once daily or

  1. Evaluation of repeated dose micronucleus assays of the liver and gastrointestinal tract using potassium bromate: a report of the collaborative study by CSGMT/JEMS.MMS.

    PubMed

    Okada, Emiko; Fujiishi, Yohei; Narumi, Kazunori; Kado, Shoichi; Wako, Yumi; Kawasako, Kazufumi; Kaneko, Kimiyuki; Ohyama, Wakako

    2015-03-01

    The food additive potassium bromate (KBrO3) is known as a renal carcinogen and causes chromosomal aberrations in vitro without metabolic activation and in vivo in hematopoietic and renal cells. As a part of a collaborative study by the Mammalian Mutagenicity Study group, which is a subgroup of the Japanese Environmental Mutagen Society, we administered KBrO3 to rats orally for 4, 14, and 28 days and examined the micronucleated (MNed) cell frequency in the liver, glandular stomach, colon, and bone marrow to confirm whether the genotoxic carcinogen targeting other than liver and gastrointestinal (GI) tract was detected by the repeated dose liver and GI tract micronucleus (MN) assays. In our study, animals treated with KBrO3 showed some signs of toxicity in the kidney and/or stomach. KBrO3 did not increase the frequency of MNed cells in the liver and colon in any of the repeated dose studies. However, KBrO3 increased the frequency of MNed cells in the glandular stomach and bone marrow. Additionally, the MNed cell frequency in the glandular stomach was not significantly affected by the difference in the length of the administration period. These results suggest that performing the MN assay using the glandular stomach, which is the first tissue to contact agents after oral ingestion, is useful for evaluating the genotoxic potential of chemicals and that the glandular stomach MN assay could be integrated into general toxicity studies. PMID:24637080

  2. Effect of high dose growth hormone with glutamine and no change in diet on intestinal absorption in short bowel patients: a randomised, double blind, crossover, placebo controlled study

    PubMed Central

    Szkudlarek, J; Jeppesen, P; Mortensen, P

    2000-01-01

    BACKGROUND—High dose growth hormone, glutamine, and a high carbohydrate diet may improve intestinal function in short bowel patients.?AIMS—To investigate if growth hormone with glutamine and no change in diet improved intestinal function.?PATIENTS AND METHODS—Eight short bowel patients were randomised in a double blind crossover study between placebo and growth hormone (mean 0.12 mg/kg/day) with oral (mean 28 g/day) and parenteral glutamine (mean 5.2 g/day) for 28 days. Balance studies were performed at baseline and five days after placebo and treatment were terminated. Dietary energy, carbohydrate, and fat were maintained as usual.?RESULTS—Growth hormone with glutamine did not improve intestinal absorption of energy (baseline, placebo, treatment, mean: 46%, 48%, 46% of oral intake, respectively), carbohydrate (71%, 70%, 71%), fat (20%, 15%, 18%), nitrogen (27%, 18%, 19%), wet weight (37%, 39%, 31%), sodium (?16%, ?16%, ?36%), potassium (43%, 47%, 33%), calcium (?16%, ?16%, ?15%) or magnesium (?3%, 4%, 2%) compared with placebo or baseline (p>0.05) five days after treatment was terminated. All patients experienced adverse effects.?CONCLUSIONS—Combined high dose growth hormone and glutamine administered for four weeks did not improve intestinal absorption five days after treatment was terminated in short bowel patients on their usual diet.???Keywords: growth hormone; glutamine; short bowel syndrome; intestinal failure; intestinal absorption; parenteral nutrition PMID:10896910

  3. Phase I Dose-Escalation Study of 5-Day Intermittent Oral Lapatinib Therapy in Patients With Human Epidermal Growth Factor Receptor 2–Overexpressing Breast Cancer

    PubMed Central

    Chien, A. Jo; Munster, Pamela N.; Melisko, Michelle E.; Rugo, Hope S.; Park, John W.; Goga, Andrei; Auerback, Glenna; Khanafshar, Elham; Ordovas, Karen; Koch, Kevin M.; Moasser, Mark M.

    2014-01-01

    Purpose The highly effective treatment of human epidermal growth factor receptor (HER) 2–amplified breast cancer has proven challenging because of a signal buffering capacity inherent in the functionally relevant HER2-HER3 target. HER2-HER3 signaling can be inactivated by doses of lapatinib that fully inactivate the HER2 kinase. In mouse models, such doses are not tolerable in continuous administration, but they are tolerable and highly effective in intermittent dosing. We pursued the clinical translation of this treatment hypothesis. Patients and Methods We conducted a phase I dose-escalation study in women with advanced HER2-overexpressing breast cancer. Lapatinib was administered on days 1 through 5 of repeating 14-day cycles. Dose escalation was conducted using a 3+3 design with plasma lapatinib level monitoring. Results Forty patients were evaluable for toxicity, and 34 patients were evaluable for dose-limiting toxicity (DLT). Lapatinib dose was escalated to 7,000 mg per day in twice-daily dosing with no DLTs; however, plasma lapatinib concentrations plateaued in this dose range. Additional cohorts evaluated strategies to increase lapatinib exposure, including the food effect, CYP3A4 inhibition, and dose fractionation. Of these, only ketoconazole was able to increase lapatinib exposure, despite highly variable lapatinib bioavailability. Intolerable exposure levels were not encountered. Eight patients (20%) experienced grade 3 diarrhea. Six patients achieved a response, and dramatic responses were seen in three patients with lapatinib concentrations approaching 10,000 ng/mL. Conclusion Lapatinib exposure can be safely and significantly increased through intermittent dosing but reaches a ceiling that currently impedes clinical translation of the treatment hypothesis. Preliminary efficacy data suggest that exposures approaching those seen in mouse models can result in highly significant tumor responses. PMID:24711549

  4. Oral diuretic activity of hot water infusion of Sri Lankan black tea (Camellia sinensis L.) in rats

    PubMed Central

    Abeywickrama, K. R. W.; Ratnasooriya, W. D.; Amarakoon, A. M. T.

    2010-01-01

    Background: Black tea [Camellia sinensis (L.) O. Kuntze (family: Theaceae)] has been used by Sri Lankan traditional practitioners to promote diuresis. However, the type and grade of tea is not specified. Materials and Methods: This study investigates the diuretic activity of black tea infusion (BTI) in rats using Broken Orange Pekoe Fannings (BOPF) grade from major agroclimatic elevations: high-, mid-, and low-grown. Different concentrations of BTI, furosemide (positive control), and water (vehicle) were orally administered to starved (18 h) male rats (n = 9/group), then hydrated. Acute and chronic (28 days) diuretic activities were assessed by measuring cumulative urine output at hourly intervals for 6 h. Electrolyte levels (Na+, K+, Ca2+, H+, Cl?, HCO3?), pH, osmolarity of urine, and glomerular filtration rate (GFR) of treated rats were determined. Results: Administration of BTI induced a significant (P < 0.05) and dose-dependent diuretic activity, which varied with the tea produced in different agroclimatic elevations. Diuretic activity had a rapid onset (1st h), peaked at 2nd h and maintained up to 4th h (except the low dose). Furthermore, there was a dose-dependent increase in micturition frequency, which peaked at 2nd h. A close association between the caffeine content of tea and diuretic activity was evident. BTI-induced diuresis was accompanied with an increased urine Na+ level and GFR. The diuretic activity of BTI was mediated via multiple mechanisms: inhibition of both aldosterone secretion (with increased Na+/K+ ratio) and carbonic anhydrase [with decreased Cl?/(Na+ + K+) ratio] and via thiazide type of diuretic action (evaluated with increased Na+/Cl? ratio). Conclusion: The Sri Lankan BOPF grade black tea possesses mild oral diuretic activity whose efficacy differs with the agroclimatic elevation of production. Furthermore, it supports the traditional claim that the black tea acts as a diuretic. PMID:21120027

  5. A COMPARISON OF EFFICACY AND SAFETY OF A SINGLE DOSE OF INTRAMUSCULAR DEXAMETHASONE ACETATE WITH ORAL PREDNISOLONE IN THE MANAGEMENT OF ASTHMA EXACERBATIONS IN CHILDREN

    Microsoft Academic Search

    Adel Al-wahadneh; Samah Jboor; Muna Dahabreh

    Background: Because corticosteroid improves pulmonary function, reduces the rate of hospitalization, and decreases the relapse rates in patients with acute asthma exacerbation, it is recommended for outpatient use after asthma exacerbation.????????? Objective: To determine whether a single intramuscular dexamethasone acetate injection is as effective as 5 days of oral prednisolone in improving symptoms and preventing relapse in children with acute

  6. Magnesium hydroxide as a complementary aluminium-free phosphate binder to moderate doses of oral calcium in uraemic patients on chronic haemodialysis: lack of deleterious effect on bone mineralisation.

    PubMed

    Moriničre, P; Vinatier, I; Westeel, P F; Cohemsolal, M; Belbrik, S; Abdulmassih, Z; Hocine, C; Marie, A; Leflon, P; Roche, D

    1988-01-01

    To control hyperphosphataemia without hyperaluminaemia, A1(OH)3, which was given in addition to high doses of oral calcium, was replaced by Mg(OH)2 for 6 months in 20 haemodialysed patients and for 20 months in 12. The treatment during the control period was 110 +/- 91 mmol/day of oral calcium element given as CaCO3 and/or Calcium Sorbisterit and 1.05 +/- 1.47 g/day of A1(OH)3. Haemodialysis treatment was 4 h, thrice weekly. To prevent hypermagnesaemia, dialysate magnesium was decreased from 0.75 mmol/l to 0.375 mmol/l. After a control period of 3 months, Mg(OH)2 was given at a mean dose of 2.6 +/- 2 g/day and oral calcium supplements were decreased to 76 mmol/day. Two subsequent bone histomorphometry studies were performed at 8 month intervals in four patients and at 20 month intervals in seven patients. The results show a good control of plasma calcium (mean +/- SD: 2.43 +/- 0.1 mumol/l); phosphate (1.76 +/- 0.4 to 1.66 +/- 0.3 mmol/l); aluminum (1.3 +/- 0.1 mumol/l to 0.6 +/- 0.1 mumol/l); alkaline phosphatase (135 +/- 65 to 125 +/- 40 IU); and PTH fragments (PTH C terminal decreased from 260 +/- 214 to 185 +/- 182 pg/ml, PTH medium from 4185 +/- 5113 to 2270 +/- 4880 pg/ml). Plasma magnesium increased from 0.96 +/- 0.2 to 1.54 +/- 0.2 mmol/l. Bone histomorphometry shows no change in mineralisation, and a borderline decrease of resorption parameters. The main side-effects are (1) diarrhoea, which was well controlled by transient treatment with karaya gum, and (2) an increased need for potassium binders.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3146723

  7. Development of an extemporaneous oral liquid formulation of oxandrolone and its stability evaluation.

    PubMed

    Garg, Alka; Garg, Sanjay; She, Richard Wong

    2011-11-01

    Many references exist in the literature identifying the usefulness of oxandrolone in treating muscle wasting due to various conditions including severe burns. However, there is an absence of dosage form alternatives as it is only available as tablets. The dose for children is weight based (0.1 mg/kg) which is difficult to achieve with the currently available tablets of 2.5 mg and 10 mg. The literature provides ample evidence of clinical importance but little guidance on extemporaneous oral liquid formulation of oxandrolone. In order to develop and validate an extemporaneous liquid formulation, suspensions of oxandrolone were developed using locally available (New Zealand) vehicles. Combinations of these vehicles with ethanol, as advised in some articles were also tried. Assay method was developed for oxandrolone using High Performance Liquid Chromatography (HPLC) and Mass Spectroscopy (LC-MS). The formulations were evaluated for stability as per the International Conference on Harmonization (ICH) stability guidelines. They were observed for physical and chemical stability at different time points over a period of 28 days. A stable and validated liquid formulation of oxandrolone has been developed which can be made under the hospital and community pharmacy conditions. The formula utilises commercially available oxandrolone tablets, crushed and dispersed in Simple Syrup BP or Orablend(®) vehicle. The formulation has confirmed stability for 21 days and can be easily made with locally available vehicles. PMID:21764219

  8. [Twenty-eight-day repeated dose toxicity test for tetrachlorvinphos in Wistar rat].

    PubMed

    Ogawa, Y; Suzuki, S; Takada, K; Sai, K; Kamata, E; Umemura, T; Kaneko, T; Kurokawa, Y

    1990-01-01

    A 28-day oral toxicity test of tetrachlorvinphos (TCV) was conducted in male and female Slc: Wistar rats by gavage at dose levels of 0, 10, 100 or 1000 mg/kg/day. The male and female rats showed dose-related inhibition of serum cholinesterase activity and erythrocyte acetylcholinesterase activity. At a dose of 1000 mg/kg, body weight gain was decreased in males, and there were 6 deaths in females. Adrenal gland, liver, kidney and thyroid gland weights were increased. The adrenal lesions were characterized by vacuolization and swelling of the cortex cells. The hepatic lesions consisted of vacuolization and necrosis of the hepatocytes. The renal lesions consisted of regeneration and necrosis of the tubular epithelial cells. These lesions were mostly observed at a dose of 1000 mg/kg. After a 14-day recovery period in the 1000 mg/kg group, the changes of cholinesterase, total cholesterol, gamma-glutamyltransferase, alkaline phosphatase, aspartate aminotransferase and blood urea nitrogen in serum were restored or showed a tendency toward recovery. However, the lesions in the kidney and adrenal remained. More than 14 days are therefore considered to be needed for recovery. At doses of more than 10 mg/kg, significant inhibition of the serum cholinesterase activity in both sexes, erythrocyte acetylcholinesterase activity in males, and lesions of the adrenal gland in females were observed. Target organs for TCV-treated rats were the adrenal, liver and kidney. It was concluded that the NOEL under this experimental condition is less than 10 mg/kg/day. PMID:1364360

  9. Macrophage activity and histopathology of the lymphohematopoietic organs in male Wistar rats orally exposed to single or mixed pesticides.

