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Sample records for dose 28-day oral

  1. 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.

  2. 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

  3. 28-day repeated dose oral toxicity of human copper-zinc superoxide dismutase from recombinant Pichia pastori in rats.

    PubMed

    Zhu, Liang; Tian, Ying-Juan; Zhu, Si-Ming

    2012-04-01

    Human copper/zinc superoxide dismutase from recombinant Pichia pastori (RH-Cu/Zn-SOD) was orally administered, via gavage, to Sprague-Dawley rats at 500, 1,000, and 2,000 mg/kg body weight/day for 28 days. During the 28-day period, animals were examined for evidence of toxicity; there were no deaths, and in-life physical signs were normal. On day 29, the animals were exsanguinated, examined for gross pathology, and tissues were preserved for histopathology. Although statistical differences were noted in some hematology and clinical chemistry, they were of questionable biological significance. The results of the 28-day oral administration demonstrated a lack of toxicity of RH-Cu/Zn-SOD in rats. There were no treatment-related, toxicologically relevant changes in clinical signs, growth, food consumption, hematology, clinical chemistry, organ weights, or pathology. The no observed adverse effect level was greater than 2,000 mg/kg/day for RH-Cu/Zn-SOD in rats.

  4. Correlation among the toxicity profiling (28-days repeated oral dose toxicity), toxicokinetics and tissue distribution data of ulifloxacin, the active metabolite of prulifloxacin in Wistar albino rats.

    PubMed

    Nandi, Utpal; Roy, Bikash; Das, Anjan Kumar; Pal, Tapan Kumar

    2012-09-01

    This experiment was designed to investigate correlation among 28-days repeated oral dose toxicity, toxicokinetics and tissue distribution data of ulifloxacin (active metabolite of prulifloxacin) in Wistar albino rats. Prulifloxacin was administered for 28-days in rats at 0, 100, 200, 400mg/kg/day followed by 14-days recovery period. Simultaneously different toxicokinetic parameters and tissue distributions of ulifloxacin was examined by LC-MS/MS method. Plasma levels and tissue concentrations of ulifloxacin were increased with dose-related manner. Ulifloxacin was also distributed to many tissues, and concentration in lungs nearly equivalent to the plasma concentration. Based on these results it was concluded that long-term repeated dose of prulifloxacin may produce different blood parameters abnormality, liver damage, stomach ulcer, joint damage and dysfunction of lungs in rats which relates to high tissue distribution and accumulation of ulifloxacin in these tissues. These findings help in management of prulifloxacin induced adverse effects by appropriate dose selection in clinical practice.

  5. Repeated dose 28-days oral toxicity study of Carica papaya L. leaf extract in Sprague Dawley rats.

    PubMed

    Afzan, Adlin; Abdullah, Noor Rain; Halim, Siti Zaleha; Rashid, Badrul Amini; Semail, Raja Hazlini Raja; Abdullah, Noordini; Jantan, Ibrahim; Muhammad, Hussin; Ismail, Zakiah

    2012-04-10

    Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from 'Sekaki' C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub-acute study, the C. papaya extract did not cause mortality nor were treatment-related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent.

  6. A repeated 28-day oral dose toxicity study of nonylphenol in rats, based on the 'Enhanced OECD Test Guideline 407' for screening of endocrine-disrupting chemicals.

    PubMed

    Woo, Gye-Hyeong; Shibutani, Makoto; Ichiki, Tsutomu; Hamamura, Masao; Lee, Kyoung-Youl; Inoue, Kaoru; Hirose, Masao

    2007-02-01

    A 28-day repeated oral dose toxicity study of nonylphenol (NP) was performed for an international validation of the 'Enhanced OECD Test Guideline 407' paying particular attention to the sensitivity of individual endocrine-related parameters. Sprague-Dawley rats, each group consisting of ten males and ten females, were administered NP once daily by gavage at doses of 0 (control), 10, 50, or 250 mg/kg body weight. At 250 mg/kg, three females died or became moribund during the experiment. At this dose, hepatic and renal toxicity was evident in both sexes with increase of relative liver and kidney weights as well as histopathological changes, such as centrilobular liver cell hypertrophy and a variety of renal tubular lesions, and alteration of serum biochemical parameters, some of them being evident from 50 mg/kg in females (glucose and inorganic phosphates). Hematologically, development of anemia was evident at 250 mg/kg in both sexes. Regarding endocrine-related effects, increase of thyroid weight in males was detected from 50 mg/kg. At 250 mg/kg, males exhibited reduction of relative weights of the ventral prostate and seminal vesicles, and females developed irregular estrous cyclicity and vaginal mucosal hyperplasia. Although changes in serum hormone levels were detected in both sexes, magnitude of the changes was small to be regarded as a low toxicological significance. In summary, repeated oral doses of NP to rats for 28 days resulted in hepato-renal toxicity from 50 mg/kg and anemia at 250 mg/kg. Effects on the endocrine system were observed from 50 mg/kg, and assessment of weights and histopathology of endocrine-related organs and estrous cyclicity may be valid in a battery for detecting endocrine effects of NP. The no-observed-adverse-effect level of NP was estimated to be 10 mg/kg per day.

  7. Estimation of acute oral toxicity using the No Observed Adverse Effect Level (NOAEL) from the 28 day repeated dose toxicity studies in rats.

    PubMed

    Bulgheroni, Anna; Kinsner-Ovaskainen, Agnieszka; Hoffmann, Sebastian; Hartung, Thomas; Prieto, Pilar

    2009-02-01

    Acute systemic toxicity is one of the areas of particular concern due to the 2009 deadline set by the 7th Amendment of the Cosmetics Directive (76/768/EEC), which introduces a testing and marketing ban of cosmetic products with ingredients tested on animals. The scientific community is putting considerable effort into developing and validating non-animal alternatives in this area. However, it is unlikely that validated and regulatory accepted alternative methods and/or strategies will be available in March 2009. Following the initiatives undertaken in the pharmaceutical industry to waive the acute oral toxicity testing before going to clinical studies by using information from other in vivo studies, we proposed an approach to identify non-toxic compounds (LD50>2000mg/kg) using information from 28 days repeated dose toxicity studies. Taking into account the high prevalence of non-toxic substances (87%) in the New Chemicals Database, it was possible to set a NOAEL threshold of 200mg/kg that allowed the correct identification of 63% of non-toxic compounds, while <1% of harmful compounds were misclassified as non-toxic. Since repeated dose toxicity studies can be performed in vivo until 2013, the proposed approach could have an immediate impact for the testing of cosmetic ingredients.

  8. Liver and kidney damage induced by 4-aminopyridine in a repeated dose (28 days) oral toxicity study in rats: gene expression profile of hybrid cell death.

    PubMed

    Frejo, María Teresa; Del Pino, Javier; Lobo, Margarita; García, Jimena; Capo, Miguel Andrés; Díaz, María Jesús

    2014-03-03

    4-Aminopyridine (4-AP) is an orphan drug indicated for the treatment of neuromuscular disorders. There is a great controversy around the use of this drug because of its narrow safety index and because a large number of adverse effects have been reported. Moreover, it was shown to induce cell death in different cell lines, being reported mainly apoptosis and necrosis as the principal pathways of cell death mediated by blockage of K channels or the Na, K-ATPase, but until now it was not described in vivo cell death induced by 4-aminipyridine. To provide new subchronic toxicity data and specifically, evaluate if 4-AP is able to induce in vivo cell death process and the main pathways related to it, a repeated dose (28 days) oral toxicity study, at therapeutic range of doses, was conducted in rats. The anatomical pathology, the biochemical and hematological parameters were analyzed and a real-time PCR array analysis was developed with an Ingenuity Pathway Analysis (IPA). The leucocytes number, the lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) enzymatic activity were increased at all dose but the erythrocytes number, the hemoglobin concentration, the alkaline phosphatase (FAL) and alanine aminotransferase (ALT) enzymatic activity were increased only at highest dose studied. However, glucose levels decreased at all doses. The biochemical results are indicative of hepatic damage. The anatomy pathology studies showed cell death only on liver and kidney, and the real-time PCR array on liver tissue expressed a gene expression profile of necrotic and apoptotic induced cell death. The present work shows for the first time in vivo cell death on liver and kidney with features of apoptosis and necrosis induced by 4-AP and the gene expression profile shows that the cell death is mediated by necrotic and apoptotic pathways that support this finding.

  9. Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study

    SciTech Connect

    Abe, Hajime; Tanaka, Takeshi; Kimura, Masayuki; Mizukami, Sayaka; Saito, Fumiyo; Imatanaka, Nobuya; Akahori, Yumi; Yoshida, Toshinori; Shibutani, Makoto

    2015-09-15

    Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600 mg/kg body weight/day for 28 days. In the subgranular zone (SGZ), 600 mg/kg CPZ increased the number of cleaved caspase-3{sup +} apoptotic cells. At ≥ 120 mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥ 120 mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥ 120 mg/kg decreased phosphorylated TRKB{sup +} interneurons, although the number of reelin{sup +} interneurons was unchanged. At 600 mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells. - Highlights: • Effect of 28-day CPZ exposure on hippocampal neurogenesis was examined in rats. • CPZ suppressed intermediate neurogenesis and late-stage neurogenesis in the dentate gyrus. • CPZ suppressed BDNF signals to interneurons by decrease of

  10. Cuprizone decreases intermediate and late-stage progenitor cells in hippocampal neurogenesis of rats in a framework of 28-day oral dose toxicity study.

    PubMed

    Abe, Hajime; Tanaka, Takeshi; Kimura, Masayuki; Mizukami, Sayaka; Saito, Fumiyo; Imatanaka, Nobuya; Akahori, Yumi; Yoshida, Toshinori; Shibutani, Makoto

    2015-09-15

    Developmental exposure to cuprizone (CPZ), a demyelinating agent, impairs intermediate-stage neurogenesis in the hippocampal dentate gyrus of rat offspring. To investigate the possibility of alterations in adult neurogenesis following postpubertal exposure to CPZ in a framework of general toxicity studies, CPZ was orally administered to 5-week-old male rats at 0, 120, or 600mg/kg body weight/day for 28days. In the subgranular zone (SGZ), 600mg/kg CPZ increased the number of cleaved caspase-3(+) apoptotic cells. At ≥120mg/kg, the number of SGZ cells immunoreactive for TBR2, doublecortin, or PCNA was decreased, while that for SOX2 was increased. In the granule cell layer, CPZ at ≥120mg/kg decreased the number of postmitotic granule cells immunoreactive for NEUN, CHRNA7, ARC or FOS. In the dentate hilus, CPZ at ≥120mg/kg decreased phosphorylated TRKB(+) interneurons, although the number of reelin(+) interneurons was unchanged. At 600mg/kg, mRNA levels of Bdnf and Chrna7 were decreased, while those of Casp4, Casp12 and Trib3 were increased in the dentate gyrus. These data suggest that CPZ in a scheme of 28-day toxicity study causes endoplasmic reticulum stress-mediated apoptosis of granule cell lineages, resulting in aberrations of intermediate neurogenesis and late-stage neurogenesis and following suppression of immediate early gene-mediated neuronal plasticity. Suppression of BDNF signals to interneurons caused by decreased cholinergic signaling may play a role in these effects of CPZ. The effects of postpubertal CPZ on neurogenesis were similar to those observed with developmental exposure, except for the lack of reelin response, which may contribute to a greater decrease in SGZ cells.

  11. 28-Day repeated dose toxicity study of dried microorganism in rats.

    PubMed

    Kitano, M; Hosoe, K; Fukutomi, N; Hidaka, T; Imai, N; Kawabe, M

    2004-11-01

    Ubidecarenone, also known as CoQ(10), is currently sold as a dietary supplement in the United States, with a majority of these products derived from the fermentation of carbohydrates or tobacco leaf extracts. In addition to its availability in dietary supplements, CoQ(10) is now being considered for use in foods. Accordingly, as part of the process for attaining "Generally Recognized as Safe" status, and to supplement information already available regarding the safety of CoQ(10) per se, a 28-day oral toxicity study in rats was conducted to evaluate the subacute safety of a microorganism biomass used as a new source in CoQ(10) production. Groups of Crj:CD(SD) rats (SPF) (6 males or females per group, 4 groups per sex) received dried microorganism at doses of 0, 500, 1000 or 2000 mg/kg/day via intragastric intubation. Clinical observations were recorded, and body weight, and food and water consumptions measured throughout the study. At the end of the study, aortic blood samples were collected from all animals for analysis of hematological and clinical chemistry parameters, and gross pathologic examination was performed. Histopathologic examination was performed on select tissues from the control and high-dose groups. There were no treatment-related changes that were considered to be of toxicological significance. Since rats treated with 2000 mg/kg of dried microorganism did not demonstrate any treatment-related changes, the no-observable-adverse-effect level (NOAEL) for dried microorganism was estimated to be greater than 2000 mg/kg/day under the present study conditions.

  12. Acute toxicity and the 28-day repeated dose study of a Siddha medicine Nuna Kadugu in rats

    PubMed Central

    2012-01-01

    Background Nuna Kadugu (NK), a Siddha medicine prepared from leaves and fruits of Morinda Pubescens, used for the treatment of various skin diseases. Though NK has been widely used for several decades, no scientific report was available on its safety. Present study was undertaken to demonstrate the oral toxicity of NK in Sprague Dawley rats. Methods Acute and 28-day repeated oral toxicity studies were performed following OECD test guidelines 423 and 407, respectively, with minor modifications. In acute oral toxicity study, NK was administered at 2000mg/kg b.wt., p.o and animals were observed for toxic signs at 0, 0.5, 1, 4, 24 h and for next 14 days. Gross pathology was performed at the end of the study. In repeated dose, the 28- day oral toxicity study, NK was administered at 300, 600 and 900 mg/kg b.wt./p.o/day. Two satellite groups (control and high dose) were also maintained to determine the delayed onset toxicity of NK. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Haematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight and histopathological examination were performed. Results In acute toxicity study, no treatment related death or toxic signs were observed with NK administration. In the repeated dose study, no significant differences in body weight changes, food / water intake, haematology, clinical biochemistry and electrolytes content were observed between control and NK groups. No gross pathological findings and difference in relative organ weights were observed between control and NK treated rats. Histopathological examination revealed no abnormalities with NK treatment. Conclusion Acute study reveals that the LD50 of NK is greater than 2000mg/kg, b.wt. in fasted female rats and can be classified as Category 5. 28-day repeated oral toxicity demonstrates that the No Observed Adverse Effect Level of NK is greater than 900 mg/kg b.wt./day, p.o in rats. There were no delayed effects

  13. 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

  14. 28-day intraocular pressure reduction with a single dose of brimonidine tartrate-loaded microspheres.

    PubMed

    Fedorchak, Morgan V; Conner, Ian P; Medina, Carlos A; Wingard, Jeremy B; Schuman, Joel S; Little, Steven R

    2014-08-01

    Treatment of glaucoma by intraocular pressure (IOP) reduction is typically accomplished through the administration of eye drops, the difficult and frequent nature of which contributes to extremely low adherence rates. Poor adherence to topical treatment regimens in glaucoma patients can lead to irreversible vision loss and increased treatment costs. Currently there are no approved treatments for glaucoma that address the inherent inefficiencies in drug delivery and patient adherence. Brimonidine tartrate (BT), a common glaucoma medication, requires dosing every 8-12 h, with up to 97% of patients not taking it as prescribed. This study provides proof-of-principle testing of a controlled release BT formulation. BT was encapsulated in poly(lactic-co-glycolic) acid microspheres and drug release was quantified using UV-Vis spectroscopy. For in vivo studies, rabbits were randomized to receive a single subconjunctival injection of blank (no drug) or BT-loaded microspheres or twice daily topical 0.2% BT drops. The microspheres released an average of 2.1 ± 0.37 μg BT/mg microspheres/day in vitro. In vivo, the percent decrease in IOP from baseline was significantly greater in the treated eye for both topical drug and drug-loaded microspheres versus blank microspheres throughout the 4-week study, with no evidence of migration or foreign body response. IOP measurements in the contralateral, untreated eyes also suggested a highly localized effect from the experimental treatment. A treatment designed using the release systems described in this study would represent a vast improvement over the current clinical standard of 56-84 topical doses over 28 days.

  15. 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

  16. 28-day repeated dose response study of diglycolic acid: Renal and hepatic effects.

    PubMed

    Sprando, Robert L; Mossoba, Miriam E; Black, Thomas; Keltner, Zachary; Vohra, Sanah; Olejnik, Nicholas; Toomer, Howard; Stine, Cynthia; Evans, Eric; Sprando, Jessica L; Ferguson, Martine

    2017-03-25

    The acute oral toxicity of diglycolic acid (DGA) was evaluated. Groups of female rats (n = 8 rats/group) received 28 consecutive daily single doses of 0.3, 1.0, 3.0, 10.0, 30.0, 100.0 or 300.0 mg DGA/kg body weight by gastric intubation. One group of animals served as vehicle control. Tissues and blood serum were collected at necropsy on day 29. Select organs were weighed and fixed in formalin for histopathological analysis. Animals from the 300 mg/kg bw dose group were removed from the study after 5 consecutive days of treatment as a consequence of adverse treatment related effects. The animals in the remaining treatment groups survived the exposure period. No adverse clinical signs were observed throughout the exposure period in the surviving animals. No significant differences from controls were observed for feed and fluid consumption or body weight gain in the surviving animals. Lesions were observed in the kidneys, liver, stomach, intestine, thymus, spleen and bone marrow in animals from the 300 mg/kg dose group and signs of renal tubular regeneration were observed only in the 100 mg/kg dose group. These results suggest that high levels of pure DGA would need to be consumed before renal and other forms of organ toxicity are observed.

  17. Toxicological evaluation of silver nanoparticles and silver nitrate in rats following 28 days of repeated oral exposure.

    PubMed

    Qin, Guangqiu; Tang, Song; Li, Shibin; Lu, Haoliang; Wang, Yanwu; Zhao, Peng; Li, Bin; Zhang, Jiehong; Peng, Liang

    2017-02-01

    The increasing application of silver nanoparticles (AgNPs) has been raising concerns about their potential adverse effects to human and the environment. However, the knowledge on the systemic toxicity of AgNPs in mammalian systems is still limited. The present study investigated the toxicity of PVP-coated AgNPs in rats treated with repeated oral administration, and compared that with equivalent dose of AgNO3 . Specifically, one hundred male and female rats were orally administrated with particulate or ionic forms of silver (Ag) separately at doses of 0.5 and 1 mg kg(-1) body weight daily for 28 days. The results reveal no significant toxic effects of AgNPs and AgNO3 up to 1 mg kg(-1) body weight, with respect to the body weight, organ weight, food intake, and histopathological examination. Ag distribution pattern in organs of rats treated with AgNPs was similar to that of AgNO3 treated rats, showing liver and kidneys are the main target organs followed by testis and spleen. The total Ag contents in organs were significantly lower in the AgNPs treated rats than those in the AgNO3 treated rats. However, the comparisons between AgNPs and AgNO3 treatments further indicated more potent of AgNPs in biochemical and hematological parameters in rats, including red blood cell count (RBC), platelet count (PLT), white blood cell count (WBC) and aspartate transaminase (AST). Results of this study suggested that particulate Ag at least partially contributed to the observed toxicity of AgNPs, and both ionic and particulate Ag should be taken into consideration in toxicological evaluation of AgNPs. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 609-618, 2017.

  18. Evaluation of in vivo genotoxicity by thioacetamide in a 28-day repeated-dose liver micronucleus assay using male young adult rats.

    PubMed

    Sui, Hajime; Matsumoto, Hirotaka; 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 general toxicological studies. In this study, thioacetamide (TAA) was tested in 14- and 28-day RDLMN assays to assess the performance of the assay. The test substance, TAA, was administered orally to 6-week-old male Crl:CD (SD) rats once daily for 14 or 28 days at a dosage of 5, 10 or 20mg/kg/day. Hepatocytes were collected approximately 24h after the last TAA administration, and the incidence of micronuclei was assessed. In this study, bone marrow micronucleus assays were also conducted in the same animals. The 14- and 28-day RDLMN assays indicated that none of the TAA dosages significantly increased the proportion of micronucleated hepatocytes. Bone marrow micronucleus assays with TAA also provided negative results. It is known that TAA is a liver carcinogen in mice and rats. In the previous genotoxic studies, the Ames test and the chromosomal aberration test using CHL/IU cells have yielded negative results [1-4]. The liver micronucleus assay using young adult rats singly dosed with TAA (75 and 150mg/kg) also produced negative results [5]. TAA gave positive results only in the mouse bone marrow micronucleus assays [6,7].

  19. Repeated dose (28-day) administration of silver nanoparticles of varied size and coating does not significantly alter the indigenous murine gut microbiome.

    PubMed

    Wilding, Laura A; Bassis, Christine M; Walacavage, Kim; Hashway, Sara; Leroueil, Pascale R; Morishita, Masako; Maynard, Andrew D; Philbert, Martin A; Bergin, Ingrid L

    2016-01-01

    Silver nanoparticles (AgNPs) have been used as antimicrobials in a number of applications, including topical wound dressings and coatings for consumer products and biomedical devices. Ingestion is a relevant route of exposure for AgNPs, whether occurring unintentionally via Ag dissolution from consumer products, or intentionally from dietary supplements. AgNP have also been proposed as substitutes for antibiotics in animal feeds. While oral antibiotics are known to have significant effects on gut bacteria, the antimicrobial effects of ingested AgNPs on the indigenous microbiome or on gut pathogens are unknown. In addition, AgNP size and coating have been postulated as significantly influential towards their biochemical properties and the influence of these properties on antimicrobial efficacy is unknown. We evaluated murine gut microbial communities using culture-independent sequencing of 16S rRNA gene fragments following 28 days of repeated oral dosing of well-characterized AgNPs of two different sizes (20 and 110 nm) and coatings (PVP and Citrate). Irrespective of size or coating, oral administration of AgNPs at 10 mg/kg body weight/day did not alter the membership, structure or diversity of the murine gut microbiome. Thus, in contrast to effects of broad-spectrum antibiotics, repeat dosing of AgNP, at doses equivalent to 2000 times the oral reference dose and 100-400 times the effective in vitro anti-microbial concentration, does not affect the indigenous murine gut microbiome.

  20. Phenolic acid protects of renal damage induced by ochratoxin A in a 28-days-oral treatment in rats.

    PubMed

    Cariddi, L N; Escobar, F M; Sabini, M C; Campra, N A; Bagnis, G; Decote-Ricardo, D; Freire-de-Lima, C G; Mañas, F; Sabini, L I; Dalcero, A M

    2016-04-01

    The present study aimed to characterize the chlorogenic acid (ChlA) capacity to reverse the toxic effects induced by ochratoxin A (OTA) in a subacute toxicity test in rats. Male Wistar rats were fed orally by gavage for 28 days with OTA (0.4mg/kg bw/day), ChlA (5mg/kg bw/day) or the combination OTA (0.4mg/kg bw/day)+ChlA (5mg/kg bw/day). No deaths, no decrease in feed intake or body weight in any experimental group were recorded. The negative control group and the animals treated with ChlA alone showed no changes in any parameters evaluated. In OTA-treated group significant changes such as decrease in urine volume, proteinuria, occult blood, increase in serum creatinine values; decrease in absolute and relative kidney weight and characteristics histopathological lesions that indicated kidney damage were observed. However, limited effect on oxidative stress parameters were detected in kidneys of OTA-treated group. Animals treated with the combination OTA+ChlA were showed as negative control group in the evaluation of several parameters of toxicity. In conclusion, ChlA, at given concentration, improved biochemical parameters altered in urine and serum and pathological damages in kidneys induced by OTA exposure, showing a good protective activity, but not by an apparent antioxidant mechanism.

  1. 17alpha-methyltestosterone: 28-day oral toxicity study in the rat based on the "Enhanced OECD Test Guideline 407" to detect endocrine effects.

    PubMed

    Wason, Sheila; Pohlmeyer-Esch, Gabriele; Pallen, Catherine; Palazzi, Xavier; Espuña, Gemma; Bars, Remi

    2003-11-05

    A 28-day oral gavage toxicity study in the rat with 17alpha-methyltestosterone was conducted as part of the international validation exercise on the modified Enhanced OECD Test Guideline 407 (Organisation for Economic Co-operation and Development, Paris). Special emphasis was placed on the endocrine mediated effects exerted by 17alpha-methyltestosterone, a potent androgen agonist. The test compound was administered daily by oral gavage for at least 28 days to groups of 7-week-old-Wistar rats. Dose levels were 0, 10, 40 and 200 mg/kg body weight per day for males and 0, 10, 100 and 600 mg/kg body weight per day for females. In addition, and outside the remit of the enhanced protocol, testosterone levels in males, oestradiol levels in females and luteinizing hormone (LH) levels in both sexes were measured, to provide a broader profile on the hormonally mediated effects of 17alpha-methyltestosterone. Furthermore, stage-specific quantification of Terminal deoxynucleotidyl transferase-mediated dUTP Nick-End Labeling (TUNEL)-labeled germ cells (apoptotic germ cells) in the seminiferous tubules was also performed, in an effort to demonstrate the precise stages in the spermatogenic cycle 17alpha-methyltestosterone exerts its effect. In this study, the most critical additional parameters contained in the Enhanced OECD Test Guideline 407 for the detection of endocrine disruption were considered to be the histopathological assessment and organ weight data of endocrine-related tissues. Beyond the scope of this validation exercise, an increase in apoptosis in specific germ cell types was detected using the TUNEL assay in male rats treated at 200 and 40 mg/kg.

  2. 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.

  3. 28-day oral safety evaluation of extracellular polysaccharopeptides produced in submerged culture from the turkey tail medicinal mushroom Trametes versicolor (L.:Fr.) Pilát LH-1 in mice.

    PubMed

    Lai, Chun-Hong; Teng, Ju-Fang; Hsu, Tai-Hao; Lin, Fang-Yi; Yang, Po-Wen; Lo, Hui-chen

    2011-01-01

    Turkey tail medicinal mushroom, Trametes versicolor (TV), is a species with a variety of pharmacological activities. Its intracellular polysaccharopeptides are widely commercialized. Recently, we found a novel TV strain LH-1 in Taiwan and demonstrated that the extracellular polysaccharopeptide (ePSP) of LH-1 obtained from submerged culture exhibits significant immunomodulatory activity. In this in vivo study, we further evaluated the safety of orally administered LH-1 ePSP using both male and female ICR mice. The LH-1 ePSP was orally administered to mice at levels of 0 (water), 100 (low dose), 500 (medium dose), or 1000 mg/kg/day (high dose) for 28 days. Clinical observations, growth, food consumption, histopathological examination, and clinical biochemical analyses revealed no adverse effects of LH-1 ePSP in mice. There were no significant differences in the results of target organ weights, hematological analyses, and urinalysis examination among groups. However, male mice that ingested high doses of LH-1 ePSP tended to have decreased lung weights and platelet numbers. In conclusion, the results of the present study suggested that oral administration of LH-1 ePSP for 28 days is accompanied by no obvious signs of toxicity. The lack of toxicity supports the potential use of LH-1 ePSP as a food or dietary supplement.

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

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ... indication of immunological effects and reproductive organ toxicity. (c) Definitions. The definitions in...—(1) Number and sex of animals. At least 10 animals (five female and five male) should be used at each... should be carefully recorded, preferably using scoring systems, explicitly defined by the...

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

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ... indication of immunological effects and reproductive organ toxicity. (c) Definitions. The definitions in...—(1)Number and sex of animals. At least 10 animals (five female and five male) should be used at each... should be carefully recorded, preferably using scoring systems, explicitly defined by the...

  6. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... indication of immunological effects and reproductive organ toxicity. (c) Definitions. The definitions in...—(1) Number and sex of animals. At least 10 animals (five female and five male) should be used at each... should be carefully recorded, preferably using scoring systems, explicitly defined by the...

  7. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ... indication of immunological effects and reproductive organ toxicity. (c) Definitions. The definitions in...—(1)Number and sex of animals. At least 10 animals (five female and five male) should be used at each... should be carefully recorded, preferably using scoring systems, explicitly defined by the...

  8. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ... indication of immunological effects and reproductive organ toxicity. (c) Definitions. The definitions in...—(1)Number and sex of animals. At least 10 animals (five female and five male) should be used at each... should be carefully recorded, preferably using scoring systems, explicitly defined by the...

  9. Effects of SiO₂, ZrO₂, and BaSO₄ nanomaterials with or without surface functionalization upon 28-day oral exposure to rats.

    PubMed

    Buesen, Roland; Landsiedel, Robert; Sauer, Ursula G; Wohlleben, Wendel; Groeters, Sibylle; Strauss, Volker; Kamp, Hennicke; van Ravenzwaay, Bennard

    2014-10-01

    The effects of seven nanomaterials (four amorphous silicon dioxides with or without surface functionalization, two surface-functionalized zirconium dioxides, and barium sulfate) upon 28-day oral exposure to male or female rats were investigated. The studies were performed as limit tests in accordance with OECD Test Guideline 407 applying 1,000 mg test substance/kg body weight/day. Additionally, the acute phase proteins haptoglobin and α2-macroglobulin as well as cardiac troponin I were determined, and metabolome analysis was performed in plasma samples. There were no test substance-related adverse effects for any of the seven nanomaterials. Moreover, metabolomics changes were below the threshold of effects. Since test substance organ burden was not analyzed, it was not possible to establish whether the lack of findings related to the absence of systemic exposure of the tested nanomaterials or if the substances are devoid of any potential for toxicity. The few published subacute oral or short-term inhalation studies investigating comparable nanomaterials (SiO₂, ZrO₂, and BaSO₄) also do not report the occurrence of pronounced treatment-related findings. Overall, the results of the present survey provide a first indication that the tested nanomaterials neither cause local nor systemic effects upon subacute oral administration under the selected experimental conditions. Further investigations should aim at elucidating the extent of gastrointestinal absorption of surface-functionalized nanomaterials.

  10. A 28-day repeat dose toxicity study of steroidal glycoalkaloids, alpha-solanine and alpha-chaconine in the Syrian Golden hamster.

    PubMed

    Langkilde, Søren; Mandimika, Tafadzwa; Schrøder, Malene; Meyer, Otto; Slob, Wout; Peijnenburg, Ad; Poulsen, Morten

    2009-06-01

    Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanumtuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios resulted in distended and fluid filled small intestines and stomach. Animals receiving the ratio with the reduced content of alpha-solanine were less affected compared to those receiving the other ratio. Gene expression profiling experiments were conducted using RNA from epithelial scrapings from the small intestines of the hamsters administered the highest doses of the glycoalkaloid treatments. In general, more differential gene expression was observed in the epithelial scrapings of the hamsters fed the ratio of 1:3.7. Mostly, pathways involved in lipid and energy metabolism were affected by the ratio of 1:3.7.