    PubMed

    De Camargo, Marcela Rodrigues; Barbisan, Luís Fernando; Martinez, Meire França; Da Silva Franchi, Carla Adriene; De Camargo, Joăo Lauro Viana; Spinardi-Barbisan, Ana Lúcia Tozzi

    2013-01-01

    The noxious effects of low or effective dose exposure to single or mixed pesticides on macrophage activity and the lymphohematopoietic organs were investigated. Male Wistar rats were orally exposed to dichlorvos, dicofol, endosulfan, dieldrin and permethrin, either as single or combined mixtures during a 28-day study containing eight groups: one group received a semipurified diet (non-treated); two groups received a semipurified diet containing low dose mixture (dieldrin 0.025 mg/kg, endosulfan, 0.6 mg/kg, dicofol 0.22 mg/kg, dichlorvos 0.23 mg/kg, permethrin 5 mg/kg) or an effective dose mixture (dichlorvos 2.3 mg/kg, dicofol 2.5 mg/kg, endosulfan 2.9 mg/kg, dieldrin 0.05 mg/kg and permethrin 25.0 mg/kg), respectively; the other five groups received a semipurified diet containing each single pesticide in effective doses. At sacrifice, the thymus, spleen, mesenteric lymph nodes, Payer's patches and bone marrow were removed for histological analysis. Peritoneal macrophages were obtained to determine the phagocytosis and spreading indexes and tumoral necrosis factor alpha (TNF-?), nitric oxide (NO) and H?O? production. Exposure to pesticide mixtures did not alter the percentage of macrophage phagocytosis and spreading, TNF-? production or the NO and H?O? release when compared to the non-treated group. Neither was there any apparent evidence that a pesticide mixture at low or effective doses altered the histological structure of the lymphohematopoietic organs. The findings indicate that short-term treatment with pesticide mixtures did not induce an apparent immunotoxic effect in male Wistar rats. PMID:23581695

  10. A First-in-Human Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study of Novel Antimalarial Spiroindolone KAE609 (Cipargamin) To Assess Its Safety, Tolerability, and Pharmacokinetics in Healthy Adult Volunteers

    PubMed Central

    Li, Ruobing; Jain, Jay Prakash; Lefčvre, Gilbert; Magnusson, Baldur; Diagana, Thierry T.; Pertel, Peter

    2014-01-01

    This first-in-human randomized, double-blind, placebo-controlled, ascending-single and -multiple oral dose study was designed to evaluate the safety, tolerability, and pharmacokinetics in healthy volunteers of KAE609 (cipargamin; formerly NITD609), a spiroindolone now in trials for malaria treatment. It was studied in single-dose cohorts (1 to 300 mg, including one 30-mg food effect cohort) with 4 to 10 subjects in each cohort and in multiple-dose cohorts (10 to 150 mg once daily for 3 days) with 8 subjects in each cohort. The follow-up period was 6 to 8 days post-last dose. Safety and pharmacokinetics were assessed at scheduled time points during the study. Systemic exposure in terms of the area under the concentration-time curve from 0 h extrapolated to infinity (AUC0–?) increased in a dose-proportional manner over the dose range of 1 to 300 mg. The AUC from time zero to the time of the last quantifiable concentration (AUClast) and the maximum concentration of drug in plasma (Cmax) also increased in an approximately dose-proportional manner. When administered daily for 3 days, the accumulation ratio on day 3 (the AUC from time zero to 24 h postdosing [AUC0–24] on day 3/AUC0–24 on day 1) was in the range of 1.5 to 2 in the studied dose range (10 to 150 mg) and was consistent with an elimination half-life of around 24 h. Urine analysis for unchanged KAE609 revealed negligible amounts (?0.01%) were excreted renally. The high fat food intake did not affect the extent of KAE609 absorption (AUC); however, the Cmax was reduced by around 27%. KAE609 was tolerated in this study, with transient gastrointestinal and genitourinary adverse events of mild to moderate intensity (semen discoloration, diarrhea, nausea and abdominal discomfort, dizziness and headache, catheter site hematoma). Gastrointestinal and genitourinary adverse events increased with rising doses. PMID:25114127

  11. Halitosis, Oral Health and Quality of Life during Treatment with Invisalign ® and the Effect of a Low-dose Chlorhexidine Solution

    Microsoft Academic Search

    Isabelle Schaefer; Bert Braumann

    2010-01-01

    \\u000a Abstract\\u000a \\u000a \\u000a Aim:\\u000a   This study examined how halitosis, oral dryness and\\u000a general oral health were impacted during treatment with\\u000a the Invisalign® system. Furthermore, the effect of a lowdose\\u000a chlorhexidine solution (CHX) was evaluated.\\u000a \\u000a \\u000a \\u000a \\u000a \\u000a Patients and Methods:\\u000a   Thirtyone patients with good periodontal\\u000a health participated in this crossover study and were\\u000a divided into two groups (group 1: CHX\\/no CHX, group 2:\\u000a no CHX\\/CHX).

  12. Improvement in bronchiolitis obliterans organizing pneumonia in a child after allogeneic bone marrow transplantation by a combination of oral prednisolone and low dose erythromycin

    Microsoft Academic Search

    T Ishii; A Manabe; Y Ebihara; T Ueda; H Yoshino; T Mitsui; H Hisakawa; H Yagasaki; A Kikuchi; T Yoshimasu; R Tanaka; T Takahashi; A Masunaga; K-I Sugita; T Nakahata; S Asano; K Tsuji

    2000-01-01

    We report a 13-year-old boy who developed dyspnea at rest 1 year after the occurrence of cGVHD following an allogeneic bone marrow transplant (BMT). Pulmonary function data, imaging studies, lung biopsy, and bronchoalveolar lavage were consistent with the diagnosis of bronchiolitis obliterans organizing pneumonia (BOOP). Although reports suggest that oral methylprednisolone or methylprednisolone pulse therapies improve BOOP after BMT, we

  13. Low-dose oral immunization with lyophilized tissue of herbicide-resistant lettuce expressing hepatitis B surface antigen for prototype plant-derived vaccine tablet formulation

    Microsoft Academic Search

    Tomasz Pniewski; Józef Kapusta; Piotr Boci?g; Jacek Wojciechowicz; Anna Kostrzak; Micha? Gdula; Olga Fedorowicz-Stro?ska; Piotr Wójcik; Halina Otta; S?awomir Samardakiewicz; Bogdan Wolko; Andrzej P?ucienniczak

    2011-01-01

    Efficient immunization against hepatitis B virus (HBV) and other pathogens with plant-based oral vaccines requires appropriate plant expressors and the optimization of vaccine compositions and administration protocols. Previous immunization studies were mainly based on a combination of the injection of a small surface antigen of HBV (S-HBsAg) and the feeding with raw tissue contain- ing the antigen, supplemented with an

  14. Oral administration of the GnRH antagonist acyline, in a GIPET ® -enhanced tablet form, acutely suppresses serum testosterone in normal men: single-dose pharmacokinetics and pharmacodynamics

    Microsoft Academic Search

    John Kenneth Amory; Thomas W. Leonard; Stephanie T. Page; Edel O’Toole; Michael J. McKenna; William J. Bremner

    2009-01-01

    Purpose  GnRH analogs are useful for the treatment of prostate cancer, but require parenteral administration. The peptide GnRH antagonist\\u000a acyline potently suppresses luteinizing hormone (LH) and testosterone in man; however, its clinical utility is limited by\\u000a the requirement for frequent injections. The use of a proprietary enhancer system called GIPET®, which is based on medium-chain fatty acids, facilitates the oral bioavailability

  15. Simultaneous Detection of Deoxyadenosine and Deoxyguanosine Adducts in the Tongue and Other Oral Tissues of Mice Treated with Dibenzo[a,l]pyrene

    PubMed Central

    2015-01-01

    We were the first to demonstrate that direct application of the environmental pollutant and tobacco smoke constituent dibenzo[a,l]pyrene (DB[a,l]P) into the oral cavity of mice induced squamous cell carcinoma (SCC) in oral tissues but not in the tongue; however, the mechanisms that can account for the varied carcinogenicity remain to be determined. Furthermore, we also showed that not only dA adducts, but also dG adducts can account for the mutagenic activity of DB[a,l]P in the oral tissues in vivo. In this study, we initially focused on DB[a,l]P-induced genotoxic effects in both oral and tongue tissues. Therefore, to fully assess the contribution of these DNA adducts in the initiation stage of carcinogenesis induced by DB[a,l]P, an LC-MS/MS method to simultaneously detect and quantify DB[a,l]PDE-dG and -dA adducts was developed. Mice were orally administered with DB[a,l]P (24 nmole, 3 times per week for 5 weeks) or its fjord region diol epoxide, (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE, 12 nmole, single application); animals were sacrificed at 2, 7, 14, and 28 days after the last dose of carcinogen administration. Oral and tongue tissues were obtained and DNA were isolated followed by enzymatic hydrolysis. Following the development of an isotope dilution LC-MS/MS method, we successfully detected (?)-anti-cis- and (?)-anti-trans-DB[a,l]PDE-N2-dG, as well as (?)-anti-cis- and (?)-anti-trans-DB[a,l]PDE-N6-dA in oral and tongue tissues of mice treated with DB[a,l]P. Levels of (?)-anti-trans-DB[a,l]PDE-N6-dA were ?2 folds higher than (?)-anti-cis-DB[a,l]PDE-N6-dA adduct and those of dG adducts in the oral tissues and tongue at all time points selected after the cessation of DB[a,l]P treatment. Levels of dG adducts were comparable in both tissues. Collectively, our results support that DB[a,l]P is predominantly metabolized to (?)-anti-DB[a,l]PDE, and the levels and persistence of (?)-anti-trans-DB[a,l]PDE-N6-dA may, in part, explain the carcinogenicity of DB[a,l]P in the oral tissues but not in the tongue. PMID:24911113

  16. Dose-dense regimen of temozolomide given every other week in patients with primary central nervous system tumors

    Microsoft Academic Search

    K. Vera; L. Djafari; S. Faivre; J.-S. Guillamo; K. Djazouli; M. Osorio; F. Parker; C. Cioloca; B. Abdulkarim; J.-P. Armand; E. Raymond

    2004-01-01

    2 \\/day on days 1-5 every 4 weeks. In this study, a new alternative dose-dense regimen of temozolomide was explored in patients with recurrent brain tumors. Patients and methods: In this study, we evaluated the safety, dose-limiting toxicity, maximum tolerated dose, recommended dose and activity of temozolomide given on days 1-3 and 14-16 every 28 days (one cycle). The starting

  17. Hematological effects of repeated graded doses of the methanol extract of Paullinia pinnata (Linn.) leaves in Wistar albino rats

    PubMed Central

    Adeyemo-Salami, Oluwatoyin A.; Ewuola, Emmanuel O.

    2015-01-01

    Background: Paullinia pinnata is a medicinal plant used for the treatment of various diseases, including anemia in West Africa. Aim: This study was carried out to investigate the effect of increasing doses of the methanolic leaves extract of P. pinnata on hematological parameters in rats. Materials and Methods: Thirty-six male Wistar albino rats were grouped into six groups of six animals each. Five doses; 50,100, 200, 400 and 800 mg/kg body weight of the P. pinnata extract were administered separately to five groups. The sixth group served as a control and received only the vehicle (70% physiological saline: 30% Tween 80 [v/v]). Administration was done orally daily for 28 days at 24 h interval. On day 29, the animals were made inactive, blood was then collected from the heart and various hematological parameters were evaluated. Statistical Analysis: Analysis of variance was employed. Results: The packed cell volume and red blood cell count increased significantly (P < 0.05) in the treatment groups except at 200 mg/kg dose. The hemoglobin concentration increased in all the treatment groups. The values for the neutrophils at 50, 100, 200 and 800 mg/kg doses were higher than that of the control. The white blood cell count increased significantly (P < 0.05) at 50 and 400 mg/kg doses compared to the control and exceeded the normal physiological range. Conclusion: The maximum tolerable dose is 200 mg/kg body weight of the methanolic leaves extract of P. pinnata and the extract has anti-anemic property with the ability to increase neutrophils count. PMID:26109785

  18. Short-term effects of high-dose oral vitamin D3 in critically ill vitamin D deficient patients: a randomized, double-blind, placebo-controlled pilot study

    PubMed Central

    2011-01-01

    Introduction Vitamin D deficiency is encountered frequently in critically ill patients and might be harmful. Current nutrition guidelines recommend very low vitamin D doses. The objective of this trial was to evaluate the safety and efficacy of a single oral high-dose vitamin D3 supplementation in an intensive care setting over a one-week observation period. Methods This was a randomized, double-blind, placebo-controlled pilot study in a medical ICU at a tertiary care university center in Graz, Austria. Twenty-five patients (mean age 62 ± 16yrs) with vitamin D deficiency [25-hydroxyvitamin D (25(OH)D) ?20 ng/ml] and an expected stay in the ICU >48 hours were included and randomly received either 540,000 IU (corresponding to 13.5 mg) of cholecalciferol (VITD) dissolved in 45 ml herbal oil or matched placebo (PBO) orally or via feeding tube. Results The mean serum 25(OH)D increase in the intervention group was 25 ng/ml (range 1-47 ng/ml). The highest 25(OH)D level reached was 64 ng/ml, while two patients showed a small (7 ng/ml) or no response (1 ng/ml). Hypercalcemia or hypercalciuria did not occur in any patient. From day 0 to day 7, total serum calcium levels increased by 0.10 (PBO) and 0.15 mmol/L (VITD; P < 0.05 for both), while ionized calcium levels increased by 0.11 (PBO) and 0.05 mmol/L (VITD; P < 0.05 for both). Parathyroid hormone levels decreased by 19 and 28 pg/ml (PBO and VITD, ns) over the seven days, while 1,25(OH)D showed a transient significant increase in the VITD group only. Conclusions This pilot study shows that a single oral ultra-high dose of cholecalciferol corrects vitamin D deficiency within 2 days in most patients without causing adverse effects like hypercalcemia or hypercalciuria. Further research is needed to confirm our results and establish whether vitamin D supplementation can affect the clinical outcome of vitamin D deficient critically ill patients. EudraCT Number 2009-012080-34 German Clinical Trials Register (DRKS) DRKS00000750 PMID:21443793

  19. Effects of high dose inhaled beclomethasone dipropionate, 750 micrograms and 1500 micrograms twice daily, and 40 mg per day oral prednisolone on lung function, symptoms, and bronchial hyperresponsiveness in patients with non-asthmatic chronic airflow obstruction.

    PubMed Central

    Weir, D C; Burge, P S

    1993-01-01

    BACKGROUND--The effect of treatment with inhaled corticosteroids in patients with non-asthmatic chronic airflow obstruction is still disputed. Whether any physiological improvements seen are accompanied by changes in bronchial responsiveness and symptoms and quality of life is also still unclear. METHODS--A sequential placebo controlled, blinded parallel group study investigating the effect of three weeks of treatment with inhaled beclomethasone dipropionate (BDP), 750 micrograms or 1500 micrograms twice daily, and oral prednisolone, 40 mg per day, was carried out in 105 patients with severe non-asthmatic chronic airflow obstruction (mean age 66 years, mean forced expiratory volume in one second (FEV1) 1.05 litres [40% predicted], geometric mean PD20 0.52 mumol). End points assessed were FEV1, forced vital capacity (FVC), and peak expiratory flow (PEF), bronchial responsiveness to inhaled histamine, and quality of life as measured by a formal quality of life questionnaire. RESULTS--Both doses of BDP produced equivalent, small, but significant improvements in FEV1 (mean 48 ml), FVC (mean 120 ml), and PEF (mean 12.4 l/min). The addition of oral prednisolone to the treatment regime in two thirds of the patients did not produce any further improvement in these parameters. Inhaled BDP produced a treatment response in individual patients (defined as an improvement in FEV1, FVC, or mean PEF of at least 20% compared with baseline values) more commonly than placebo (34% v 15%). The two doses of BDP were equally effective in this respect and again no further benefit of treatment with oral prednisolone was noted. Treatment with BDP for up to six weeks did not affect bronchial responsiveness to histamine. Small but significant improvements were seen in dyspnoea during daily activities, and the feeling of mastery over the disease. CONCLUSIONS--High dose inhaled BDP is an effective treatment for patients with chronic airflow obstruction not caused by asthma. Both objective and subjective measures show improvement. Unlike asthma, no improvement in bronchial responsiveness was detected after six weeks of treatment. PMID:8511727

  20. Persistent increase of blood lead level and suppression of ?-ALAD activity in northern bobwhite quail orally dosed with even a single 2-mm spent lead shot.

    PubMed

    Holladay, S D; Kerr, R; Holladay, J P; Meldrum, B; Williams, S M; Gogal, R M

    2012-10-01

    Birds that display grit ingestion behavior are potentially at risk of lead (Pb) poisoning from mistaken ingestion of spent Pb shot pellets. The majority of available studies designed to assess such risk have used unspent shot pellets rather than field-obtained spent shot, which is oxidized and otherwise changed by weathering. Available studies also often administered more or heavier shot pellets to a bird than it might be expected to ingest. The current study dosed northern bobwhite quail (Colinus virginianus) weighing 194.6 ± 23.1 g (female birds) and 199.3 ± 12.2 g (male birds) with one to three spent no. 9 Pb shot collected from a skeet range, with particular interest in the toxicity that may occur from ingestion of a single 2-mm, 50 mg shot. An 8 week post-dosing clinical observation period was employed, over which feed consumption, body weight, blood Pb levels, and a battery of blood physiological parameters were made. Weight loss occurred in the birds, including male birds dosed with one Pb pellet. Erythrocyte delta aminolevulinic acid dehydratase (?-ALAD) levels were decreased for the duration of the study across exposures and to levels associated with injury in wild bird populations. Decreased ALAD was particularly severe in female birds dosed with one Pb pellet and was still 92 % decreased at 8 weeks after dosing. Together, these results suggest that inadvertent ingestion of a single no. 9 Pb shot pellet can adversely affect the health of northern bobwhite quail. PMID:22562752

  1. Course and transmission characteristics of oral low-dose infection of domestic pigs and European wild boar with a Caucasian African swine fever virus isolate.

    PubMed

    Pietschmann, Jana; Guinat, Claire; Beer, Martin; Pronin, Valery; Tauscher, Kerstin; Petrov, Anja; Keil, Günther; Blome, Sandra

    2015-07-01

    In 2007, African swine fever virus (ASFV) was introduced into the Transcaucasian countries and Russia. Since then, it has spread alarmingly and reached the European Union. ASFV strains are highly virulent and lead to almost 100 % mortality under experimental conditions. However, the possibility of dose-dependent disease courses has been discussed. For this reason, a study was undertaken to assess the risk of chronic disease and the establishment of carriers upon low-dose oronasal infection of domestic pigs and European wild boar. It was demonstrated that very low doses of ASFV are sufficient to infect especially weak or runted animals by the oronasal route. Some of these animals did not show clinical signs indicative of ASF, and they developed almost no fever. However, no changes were observed in individual animal regarding the onset, course and outcome of infection as assessed by diagnostic tests. After amplification of ASFV by these animals, pen- and stablemates became infected and developed acute lethal disease with similar characteristics in all animals. Thus, we found no indication of prolonged or chronic individual courses upon low-dose infection in either species. The scattered onset of clinical signs and pathogen detection within and among groups confirms moderate contagiosity that is strongly linked with blood contact. In conclusion, the prolonged course at the "herd level" together with the exceptionally low dose that proved to be sufficient to infect a runted wild boar could be important for disease dynamics in wild-boar populations and in backyard settings. PMID:25916610

  2. Oral electricity.

    PubMed

    Certosimo, A J; O'Connor, R P

    1996-01-01

    "Oral electricity," "electrogalvanism," or "galvanic currents" has long been recognized as a potential source of oral pain and discomfort. This phenomenon of oral galvanism results from the difference in electrical potential between dissimilar restorative metals located in the mouth. In this case report, the literature is reviewed, and an interesting case study'is presented. The patient's clinical presentation, and the duration and constancy of the oral symptoms, pose diagnostic challenges. A simple, yet effective treatment regimen is proposed. PMID:8957826

  3. Gamma-ray dose assessment after the 1994 radiation accident in Kiisa (Estonia): Preliminary results

    Microsoft Academic Search

    G. Hütt; L. Brodski; V. Polyakov

    1996-01-01

    Dose reconstruction using thermoluminescence (TL) of quartz, extracted from the ceramic plant pots, and using EPR of the sugar samples, was performed after the 1994 radiation accident in the village Kiisa (Estonai). A gamma-ray source 137Cs was located during approx. 28 days in one of the village dwelling houses. On the basis of preliminary results, some important details of the

  4. Oral immunization with recombinant Salmonella typhimurium expressing surface protein antigen A of Streptococcus sobrinus: dose response and induction of protective humoral responses in rats.

    PubMed Central

    Redman, T K; Harmon, C C; Lallone, R L; Michalek, S M

    1995-01-01

    An attenuated, recombinant Salmonella typhimurium mutant, chi 4072(pYA2905), expressing the surface protein antigen A (SpaA) of Streptococcus sobrinus was investigated for its effectiveness in inducing protective immune responses against S. sobrinus-induced dental caries in an experimental caries model. Fischer rats were orally immunized with either 10(8) or 10(9) CFU of S. typhimurium chi 4072(pYA2905). Persistence of salmonellae in Peyer's patches and spleens and the induction of immune responses were determined. Maximum numbers of salmonellae were recovered from Peyer's patches of rats within the first week of immunization, with higher numbers recovered from rats given 10(9) CFU than from those given 10(8) CFU. Serum anti-Salmonella and anti-SpaA responses increased more rapidly in rats given 10(9) CFU than in rats given 10(8) CFU. The salivary antibody response to SpaA increased with time, but the response varied in the two groups. In a separate study, rats were orally immunized with the recombinant Salmonella mutant and then challenged with cariogenic S. sobrinus 6715. The levels of serum and salivary antibody and caries activity were assessed at the termination of the experiment. Higher levels of salivary immunoglobulin A antibody to SpaA and Salmonella carrier were detected in rats given 10(9) CFU than in those given 10(8) CFU, and these responses were higher than those in nonimmunized controls. Mandibular molars from immunized rats had lower numbers of recoverable streptococci and less extensive carious lesions than those from nonimmunized, control rats. These data indicate that oral immunization with an attenuated recombinant S. typhimurium expressing SpaA of S. sobrinus induces the production of antigen-specific mucosal antibody and confers protection against dental caries. PMID:7729915

  5. Subchronic Oral Exposure to Benzo(a)pyrene Leads to Distinct Transcriptomic Changes in the Lungs That Are Related to Carcinogenesis

    PubMed Central

    Halappanavar, Sabina

    2012-01-01

    We have previously shown that acute oral exposure to the environmental carcinogen benzo(a)pyrene (BaP) elicits comparable levels of DNA adducts, but distinct transcriptomic changes, in mouse lungs and livers, the two main BaP bioactivating organs. Oral BaP exposure is predominantly associated with lung cancer and not hepatic cancer in some animal models, suggesting that gene expression differences may provide insight into the drivers of tissue-specific carcinogenesis. In the present study, we examine pulmonary DNA adduct formation, lacZ mutant frequency, and mRNA profiles in adult male MutaMouse following subchronic (28 day) oral exposure to BaP (0, 25, 50, and 75mg/kg/day) and sacrificed 3 days postexposure. The results are compared with those obtained from livers of the same mice (previously published). Although there was a 1.8- to 3.3-fold increase in the levels of DNA adducts in lung compared with liver, the lacZ transgene mutant frequency was similar in both tissues. At the transcriptomic level, a transition from activation of the DNA damage response p53 pathway at the low dose to the induction of genes involved in angiogenesis, evasion of apoptosis and growth signals at the high doses was evident only in the lungs. These results suggest that tissue DNA adducts and mutant frequency are sensitive markers of target tissue exposure and mode of action, whereas early changes in gene expression may provide a better indication of the likelihood of carcinogenic transformation in selected tissues. Moreover, the study provides new information on the underlying mecha- nisms that contribute to tissue-specific responses to BaP. PMID:22610609

  6. Clenbuterol Distribution and Residues in Goat Tissues After the Repeated Administration of a Growth-Promoting Dose.

    PubMed

    Zhao, Zhen; Yao, Ting; Qin, Yuchang; Yang, Xiaowei; Li, Jun; Li, Junguo; Gu, Xu

    2015-07-01

    This study was conducted to investigate the deposition and depletion process of clenbuterol (CL) in goat tissues, plasma and urine after the repeated administration of a growth-promoting dose. The experiment was conducted in 24 goats (21 treated and 3 controls). Treated animals were administered orally in a dose of 16 µg/kg body mass once daily for 21 consecutive days and randomly sacrificed on days 0.25, 1, 3, 7, 14, 21 and 28 of the withdrawal period. CL in goat tissues was extracted with organic solvents and determined using liquid chromatography tandem mass spectrometry. The depletion rates of tissue differed significantly. The highest concentrations of CL in all tissues are detected on day 0.25 of treatment discontinuation. After administration had been discontinued for 28 days, CL still residues in all tissues, especially, in whole eye, where the concentrations reach 363.29 ± 31.60 ?g/kg. These findings confirmed that the whole eye, which are rich in pigment, showed a much higher concentration than any other studied tissue during the withdrawal period. PMID:25910488

  7. Oral tolerance: immune mechanisms and treatment of autoimmune diseases

    Microsoft Academic Search

    Howard L. Weiner

    1997-01-01

    Orally administered proteins induce systemic hyporesponsiveness to the fed protein. The mechanism underlying such ‘oral tolerance’ depends on the amount of antigen fed. with higher doses inducing deletion and anergy, and lower doses inducing regulatory cells. Orally administered autoantigens suppress many experimental autoimmune diseases, as discussed here by Howard Weiner.

  8. Effects of 28 days of resistance exercise and consuming a commercially available pre-workout supplement, NO-Shotgun®, on body composition, muscle strength and mass, markers of satellite cell activation, and clinical safety markers in males

    PubMed Central

    Shelmadine, Brian; Cooke, Matt; Buford, Thomas; Hudson, Geoffrey; Redd, Liz; Leutholtz, Brian; Willoughby, Darryn S

    2009-01-01

    Purpose This study determined the effects of 28 days of heavy resistance exercise combined with the nutritional supplement, NO-Shotgun®, on body composition, muscle strength and mass, markers of satellite cell activation, and clinical safety markers. Methods Eighteen non-resistance-trained males participated in a resistance training program (3 × 10-RM) 4 times/wk for 28 days while also ingesting 27 g/day of placebo (PL) or NO-Shotgun® (NO) 30 min prior to exercise. Data were analyzed with separate 2 × 2 ANOVA and t-tests (p < 0.05). Results Total body mass was increased in both groups (p = 0.001), but without any significant increases in total body water (p = 0.77). No significant changes occurred with fat mass (p = 0.62); however fat-free mass did increase with training (p = 0.001), and NO was significantly greater than PL (p = 0.001). Bench press strength for NO was significantly greater than PL (p = 0.003). Myofibrillar protein increased with training (p = 0.001), with NO being significantly greater than PL (p = 0.019). Serum IGF-1 (p = 0.046) and HGF (p = 0.06) were significantly increased with training and for NO HGF was greater than PL (p = 0.002). Muscle phosphorylated c-met was increased with training for both groups (p = 0.019). Total DNA was increased in both groups (p = 0.006), while NO was significantly greater than PL (p = 0.038). For DNA/protein, PL was decreased and NO was not changed (p = 0.014). All of the myogenic regulatory factors were increased with training; however, NO was shown to be significantly greater than PL for Myo-D (p = 0.008) and MRF-4 (p = 0.022). No significant differences were located for any of the whole blood and serum clinical chemistry markers (p > 0.05). Conclusion When combined with heavy resistance training for 28 days, NO-Shotgun® is not associated with any negative side effects, nor does it abnormally impact any of the clinical chemistry markers. Rather, NO-Shotgun® effectively increases muscle strength and mass, myofibrillar protein content, and increases the content of markers indicative of satellite cell activation. PMID:19656392

  9. 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. PMID:19011437

  10. The comparative effects of povidone-iodine and normal saline mouthwashes on oral mucositis in patients after high-dose chemotherapy and APBSCT--results of a randomized multicentre study.

    PubMed

    Vokurka, Samuel; Bystrická, Eva; Koza, Vladimír; Scudlová, Jana; Pavlicová, Vladislava; Valentová, Dana; Bocková, Jana; Misaniová, Lubica

    2005-07-01

    Antimicrobial solutions are widely used in the nursing care of chemotherapy induced oral mucositis (OM). There is little evidence, however, supporting their use for reducing mucosal damage. In our study, 132 patients were randomized to use normal saline (n=65) or povidone-iodine diluted 1:100 (n=67) mouthwashes for OM prophylaxis and treatment after high-dose chemotherapy comprising BEAM or HD-L-PAM followed by autologous peripheral stem cell transplantation. The study groups were well balanced in respect of age, sex, chemotherapy and the number of CD34+ cells in the graft. No significant difference was found between the groups in respect of OM characteristics, fever of unknown origin (FUO) and other infections. The antimicrobial solution was less tolerable for patients. OM occurred significantly more often in females than in males (86% vs 60%, P=0.0016) and was worse and of longer duration. The mechanical effect of mouthwashes might have a certain importance in FUO prevention. When indicating oral rinses, the patient's individual preference and tolerance of solutions offered should be considered. PMID:15798915

  11. Continuous, low-dose oral exposure to sodium chlorate reduces fecal Enterobacteriaceae coliforms in sheep feces without inducing subclinical chlorate toxicosis

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Our objectives were to determine a minimal daily dose of sodium chlorate, to be included in the drinking water for 5 days, that is safe yet maintains efficacy in reducing fecal shedding of Escherichia coli in mature ewes. In a complete randomized experimental design, 25 Targhee ewes (age = 18- to 20...

  12. Di-n-butyl Phthalate (DNBP) and Diisobutyl Phthalate (DiBP) Metabolism in a Human Volunteer after Single Oral Doses [Journal Article

    EPA Science Inventory

    An individual (male, 36 years, 87 kg) ingested two separate doses of di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) at a rate of ~60 µg/kg. Key monoester and oxidized metabolites were identified and quantified in urine continuously collected until 48 hours post dos...

  13. A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the ?-secretase inhibitor avagacestat

    PubMed Central

    Tong, Gary; Wang, Jun-Sheng; Sverdlov, Oleksandr; Huang, Shu-Pang; Slemmon, Randy; Croop, Robert; Castaneda, Lorna; Gu, Huidong; Wong, Oi; Li, Hewei; Berman, Robert M; Smith, Christina; Albright, Charles F; Dockens, Randy

    2013-01-01

    AIM To evaluate the single dose pharmacokinetics, pharmacodynamics, and preliminary tolerability of the ?-secretase inhibitor BMS-708163 (avagacestat) in young and elderly men and women. METHODS All subjects received double-blinded administration of a single 50 mg dose of avagacestat in capsule form or matching placebo. Main evaluations included pharmacokinetics, safety, plasma amyloid-? (A?)1–40 concentratios and exploration of Notch biomarkers. RESULTS Avagacestat 50 mg capsule was well tolerated and rapidly absorbed among young and elderly subjects, with a median tmax between 1 and 2 h post dose and an average half-life between 41 and 71 h. In general, subjects aged 75 years or more had higher AUC(0,?) values than those aged less than 75 years. An exploratory analysis of A?1–40 serum concentrations showed a pattern of decreasing concentrations over the first 4–6 h followed by a rise above baseline that was maintained until the end of the assessment period. Adverse events were generally mild, occurring more frequently in elderly subjects, with no observed difference between subjects receiving avagacestat and placebo. No dose limiting gastrointestinal effects of avagacestat were observed and exploratory biomarkers of Notch inhibition did not change significantly. CONCLUSIONS The favourable safety profile and pharmacokinetic effects of avagacestat in this study support its continued development, especially in the target population of elderly subjects with mild cognitive impairment or Alzheimer's disease. PMID:22616739

  14. A phase I open-labeled, single-arm, dose-escalation, study of dichloroacetate (DCA) in patients with advanced solid tumors.

    PubMed

    Chu, Quincy Siu-Chung; Sangha, Randeep; Spratlin, Jennifer; J Vos, Larissa; Mackey, John R; McEwan, Alexander J B; Venner, Peter; Michelakis, Evangelos D

    2015-06-01

    Purpose Preclinical evidence suggests dichloroacetate (DCA) can reverse the Warburg effect and inhibit growth in cancer models. This phase 1 study was undertaken to assess the safety, recommended phase 2 dose (RP2D), and pharmacokinetic (PK) profile of oral DCA in patients with advanced solid tumors. Patients and Methods Twenty-four patients with advanced solid malignancies were enrolled using a standard 3?+?3 protocol at a starting dose of 6.25 mg/kg twice daily (BID). Treatment on 28 days cycles was continued until progression, toxicity, or consent withdrawal. PK samples were collected on days 1 and 15 of cycle 1, and day 1 of subsequent cycles. PET imaging ((18)?F-FDG uptake) was investigated as a potential biomarker of response. Results Twenty-three evaluable patients were treated with DCA at two doses: 6.25 mg/kg and 12.5 mg/kg BID (median of 2 cycles each). No DLTs occurred in the 6.25 mg/kg BID cohort so the dose was escalated. Three of seven patients had DLTs (fatigue, vomiting, diarrhea) at 12.5 mg/kg BID. Thirteen additional patients were treated at 6.25 mg/kg BID. Most toxicities were grade 1-2 with the most common being fatigue, neuropathy and nausea. No responses were observed and eight patients had stable disease. The DCA PK profile in cancer patients was consistent with previously published data. There was high variability in PK values and neuropathy among patients. Progressive increase in DCA trough levels and a trend towards decreased (18)?F-FDG uptake with length of DCA therapy was observed. Conclusions The RP2D of oral DCA is 6.25 mg/kg BID. Toxicities will require careful monitoring in future trials. PMID:25762000

  15. Pharmacokinetics of Different Dosing Strategies of Oral Posaconazole in Patients with Compromised Gastrointestinal Function and Who Are at High Risk for Invasive Fungal Infection

    PubMed Central

    Helfgott, David; Langston, Amelia; Heinz, Werner; Vehreschild, Jörg-Janne; Vehreschild, Maria J. G. T.; Krishna, Gopal; Ma, Lei; Huyck, Susan; McCarthy, Michael C.