  11. A 28-day repeated dose toxicity study of ultraviolet absorber 2-(2'-hydroxy-3',5'-di-tert-butylphenyl) benzotriazole in rats.

    PubMed

    Hirata-Koizumi, Mutsuko; Watari, Nobuaki; Mukai, Daisuke; Imai, Toshio; Hirose, Akihiko; Kamata, Eiichi; Ema, Makoto

    2007-01-01

    To examine the possible repeated-dose toxicity of an ultraviolet absorber, 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB), CD(SD)IGS rats were administered HDBB by gavage at a dose of 0 (vehicle: corn oil), 0.5, 2.5, 12.5, or 62.5 mg kg(-1) day(-1) for 28 days. At the completion of the administration period, a decrease in red blood cells, hemoglobin, and hematocrit was noted only in males at 2.5 mg/kg and more. Blood biochemical changes were noted at 0.5 mg/kg and more in males and at 62.5 mg/kg in females. Histopathologic changes were observed principally in the liver (vacuolar degeneration and hypertrophy of hepatocytes, bile duct proliferation, etc.) and in the heart (degeneration and hypertrophy of myocardium and cell infiltration). These changes were noted at 0.5 mg/kg and more in males and at 12.5 mg/kg and more in females. At higher doses, hypertrophy of tubular epithelium in the kidneys and diffuse follicular cell hyperplasia in the thyroids in both sexes and increased severity of basophilic tubules in the kidneys and extramedullary hematopoiesis in the spleen in males were also detected. After the 14-day recovery period, these changes mostly recovered in females but not in males. Based on these findings, no observed adverse effect level (NOAEL) was concluded to be less than 0.5 mg kg(-1) day(-1) in male rats and 2.5 mg kg(-1) day(-1) in female rats.

  12. Safety profile and gender specific differences of a methanol extract of Eriosema laurentii (Leguminosae) in acute and subchronic (28 days) oral toxicity studies in Wistar rats.

    PubMed

    Ateba, Sylvin Benjamin; Simo, Rudy Valdès; Mbanya, Jean Claude; Krenn, Liselotte; Njamen, Dieudonné

    2014-03-01

    Despite widespread use of Eriosema laurentii De Wild (Leguminosae) in West and Central Africa as herbal medicine and food additive the toxicity of this plant is unknown. Therefore, we performed the safety evaluation of a methanol extract (AEL). In acute toxicity, single oral administration of 2000mg/kg AEL caused neither toxicological symptoms nor mortality and the LD50 was estimated >5000mg/kg. In the subchronic oral toxicity, AEL induced no phenotypical signs of toxicity during and after treatment. Only a delayed decrease of relative spleen weight in males at the highest dose of 400mg/kg occurred. High density lipoprotein (HDL) increased significantly in females at 200 and 400mg/kg. Non-persistent increases in alanine aminotransferase activity within normal ranges were noted at 200mg/kg in males and at all doses in females. In males, AEL induced a decrease of white blood cell count at 400mg/kg, whereas lymphocytes increased at 200 and 400mg/kg and granulocytes at 400mg/kg. In females, no differences in haematological parameters occurred. Neither differences in bilirubin, creatinine and total protein levels were observed nor histological alterations in organs. The results indicate a broad safety margin for AEL.

  13. A 28-day oral gavage toxicity study of 3-monochloropropane-1,2-diol (3-MCPD) in CB6F1-non-Tg rasH2 mice.

    PubMed

    Lee, Byoung-Seok; Park, Sang-Jin; Kim, Yong-Bum; Han, Ji-Seok; Jeong, Eun-Ju; Moon, Kyoung-Sik; Son, Hwa-Young

    2015-12-01

    3-Monochloro-1,2-propanediol (3-MCPD) is a well-known contaminant of foods containing hydrolyzed vegetable protein. However, limited toxicity data are available for the risk assessment of 3-MCPD and its carcinogenic potential is controversial. To evaluate the potential toxicity and determine the dose levels for a 26-week carcinogenicity test using Tg rasH2 mice, 3-MCPD was administered once daily by oral gavage at doses of 0, 25, 50, and 100 mg/kg body weight (b.w.)/day for 28 days to male and female CB6F1-non-Tg rasH2 mice (N = 5 males and females per dose). The standard toxicological evaluations were conducted during the in-life and post-mortem phase. In the 100 mg/kg b.w./day group, 3 males and 1 female died during the study and showed clinical signs such as thin appearance and subdued behavior accompanied by significant decreases in mean b.w. Microscopy revealed tubular basophilia in the kidneys, exfoliated degenerative germ cells in the lumen of the seminiferous tubule of the testes, vacuolation in the brain, axonal degeneration of the sciatic nerve, and cardiomyopathy in the 100, ≥25, ≥50, 100, and 100 mg/kg b.w./day groups, respectively. In conclusion, 3-MCPD's target organs were the kidneys, testes, brain, sciatic nerve, and heart. The "no-observed-adverse-effect level" (NOAEL) of 3-MCPD was ≤25 and 25 mg/kg b.w./day in males and females, respectively.

  14. Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study

    PubMed Central

    Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

    2017-01-01

    The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3+, CD4+, CD8+, and CD19+) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs. PMID:28280324

  15. Systemic and immunotoxicity of pristine and PEGylated multi-walled carbon nanotubes in an intravenous 28 days repeated dose toxicity study.

    PubMed

    Zhang, Ting; Tang, Meng; Zhang, Shanshan; Hu, Yuanyuan; Li, Han; Zhang, Tao; Xue, Yuying; Pu, Yuepu

    2017-01-01

    The numerous increasing use of carbon nanotubes (CNTs) derived from nanotechnology has raised concerns about their biosafety and potential toxicity. CNTs cause immunologic dysfunction and limit the application of CNTs in biomedicine. The immunological responses induced by pristine multi-walled carbon nanotubes (p-MWCNTs) and PEGylated multi-walled carbon nanotubes (MWCNTs-PEG) on BALB/c mice via an intravenous administration were investigated. The results reflect that the p-MWCNTs induced significant increases in spleen, thymus, and lung weight. Mice treated with p-MWCNTs showed altered lymphocyte populations (CD3(+), CD4(+), CD8(+), and CD19(+)) in peripheral blood and increased serum IgM and IgG levels, and splenic macrophage ultrastructure indicated mitochondria swelling. p-MWCNTs inhibited humoral and cellular immunity function and were associated with decreased immune responses against sheep erythrocytes and serum hemolysis level. Natural killer (NK) activity was not modified by two types of MWCNTs. In comparison with two types of MWCNTs, for a same dose, p-MWCNTs caused higher levels of inflammation and immunosuppression than MWCNTs-PEG. The results of immunological function suggested that after intravenous administration with p-MWCNTs caused more damage to systemic immunity than MWCNTs-PEG. Here, we demonstrated that a surface functional modification on MWCNTs reduces their immune perturbations in vivo. The chemistry-modified MWCNTs change their preferred immune response in vivo and reduce the immunotoxicity of p-MWCNTs.

  16. 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 μg levonorgestrel [LNG]/30 μg ethinylestradiol [EE] for 84 days, followed by 10 μg EE for seven days [Treatment 1]) compared with two traditional 21/7 regimens (21 days 150 μg LNG/30 μg EE [Treatment 2] or 150 μg desogestrel [DSG]/30 μg 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

  17. Acute, 28days sub acute and genotoxic profiling of Quercetin-Magnesium complex in Swiss albino mice.

    PubMed

    Ghosh, Nilanjan; Sandur, Rajendra; Ghosh, Deepanwita; Roy, Souvik; Janadri, Suresh

    2017-02-01

    Quercetin-Magnesium complex is one of the youngest alkaline rare earth metal (Magnesium) complexes with flavonoids (Quercetin) in organo-metalic family. Earlier studies describe the details of the complex formation, characterization and antioxidant study of the complex but toxicity profile is still under darkness. The present study was taken up to investigate the oral acute toxicity, 28days repeated oral sub-acute toxicity study and genotoxicity study of Quercetin-Magnesium complex in Swiss albino mice. Quercetin-Magnesium complex showed mortality at a dose of 185mg/kg in the Swiss albino mice. In 28days repeated oral toxicity study, Quercetin-Magnesium complex was administered to both sex of Swiss albino mice at dose levels of 150, 130 and 100mg/kg body weight respectively. Where 150mg/kg dose shows increased levels of white blood cells and changes in total protein, serum creatinine and blood urea nitrogen. Histopathological study of Quercetin-Magnesium complex shows minor structural alteration in kidney at 150mg/kg dose. No observed toxic level found in 130mg/kg or below doses. No genotoxic effect found in any doses of the complex. Therefore 130mg/kg or below dose level could be better for further study.

  18. Repeated dosing with oral cocaine in humans: assessment of direct effects, withdrawal, and pharmacokinetics.

    PubMed

    Walsh, Sharon L; Stoops, William W; Moody, David E; Lin, Shen-Nan; Bigelow, George E

    2009-08-01

    Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n = 9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1-4 & Days 9-12, cocaine 175 mg, p.o.; 5 hourly doses; 875 mg/day) separated by a 4-day matched placebo exposure period (Days 5-8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13-40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) two to threefold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects (liking, high, good effects) and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours.

  19. Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes

    PubMed Central

    Garcia-Manero, G; Gore, S D; Kambhampati, S; Scott, B; Tefferi, A; Cogle, C R; Edenfield, W J; Hetzer, J; Kumar, K; Laille, E; Shi, T; MacBeth, K J; Skikne, B

    2016-01-01

    CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31–87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2–24) for the 14-day dosing schedule and 6 (1–24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS. PMID:26442612

  20. Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes.

    PubMed

    Garcia-Manero, G; Gore, S D; Kambhampati, S; Scott, B; Tefferi, A; Cogle, C R; Edenfield, W J; Hetzer, J; Kumar, K; Laille, E; Shi, T; MacBeth, K J; Skikne, B

    2016-04-01

    CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31-87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2-24) for the 14-day dosing schedule and 6 (1-24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS.

  1. Absorption of cyclosporine A after oral dosing.

    PubMed

    Grevel, J

    1986-12-01

    Variability in the absorption of CsA seems to contribute to the observed lack of correlation between the size of the oral dose and the trough concentration at steady state. Absorption is probably improved by thorough dispersion of the oral solution of CsA in the drink the patient prefers. Evidence for GI metabolism of CsA has only been gathered in animal experiments. The importance of bile for absorption of CsA into the portal blood is established. The bioavailability of CsA does not seem to be determined by the metabolism during the first passage through the liver. Enterohepatic recycling is likely for CsA metabolites and unlikely for unchanged CsA. A pharmacokinetic model that assumes zero-order absorption of CsA describes human data better than a model with first-order absorption. According to the zero-order model, CsA is absorbed only in the upper part of the small intestine by a mechanism that operates under saturation. Two independent findings in transplantation patients support this model. First, it was shown that small doses of CsA produce disproportionally high blood concentrations, probably due to a better bioavailability. Second, accelerated transit times in the intestine (diarrhea) lead to unexpectedly low blood concentrations, probably due to poor bioavailability. Further factors have been identified that cause low absorption of CsA: liver dysfunction and external bile drainage after liver transplantation. The influence of food on the absorption of CsA is still not determined conclusively, but it seems that giving CsA together with a standard breakfast results in higher blood concentrations. The observed increase in the bioavailability of CsA with time after transplantation could be caused by the attempt to steadily lower the dose.

  2. Acute and 28-Day Subacute Toxicity Studies of Hexane Extracts of the Roots of Lithospermum erythrorhizon in Sprague-Dawley Rats

    PubMed Central

    Han, Chung-Tack; Kim, Myoung-Jun; Moon, Seol-Hee; Jeon, Yu-Rim; Hwang, Jae-Sik; Nam, Chunja; Park, Chong-Woo; Lee, Sun-Ho; Na, Jae-Bum; Park, Chan-Sung; Park, Hee-Won; Lee, Jung-Min; Jang, Ho-Song; Park, Sun-Hee; Han, Kyoung-Goo; Choi, Young Whan

    2015-01-01

    Lithospermum erythrorhizon has long been used as a traditional oriental medicine. In this study, the acute and 28-day subacute oral dose toxicity studies of hexane extracts of the roots of L. erythrorhizon (LEH) were performed in Sprague-Dawley rats. In the acute toxicity study, LEH was administered once orally to 5 male and 5 female rats at dose levels of 500, 1,000, and 2,000 mg/kg. Mortality, clinical signs, and body weight changes were monitored for 14 days. Salivation, soft stool, soiled perineal region, compound-colored stool, chromaturia and a decrease in body weight were observed in the extract-treated groups, and no deaths occurred during the study. Therefore, the approximate lethal dose (ALD) of LEH in male and female rats was higher than 2,000 mg/kg. In the subacute toxicity study, LEH was administered orally to male and female rats for 28 days at dose levels of 25, 100, and 400 mg/kg/day. There was no LEH-related toxic effect in the body weight, food consumption, ophthalmology, hematology, clinical chemistry and organ weights. Compound-colored (black) stool, chromaturia and increased protein, ketone bodies, bilirubin and occult blood in urine were observed in the male and female rats treated with the test substance. In addition, the necropsy revealed dark red discoloration of the kidneys, and the histopathological examination showed presence of red brown pigment or increased hyaline droplets in the renal tubules of the renal cortex. However, there were no test substance-related toxic effects in the hematology and clinical chemistry, and no morphological changes were observed in the histopathological examination of the kidneys. Therefore, it was determined that there was no significant toxicity because the changes observed were caused by the intrinsic color of the test substance. These results suggest that the no-observed-adverse-effect Level (NOAEL) of LEH is greater than 400 mg/kg/day in both sexes. PMID:26877842

  3. Biochemical observation during 28 days of space flight

    NASA Technical Reports Server (NTRS)

    Leach, C. S.; Kambaut, P. C.

    1975-01-01

    With the completion of the 28-day flight of Skylab 2, the sum of biochemical data on human reaction to the weightless environment was significantly extended both quantitatively and qualitatively. The biochemical studies were divided into two broad categories. One group included the more routine blood studies similar to those used in everyday medical practice. The second category encompassed those analyses used to investigate more thoroughly the endocrinological and fluid changes first seen in the crewmembers following the Gemini, Apollo, and Soviet missions. Significant biochemical changes were observed that varied in magnitude and direction, but all disappeared shortly after return to earth. Most of changes indicate successful adaptation by the body to the combined stresses of weightlessness. Results of the biochemical observation are presented in the form of data tables and graphs.

  4. 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...

  5. Comparative oral dose toxicokinetics of sodium selenite and selenomethionine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The toxicokinetics of selenium (Se) absorption, distribution, and elimination were determined in serum and whole blood of lambs that were orally dosed with various doses of Se as sodium selenite (inorganic Se) or selenomethionine (organic Se). Thirty-two lambs were randomly assigned to eight treatm...

  6. 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

  7. Single oral dose safety of D-allulose in dogs

    PubMed Central

    NISHII, Naohito; NOMIZO, Toru; TAKASHIMA, Satoshi; MATSUBARA, Tatsuya; TOKUDA, Masaaki; KITAGAWA, Hitoshi

    2016-01-01

    Healthy dogs were administered acute oral doses of D-allulose (also called D-psicose) to evaluate its toxicity. Six dogs received oral doses of either a placebo or D-allulose solution (1 and 4 g/kg) on three different study days. One dog experienced vomiting, and five dogs showed transient diarrhea when 4 g/kg of D-allulose was administered. All dogs were active and had a good appetite throughout the study period. Blood glucose concentration slightly decreased without a rise in plasma insulin concentration 2 hr after D-allulose administration. Plasma alkaline phosphatase activities showed a mild increase between 12 and 48 hr after D-allulose administration. These data suggested that a single oral dose of D-allulose does not show severe toxicity in dogs. PMID:26972334

  8. Single-Dose Pharmacokinetics of Different Oral Sodium Nitrite Formulations in Diabetes Patients

    PubMed Central

    Predmore, Benjamin L.; Flanagan, Douglas R.; Giordano, Tony; Qiu, Yang; Brandon, Angela; Lefer, David J.; Patel, Rakesh P.; Kevil, Christopher G.

    2012-01-01

    Abstract Background Diabetic foot ulcers, although associated with macrovascular disease and neuropathy, have a microvascular disease causing ischemia not amenable to surgical intervention. Nitrite selectively releases nitric oxide in ischemic tissues, and diabetes subjects have low nitrite levels that do not increase with exercise. This study explores the safety and pharmacokinetics of a single dose of sodium nitrite in subjects with diabetic foot ulcers. Subjects and Methods Using a blinded, randomized crossover study design, 12 subjects with diabetes mellitus and active or healed foot ulcers received a single dose of sodium nitrite on two occasions 7–28 days apart, once with an immediate release (IR) formulation and once with an enteric-coated (EC) formulation for delayed release. Serum nitrite, nitrate, methemoglobin, sulfhemoglobin, blood pressure, pulse rate, complete blood count, chemistry panel, electrocardiogram, and adverse events were followed for up to 6 h after each dose. The IR and EC nitrite levels were analyzed by one-way analysis of variance and by pharmacokinetic modeling. Results The IR formulation elevated nitrite levels between 0.25 and 0.75 h (P<0.05). The EC formulation did not elevate nitrite levels significantly, but both formulations gave plasma nitrite levels previously suggested to be therapeutic (approximately 2–5 μM). The IR formulation gave an asymptomatic blood pressure drop of 10/6 mm Hg (P<0.003), and two subjects experienced mild flushing. There was no elevation of methemoglobin or other safety concerns. Pharmacokinetic modeling of plama nitrite levels gave r2 values of 0.81 and 0.97 for the fits for IR and EC formulations, respectively. Conclusions Oral sodium nitrite administration is well tolerated in diabetes patients. PMID:22468627

  9. Physiological effects following administration of Citrus aurantium for 28 days in rats

    SciTech Connect

    Hansen, Deborah K.; Pellicore, Linda S.

    2012-06-15

    Background: Since ephedra-containing dietary supplements were banned from the US market, manufacturers changed their formulations by eliminating ephedra and replacing with other botanicals, including Citrus aurantium, or bitter orange. Bitter orange contains, among other compounds, synephrine, a chemical that is chemically similar to ephedrine. Since ephedrine may have cardiovascular effects, the goal of this study was to investigate the cardiovascular effects of various doses of bitter orange extract and pure synephrine in rats. Method: Female Sprague–Dawley rats were dosed daily by gavage for 28 days with synephrine from two different extracts. One extract contained 6% synephrine, and the other extract contained 95% synephrine. Doses were 10 or 50 mg synephrine/kg body weight from each extract. Additionally, caffeine was added to these doses, since many dietary supplements also contain caffeine. Telemetry was utilized to monitor heart rate, blood pressure, body temperature and QT interval in all rats. Results and conclusion: Synephrine, either as the bitter orange extract or as pure synephrine, increased heart rate and blood pressure. Animals treated with 95% synephrine showed minimal effects on heart rate and blood pressure; more significant effects were observed with the bitter orange extract suggesting that other components in the botanical can alter these physiological parameters. The increases in heart rate and blood pressure were more pronounced when caffeine was added. None of the treatments affected uncorrected QT interval in the absence of caffeine.

  10. Prophylactic oral ganciclovir after renal transplantation-dosing and pharmacokinetics.

    PubMed

    Filler, G; Lampe, D; von Bredow, M A; Lappenberg-Pelzer, M; Rocher, S; Strehlau, J; Ehrich, J H

    1998-01-01

    Ganciclovir alone or in combination with hyperimmunoglobulin is replacing other treatment modalities for the prophylactic treatment of cytomegalovirus (CMV) infections. No dose recommendations are available for oral ganciclovir therapy in children with impaired renal function after renal transplantation of a kidney from a CMV IgG-positive donor. We undertook a pharmacokinetic study in 14 pediatric renal transplant recipients who were CMV IgG negative and had received a graft from a CMV IgG-positive donor. We estimated the daily dosage of oral ganciclovir in relation to the glomerular filtration rate (GFR). Oral ganciclovir was administered at a starting dose of 3 x 1 g for children with a weight above 50 kg, 3 x 750 mg for children between 50 and 37.5 kg, and 3 x 500 mg for children between 37.5 and 24 kg. The starting dose was reduced by 50% for GFR values < or = 50 ml/min per 1.73 m2 and by 75% for GFR values < or = 25 ml/min per 1.73 m2. The daily dose was divided into three daily doses unless GFR was < 40 ml/ min per 1.73 m2, when only two daily doses were given. Doses were adjusted according to the measured plasma trough concentrations (c) using the simple formula: c(ganciclovir)(measured)/c(ganciclovir)(desired) = dosage rate(used)/dosage rate(adjusted). Mean stable plasma trough concentration was 0.91 +/- 0.68 microg/ml. The dosage rate, adjusted to a trough concentration of 1.0 microg/ml, correlated with the GFR. The dose per day could be calculated according to a simple equation for a GFR < 100 ml/min per 1.73 m2: dosage per day (mg/kg per day) = GFR. No CMV disease developed in any of the patients during oral ganciclovir, but 1 patient developed an acute rejection episode and a positive pp65 antigen 5 weeks after discontinuation of ganciclovir. The drug was well tolerated and without side effects.

  11. Disposition of 2-mercaptobenzimidazole in rats dosed orally or intravenously

    SciTech Connect

    El Dareer, S.M.; Kalin, J.R.; Tillery, K.F.; Hill, D.L.

    1984-01-01

    The disposition of (/sup 14/C)-labeled 2-mercaptobenzimidazole (MBI) in male Fischer-344 rats dosed orally (49 or 0.5 mg/kg) or intravenously (0.5 mg/kg) was determined. Absorption of the oral dose was evident, since, in 72 h, most of the radioactivity administered by either route appeared in the urine. Smaller amounts appeared in the feces. In 4 h, 12% of the radioactivity from an intravenous dose of 0.5 mg/kg was excreted in the bile of rats with biliary cannulas. For rats dosed intravenously, the half-life for disappearance of unchanged MBI from plasma was 125 min. In contrast, the terminal half-life for loss of radioactivity from blood was 83 h. The concentration of total radioactivity was higher in liver and kidney tissue than in blood. One of the major urinary metabolites was identified as benzimidazole, and a minor component was tentatively identified as unchanged MBI. Neither of these could be detected in bile. 8 references, 6 figures, 1 table.

  12. Derivation of a chronic oral reference dose for cobalt.

    PubMed

    Finley, Brent L; Monnot, Andrew D; Paustenbach, Dennis J; Gaffney, Shannon H

    2012-12-01

    Cobalt (Co) is an essential element in humans as a component of vitamin B12. However, at high levels Co exposure has been shown to have detrimental effects. This study was designed to identify a chronic oral reference dose (RfD) for Co. Currently available data indicate that non-cancer health effects associated with Co exposure may include hematological, neurological, immunological, reproductive, cardiovascular, and endocrine responses. This analysis employs the standard US EPA risk assessment methodology for establishing a chronic RfD. In this analysis, the Jaimet and Thode (1955) 10-week, multiple dose human study of thyroid effects (decreased iodine uptake) in children was determined to be the most robust and sensitive study for identifying a potential point of departure dose (POD). A dose of 0.9 mgCo/kg-day was chosen as the POD. Consistent with the US EPA's previous derivation of the perchlorate RfD, which is also based on decreased iodine uptake in humans, we considered several uncertainly factors (UFs), and determined that a factor of 10 for human variability was appropriate, as well as a factor of three for database adequacy. Applying an aggregate uncertainty factor of 30 to the POD yields a chronic oral RfD of 0.03 mg/kg-day. We believe this value would be protective of non-cancer health effects in the general population for a lifetime of daily exposure to Co.

  13. Pharmacology of rising oral doses of 5-hydroxytryptophan with carbidopa.

    PubMed

    Smarius, L J C A; Jacobs, G E; Hoeberechts-Lefrandt, D H M; de Kam, M L; van der Post, J P; de Rijk, R; van Pelt, J; Schoemaker, R C; Zitman, F G; van Gerven, J M A; Gijsman, H J

    2008-06-01

    5-hydroxytryptophan (5-HTP) is a direct 5-hydroxytryptamine (5-HT) precursor used to assess central serotonergic function. Its use has been limited by a narrow window between neuroendocrine changes and side effects, and variable kinetics related to inconsistent administration modes. By combining 5-HTP with carbidopa (CBD), increased bioavailability for brain penetration and decreased peripheral side effects would be expected, due to reduced peripheral decarboxylation of 5-HTP to 5-HT. A double-blind, placebo-controlled, single rising dose, four-way crossover trial with placebo randomisation was performed in 15 healthy male volunteers to investigate the neuroendocrine dose-response relationship at various 5-HTP levels; the tolerability and subjective effects of oral 5-HTP at 100, 200 and 300 mg combined with CBD and the pharmacokinetic properties of the 5-HTP/CBD-challenge. Dose-dependent increases in average cortisol concentrations were observed. Mean response (area-under-the-curve) over the first 4 hours (SD): 172.0 nmol/L (22.3) for placebo, 258.3 nmol/L (72.6) for 100 mg, 328.47 nmol/L (84.6) for 200 mg and 387.3 nmol/L (82.4) for 300 mg 5-HTP. Similar dose-dependent increases for prolactin were seen while adreno-corticotrophic hormone response was more variable. 5-HTP kinetics were adequately described using a one-compartment model with first-order absorption and a lag time (mean oral clearance 28 L/h interindividual coefficient of variation 31%). Nausea and vomiting occurred dose-dependently as most frequent side effects, resulting in dose-related dropout of 6.6% at 100 mg and 45.5% at 300 mg 5-HTP. Orally administered 5-HTP combined with CBD is an effective serotonergic challenge test, exhibiting dose-related plasma concentrations and neuroendocrine responsiveness. Frequent occurrence of nausea and vomiting limits the applicability of this challenge at 5-HTP doses above 100 mg.

  14. Downregulation of immediate-early genes linking to suppression of neuronal plasticity in rats after 28-day exposure to glycidol

    SciTech Connect

    Akane, Hirotoshi; Saito, Fumiyo; Shiraki, Ayako; Takeyoshi, Masahiro; Imatanaka, Nobuya; Itahashi, Megu; Murakami, Tomoaki; Shibutani, Makoto

    2014-09-01

    We previously found that the 28-day oral toxicity study of glycidol at 200 mg/kg/day in rats resulted in axonopathy in both the central and peripheral nervous systems and aberrations in the late-stage of hippocampal neurogenesis targeting the process of neurite extension. To capture the neuronal parameters in response to glycidol toxicity, these animals were subjected to region-specific global gene expression profiling in four regions of cerebral and cerebellar architectures, followed by immunohistochemical analysis of selected gene products. Expression changes of genes related to axonogenesis and synaptic transmission were observed in the hippocampal dentate gyrus, cingulate cortex and cerebellar vermis at 200 mg/kg showing downregulation in most genes. In the corpus callosum, genes related to growth, survival and functions of glial cells fluctuated their expression. Immunohistochemically, neurons expressing gene products of immediate-early genes, i.e., Arc, Fos and Jun, decreased in their number in the dentate granule cell layer, cingulate cortex and cerebellar vermis. We also applied immunohistochemical analysis in rat offspring after developmental exposure to glycidol through maternal drinking water. The results revealed increases of Arc{sup +} neurons at 1000 ppm and Fos{sup +} neurons at ≥ 300 ppm in the dentate granule cell layer of offspring only at the adult stage. These results suggest that glycidol suppressed neuronal plasticity in the brain after 28-day exposure to young adult animals, in contrast to the operation of restoration mechanism to increase neuronal plasticity at the adult stage in response to aberrations in neurogenesis after developmental exposure. - Highlights: • Neuronal toxicity parameters after 28-day glycidol treatment were examined in rats. • Region-specific global gene expression profiling was conducted in brain regions. • Cortical tissues downregulated genes on axonogenesis and synaptic transmission. • Cortical tissues

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

    PubMed

    Smith, D J; Taylor, J B

    2012-06-01

    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 hours after exposure chlorate residues were dose dependent (P < 0.05) in small intestinal contents, serum, and urine, but chlorate residues were not consistently detected in cecal or colonic contents. In Exp. 2, non-pregnant yearling ewes (BW = 74.8 ± 5.6 kg; mean ± SD) were orally dosed with 0, 150, 300, or 450 mg/kg BW of sodium chlorate. Across dose, chlorate residues averaged from 47 to 114, 0.6 to 4.5, and were not detectable to 0.2 μg/mL at 24, 48, and 72 h, respectively, in serum of treated animals; in feces, residues averaged 29 to 82, 0.8 to 14, and were not detectable to 1.2 μg/mL at the same respective time periods. In Exp. 3, six lactating ewes (BW = 76.3 ± 8.0 kg) were dosed orally with 450 mg/kg BW of sodium chlorate; residues were measured in serum, milk, urine and feces in periods encompassing 0 to 8, 8 to 16, 16 to 24, 24 to 32, 32 to 40, and 40 to 48 h. Chlorate residues in milk were detectable at all time periods with concentrations averaging from 287 ± 67 to 26 ± 13 μg/mL during the first and last collection periods, respectively. Urine contained the greatest concentration of chlorate at each time point and averaged 480 ± 268 μg/mL at 40 to 48 h. Depletion half-lives in serum, milk, urine, and feces were estimated to be 6.2, 27, 19, and 10 h, respectively; milk, urinary and fecal half-lives are likely overestimated due to the fact that 8-h sample pools were used in half-life estimations. In Exp. 4, three wethers (BW = 87.1 ± 5.3 kg) each were orally dosed with 14 or 42 mg/kg BW of sodium chlorate; blood samples were serially collected for 48 h, and urine samples were collected at 0 to 8, 8 to 16, 16 to 24, 24 to 36, and 36 to 48 h. Estimates of absorption and

  16. New approach for food allergy management using low-dose oral food challenges and low-dose oral immunotherapies.

    PubMed

    Yanagida, Noriyuki; Okada, Yu; Sato, Sakura; Ebisawa, Motohiro

    2016-04-01

    A number of studies have suggested that a large subset of children (approximately 70%) who react to unheated milk or egg can tolerate extensively heated forms of these foods. A diet that includes baked milk or egg is well tolerated and appears to accelerate the development of regular milk or egg tolerance when compared with strict avoidance. However, the indications for an oral food challenge (OFC) using baked products are limited for patients with high specific IgE values or large skin prick test diameters. Oral immunotherapies (OITs) are becoming increasingly popular for the management of food allergies. However, the reported efficacy of OIT is not satisfactory, given the high frequency of symptoms and requirement for long-term therapy. With food allergies, removing the need to eliminate a food that could be consumed in low doses could significantly improve quality of life. This review discusses the importance of an OFC and OIT that use low doses of causative foods as the target volumes. Utilizing an OFC or OIT with a low dose as the target volume could be a novel approach for accelerating the tolerance to causative foods.