    2012-01-01

    The aim of this study was to assess different dosing strategies that may result in increased posaconazole bioavailability in patients with compromised gastrointestinal function and at high risk for invasive fungal infections. Patients undergoing chemotherapy and at risk for compromised gastrointestinal function received open-label posaconazole at 200 mg three times daily (TID) on days 1 to 8. Patients were randomized to one of three open-label dosing regimens of posaconazole on days 9 to 15: 200 mg TID, 400 mg twice daily (BID), or 400 mg TID. The plasma concentrations of interest on days 8 and 15 were 500 and 700 ng/ml, respectively; day 2 plasma concentrations of 250 and 350 ng/ml were chosen as levels that might result in steady-state concentrations of >500 and >700 ng/ml, respectively. A total of 75 patients enrolled; 52/75 (69%) completed the study, and 49/75 were included in the pharmacokinetic analyses. Mean plasma concentrations were 230, 346, and 637 ng/ml on days 2, 3, and 8, respectively. The day 15 values were 660, 930, and 671 ng/ml for 200 mg TID, 400 mg BID, and 400 mg TID, respectively. In 12 patients with a day 8 posaconazole concentration of <250 ng/ml, an overall benefit of the higher two doses was not apparent, suggesting that a subset of patients has low steady-state plasma concentrations. A change in dosing regimen on day 9 did not lead to higher exposures in these “poor absorbers” on day 15. Poor absorption may be enhanced with a high-fat meal, a nutritional supplement, or acidification. PMID:22290953

  16. Evaluation of the repeated-dose liver and gastrointestinal tract micronucleus assays with 22 chemicals using young adult rats: Summary of the collaborative study by the Collaborative Study Group for the Micronucleus Test (CSGMT)/The Japanese Environmental Mutagen Society (JEMS) - Mammalian Mutagenicity Study Group (MMS).

    PubMed

    Hamada, Shuichi; Ohyama, Wakako; Takashima, Rie; Shimada, Keisuke; Matsumoto, Kazumi; Kawakami, Satoru; Uno, Fuyumi; Sui, Hajime; Shimada, Yasushi; Imamura, Tadashi; Matsumura, Shoji; Sanada, Hisakazu; Inoue, Kenji; Muto, Shigeharu; Ogawa, Izumi; Hayashi, Aya; Takayanagi, Tomomi; Ogiwara, Yosuke; Maeda, Akihisa; Okada, Emiko; Terashima, Yukari; Takasawa, Hironao; Narumi, Kazunori; Wako, Yumi; Kawasako, Kazufumi; Sano, Masaki; Ohashi, Nobuyuki; Morita, Takeshi; Kojima, Hajime; Honma, Masamitsu; Hayashi, Makoto

    2015-03-01

    The repeated-dose liver micronucleus (RDLMN) assay using young adult rats has the potential to detect hepatocarcinogens. We conducted a collaborative study to assess the performance of this assay and to evaluate the possibility of integrating it into general toxicological studies. Twenty-four testing laboratories belonging to the Mammalian Mutagenicity Study Group, a subgroup of the Japanese Environmental Mutagen Society, participated in this trial. Twenty-two model chemicals, including some hepatocarcinogens, were tested in 14- and/or 28-day RDLMN assays. As a result, 14 out of the 16 hepatocarcinogens were positive, including 9 genotoxic hepatocarcinogens, which were reported negative in the bone marrow/peripheral blood micronucleus (MN) assay by a single treatment. These outcomes show the high sensitivity of the RDLMN assay to hepatocarcinogens. Regarding the specificity, 4 out of the 6 non-liver targeted genotoxic carcinogens gave negative responses. This shows the high organ specificity of the RDLMN assay. In addition to the RDLMN assay, we simultaneously conducted gastrointestinal tract MN assays using 6 of the above carcinogens as an optional trial of the collaborative study. The MN assay using the glandular stomach, which is the first contact site of the test chemical when administered by oral gavage, was able to detect chromosomal aberrations with 3 test chemicals including a stomach-targeted carcinogen. The treatment regime was the 14- and/or 28-day repeated-dose, and the regime is sufficiently promising to incorporate these methods into repeated-dose toxicological studies. The outcomes of our collaborative study indicated that the new techniques to detect chromosomal aberrations in vivo in several tissues worked successfully. PMID:25892619

  17. Phase I study of continuous MKC-1 in patients with advanced or metastatic solid malignancies using the modified Time-to-Event Continual Reassessment Method (TITE-CRM) dose escalation design

    PubMed Central

    Tevaarwerk, Amye; Wilding, George; Eickhoff, Jens; Chappell, Rick; Sidor, Carolyn; Arnott, Jamie; Bailey, Howard; Schelman, William; Liu, Glenn

    2011-01-01

    Background MKC-1 is an oral cell-cycle inhibitor with broad antitumor activity in preclinical models. Clinical studies demonstrated modest antitumor activity using intermittent dosing schedule, however additional preclinical data suggested continuous dosing could be efficacious with additional effects against the mTor/AKT pathway. The primary objectives were to determine the maximum tolerated dose (MTD) and response of continuous MKC-1. Secondary objectives included characterizing the dose limiting toxicities (DLTs) and pharmacokinetics (PK). Methods Patients with solid malignancies were eligible, if they had measurable disease, ECOG PS ?1, and adequate organ function. Exclusions included brain metastases and inability to receive oral drug. MKC-1 was dosed twice daily, continuously in 28-day cycles. Other medications were eliminated if there were possible drug interactions. Doses were assigned using a TITE-CRM algorithm following enrollment of the first 3 pts. Disease response was assessed every 8 weeks Results Between 5/08-9/09, 24 patients enrolled (15 M/9 F, median 58 years, range 44-77). Patients 1-3 received 120 mg/d of MKC-1; patients 4-24 were dosed per the TITE-CRM algorithm: 150 mg [n=1], 180 [2], 200 [1], 230 [1], 260 [5], 290 [6], 320 [5]. The median time on drug was 8 weeks (range 4-28). The only DLT occurred at 320 mg (grade 3 fatigue). Stable disease occurred at 150 mg/d (28 weeks; RCC) and 320 mg/d (16 weeks; breast, parotid). Escalation halted at 320 mg/d. Day 28 pharmacokinetics indicated absorption and active metabolites. Conclusion Continuous MKC-1 was well-tolerated; there were no RECIST responses, although clinical benefit occurred in 3/24 pts. Dose escalation stopped at 320 mg/d, and this is the MTD as defined by the CRM dose escalation algorithm; this cumulative dose/cycle exceeds that determined from intermittent dosing studies. A TITE-CRM allowed for rapid dose escalation and was able to account for late toxicities with continuous dosing via a modified algorithm. PMID:21225315

  18. Drug- not carrier-dependent haematological and biochemical changes in a repeated dose study of cyclosporine encapsulated polyester nano- and micro-particles: size does not matter.

    PubMed

    Venkatpurwar, V P; Rhodes, S; Oien, K A; Elliott, M A; Tekwe, C D; Jřrgensen, H G; Kumar, M N V Ravi

    2015-04-01

    Biodegradable nanoparticles are being considered more often as drug carriers to address pharmacokinetic/pharmacodynamic issues, yet nano-product safety has not been systematically proven. In this study, haematological, biochemical and histological parameters were examined on 28 day daily dosing of rats with nano- or micro-particle encapsulated cyclosporine (CsA) to confirm if any changes observed were drug or carrier dependent. CsA encapsulated poly(lactide-co-glycolide) [PLGA] nano- (nCsA) and micro-particles (mCsA) were prepared by emulsion techniques. CsA (15, 30, 45 mg/kg) were administered by oral gavage to Sprague Dawley (SD) rats over 28 days. Haematological and biochemical metrics were followed with tissue histology performed on sacrifice. Whether presented as nCsA or mCsA, 45 mg/kg dose caused significant loss of body weight and lowered food consumption compared to untreated control. Across the doses, both nCsA and mCsA produce significant decreases in lymphocyte numbers compared to controls, commensurate with the proprietary product, Neoral(®) 15. Dosing with nCsA showed higher serum drug levels than mCsA presumably owing to the smaller particle size facilitating absorption. The treatment had no noticeable effects on inflammatory/oxidative stress markers or antioxidant enzyme levels, except an increase in ceruloplasmin (CP) levels for high dose nCsA/mCsA group. Further, only subtle, sub-lethal changes were observed in histology of nCsA/mCsA treated rat organs. Blank (drug-free) particles did not induce changes in the parameters studied. Therefore, it is extremely important that the encapsulated drug in the nano-products is considered when safety of the overall product is assessed rather than relying on just the particle size. This study has addressed some concerns surrounding particulate drug delivery, demonstrating safe delivery of CsA whilst achieving augmented serum concentrations. PMID:25637670

  19. Distribution of vitamin C is tissue specific with early saturation of the brain and adrenal glands following differential oral dose regimens in guinea pigs.

    PubMed

    Hasselholt, Stine; Tveden-Nyborg, Pernille; Lykkesfeldt, Jens

    2015-05-01

    Vitamin C (VitC) deficiency is surprisingly common in humans even in developed parts of the world. The micronutrient has several established functions in the brain; however, the consequences of its deficiency are not well characterised. To elucidate the effects of VitC deficiency on the brain, increased knowledge about the distribution of VitC to the brain and within different brain regions after varying dietary concentrations is needed. In the present study, guinea pigs (like humans lacking the ability to synthesise VitC) were randomly divided into six groups (n 10) that received different concentrations of VitC ranging from 100 to 1500 mg/kg feed for 8 weeks, after which VitC concentrations in biological fluids and tissues were measured using HPLC. The distribution of VitC was found to be dynamic and dependent on dietary availability. Brain saturation was region specific, occurred at low dietary doses, and the dose-concentration relationship could be approximated with a three-parameter Hill equation. The correlation between plasma and brain concentrations of VitC was moderate compared with other organs, and during non-scorbutic VitC deficiency, the brain was able to maintain concentrations from about one-quarter to half of sufficient levels depending on the region, whereas concentrations in other tissues decreased to one-sixth or less. The adrenal glands have similar characteristics to the brain. The observed distribution kinetics with a low dietary dose needed for saturation and exceptional retention ability suggest that the brain and adrenal glands are high priority tissues with regard to the distribution of VitC. PMID:25865869

  20. Effects of graded oral doses of a new 5-hydroxytryptamine/noradrenaline uptake inhibitor (Ro 15-8081) in comparison with 60 mg codeine and placebo on experimentally induced pain and side effect profile in healthy men.

    PubMed Central

    Stacher, G; Steinringer, H; Schneider, S; Mittelbach, G; Gaupmann, G; Abatzi, T A; Stacher-Janotta, G

    1987-01-01

    1. Ro 15-8081 (Hoffmann-La Roche, Basle, Switzerland) is a novel mixed 5-HT/noradrenaline uptake inhibitor producing potent antinociceptive effects in animal pain models. 2. In healthy man, two models with electrically and thermally induced pain, respectively, have been shown to reliably discriminate between the effects of opioid as well as of antipyretic analgesics and placebo. 3. This study investigated the effects of single oral doses of 10, 25, and 50 mg Ro 15-8081 in comparison with 60 mg codeine and placebo on threshold and tolerance to electrically induced pain and on threshold to thermally induced pain. Furthermore, the effects on psychomotor function, self-rated subjective feelings, and side effect profile were studied. 4. Twenty healthy males participated each in five experiments in which they received, in random double-blind fashion, each of the treatments. Every experiment comprised two series of measurements before and twelve after drug administration, carried out at 30 min intervals. 5. Ro 15-8081 produced marked elevations of threshold and tolerance to electrically and of threshold to thermally induced pain. The effects of all doses of Ro 15-8081 were significantly superior to those of placebo. Threshold and tolerance to electrically induced pain were not affected differently by the three doses of Ro 15-8081, whereas the threshold to thermally induced pain was elevated significantly more by 50 mg than by 10 and 25 mg Ro 15-8081. 6. Codeine 60 mg had a more rapid onset of action and greater maximal effects than Ro 15-8081.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3501728

  1. A Dose- rather than Delivery Profile–Dependent Mechanism Regulates the “Muscle-Full” Effect in Response to Oral Essential Amino Acid Intake in Young Men12

    PubMed Central

    Mitchell, William Kyle; Phillips, Beth E; Williams, John P; Rankin, Debbie; Lund, Jonathan N; Smith, Kenneth; Atherton, Philip J

    2015-01-01

    Background: The anabolic response of skeletal muscle to essential amino acids (EAAs) is dose dependent, maximal at modest doses, and short lived, even with continued EAA availability, a phenomenon termed “muscle-full.” However, the effect of EAA ingestion profile on muscle metabolism remains undefined. Objective: We determined the effect of Bolus vs. Spread EAA feeding in young men and hypothesized that muscle-full is regulated by a dose-, not delivery profile–, dependent mechanism. Methods: We provided 16 young healthy men with 15 g mixed-EAA, either as a single dose (“Bolus”; n = 8) or in 4 fractions at 45-min intervals (“Spread”; n = 8). Plasma insulin and EAA concentrations were assayed by ELISA and ion-exchange chromatography, respectively. Limb blood flow by was determined by Doppler ultrasound, muscle microvascular flow by Sonovue (Bracco) contrast-enhanced ultrasound, and phosphorylation of mammalian target of rapamycin complex 1 substrates by immunoblotting. Intermittent muscle biopsies were taken to quantify myofibrillar-bound 13C6-phenylalanine to determine muscle protein synthesis (MPS). Results: Bolus feeding achieved rapid insulinemia (13.6 ?IU · mL?1, 25 min after commencement of feeding), aminoacidemia (?2500 ?M at 45 min), and capillary recruitment (+45% at 45 min), whereas Spread feeding achieved attenuated insulin responses, gradual low-amplitude aminoacidemia (peak: ?1500 ?M at 135 min), and no detectable capillary recruitment (all P < 0.01 vs. Bolus). Despite these differences, identical anabolic responses were observed; fasting fractional synthetic rates of 0.054% · h?1 (Bolus) and 0.066% · h?1 (Spread) increased to 0.095% and 0.104% · h?1 (no difference in increment or final values between regimens). With both Spread and Bolus feeding strategies, a latency of at least 90 min was observed before an upswing in MPS was evident. Similarly with both feeding strategies, MPS returned to fasting rates by 180 min despite elevated circulating EAAs. Conclusion: These data do not support EAA delivery profile as an important determinant of anabolism in young men at rest, nor rapid aminoacidemia/leucinemia as being a key factor in maximizing MPS. This trial was registered at clinicaltrials.gov as NCT01735539. PMID:25644339

  2. Effect of renal impairment on the pharmacokinetics of levomilnacipran following a single oral dose of levomilnacipran extended-release capsule in humans

    PubMed Central

    Chen, Laishun; Greenberg, William M; Brand-Schieber, Elimor; Wangsa, Julie; Periclou, Antonia; Ghahramani, Parviz

    2015-01-01

    Purpose Levomilnacipran extended-release (ER) is indicated for treatment of major depressive disorder in adults. We evaluated the pharmacokinetic and safety profile of levomilnacipran ER in individuals with impaired renal function. Methods A total of 32 individuals participated in four groups (eight in each group) with normal, mild, moderately, or severely impaired renal function. Each participant received one dose of levomilnacipran ER 40 mg. Blood and urine were assayed using liquid chromatography/tandem mass spectrometry. Results between normal and renally impaired groups were compared using analysis of variance. Safety measures included adverse events, laboratory evaluations, vital signs, suicidality, and electrocardiograms. Results Following administration of levomilnacipran, mean (standard deviation) maximum plasma concentration in participants with normal renal function, and mild, moderate, or severe renal impairment was 83.9 (21.0), 81.8 (23.4), 98.7 (18.1), and 122.1 (35.1) (ng/mL), respectively; area under the curve from time zero to infinity was 2,101.0 (516.9), 2,587.8 (649.9), 4,016.4 (995.4), and 5,900.8 (1,799.3) (h·ng/mL), respectively; terminal elimination half-life was 13.5 (2.8), 17.3 (3.5), 19.1 (4.6), and 27.7 (7.4) (hours), respectively; and renal clearance was 175.9 mL/min, 114.7 mL/min, 69.9 mL/min, and 28.6 mL/min, respectively. Levomilnacipran ER was generally well tolerated with no safety issues of concern identified. Conclusion Renal impairment was associated with increased plasma levels of levomilnacipran and prolonged half-life. No dose adjustment is required for individuals with mild renal impairment; the recommended maximum daily maintenance dose of levomilnacipran ER should not exceed 80 mg for individuals with moderate renal impairment and 40 mg for individuals with severe renal impairment. PMID:26150701

  3. Oral activated charcoal and dapsone elimination

    Microsoft Academic Search

    Periti J Neuvonen; Erkki Elonen; Mauri J Mattila

    1980-01-01

    The effect of orally given activated charcoal on the elimination of therapeutic and toxic doses of dapsone was studied in 5 healthy subjects and in 2 intoxicated patients. In a randomized crossover study the subjects took a total dose of 500 mg dapsone over 4 days; 10 hr after the last 100-mg dose of dapsone 50 gm activated charcoal as

  4. Oral Health

    MedlinePLUS

    ... be caused by several things, including: Poor oral hygiene Some foods Dentures Gum disease Dry mouth Tobacco use Respiratory, ... other health problems Some medicines Practicing good oral hygiene and avoiding tobacco and some foods often helps people with bad-smelling breath. You ...

  5. Modified oral metronidazole desensitization protocol.

    PubMed

    Gendelman, Samantha R; Pien, Lily C; Gutta, Ravi C; Abouhassan, Susan R

    2014-03-01

    The Center for Disease Control guidelines recommend desensitization to metronidazole in patients with trichomoniasis and hypersensitivity to metronidazole. There is only one published oral metronidazole desensitization protocol. The purpose of this study was to design a new, more gradual oral desensitization protocol to decrease systemic reactions that may occur when using the previously published protocol. We present two patients with presumed IgE-mediated allergy to metronidazole who underwent oral desensitization using our modified protocol. Case 1 was a 65-year-old woman with trichomoniasis who presented for metronidazole desensitization with a history of intraoperative anaphylaxis and positive skin tests to metronidazole. The patient tolerated six doses of the modified desensitization but developed systemic symptoms of nasal congestion and diffuse pruritus after the 25- and 100-mg doses. Both reactions were treated with intravenous (i.v.) antihistamines. Because of gastrointestinal irritation, the desensitization was completed at a dose of 250 mg orally every 6 hours. Case 2 was a 42-year-old woman with trichomoniasis and a history of hives immediately after administration of i.v. metronidazole who presented for desensitization. The patient had negative skin-prick and intradermal testing to metronidazole. She developed lip tingling and pruritus on her arms 15 minutes after the 10-mg dose. Fexofenadine at 180 mg was given orally and symptoms resolved. She tolerated the rest of the protocol without reaction and received a total dose of 2 g of metronidazole. Our oral metronidazole desensitization for presumed IgE-mediated reactions offers a second option for physicians wishing to use a more gradual escalation in dose. PMID:24612959

  6. Effect of high-dose ciclosporin on the immune response to primary and booster vaccination in immunocompetent cats.

    PubMed

    Roberts, Elizabeth S; VanLare, Karen A; Roycroft, Linda M; King, Stephen

    2015-02-01

    Ciclosporin (Atopica oral solution for cats 100 mg/ml; Novartis Animal Health) was recently approved for use in cats with feline hypersensitivity dermatitis. The immunosuppressant effect of ciclosporin on the ability of cats to mount an immune response following vaccination was determined. Thirty-two healthy, immunocompetent adult cats (16 cats/group) were treated with either ciclosporin for 56 days at a dose of 24 mg/kg once daily or sham dosed. Prior to treatment, cats had an adequate antibody response to primary vaccination against feline calicivirus (FCV), feline herpesvirus-1 (FHV-1), feline panleukopenia virus (FPV), feline leukemia virus (FeLV) and rabies. Booster vaccination or novel vaccination with feline immunodeficiency virus (FIV) was administered 28 days after initiation of treatment with ciclosporin. There were no differences between the ciclosporin-treated and control cats for FCV and FPV antibody titers following booster vaccination. There were delays/reductions in antibody response to FHV-1, FeLV and rabies in treated cats; however, adequate protection was achieved in response to all booster vaccinations. Following primary vaccination with FIV, control cats showed a response, but treated cats showed no antibody production. Adverse events commonly associated with ciclosporin treatment, including diarrhea/loose stool, vomiting, salivation and regurgitation, were reported. In adult cats treated with 24 mg/kg/day of ciclosporin (more than three times the therapeutic dose), vaccine titer levels were adequate for protection following booster vaccination. In contrast, treated cats failed to mount a humoral response to a novel (FIV) vaccination, suggesting that memory B-cell immune responses remain intact during repeated high-dose ciclosporin administration in cats, but that primary immune responses are impaired. PMID:24820998

  7. Vitamin D supplementation in older people (VDOP): Study protocol for a randomised controlled intervention trial with monthly oral dosing with 12,000 IU, 24,000 IU or 48,000 IU of vitamin D3

    PubMed Central

    2013-01-01

    The randomised, double blind intervention trial ‘Optimising Vitamin D Status in Older People’ (VDOP) will test the effect of three oral dosages of vitamin D given for one year on bone mineral density (BMD) and biochemical markers of vitamin D metabolism, bone turnover and safety in older people. VDOP is funded by Arthritis Research UK, supported through Newcastle University and MRC Human Nutrition Research and sponsored by the Newcastle upon Tyne Hospitals NHS Foundation Trust.a Background Vitamin D insufficiency is common in older people and may lead to secondary hyperparathyroidism, bone loss, impairment of muscle function and increased risk of falls and fractures. Vitamin D supplementation trials have yielded conflicting results with regard to decreasing rates of bone loss, falls and fractures and the optimal plasma concentration of 25 hydroxy vitamin D (25OHD) for skeletal health remains unclear. Method/design Older (?70 years) community dwelling men and women are recruited through General Practices in Northern England and 375 participants are randomised to take 12,000 international units (IU), 24,000 IU or 48,000 IU of vitamin D3 orally each month for one year starting in the winter or early spring. Hip BMD and anthropometry are measured at baseline and 12 months. Fasting blood samples are collected at baseline and three-month intervals for the measurement of plasma 25OHD, parathyroid hormone (PTH), biochemical markers of bone turnover and biochemistry to assess the dose–response and safety of supplementation. Questionnaire data include falls, fractures, quality of life, adverse events and outcomes, compliance, dietary calcium intake and sunshine exposure. Discussion This is the first integrated vitamin D supplementation trial in older men and women using a range of doses given at monthly intervals to assess BMD, plasma 25OHD, PTH and biochemical markers of bone turnover and safety, quality of life and physical performance. We aim to investigate the vitamin D supplementation and plasma 25OHD concentration required to maintain bone health and to develop a set of biochemical markers that reflects the effect of vitamin D on bone. This will aid future studies investigating the effect of vitamin D supplementation on fracture risk. #ISRCTN 35648481 (assigned 16 August 2012), EudraCT 2011-004890-10. PMID:24041337

  8. A Phase II Study of Fixed-Dose Rate Gemcitabine Plus Low-Dose Cisplatin Followed by Consolidative Chemoradiation for Locally Advanced Pancreatic Cancer

    SciTech Connect

    Ko, Andrew H. [Division of Hematology/Oncology, University of California at San Francisco, San Francisco, CA (United States)]. E-mail: andrewko@medicine.ucsf.edu; Quivey, Jeanne M. [Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA (United States); Venook, Alan P. [Division of Hematology/Oncology, University of California at San Francisco, San Francisco, CA (United States); Bergsland, Emily K. [Division of Hematology/Oncology, University of California at San Francisco, San Francisco, CA (United States); Dito, Elizabeth R.N. [Division of Hematology/Oncology, University of California at San Francisco, San Francisco, CA (United States); Schillinger, Brian R.N. [Division of Hematology/Oncology, University of California at San Francisco, San Francisco, CA (United States); Tempero, Margaret A. [Division of Hematology/Oncology, University of California at San Francisco, San Francisco, CA (United States)

    2007-07-01

    Purpose: The optimal strategy for treating locally advanced pancreatic cancer remains controversial, including the respective roles and timing of chemotherapy and radiation. We conducted a Phase II nonrandomized trial to evaluate sequential chemotherapy followed by chemoradiation in this patient population. Methods and Materials: Chemotherapy naive patients with locally advanced pancreatic adenocarcinoma were treated with fixed-dose rate gemcitabine (1,000 mg/m{sup 2} at 10 mg/m{sup 2}/min) plus cisplatin 20 mg/m{sup 2} on Days 1 and 15 of a 28-day cycle. Those without evidence of extrapancreatic metastases after six cycles of chemotherapy received radiation (5,040 cGy over 28 fractions) with concurrent capecitabine (800 mg/m{sup 2} orally twice daily on the day of radiation) as a radiosensitizer. Results: A total of 25 patients were enrolled with a median follow-up time of 656 days. Twelve patients (48%) successfully received all six cycles of chemotherapy plus chemoradiation. Eight patients (32%) progressed during chemotherapy, including 7 with extrapancreatic metastases. Grade 3/4 hematologic toxicities were uncommon. Two patients sustained myocardial infarctions during chemotherapy, and 4 were hospitalized for infectious complications, although none in the setting of neutropenia. Median time to progression was 10.5 months and median survival was 13.5 months, with an estimated 1-year survival rate of 62%. Patients receiving all components of therapy had a median survival of 17.0 months. Conclusions: A strategy of initial fixed-dose rate gemcitabine-based chemotherapy, followed by chemoradiation, shows promising efficacy for treatment of locally advanced disease. A substantial proportion of patients will be identified early on as having extrapancreatic disease and spared the potential toxicities associated with radiation.

  9. Comparative bioavailability and pharmacokinetics of two oral formulations of flurbiprofen: a single-dose, randomized, open-label, two-period, crossover study in Pakistani subjects.

    PubMed

    Qayyum, Aisha; Najmi, Muzammil Hasan; Abbas, Mateen

    2013-11-01

    Comparative bioavailability studies are conducted to establish the bioequivalence of generic formulation with that of branded reference formulation, providing confidence to clinicians to use these products interchangeably. This study was carried out to compare a locally manufactured formulation of flurbiprofen with that of a branded product. Twenty two healthy male adults received a single dose of flurbiprofen (100mg) either generic or branded product according to randomization scheme on each of 2 periods. Blood samples were collected and plasma flurbiprofen concentration was determined by a validated HPLC method. Pharmacokinetic parameters like AUC(0-t), AUC(0-oo), Cmax, Tmax, t˝, Vd and clearance were determined. The 90% CI for the ratio of geometric means of test to reference product's pharmacokinetic variables was calculated. Pharmacokinetic parameters for two formulations were comparable. Ratio of means of AUC(0-24), AUC(0-oo) and Cmax for test to reference products and 90% CI for these ratios were within the acceptable range. The p-values calculated by TOST were much less than the specified value (p-0.05). ANOVA gave p-values which were more than the specified value (p-0.05) for sequence, subject, period and formulation. Test formulation of flurbiprofen (tablet Flurso) was found to meet the criteria for bioequivalence to branded product (tablet Ansaid) based on pharmacokinetic parameters. PMID:24191330

  10. Assessment of methyl methanesulfonate using the repeated-dose liver micronucleus assay in young adult rats.

    PubMed

    Muto, Shigeharu; Yamada, Katsuya; Kato, Tatsuya; Wako, Yumi; Kawasako, Kazufumi; Iwase, Yumiko; Uno, Yoshifumi

    2015-03-01

    A repeated-dose liver micronucleus assay using young adult rats was conducted with methyl methanesulfonate (MMS) as a part of a collaborative study supported by the Collaborative Study Group for the Micronucleus Test/the Japanese Environmental Mutagen Society-Mammalian Mutagenicity Study Group. MMS is a classical DNA-reactive carcinogen, but it is not a liver carcinogen. In the first experiment (14-day study), MMS was administered per os to 6-week-old male Crl:CD (SD) rats every day for 14 days at a dose of 12.5, 25, or 50mg/kg/day. In the second experiment (28-day study), 6-week-old male SD rats were treated with MMS at 7.5, 15, or 30mg/kg/day for 28 days, because the highest dose used in the 14-day study (50mg/kg/day) caused mortality. Hepatocyte and bone marrow cell specimens were prepared on the day after the final dose. The frequency of micronucleated hepatocytes (MNHEPs) in the liver and that of micronucleated immature erythrocytes (MNIMEs) in the bone marrow were evaluated. Exposure to 50mg/kg/day MMS for 14 days resulted in an increased frequency of MNHEPs, but MMS had no effect on the frequency of MNHEPs in the rats exposed to the chemical for 28 days at doses up to 30mg/kg/day. MMS induced MNIMEs production at doses of 25 and 50mg/kg/day in the 14-day study and at doses of 15 and 30mg/kg/day in the 28-day study. Overall, the effect of MMS on the frequency of MNHEPs was considered to be equivocal. PMID:25892629

  11. Cryotherapy in the prevention of oral mucositis in patients receiving low-dose methotrexate following myeloablative allogeneic stem cell transplantation: a prospective randomized study of the Gruppo Italiano Trapianto di Midollo Osseo nurses group

    Microsoft Academic Search

    E Gori; M Arpinati; F Bonifazi; A Errico; A Mega; F Alberani; V Sabbi; G Costazza; S Leanza; C Borrelli; M Berni; C Feraut; E Polato; M C Altieri; E Pirola; M C Loddo; M Banfi; L Barzetti; S Calza; C Brignoli; G Bandini; A De Vivo; A Bosi; M Baccarani

    2007-01-01

    Severe oral mucositis is a major cause of morbidity following allogeneic hematopoietic stem cell transplantation (AHSCT). Cryotherapy, that is, the application of ice chips on the mucosa of the oral cavity during the administration of antineoplastic agents, may reduce the incidence and severity of chemotherapy-related oral mucositis. In this multicenter randomized study, we addressed whether cryotherapy during MTX administration is

  12. Nateglinide Oral

    MedlinePLUS

    Nateglinide comes as a tablet to take by mouth. It is usually taken three times daily. Take ... that contain alcohol or sugar; mesoridazine (Serentil); niacin; oral contraceptives (birth control pills); perphenazine (Trilafon); phenelzine (Nardil); ...

  13. Ampicillin Oral

    MedlinePLUS

    ... capsule, liquid, and pediatric drops to take by mouth. It is usually taken every 6 hours (four ... blood thinners') such as warfarin (Coumadin), atenolol (Tenormin), oral contraceptives, probenecid (Benemid), rifampin, sulfasalazine, and vitamins.tell ...

  14. Oral vaccines

    PubMed Central

    Zhu, Qing; Berzofsky, Jay A.