  17. Pharmacokinetics of single-dose oral ponazuril in weanling goats.

    PubMed

    Love, D; Gibbons, P; Fajt, V; Jones, M

    2016-06-01

    Ponazuril (toltrazuril sulfone) is a triazine antiprotozoal agent that targets apicomplexan organisms. Ponazuril may have clinical application in the treatment of clinical coccidiosis due to Eimeria species in goats, along with other protozoal infections. To evaluate the absorption, distribution and elimination characteristics of ponazuril in goats, a sensitive, validated high-pressure liquid chromatography and mass spectroscopy method for ponazuril in caprine plasma was developed. After a single oral dose of ponazuril at 10 mg/kg, plasma samples from seven weanling goats were collected and assayed. Plasma concentrations of ponazuril in the goats peaked at 36 ± 13 h post drug administration at a concentration of 9 ± 2 μg/mL. Concentrations declined to an average of 4.2 ± 0.8 μg/mL after 168 h with an average elimination half-life of 129 ± 72 h post drug administration. This study shows that ponazuril is relatively well absorbed after a single oral dose in goats. Efficacy trials are underway to determine clinical efficacy of ponazuril in the treatment of clinical coccidiosis in goats at 10 mg/kg dosage.

  18. Pharmacokinetic Evaluation of a Single Intramuscular High Dose versus an Oral Long-Term Supplementation of Cholecalciferol

    PubMed Central

    Krannich, Alexander; Heine, Guido; Dölle, Sabine; Worm, Margitta

    2017-01-01

    Background and Objectives Vitamin D deficiency is frequent during the winter and occurs throughout the year in the elderly or patients suffering from autoimmune diseases. The objective of this study was to evaluate the pharmacokinetic properties of oral supplementation versus a single intramuscular injection of cholecalciferol in healthy individuals. Research design and methods Up to 8,000 I.U. oral cholecalciferol was administered daily for 84 days in a 4 week dose-escalation setting to vitamin D deficient individuals. In another cohort, a single intramuscular injection of 100,000 I.U. cholecalciferol was given. In both cohorts, individuals without vitamin D intake served as the comparison group. 25-hydroxyvitamin D (25(OH)D) concentrations were measured in all individuals at defined time points throughout the studies. Results The mean 25(OH)D serum concentration increased significantly after oral cholecalciferol intake compared to the control group (day 28: 83.4 nmol/l and 42.5 nmol/l; day 56: 127.4 nmol/l and 37.3 nmol/l; day 84: 159.7 nmol/l and 30.0 nmol/l). In individuals receiving 100,000 I.U. cholecalciferol intramuscular, the mean 25(OH)D serum concentration peaked after 4 weeks measuring 70.9 nmol/l compared to 32.7 nmol/l in the placebo group (p = 0.002). The increase of 25(OH)D serum concentrations after 28 days was comparable between both routes of administration (p = 0.264). Conclusions Oral and intramuscular cholecalciferol supplementation effectively increased serum 25(OH)D concentrations. PMID:28114352

  19. Terbinafine pharmacokinetics after single dose oral administration in the dog.

    PubMed

    Sakai, Mary R; May, Elizabeth R; Imerman, Paula M; Felz, Charles; Day, Timothy A; Carlson, Steve A; Noxon, James O

    2011-12-01

    Terbinafine is an allylamine antifungal prescribed for the treatment of mycoses in humans. It is increasingly being used in veterinary patients. The purpose of this study was to evaluate the pharmacokinetic properties of terbinafine in dogs after a single oral dose. Ten healthy adult dogs were included in the study. A single dose of terbinafine (30-35 mg/kg) was administered orally, and blood samples were periodically collected over a 24 h period during which dogs were monitored for adverse effects. Two of 10 dogs developed transient ocular changes. A high-performance liquid chromatography assay was developed and used to determine plasma terbinafine concentrations. Pharmacokinetic analysis was performed using PK Solutions(®) computer software. Area under the curve (AUC) from time 0 to 24 h was 15.4 μg·h/mL (range 5-27), maximal plasma concentration (C(max) ) was 3.5 μg/mL (range 3-4.9 μg/mL) and time to C(max) (T(max) ) was 3.6 h (range 2-6 h). The time above minimal inhibitory concentration (T > MIC) as well as AUC/MIC was calculated for important invasive fungal pathogens and dermatophytes. The T > MIC was 17-18 h for Blastomyces dermatitidis, Histoplasma capsulatum and dermatophytes (Microsporum spp. and Trichophyton mentagrophytes), while the MIC for Sporothrix schenckii and Coccidioides immitis was exceeded for 9.5-11 h. The AUC/MIC values ranged from 9 to 13 μg h/mL for these fungi. Our results provide evidence supporting the use of terbinafine as an oral therapeutic agent for treating systemic and subcutaneous mycoses in dogs.

  20. Reliable evidence for efficacy of single dose oral analgesics.

    PubMed

    Spivakovsky, Silvia; Spivakovsky, Yael

    2016-06-01

    Data sourcesThe Cochrane library was searched for Cochrane systematic reviews.Study selectionCochrane reviews on single pain medications for the treatment of acute pain were included. Non-Cochrane reviews were included for tramadol.Data extraction and synthesisTwo reviewers independently searched, selected reviews for inclusion, assessed quality and performed data extraction. A protocol in case of disagreement was in place. Data were collected on number of included studies and participants, drug, dose and formulation and pain model. The authors concentrated on the amount of information and the potential for publication bias.Pain relief was calculated using at least 50% maximum pain relief, as a percentage, and as NNTs. Duration of analgesia was measured as mean or median and time to remedication was calculated as percentage of patients.ResultsThirty-nine reviews including 41 interventions were analysed and NNTs for at least 50% maximum pain relief were summarised in a graphic. NNTs range from almost one all the way to five. Only one intervention, codeine 60, had an NNT ≥10. Results judged to be reliable were listed in detail. Mean or median time to remedication was also presented in a graphic.The authors conclude that there is a great amount of quality information on single dose analgesics, and highlighted the potential benefit of fast acting formulations and fixed formulations to achieve good long-lasting analgesia.ConclusionsThere is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. Fast acting formulations and fixed dose combinations of analgesics can produce good and often long-lasting analgesia at relatively low doses. 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.

  1. Single dose oral ibuprofen for acute postoperative pain in adults

    PubMed Central

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

    2014-01-01

    Background This review updates a 1999 Cochrane review showing that ibuprofen at various doses was effective in postoperative pain in single dose studies designed to demonstrate analgesic efficacy. New studies have since been published. Ibuprofen is one of the most widely used non-steroidal anti-inflammatory (NSAID) analgesics both by prescription and as an over-the-counter medicine. Ibuprofen is used for acute and chronic painful conditions. Objectives To assess analgesic efficacy of ibuprofen in single oral doses for moderate and severe 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 trials of single dose orally administered ibuprofen (any formulation) 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 were collected. Main results Seventy-two studies compared ibuprofen and placebo (9186 participants). Studies were predominantly of high reporting quality, and the bulk of the information concerned ibuprofen 200 mg and 400 mg. For at least 50% pain relief compared with placebo the NNT for ibuprofen 200 mg (2690 participants) was 2.7 (2.5 to 3.0) and for ibuprofen 400 mg (6475 participants) it was 2.5 (2.4 to 2.6). The proportion with at least 50% pain relief was 46% with 200 mg and 54% with 400 mg. Remedication within 6 hours was less

  2. Single dose oral tenoxicam for acute postoperative pain in adults

    PubMed Central

    Moore, Owen A; McIntyre, Mairead; Moore, R Andrew; Derry, Sheena; McQuay, Henry J

    2014-01-01

    Background Tenoxicam is a non-steroidal anti-inflammatory drug (NSAID) licensed for use in rheumatic disease and other musculoskeletal disorders in the UK, and is widely available in other countries worldwide. This review sought to evaluate the efficacy and safety of oral tenoxicam 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 tenoxicam in acute postoperative pain, and any associated adverse events. Search methods We searched The Cochrane Library (Issue 1, 2009), MEDLINE (March 2009); EMBASE via Ovid (March 2009); the Oxford Pain Relief Database. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of oral tenoxicam 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 tenoxicam 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 Not one of sixteen studies identified by the searches and examined in detail studied oral tenoxicam in patients with established postoperative pain and therefore no results are available. Authors’ conclusions In the absence of evidence of efficacy for oral tenoxicam in acute postoperative pain, its use in this indication is not justified at present. Because trials clearly

  3. 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

  4. 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.

  5. D-aspartic acid supplementation combined with 28 days of heavy resistance training has no effect on body composition, muscle strength, and serum hormones associated with the hypothalamo-pituitary-gonadal axis in resistance-trained men.

    PubMed

    Willoughby, Darryn S; Leutholtz, Brian

    2013-10-01

    It was hypothesized that D-aspartic acid (D-ASP) supplementation would not increase endogenous testosterone levels or improve muscular performance associated with resistance training. Therefore, body composition, muscle strength, and serum hormone levels associated with the hypothalamo-pituitary-gonadal axis were studied after 28 days of resistance training and D-ASP supplementation. Resistance-trained men resistance trained 4 times/wk for 28 days while orally ingesting either 3 g of placebo or 3 g of D-ASP. Data were analyzed with 2 × 2 analysis of variance (P < .05). Before and after resistance training and supplementation, body composition and muscle strength, serum gonadal hormones, and serum D-ASP and d-aspartate oxidase (DDO) were determined. Body composition and muscle strength were significantly increased in both groups in response to resistance training (P < .05) but not different from one another (P > .05). Total and free testosterone, luteinizing hormone, gonadotropin-releasing hormone, and estradiol were unchanged with resistance training and D-ASP supplementation (P > .05). For serum D-ASP and DDO, D-ASP resulted in a slight increase compared with baseline levels (P > .05). For the D-ASP group, the levels of serum DDO were significantly increased compared with placebo (P < .05). The gonadal hormones were unaffected by 28 days of D-ASP supplementation and not associated with the observed increases in muscle strength and mass. Therefore, at the dose provided, D-ASP supplementation is ineffective in up-regulating the activity of the hypothalamo-pituitary-gonadal axis and has no anabolic or ergogenic effects in skeletal muscle.

  6. Oral anticancer drugs: how limited dosing options and dose reductions may affect outcomes in comparative trials and efficacy in patients.

    PubMed

    Prasad, Vinay; Massey, Paul R; Fojo, Tito

    2014-05-20

    Historically, cancer medicine has avoided the problem of unequal dosing by comparing maximum-tolerated doses of intravenous regimens with proportionate dose reductions for toxicity. However, in recent years, with the development of numerous oral anticancer agents, dosing options are arbitrarily and increasingly limited by the size of pills. We contend that an underappreciated consequence of pill size is unequal dosing in comparative clinical trials and that this can have an impact on outcomes. We discuss how comparative effectiveness trials can be unbalanced and how the use of doses that are not sustainable might affect outcomes, especially marginal ones. We further argue that because of their poor tolerability and their limited dosing options, which often result in large dose adjustments in response to toxicity, the real-world clinical effectiveness of oral anticancer agents may be diminished and may not emulate results achieved in registration trials.

  7. Oral Anticancer Drugs: How Limited Dosing Options and Dose Reductions May Affect Outcomes in Comparative Trials and Efficacy in Patients

    PubMed Central

    Prasad, Vinay; Massey, Paul R.; Fojo, Tito

    2014-01-01

    Historically, cancer medicine has avoided the problem of unequal dosing by comparing maximum-tolerated doses of intravenous regimens with proportionate dose reductions for toxicity. However, in recent years, with the development of numerous oral anticancer agents, dosing options are arbitrarily and increasingly limited by the size of pills. We contend that an underappreciated consequence of pill size is unequal dosing in comparative clinical trials and that this can have an impact on outcomes. We discuss how comparative effectiveness trials can be unbalanced and how the use of doses that are not sustainable might affect outcomes, especially marginal ones. We further argue that because of their poor tolerability and their limited dosing options, which often result in large dose adjustments in response to toxicity, the real-world clinical effectiveness of oral anticancer agents may be diminished and may not emulate results achieved in registration trials. PMID:24711558

  8. 28-Day emergency surgical re-admission rates as a clinical indicator of performance.

    PubMed Central

    Courtney, Edward D. J.; Ankrett, Sarah; McCollum, Peter T.

    2003-01-01

    With the introduction of clinical governance, the NHS Executive has identified 28-day emergency re-admission rates as a clinical indicator to be used to assess and compare performance between NHS trusts. We undertook a 3-month retrospective audit of patients identified from the trust computer as having been re-admitted as an emergency within 28 days of discharge from the general surgical division. We wanted to examine reasons for re-admission, possible errors in coding and any preventable factors in these patients subsequently re-admitted acutely. PMID:12648333

  9. Corn rootworm-active RNA DvSnf7: Repeat dose oral toxicology assessment in support of human and mammalian safety.

    PubMed

    Petrick, Jay S; Frierdich, Gregory E; Carleton, Stephanie M; Kessenich, Colton R; Silvanovich, Andre; Zhang, Yuanji; Koch, Michael S

    2016-11-01

    Genetically modified (GM) crops have been developed and commercialized that utilize double stranded RNAs (dsRNA) to suppress a target gene(s), producing virus resistance, nutritional and quality traits. MON 87411 is a GM maize variety that leverages dsRNAs to selectively control corn rootworm through production of a 240 base pair (bp) dsRNA fragment targeting for suppression the western corn rootworm (Diabrotica virgifera virgifera) Snf7 gene (DvSnf7). A bioinformatics assessment found that endogenous corn small RNAs matched ∼450 to 2300 unique RNA transcripts that likely code for proteins in rat, mouse, and human, demonstrating safe dsRNA consumption by mammals. Mice were administered DvSnf7 RNA (968 nucleotides, including the 240 bp DvSnf7 dsRNA) at 1, 10, or 100 mg/kg by oral gavage in a 28-day repeat dose toxicity study. No treatment-related effects were observed in body weights, food consumption, clinical observations, clinical chemistry, hematology, gross pathology, or histopathology endpoints. Therefore, the No Observed Adverse Effect Level (NOAEL) for DvSnf7 RNA was 100 mg/kg, the highest dose tested. These results demonstrate that dsRNA for insect control does not produce adverse health effects in mammals at oral doses millions to billions of times higher than anticipated human exposures and therefore poses negligible risk to mammals.

  10. Low-dose gamma irradiation of food protein increases its allergenicity in a chronic oral challenge.

    PubMed

    Vaz, A F M; Souza, M P; Medeiros, P L; Melo, A M M A; Silva-Lucca, R A; Santana, L A; Oliva, M L V; Perez, K R; Cuccovia, I M; Correia, M T S

    2013-01-01

    Few chronic food protein models have described the relationship between allergenicity and the molecular structure of food protein after physical processing. The effect of γ-radiation on the structure of food protein was measured by fluorescence, circular dichroism and microcalorimetry. BALB/c mice were intraperitoneally sensitized and then given non-irradiated and irradiated Con-A by daily gavage for 28days. The tendency to form insoluble amorphous aggregates and partially unfolded species was observed after irradiation. The administration of non-irradiated and irradiated samples at low-dose significantly increased weight loss as well as plasma levels of eotaxin in animals repeatedly exposed to Con-A. Significant lymphocytic infiltrate filling completely the stroma of microvilli and tubular glands was observed in the small intestinal of the group given Con-A irradiated at a low dose. This phenotype was not observed in animals treated with Con-A irradiated at a high dose.

  11. 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...

  12. The Return Home: Transitioning from a 28-Day Remote Outdoor Education Programme

    ERIC Educational Resources Information Center

    McNatty, Shannon

    2016-01-01

    This article addresses the challenges for students transitioning from the remote Te Kahu (pseudonym) outdoor education programme back into their home and school city environments. Students must develop methods of coping and readjust to society to continue the personal growth and process the learning affected through the 28-day programme. The…

  13. Single dose oral dihydrocodeine for acute postoperative pain

    PubMed Central

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

    2014-01-01

    Background This is an updated version of the original Cochrane review published in Issue 2, 2000. Dihydrocodeine is a synthetic opioid analgesic developed in the early 1900s. Its structure and pharmacokinetics are similar to that of codeine and it is used for the treatment of postoperative pain or as an antitussive. It is becoming increasingly important to assess the relative efficacy and harm caused by different treatments. Relative efficacy can be determined when an analgesic is compared with control under similar clinical circumstances. Objectives To quantitatively assess the analgesic efficacy and adverse effects of single-dose dihydrocodeine compared with placebo in randomised trials in moderate to severe postoperative pain. Search methods Published reports were identified from electronic databases (MEDLINE, EMBASE, CENTRAL, the Oxford Pain Relief Database in December 2007, the original search was conducted in October 1999). Additional studies were identified from the reference lists of retrieved reports. Selection criteria Inclusion criteria: full journal publication, clinical trial, random allocation of participants to treatment groups, double blind design, adult participants, baseline pain of moderate to severe intensity, postoperative administration of study drugs, treatment arms which included dihydrocodeine and placebo and either oral or injected (intramuscular or intravenous) administration of study drugs. Data collection and analysis Data collection and analysis: summed pain intensity and pain relief data over four to six hours were extracted and converted into dichotomous information to yield the number of participants obtaining at least 50% pain relief. This was used to calculate relative benefit and number-needed-to-treat-to-benefit (NNT) for one participant to obtain at least 50% pain relief. Single-dose adverse effect data were collected and used to calculate relative risk and number-needed-to-treat-to-harm (NNH). Main results Fifty-two reports

  14. Metabolism of oral ALA combined small dose HPD in the small rat glioma

    NASA Astrophysics Data System (ADS)

    Wang, Yu; Zhu, Jing; Zhang, Hui-Guo; Yan, Ming; Lu, Liping

    2005-07-01

    Objective: Research on the metabolism of oral ALA combined small dose HPD in the small rat glioma to find the optimal oral dose and diagnostic time for the ALA-photodynamic diagnosis and therapy of brain glioma. Methods: Measure the fluorescence spectra of tumor in the treatment groups and control group and of brain tissue of no-tumor group with different doses of ALA taken orally combined injectd small dose HPD and different time before and after take ALA when irradiated by laser. We analyzed the spectrum of fluorescence of every groups with optical multichannel analyzer (OMA) and compared it each other. Result: The maximum ratio (Itumor/Inomal ) of fluorescence was obtained at 60mg/kg of ALA taken orally and 6-8h after ALA taken. Conclusion: The optimal oral dose is 60mg/kg of ALA and the optimal measure time is 6-8 hours after ALA taken.

  15. Integration of Pig-a, micronucleus, chromosome aberration and comet assay endpoints in a 28-day rodent toxicity study with urethane

    PubMed Central

    Stankowski, Leon F.; Aardema, Marilyn J.; Lawlor, Timothy E.; Pant, Kamala; Roy, Shambhu; Xu, Yong; Elbekai, Reem

    2015-01-01

    As part of the international Pig-a validation trials, we examined the induction of Pig-a mutant reticulocytes and red blood cells (RETCD59− and RBCCD59−, respectively) in peripheral blood of male Sprague Dawley® rats treated with urethane (25, 100 and 250mg/kg/day) or saline by oral gavage for 29 days. Additional endpoints integrated into this study were: micronucleated reticulocytes (MN-RET) in peripheral blood; chromosome aberrations (CAb) and DNA damage (%tail intensity via the comet assay) in peripheral blood lymphocytes (PBL); micronucleated polychromatic erythrocytes (MN-PCE) in bone marrow; and DNA damage (comet) in various organs at termination (the 29th dose was added for the comet endpoint at sacrifice). Ethyl methanesulfonate (EMS; 200mg/kg/day on Days 3, 4, 13, 14, 15, 27, 28 and 29) was evaluated as the concurrent positive control (PC). All animals survived to termination and none exhibited overt toxicity, but there were significant differences in body weight and body weight gain in the 250-mg/kg/day urethane group, as compared with the saline control animals. Statistically significant, dose-dependent increases were observed for urethane for: RETCD59− and RBCCD59− (on Days 15 and 29); MN-RET (on Days 4, 15 and 29); and MN-PCE (on Day 29). The comet assay yielded positive results in PBL (Day 15) and liver (Day 29), but negative results for PBL (Days 4 and 29) and brain, kidney and lung (Day 29). No significant increases in PBL CAb were observed at any sample time. Except for PBL CAb (likely due to excessive cytotoxicity), EMS-induced significant increases in all endpoints/tissues. These results compare favorably with earlier in vivo observations and demonstrate the utility and sensitivity of the Pig-a in vivo gene mutation assay, and its ability to be easily integrated, along with other standard genotoxicity endpoints, into 28-day rodent toxicity studies. PMID:25934985

  16. 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.

  17. Downregulation of immediate-early genes linking to suppression of neuronal plasticity in rats after 28-day exposure to glycidol.

    PubMed

    Akane, Hirotoshi; Saito, Fumiyo; Shiraki, Ayako; Takeyoshi, Masahiro; Imatanaka, Nobuya; Itahashi, Megu; Murakami, Tomoaki; Shibutani, Makoto

    2014-09-01

    We previously found that the 28-day oral toxicity study of glycidol at 200mg/kg/day in rats resulted in axonopathy in both the central and peripheral nervous systems and aberrations in the late-stage of hippocampal neurogenesis targeting the process of neurite extension. To capture the neuronal parameters in response to glycidol toxicity, these animals were subjected to region-specific global gene expression profiling in four regions of cerebral and cerebellar architectures, followed by immunohistochemical analysis of selected gene products. Expression changes of genes related to axonogenesis and synaptic transmission were observed in the hippocampal dentate gyrus, cingulate cortex and cerebellar vermis at 200mg/kg showing downregulation in most genes. In the corpus callosum, genes related to growth, survival and functions of glial cells fluctuated their expression. Immunohistochemically, neurons expressing gene products of immediate-early genes, i.e., Arc, Fos and Jun, decreased in their number in the dentate granule cell layer, cingulate cortex and cerebellar vermis. We also applied immunohistochemical analysis in rat offspring after developmental exposure to glycidol through maternal drinking water. The results revealed increases of Arc(+) neurons at 1000ppm and Fos(+) neurons at ≥300ppm in the dentate granule cell layer of offspring only at the adult stage. These results suggest that glycidol suppressed neuronal plasticity in the brain after 28-day exposure to young adult animals, in contrast to the operation of restoration mechanism to increase neuronal plasticity at the adult stage in response to aberrations in neurogenesis after developmental exposure.

  18. Toxicological evaluation of ammonium perfluorobutyrate in rats: Twenty-eight-day and ninety-day oral gavage studies

    EPA Science Inventory

    Sequential 28-day and 90-day oral toxicity studies were performed in male and female rats with ammonium perfluorobutyrate (NH4+PFBA) at doses up to 150 and 30 mg/kg/d, respectively. Ammonium perfluorooctanoate was used as a comparator at a dose of 30 mg/kg/d in the 28-d study. Fe...

  19. Pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of Δ(9) -THC in cannabis users.

    PubMed

    Lile, Joshua A; Kelly, Thomas H; Charnigo, Richard J; Stinchcomb, Audra L; Hays, Lon R

    2013-07-01

    Oral Δ(9) -tetrahydrocannabinol (Δ(9) -THC) has been evaluated as a medication for cannabis dependence, but repeated administration of acute oral doses up to 40 mg has not been effective at reducing drug-taking behavior. Larger doses might be necessary to affect cannabis use. The purpose of the present study was therefore to determine the physiological and behavioural effects of oral Δ(9) -THC at acute doses higher than those tested previously. The pharmacokinetic and pharmacodynamic profile of oral Δ(9) -THC, administered in ascending order in 15 mg increments across separate sessions, up to a maximum of 90 mg, was determined in seven cannabis users. Five subjects received all doses and two experienced untoward side effects at lower doses. Δ(9) -THC produced a constellation of effects consistent with previous clinical studies. Low cannabinoid concentrations were associated with significant effects on drug-sensitive measures, although progressively greater levels did not lead to proportionately larger drug effects. Considerable variability in Cmax and tmax was observed. Doses of oral Δ(9) -THC larger than those tested previously can be administered to individuals with a history of cannabis use, although given the pharmacokinetic variability of oral Δ(9) -THC and individual differences in sensitivity, individualized dose adjustment is needed to avoid side effects and maximize therapeutic response.

  20. Biotransformation and pharmacokinetics of ethylmorphine after a single oral dose.

    PubMed Central

    Aasmundstad, T A; Xu, B Q; Johansson, I; Ripel, A; Bjørneboe, A; Christophersen, A S; Bodd, E; Mørland, J

    1995-01-01

    1. The pharmacokinetics of ethylmorphine after administration of a single dose of the cough mixture Cosylan were investigated in 10 healthy subjects. 2. The median urinary recovery of ethylmorphine and measured metabolites was 77% over 48 h. The median tmax of unchanged ethylmorphine was 45 min, and the terminal elimination t1/2 was 2 h. Ethylmorphine-6-glucuronide was found to be the major metabolite. 3. Two subjects had significantly lower urinary recovery (0.48 h) of morphine and morphine-glucuronides than the remainder. Furthermore, these two had urinary metabolic ratios (MRO) and partial metabolic clearances (CLmO) for O-deethylation of ethylmorphine tentatively classifying them phenotypically as poor metabolisers of the debrisoquine/sparteine type. 4. Genotyping for cytochrome P450 (CYP) 2D6 alleles revealed five homozygote (wt/wt) and five heterozygote subjects. Two subjects phenotypically classified as poor metabolisers were genotypically CYP2D6A/wt and CYP2D6D/wt, respectively. 5. Serum and urine samples taken more than 8 and 24 h after administration of ethyl-morphine respectively, contained morphine and morphine-glucuronides, but no ethylmorphine, ethylmorphine-6-glucuronide or (serum only) norethylmorphine. Norethylmorphine could be detected after hydrolysis of urine samples in all subjects. The urinary recovery of the active metabolites morphine and morphine-6-glucuronide after administration of ethylmorphine varied by a factor of 9 between individuals. 6. The wide variation in recovery of morphine and morphine-glucuronides after oral administration of ethylmorphine could not be explained simply by a difference in CYP2D6 genotype. Constitutional variation in other enzymatic pathways involved in ethylmorphine metabolism is probably crucial. Ratios of morphine to parent drug cannot be used to distinguish the source of morphine after administration of ethylmorphine. Norethylmorphine should be included in urine assays for opiates in forensic toxicology

  1. Doxylamine and diphenhydramine pharmacokinetics in women on low-dose estrogen oral contraceptives.

    PubMed

    Luna, B G; Scavone, J M; Greenblatt, D J

    1989-03-01

    Thirteen women chronically using low-dose estrogen-containing oral contraceptives (50 micrograms or less of ethinyl estradiol or its equivalent for a minimum of 3 months) and 12 age-matched drug-free control women received a single 25 mg oral dose of doxylamine succinate in the fasting state. Ten women taking oral contraceptives and ten controls received a single 50 mg oral dose of diphenhydramine hydrochloride. Multiple plasma samples drawn during 30 hours following the dose of doxylamine, and 12 hours after diphenhydramine dosage, were analyzed by gas chromatography using nitrogen-phosphorus detection. Mean pharmacokinetic variables for doxylamine in control and oral contraceptive groups were: peak plasma concentration, 103 vs 100 ng/ml; time of peak, 2.40 vs 1.87 hours after dosage, elimination half-life, 10.1 vs 10.2 hours; and total clearance, 3.70 vs 3.88 ml/min/kg. Mean pharmacokinetic variables for diphenhydramine in control and oral contraceptive groups were: peak plasma concentration, 63.7 vs 73.8 ng/ml; time of peak, 2.7 vs 2.2 hours after dosage; elimination half-life, 6.0 vs 5.1 hours; and total clearance, 21.8 vs 25.5 ml/min/kg. None of these differences were statistically significant. Thus, low-dose estrogen-containing oral contraceptives do not significantly influence the pharmacokinetics of the antihistamines doxylamine or diphenhydramine.

  2. 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.

  3. Comparative metabolism studies of hexabromocyclododecane (HBCD) diastereomers in male rats following a single oral dose

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Male Sprague-Dawley rats were dosed orally with 3 mg/kg of one of three hexabromocyclododecane (HBCD) diastereomers. Each diastereomer was well absorbed (73-83%), and distributed preferentially to lipophilic tissues. Feces were the major route of excretion; cumulatively 42% of dose for alpha-HBCD,...

  4. Effect of beam arrangement on oral cavity dose in external beam radiotherapy of nasopharyngeal carcinoma

    SciTech Connect

    Wu, Vincent W.C.; Yang Zhining; Zhang Wuzhe; Wu Lili; Lin Zhixiong

    2012-07-01

    This study compared the oral cavity dose between the routine 7-beam intensity-modulated radiotherapy (IMRT) beam arrangement and 2 other 7-beam IMRT with the conventional radiotherapy beam arrangements in the treatment of nasopharyngeal carcinoma (NPC). Ten NPC patients treated by the 7-beam routine IMRT technique (IMRT-7R) between April 2009 and June 2009 were recruited. Using the same computed tomography data, target information, and dose constraints for all the contoured structures, 2 IMRT plans with alternative beam arrangements (IMRT-7M and IMRT-7P) by avoiding the anterior facial beam and 1 conventional radiotherapy plan (CONRT) were computed using the Pinnacle treatment planning system. Dose-volume histograms were generated for the planning target volumes (PTVs) and oral cavity from which the dose parameters and the conformity index of the PTV were recorded for dosimetric comparisons among the plans with different beam arrangements. The dose distributions to the PTVs were similar among the 3 IMRT beam arrangements, whereas the differences were significant between IMRT-7R and CONRT plans. For the oral cavity dose, the 3 IMRT beam arrangements did not show significant difference. Compared with IMRT-7R, CONRT plan showed a significantly lower mean dose, V30 and V-40, whereas the V-60 was significantly higher. The 2 suggested alternative beam arrangements did not significantly reduce the oral cavity dose. The impact of varying the beam angles in IMRT of NPC did not give noticeable effect on the target and oral cavity. Compared with IMRT, the 2-D conventional radiotherapy irradiated a greater high-dose volume in the oral cavity.

  5. Effect of beam arrangement on oral cavity dose in external beam radiotherapy of nasopharyngeal carcinoma.

    PubMed

    Wu, Vincent W C; Yang, Zhi-Ning; Zhang, Wu-Zhe; Wu, Li-li; Lin, Zhi-xiong

    2012-01-01

    This study compared the oral cavity dose between the routine 7-beam intensity-modulated radiotherapy (IMRT) beam arrangement and 2 other 7-beam IMRT with the conventional radiotherapy beam arrangements in the treatment of nasopharyngeal carcinoma (NPC). Ten NPC patients treated by the 7-beam routine IMRT technique (IMRT-7R) between April 2009 and June 2009 were recruited. Using the same computed tomography data, target information, and dose constraints for all the contoured structures, 2 IMRT plans with alternative beam arrangements (IMRT-7M and IMRT-7P) by avoiding the anterior facial beam and 1 conventional radiotherapy plan (CONRT) were computed using the Pinnacle treatment planning system. Dose-volume histograms were generated for the planning target volumes (PTVs) and oral cavity from which the dose parameters and the conformity index of the PTV were recorded for dosimetric comparisons among the plans with different beam arrangements. The dose distributions to the PTVs were similar among the 3 IMRT beam arrangements, whereas the differences were significant between IMRT-7R and CONRT plans. For the oral cavity dose, the 3 IMRT beam arrangements did not show significant difference. Compared with IMRT-7R, CONRT plan showed a significantly lower mean dose, V30 and V-40, whereas the V-60 was significantly higher. The 2 suggested alternative beam arrangements did not significantly reduce the oral cavity dose. The impact of varying the beam angles in IMRT of NPC did not give noticeable effect on the target and oral cavity. Compared with IMRT, the 2-D conventional radiotherapy irradiated a greater high-dose volume in the oral cavity.

  6. Adverse effects of oral corticosteroids in relation to dose in patients with lung disease

    PubMed Central

    Walsh, L; Wong, C; Oborne, J; Cooper, S; Lewis, S; Pringle, M; Hubbard, R; Tattersfield, A

    2001-01-01

    BACKGROUND—The adverse effects of oral corticosteroids are widely recognised but there are few quantitative data on which to base advice to patients. In a two part cross sectional study we compared adverse effects in patients with lung disease taking oral corticosteroids and control subjects and related the adverse effects to corticosteroid dose in the patient group.
METHODS—Data on oral corticosteroid use, lifestyle, fractures, and other possible adverse effects were collected by questionnaire and compared between a community based cohort of patients taking continuous or frequent intermittent oral corticosteroids for asthma, chronic obstructive pulmonary disease, or alveolitis and age and sex matched control subjects. Dose related effects were explored in the corticosteroid group using cumulative dose quartiles and multiple logistic regression.
RESULTS—A total of 367 patients (⩾50 years, 48% female) and 734 control subjects completed the questionnaire. The cumulative incidence of fractures since the time of diagnosis was 23% for patients taking oral corticosteroids and 15% in the control group (odds ratio (OR) 1.8; 95% confidence interval (CI) 1.3 to 2.6). Patients were more likely to have had a fracture of the vertebrae (OR 10; 95% CI 2.9 to 34), hip (OR 6; 95% CI 1.2 to 30), and ribs or sternum (OR 3.2, 95% CI 1.6 to 6.6) than control subjects. They also reported a significant increase in cataracts, use of antacids, muscle weakness, back pain, bruising, oral candidiasis, and having fewer teeth. The effects of oral corticosteroids were dose related: the odds ratio for patients in the highest compared with the lowest cumulative dose quartile (median prednisolone dose 61 g versus 5 g) ranged from 2 for all fractures to 9 for vertebral fractures and bruising.
CONCLUSIONS—By quantifying the morbidity associated with the use of oral corticosteroids, this study should help to rationalise their long term use.

 PMID:11254818

  7. Consuming a multi-ingredient thermogenic supplement for 28 days is apparently safe in healthy adults

    PubMed Central

    Vogel, Roxanne M.; Joy, Jordan M.; Falcone, Paul H.; Mosman, Matt M.; Kim, Michael P.; Moon, Jordan R.

    2015-01-01

    Background Thermogenic (TRM) supplements are often used by people seeking to decrease body weight. Many TRM supplements are formulated with multiple ingredients purported to increase energy expenditure and maximize fat loss. However, in the past some TRM ingredients have been deemed unsafe and removed from the market. Therefore, it is important to verify the safety of multi-ingredient TRM supplements with chronic consumption. Objective To assess the safety of daily consumption of a multi-ingredient TRM supplement over a 28-day period in healthy adults. Design Twenty-three recreationally active adults (11M, 12F; 27.1±5.4 years, 171.6±9.6 cm, 76.8±16.1 kg, 26±5 BMI) were randomly assigned either to consume a multi-ingredient TRM supplement (SUP; n=9) or remain unsupplemented (CRL; n=14) for 28 days. Participants maintained their habitual dietary and exercise routines for the duration of the study. Fasting blood samples, resting blood pressure, and heart rate were taken before and after the supplementation period. Samples were analyzed for complete blood counts, comprehensive metabolic, and lipid panels. Results Significant (p<0.05) group by time interactions were present for diastolic BP, creatinine, estimated glomerular filtration rate (eGFR), chloride, CO2, globulin, albumin:globulin (A/G), and high-density lipoprotein (HDL). Dependent t-tests conducted on significant variables revealed significant (p<0.05) within-group differences in SUP for diastolic BP (+6.2±5.3 mmHG), creatinine (+0.09±0.05 mg/dL), eGFR (−11.2±5.8 mL/min/1.73), globulin (−0.29±0.24 g/dL), A/G (+0.27±0.23), and HDL (−5.0±5.5 mg/dL), and in CRL for CO2 (−1.9±1.5 mmol/L) between time points. Each variable remained within the accepted physiological range. Conclusion Results of the present study support the clinical safety of a multi-ingredient TRM containing caffeine, green tea extract, and cayenne powder. Although there were statistically significant (p<0.05) intragroup

  8. A phase I dose-escalation study of TAK-733, an investigational oral MEK inhibitor, in patients with advanced solid tumors.

    PubMed

    Adjei, Alex A; LoRusso, Patricia; Ribas, Antoni; Sosman, Jeffrey A; Pavlick, Anna; Dy, Grace K; Zhou, Xiaofei; Gangolli, Esha; Kneissl, Michelle; Faucette, Stephanie; Neuwirth, Rachel; Bózon, Viviana

    2017-02-01

    Purpose TAK-733, an investigational, selective, allosteric MEK1/2 inhibitor, has demonstrated antitumor effects against multiple cancer cell lines and xenograft models. This first-in-human study investigated TAK-733 in patients with solid tumors. Methods Patients received oral TAK-733 once daily on days 1-21 in 28-day treatment cycles. Adverse events (AEs) were graded using the Common Terminology Criteria for AEs version 3.0. Response was assessed using RECIST v1.1. Blood samples for TAK-733 pharmacokinetics and pharmacodynamics (inhibition of ERK phosphorylation) were collected during cycle 1. Results Fifty-one patients received TAK-733 0.2-22 mg. Primary diagnoses included uveal melanoma (24 %), colon cancer (22 %), and cutaneous melanoma (10 %). Four patients had dose-limiting toxicities of dermatitis acneiform, plus fatigue and pustular rash in one patient, and stomatitis in one patient. The maximum tolerated dose was 16 mg. Common drug-related AEs included dermatitis acneiform (51 %), diarrhea (29 %), and increased blood creatine phosphokinase (20 %); grade ≥ 3 AEs were reported in 27 (53 %) patients. Median Tmax was 3 h; systemic exposure increased less than dose-proportionally over the dose range 0.2-22 mg. On day 21 maximum inhibition of ERK phosphorylation in peripheral blood mononuclear cells of 46-97 % was seen in patients receiving TAK-733 ≥ 8.4 mg. Among 41 response-evaluable patients, 2 (5 %) patients with cutaneous melanoma (one with BRAF L597R mutant melanoma) had partial responses. Conclusions TAK-733 had a generally manageable toxicity profile up to the maximum tolerated dose, and showed the anticipated pharmacodynamic effect of sustained inhibition of ERK phosphorylation. Limited antitumor activity was demonstrated. Further investigation is not currently planned.

  9. A microfluidic culture model of the human reproductive tract and 28-day menstrual cycle

    PubMed Central

    Xiao, Shuo; Coppeta, Jonathan R.; Rogers, Hunter B.; Isenberg, Brett C.; Zhu, Jie; Olalekan, Susan A.; McKinnon, Kelly E.; Dokic, Danijela; Rashedi, Alexandra S.; Haisenleder, Daniel J.; Malpani, Saurabh S.; Arnold-Murray, Chanel A.; Chen, Kuanwei; Jiang, Mingyang; Bai, Lu; Nguyen, Catherine T.; Zhang, Jiyang; Laronda, Monica M.; Hope, Thomas J.; Maniar, Kruti P.; Pavone, Mary Ellen; Avram, Michael J.; Sefton, Elizabeth C.; Getsios, Spiro; Burdette, Joanna E.; Kim, J. Julie; Borenstein, Jeffrey T.; Woodruff, Teresa K.

    2017-01-01

    The endocrine system dynamically controls tissue differentiation and homeostasis, but has not been studied using dynamic tissue culture paradigms. Here we show that a microfluidic system supports murine ovarian follicles to produce the human 28-day menstrual cycle hormone profile, which controls human female reproductive tract and peripheral tissue dynamics in single, dual and multiple unit microfluidic platforms (Solo-MFP, Duet-MFP and Quintet-MPF, respectively). These systems simulate the in vivo female reproductive tract and the endocrine loops between organ modules for the ovary, fallopian tube, uterus, cervix and liver, with a sustained circulating flow between all tissues. The reproductive tract tissues and peripheral organs integrated into a microfluidic platform, termed EVATAR, represents a powerful new in vitro tool that allows organ–organ integration of hormonal signalling as a phenocopy of menstrual cycle and pregnancy-like endocrine loops and has great potential to be used in drug discovery and toxicology studies. PMID:28350383

  10. 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.

  11. Voclosporin food effect and single oral ascending dose pharmacokinetic and pharmacodynamic studies in healthy human subjects.

    PubMed

    Mayo, Patrick R; Huizinga, Robert B; Ling, Spencer Y; Freitag, Derrick G; Aspeslet, Launa J; Foster, Robert T

    2013-08-01

    Voclosporin (VCS) is a novel calcineurin (CN) inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. These studies evaluated the single ascending dose pharmacokinetics (PK) and pharmacodynamics (PD, CN activity) of VCS and the effect of food. VCS was administered orally in single doses of 0.25 through 4.5 mg/kg in 62 subjects in the single ascending dose study and as a single oral 1.5 mg/kg dose to 18 subjects after fasting, consumption of a low-fat and high-fat meal. Non-compartmental PK, PD, and PKPD correlation were evaluated. Following single oral doses, systemic exposure increased in a linear manner and demonstrated 1:1 dose-proportional, first-order linear PK above 1.5 mg/kg. VCS inhibited CN activity in a dose-related fashion with maximal inhibition peaking at 3.0 mg/kg. PKPD correlation indicated an EC50 of 78.3 ± 6.8 ng/mL. Administration of VCS with a low-fat and high-fat meal decreased C(max) by 29% and 53%, respectively, and AUC(inf) by 15% and 25%, respectively. Following ascending single doses of VCS, exposure increased in a linear fashion. A food effect on exposure was demonstrated, with a more pronounced effect following a high-fat meal. VCS concentrations were also found to correlate with CN activity.

  12. Behavioral toxicity and physiological changes from repeated exposure to fluorene administered orally or intraperitoneally to adult male Wistar rats: A dose-response study.

    PubMed

    Peiffer, Julie; Grova, Nathalie; Hidalgo, Sophie; Salquèbre, Guillaume; Rychen, Guido; Bisson, Jean-François; Appenzeller, Brice M R; Schroeder, Henri

    2016-03-01

    Fluorene is one of the most abundant polycyclic aromatic hydrocarbons (PAHs) in the environment by reason of its high volatility. Demonstrated to be a neurotoxicant through inhalation, it was also identified as a contributive PAH to food contamination. Since no data are available on its oral neurotoxicity, the purpose of the present study was to assess the behavioral and physiological toxicity of repeated oral administration of fluorene to adult Wistar male rats. Animals were daily treated with fluorene at 1, 10 or 100mg/kg/day for 28 consecutive days. Administration was intraperitoneal (i.p.) or oral (p.o.) to evaluate the influence of the route of exposure on fluorene toxicity. Following this period of treatment, animals in both groups were subjected to similar cognitive evaluations, namely anxiety (elevated-plus maze), locomotor activity (open-field) and learning and memory abilities (eight-arm maze and avoidance test of an aversive light stimulus), as well as physiological measurements. The behavioral testing occurred from the 28th to the 60th day of the experiment during which fluorene treatment continued uninterrupted. At the end of this period, the concentration levels of fluorene and of three of its monohydroxylated metabolites in blood and brain were determined using a GC-MS/MS method. The results demonstrated a reduction in rat anxiety level at the lowest doses administered (1 and 10mg/kg/day) regardless of the treatment route, whereas locomotor activity and learning abilities remained unchanged. Moreover, a less significant weight gain was noticed in animals i.p.- and p.o.-treated with 100mg/kg/day during the 28-day period of treatment, which, upon comparison with the three other groups, induced a body weight gap that was maintained throughout the experiment. Significant increases in relative liver weight were also observed in a dose-dependent manner in orally treated rats and only in animal treated i.p. with 100mg/kg/day. According to the dose, higher

  13. 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

  14. Pharmacokinetics of Amoxicillin: Dose Dependence After Intravenous, Oral, and Intramuscular Administration

    PubMed Central

    Spyker, Daniel A.; Rugloski, Raymond J.; Vann, Robert L.; O'Brien, William M.

    1977-01-01

    Amoxicillin was studied in normal subjects after intravenous, oral, and intramuscular administration of 250-, 500-, and 1,000-mg doses. Serum drug levels were analyzed using a two-compartment open model, as well as area under the curve (AUC) and urinary recovery. The variations of these pharmacokinetic parameters were then examined using the three-way analysis of variance and linear regression equations. These results confirmed nearly complete oral absorption: AUC was 93% of intravenous absorption, and urinary recovery was 86%. The intramuscular administration of amoxicillin results in complete and reliable absorption with peak drug levels, AUCs, and urinary recovery equivalent to oral dosage. The absorption of lyophilized amoxicillin after intramuscular injection resulted in an AUC that was 92% of intravenous absorption and urinary recovery of 91%. The peak serum levels, time to peak, and other pharmacokinetic parameters for intramuscular injection were nearly identical to those for oral administration. Kinetics of both intramuscular and oral administration exhibited dose-dependent absorption (absorption rate constant, 1.3/h for 250 mg and 0.7/h for 1,000 mg). This resulted in relatively later and lower peak serum levels for increasing dose. Total absorption, however, showed no dose dependence, as indicated by urinary recovery and AUC, which changed by less than 10%. PMID:836010

  15. Oral microflora and selection of resistance after a single dose of amoxicillin.

    PubMed

    Khalil, D; Hultin, M; Rashid, M U; Lund, B

    2016-11-01

    The study aimed to determine the effects of a single-dose antibiotic prophylaxis on normal oral microflora. A single dose of 2 g amoxicillin was given to 29 healthy volunteers. Saliva was collected before antibiotic administration (day 1), and again on days 2, 5, 10, 17 and 24 and subjected to culturing and antibiotic sensitivity analysis. Twenty-one per cent (6/29) of the individuals carried penicillin-V- and amoxicillin-resistant viridans streptococci before antibiotic administration. After a single dose of amoxicillin there was a significant reduction in Streptococcus salivarius on days 2 and 5, a significant reduction in other viridans streptococci on day 2 and the proportion of viridans streptococci with reduced susceptibility to amoxicillin was significantly increased on days 2 and 5. A single dose of amoxicillin can cause an ecological disturbance and induce selection of resistant strains in the oral microflora.

  16. Identification of hydroxylated metabolites of hexabromocyclododecane in wildlife and 28-days exposed Wistar rats.

    PubMed

    Brandsma, Sicco H; Van der Ven, Leo T M; De Boer, Jacob; Leonards, Pim E G

    2009-08-01

    We studied the presence of hydroxylated metabolites of hexabromocyclododecane (HBCD) in three wildlife species (tern egg, seal, and flounder) and in Wistar rats exposed to 30 and 100 mg HBCD/kg bw/day for 28 days. A nondestructive extraction, fractionation, and cleanup method was developed to separate the hydroxylated HBCD metabolites from the biotic sample matrix. Four different groups of hydroxylated HBCD metabolites were identified in rat adipose, liver, lung, and muscle tissues by liquid and gas chromatography (LC and GC) combined with mass spectrometry (MS): monohydroxy metabolites of HBCD, pentabromocyclododecene (PBCDe), tetrabromocyclododecene (TBCDe), and dihydroxy-HBCD. Dihydroxy-PBCDe was identified by GC-MS but could not be confirmed by LCMS. Debromination of HBCD to PBCDe was another metabolic pathway observed. In tern eggs from the Western Scheldt the monohydroxy-HBCD was found and in the blubber of harbor seal (Wadden Sea) the monohydroxy metabolites of HBCD and PBCDe were found. No hydroxylated metabolites were detected in the tissue of flounder (Wadden Sea). To our knowledge, this is the first study to identify different hydroxylated metabolite groups of HBCD in rat and wildlife samples.

  17. Sex hormone-binding globulin and antithrombin III activity in women with oral ultra-low-dose estradiol.

    PubMed

    Matsui, Sumika; Yasui, Toshiyuki; Kasai, Kana; Keyama, Kaoru; Yoshida, Kanako; Kato, Takeshi; Uemura, Hirokazu; Kuwahara, Akira; Matsuzaki, Toshiya; Irahara, Minoru

    2017-03-20

    Oral oestrogen increases the risk of venous thromboembolism (VTE) and increases production of sex hormone-binding globulin (SHBG) in a dose-dependent manner. SHBG has been suggested to be involved in venous thromboembolism. We examined the effects of oral ultra-low-dose oestradiol on circulating levels of SHBG and coagulation parameters, and we compared the effects to those of transdermal oestradiol. Twenty women received oral oestradiol (500 μg) every day (oral ultra-low-dose group) and 20 women received a transdermal patch (50 μg) as a transdermal group. In addition, the women received dydrogesterone continuously (5 mg) except for women who underwent hysterectomy. Circulating SHBG, antithrombin III (ATIII) activity, d-dimer, thrombin-antithrombin complex and plasmin-α2 plasmin inhibitor complex were measured before and 3 months after the start of treatment. SHBG was significantly increased at 3 months in the oral ultra-low-dose group, but not in the transdermal group. However, percent changes in SHBG were not significantly different between the two groups. In both groups, ATIII was significantly decreased at 3 months. In conclusion, even ultra-low-dose oestradiol orally increases circulating SHBG level. However, the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. Impact statement Oral oestrogen replacement therapy increases production of SHBG which may be related to increase in VTE risk. However, the effect of oral ultra-low-dose oestradiol on SHBG has not been clarified. Even ultra-low-dose oestradiol orally increases circulating SHBG levels, but the magnitude of change in SHBG caused by oral ultra-low-dose oestradiol is small and is comparable to that caused by transdermal oestradiol. VTE risk in women receiving oral ultra-low-dose oestradiol may be comparable to that in women receiving transdermal oestradiol.

  18. Another promising treatment option for neuroblastoma-associated opsoclonus-myoclonus syndrome by oral high-dose dexamethasone pulse: lymphocyte markers as disease activity.

    PubMed

    Oguma, Makiko; Morimoto, Akira; Takada, Akiko; Kashii, Yoshifumi; Fukuda, Tokiko; Mori, Masato; Yamagata, Takanori; Sugie, Hideo; Momoi, Mariko Y

    2012-03-01

    A one-year-old boy with neuroblastoma (NBoma)-associated opsoclonus-myoclonus syndrome (OMS) was treated by oral high-dose dexamethasone (DEX) pulses (20 mg/m(2)/day of DEX for three consecutive days) every 28 days for 6 months after resection of the tumor. All OMS symptoms improved after the first course of DEX pulse therapy and disappeared after the last course. No adverse effects were observed. Minor deterioration of his developmental quotient was noted 33 months after the onset of the disease. NBoma remission has been maintained since treatment. Before DEX pulse therapy, frequency of T lymphocyte, in particular CD4-positive cell decreased markedly resulted in low CD4/8 ratio in the peripheral blood (PB). The frequency of B lymphocyte increased, especially in cerebrospinal fluid. These aberrant values in PB were reversed by DEX pulse therapy and correlated well with the neurological symptoms. A prospective study that assesses the efficacy of this promising and inexpensive treatment for OMS is warranted.

  19. Low-dose oral contraceptives: progestin potency, androgenicity, and atherogenic potential.

    PubMed

    Ellis, J

    1986-01-01

    The effects of oral contraceptives and estrogen replacement drugs on blood lipids that affect cardiovascular disease (atherogenic effects) are reviewed by comparing their androgenicity and progestin potency. Although early oral contraceptives with high doses of estrogen were indicted for increasing risk of thromboembolic disorders and heart attacks, today's pills low in estrogen still bear the same risk for cardiovascular events. A brief explanation of the lipoproteins is presented, emphasizing the importance of High Density Lipoprotein (HDL) in protecting against heart disease and stroke. Menstruating women have naturally high HDL. The estrogen in oral contraceptives and postmenopausal estrogen replacements increases HDL as much as 30%, while decreasing LDL, the component carrying most of the cholesterol. It seems that the progestin in oral contraceptives will lower HDL, and studies show that this action is related to androgenicity and dose of the progestin. Progestins such as levonorgestrel and norgestrel are more androgenic, while norethynodrel, ethynodiol diacetate and norethindrone are less so. When used in combination with estrogens, progestins are less androgenic, but when used alone, the androgenic and atherogenic effects dominate. The lower the estrogen dose in the combination, say around 20-35 mcg ethinyl estradiol, the more atherogenic the progestin. These actions are confirmed theoretically by measurements of sex hormone binding globulin, a blood protein that reflects estrogen activity, as well as by epidemiologic studies in Sweden and Great Britain, where rates of heart attack and stroke in pill users remain as high as they were when pills contained high doses of estrogen.

  20. Micro-thermography in millimeter-scale animals by using orally-dosed fluorescent nanoparticle thermosensors.

    PubMed

    Arai, Satoshi; Ferdinandus; Takeoka, Shinji; Ishiwata, Shin'ichi; Sato, Hirotaka; Suzuki, Madoka

    2015-11-21

    We propose an instant micro-thermography method using a fluorescent-nanoparticle thermosensor capable of reporting temperature as the fluorescence intensity ratio of the temperature-sensitive dye to the reference. We demonstrate "temperature mapping" inside a fruit fly larva that was orally dosed with nanoparticle thermosensors.

  1. Proposed Oral Reference Dose (RfD) for Barium and Compounds (Final Report, 2004)

    EPA Science Inventory

    This document is the final report from the 2004 external peer review of the Proposed Oral Reference Dose (RfD) for Barium and Compounds, prepared by the U.S. Environmental Protection Agency (EPA), National Center for Environmental Assessment (NCEA), for the Integrated Risk...

  2. Neutral red uptake cytotoxicity tests for estimating starting doses for acute oral toxicity tests.

    PubMed

    Stokes, William S; Casati, Silvia; Strickland, Judy; Paris, Michael

    2008-05-01

    In vitro cytotoxicity assays can be used as alternative toxicity tests to reduce the total number of animals needed for acute oral toxicity tests. This unit describes two methods for determining the in vitro cytotoxicity of test substances using neutral red uptake (NRU) and using the in vitro data to determine starting doses for in vivo acute oral systemic toxicity tests, e.g., the up-and-down procedure or the acute toxic class method. The use of the NRU methods to determine starting doses for acute oral toxicity tests may reduce the number of animals required, and for relatively toxic substances, this approach may also reduce the number of animals that die or require humane euthanasia due to severe toxicity. An interlaboratory validation study has demonstrated that the methods are useful and reproducible for these purposes. Two standardized protocols provide details for performing NRU tests with rodent and human cells.

  3. Comparative pharmacokinetics of single doses of doxylamine succinate following intranasal, oral and intravenous administration in rats.

    PubMed

    Pelser, Andries; Müller, Douw G; du Plessis, Jeanetta; du Preez, Jan L; Goosen, Colleen

    2002-09-01

    The intranasal route of administration provides a potential useful way of administering a range of systemic drugs. In order to assess the feasibility of this approach for the treatment of nausea and vomiting, doxylamine succinate was studied in rats for the pharmacokinetics (AUC, C(max), t(max)) following intranasal, oral and intravenous administrations. Subjects (six male Sprague-Dawley rats per time interval for each route of administration) received 2-mg doses of doxylamine succinate orally and I-mg doses intranasally and intravenously, respectively. The various formulations were formulated in isotonic saline (0.9% w/v) at 25 +/- 1 degrees C. Doxylamine succinate concentrations in plasma were determined with a high-performance liquid chromatographic assay and a liquid-liquid extraction procedure. Intranasal and oral bioavailabilities were determined from AUC values relative to those after intravenous dosing. Intranasal bioavailability was greater than that of oral doxylamine succinate (70.8 vs 24.7%). The intranasal and oral routes of administration differed significantly from the intravenous route of administration. Peak plasma concentration (C(max)) was 887.6 ng/ml (S.D. 74.4), 281.4 ng/ml (S.D. 24.6) and 1296.4 ng/ml (S.D. 388.9) for the intranasal, oral and intravenous routes, respectively. The time to achieve C(max) for the intranasal route (t(max)=0.5 h) was faster than for the oral route (t(max)=1.5 h), but no statistically significant differences between the C(max) values were found using 95% confidence intervals. The results of this study show that doxylamine succinate is rapidly and effectively absorbed from the nasal mucosa.

  4. Toxicological evaluation of isopropylparaben and isobutylparaben mixture in Sprague-Dawley rats following 28 days of dermal exposure.

    PubMed

    Kim, Min Ji; Kwack, Seung Jun; Lim, Seong Kwang; Kim, Yeon Joo; Roh, Tae Hyun; Choi, Seul Min; Kim, Hyung Sik; Lee, Byung Mu

    2015-11-01

    The alkyl esters of p-hydroxybenzoic acid (Parabens) have been of concern due to their probable endocrine disrupting property especially in baby consumer products. The safety of parabens for use as a preservative in cosmetics has come into controversy, and thus consumer demand for paraben-free products is ever increasing. Thus, more comprehensive studies are needed to conclusively determine the safety of the multiple prolonged exposure to parabens with cosmetic ingredients. This study was conducted to investigate the potential repeated 28 days dermal toxicity (50, 100, 300, or 600 mg/kg bw/day) of isopropylparaben (IPP), isobutylparaben (IBP), or the mixture of IPP and IBP in rats. There were no significant changes in body and organ weights in any group. However, histopathological examinations showed that weak or moderate skin damages were observed in female rats by macroscopic and microscopic evaluations. In female rats, no observed adverse effect levels (NOAELs) of IPP with no skin lesion and IBP for skin hyperkeratosis, were estimated to be 600 mg/kg bw/day, and 50 mg/kg bw/day, respectively. With regard skin hyperkeratosis, the lowest observed adverse effect level (LOAEL) of the mixture of IPP and IBP was estimated to be 50 mg/kg bw/day. Analysis of six serum hormones (estrogen, testosterone, insulin, T3, TSH, or FSH) in animals showed that only FSH was dose-dependently decreased in the mixture groups of 100 mg/kg bw/day or higher. These data suggest that the mixture of IPP and IBP showed a synergistic dermal toxicity in rats and should be considered for future use in consumer products.

  5. High-dose-rate and pulsed-dose-rate brachytherapy for oral cavity cancer and oropharynx cancer

    PubMed Central

    2010-01-01

    Interstitial brachytherapy represents the treatment of choice for small tumours, regionally localized in the oral cavity and the oropharynx. In the technical setting, continuous low-dose-rate (LDR) brachytherapy represented for many years the gold standard for administering radiation in head and neck brachytherapy. Large series of head and neck cancer patients treated with LDR brachytherapy have been reported, constituting an invaluable source of clinical data and the gold standard to compare results of new techniques. Nowadays, LDR brachytherapy competes with fractionated HDR and hyperfractionated PDR. In the paper an overview of the different time-dose-fraction alternatives to LDR brachytherapy in head and neck cancer is presented, as well as the radiobiological basis of different dose-rate schedules, the linear-quadratic model, interconversion of fractionation schedules and the repair half-times for early- and late-responding tissues. In subsequent sections essentials of switching from LDR to HDR and from LDR to PDR are discussed. Selected clinical results using HDR and PDR brachytherapy in oral cavity and oropharynx cancer are presented. PMID:28050175

  6. Single-dose bioavailability of oral and intramuscular thiocolchicoside in healthy volunteers.

    PubMed

    Sandouk, P; Bouvier d'Yvoire, M; Chretien, P; Tillement, J P; Scherrmann, J M

    1994-01-01

    A single dose of 8 mg of thiocolchicoside was administered to 12 healthy volunteers according to a Latin square design, either as tablets (reference), oral solution, or intramuscular injection. Serum thiocolchicoside concentrations showed an absorption phase followed by a biexponential decay with a terminal half-life (t1/2 beta) of approximately 5 h, similar for the three formulations. The relative bioavailability of both oral formulations was approximately 25%, compared to the intramuscular formulation. There was a trend for the oral solution to have a slightly larger AUC and Cmax, as well as a slightly shorter Tmax, than the tablet formulation. However, the comparison of the two oral forms did not show statistically significant differences in the pharmacokinetic parameters Cmax, Tmax, and AUC, suggesting that the Coltramyl tablets have an adequate in vivo dissolution profile.