    2013-01-01

    Oral vaccines are safe and easy to administer and convenient for all ages. They have been successfully developed to protect from many infectious diseases acquired through oral transmission. We recently found in animal models that formulation of oral vaccines in a nanoparticle-releasing microparticle delivery system is a viable approach for selectively inducing large intestinal protective immunity against infections at rectal and genital mucosae. These large-intestine targeted oral vaccines are a potential substitute for the intracolorectal immunization, which has been found to be effective against rectogenital infections but is not feasible for mass vaccination. Moreover, the newly developed delivery system can be modified to selectively target either the small or large intestine for immunization and accordingly revealed a regionalized immune system in the gut. Future applications and research endeavors suggested by the findings are discussed. PMID:23493163

  15. Oral Warts

    MedlinePLUS

    ... High School and College Students Recent College Graduates Dental and Medical Students See All Careers & Training Opportunities Job Openings Loan Repayment Programs Careers in Dental Research See All Continuing Education Practical Oral Care ...

  16. Oral Cancer

    MedlinePLUS

    ... High School and College Students Recent College Graduates Dental and Medical Students See All Careers & Training Opportunities Job Openings Loan Repayment Programs Careers in Dental Research See All Continuing Education Practical Oral Care ...

  17. Oral Herpes

    MedlinePLUS

    ... High School and College Students Recent College Graduates Dental and Medical Students See All Careers & Training Opportunities Job Openings Loan Repayment Programs Careers in Dental Research See All Continuing Education Practical Oral Care ...

  18. Herpes - oral

    MedlinePLUS

    ... virus type 2 (HSV-2) most often causes genital herpes . However, sometimes HSV-2 is spread to the ... the virus to the genitals. Both oral and genital herpes viruses can sometimes be spread, even when you ...

  19. The Importance of Body Weight for the Dose Response Relationship of Oral Vitamin D Supplementation and Serum 25-Hydroxyvitamin D in Healthy Volunteers

    PubMed Central

    Ekwaru, John Paul; Zwicker, Jennifer D.; Holick, Michael F.; Giovannucci, Edward; Veugelers, Paul J.

    2014-01-01

    Unlike vitamin D recommendations by the Institute of Medicine, the Clinical Practice Guidelines by the Endocrine Society acknowledge body weight differentials and recommend obese subjects be given two to three times more vitamin D to satisfy their body's vitamin D requirement. However, the Endocrine Society also acknowledges that there are no good studies that clearly justify this. In this study we examined the combined effect of vitamin D supplementation and body weight on serum 25-hydroxyvitamin (25(OH)D) and serum calcium in healthy volunteers. We analyzed 22,214 recordings of vitamin D supplement use and serum 25(OH)D from 17,614 healthy adult volunteers participating in a preventive health program. This program encourages the use of vitamin D supplementation and monitors its use and serum 25(OH)D and serum calcium levels. Participants reported vitamin D supplementation ranging from 0 to 55,000 IU per day and had serum 25(OH)D levels ranging from 10.1 to 394 nmol/L. The dose response relationship between vitamin D supplementation and serum 25(OH)D followed an exponential curve. On average, serum 25(OH)D increased by 12.0 nmol/L per 1,000 IU in the supplementation interval of 0 to 1,000 IU per day and by 1.1 nmol/L per 1,000 IU in the supplementation interval of 15,000 to 20,000 IU per day. BMI, relative to absolute body weight, was found to be the better determinant of 25(OH)D. Relative to normal weight subjects, obese and overweight participants had serum 25(OH)D that were on average 19.8 nmol/L and 8.0 nmol/L lower, respectively (P<0.001). We did not observe any increase in the risk for hypercalcemia with increasing vitamin D supplementation. We recommend vitamin D supplementation be 2 to 3 times higher for obese subjects and 1.5 times higher for overweight subjects relative to normal weight subjects. This observational study provides body weight specific recommendations to achieve 25(OH)D targets. PMID:25372709

  20. Oral feeding.

    PubMed

    Alvárez-Falcón, Ana; Ruiz-Santana, Sergio

    2013-01-01

    Early nutrition can help to improve energy and protein intake and decrease the negative impact of the metabolic response to surgery. A key goal is to identify patients who exhibit increased respiration risk before beginning oral alimentation. Once a simple bedside 3-oz (90 ml) challenge, or early intervention in the oral care, administered by a trained provider is passed, specific diet recommendations can be made safely and confidently without the need for further objective dysphagia testing. Gastrointestinal motility disorders occur as part of the pathophysiology of diseases and critical illness, or are a result of medication therapies or enteral feeding complications. Inadequate energy intake in the first 7 days following extubation have recently been described. It would be highly beneficial to determine when it is best to initiate timely oral alimentation for recovering extubated intensive care unit (ICU) and more specifically surgical ICU patients to support the maintenance and rebuilding of lean body mass, maintain hydration, and permit the ingestion of oral medications. In a cross-sectional multicenter study conducted in 18 Spanish ICUs, within the scope of the 2007 European Nutrition Day, only 95 of 348 investigated patients (27.3%) received oral nutritional support. Constipation and diarrhea were common adverse effects. Unexpectedly, however, constipation episodes were more frequent than diarrhea in the patients not receiving oral nutritional support. PMID:23075585

  1. Effects of SiC nanoparticles orally administered in a rat model: Biodistribution, toxicity and elemental composition changes in feces and organs

    SciTech Connect

    Lozano, Omar, E-mail: omar.lozanogarcia@fundp.ac.be [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium) [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Research Centre for the Physics of Matter and Radiation (PMR-LARN), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Laloy, Julie; Alpan, Lütfiye [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium) [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Department of Pharmacy, NAMEDIC, Namur Thrombosis and Hemostasis Center (NTHC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Mejia, Jorge [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium) [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Research Centre for the Physics of Matter and Radiation (PMR-LARN), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Rolin, Stéphanie [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium) [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Department of Pharmacy, NAMEDIC, Namur Thrombosis and Hemostasis Center (NTHC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Toussaint, Olivier [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium) [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Laboratory of Biochemistry and Cellular Biology (URBC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Dogné, Jean-Michel [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium) [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Department of Pharmacy, NAMEDIC, Namur Thrombosis and Hemostasis Center (NTHC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); and others

    2012-10-15

    Background: Silicon carbide (SiC) presents noteworthy properties as a material such as high hardness, thermal stability, and photoluminescent properties as a nanocrystal. However, there are very few studies in regard to the toxicological potential of SiC NPs. Objectives: To study the toxicity and biodistribution of silicon carbide (SiC) nanoparticles in an in vivo rat model after acute (24 h) and subacute (28 days) oral administrations. The acute doses were 0.5, 5, 50, 300 and 600 mg·kg{sup ?1}, while the subacute doses were 0.5 and 50 mg·kg{sup ?1}. Results: SiC biodistribution and elemental composition of feces and organs (liver, kidneys, and spleen) have been studied by Particle-Induced X-ray Emission (PIXE). SiC and other elements in feces excretion increased by the end of the subacute assessment. SiC did not accumulate in organs but some elemental composition modifications were observed after the acute assessment. Histopathological sections from organs (stomach, intestines, liver, and kidneys) indicate the absence of damage at all applied doses, in both assessments. A decrease in the concentration of urea in blood was found in the 50 mg·kg{sup ?1} group from the subacute assessment. No alterations in the urine parameters (sodium, potassium, osmolarity) were found. Conclusion: This is the first study that assesses the toxicity, biodistribution, and composition changes in feces and organs of SiC nanoparticles in an in vivo rat model. SiC was excreted mostly in feces and low traces were retrieved in urine, indicating that SiC can cross the intestinal barrier. No sign of toxicity was however found after oral administration. -- Highlights: ? SiC nanoparticles were orally administered to rats in acute and subacute doses. ? SiC was found in low traces in urine. It is mostly excreted in feces within 5 days. ? SiC excretion rate, feces and organ elemental composition change with time. ? No morphological alteration were found on GI tract, liver, kidneys, or spleen. ? Urea increased in blood in the subacute assessment. No change in urine properties.

  2. Efficacy and safety of the six-dose regimen of artemether–lumefantrine for treatment of uncomplicated Plasmodium falciparum malaria in adolescents and adults: A pooled analysis of individual patient data from randomized clinical trials

    Microsoft Academic Search

    Edgar A. Mueller; Michele van Vugt; Wilhelm Kirch; Kim Andriano; Philip Hunt; Patricia Ibarra de Palacios

    2006-01-01

    To demonstrate the superiority of the six-dose over the four-dose regimen of artemether–lumefantrine (co-artemether, Coartem®) in patients >12 years, data from 11 randomized clinical trials were pooled and analyzed. A total of 1368 patients with uncomplicated Plasmodium falciparum malaria (six-dose: 598; four-dose: 770) were included in the analysis, together with 717 patients treated with comparators. Analysis of the 28-day cure

  3. Bioequivalence of zonisamide orally dispersible tablet and immediate-release capsule formulations: Results from two open-label, randomized-sequence, single-dose, two-period, two-treatment crossover studies in healthy male volunteers

    Microsoft Academic Search

    Rob van Maanen; Darren Bentley

    2009-01-01

    Background: To make it easier for patients who are prescribed zonisamide to administer their medicine, a rapidly disintegrating oral tablet formulation has been developed.Objective: These 2 trials assessed the bioequiva-lence of a new orally dispersible tablet formulation of zonisamide (test) versus an immediate-release reference capsule.Methods: Study 1 assessed the bioequivalence of a 100-mg orally dispersible tablet versus a 100-mg reference

  4. Cryotherapy in the prevention of oral mucositis in patients receiving low-dose methotrexate following myeloablative allogeneic stem cell transplantation: a prospective randomized study of the Gruppo Italiano Trapianto di Midollo Osseo nurses group.

    PubMed

    Gori, E; Arpinati, M; Bonifazi, F; Errico, A; Mega, A; Alberani, F; Sabbi, V; Costazza, G; Leanza, S; Borrelli, C; Berni, M; Feraut, C; Polato, E; Altieri, M C; Pirola, E; Loddo, M C; Banfi, M; Barzetti, L; Calza, S; Brignoli, C; Bandini, G; De Vivo, A; Bosi, A; Baccarani, M

    2007-03-01

    Severe oral mucositis is a major cause of morbidity following allogeneic hematopoietic stem cell transplantation (AHSCT). Cryotherapy, that is, the application of ice chips on the mucosa of the oral cavity during the administration of antineoplastic agents, may reduce the incidence and severity of chemotherapy-related oral mucositis. In this multicenter randomized study, we addressed whether cryotherapy during MTX administration is effective in the prevention of severe oral mucositis in patients undergoing myeloablative AHSCT. One hundred and thirty patients undergoing myeloablative AHSCT and MTX-containing GVHD prophylaxis were enrolled and randomized to receive or not receive cryotherapy during MTX administration. The incidence of severe (grade 3-4) oral mucositis, the primary end point of the study, was comparable in patients receiving or not cryotherapy. Moreover, no difference was observed in the incidence of oral mucositis grade 2-4 and the duration of oral mucositis grade 3-4 or 2-4, or in the kinetics of mucositis over time. In univariate and multivariate analysis, severe oral mucositis correlated with TBI in the conditioning regimen and lack of folinic acid rescue following MTX administration. Thus, cryotherapy during MTX administration does not reduce severe oral mucositis in patients undergoing myeloablative allogeneic HSCT. Future studies will assess cryotherapy before allogeneic HSCT. PMID:17277790

  5. Multiple hepatocellular tumours in a patient treated with oral contraceptives

    Microsoft Academic Search

    William L. Brander; Gregory Vosnides; Chisholm S. Ogg; Iain E. West

    1976-01-01

    A case of multiple hepatic tumours in a patient treated for four years with high doses of oral contraceptives is described. Solitary hepatocellular lesions associated with conventional doses of oral contraceptives have been reported previously in twenty nine cases. Haemorrhage has been a common mode of presentation and is attributed to the marked vascularity of the lesions, an appearance referred

  6. Hypocalcaemia following thyroidectomy unresponsive to oral therapy.

    PubMed

    Etheridge, Zac C; Schofield, Christopher; Prinsloo, Peter J J; Sturrock, Nigel D C

    2014-01-01

    Hypocalcaemia due to hypoparathyroidism following thyroidectomy is a relatively common occurrence. Standard treatment is with oral calcium and vitamin D replacement therapy; lack of response to oral therapy is rare. Herein we describe a case of hypoparathyroidism following thyroidectomy unresponsive to oral therapy in a patient with a complex medical history. We consider the potential causes in the context of calcium metabolism including: poor adherence, hungry bone syndrome, malabsorption, vitamin D resistance, bisphosphonate use and functional hypoparathyroidism secondary to magnesium deficiency. Malabsorption due to intestinal hurry was likely to be a contributory factor in this case and very large doses of oral therapy were required to avoid symptomatic hypocalcaemia. PMID:24776629

  7. First-in-Human Dose Study of the Novel Transforming Growth Factor-? Receptor I Kinase Inhibitor LY2157299 Monohydrate in Patients with Advanced Cancer and Glioma

    PubMed Central

    Rodon, Jordi; Carducci, Michael A.; Sepulveda-Sánchez, Juan M; Azaro, Analia; Calvo, Emiliano; Seoane, Joan; Brańa, Irene; Sicart, Elisabet; Gueorguieva, Ivelina; Cleverly, Ann L.; Pillay, N. Sokalingum; Desaiah, Durisala; Estrem, Shawn T.; Paz-Ares, Luis; Holdhoff, Matthias; Blakeley, Jaishri; Lahn, Michael M.; Baselga, Jose

    2015-01-01

    Purpose TGF? signaling plays a key role in tumor progression, including malignant glioma. Small-molecule inhibitors such as LY2157299 monohydrate (LY2157299) block TGF? signaling and reduce tumor progression in preclinical models. To use LY2157299 in the treatment of malignancies, we investigated its properties in a first-in-human dose (FHD) study in patients with cancer. Experimental Design Sixty-five patients (58 with glioma) with measurable and progressive malignancies were enrolled. Oral LY2157299 was given as a split dose morning and evening on an intermittent schedule of 14 days on and 14 days off (28-day cycle). LY2157299 monotherapy was studied in dose escalation (part A) first and then evaluated in combination with standard doses of lomustine (part B). Safety was assessed using Common Terminology Criteria for Adverse Events version 3.0, echocardiography/Doppler imaging, serum troponin I, and brain natriuretic peptide (BNP) levels. Antitumor activity was assessed by RECIST and Macdonald criteria. Results In part A, 16.6% (5/30) and in part B, 7.7% (2/26) of evaluable patients with glioma had either a complete (CR) or a partial response (PR). In both parts, 15 patients with glioma had stable disease (SD), 5 of whom had SD ?6 cycles of treatment. Therefore, clinical benefit (CR+PR+SD ?6 cycles) was observed in 12 of 56 patients with glioma (21.4%). LY2157299 was safe, with no cardiac adverse events. Conclusions On the basis of the safety, pharmacokinetics, and antitumor activity in patients with glioma, the intermittent administration of LY2157299 at 300 mg/day is safe for future clinical investigation. PMID:25424852

  8. A comparative, randomized clinical trial of artemisinin/naphtoquine twice daily one day versus artemether/lumefantrine six doses regimen in children and adults with uncomplicated falciparum malaria in Côte d'Ivoire

    PubMed Central

    Toure, Offianan A; Penali, Louis K; Yapi, Jean-Didier; Ako, Berenger A; Toure, Walamtchin; Djerea, Kali; Gomez, Genevieve O; Makaila, Oyewole