  7. Comparative oral dose toxicokinetics of selenium compounds commonly found in selenium accumulator plants.

    PubMed

    Davis, T Z; Stegelmeier, B L; Welch, K D; Pfister, J A; Panter, K E; Hall, J O

    2013-09-01

    Consumption of Se accumulator plants by livestock can result in Se intoxication. Recent research indicates that the Se forms most common in Se accumulator plants are selenate and Se-methylselenocysteine (MeSeCys). In this study the absorption, distribution, and elimination kinetics of Se in serum and whole blood of lambs dosed with a single oral dose of (1, 2, 3, or 4 mg Se/kg BW) of sodium selenate or MeSeCys were determined. The Se concentrations in serum and whole blood for both chemical forms of Se followed simple dose-dependent relationships. Se-methylselenocysteine was absorbed more quickly and to a greater extent in whole blood than sodium selenate, as observed by a greater peak Se concentration (Cmax; P < 0.0001), and faster time to peak concentration (Tmax; P < 0.0001) and rate of absorption (P < 0.0001). The rate of absorption and Tmax were also faster (P < 0.0001) in serum of lambs dosed with MeSeCys compared with those dosed sodium selenate at equimolar doses; however, Cmax in serum was greater (P < 0.0001) in lambs dosed with sodium selenate compared with those dosed MeSeCys at equimolar doses. The MeSeCys was absorbed 4 to 5 times faster into serum and 9 to 14 times faster into whole blood at equimolar Se doses. There were dose-dependent increases in the area under the curve (AUC) for Se in serum and whole blood of lambs dosed with both sodium selenate and MeSeCys. In whole blood the MeSeCys was approximately twice as bioavailable as sodium selenate at equimolar doses as observed by the AUC, whereas in serum there were no differences (P > 0.05) in AUC at the same doses. At 168 h postdosing the Se concentration in whole blood remained much greater (P < 0.0001) in lambs dosed with MeSeCys as compared with lambs dosed with sodium selenate; however, the serum Se concentrations were not different between treatments at the same time point. The results presented in this study demonstrate that there are differences between the kinetics of different

  8. Human pharmacokinetics and toxicity of high-dose metronidazole administered orally and intravenously

    SciTech Connect

    Urtasun, R.C.; Rabin, H.R.; Partington, J.

    1983-01-01

    This study is part of a clinical program to assess the use of nitroimidazoles as radiosensitizers of hypoxic tumor cells. A total of 37 patients with malignant tumors have been entered into the study to receive oral high-dose metronidazole in conjunction with radiation. Twenty-eight patients with malignant brain tumors received 6 gm/m2 three times a week for 3 weeks (a mean total dose of 5.3 gm/m2). Maximum mean plasma drug concentration of 1 mM was obtained at 4 hours after drug ingestion with a mean half-life of 13 hours. Tissue and cerebrospinal fluid levels of 80% to 90% of the plasma levels were obtained at 4 to 6 hours. A linear relationship between increased drug dose and increased plasma concentration was observed at doses of 2.5 gm/m2 up to 6 gm/m2. Acute gastrointestinal and central nervous system toxicity was the dose-limiting factor (50% and 25%, respectively, at total doses of 5.3 gm/m2). Pharmacokinetic studies of intravenous metronidazole were performed in eight consenting patients. Single doses of 0.5, 1, 1.5, and 2 gm were administered intravenously by zero-order infusion pump. Seven of the eight patients received a second identical dose orally 1 week later and the results were compared. Open two-compartment kinetic characteristics of metronidazole were computed from simultaneous plasma infusion and urine excretion rate equations, by use of a nonlinear least-squares regression analysis program (NONLIN). The mean (+/- SD) for alpha half-life was 1.2 +/- 1.3 hours, and that for the beta half-life was 9.8 +/- 5.9 hours. The absolute oral bioavailability was estimated to approximate 100%.

  9. Artemisinin pharmacokinetics in healthy adults after 250, 500 and 1000 mg single oral doses.

    PubMed

    Ashton, M; Gordi, T; Trinh, N H; Nguyen, V H; Nguyen, D S; Nguyen, T N; Dinh, X H; Johansson, M; Le, D C

    1998-05-01

    Eight healthy male, Vietnamese subjects were administered 1 x 250, 2 x 250, and 4 x 250 mg artemisinin capsules in a cross-over design with randomized sequence with a 7-day washout period between administrations. The inter-individual variability in artemisinin pharmacokinetics was large with parameter coefficient of variation (CV) typically between 50-70%. The parameter with the smallest variability was the elimination half-life (CV approximately equal to 30-40%). Analysis of variance indicated also a large intra-subject variability. (CV, or = 24%) for the dose-normalized area under the plasma concentration-time curve (AUC/dose). The pharmacokinetic results suggested artemisinin to be subject to high pre-systemic extraction. Artemisinin half-life could not predict the extent of in vivo exposure to the drug, there being no correlation between half-life and oral clearance. Artemisinin oral plasma clearance was about 400 L h-1 exhibiting a slight decrease with dose, although the effect was weak. Thus results from studies using different artemisinin doses may, within the studied dose range, be compared without the complication of disproportionate changes in drug exposure with varying dose levels. Half-lives appeared to increase with dose. An observed period effect in the analysis of variance was tentatively associated with time-dependency in artemisinin pharmacokinetics. There was a high correlation between artemisinin plasma concentrations determined at various time-points after drug administration and the AUCs after the 500 and 1000 mg doses, but less so after the 250 mg dose. This may show a tentative approach to assess the systemic exposure of the patients to artemisinin from the determination of artemisinin plasma concentrations in one or two plasma samples only. Artemisinin was well tolerated with no apparent dose or time dependent effects on blood pressure, heart rate or body temperature.

  10. Incremental effects of 28 days of beta-alanine supplementation on high-intensity cycling performance and blood lactate in masters female cyclists.

    PubMed

    Glenn, J M; Gray, M; Stewart, R; Moyen, N E; Kavouras, S A; DiBrezzo, R; Turner, R; Baum, J

    2015-12-01

    Within the aging population, there exists a subset of individuals termed masters athletes (MA). As masters-level competition increases in popularity, MA must find methods to enhance individual athletic performance. Longitudinal beta-alanine (BA) supplementation is suggested to enhance physical capability during exercise; however, these effects have not been evaluated in MA. To examine the longitudinal effects of BA on time to exhaustion (TTE), total work completed (TWC), and lactate clearance in female MA cyclists. Twenty-two female MA (age = 53.3 ± 1.0) participated in this double-blind design. Subjects were randomly assigned to BA (n = 11; 800 mg BA + 8 g dextrose) or placebo (PLA; n = 11; 8 g dextrose) groups and supplemented 4 doses/day over 28 days. Every 7 days, subjects completed a cycling TTE at 120% VO2max, and TWC was calculated. Blood lactate was measured at baseline, immediate post, and 20-min post each TTE. No significant differences existed between groups for any variable at baseline (p > 0.05). After 28 days supplementation, BA had greater TTE (23 vs 1% change) and TWC (21 vs 2% change) than PLA (p < 0.05). Following the 20-min TTE recovery, lactate was 24% lower in BA compared to PLA (4.35 vs. 5.76 mmol/L, respectively). No differences existed for variables during intermittent weeks. 28 days of BA supplementation increased cycling performance via an enhanced time to exhaustion and total work completed with associated lactate clearance during passive rest in female MA.

  11. Metabolite profiles of rats in repeated dose toxicological studies after oral and inhalative exposure.

    PubMed

    Fabian, E; Bordag, N; Herold, M; Kamp, H; Krennrich, G; Looser, R; Ma-Hock, L; Mellert, W; Montoya, G; Peter, E; Prokudin, A; Spitzer, M; Strauss, V; Walk, T; Zbranek, R; van Ravenzwaay, B

    2016-07-25

    The MetaMap(®)-Tox database contains plasma-metabolome and toxicity data of rats obtained from oral administration of 550 reference compounds following a standardized adapted OECD 407 protocol. Here, metabolic profiles for aniline (A), chloroform (CL), ethylbenzene (EB), 2-methoxyethanol (ME), N,N-dimethylformamide (DMF) and tetrahydrofurane (THF), dosed inhalatively for six hours/day, five days a week for 4 weeks were compared to oral dosing performed daily for 4 weeks. To investigate if the oral and inhalative metabolome would be comparable statistical analyses were performed. Best correlations for metabolome changes via both routes of exposure were observed for toxicants that induced profound metabolome changes. e.g. CL and ME. Liver and testes were correctly identified as target organs. In contrast, route of exposure dependent differences in metabolic profiles were noted for low profile strength e.g. female rats dosed inhalatively with A or THF. Taken together, the current investigations demonstrate that plasma metabolome changes are generally comparable for systemic effects after oral and inhalation exposure. Differences may result from kinetics and first pass effects. For compounds inducing only weak changes, the differences between both routes of exposure are visible in the metabolome.

  12. Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study

    PubMed Central

    Eissa, Maha M.; El-Moslemany, Riham M.; Ramadan, Alyaa A.; Amer, Eglal I.; El-Azzouni, Mervat Z.; El-Khordagui, Labiba K.

    2015-01-01

    Miltefosine (MFS) is an alkylphosphocholine used for the local treatment of cutaneous metastases of breast cancer and oral therapy of visceral leishmaniasis. Recently, the drug was reported in in vitro and preclinical studies to exert significant activity against different developmental stages of schistosomiasis mansoni, a widespread chronic neglected tropical disease (NTD). This justified MFS repurposing as a potential antischistosomal drug. However, five consecutive daily 20 mg/kg doses were needed for the treatment of schistosomiasis mansoni in mice. The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs) as oral nanovectors. MFS was incorporated in LNCs both as membrane-active structural alkylphospholipid component and active antischistosomal agent. MFS-LNC formulations showed high entrapment efficiency (EE%), good colloidal properties, sustained release pattern and physical stability. Further, LNCs generally decreased MFS-induced erythrocyte hemolytic activity used as surrogate indicator of membrane activity. While MFS-free LNCs exerted no antischistosomal effect, statistically significant enhancement was observed with all MFS-LNC formulations. A maximum effect was achieved with MFS-LNCs incorporating CTAB as positive charge imparting agent or oleic acid as membrane permeabilizer. Reduction of worm load, ameliorated liver pathology and extensive damage of the worm tegument provided evidence for formulation-related efficacy enhancement. Non-compartmental analysis of pharmacokinetic data obtained in rats indicated independence of antischistosomal activity on systemic drug exposure, suggesting possible gut uptake of the stable LNCs and targeting of the fluke tegument which was verified by SEM. The study findings put forward MFS-LNCs as unique oral nanovectors combining the bioactivity of MFS and biopharmaceutical advantages of LNCs, allowing targeting

  13. 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 μg 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 μg/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.

  14. Acute buspirone dosing enhances abuse-related subjective effects of oral methamphetamine.

    PubMed

    Pike, Erika; Stoops, William W; Rush, Craig R

    There is not an approved pharmacotherapy for treating methamphetamine use disorder. This study sought to determine the effects of acute buspirone treatment on the subjective and cardiovascular effects of oral methamphetamine in order to provide an initial assessment of the utility, safety, and tolerability of buspirone for managing methamphetamine use disorder. We predicted that acute buspirone administration would reduce the subjective effects of methamphetamine. We also predicted that the combination of buspirone and methamphetamine would be safe and well tolerated. Ten subjects completed the protocol, which tested three methamphetamine doses (0, 15, and 30mg) in combination with two buspirone doses (0 and 30mg) across 6 experimental sessions. Subjective effects and physiological measures were collected at regular intervals prior to and after dose administration. Methamphetamine produced prototypical subjective and cardiovascular effects. Acute buspirone administration increased some of the abuse-related subjective effects of methamphetamine and also attenuated some cardiovascular effects. The combination of oral methamphetamine and buspirone was safe and well tolerated. Acute buspirone administration may increase the abuse liability of oral methamphetamine. Chronic buspirone dosing studies remain to be conducted, but given preclinical findings and the outcomes of this work, the utility of buspirone for treating methamphetamine use disorder appears limited.

  15. Salmonella enteritidis deposition in eggs after experimental infection of laying hens with different oral doses.

    PubMed

    Gast, Richard K; Guraya, Rupa; Guard, Jean

    2013-01-01

    The continuing attribution of human Salmonella Enteritidis infections to internally contaminated eggs has necessitated the commitment of substantial public and private resources to Salmonella Enteritidis testing and control programs in commercial laying flocks. Cost-effective risk-reduction requires a detailed and comprehensive understanding of how Salmonella Enteritidis infections in hens result in deposition of the pathogen inside eggs. The present study sought to resolve some incompletely defined aspects of the relationship between Salmonella Enteritidis oral-exposure dose levels in experimentally infected laying hens and the frequency and location of subsequent egg contamination. In two trials, groups of specific-pathogen-free hens were experimentally inoculated with oral doses of 10(4), 10(6), or 10(8) CFU of a phage type 4 Salmonella Enteritidis strain. Eggs were collected 5 to 23 days postinoculation, and the yolk and albumen of each egg were cultured separately to detect Salmonella Enteritidis contamination. Larger oral doses of Salmonella Enteritidis administered to hens were associated with significant increases in the frequencies of both yolk and albumen contamination. Moreover, Salmonella Enteritidis was found in the albumen of a far-higher proportion of contaminated eggs from hens given the largest dose than from the other two groups. Salmonella Enteritidis contamination was detected in 0.7% of yolk and 0.2% of albumen samples after inoculation of hens with 10(4) CFU, 4.0% of yolk and 1.7% of albumen samples after inoculation with 10(6) CFU, and 6.5% of yolk and 10.8% of albumen samples after inoculation with 10(8) CFU. These results demonstrate that oral-exposure doses of Salmonella Enteritidis for laying hens can significantly affect both the frequency and location of deposition of this pathogen inside eggs.

  16. Dose finding in a low-dose 21-day combined oral contraceptive containing gestodene.

    PubMed

    Lüdicke, F; Sullivan, H; Spona, J; Elstein, M

    2001-10-01

    An open label, non-comparative study was carried out in 22 women over a total of five cycles. After an untreated cycle, oral administration of 20 microg ethinyl estradiol (EE) with 50 microg gestodene (GST) (tablets taken daily for 21 days with a break of 7 days) was commenced, and three treatment cycles were followed by an untreated follow-up control cycle. The ability of this formulation to inhibit ovulation and suppress ovarian activity was assessed by using hormonal parameters and ultrasound. One ovulation occurred during treatment. Luteinized unruptured follicles were observed in three cases in the second treatment cycle and in one case during the third treatment cycle. Follicle-like structures larger than 13 mm associated with a serum estradiol level of more than 30 pg/mL were noted in 19% of the women in the first treatment cycle. The rate of active follicle-like structures was 43% in the second treatment cycle and 28% in the third treatment cycle. The results were compared with previously reported findings of a preparation containing 20 microg EE and 75 microg GST. With regard to ovarian grading and endogenous hormone secretion, considerably more residual ovarian activity, with all parameters examined, was found in the 20 microg EE and 50 microg GST preparation compared to the 20 microg EE and 75 microg GST preparation. It was concluded that the 20 microg EE and 50 microg GST preparation administered for 21 days does not meet the requirements of a combined oral contraceptive with respect to ovulation inhibition.

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

    PubMed Central

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

    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 was doubled to 60 mg/day, or after a second week of treatment with 30 mg/day. One week after stopping treatment with omeprazole (14 doses) there was a significant 26% decrease of 24 hour intragastric acidity, with full recovery seven weeks later. Fasting plasma gastrin concentration was significantly raised during treatment with all doses of omeprazole. Omeprazole 30 mg/day is the optimal dose for a maximal decrease of 24 hour intragastric acidity in duodenal ulcer patients. PMID:6469081

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

    SciTech Connect

    Lee, Ik Jae; Koom, Woong Sub; Lee, Chang Geol; Kim, Yong Bae; Yoo, Sei Whan; Keum, Ki Chang; Kim, Gwi Eon; Choi, Eun Chang; Cha, In Ho

    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.

  19. Pharmacokinetics of cefetamet pivoxil (Ro 15-8075) with ascending oral doses in normal healthy volunteers.

    PubMed Central

    Tam, Y K; Kneer, J; Dubach, U C; Stoeckel, K

    1989-01-01

    The pharmacokinetics of cefetamet pivoxil during administration of ascending oral doses were studied in 16 male normal healthy volunteers (age, 24.5 +/- 2.1 years; weight, 73.5 +/- 8.5 kg). The subjects were randomly assigned to four oral treatments of 500, 1,000, 1,500, and 2,000 mg of cefetamet pivoxil according to a four-by-four Latin square design. After an overnight fast, the drug was administered 10 min after a standard breakfast. It was found that both the rate and extent of prodrug absorption, measured as cefetamet adsorption, were reduced with increasing doses. The time to maximum concentration of cefetamet in serum was delayed from 4.00 +/- 0.81 to 4.88 +/- 0.96 h (P less than 0.05) when the dose of cefetamet pivoxil was increased from 500 to 2,000 mg. The dose-normalized values of area under the curve from 0 h to infinity for cefetamet and fraction of dose excreted as cefetamet were reduced by averages of 10.3 and 12.5%, respectively, over the dose range studied (P less than 0.05). The changes in rate and extent of prodrug absorption are thought to be the main factors contributing to the nonlinear relationship between maximum concentration in serum and dose. The change in absorption characteristics of cefetamet pivoxil with dose is, however, expected to have few clinical consequences because the magnitudes of these changes are comparable with their respective intragroup variations. PMID:2764545

  20. Opioid-induced myoclonus and hyperalgesia following a short course of low-dose oral morphine

    PubMed Central

    Woodward, Owen Bleddyn; Naraen, Sangeeta; Naraen, Akriti

    2016-01-01

    A 76-year-old man was admitted to hospital with a right-sided fractured neck of femur requiring repair via a cemented hemiarthroplasty. Intraoperatively he received 10 mg of intravenous morphine. Post-operatively he received a short course of low-dose oral opioids and subsequently developed myoclonic jerks and hyperalgesia. The opioids were discontinued and both adverse effects resolved. This case report discusses the concurrent development of myoclonus and hyperalgesia following a low dose of opioids and explores possible management options. PMID:28386402

  1. Toxicokinetics and toxicodynamics of gonyautoxins after an oral toxin dose in cats.

    PubMed

    Andrinolo, Darío; Iglesias, Verónica; García, Carlos; Lagos, Néstor

    2002-06-01

    Although the action of Gonyautoxins (GTXs) and Saxitoxin (STX) mechanisms is well known at the molecular level, there are still many unresolved questions associated with the intoxication syndrome in mammals. For example, how are these toxins absorbed in the digestive system? Where are they absorbed? What is the absorption rate? What is the maximal concentration in plasma (C(max)) and the time taken to reach this C(max) (T(max)) in the case of oral toxin administration? These questions are addressed in this paper, which describes an experimental design which allowed us to follow the toxicokinetics and toxicodynamics of GTX 2/3 epimers poisoning in vivo, when an oral dose of toxin was administered to an anaesthetized cat permanently coupled to an artificial ventilator. The GTX 2/3 epimers was orally administered with a dose of 70 microg/kg, then urine and blood samples were collected during a 5 h experimental period. The toxins were quantified using a post column derivatisation high performance liquid chromatography method. Procedure of extraction, clean up and detection of GTX 2/3 epimers are described. The arterial pressure of the cats was continuously monitored. The GTX 2/3 epimers oral dose was completely absorbed at intestinal level. This dose was sufficient to decrease arterial pressure and to produce death within the experimental time. However, with the intravenous (i.v.) administration of 2.5 microg/min kg of dobutamine, hemodynamic parameters were restored which allowed the animal to overcome the cardiovascular shock. The renal clearance of GTX 2/3 epimers measured in the cats was 4.6 ml/min kg, indicating that like STX, in cats with normal cardiovascular parameters and diuresis, the GTX 2/3 excretion mainly involves glomerular filtration. Oral doses of 35 microg/kg of GTX 2/3 epimers and plasma level of 36 ng/ml are lethal limits for cats. This is the first report that shows the effects of the GTX 2/3 epimers at different plasmatic levels and their

  2. Oral dosing of chemical indicators for in vivo monitoring of Ca2+ dynamics in insect muscle.

    PubMed

    Ferdinandus; Arai, Satoshi; Ishiwata, Shin'ichi; Suzuki, Madoka; Sato, Hirotaka

    2015-01-01

    This paper proposes a remarkably facile staining protocol to visually investigate dynamic physiological events in insect tissues. We attempted to monitor Ca2+ dynamics during contraction of electrically stimulated living muscle. Advances in circuit miniaturization and insect neuromuscular physiology have enabled the hybridization of living insects and man-made electronic components, such as microcomputers, the result of which has been often referred as a Living Machine, Biohybrid, or Cyborg Insect. In order for Cyborg Insects to be of practical use, electrical stimulation parameters need to be optimized to induce desired muscle response (motor action) and minimize the damage in the muscle due to the electrical stimuli. Staining tissues and organs as well as measuring the dynamics of chemicals of interest in muscle should be conducted to quantitatively and systematically evaluate the effect of various stimulation parameters on the muscle response. However, existing staining processes require invasive surgery and/or arduous procedures using genetically encoded sensors. In this study, we developed a non-invasive and remarkably facile method for staining, in which chemical indicators can be orally administered (oral dosing). A chemical Ca2+ indicator was orally introduced into an insect of interest via food containing the chemical indicator and the indicator diffused from the insect digestion system to the target muscle tissue. We found that there was a positive relationship between the fluorescence intensity of the indicator and the frequency of electrical stimulation which indicates the orally dosed indicator successfully monitored Ca2+ dynamics in the muscle tissue. This oral dosing method has a potential to globally stain tissues including neurons, and investigating various physiological events in insects.

  3. Oral Dosing of Chemical Indicators for In Vivo Monitoring of Ca2+ Dynamics in Insect Muscle

    PubMed Central

    Ferdinandus; Arai, Satoshi; Ishiwata, Shin’ichi; Suzuki, Madoka; Sato, Hirotaka

    2015-01-01

    This paper proposes a remarkably facile staining protocol to visually investigate dynamic physiological events in insect tissues. We attempted to monitor Ca2+ dynamics during contraction of electrically stimulated living muscle. Advances in circuit miniaturization and insect neuromuscular physiology have enabled the hybridization of living insects and man-made electronic components, such as microcomputers, the result of which has been often referred as a Living Machine, Biohybrid, or Cyborg Insect. In order for Cyborg Insects to be of practical use, electrical stimulation parameters need to be optimized to induce desired muscle response (motor action) and minimize the damage in the muscle due to the electrical stimuli. Staining tissues and organs as well as measuring the dynamics of chemicals of interest in muscle should be conducted to quantitatively and systematically evaluate the effect of various stimulation parameters on the muscle response. However, existing staining processes require invasive surgery and/or arduous procedures using genetically encoded sensors. In this study, we developed a non-invasive and remarkably facile method for staining, in which chemical indicators can be orally administered (oral dosing). A chemical Ca2+ indicator was orally introduced into an insect of interest via food containing the chemical indicator and the indicator diffused from the insect digestion system to the target muscle tissue. We found that there was a positive relationship between the fluorescence intensity of the indicator and the frequency of electrical stimulation which indicates the orally dosed indicator successfully monitored Ca2+ dynamics in the muscle tissue. This oral dosing method has a potential to globally stain tissues including neurons, and investigating various physiological events in insects. PMID:25590329

  4. Interaction of St John's wort with low-dose oral contraceptive therapy: a randomized controlled trial

    PubMed Central

    Pfrunder, Arabelle; Schiesser, Monika; Gerber, Simone; Haschke, Manuel; Bitzer, Johannes; Drewe, Juergen

    2003-01-01

    Aims Breakthrough bleeding or even unwanted pregnancies have been reported in women during concomitant therapy with oral contraceptives and St John's wort extract. The aim of the present study was to investigate the effects of St John's wort extract on oral contraceptive therapy with respect to ovarian activity, breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel. Methods Eighteen healthy females were treated with a low-dose oral contraceptive (0.02 mg ethinyloestradiol, 0.150 mg desogestrel) alone (control cycle) or combined with 300 mg St John's wort extract given twice daily (cycle A) or three times daily (cycle B). Ovarian activity was assessed by measuring follicle maturation and serum oestradiol and progesterone concentrations. The number of breakthrough bleeding episodes and the pharmacokinetics of ethinyloestradiol and 3-ketodesogestrel were assessed under steady-state conditions. Results During concomitant administration of low-dose oral contraceptive and St John's wort, there was no significant change in follicle maturation, serum oestradiol or progesterone concentrations when compared with oral contraceptive treatment alone. However, significantly more subjects reported intracyclic bleeding during cycles A (13/17 (77%), P < 0.015) and cycle B (15/17 (88%), P < 0.001) than with oral contraceptives alone (6/17 (35%)). The AUC(0,24 h) and Cmax of ethinyloestradiol remained unchanged during all study cycles, whereas the AUC(0,24 h) and Cmax of 3-ketodesogestrel decreased significantly from 31.2 ng ml−1 h to 17.7 ng ml−1 h (43.9%; 95% confidence interval (CI) −49.3, −38.5, P = 0.001) and from 3.6 ng ml −1 to 3.0 ng ml −1(17.8%; CI −29.9, −5.7, P = 0.005), respectively, during cycle A and by 41.7% (CI −47.9, −35.6; P = 0.001) and by 22.8% (CI −31.2, −13.3; P < 0.001) during cycle B respectively, compared with the control cycle. Conclusions There was no evidence of ovulation during low-dose

  5. 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

  6. Effect of increasing oral doses of loperamide on gallbladder motility in man.

    PubMed Central

    Hopman, W P; Rosenbusch, G; Jansen, J B; Lamers, C B

    1990-01-01

    1. Loperamide, a peripherally acting opiate receptor agonist with antidiarrhoeal action, inhibits ileal and colonic motor function. To determine the effect of loperamide on gallbladder motility, we have pretreated five healthy volunteers with 2 mg oral loperamide 24 h, 20, 12 and 2.5 h before; six healthy volunteers with 16 mg oral loperamide 2.5 h before; and eight healthy volunteers with 16 mg oral loperamide 12 and 2.5 h before intravenous infusion of a 'physiological dose' of 12.5 pmol kg-1 cholecystokinin (CCK) for 1 h to stimulate gallbladder contraction. All subjects served as their own controls. Gallbladder volume was measured by ultrasonography and plasma CCK by radioimmunoassay until 90 min after start of the CCK infusion. 2. Infusion of CCK resulted in plasma CCK concentrations similar to those after intraduodenal fat. Integrated gallbladder contraction after 4 X 2 mg loperamide (4600 +/- 891% min) was similar to that without pretreatment (5270 +/- 1037% min; NS). Integrated gallbladder contraction after 1 X 16 mg loperamide diminished from 5458 +/- 412% min without to 2632 +/- 816% min with loperamide (P less than 0.05), and was completely abolished to -596 +/- 762% min (P less than 0.0005 vs without loperamide) after 2 X 16 mg loperamide. 3. It is concluded that loperamide inhibits gallbladder contraction in response to a physiological dose of cholecystokinin in a dose-dependent manner. PMID:2297461

  7. Pharmacokinetics and physiologic effects of alprazolam after a single oral dose in healthy mares.

    PubMed

    Wong, D M; Davis, J L; Alcott, C J; Hepworth-Warren, K L; Galow-Kersh, N L; Rice, S; Coetzee, J F

    2015-06-01

    The objective of this study was to evaluate the pharmacokinetic properties and physiologic effects of a single oral dose of alprazolam in horses. Seven adult female horses received an oral administration of alprazolam at a dosage of 0.04 mg/kg body weight. Blood samples were collected at various time points and assayed for alprazolam and its metabolite, α-hydroxyalprazolam, using liquid chromatography/mass spectrometry. Pharmacokinetic disposition of alprazolam was analyzed by a one-compartmental approach. Mean plasma pharmacokinetic parameters (±SD) following single-dose administration of alprazolam were as follows: Cmax 14.76 ± 3.72 ng/mL and area under the curve (AUC0-∞ ) 358.77 ± 76.26 ng·h/mL. Median (range) Tmax was 3 h (1-12 h). Alpha-hydroxyalprazolam concentrations were detected in each horse, although concentrations were low (Cmax 1.36 ± 0.28 ng/mL). Repeat physical examinations and assessment of the degree of sedation and ataxia were performed every 12 h to evaluate for adverse effects. Oral alprazolam tablets were absorbed in adult horses and no clinically relevant adverse events were observed. Further evaluation of repeated dosing and safety of administration of alprazolam to horses is warranted.

  8. Evidence for CVD 103-HgR as an effective single-dose oral cholera vaccine.

    PubMed

    Jackson, Sarah S; Chen, Wilbur H

    2015-01-01

    We propose the ideal oral cholera vaccine (OCV) should be an inexpensive, single, oral dose that rapidly confers immunity for a long duration, and is well tolerated by individuals vulnerable to cholera. Vaccine trials in industrialized countries of a single oral dose of 5 × 10(8) colony forming units (CFU) of the live, attenuated cholera strain CVD 103-HgR have shown 88-97% serum vibriocidal antibody seroconversion rates, a correlate of protection and documented vaccine efficacy of ≥80% using volunteer challenge studies with wild-type cholera. For individuals of developing countries, a 5 × 10(9) CFU dose of CVD 103-HgR is necessary to elicit similar antibody responses. Presently, a reformulation of CVD 103-HgR is in late-stage clinical development for prospective US FDA licensure; making a cholera vaccine for US travelers potentially accessible in 2016. The availability of CVD 103-HgR should be a welcome addition to the currently available OCVs.

  9. Doxylamine pharmacokinetics following single dose oral administration in children ages 2-17 years.

    PubMed

    Balan, Guhan; Thompson, Gary A; Gibb, Roger; Li, Lijuan; Hull, David; Seeck, Molly

    2013-11-01

    To characterize doxylamine pharmacokinetics in children. This study was conducted in 41 subjects, ages 2-17 years. Doxylamine succinate doses based on age/weight ranged from 3.125 to 12.5 mg. A single oral dose was administered with 2 to 4 oz. of water or decaffeinated beverages ∼2 hours after a light breakfast. Plasma samples were obtained before and for 72 hours after dosing and analyzed for doxylamine using HPLC MS/MS. Pharmacokinetic parameters were estimated using non-compartmental methods and relationships with age were assessed using linear regression. Over the fourfold dose range, Cmax was similar while AUC increased only 60%, although not statistically significant (P-value = 0.0517). As expected due to increasing body size, CLo and Vz /F increased with age. Due to a similar increase with age for Clo and Vz /F, no age-related differences in t1/2,z were observed (∼16 hours). Allometric scaling indicated no maturation related changes in CLo ; although Vz /F remained age-dependent, the predicted range decreased ∼70%. Overall, the single doses were well tolerated. Somnolence was the most common reported AE with no apparent differences in incidence noted with age. An age/weight dosing nomogram utilizing a fourfold range of doses achieves similar Cmax , whereas AUC increases only 60%.

  10. 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. PMID:26034495

  11. Pharmacokinetics of a Single Dose of Oral and Subcutaneous Meloxicam in Caribbean Flamingos ( Phoenicopterus ruber ruber).