    2009-01-01

    Background Drug resistance in Plasmodium falciparum poses a major threat to malaria control. Combination anti-malarial therapy, including artemisinins, has been advocated to improve efficacy and limit the spread of resistance. The fixed combination of oral artemether-lumefantrine (AL) is highly effective and well-tolerated. Artemisinin/naphtoquine (AN) is a fixed-dose ACT that has recently become available in Africa. The objectives of the study were to compare the efficacy and safety of AN and AL for the treatment of uncomplicated falciparum malaria in a high transmission-intensity site in Ivory Coast. Methods We enrolled 122 participants aged 6 months or more with uncomplicated falciparum malaria. Participants were randomized to receive either artemisinin/naphtoquine or artemether/lumefantrine with variable dose according to their weight. Primary endpoints were the risks of treatment failure within 28 days, either unadjusted or adjusted by genotyping to distinguish recrudescence from new infection. Results Among 125 participants enrolled, 123 (98.4%) completed follow-up. Clinical evaluation of the 123 participants showed that cumulative PCR-uncorrected cure rate on day 28 was 100% for artemisinin/naphtoquine and 98.4% for artemether/lumefantrine. Both artemisinin-based combinations effected rapid fever and parasite clearance. Interpretation These data suggest that Arco® could prove to be suitable for use as combination antimalarial therapy. Meanwhile, pharmacokinetic studies and further efficacy assessment should be conducted before its widespread use can be supported. PMID:19575797

  9. Pharmacogenetic aspects of coumarinic oral anticoagulant therapies.

    PubMed

    Rathore, Saurabh Singh; Agarwal, Surendra Kumar; Pande, Shantanu; Singh, Sushil Kumar; Mittal, Tulika; Mittal, Balraj

    2011-07-01

    Coumarinic oral-anticoagulants (COAs) are commonly used for treatment of thromboembolic events. However, these medications have a narrow therapeutic range and there are large inter-individual variations in drug response. This is especially important in the initial phases of oral-anticoagulant therapy. Recent advancements in pharmacogenetics have established that clinical outcomes in oral-anticoagulant therapy are affected by genetic factors. The allelic variants of genes like cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1) are closely associated with maintenance dose of oral anti-coagulants. In addition, GGCX (Gamma-glutamyl carboxylase) polymorphism at position 12970 (rs11676382), CYP4F2 (rs2108622; V433M; 1347 C > T) and Apolipoprotein E (APOE) variants have been shown to explain a small but significant influence on dose requirements. There are large differences in the frequencies of these polymorphisms between different world populations which are also related to the requirements of oral anticoagulants. However, the final drug dosage in an individual is determined by complex sets of genetic and environmental factors and several dosing algorithms which combine clinical and genetic parameters to predict therapeutic COA doses have also been developed. The algorithm based dose prediction shows the importance of pharmacogenetic testing in patients undergoing oral anticoagulant therapies. PMID:22754184

  10. Oral Cancer

    MedlinePLUS

    ... What are the effects of oral cancer on speech and swallowing? The effects of cancer on speech and swallowing depend on the location and size ... movement. This could result in unclear production of speech sounds made with the lips such as /p/, / ...

  11. Oral Care

    Microsoft Academic Search

    Irčne Hitz Lindenmüller; J. Thomas Lambrecht

    2011-01-01

    Adequate dental and oral hygiene may become a challenge for all users and especially for elderly people and young children because of their limited motor skills. The same holds true for patients undergoing\\/recovering from chemo-\\/radiotherapy with accompanying sensitive mucosal conditions. Poor dental hygiene can result in tooth decay, gingivitis, periodontitis, tooth loss, bad breath (halitosis), fungal infection and gum diseases.

  12. Oral Tolerance: Therapeutic Implications for Autoimmune Diseases

    PubMed Central

    Faria, Ana M. C.; Weiner, Howard L.

    2006-01-01

    Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-?) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-?, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy. PMID:17162357

  13. Chemical Warfare Agents: Estimating Oral Reference Doses

    Microsoft Academic Search

    Dennis M. Opresko; Robert A. Young; Rosmarie A. Faust; Sylvia S. Talmage; Annetta P. Watson; Robert H. Ross; Kowetha A. Davidson; Joe King

    \\u000a The FY 1993 Defense Authorization Act [Public Law (PL) 102–484, Sect. 176] directed the U.S. Department of the Army (DA) 1 to examine the scale of effort and consider plans needed to safely dispose of nonstockpile chemical materiel (NSCM), previously\\u000a identified as an area of national concern in House Appropriations Report 101–822 from the FY 1991 Defense Appropriations Act.\\u000a Non-stockpile

  14. Safety of Oral Sulfates in Rats and Dogs Contrasted With Phosphate-Induced Nephropathy in Rats

    Microsoft Academic Search

    Russell W. Pelham; Robert G. Russell; Eric L. Padgett; Frederick E. Reno; Mark v B. Cleveland

    2009-01-01

    An oral sulfate salt solution (OSS), under development as a bowel cleansing agent for colonoscopy in humans, is studied in rats and dogs. In rats, a maximum practical oral OSS dose (5 g\\/kg\\/d) is compared with an oral sodium phosphate (OSP) solution, both at about 7 times the clinical dose. OSS induces the intended effects of loose stools and diarrhea.

  15. Prophylaxis and treatment of chemo- and radiotherapy-induced oral mucositis – are there new strategies?

    Microsoft Academic Search

    M Karthaus; C Rosenthal; A Ganser

    1999-01-01

    Oral mucositis is a major dose-limiting toxic effect of intensive cancer chemotherapy. Oral complications may lead to dose reduction or delay in further cancer treatment. Mucositis can be caused directly by cytotoxic effects and indirectly by sustained neutropenia after cytostatic therapy. An impaired mucosal barrier predisposes to life-threatening septic complications during aplasia. The prevalence of an oral focus in febrile

  16. Oral contraceptives and liver function

    PubMed Central

    Hargreaves, Tom

    1969-01-01

    Oral contraceptives can cause liver damage and jaundice but this is very rare in women in the United Kingdom. The drugs are contraindicated where there is a history of recurrent intrahepatic cholestasis of pregnancy and acute or chronic disturbance of liver function which can be congenital or acquired. It is not yet known whether the oestrogenic or progestogenic components of oral contraceptives cause the hepatic abnormalities. The available data suggest that neither oestrogens nor progestogens in low doses impair hepatic excretory processes. The full implications of the continued administration of oestrogens and progestogens for many years on liver proteins are not yet known.

  17. Evaluation of a repeated dose liver micronucleus assay in rats treated with two genotoxic hepatocarcinogens, dimethylnitrosamine and 2-acetylaminofluorene: the possibility of integrating micronucleus tests with multiple tissues into a repeated dose general toxicity study.

    PubMed

    Takashima, Rie; Takasawa, Hironao; Kawasako, Kazufumi; Ohyama, Wakako; Okada, Emiko; Narumi, Kazunori; Fujiishi, Yohei; Wako, Yumi; Yasunaga, Katsuaki; Hattori, Akiko; Kawabata, Masayoshi; Nakadate, Kiyoko; Nakagawa, Munehiro; Hamada, Shuichi

    2015-03-01

    As part of a collaborative study by the Collaborative Study Group for Micronucleus Test (CSGMT) of the Mammalian Mutagenicity Study Group (MMS) in the Japanese Environmental Mutagen Society (JEMS), the present study evaluated the effectiveness of the repeated dose liver micronucleus (RDLMN) assay. Two genotoxic hepatocarcinogens, dimethylnitrosamine (DMN) and 2-acetylaminofluorene (2-AAF), were administered orally to male rats (6 weeks old at the initial dosing) once daily for 14 and 28 days to evaluate the micronucleus (MN) inducibility in the liver. In addition, these chemicals were evaluated for MN inducibility in the bone marrow (BM) and gastrointestinal (GI) tract, i.e. glandular stomach and colon of the same animals used in the RDLMN assay. As a result, both chemicals produced positive results in the liver, although a weak positive response was given by 2-AAF. DMN gave negative results in the tissues other than the liver. 2-AAF produced positive responses in the BM and glandular stomach, and a prominent response was particularly observed in the glandular stomach, which is directly exposed to the test chemicals by gavage. The present results suggest that the RDLMN assay is a useful method for detecting genotoxic hepatocarcinogens, and that it is especially effective for evaluating test chemicals, such as DMN, undetectable by the BM and GI tract MN assay. Moreover, the results in this investigation indicate that the use of multiple tissues in the study integrating the MN tests is more effective than using a single tissue, for detection of the MN induction produced by chemical exposure to rats, and helps to determine the characteristics of the test chemicals. PMID:25892620

  18. Oral Mucositis

    Microsoft Academic Search

    Nathaniel Treister

    Mucositis is a common, painful, treatment-disrupting toxicity of both radiotherapy and chemotherapy. Patients with cancers\\u000a of the head and neck receiving radiation therapy with and without induction or concomitant chemotherapy, and individuals being\\u000a treated with high-dose chemotherapy regimens are at particularly high risk. Importantly, even patients receiving conventional\\u000a dosing schemes for other forms of cancer have a meaningful chance of

  19. Repeated dose liver micronucleus assay using clofibrate in young adult rats.

    PubMed

    Takayanagi, Tomomi; Takashima, Rie; Wako, Yumi; Kawasako, Kazufumi; Tanaka, Yasuhiro; Hori, Hisako; Fujii, Wataru

    2015-03-01

    The repeated-dose liver micronucleus (MN) assay is a newly established in vivo genotoxicity test for evaluation of liver carcinogens. It may be integrated into general toxicity studies, thereby reducing the numbers of animals required for assessment of chemical safety. A collaborative study by the Mammalian Mutagenicity Study (MMS) Group further evaluated this assay using a wide range of chemicals, including carcinogens and non-carcinogens in young adult rats. In this study, we administered clofibrate (125, 250, or 500mg/kg/day) for 14 or 28 days, and examined the micronucleated (MNed) cell frequencies in the liver and bone marrow. Clofibrate is a known liver carcinogen specific to rodents and has been shown to yield negative results in many in vitro genotoxicity and carcinogenicity tests in monkeys. Clofibrate is categorized as a Group 3 chemical by the International Agency for Research on Cancer and is considered a non-genotoxic carcinogen. After treatment with clofibrate for 14 or 28 days, frequencies of hepatic MNed cells were significantly increased, but there were no differences in the ratios of hepatic M-phase cells. Clofibrate did not increase the frequency of MNed cells in the bone marrow in the 14-day study, whereas a slight increase was observed at the highest dose in the 28-day study. These results suggested that the repeated-dose liver MN assay is more sensitive to clofibrate, an indirect liver carcinogen in rodents, than the conventional bone marrow MN assay. PMID:25892631

  20. Low-Dose Oral Tolerance due to Antigen in the Diet Suppresses Differentially the Cholera Toxin-Adjuvantized IgE, IgA and IgG Response

    Microsoft Academic Search

    Hanne R. Christensen; Tanja M. R. Kjćr; Hanne Frřkićr

    2003-01-01

    Background: Cholera toxin (CT) is used as a mucosal adjuvant amongst other applications for studying food allergy because oral administration of antigen with CT induces an antigen-specific type 2 response, including IgE and IgA production. Priorly established oral tolerance due to antigen in the diet may radically impact on the CT-adjuvantized immune response. The present study served to evaluate the

  1. A phase 1 study of SNS032 (formerly BMS-387032), a potent inhibitor of cyclin-dependent kinases 2, 7 and 9 administered as a single oral dose and weekly infusion in patients with metastatic refractory solid tumors

    Microsoft Academic Search

    Elisabeth I. Heath; Keith Bible; Robert E. Martell; Daniel C. Adelman; Patricia M. LoRusso

    2008-01-01

    Summary  \\u000a Purpose: SNS-032, (formerly BMS-387032) is a potent and selective inhibitor of cyclin-dependent kinases (CDK) 2, 7 and 9. The primary\\u000a objective of the study was to establish the maximum tolerated dose (MTD), the maximum administered dose (MAD), dose limiting\\u000a toxicity (DLT), and the recommended phase 2 dose for SNS-032 when administered as a weekly 1-h infusion. The secondary objective

  2. Oral contraception.

    PubMed

    Evans, Ginger; Sutton, Eliza L

    2015-05-01

    Oral contraception (OC) remains a popular noninvasive, readily reversible approach for pregnancy prevention and, largely off label, for control of acne, hirsutism, dysmenorrhea, irregular menstruation, menorrhagia, and other menstrual-related symptoms. Many OC formulations exist, with generics offering lower cost and comparable efficacy. Certain medical conditions, including hypertension, migraine, breast cancer, and risk of venous thromboembolism (VTE), present contraindications. Blood pressure measurement is the only physical examination or testing needed before prescription. Although no OC is clearly superior to others, OCs containing the second-generation progestin levonorgestrel have been associated with lower VTE risk than those containing other progestins. PMID:25841596

  3. Oral Rivaroxaban for Symptomatic Venous Thromboembolism

    Microsoft Academic Search

    R. Bauersachs; S. D. Berkowitz; B. Brenner; H. R. Büller; H. Decousus; A. S. Gallus; A. W. Lensing; F. Misselwitz; M. H. Prins; G. E. Raskob; A. Segers; P. Verhamme; P. Wells; G. Agnelli; H. Bounameaux; A. Cohen; B. L. Davidson; F. Piovella; S. Schellong

    2010-01-01

    Background: Rivaroxaban, an oral factor Xa inhibitor, may provide a simple, fixed-dose regimen for treating acute deep-vein thrombosis (DVT) and for continued treatment, without the need for laboratory monitoring. Methods: We conducted an open-label, randomized, event-driven, noninferiority study that compared oral rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous enoxaparin followed

  4. Nicotine Oral Inhalation

    MedlinePLUS

    Nicotine oral inhalation is used to help people stop smoking. Nicotine oral inhalation should be used together with a smoking ... Nicotine oral inhalation comes as a cartridge to inhale by mouth using a special inhaler. Follow the directions on ...

  5. Repeated dose toxicity of alfa-cypermethrin in rats

    Microsoft Academic Search

    D Bhattacharyya

    2004-01-01

    The present study was performed to investigate the subacute effect of ?-cypermethrin (?-CP) in rats. Alfa- cypermethrin a synthetic pyrethroid insecticide, dissolved in dimethyl sulfoxide (DMSO) and oral LD50 was investigated after administering orally different doses in rats and was determined as 145 mg\\/kg. Other groups of rats were given repeated daily oral dose (1\\/10 LD50) of ?- CP for

  6. Efficacy and tolerance of repeated oral doses of tolperisone hydrochloride in the treatment of painful reflex muscle spasm: results of a prospective placebo-controlled double-blind trial

    Microsoft Academic Search

    H. G. Pratzel; R.-G. Alken; S. Ramm

    1996-01-01

    The efficacy and safety of oral tolperisone hydrochloride (Mydocalm®) in the treatment of painful reflex muscle spasm was assessed in a prospective, randomized, double-blind, placebo-controlled trial. A total of 138 patients, aged between 20 and 75 years, with painful reflex muscle spasm associated with diseases of the spinal column or proximal joints were enrolled in eight rehabilitation centers. Patients were

  7. Pharmacokinetic and bioequivalence comparison between orally disintegrating and conventional tablet formulations of flurbiprofen: A single-dose, randomized-sequence, open-label, two-period crossover study in healthy chinese male volunteers

    Microsoft Academic Search

    Yan-Mei Liu; Gang-Yi Liu; Yun Liu; Shui-Jun Li; Jing-Ying Jia; Meng-Qi Zhang; Chuan Lu; Yong-Mei Zhang; Xue-Ning Li; Chen Yu

    2009-01-01

    Background: Flurbiprofen, an NSAID, is used for the treatment of inflammation and pain caused by rheumatoid arthritis and osteoarthritis as well as soft-tissue injuries. A new orally disintegrating tablet (ODT) of flurbiprofen has recently been developed; this study was conducted to provide support for this drug to obtain marketing authorization in China.Objective: The aim of the study was to compare

  8. Bioequivalence of a single 10-mg dose of finasteride 5-mg oral disintegrating tablets and standard tablets in healthy adult male Han Chinese volunteers: A randomized sequence, open-label, two-way crossover study

    Microsoft Academic Search

    Li Chen; Xuehua Jiang; Liang Huang; Ke Lan; Haiying Wang; Lina Hu; Jing Ren; Xihong Li; Qin Zou

    2009-01-01

    Background: Finasteride, an inhibitor of the steroid 5?-reductase, has been approved for the treatment of benign prostatic hyperplasia and androgenetic alopecia. An orally disintegrating tablet (ODT) 5-mg formulation of finasteride was recently developed. Information regarding its pharmacokinetics and bioequivalence was required to assess the efficacy and safety of this formulation before marketing it in China.Objectives: The aims of this study

  9. Biomimetic Actinide Chelators: An Update on the Preclinical Development of the Orally Active Hydroxypyridonate Decorporation Agents 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO)

    PubMed Central

    Abergel, Rebecca J.; Durbin, Patricia W.; Kullgren, Birgitta; Ebbe, Shirley N.; Xu, Jide; Chang, Polly Y.; Bunin, Deborah I.; Blakely, Eleanor A.; Bjornstad, Kathleen A.; Rosen, Chris J.; Shuh, David K.; Raymond, Kenneth N.

    2010-01-01

    The threat of a dirty bomb or other major radiological contamination presents a danger of large-scale radiation exposure of the population. Because major components of such contamination are likely to be actinides, actinide decorporation treatments that will reduce radiation exposure must be a priority. Current therapies for the treatment of radionuclide contamination are limited and extensive efforts must be dedicated to the development of therapeutic, orally bioavailable, actinide chelators for emergency medical use. Using a biomimetic approach based on the similar biochemical properties of plutonium(IV) and iron(III), siderophore-inspired multidentate hydroxypyridonate ligands have been designed and are unrivaled in terms of actinide-affinity, selectivity and efficiency. A perspective on the preclinical development of two hydroxypyridonate actinide decorporation agents, 3,4,3-LI(1,2-HOPO) and 5-LIO(Me-3,2-HOPO), is presented. The chemical syntheses of both candidate compounds have been optimized for scale-up. Baseline preparation and analytical methods suitable for manufacturing large amounts have been established. Both ligands show much higher actinide-removal efficacy than the currently approved agent, diethylenetriaminepentaacetic acid (DTPA), with different selectivity for the tested isotopes of plutonium, americium, uranium and neptunium. No toxicity is observed in cells derived from three different human tissue sources treated in vitro up to ligand concentrations of 1 mM, and both ligands were well tolerated in rats when orally administered daily at high doses (> 100 ?mol kg?1 day?1) over 28 days under good laboratory practice (GLP) guidelines. Both compounds are on an accelerated development pathway towards clinical use. PMID:20699704

  10. Immunogenicity Is Not Improved by Increased Antigen Dose or Booster Dosing of Seasonal Influenza Vaccine in a Randomized Trial of HIV Infected Adults

    PubMed Central

    Cooper, Curtis; Thorne, Anona; Klein, Marina; Conway, Brian; Boivin, Guy; Haase, David; Shafran, Stephen; Zubyk, Wendy; Singer, Joel; Halperin, Scott; Walmsley, Sharon

    2011-01-01

    Introduction The risk of poor vaccine immunogenicity and more severe influenza disease in HIV necessitate strategies to improve vaccine efficacy. Methods A randomized, multi-centered, controlled, vaccine trial with three parallel groups was conducted at 12 CIHR Canadian HIV Trials Network sites. Three dosing strategies were used in HIV infected adults (18 to 60 years): two standard doses over 28 days, two double doses over 28 days and a single standard dose of influenza vaccine, administered prior to the 2008 influenza season. A trivalent killed split non-adjuvanted influenza vaccine (Fluviral™) was used. Serum hemagglutinin inhibition (HAI) activity for the three influenza strains in the vaccine was measured to assess immunogenicity. Results 297 of 298 participants received at least one injection. Baseline CD4 (median 470 cells/µL) and HIV RNA (76% of patients with viral load <50 copies/mL) were similar between groups. 89% were on HAART. The overall immunogenicity of influenza vaccine across time points and the three influenza strains assessed was poor (Range HAI ?40?=?31–58%). Double dose plus double dose booster slightly increased the proportion achieving HAI titre doubling from baseline for A/Brisbane and B/Florida at weeks 4, 8 and 20 compared to standard vaccine dose. Increased immunogenicity with increased antigen dose and booster dosing was most apparent in participants with unsuppressed HIV RNA at baseline. None of 8 serious adverse events were thought to be immunization-related. Conclusion Even with increased antigen dose and booster dosing, non-adjuvanted influenza vaccine immunogenicity is poor in HIV infected individuals. Alternative influenza vaccines are required in this hyporesponsive population. Trial Registration ClinicalTrials.gov NCT00764998 PMID:21512577

  11. 21 CFR 520.88c - Amoxicillin trihydrate oral suspension.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ...Swine (1) Amount. 40 milligrams orally, twice a day using a dosing pump. (2) Indications for use. Treatment of baby pigs under 10 pounds for porcine colibacillosis caused by Escherichia coli susceptible to amoxicillin. (3)...

  12. 21 CFR 520.88c - Amoxicillin trihydrate oral suspension.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ...Swine —(1) Amount . 40 milligrams orally, twice a day using a dosing pump. (2) Indications for use. Treatment of baby pigs under 10 pounds for porcine colibacillosis caused by Escherichia coli susceptible to amoxicillin. (3)...

  13. Oral muscosal melanomas

    Microsoft Academic Search

    Bruce F Barker; William M Carpenter; Troy E Daniels; Michael A Kahn; Alan S Leider; Francina Lozada-Nur; Denis P Lynch; Raymond Melrose; Philip Merrell; Thomas Morton; Edmund Peters; Joseph A Regezi; Susan D Richards; Gordon M Rick; Michael D Rohrer; Lee Slater; Jeffery C. B Stewart; Charles E Tomich; Robert A Vickers; Norman K Wood; Stephen K Young

    1997-01-01

    A workshop to discuss primary oral melanomas was convened at the annual Western Society of Teachers of Oral Pathology meeting in Bannf, Alberta, Canada. Fifty oral melanomas, identified from the files of the participants, were reviewed in order to better understand the clinical features, histologic spectrum, and natural history of these perplexing lesions. Results confirmed that oral melanomas occur in

  14. Nutrition and oral cancer

    Microsoft Academic Search

    James R. Marshall; Peter Boyle

    1996-01-01

    Epidemiologic evidence on the relationship between nutrition and oral cancer is reviewed. Ecologic and case-control studies provide most of the evidence regarding the nutritional epidemiology of oral cancer. The ecologic evidence is that the considerable geographic variation in the incidence of oral cancer is consistent with variation in nutrition. Because incipient oral cancer is likely to affect the diets of

  15. Oral candidiasis prevention in transplantation patients: a comparative study

    Microsoft Academic Search

    Sharon Elad; Alon Wexler; Adi A. Garfunkel; Michael Y. Shapira; Menachem Bitan

    2006-01-01

    Aim: Oral candidiasis occurs commonly in haematopoietic -stem cell transplantation (HSCT) patients carrying a risk of systemic candidemia and mortality. The aim of this pilot study was to design an effective protocol that prevents oral candidiasis and improves tolerability. Methods: A prospective, randomized, longitudinal study with two treat- ment groups, (A) chlorhexidine (CHX) and (B) CHX combined with medium-dose amphotericin

  16. Abstinence symptoms following oral THC administration to humans

    Microsoft Academic Search

    Margaret Haney; Amie S. Ward; Sandra D. Comer; Richard W. Foltin; Marian W. Fischman

    1999-01-01

    Symptoms of dependence and withdrawal after the frequent administration of high doses (210 mg\\/day) of oral ?9-tetrahydrocannabinol (THC) have been reported, yet little is known about dependence on lower oral THC doses, more relevant\\u000a to levels attained by smoking marijuana. In a 20-day residential study, male (n?=?6) and female (n?=?6) marijuana smokers worked on five psychomotor tasks during the day

  17. Effect of maalox on the oral absorption of sparfloxacin

    Microsoft Academic Search

    Robert D. Johnson; Mary Beth Dorr; George H. Talbot; Gilles Caille

    1998-01-01

    Sparfloxacin is a broad-spectrum oral fluoroquinolone antimicrobial agent with a long elimination half-life (t12). Concurrent treatment with antacids has demonstrated a reduction in the oral absorption of many quinolones. This study was undertaken to determine an optimal time for dosing antacids in relation to sparfloxacin administration to minimize antacid-induced reduction in sparfloxacin bioavailability. This open-label, single-dose, randomized, four-way crossover study

  18. A multicentre, double-blind, randomized, parallel group study to evaluate the tolerability and efficacy of two oral doses of levetiracetam, 2000 mg daily and 4000 mg daily, without titration in patients with refractory epilepsy

    Microsoft Academic Search

    T Betts; T Waegemans; P Crawford

    2000-01-01

    The aim of this study was to determine the tolerability and efficacy of two oral regimens of levetiracetam, 1000 mg and 2000 mg twice daily, as add-on treatment without titration in patients with refractory epilepsy. After a 1- to 4-week baseline, 119 patients were randomized to receive levetiracetam 2000 mg daily, 4000 mg daily, or placebo for a 24-week double-blind

  19. Detection of fenspiride and identification of in vivo metabolites in horse body fluids by capillary gas chromatography–mass spectrometry: administration, biotransformation and urinary excretion after a single oral dose

    Microsoft Academic Search

    M. C Dumasia; E Houghton; W Hyde; D Greulich; T Nelson; Jackie Peterson

    2002-01-01

    Studies related to the in vivo biotransformation and urinary excretion of fenspiride hydrochloride in the horse are described. After oral administration, the drug is metabolised by both phase I functionalisation and phase II conjugation pathways. Following enzymatic deconjugation, fenspiride and its phase I metabolites were isolated from post-administration biofluids using bonded co-polymeric mixed mode solid-phase extraction cartridges to isolate the

  20. Can a Controlled-Release Oral Dose Form of Oxycodone Be Used as Readily as an Immediate-Release Form for the Purpose of Titrating to Stable Pain Control?

    Microsoft Academic Search

    Robert T. Salzman; Michael S. Roberts; James Wild; Carol Fabian; Robert F. Reder; Paul D. Goldenheim

    1999-01-01

    Two separate trials compared controlled-release (CR) oral oxycodone (administered every 12 hours) with immediate-release (IR) oxycodone (4 times a day) to determine whether patients with chronic pain could be titrated to stable pain control as readily with the CR as with the IR formulation. In one study, 48 patients with cancer pain were randomized to open-label titration with either CR

  1. Oral benzo[a]pyrene-induced cancer: two distinct types in different target organs depend on the mouse Cyp1 genotype

    PubMed Central

    Shi, Zhanquan; Dragin, Nadine; Miller, Marian L.; Stringer, Keith F.; Johansson, Elisabet; Chen, Jing; Uno, Shigeyuki; Gonzalez, Frank J.; Rubio, Carlos A.; Nebert, Daniel W.

    2010-01-01

    Benzo[a]pyrene (BaP) is a prototypical polycyclic aromatic hydrocarbon (PAH) found in combustion processes. Cytochrome P450 1A1 and 1B1 enzymes (CYP1A1, CYP1B1) can both detoxify PAHs and activate them to cancer-causing reactive intermediates. Following high dosage of oral BaP (125 mg/kg/day), ablation of the mouse Cyp1a1 gene causes immunosuppression and death within ~28 days, whereas Cyp1(+/+) wild-type mice remain healthy for >12 months on this regimen. In the present study, male Cyp1(+/+) wild-type, Cyp1a1(?/?) and Cyp1b1(?/?) single-knockout, and Cyp1a1/1b1(?/?) double-knockout mice received a lower dose (12.5 mg/kg/day) of oral BaP. Tissues from 16 different organs––including proximal small intestine (PSI), liver, preputial gland duct (PGD)––were evaluated; microarray cDNA expression and >30 mRNA levels were measured. Cyp1a1(?/?) mice revealed markedly increased CYP1B1 mRNA levels in the PSI, and between 8 and 12 weeks developed unique PSI adenomas and adenocarcinomas. Cyp1a1/1b1(?/?) mice showed no PSI tumors but instead developed squamous cell carcinoma of the PGD. Cyp1(+/+) and Cyp1b1(?/?) mice remained healthy with no remarkable abnormalities in any tissue examined. PSI adenocarcinomas exhibited striking up-regulation of the Xist gene, suggesting epigenetic silencing of specific genes on the Y-chromosome; the Rab30 oncogene was up-regulated; the Nr0b2 tumor suppressor gene was down-regulated; paradoxical over-expression of numerous immunoglobulin kappa and heavy chain variable genes was found––although the adenocarcinoma showed no immunohistochemical evidence of being lymphatic in origin. This oral BaP mouse paradigm represents an example of “gene-environment interactions” in which the same exposure of carcinogen results in altered target organ and tumor type, as a function of just one or two globally absent genes. PMID:20127859

  2. TREATMENT OF PSORIASIS WITH ORAL MYCOPHENOLIC ACID

    Microsoft Academic Search

    E. Linn Jones; Warren W. Epinette; Victor C. Hackney; Luis Menendez; Phillip Frost

    1975-01-01

    Mycophenolic acid (MPA), an inhibitor of purine synthesis, was evaluated for its therapeutic and adverse effects in 29 patients with psoriasis. MPA was administered orally for at least 12 weeks, during which time the daily dose was increased from 1600 to 4800 mg depending on occurrence of adverse reactions. Complete clearing occurred in 1 of the patients, almost complete clearing

  3. Recent innovations in oral contraception.

    PubMed

    Cremer, Miriam; Phan-Weston, Scarlett; Jacobs, Adam

    2010-03-01

    Traditional forms of oral contraception contain 21 days of hormone-containing pills and 7 days of placebo during the hormone-free interval (HFI). Since 2003, the Food and Drug Administration has approved 24/4, 84/7, and 365-day regimens. These regimens shorten the HFI in an attempt to decrease bleeding and menstrual-associated side effects. Safety and efficacy of these regimens is comparable with traditional 21/7 dosing. Extended regimens are associated with high patient satisfaction. Bleeding patterns are similar or shorter in women using extended regimens, along with improvement in menstrual symptoms. One of the new formulations contains the new progestin drospirenone, which has antimineralocorticoid and antiandrogenic properties. This review summarizes the data about new formulations of oral contraception available in the United Sates and also provides a summary of the current literature on drospirenone. PMID:20391327

  4. A Phase II Study of the Oral VEGF Receptor Tyrosine Kinase Inhibitor Vatalanib (PTK787/ZK222584) in Myelodysplastic Syndrome: Cancer and Leukemia Group B Study 10105 (Alliance)

    PubMed Central

    Gupta, Pankaj; Mulkey, Flora; Hasserjian, Robert P.; Sanford, Ben L.; Vij, Ravi; Hurd, David D.; Odenike, Olatoyosi M.; Bloomfield, Clara D.; Owzar, Kouros; Stone, Richard M.; Larson, Richard A.

    2013-01-01

    Background Angiogenesis is implicated in the pathophysiology and progression of myelodysplastic syndromes (MDS). Vatalanib (PTK787/ZK222584; Novartis and Schering AG) inhibits receptor tyrosine kinases of vascular endothelial growth factor, platelet derived growth factor and c-Kit. We examined whether vatalanib induces hematological responses in MDS and/or delays progression to acute myeloid leukemia (AML) or death. Methods Two cohorts were studied. Vatalanib 1250 mg orally was given once daily (cohort 1) or 750–1250 mg once daily in an intra-patient dose escalating schedule (cohort 2) in 28-day cycles to 155 patients with MDS; 142 patients were evaluable for response and 153 for toxicity. Results The median age was 70.5 years; 51% had low risk (International Prognostic Scoring System {IPSS} Low/Intermediate-1) and 32% had high risk (IPSS Intermediate-2/High) MDS. Hematological improvement was achieved in 7/142 (5%) patients; all 7 were amon