    PubMed

    Lindemann, Dana M; Carpenter, James W; KuKanich, Butch

    2016-03-01

    To determine the pharmacokinetics of meloxicam in Caribbean flamingos ( Phoenicopterus ruber ruber), a pilot study was performed first, followed by a complete pharmacokinetic study. Four healthy birds were divided into 2 groups and administered 1 mg/kg of either oral (n = 2) or subcutaneous (n = 2) meloxicam. Plasma meloxicam concentrations were determined with liquid chromatography-mass spectrometry. Based on the pilot study results, 12 healthy birds were assigned into 2 groups and administered either 3 mg/kg PO (n = 6) or 1.5 mg/kg SC (n = 6) of meloxicam. Blood samples were collected at baseline and at 9 time intervals per group after administration of meloxicam in all flamingos. Plasma concentrations after administration of 3 mg/kg PO meloxicam reached a mean maximum plasma concentration of 1.449 μg/mL at 2.35 hours with a terminal half-life of 1.832 hours. After administration of 1.5 mg/kg SC meloxicam, maximum plasma concentration was 4.059 μg/mL at 0.91 hour with a terminal half-life of 1.104 hours. The plasma profile from the main oral study (3 mg/kg PO) differed markedly from the pilot study (1 mg/kg PO), suggesting a delayed absorption with the higher dose and lack of dose proportionality. The different doses for subcutaneous administration resulted in a proportional change in plasma concentrations. Further studies are needed to evaluate the effects of the drug volume administered and fasting status when oral dosing is used. Future studies are also needed to investigate multiple-dose pharmacokinetics of meloxicam and to determine the therapeutic meloxicam plasma concentration in Caribbean flamingos.

  12. 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.

  13. Dose-response investigation of oral ketoprofen in pigs challenged with Escherichia coli endotoxin.

    PubMed

    Mustonen, K; Banting, A; Raekallio, M; Heinonen, M; Peltoniemi, O A T; Vainio, O

    2012-07-21

    In order to determine the effective dose, the effects of orally administered ketoprofen were evaluated in pigs following intravenous challenge with Escherichia coli endotoxin. One hour after the challenge, five groups of pigs were treated with either tap water or ketoprofen (0.5 mg/kg, 1 mg/kg, 2 mg/kg or 4 mg/kg). The body temperature was measured and a total clinical score was calculated after assessing the general behaviour, respiratory rate and locomotion of the pigs. Thromboxane B(2) and ketoprofen concentrations were analysed from blood samples. Ketoprofen treatment significantly reduced the rectal temperature and total clinical scores, and lowered blood thromboxane B(2) concentrations when compared with the control group. Ketoprofen plasma concentrations were lower than previously reported in healthy pigs after similar doses. The appropriate dose of orally administered ketoprofen in pigs in this model is 2 mg/kg, as the higher dose of 4 mg/kg failed to provide an additional benefit.

  14. 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

  15. Development of a chronic noncancer oral reference dose and drinking water screening level for sulfolane using benchmark dose modeling.

    PubMed

    Thompson, Chad M; Gaylor, David W; Tachovsky, J Andrew; Perry, Camarie; Carakostas, Michael C; Haws, Laurie C

    2013-12-01

    Sulfolane is a widely used industrial solvent that is often used for gas treatment (sour gas sweetening; hydrogen sulfide removal from shale and coal processes, etc.), and in the manufacture of polymers and electronics, and may be found in pharmaceuticals as a residual solvent used in the manufacturing processes. Sulfolane is considered a high production volume chemical with worldwide production around 18 000-36 000 tons per year. Given that sulfolane has been detected as a contaminant in groundwater, an important potential route of exposure is tap water ingestion. Because there are currently no federal drinking water standards for sulfolane in the USA, we developed a noncancer oral reference dose (RfD) based on benchmark dose modeling, as well as a tap water screening value that is protective of ingestion. Review of the available literature suggests that sulfolane is not likely to be mutagenic, clastogenic or carcinogenic, or pose reproductive or developmental health risks except perhaps at very high exposure concentrations. RfD values derived using benchmark dose modeling were 0.01-0.04 mg kg(-1) per day, although modeling of developmental endpoints resulted in higher values, approximately 0.4 mg kg(-1) per day. The lowest, most conservative, RfD of 0.01 mg kg(-1) per day was based on reduced white blood cell counts in female rats. This RfD was used to develop a tap water screening level that is protective of ingestion, viz. 365 µg l(-1). It is anticipated that these values, along with the hazard identification and dose-response modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for sulfolane.

  16. 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

  17. Effective dose equivalent to the operator in intra-oral dental radiography

    SciTech Connect

    de Haan, R.A.; van Aken, J. )

    1990-08-01

    The effective dose equivalent to the operator in intra-oral dental radiography has been determined. The exposure from a bitewing radiograph and periapical views of the left maxillary incisors and first molar was measured at nine heights and 16 positions, all 1 m from the patient. The effective dose equivalent was determined using data from ICRP 51 (International Commission on Radiological Protection: Data for Use in Protection Against External Radiation). The values presented are related to an exposure of 1 C kg-1 (3876 R) measured free in air at the tube-end. They thus constitute ratios which are not influenced by the sensitivity of the film or other detector used and form standard tables which permit the calculation of the effective dose equivalent in clinical situations.

  18. Pharmacokinetics of EDP-420 after Ascending Single Oral Doses in Healthy Adult Volunteers▿

    PubMed Central

    Jiang, Li-Juan; Wang, Michelle; Or, Yat Sun

    2009-01-01

    EDP-420 (EP-013420, S-013420) is a first-in-class bicyclolide (bridged bicyclic macrolide) currently in clinical development for the treatment of respiratory tract infections. It has good preclinical pharmacokinetic properties across multiple species and potent in vitro and in vivo activity against respiratory tract infection pathogens, including Haemophilus influenzae, atypical organisms (e.g., Chlamydia pneumoniae, Mycoplasma pneumoniae, and Legionella pneumophila), and multidrug-resistant streptococci. The safety, tolerability, and pharmacokinetics of an orally administered EDP-420 suspension in 40 healthy adult subjects were assessed in a randomized, double-blind, placebo-controlled, ascending single-dose study. Eligible subjects were sequentially randomized into one of five study groups (i.e., 100-, 200-, 400-, 800-, or 1,200-mg dosing groups) consisting of eight subjects (six active and two placebo) each. EDP-420 was well tolerated. There were no serious adverse events reported, nor were there any dose-limiting clinical or laboratory adverse events reported. EDP-420 was rapidly absorbed after a single oral dose. The mean plasma terminal half-life ranged from 15.6 to 20.1 h with low clearance. At the 400-mg dose, the area under the curve was 14.4 μg·h/ml, which well exceeded the required area under the concentration-time curve to cover common respiratory tract infection pathogens based on preclinical pharmacokinetic/pharmacodynamic modeling. The long half-life and high systemic exposure of EDP-420 support once-daily dosing and may allow for shorter treatment durations compared to other macrolide antibiotics. Based on its human pharmacokinetic profiles, taken together with its in vitro/in vivo activity against common respiratory pathogens, EDP-420 warrants efficacy trials for the treatment of respiratory tract infections. PMID:19223626

  19. Supra-nutritional vitamin E supplementation for 28 days before slaughter maximises muscle vitamin E concentration in finisher pigs.

    PubMed

    Kim, J C; Jose, C G; Trezona, M; Moore, K L; Pluske, J R; Mullan, B P

    2015-12-01

    A 4 × 3 factorial experiment (n=8 pigs per treatment combination) was conducted with 96 female Landrace × Large White pigs to examine the required level of dietary vitamin E and optimum feeding duration before slaughter to maximise muscle vitamin E content in the Longissimus thoracis et lumborum (LTL) muscle. The respective factors were four dietary levels of vitamin E (supplemented as dl-α-tocopheryl acetate; 35, 300, 500, and 700 IU/kg) and three feeding durations (14, 28 and 42 days before slaughter). Vitamin E concentration in the LTL was maximised at 6 mg/kg, which was achieved by feeding a 700 IU vitamin E diet for 28 days before slaughter (P<0.001). There was no further increase in the vitamin E content of the LTL by feeding the high vitamin E diet more than 28 days before slaughter.

  20. Toxicokinetics of acrylamide in rats and humans following single oral administration of low doses

    SciTech Connect

    Kopp, Eva Katharina; Dekant, Wolfgang

    2009-03-01

    The rodent carcinogen acrylamide (AA) is formed during preparation of starch-containing foods. AA is partly metabolized to the genotoxic epoxide glycidamide (GA). After metabolic processing, the mercapturic acids N-acetyl-S-(2-carbamoylethyl)-L-cysteine (AAMA), rac-N-acetyl-S-(2-carbamoyl-2-hydroxyethyl)-L-cysteine (GAMA) and rac-N-acetyl-S-(1-carbamoyl-moyl-2-hydroxyethyl)-L-cysteine (iso-GAMA) are excreted with urine. In humans, AAMA can be sulfoxidized to AAMA-sulfoxide. The aim of this study was to assess potential species-differences in AA-toxicokinetics in rats and humans after single oral administration of doses similar to the daily human dietary exposure. Male Fischer 344 rats (n = 5/dose group) were administered 20 and 100 {mu}g/kg b.w. {sup 13}C{sub 3}-AA in deionized water via oral gavage. Human subjects (n = 3/gender) were orally administered 0.5 and 20 {mu}g/kg b.w. {sup 13}C{sub 3}-AA with drinking water. Urine samples were collected in intervals for 96 and 94 h, respectively. Urinary concentrations of {sup 13}C{sub 3}-AAMA, {sup 13}C{sub 3}-GAMA and {sup 13}C{sub 3}-AAMA-sulfoxide were monitored by liquid chromatography-tandem mass spectrometry. The recovered urinary metabolites accounted for 66.3% and 70.5% of the 20 and 100 {mu}g/kg b.w. doses in rats and for 71.3% and 70.0% of the 0.5 and 20 {mu}g/kg b.w. doses in humans. In rats, {sup 13}C{sub 3}-AAMA accounted for 33.6% and 38.8% of dose and 32.7% and 31.7% of dose was recovered as {sup 13}C{sub 3}-GAMA; {sup 13}C{sub 3}-AAMA-sulfoxide was not detected in rat urine. In humans, {sup 13}C{sub 3}-AAMA, {sup 13}C{sub 3}-GAMA and {sup 13}C{sub 3}-AAMA-sulfoxide accounted for 51.7% and 49.2%, 6.3% and 6.4% and 13.2% and 14.5% of the applied dose, respectively. The obtained results suggest that the extent of AA bioactivation to GA in humans is lower than in rodents.

  1. Oral dose of citrus peel extracts promotes wound repair in diabetic rats.

    PubMed

    Ahmad, M; Ansari, M N; Alam, A; Khan, T H

    2013-10-15

    Diabetic patients wound healing is slower than the healthy individuals. Three citrus peel extracts; Lemon (Citrus limon), Grapes fruits (Citrus paradise) and Orange (Citrus sinensis) promote wound healing in experimental animals. This study investigated the effect of oral treatment with citrus peel extracts on wound repair of the skin of diabetic rats. The extracts were estimated for vitamin C and total carotenoid contents prior to animal study. Diabetes mellitus was induced in rats by intraperitoneal injection of a single dose of streptozotocin (STZ, 75 mg kg(-1) b.wt.). One week after diabetes induction, full thickness excision wounds were made in hyperglycemic rats and were divided groups, each containing 6 rats. The different test group animals were treated with different citrus peel extract orally at the dose of 400 mg kg(-1) body weight daily for 12 days. The blood glucose, body weight and rate of wound closure of each rat were measured every 3rd day during the experimental period. At the end of experiment, granular tissues of wounds were removed and estimated for hydroxylproline and total protein content. The results showed significant reduction in blood glucose and time to wound closure. Tissue growth and collagen synthesis were significantly higher as determined by total protein and hydroxyl proline content. From our experimental data, we propose that oral administration of citrus peel extracts has a therapeutic potential in the treatment of chronic wounds in diabetes.

  2. Long-term experience with a low-dose oral contraceptive.

    PubMed

    Brill, K; Schnitker, J; Albring, M

    1990-12-01

    Oral contraception has proved to be the most efficient reversible method of fertility control for over 25 years. During this period, various investigations and epidemiological studies have suggested that some risks may be involved, but, on the other hand, a number of non-contraceptive benefits have become obvious. The results of these investigations were taken into account when new formulations had to be developed, with an aim to improving hormonal fertility control with regard to its tolerance, cycle control, and impact on metabolism. Since then, the objective of research has been to contrive new hormonal contraceptives which ensure safety to the largest possible extent, from a medical point of view, for the sake of the patient, without affecting contraceptive effectiveness. The aim to reduce side-effects connected with the use of oral contraception, as well as to lower the risks possibly involved, has obviously been achieved by extensive research. Both by devising a new substance and reducing doses, the criteria of modern low-dose oral contraception have been met, as has become evident in the course of the clinical experience gathered with Femovan.

  3. Responses in the respiratory tract of rats following exposure to sulphuric acid aerosols for 5 or 28 days.

    PubMed

    Kilgour, Joanne D; Foster, John; Soames, Anthony; Farrar, David G; Hext, Paul M

    2002-01-01

    Sulphuric acid mists have been classified by the International Agency for Research on Cancer as being carcinogenic to humans based on epidemiological findings of respiratory tract tumours. To determine if early changes in the respiratory tract following exposure to sulphuric acid (H(2)SO(4)) aerosols are consistent with the possible development of tumours after extended periods of exposure, groups of female rats were exposed to respirable aerosols of H(2)SO(4) at target concentrations of 0, 0.2, 1.0 or 5.0 mg m(-3) for 6 h per day for either 5 days or for 5 days a week over a 28-day period. Additional groups exposed to 0 or 5.0 mg m(-3) over the 28-day period were retained after exposure for 4 or 8 weeks to assess recovery. Histopathological examinations and quantitative cell proliferation measurements were conducted on the nasal passages, larynx and lung. Achieved concentrations were 0.3, 1.38 and 5.52 mg m(-3) H(2)SO(4). Histological and cell proliferative changes were confined to the larynx and no effects were seen in the nasal passages or lungs. At the two highest concentrations, squamous metaplasia accompanied by significant cell proliferation was apparent after 5 and 28 days of exposure and there was a reduction in the severity of the pathological changes following the recovery periods. No effects were seen at 0.3 mg m(-3) after 5 days of exposure and only minimal metaplastic change was seen after 28 days in a few animals and was not accompanied by cell proliferation. The toxicological relevance of these findings is discussed.

  4. Human metabolism and excretion kinetics of aniline after a single oral dose.

    PubMed

    Modick, Hendrik; Weiss, Tobias; Dierkes, Georg; Koslitz, Stephan; Käfferlein, Heiko Udo; Brüning, Thomas; Koch, Holger Martin

    2016-06-01

    Aniline is an important source material in the chemical industry (e.g., rubber, pesticides, and pharmaceuticals). The general population is known to be ubiquitously exposed to aniline. Thus, assessment of aniline exposure is of both occupational and environmental relevance. Knowledge on human metabolism of aniline is scarce. We orally dosed four healthy male volunteers (two fast and two slow acetylators) with 5 mg isotope-labeled aniline, consecutively collected all urine samples over a period of 2 days, and investigated the renal excretion of aniline and its metabolites by LS-MS/MS and GC-MS. After enzymatic hydrolysis of glucuronide and sulfate conjugates, N-acetyl-4-aminophenol was the predominant urinary aniline metabolite representing 55.7-68.9 % of the oral dose, followed by the mercapturic acid conjugate of N-acetyl-4-aminophenol accounting for 2.5-6.1 %. Acetanilide and free aniline were found only in minor amounts accounting for 0.14-0.36 % of the dose. Overall, these four biomarkers excreted in urine over 48 h post-dose represented 62.4-72.1 % of the oral aniline dose. Elimination half-times were 3.4-4.3 h for N-acetyl-4-aminophenol, 4.1-5.5 h for the mercapturic acid conjugate, and 1.3-1.6 and 0.6-1.2 h for acetanilide and free aniline, respectively. Urinary maximum concentrations of N-acetyl-4-aminophenol were reached after about 4 h and maximum concentrations of the mercapturic acid conjugate after about 6 h, whereas concentrations of acetanilide and free aniline peaked after about 1 h. The present study is one of the first to provide reliable urinary excretion factors for aniline and its metabolites in humans after oral dosage, including data on the predominant urinary metabolite N-acetyl-4-aminophenol, also known as an analgesic under the name paracetamol/acetaminophen.

  5. Pharmacokinetics of grepafloxacin after oral administration of single and repeat doses in healthy young males.

    PubMed

    Efthymiopoulos, C; Bramer, S L; Maroli, A

    1997-01-01

    The pharmacokinetics of grepafloxacin in healthy male subjects following single oral administration of doses ranging from 200 to 1200 mg, and following repeated oral administration of 400 and 800 mg doses are reported. Plasma levels of grepafloxacin reached a peak within 2 hours (on average) following drug administration and then declined bi-exponentially with concentrations being detectable (> 5 micrograms/L) in the plasma for at least up to 72 hours postdose. The high values for the apparent volume of distribution (5 to 8 L/kg) suggested extensive distribution of grepafloxacin in the tissues. Only a small percentage of the administered dose (ranging from 6% to 9.5%) was recovered in the urine as unchanged grepafloxacin, suggesting that metabolism, rather than urinary excretion, is the major elimination route. The half-life of grepafloxacin was about 12 hours after single doses and about 15 hours after repeat doses. The trough levels increased significantly over the first 3 days of repeat administration; thereafter, the changes were small, with steady-state being reached by the fifth day. The area under the concentration-time curve (AUC24 h) values observed on days 7 and 14 of repeat administration, at each dose level, were similar, suggesting that steady-state is maintained. The area values increased more than proportionally after administration of increasing single and repeat doses, suggesting nonlinear kinetics. The elimination half-life and renal clearance did not change with increasing doses. Saturation in the metabolism of grepafloxacin and possibly in the distribution into a peripheral compartment, as suggested by a decrease in the total plasma clearance and in the apparent volume of distribution, could be the origin of the nonlinear kinetics. However, this deviation from linearity is unlikely to be of clinical significance, since it was very small over the recommended range of therapeutic doses (400 to 600 mg once daily). Compared with other quinolones

  6. Effects of oral contrast on dose in abdominopelvic computed tomography with pure iterative reconstruction

    PubMed Central

    Murphy, Kevin P; Healy, Liam J; Crush, Lee; Twomey, Maria; Moloney, Fiachra; Sexton, Sylvia; O’Connor, Owen J; Maher, Michael M

    2016-01-01

    AIM To assess the effect of neutral (NC) and positive (PC) oral contrast use on patient dose in low-dose abdominal computed tomography (CT). METHODS Low-dose clinically indicated CTs were performed on 79 Crohn’s patients (35 = PC, 1 L 2% gastrografin; 44 = NC, 1.5 L polyethylene glycol). Scanner settings for both acquisitions were identical apart from 25 s difference in intravenous contrast timing. Body mass index (BMI), scan-ranges, dose-length product and size-specific dose estimated were recorded. Data was reconstructed with pure model-based iterative reconstruction. Image quality was objectively and subjectively analysed. Data analysis was performed with Statistical Package for Social Scientists. RESULTS Higher doses were seen in neutral contrast CTs (107.60 ± 78.7 mGy.cm, 2.47 ± 1.21 mGy vs 85.65 ± 58.2 mGy.cm, 2.18 ± 0.96 mGy). The difference was significant in 2 of 4 BMI groups and in those that had both NC and PC investigations. Image-quality assessment yielded 6952 datapoints. NC image quality was significantly superior (P < 0.001) (objective noise, objective signal to noise ratio, subjective spatial resolution, subjective contrast resolution, diagnostic acceptability) at all levels. NC bowel distension was significantly (P < 0.001) superior. CONCLUSION The use of polyethylene glycol as a neutral OC agent leads to higher radiation doses than standard positive contrast studies, in low dose abdominal CT imaging. This is possibly related to the osmotic effect of the agent resulting in larger intraluminal fluid volumes and resultant increased overall beam attenuation. PMID:27721943

  7. Comparative disposition of codeine and pholcodine in man after single oral doses.

    PubMed Central

    Findlay, J W; Fowle, A S; Butz, R F; Jones, E C; Weatherley, B C; Welch, R M; Posner, J

    1986-01-01

    Four healthy male subjects received single oral doses of 15, 30 and 60 mg of codeine and pholcodine according to a balanced cross-over design with an interval of 7 days between the six treatments. Blood samples were collected for 8 h after each drug administration. In phase 2 of the study six different male volunteers received single oral doses of 60 mg of codeine and pholcodine with a 14 day interval between successive drug treatments. Blood was sampled for 12 h after codeine and 121 h after pholcodine administration. Plasma concentrations of free (unconjugated) and total (unconjugated plus conjugated) codeine, pholcodine and morphine were determined by radioimmunoassay and selected pharmacokinetic parameters were derived from these data. Pharmacokinetics of both drugs were independent of dose. Codeine was absorbed and eliminated relatively rapidly [elimination t1/2 = 2.3 +/- 0.4 h (mean +/- s.d.)]. While codeine kinetics were adequately described by a one-compartment open model with first-order absorption, a two-compartment model was required to describe pholcodine elimination from plasma (t1/2,z = 37.0 +/- 4.2 h). Plasma concentrations of conjugated codeine were much greater than those of the unconjugated alkaloid. By contrast, pholcodine appeared to undergo little conjugation. Biotransformation of codeine to morphine was evident in all subjects, although the extent of this metabolic conversion varied considerably between subjects. Morphine was not detectable in the plasma of any subject after pholcodine administration. PMID:3741728

  8. Population Pharmacokinetics and Dose Optimization of Mycophenolic Acid in HCT Recipients Receiving Oral Mycophenolate Mofetil

    PubMed Central

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2012-01-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. 4,496 MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance and volume of the central compartment were 24.2 L/hr and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA clearance by 33.8%. The optimal LSS was immediately before and at 0.25, 1.25, 2, and 4hr after oral MMF administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. PMID:23382105

  9. Population pharmacokinetics and dose optimization of mycophenolic acid in HCT recipients receiving oral mycophenolate mofetil.

    PubMed

    Li, H; Mager, D E; Sandmaier, B M; Maloney, D G; Bemer, M J; McCune, J S

    2013-04-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2 L/hour and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25 hours, 1.25 hours, 2 hours, and 4 hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation.

  10. Prescription and consumption of solid oral drugs dispensed as unitary doses in a third level hospital

    PubMed Central

    Calderón-Guzmán, David; Juárez-Olguín, Hugo; Hernández-García, Ernestina; Medina-Andrade, Alejandro; Juarez Tapia, Belen

    2015-01-01

    Background: The knowledge about the pattern of prescription and consumption of solid oral drugs dispensed as unitary doses (UD) in Mexico is sparing. Purpose: The aim of this study was to describe the pattern of prescription and consumption of solid oral drugs dispensed as unitary doses (UD) in a third level private hospital of Mexico. A retrospective study of a 60-month period (from 2007 to 2011) was carried out to know the pattern of drugs dispensed as UD in a third level hospital. Results: Among the principal drugs consumed were analgesic, antihypertensive, antibiotic, anti-inflammatory, antiepileptic, and diuretics. The dispensation of drugs per year was as follows: 181 drugs with 85,167 UD in 2007; 199 with 90,519 UD in 2008; 193 with 101,479 UD in 2009; 195 with 100,798 UD in 2010; and 198 with 103,913 UD in 2011. Conclusion: The findings confirmed that prescription and consumption of unitary doses in the hospitalization service increased, and revealed the extensive use of analgesics as the principal prescribed drug in this kind of hospital. PMID:27013914

  11. High-dose oral acyclovir in acute herpes zoster ophthalmicus: the end of the corticosteroid era.

    PubMed

    Herbort, C P; Buechi, E R; Piguet, B; Zografos, L; Fitting, P

    1991-01-01

    Systemic acyclovir (ACV), a new potent anti-herpes drug, was shown to reduce effectively the morbidity in the acute phase of herpes zoster ophthalmicus (AHZO). Using high dose oral ACV (5 X 800 mg/day) our aim in this study was: (1) to compare disease profiles in the ACV-treated group and in a group of zoster patients having had no ACV, analysed retrospectively; (2) to establish if high-dose ACV was able to prevent severe long term complications of AHZO; and (3) to determine the present role of corticosteroids in AHZO. From 1984 to 1988, 48 patients with AHZO of less than 3 days' duration were included. All patients received at least 7 days of oral ACV (5 X 800 mg/d) associated with topical ACV. Steroids were not given unless severe uveitis occurred. Follow-up was 2 years in 43 patients and 1 year in all 48 patients. Main conclusions from our study are: 1. Ocular involvement occurred in 67% of ACV-treated cases, a rate comparable to our retrospective group (59%) and to the literature (71%). However the rate of severe long term complications was minimal (4%) when compared to our non-treated retrospective group (21%). 2. Steroid treatment was not necessary in any of the ACV-treated patients. 3. ACV was well tolerated and did not have to be discontinued in any of the patients. High dose ACV and avoidance of steroids seems to eliminate the severe complications of AHZO.

  12. Selection of generic preparations of famotidine orally disintegrating tablets for use in unit-dose packages.

    PubMed

    Yamazaki, N; Iizuka, R; Miyazawa, S; Wada, Y; Shimokawa, K; Ishii, F

    2012-10-01

    Changes in the hardness, dissolution, and the disintegration time of brand name and generic preparations (6 preparations) of famotidine orally disintegrating tablets were investigated. Tablets had been stored in a thermo-hygrostat-controlled environment set to simulate the home conditions of patients up to 8 weeks after unit-dose packaging. Among the tablets in unit-dose packaging prepared immediately after blister packs (BP) were opened, one generic had decreased hardness to less than 2.0 kg after 1 week, 55.1% of its initial hardness value, and a shorter disintegration time of about 1/5 of its initial disintegration time. Generics met the standard for dissolution 8 weeks after unit-dose packaging. The decrease in hardness after unit-dose packaging is presumed to be associated with additives, and particularly the types and amounts of binding agents, but evidence of this association was lacking. The hardness noted in drug interview forms (IFs) and the state of sales of bulk tablet packages must be determined to facilitate the selection of generics that remain hard even after unit-dose packaging.

  13. Successful treatment for subinvolution of placental sites in the bitch with low oral doses of progestagen.

    PubMed

    Voorhorst, M J; van Brederode, J C; Albers-Wolthers, C H J; de Gier, J; Schaefers-Okkens, A C

    2013-10-01

    Subinvolution of placental sites (SIPS) is the major cause of persistent sanguineous vaginal discharge after parturition in the bitch. Spontaneous remission is common but may take several months, and hence, medical therapy to end the discharge is often requested. In this retrospective study, we evaluated the effect of treatment for SIPS with low oral doses of a progestagen. Nine bitches with SIPS, but otherwise clinically healthy, were found in the computer database of the Department of Clinical Sciences of Companion Animals. Seven of these bitches were treated with low oral doses of a progestagen (megestrol acetate, 0.1 mg/kg body weight (bw) once daily for the 1st week, then 0.05 mg/kg bw once daily for the 2nd week). The other two bitches were untreated. Treatment results were evaluated by a telephone questionnaire. Progestagen treatment was successful in all of the treated dogs; sanguineous vaginal discharge stopped within the treatment period. One of the two untreated dogs remained symptomatic until the next oestrus, approximately 120 days after parturition, and the other remained symptomatic until 6 weeks before the start of the next pro-oestrus, 270 days after parturition. No side effects of the progestagen treatment were observed. Subsequent gestations, parturitions and puerperal periods of 5 mated bitches were uneventful. One bitch did not become pregnant after mating. In conclusion, the results of this study indicate that oral administration of low doses of progestagen for 2 weeks is effective in stopping persistent sanguineous vaginal discharge in bitches with SIPS, with neither side effects nor reduced subsequent fertility.

  14. Effect of renal function on risedronate pharmacokinetics after a single oral dose

    PubMed Central

    Mitchell, D Y; St Peter, J V; Eusebio, R A; Pallone, K A; Kelly, S C; Russell, D A; Nesbitt, J D; Thompson, G A; Powell, J H

    2000-01-01

    Aims To determine the relationship between risedronate pharmacokinetics and renal function. Methods Risedronate was administered to adult men and women (n = 21) with various degrees of renal function (creatinine clearance 15–126 ml min−1) as a single oral dose of 30 mg. Serum samples were obtained for 72 h after dosing, and urine samples were collected for 72 h after dosing and then periodically for 6 weeks. Risedronate concentrations were determined using an enzyme-linked immunosorbent assay (ELISA). Risedronate serum concentration-time and urinary excretion rate-time profiles were analysed simultaneously using nonlinear regression. Results Renal clearance and volume of distribution were linearly related to creatinine clearance (r2 = 0.854, P < 0.001; and r2 = 0.317, P < 0.01, respectively). Decreases in predicted renal clearance and volume of distribution of 82 and 69%, respectively, were observed when creatinine clearance decreased from 120 to 20 ml min−1. A 64% decrease in predicted oral clearance was observed when creatinine clearance decreased from 120 to 20 ml min−1 (P = 0.064). Iohexol clearance, a predictor of renal function, produced similar results to those observed with creatinine clearance. Risedronate was well tolerated by the study population. Conclusions Risedronate renal clearance was significantly related to a decrease in renal function. There was a consistent reduction in oral clearance with a decrease in creatinine clearance. However, based on the regression analysis, generally no dosage adjustment appears to be necessary for most patients with mild or moderate renal impairment (creatinine clearance > 20 ml min−1). PMID:10718776

  15. Impact of 30-Day Oral Dosing With N-Acetyl-L-Cysteine on Sprague-Dawley Rat Physiology

    DTIC Science & Technology

    2004-07-01

    A number of studies have demonstrated a protective effect associated with N- acetyl -L- cysteine ( NAC ) against toxic chemical exposure. However, the...impact of long-term oral dosing on tssue pathology has not been determined. In this study, we assessed the impact of long-term oral NAC administration on...SD rats (10 male, 10 female), 8 weeks of age, were dosed daily by oral gavage with deionized H2O (negative controls) or NAC solution at a rate of 600

  16. 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.

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

    PubMed

    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.

  18. The absorption of bismuth from oral doses of tripotassium dicitrato bismuthate.

    PubMed

    Nwokolo, C U; Gavey, C J; Smith, J T; Pounder, R E

    1989-02-01

    Two studies measured plasma concentrations of bismuth during dosing with tripotassium dicitrato bismuthate (De-Noltab). The first study compared 24 h plasma bismuth concentration and urinary bismuth excretion in six patients who had already received 29-131 days (median 47 days) of treatment with De-Noltab 2 b.d., and six healthy subjects who only received De-Noltab 2 b.d. on the day of study. There was a prompt rise in plasma bismuth concentration after each dose of De-Noltabs. The median 24 h integrated plasma bismuth concentration was similar in both groups, but the median 24 h urinary bismuth excretion was 5.4-fold higher in the patients. The second study compared the plasma bismuth concentrations after the first and third doses of De-Noltab 2 b.d. in 16 healthy subjects. The median peak bismuth concentration occurred 30 min (range 15-105 min) post-dosing. The peak plasma bismuth concentration was greater than 50 ng/ml in 14 of the 16 subjects, and greater than 100 ng/ml in nine of the subjects. There was no significant difference in the median integrated 10-h plasma bismuth concentration after the first or third dose of De-Noltabs. The results of these studies confirm that bismuth is absorbed and sequestrated during dosing with De-Noltabs. Bismuth is absorbed rapidly after oral dosing with De-Noltabs, to produce peak plasma bismuth concentrations hitherto considered to be in the range associated with bismuth neurotoxicity.

  19. The intravenous to oral relative milligram potency ratio of morphine during chronic dosing in cancer pain.

    PubMed

    Lasheen, Wael; Walsh, Declan; Mahmoud, Fade; Sarhill, Nabeel; Rivera, Nilo; Davis, Mellar; Lagman, Ruth; Legrand, Susan

    2010-01-01

    Morphine (M) is the opioid analgesic of choice for severe cancer pain. The IV to PO M equipotent switch ratio (CR) is controversial. We designed this prospective observational cohort to confirm the efficacy and safety of M IV to PO CR of 1:3. Consecutive cancer patients admitted to an inpatient palliative medicine unit were screened for inclusion. Pain was managed by palliative medicine specialists. They were blinded to the patient data collected, and the calculated CR. The switch was considered successful if the following criteria were met: (1) Pain adequately controlled: pain rated as none or mild (2) Number of RD less than 4 (for non incident pain) per 24 hours (3) No limiting side effects. We used Day 3 ATC M dose for CR calculations. The major outcome measures were the IV : PO CR ratio, morphine doses (mg/day), pain severity, number of PRN doses, and day 1 and day 3side effects. Descriptive statistics were used to report mean, median, standard deviation and range of different variables. Two hundred and fifty six consecutive admissions were screened, and 106 were eligible for the study. Sixty two underwent a successful M route switch and were included in this analysis. A ratio of 1:3 was safely implemented over a wide M dose range. About 80% were successfully switched with a calculated CR of 1:3. 20% required an oral M dose adjustment after route switch either to better pain control or reduce side effects with a resultant higher (e.g. 1:4) or lower (e.g. 1:2) calculated potency ratios respectively. A potency ratio of 1:3 was safe as evaluated by common M side-effects, the dose also easy to calculate. The 1: 3 M IV to PO relative milligram potency ratio appears correct and practical for most patients over a wide M dose range.

  20. 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 μg/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

  1. Toxicologic evaluation of tungsten: 28-day inhalation study of tungsten blue oxide in rats.

    PubMed

    Rajendran, Narayanan; Hu, Shu-Chieh; Sullivan, Dennis; Muzzio, Miguel; Detrisac, Carol J; Venezia, Carmen

    2012-12-01

    The toxicity and toxicokinetics of tungsten blue oxide (TBO) were examined. TBO is an intermediate in the production of tungsten powder, and has shown the potential to cause cellular damage in in vitro studies. However, in vivo evidence seems to indicate a lack of adverse effects. The present study was undertaken to address the dearth of longer-term inhalation toxicity studies of tungsten oxides by investigating the biological responses induced by TBO when administered via nose-only inhalation to rats at levels of 0.08, 0.325, and 0.65 mg TBO/L of air for 6 h/day for 28 consecutive days, followed by a 14-day recovery period. Inhaled TBO was absorbed systemically and blood levels of tungsten increased as inhaled concentration increased. Among the tissues analyzed for tungsten levels, lung, femur and kidney showed increased levels, with lung at least an order of magnitude greater than kidney or femur. By exposure day 14, tungsten concentration in tissues had reached steady-state. Increased lung weight was noted for both terminal and recovery animals and was attributed to deposition of TBO in the lungs, inducing a macrophage influx. Microscopic evaluation of tissues revealed a dose-related increase in alveolar pigmented macrophages, alveolar foreign material and individual alveolar foamy macrophages in lung. After a recovery period there was a slight reduction in the incidence and severity of histopathological findings. Based on the absence of other adverse effects, the increased lung weights and the microscopic findings were interpreted as nonadverse response to exposure and were not considered a specific reaction to TBO.

  2. VS411 Reduced Immune Activation and HIV-1 RNA Levels in 28 Days: Randomized Proof-of-Concept Study for AntiViral-HyperActivation Limiting Therapeutics

    PubMed Central

    Lori, Franco; De Forni, Davide; Katabira, Elly; Baev, Denis; Maserati, Renato; Calarota, Sandra A.; Cahn, Pedro; Testori, Marco; Rakhmanova, Aza; Stevens, Michael R.

    2012-01-01

    Background A new class of antiretrovirals, AntiViral-HyperActivation Limiting Therapeutics (AV-HALTs), has been proposed as a disease-modifying therapy to both reduce Human Immunodeficiency Virus Type 1 (HIV-1) RNA levels and the excessive immune activation now recognized as the major driver of not only the continual loss of CD4+ T cells and progression to Acquired Immunodeficiency Syndrome (AIDS), but also of the emergence of both AIDS-defining and non-AIDS events that negatively impact upon morbidity and mortality despite successful (ie, fully suppressive) therapy. VS411, the first-in-class AV-HALT, combined low-dose, slow-release didanosine with low-dose hydroxycarbamide to accomplish both objectives with a favorable toxicity profile during short-term administration. Five dose combinations were administered as VS411 to test the AV-HALT Proof-of-Concept in HIV-1-infected subjects. Methods Multinational, double-blind, 28-day Phase 2a dose-ranging Proof-of-Concept study of antiviral activity, immunological parameters, safety, and genotypic resistance in 58 evaluable antiretroviral-naïve HIV-1-infected adults. Randomization and allocation to study arms were carried out by a central computer system. Results were analyzed by ANOVA, Kruskal-Wallis, ANCOVA, and two-tailed paired t tests. Results VS411 was well-tolerated, produced significant reductions of HIV-1 RNA levels, increased CD4+ T cell counts, and led to significant, rapid, unprecedented reductions of immune activation markers after 28 days despite incomplete viral suppression and without inhibiting HIV-1-specific immune responses. The didanosine 200 mg/HC 900 mg once-daily formulation demonstrated the greatest antiviral efficacy (HIV-1 RNA: −1.47 log10 copies/mL; CD4+ T cell count: +135 cells/mm3) and fewest adverse events. Conclusions VS411 successfully established the Proof-of-Concept that AV-HALTs can combine antiviral efficacy with rapid, potentially beneficial reductions in the excessive immune system

  3. Comparison of the toxicity of several fumonisin derivatives in a 28-day feeding study with female B6C3F(1) mice.

    PubMed

    Howard, Paul C; Couch, Letha H; Patton, Ralph E; Eppley, Robert M; Doerge, Daniel R; Churchwell, Mona I; Marques, M Matilde; Okerberg, Carlin V

    2002-12-15

    Fumonisinmycotoxins are produced by Fusaria fungi that grow worldwide primarily on corn. Fumonisin B(1), the most predominant form in corn samples, is a renal carcinogen in male F344/N rats and a hepatocarcinogen in female B6C3F(1) mice when fed at concentrations higher than 50 ppm (70 micromol/kg) in the diet for 2 years. We sought to determine the relative toxicities of several naturally occurring fumonisin derivatives when included in the diet of female B6C3F(1) mice. Mice were fed diets containing fumonisin B(1), fumonisin B(2), fumonisin B(3), fumonisin P1, hydrolyzed-fumonisin B(1), N-(acetyl)fumonisin B(1), or N-(carboxymethyl)fumonisin B(1) (approximately 0, 14, 70, and 140 micromol/kg diet) for 28 days. None of the doses used caused a decrease in body weight gain over the 28 days. Serum levels of total bile acids, cholesterol, and alkaline phosphatase were increased only in mice receiving 72 and 143 micromol/kg fumonisin B(1), suggesting that only fumonisin B(1) was hepatotoxic in the mice. Corroborating this observation, the liver weight, relative to body weight, was decreased only in the mice that consumed 143 micromol/kg fumonisin B(1). Consistent with fumonisin B(1) inhibition of ceramide synthase, the liver sphinganine-to-sphingosine ratio was increased and the liver ceramide levels were decreased only in the mice receiving 72 and 143 micromol/kg fumonisin B(1). Increased hepatocellular apoptosis, hepatocellular hypertrophy, Kupffer cell hyperplasia, and macrophage pigmentation were detected in the mice consuming 72 and 143 micromol/kg fumonisin B(1). The other fumonisin derivatives did not alter serum analytes, organ weights, or hepatic structure. These results suggest that, of the naturally occurring fumonisins, fumonisin B(1) is the principal hepatotoxic derivative in the B6C3F(1) mouse.

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

    PubMed

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

    2009-10-01

    The single-dose disposition kinetics of marbofloxacin (MBX) were determined in clinically healthy loggerhead sea turtles (n=5) after oral (PO) administration of 2 mg kg(-1) bodyweight. Marbofloxacin plasma concentrations were determined by DAD-HPLC (LOD/LOQ 0.015/0.05 microg ml(-1)). Data were subjected to non-compartmental analysis. Following PO administration, marbofloxacin achieved maximum plasma concentrations of 11.66+/-2.53 mg L(-1) at 15.00+/-3.00 h. The absence of general adverse reactions in the turtles of the study, and the favourable pharmacokinetic properties (long half-life and high maximum plasma concentration) of MBX administered PO at the single-dose of 2 mg kg(-1) suggest the possibility of its safe and effective clinical use in loggerhead sea turtles.

  5. 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

  6. Single dose oral analgesics for postoperative pain have few adverse events.

    PubMed

    Wong, Yin J

    2016-09-01

    Data sourcesThe Cochrane Database of Systematic Reviews on the Cochrane Library.Study selectionAll Cochrane reviews of RCTs between 1999 to 2015, conducted in adults examining the adverse events associated with single dose oral analgesics used for acute post-operative pain were considered.Data extraction and synthesisStudies were searched, reviewed and assessed independently by two reviewers and standard data items extracted. Methodological quality was assessed using criteria adapted from AMSTAR (Assessing the Methodological Quality of Systematic Reviews).ResultsData from 39 Cochrane reviews of 41 different analgesics or analgesic combinations involving a total of 350 studies involving 35,000 adults were included. Most analgesics were tested in a narrow dose range. For most NSAIDs, paracetamol (acetaminophen), and combinations not containing opioids, the rates of adverse events were similar to that of placebos (NSAID 3% - 44% vs 4 - 46%; paracetamol 7-18% vs 6-16%; combination 11-30% vs 6-48%). However, for higher dosages, like 1000 mg aspirin, 1000 mg diflunisal, and opioids or drug combinations containing opioids, there was a statistically significant difference in the incidence of adverse events reported (NNH 7.7(95%CI; 4.8 - 20) for 1000 mg aspirin; 7.5(95%CI; 4.8-17) for 1000 mg diflunisal; 3.5-8.6 for opioids and combinations). Serious adverse events were rare, occurring at about 1 in 3,200.ConclusionsDespite ongoing problems with the measurement, recording and reporting of adverse events in clinical trials and in systematic reviews, the large amount of information available for single oral doses of analgesics provides evidence that adverse events rates are generally similar with active drug and placebo in these circumstances, except at higher doses of some drugs, and in combinations including opioids.

  7. Corticosterone in drinking water: altered kinetics of a single oral dose of corticosterone and concentrations of plasma sodium, albumin, globulin, and total protein.

    PubMed

    Pung, Thitiya; Zimmerman, Kurt; Klein, Bradley; Ehrich, Marion

    2003-10-01

    Effects of chronic exposure to corticosterone in drinking water on corticosterone kinetics, blood chemistry, and concentrations of catecholamines in parts of brain were studied in Long-Evans rats. Rats were randomly grouped into 3 x 2 treatments (n=4), with three treatments of drinking water (tap water, or 2.5% ethanol, or 400 microg/mL of corticosterone in 2.5% ethanol) for 28 days and two treatments of gavage with a single dose of either corn oil or corticosterone 20 mg/kg on day 28. Blood samples were collected at 0, 15, 30, 60, 120, 240, 480, and 720 min after dosing to determine plasma corticosterone concentrations. Blood samples were collected for clinical pathology on day 42. Hippocampus, cerebral cortex, caudate-putamen, and pons were examined to determine concentrations of catecholamines and activities of esterases. Concentrations of plasma corticosterone before gavage of the corticosterone-drinking rats (47.61 +/- 1.13 ng/mL) were lower than the water (418.47 +/- 1.13 ng/mL) or the ethanol rats (383.71 +/- 1.13 ng/mL, P < 0.0001). Plasma corticosterone rose to peak concentrations by 15 min after gavage in all three groups of drinking rats. Corticosterone-drinking rats had concentrations of plasma corticosterone that returned to basal levels slower than water- and ethanol-drinking rats. Plasma sodium and chloride concentrations were lower in the corticosterone-drinking rats than the water-drinking rats (P < 0.01). Plasma albumin, globulin, and total protein were highest in the corticosterone-drinking rats when compared to the other groups of drinking rats (P < 0.001, P < 0.05, and P < 0.001, respectively). Corticosterone in drinking water did not affect activities of brain neurotoxic esterase, carboxylesterase, acetylcholinesterase, or concentrations of monoamines and their metabolites. A single oral dose of corticosterone reduced neurotoxic esterase activity in the cerebral cortex (P < 0.05) and increased norepinephrine concentrations in the hippocampus

  8. Effects of a single, oral 60 mg caffeine dose on attention in healthy adult subjects.

    PubMed

    Wilhelmus, Micha Mm; Hay, Justin L; Zuiker, Rob Gja; Okkerse, Pieter; Perdrieu, Christelle; Sauser, Julien; Beaumont, Maurice; Schmitt, Jeroen; van Gerven, Joop Ma; Silber, Beata Y

    2017-02-01

    Caffeine induces positive effects on sustained attention, although studies assessing the acute effects of low caffeine dose (<75 mg) on sustained attention are limited and use short-term tests. Therefore, we investigated the acute effects of a 60 mg dose of caffeine on sustained attention in tests lasting up to 45 minutes using 82 low or non-caffeine-consuming healthy male ( n=41) and female ( n=41) adults aged between 40 and 60 years. Vigilance was measured using Mackworth Clock test, Rapid Visual Information Processing Test, adaptive tracking test, saccadic eye movement and attention switch test. Effects on mood and fatigue were analysed using Bond and Lader and Caffeine Research visual analogue scales, and Samn-Perelli questionnaire. Saliva sampling was performed for both compliance and caffeine pharmacokinetic analysis. Administration of a 60 mg caffeine dose resulted in a significant improvement in sustained attention compared with the placebo. Also a significantly improved peak saccadic velocity and reaction time performance was found, and decreased error rate. Significantly increased feelings of alertness, contentment and overall mood after caffeine treatment compared with placebo were observed. This study demonstrated that in healthy adult subjects oral administration of a single 60 mg caffeine dose elicited a clear enhancement of sustained attention and alertness, measured both in multiple objective performances and in subjective scales.

  9. Influence of hepatic impairment on lenvatinib pharmacokinetics following single-dose oral administration.

    PubMed

    Shumaker, Robert; Aluri, Jagadeesh; Fan, Jean; Martinez, Gresel; Pentikis, Helen; Ren, Min

    2015-03-01

    This open-label, single-dose study assessed lenvatinib pharmacokinetics (PK) in subjects with normal hepatic function (n = 8) and mild, moderate, or severe hepatic impairment (n = 6 each). Subjects received 10 mg oral lenvatinib, except those with severe hepatic impairment (5 mg). Plasma and urine samples were collected over 14 days; free and total lenvatinib and its metabolites were analyzed using validated chromatography/spectrometry. PK parameters were estimated using noncompartmental analysis. There were no clinically meaningful effects of mild or moderate hepatic impairment on lenvatinib PK. Dose-normalized Cmax for free lenvatinib was 7.0, 3.7, 5.7, and 5.6 ng/mL in subjects with normal hepatic function, mild, moderate, and severe hepatic impairment, respectively. There was no consistent trend, although dose-normalized Cmax was lower for all subjects with hepatic impairment. AUCs increased 170% and t1/2 increased (37 versus 23 hours) in subjects with severe hepatic impairment. Changes in exposure based on total plasma concentrations were generally less than those based on free concentrations, suggesting changes in plasma protein binding in subjects with severe hepatic impairment. Lenvatinib was generally well tolerated. Subjects with severe hepatic impairment should begin lenvatinib treatment at a reduced dose of 14 mg versus 24 mg for subjects with normal liver function and subjects with mild or moderate hepatic impairment.

  10. The impact of dosing interval in a novel tandem oral dosing strategy: enhancing the exposure of low solubility drug candidates in a preclinical setting.

    PubMed

    Chiang, Po-Chang; South, Sarah A; Wene, Steve P

    2011-01-01

    In drug discovery, time and resource constraints necessitate increasingly early decision making to accelerate or stop preclinical programs. Early discovery drug candidates may be potent inhibitors of new targets, but all too often exhibit poor pharmaceutical or pharmacokinetic properties that limit the in vivo exposure. Low solubility of a drug candidate often leads to poor oral bioavailability and poor dose linearity. This issue is more significant for efficacy and target safety studies where high drug exposures are desired. When solubility issues are confronted, enabling formulations are often required to improve the exposure. However, this approach often requires a substantial and lengthy investment to develop the formulation. Previously, we introduced a gastrointestinal (GI) transit time-based novel oral tandem dosing strategy that enhanced in vivo exposures in rats. In this study, a refined time interval versus dose theory was tested. The resulting in vivo exposures based on altering frequency and doses were compared, and significant impacts were found.

  11. Refining dosing by oral gavage in the dog: A protocol to harmonise welfare

    PubMed Central

    Hall, Laura E.; Robinson, Sally; Buchanan-Smith, Hannah M.

    2015-01-01

    Introduction The dog is a frequently-used, non-rodent species in the safety assessment of new chemical entities. We have a scientific and ethical obligation to ensure that the best quality of data is achieved from their use. Oral gavage is a technique frequently used to deliver a compound directly into the stomach. As with other animals, in the dog, gavage is aversive and the frequency of its use is a cause for welfare concern but little research has been published on the technique nor how to Refine it. A Welfare Assessment Framework (Hall, 2014) was previously developed for use with the laboratory-housed dog and a contrasting pattern of behaviour, cardiovascular and affective measures were found in dogs with positive and negative welfare. Methods Using the framework, this study compared the effects of sham dosing (used to attempt to habituate dogs to dosing) and a Refined training protocol against a control, no-training group to determine the benefit to welfare and scientific output of each technique. Results Our findings show that sham dosing is ineffective as a habituation technique and ‘primes’ rather than desensitises dogs to dosing. Dogs in the control group showed few changes in parameters across the duration of the study, with some undesirable changes during dosing, while dogs in the Refined treatment group showed improvements in many parameters. Discussion It is recommended that if there is no time allocated for pre-study training a no-sham dosing protocol is used. However, brief training periods show a considerable benefit for welfare and quality of data to be obtained from the dogs' use. PMID:25575806

  12. Single dose oral fluconazole vs intravaginal terconazole in treatment of Candida vaginitis. Comparison and pilot study.

    PubMed

    Slavin, M B; Benrubi, G I; Parker, R; Griffin, C R; Magee, M J

    1992-10-01

    Candida vaginitis develops in approximately one-fourth of women in their childbearing years. Conventional management consists of antifungal creams or tablets/suppositories administered intravaginally. Many patients have stated preferences for oral therapy. A randomized, double-blind placebo trial compared the efficacy of a single oral 200 mg dose of fluconazole with the application of terconazole 80 mg vaginal suppository daily for 3 days. Twenty-two patients (fluconazole = 12, terconazole = 10) were evaluated during a four-month period and favorable clinical responses were observed at both early and late evaluations. Mycologic cure was attained by 75% of the fluconazole group and 50% of the terconazole group at the early evaluation. At the late evaluation, mycologic cure was 75% and 100% respectively. The mean time to onset of symptom relief was 2.4 (1.7) days for the fluconazole group and 1.8 (1.8) days for the terconazole group. The mean time to complete relief of symptoms was 6.08 (2.84) and 6.6 (2.95) days respectively. A statistically significant difference did not exist for any of these measures. Seventy-three percent of the patients preferred oral therapy.

  13. High doses of oral folate and sublingual vitamin B12 in dialysis patients with hyperhomocysteinemia

    PubMed Central

    Naseri, Mitra; Sarvari, Gholam-Reza; Esmaeeli, Mohammad; Azarfar, Anoush; Rasouli, Zahra; Moeenolroayaa, Giti; Jahanshahi, Shohre; Farhadi, Simin; Heydari, Zohreh; Sagheb-Taghipoor, Narges

    2016-01-01

    Introduction: Folic acid and vitamin B12, alone or in combination have been used to reduce homocysteine (Hcy) levels in dialysis patients. Objectives: We aimed to assess the efficacy of high doses of oral folate and vitamin B12 in reducing plasma Hcy levels after a 12-week treatment. Patients and Methods: Thirty-two dialysis patients aged 10-324 months screened for hyperhomocysteinuria. Then cases with hyperhomocysteinemia received oral folate 10 mg/day with sublingual methylcobalamin 1 mg/day for 12 weeks. In pre- and post-intervention phases plasma Hcy concentration, serum folate, and vitamin B12 levels were measured. Changes in plasma Hcy, serum folate, and vitamin B12 concentrations were analyzed by paired t tests, and P values < 0.05 were considered significant. Results: Eighteen (56.2%) patients had hyperhomocysteinuria. Vitamin B12 and folate levels were normal or high in all cases. Two patients were lost due to transplant or irregular drugs consumption. Plasma Hcy levels were reduced in all, and reached normal values in 50%. A statistically significant differences between first Hcy levels with levels after intervention was found (95% CI, 5.1–8.9, P = 0.0001). Conclusion: Oral folate 10 mg/day in combination with sublingual vitamin B12, 1 mg/day can be considered as a favorable treatment for hyperhomocysteinemia in dialysis patients. PMID:27689109

  14. Studies on pyrazinoylguanidine. 7. Effects of single oral doses in normal human subjects.

    PubMed

    Vesell, E S; Beyer, K H

    1999-03-01

    In a three-phase study, single oral doses of placebo, followed in 1 week by pyrazinoylguanidine (PZG; 900 mg), followed in 3 weeks by pyrazinoic acid (PZA; 300 mg) were given to 8 normal male subjects. Blood analyses performed 0, 2 and 4 h after administration of placebo or drug revealed that compared to mean 0 h values, PZG and also PZA, but not placebo, decreased mean values for serum glucose, insulin, C-peptide, triglycerides and free fatty acids. In all groups, serum potassium, urea, fibrinogen, high-density lipoprotein and low-density lipoprotein were unchanged. PZA, but not PZG, increased serum uric acid. PZG significantly reduced very-low-density lipoprotein whereas PZA only tended to do so. PZG was well tolerated and without any side effect, but in 7 of the 8 normal volunteers, PZA produced a variable vasomotor response over the blush area of the face and neck lasting from 30 min in 3 subjects to 4 h in 1 subject. Collectively, these results suggest generally similar metabolic responses of normal subjects to PZG and PZA after only a single oral dose of each. Previously, it was unrecognized that acute administration of PZG and PZA could produce such rapid metabolic changes.

  15. Toxicokinetics of cyanide in rats, pigs and goats after oral dosing with potassium cyanide.

    PubMed

    Sousa, Altamir B; Manzano, Helena; Soto-Blanco, Benito; Górniak, Silvana L

    2003-06-01

    The aim of the present study was to determine the effect of the species on the toxicokinetics of cyanide and its main metabolite, thiocyanate. Forty-two rats, six pigs and six goats were dosed orally with 3.0 mg KCN/kg body weight, and cyanide and thiocyanate concentrations in blood were measured within 24 h. After the single oral dose, KCN was rapidly absorbed by rats and goats, with a time of peak concentration ( T(max)) of 15 min. The maximum plasma concentration ( C(max)) of cyanide was observed in goats (93.5 micro mol/l), whereas the C(max) of thiocyanate was higher in rats (58.1 micro mol/l). The elimination half-life ( t(1/2)) and volume of distribution ( Vd(area)) of both cyanide and thiocyanate were higher in goats (1.28 and 13.9 h, and 0.41 and 1.76 l/kg, respectively). Whereas the area under the curve (AUC) of cyanide was significantly higher in goats (234.6 micro mol.l/h), the AUC of thiocyanate was higher in rats (846.5 micro mol.l/h). In conclusion, the results of the present study support the hypothesis that the metabolism of cyanide and its main metabolite, thiocyanate, is species-linked, with the goat being more sensitive to the toxic effects of cyanide/thiocyanate.

  16. Successful comeback of the single-dose live oral cholera vaccine CVD 103-HgR.

    PubMed

    Herzog, Christian

    2016-01-01

    Effective and easy to administer cholera vaccines are in need more than ever, for at risk populations and travellers alike. In many parts of the world cholera is still endemic, causing outbreaks and constituting repeatedly serious public health problems. The oral live cholera vaccine CVD 103-HgR (Orochol, Mutachol), the first genetically modified organism (GMO) used as vaccine, was in its time (launched 1993, Switzerland) the ideal cholera vaccine: single-dose, protective efficacy of 80-100% against moderate to severe cholera, acting within 8 days and exhibiting excellent safety, indiscernible from placebo. However, there were strong headwinds: In the 1990s the indication for cholera vaccines was generally downplayed by experts and in 1997 the European Commission called for a moratorium of GMOs which blocked the registration in the European Union. Thus, demand for this vaccine remained low and in 2003 it was taken off the market for economic reasons. After a decade in obscurity it (Vaxchora) has resurfaced again, now produced in the U.S. and equipped with a U.S. FDA license (June 10, 2016). What had happened? This commentary gives a critical account of an almost unbelievable string of misadventures, emerging adverse circumstances and man-made failures which nearly killed this single-dose live oral cholera vaccine. The good news is that patience and persistence lead to success in the end, allowing good science to prevail for the benefit of those in need.

  17. Comparison of Vaginal and Oral Doses of Misoprostol for Labour Induction in Post-Term Pregnancies

    PubMed Central

    Rezaie, Masomeh; Farhadifar, Fariba; Nayebi, Morteza

    2016-01-01

    Introduction Considering maternal complications, it is preferred to induce labour after 40 weeks. Labour induction is a procedure used to stimulate uterine contractions during pregnancy before the beginning of the labour. Aim The aim of this study was to compare oral misoprostol with vaginal misoprostol for induction of labour in post-term pregnancies. Materials and Methods This double blind clinical-trial study was performed on 180 post-term pregnant women who were admitted to the labour ward of Besat Hospital Sanandaj, Iran in 2013-2014. Participants were equally divided into three groups using block randomization method. The induction was performed for the first group with 100 μg of oral misoprostol, for the second group with 50 μg of oral misoprostol, and for the third group with 25 μg of vaginal misoprostol. Vaginal examination and FHR was done before repeating each dose to determine Bishop Score. Induction time with misoprostol to the start of uterine contractions, induction time to delivery, and mode of delivery, systolic tachycardia, hyper stimulation and fetal outcomes were studied as well. Results First minute Apgar scores and medication dosage of the study groups were significantly different (p=0.0001). But labour induction, induction frequency, mode of delivery, complications, and 5 minutes Apgar score in the groups had no significant difference (p>0.05). The risk of fetal distress and neonatal hospitalization of the groups were statistically significant (p=0. 02). There was no significant difference between the three groups in terms of mean time interval from the administration of misoprostol to the start of uterine contractions (labour induction), the time interval from the start of uterine contractions to delivery and taking misoprostol to delivery. From the administration of misoprostol to start of the uterine contractions the mean difference between time intervals in the three groups were not statistically significant. Conclusion Based on our

  18. Single dose oral tiaprofenic acid for acute postoperative pain in adults

    PubMed Central

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

    2014-01-01

    Background Tiaprofenic acid is a a non-steroidal anti-inflammatory drug (NSAID). It is widely available around the world, with indications for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, periarticular disorders, and strains and sprains. This review sought to evaluate the efficacy and safety of oral tiaprofenic acid 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 tiaprofenic 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 June 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered tiaprofenic acid in adults with moderate to severe acute postoperative pain. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We planned to use area under the “pain relief versus time” curve to derive the proportion of participants with tiaprofenic acid experiencing at least 50% pain relief over 4 to 6 hours, using validated equations; to use number needed to treat to benefit (NNT); the proportion of participants using rescue analgesia over a specified time period; time to use of rescue analgesia; information on adverse events and withdrawals. Main results Not one of eleven studies identified by the searches and examined in detail studied oral tiaprofenic acid against placebo in patients with established postoperative pain and therefore no results are available. Authors’ conclusions In the absence of evidence of efficacy for oral tiaprofenic acid in acute postoperative pain, its use in this indication is not justified at present. Because trials clearly

  19. 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

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

    PubMed

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

    1995-08-01

    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)

  1. Effects of 28 days silicon dioxide aerosol exposure on respiratory parameters, blood biochemical variables and lung histopathology in rats.

    PubMed

    Deb, Utsab; Lomash, Vinay; Raghuvanshi, Suchita; Pant, S C; Vijayaraghavan, R

    2012-11-01

    Inhalation toxicity of silicon dioxide aerosol (150, 300 mg/m(3)) daily over a period of 28 days was carried out in rats. The changes in respiratory variables during the period of exposure were monitored using a computer programme that recognizes the modifications of the breathing pattern. Exposure to the aerosol caused a time dependent decrease in tidal volume, with an increase in respiratory frequency compared to the control. Biochemical variables and histopathological observation were noted at 28th day following the start of exposure. Biochemical markers of silica induced lung injury like plasma alkaline phosphatase, lactate dehydrogenase and angiotensine converting enzyme activities increased in a concentration dependent manner compared to control. Increase in the plasma enzymatic activities indicates endothelial lung damage, increased lung membrane permeability. Histopathological observation of the lungs confirmed concentration dependent granulomatous inflammation, fibrosis and proteinacious degeneration. Aggregates of mononuclear cells with entrapped silica particles circumscribed by fibroblast were observed in 300 mg/m(3) silica aerosol exposed group at higher magnification. Decrease in tidal volume and increase in respiratory frequency might be due to the thickening of the alveolar wall leading to a decreased alveolar volume and lowered elasticity of the lung tissue. The trends in histological and biochemical data are in conformity with the respiratory data in the present study. This study reports for the first time, the changes in respiratory variables during silica aerosol exposure over a period of 28 days.

  2. 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.

    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.

  3. Serum kinetics, distribution and excretion of silver in rabbits following 28 days after a single intravenous injection of silver nanoparticles.

    PubMed

    Lee, Yeonjin; Kim, Pilje; Yoon, Junheon; Lee, Byoungcheun; Choi, Kyunghee; Kil, Ki-Hyun; Park, Kwangsik

    2013-09-01

    Serum kinetics, tissue distribution, and excretion of citrate-coated silver nanoparticles (AgNPs) were investigated in rabbits (n = 4) up to 28 days after a single intravenous injection. Following a single injection of AgNPs, the AUC(last) was reported to be 3.65 ± 0.68 μg·day/ml in 5 mg/kg-treated group and 0.90 ± 0.16 μg·day/ml in 0.5 mg/kg-treated group, respectively. The accumulation of silver was observed in all the tested organs including liver, kidney, spleen, lung, brain, testis, and thymus at 1 day, 7 day, and 28 day of measurement. The liver and spleen seemed to be the major targets because of high accumulation of silver. Excretion via feces and urine was also monitored during the entire experimental period. Unexpectedly, much more excretion of silver occurred via feces than through urine after an intravenous injection, which suggests biliary excretion of AgNPs. General toxicity was analyzed and histopathological changes were also evaluated.

  4. 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

  5. Utilizing a novel tandem oral dosing strategy to enhance exposure of low-solubility drug candidates in a preclinical setting.

    PubMed

    Chiang, Po-Chang; South, Sarah A; Foster, Kimberly A; Daniels, J Scott; Wene, Steve P; Albin, Lesley A; Thompson, David C

    2010-07-01

    Time and resource constraints necessitate increasingly early decision making to accelerate or stop preclinical drug discovery programs. Early discovery drug candidates may be potent inhibitors of new targets, but all too often exhibit poor pharmaceutical and pharmacokinetic properties that limit the in vivo exposure. Low solubility of a drug candidate often leads to poor oral bioavailability and poor dose linearity that creates an issue for efficacy and target safety studies, where high drug exposures are desired. When solubility issues are encountered, enabling formulations are often used to improve the exposure. However, this approach often requires a substantial and lengthy investment to develop the formulation. In our study, two drug candidates with poor aqueous solubility were dosed in rats as simple suspension formulations using a novel tandem dosing strategy, which employs dosing orally in 2.5 h increments up to three times to simulate an oral infusion by avoiding saturation of absorption associated with bolus dosing. These compounds were also dosed using the same suspension formulations and a standard dosing strategy. The resulting in vivo exposures were compared. It was found that this novel tandem dosing strategy significantly improved the in vivo exposures.

  6. Gene Expression in Rat Hearts Following Oral Administration of a Single Hepatotoxic Dose of Acetaminophen

    PubMed Central

    Kil, Hong Ryang; Park, Kwangsik; Noh, Chung Il

    2012-01-01

    Purpose Toxicity caused by acetaminophen and its toxic mechanisms in the liver have been widely studied, including effects involving metabolism and oxidative stress. However, its adverse effects on heart have not been sufficiently investigated. This study evaluated the cardiac influence and molecular events occurring within the myocardium in rats treated with a dose of acetaminophen large enough to induce conventional liver damage. Materials and Methods Male rats were orally administered a single dose of acetaminophen at 1,000 mg/kg-body weight, and subsequently examined for conventional toxicological parameters and for gene expression alterations to both the heart and liver 24 hours after administration. Results Following treatment, serum biochemical parameters including aspartate aminotransferase and alanine aminotransferase were elevated. Histopathological alterations of necrosis were observed in the liver, but not in the heart. However, alterations in gene expression were observed in both the liver and heart 24 hours after dosing. Transcriptional profiling revealed that acetaminophen changed the expression of genes implicated in oxidative stress, inflammatory processes, and apoptosis in the heart as well as in the liver. The numbers of up-regulated and down-regulated genes in the heart were 271 and 81, respectively, based on a two-fold criterion. Conclusion The induced expression of genes implicated in oxidative stress and inflammatory processes in the myocardium reflects molecular levels of injury caused by acetaminophen (APAP), which could not be identified by conventional histopathology. PMID:22187249

  7. 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 μg/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.

  8. Comparative Metabolism Studies of Hexabromocyclododecane (HBCD) Diastereomers in Male Rats Following a Single Oral Dose.

    PubMed

    Hakk, Heldur

    2016-01-05

    Male Sprague-Dawley rats were dosed orally with 3 mg/kg of one of three hexabromocyclododecane (HBCD) diastereomers. Each diastereomer was well absorbed (73-83%), and distributed preferentially to lipophilic tissues. Feces were the major route of excretion; cumulatively accounting for 42% of dose for α-HBCD, 59% for ß-HBCD, and 53% for γ-HBCD. Urine was also an important route of HBCD excretion, accounting for 13% of dose for α-HBCD, 30% for ß-HBCD, and 21% for γ-HBCD. Total metabolism of HBCD diastereomers followed the rank order ß > γ > α, and was >65% of that administered. The metabolites formed were distinct in male rats: α-HBCD did not debrominate or stereoisomerize, but formed two hydroxylated metabolites; ß- and γ-HBCD were both extensively metabolized via pathways of stereoisomerization, oxidation, dehydrogenation, reductive debromination, and ring opening. ß-HBCD was biotransformed to two mercapturic acid pathway metabolites. The metabolites of ß- and γ-HBCD were largely distinct, and could possibly be used as markers of exposure. These isomer-specific data suggest that α-HBCD would be the most dominant HBCD diastereomer in biological tissues because it was metabolized to the lowest degree and also accumulated from the stereoisomerization of the β- and γ- diastereomers.

  9. The use of low dose oral contraceptives for the management of acne.

    PubMed

    Lemay, A; Langley, R G

    2002-12-01

    There is compelling evidence that oral contraceptives (OCs) are effective in the management of mild-moderate acne vulgaris, as well as cumulative evidence that elevated levels of androgens in acne patients, relative to appropriate controls, are an underlying pathophysiological factor in acne. All low dose OCs reduce serum free testosterone (T) to a similar extent, which is contrary to the traditional concept that a patient who has acne should not use an OC containing a progestin with androgenic properties. The efficacy of various OCs to improve acne has been reported in transverse, cohort and comparative studies, and more recently in multicenter, randomized, placebo-controlled trials. Recently, an ultra-low dose OC (Alesse, Wyeth) was shown to effectively reduce non-inflammatory and inflammatory lesions in mild-to-moderate acne, while having a profile of side-effects similar to that of a placebo. Besides its contraceptive efficacy, an ultra-low dose OC represents an attractive alternative as a single or associated medication in the management of acne.

  10. Dose linearity study of selegiline pharmacokinetics after oral administration: evidence for strong drug interaction with female sex steroids

    PubMed Central

    Laine, Kari; Anttila, Markku; Helminen, Antti; Karnani, Hari; Huupponen, Risto

    1999-01-01

    Aims The purpose of this study was to characterize the dose relationship of selegiline and desmethylselegiline pharmacokinetics within the selegiline dose range from 5 to 40 mg. Methods Eight female subjects, of whom four were using oral contraceptives, ingested a single dose of 5 mg, 10 mg, 20 mg or 40 mg of selegiline HCl in an open four-period randomized study. Concentrations of selegiline and desmethylselegiline in serum were measured by gas chromatography for 5 h. As it became evident that the use of oral steroids had a drastic effect on selegiline concentrations, the pharmacokinetic analyses were performed separately for oral contraceptive users and those not receiving any concomitant medication. Results The total AUC and Cmax of selegiline were 10-to 20-fold higher in those subjects taking oral steroids compared with subjects with no concomitant medication; this finding was consistent and statistically significant at all the four dose levels. The dose linearity of selegiline pharmacokinetics failed to be demonstrated in both groups. The AUC and Cmax of desmethylselegiline were only moderately higher (about 1.5-fold; P=NS at each dose level) in the subjects taking oral steroids than in those not receiving concomitant medication. The AUC values of desmethylselegiline increased in a dose linear manner in subjects with no concomitant medication, but not in the oral steroid group. The metabolic ratio (AUC(desmethylselegiline)/AUC(selegiline)) was several-fold lower in the group receiving oral steroids compared with the no-concomitant-medication group (P<0.005 at all the four dose levels). Conclusions Concomitant use of oral contraceptives caused a drastic (20-fold) increase in the oral bioavailability of selegiline. The highly significant difference in the metabolic ratio between the groups provides evidence that the mechanism of the interaction between selegiline and female sex steroids involves reduced N-demethylation of selegiline. The present results suggest

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

    PubMed Central

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

    2012-01-01

    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

  12. 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.

  13. Absorption, distribution, and elimination of graded oral doses of methylmercury in juvenile white sturgeon.

    PubMed

    Huang, Susie Shih-Yin; Strathe, Anders Bjerring; Fadel, James G; Lin, Pinpin; Liu, Tsung-Yun; Hung, Silas S O

    2012-10-15

    Mercury (Hg) is toxic and is released into the environment from a wide variety of anthropogenic sources. Methylmercury (MeHg), a product of microbial methylation, enables rapid Hg bioaccumulation and biomagnification in the biota. Methylmercury is sequestered and made available to the rest of the biota through the benthic-detrital component leading to the high risk of exposure to benthic fish species, such as white sturgeon (Acipenser transmontanus). In the present study, a combined technique of stomach intubation, dorsal aorta cannulation, and urinary catheterization was utilized to characterize the absorption, distribution, and elimination of Hg in white sturgeon over a 48h exposure. Mercury, as methylmercury chloride, at either 0, 250, 500, or 1000 μg Hg/kg body weight, was orally intubated into white sturgeon, in groups of five. The blood was repeatedly sampled and urine collected from the fish over the 48h post intubation period, and at 48h, the fish were sacrificed for Hg tissue concentration and distribution determinations. The fractional rate of absorption (K), blood Hg concentration (μg/ml), tissue concentration (μg/g dry weight) and distribution (%), and urinary Hg elimination flux (μg/kg/h) are significantly different (p<0.05) among the MeHg doses. Complete blood uptake of Hg was observed in all MeHg treated fish by 12h. The maximal observed blood Hg concentration peaks are 0.56±0.02, 0.70±0.02, and 2.19±0.07 μg/ml (mean±SEM) for the 250, 500, and 1000 μgHg/kg body weight dose groups, respectively. Changes in blood Hg profiles can be described by a monomolecular function in all of the MeHg treated fish. The Hg concentration asymptote (A) and K are dose dependent. The relationship between A and the intubation dose, however, is nonlinear. Mercury levels in certain tissues are comparable to field data and longer-term study, indicating that the lower doses used in the current study are ecologically relevant for the species. Tissue Hg concentrations

  14. Pharmacokinetics of difloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applications.

    PubMed

    Ding, H Z; Yang, G X; Huang, X H; Chen, Z L; Zeng, Z L

    2008-06-01

    Pharmacokinetics of difloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of five (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analyzed by a compartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t(1/2beta)) were 17.14 +/- 4.14, 25.79 +/- 8.10, 16.67 +/- 4.04 (pigs) and 6.11 +/- 1.50, 5.64 +/- 0.74, 8.20 +/- 3.12 h (broilers), respectively. After single i.m. and p.o. administration, difloxacin was rapidly absorbed, with peak plasma concentrations (C(max)) of 1.77 +/- 0.66, 2.29 +/- 0.85 (pigs) and 2.51 +/- 0.36, 1.00 +/- 0.21 microg/mL (broilers) attained at t(max) of 1.29 +/- 0.26, 1.41 +/- 0.88 (pigs) and 0.86 +/- 0.4, 4.34 +/- 2.40 h (broilers), respectively. Bioavailabilities (F) were (95.3 +/- 28.9)% and (105.7 +/- 37.1)% (pigs) and (77.0 +/- 11.8)% and (54.2 +/- 12.6)% (broilers) after i.m. and p.o. doses, respectively. Apparent distribution volumes(V(d(area))) of 4.91 +/- 1.88 and 3.10 +/- 0.67 L/kg and total body clearances(Cl(B)) of 0.20 +/- 0.06 and 0.37 +/- 0.10 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), the half-lives of both absorption and distribution(t(1/2ka), t(1/2alpha)) were also determined. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 5 mg/kg given intramuscularly every 24 h in pigs, or administered orally every 24 h at the dosage of 10 mg/kg in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC(90) are <0.25 microg/mL and <0.1 microg/mL respectively.

  15. A fourteen-day repeated dose oral toxicity study of APFO in rats.

    PubMed

    Iwai, Hiroyuki; Yamashita, Kotaro

    2006-01-01

    Ammonium perfluoroocanoate (APFO) was repeatedly administered orally to male Crj:CD(SD)IGS rats for 14 days. Doses of APFO were 0, 0.5, 5, and 50 mg/kg. Significant increases and increasing tendencies in absolute/relative weight of the liver and no change in weight of the spleen were observed in all groups. Although inductions of mitochondrion- and peroxisome-specific enzymes were increased, no decrease was seen in any hematological parameter of lipid metabolism. Red blood cell count, hemoglobin concentration, and hematocrit or these tendencies showed a significant decrease or a tendency to decrease, but no influence on lymphocyte subsets was noted. Secondary inhibition of immunocompetent cells, previously reported for mice, was not seen in this study of rats.

  16. Fatal placental hemorrhage in pregnant CD-1 mice following one oral dose of T-2 toxin.

    PubMed Central

    Rousseaux, C G; Nicholson, S; Schiefer, H B

    1985-01-01

    Forty-eight hours after oral administration of a single dose (3.0 mg/kg BW) of T-2 toxin to mice on days 7, 8, 10, 11 and 12 of pregnancy, 17% maternal mortality following vaginal hemorrhage was encountered. Necropsy examination of the dead females revealed that massive hemorrhages originating from the placental regions had occurred into the reproductive tract. This observation supports the studies in which hemorrhagic disease has been described as characteristic for intoxications with T-2 toxin. The results suggest that fatal hemorrhage during pregnancy can occur in hemochorial and hemoendotheliochorial placental mammals as a result of T-2 toxin administration. Images Fig. 1. Fig. 2. PMID:3986684

  17. In Vivo Human Time-Exposure Study of Orally Dosed Commercial Silver Nanoparticles

    PubMed Central

    Munger, Mark A.; Radwanski, Przemyslaw; Hadlock, Greg C.; Stoddard, Greg; Shaaban, Akram; Falconer, Jonathan; Grainger, David W.; Deering-Rice, Cassandra E.

    2013-01-01

    Background Human biodistribution, bioprocessing and possible toxicity of nanoscale silver receives increasing health assessment. Methods We prospectively studied commercial 10- and 32-ppm nanoscale silver particle solutions in a single-blind, controlled, cross-over, intent-to-treat, design. Healthy subjects (n=60) underwent metabolic, blood counts, urinalysis, sputum induction, and chest and abdomen magnetic resonance imaging. Silver serum and urine content was determined. Results No clinically important changes in metabolic, hematologic, or urinalysis measures were identified. No morphological changes were detected in the lungs, heart or abdominal organs. No significant changes were noted in pulmonary reactive oxygen species or pro-inflammatory cytokine generation. Conclusion In vivo oral exposure to these commercial nanoscale silver particle solutions does not prompt clinically important changes in human metabolic, hematologic, urine, physical findings or imaging morphology. Further study of increasing time exposure and dosing of silver nanoparticulate silver, and observation of additional organ systems is warranted to assert human toxicity thresholds. PMID:23811290

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

    SciTech Connect

    Narayan, Samir Lehmann, Joerg; Coleman, Matthew A.; Vaughan, Andrew; Yang, Claus Chunli; Enepekides, Danny; Farwell, Gregory; Purdy, James A.; Laredo, Grace; Nolan, Kerry A.S.; Pearson, Francesca S.; Vijayakumar, Srinivasan

    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.

  19. Utility of models to predict 28-day or 30-day unplanned hospital readmissions: an updated systematic review

    PubMed Central

    Zhou, Huaqiong; Della, Phillip R; Roberts, Pamela; Goh, Louise; Dhaliwal, Satvinder S

    2016-01-01

    Objective To update previous systematic review of predictive models for 28-day or 30-day unplanned hospital readmissions. Design Systematic review. Setting/data source CINAHL, Embase, MEDLINE from 2011 to 2015. Participants All studies of 28-day and 30-day readmission predictive model. Outcome measures Characteristics of the included studies, performance of the identified predictive models and key predictive variables included in the models. Results Of 7310 records, a total of 60 studies with 73 unique predictive models met the inclusion criteria. The utilisation outcome of the models included all-cause readmissions, cardiovascular disease including pneumonia, medical conditions, surgical conditions and mental health condition-related readmissions. Overall, a wide-range C-statistic was reported in 56/60 studies (0.21–0.88). 11 of 13 predictive models for medical condition-related readmissions were found to have consistent moderate discrimination ability (C-statistic ≥0.7). Only two models were designed for the potentially preventable/avoidable readmissions and had C-statistic >0.8. The variables ‘comorbidities’, ‘length of stay’ and ‘previous admissions’ were frequently cited across 73 models. The variables ‘laboratory tests’ and ‘medication’ had more weight in the models for cardiovascular disease and medical condition-related readmissions. Conclusions The predictive models which focused on general medical condition-related unplanned hospital readmissions reported moderate discriminative ability. Two models for potentially preventable/avoidable readmissions showed high discriminative ability. This updated systematic review, however, found inconsistent performance across the included unique 73 risk predictive models. It is critical to define clearly the utilisation outcomes and the type of accessible data source before the selection of the predictive model. Rigorous validation of the predictive models with moderate-to-high discriminative

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

    SciTech Connect

    Yoshimura, Ryo-ichi Shibuya, Hitoshi; Miura, Masahiko; Watanabe, Hiroshi; Ayukawa, Fumio; Hayashi, Keiji; Toda, Kazuma

    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.

  1. 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-κB transcription factor, which upregulates both vascular endothelial growth factor (VEGF) and Cox-2 expression in the endometrium. The use of natural NF-κB 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 μg 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

  2. Dose titration of moxidectin oral gel against gastrointestinal parasites of ponies.

    PubMed

    Monahan, C M; Chapman, M R; French, D D; Taylor, H W; Klei, T R

    1995-10-01

    Moxidectin was tested as an oral gel formulation during a controlled test performed to evaluate dosages against equine gastrointestinal parasites. Four groups of ten ponies were used. Ponies ranged from 1 to 20 years of age and were naturally infected in southern Louisiana or Mississippi. Fecal exams and fecal cultures were performed on all ponies to determine the strongyle egg counts and the percent distributions of large and small strongyles. Following these determinations, ponies were allocated to replicates of four ponies to provide an even distribution of strongyle infection, age, weight and gender. Members of each replicate were then randomly assigned to one of four treatment groups. The doses tested were 300, 400 and 500 micrograms kg-1 body weight. The oral gel vehicle alone served as control. Treatments were administered behind the tongue and the ponies were observed continuously for 4 h for any adverse reactions; thereafter, ponies were observed at least twice daily. Necropsy examinations were performed 14 days post-treatment for the recovery and identification of any parasites present. Moxidectin, at all doses tested, was 100% efficacious against adults of Strongylus vulgaris, Strongylus edentatus, Triodontophorus spp. and 22 species of small strongyles. Moxidectin was also 100% efficacious against larvae of Strongylus edentatus and Oxyuris equi, greater than 94% efficacious against Strongylus vulgaris larvae and Oxyuris equi adults at 14 days post-treatment. Moxidectin proved highly efficacious against luminal small strongyle larvae (> 99.9% against L4 and > 92% against L3) and moxidectin demonstrated some efficacy against encysted small strongyle larvae as well.(ABSTRACT TRUNCATED AT 250 WORDS)

  3. 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.

  4. The pharmacokinetics and dosing of oral 4-methylumbelliferone for inhibition of hyaluronan synthesis in mice.

    PubMed

    Kuipers, H F; Nagy, N; Ruppert, S M; Sunkari, V G; Marshall, P L; Gebe, J A; Ishak, H D; Keswani, S G; Bollyky, J; Frymoyer, A R; Wight, T N; Steinman, L; Bollyky, P L

    2016-09-01

    Recently, there has been considerable interest in using 4-methylumbelliferone (4-MU) to inhibit hyaluronan (HA) synthesis in mouse models of cancer, autoimmunity and a variety of other inflammatory disorders where HA has been implicated in disease pathogenesis. In order to facilitate future studies in this area, we have examined the dosing, treatment route, treatment duration and metabolism of 4-MU in both C57BL/6 and BALB/c mice. Mice fed chow containing 5% 4-MU, a dose calculated to deliver 250 mg/mouse/day, initially lose substantial weight but typically resume normal weight gain after 1 week. It also takes up to a week to see a reduction in serum HA in these animals, indicating that at least a 1-week loading period on the drug is required for most protocols. At steady state, more than 90% of the drug is present in plasma as the glucuronidated metabolite 4-methylumbelliferyl glucuronide (4-MUG), with the sulphated metabolite, 4-methylumbelliferyl sulphate (4-MUS) comprising most of the remainder. Chow containing 5% but not 0·65% 4-MU was effective at preventing disease in the experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis, as well as in the DORmO mouse model of autoimmune diabetes. While oral 4-MU was effective at preventing EAE, daily intraperitoneal injections of 4-MU were not. Factors potentially affecting 4-MU uptake and plasma concentrations in mice include its taste, short half-life and low bioavailability. These studies provide a practical resource for implementing oral 4-MU treatment protocols in mice.

  5. Lack of effect of tenoxicam on dynamic responses to concurrent oral doses of glucose and glibenclamide.

    PubMed Central

    Hartmann, D; Korn, A; Komjati, M; Heinz, G; Haefelfinger, P; Defoin, R; Waldhäusl, W K

    1990-01-01

    1. In a single-blind, placebo controlled study the influence of tenoxicam on responses of glucose, insulin and C-peptide to oral doses of glucose and glibenclamide was examined in 16 healthy male volunteers. 2. The subjects received once daily doses of 2.5 mg glibenclamide for 12 days. From day 5 through 12 eight subjects received concomitantly 20 mg tenoxicam once daily and the remaining eight subjects received placebo. 3. On days 1, 4, 5 and 12 glibenclamide was taken with 75 g glucose and blood glucose, serum insulin and C-peptide were measured over 5 h. Plasma levels of glibenclamide and tenoxicam (where appropriate) were followed over 10 h. 4. Characteristic parameters of blood glucose and insulin and C-peptide responses did not change significantly with time (day) and there was no difference between both treatment groups. 5. Baseline insulin increased from 11.7 mu l-1 on day 1 to 15.6 mu l-1 on day 4 (P = 0.009), likewise baseline C-peptide increased from 478 pmol l-1 to 530 pmol l-1 (P = 0.05), but there was no further change in the subsequent treatment period. 6. The AUC of the glibenclamide plasma concentration-time curve did not show changes with time or differences between treatment groups. The mean (s.d.) oral clearance of tenoxicam was 2.5 (1.5) ml min-1 and appeared slightly higher than in previous studies. 7. It was concluded that tenoxicam did not affect overall glycoregulation in healthy subjects under glibenclamide steady state conditions. PMID:2119677

  6. Repeated-dose liver micronucleus assay: an investigation with 2-nitropropane, a hepatocarcinogen.

    PubMed

    Kawakami, Satoru; Araki, Tetsuro; Nakajima, Mikio; Kusuoka, Osamu; Uchida, Keisuke; Sato, Norihiro; Tanabe, Yoko; Takahashi, Kaori; Wako, Yumi; Kawasako, Kazufumi; Tsurui, Kazuyuki

    2015-03-01

    The utility of the repeated-dose liver micronucleus (RDLMN) assay in the detection of a genotoxic hepatocarcinogen was evaluated. In this paper, a rat hepatocarcinogen, 2-nitropropane (2-NP), was administered orally to young adult rats for 14 and 28 days without a partial hepatectomy or a mitogen, and the micronucleus induction in liver was examined using a simple method to isolate hepatocytes. In addition, a bone marrow micronucleus assay was conducted concomitantly. The frequency of micronucleated hepatocytes induced by 2-NP increased significantly in both the 14- and 28-day repeated-dose studies, while the bone marrow micronucleus assays were negative in each study. These results indicate that the RDLMN assay is useful for detecting a genotoxic hepatocarcinogen that is negative in bone marrow micronucleus assays and is a suitable in vivo genotoxicity test method for integration into a repeated-dose general toxicity study.

  7. Oral Ciprofloxacin Prophylaxis in Patients Undergoing High DoseTherapy and Autologous Hematopoietic Stem Cell Transplantation

    PubMed Central

    Tabarraee, Mahdi; Tavakoli-Ardakani, Maria; Mehdizadeh, Mahshid; Ghadiani, Mojtaba; Rezvani, Hamid; Hajifathali, Abbas; khamsi, Samiyeh

    2016-01-01

    Antibiotic prophylaxis is usually used in allogeneic stem cell transplantation, but its use in Autologous Stem Cell Transplantation (ASCT) is controversial. We evaluated the efficacy of ciprofloxacin prophylaxis in ASCT. To identify the efficacy of ciprofloxacin on the incidence of neutropenic fever and its complications, 72 patients that had been admitted to Taleghani Hospital for ASCT between 2010 and 2012 were evaluated in our study. Oral ciprofloxacin 500 mg every 12 h was administered to 30 patients on the same day of high dose chemotherapy until the first febrile episode or until the recovery of neutropenia and the results were analyzed and compared with the historical control group 42 other transplanted patients who had not previously received ciprofloxacin. The incidence of neutropenic fever was 80% with no difference between the two groups. But in ciprofloxacin group, duration of fever (1.7 days VS 3.5 days P=0.017), hospitalization due to stem cell transfusion (18.2 days VS 12.2 days p=0.03), incidence of bacteremia 3.3 % VS 33.3%, p=0.002) and platelet recovery (13.9 VS 17.7 days= 0.035) and platelet transfusions (P=0.04) were significantly lower than the control group no side effects and no delay in. Based on this study oral ciprofloxacin prophylaxis is rational, efficacious and economic in ASCT. PMID:28228813

  8. Low-dose irradiation affects the functional behavior of oral microbiota in the context of mucositis.

    PubMed

    Vanhoecke, Barbara W A; De Ryck, Tine R G; De boel, Kevin; Wiles, Siouxsie; Boterberg, Tom; Van de Wiele, Tom; Swift, Simon

    2016-01-01

    The role of host-microbe interactions in the pathobiology of oral mucositis is still unclear; therefore, this study aimed to unravel the effect of irradiation on behavioral characteristics of oral microbial species in the context of mucositis. Using various experimental in vitro setups, the effects of irradiation on growth and biofilm formation of two Candida spp., Streptococcus salivarius and Klebsiella oxytoca in different culture conditions were evaluated. Irradiation did not affect growth of planktonic cells, but reduced the number of K. oxytoca cells in newly formed biofilms cultured in static conditions. Biofilm formation of K. oxytoca and Candida glabrata was affected by irradiation and depended on the culturing conditions. In the presence of mucins, these effects were lost, indicating the protective nature of mucins. Furthermore, the Galleria melonella model was used to study effects on microbial virulence. Irradiated K. oxytoca microbes were more virulent in G. melonella larvae compared to the nonirradiated ones. Our data indicate that low-dose irradiation can have an impact on functional characteristics of microbial species. Screening for pathogens like K. oxytoca in the context of mucosits could be useful to allow early detection and immediate intervention.

  9. Pharmacokinetics of doxycycline after a single intravenous, oral or intramuscular dose in Muscovy ducks (Cairina moschata).

    PubMed

    Yang, F; Sun, N; Zhao, Z S; Wang, G Y; Wang, M F

    2015-01-01

    1. The pharmacokinetics of doxycycline in ducks were investigated after a single intravenous (IV), intramuscular (IM) or oral (PO) dose at 20 mg/kg body weight. 2. The concentrations of doxycycline in plasma samples were assayed using a high performance liquid chromatography method, and pharmacokinetic parameters were calculated using a non-compartmental model. 3. After IV administration, doxycycline had a mean (±SD) distribution volume (Vz) of 1761.9 ± 328.5 ml/kg and was slowly eliminated with a terminal half-life (t₁/₂λz) of 21.21±1.47 h and a total body clearance (Cl) of 57.51 ± 9.50 ml/h/kg. Following PO and IM administration, doxycycline was relatively slowly absorbed - the peak concentrations (Cmax) were 17.57 ± 4.66 μg/ml at 2 h and 25.01 ± 4.18 μg/ml at 1.5 h, respectively. The absolute bioavailabilities (F) of doxycycline after PO and IM administration were 39.13% and 70.71%, respectively. 4. The plasma profile of doxycycline exhibited favourable pharmacokinetics characteristics in Muscovy ducks, such as wide distribution, relatively slow absorption and slow elimination, though oral bioavailability was low.

  10. 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

  11. Pharmacodynamics and pharmacokinetics of oral levosimendan and its metabolites in patients with severe congestive heart failure: a dosing interval study.

    PubMed

    Põder, Pentti; Eha, Jaan; Sundberg, Stig; Antila, Saila; Heinpalu, Marika; Loogna, Imbrit; Planken, Ulle; Rantanen, Satu; Lehtonen, Lasse

    2004-10-01

    The objective of this study was to explore the pharmacodynamics and pharmacokinetics of oral levosimendan in patients with severe congestive heart failure. This was a randomized, parallel-group, double-blind, placebo-controlled trial. Oral levosimendan 2 to 8 mg daily or placebo was administered to 25 patients with New York Heart Association class III-IV congestive heart failure for 4 weeks. Pharmacodynamic variables consisted of heart rate-corrected electromechanical systole, heart rate, and systolic and diastolic blood pressure. The pharmacokinetics of levosimendan and its metabolites, OR-1855 and OR-1896, was assessed. The 4- to 8-mg daily doses of oral levosimendan showed moderate inotropic effects. Blood pressure remained unchanged with all doses. A moderate increase in heart rate was observed except with the 2-mg dose. Pharmacokinetic parameters of the metabolites increased linearly with the dose (P < or = .002 for Cmax and AUC0-8h for both treatment groups). It was concluded that oral levosimendan has inotropic and chronotropic effects in patients with severe congestive heart failure. Plasma concentrations of its metabolites increase dose dependently.

  12. Phase I dose-escalation and pharmacokinetic study of oral gefitinib and irinotecan in children with refractory solid tumors

    PubMed Central

    Brennan, R. C.; Furman, W.; Mao, S.; Wu, J.; Turner, D. C.; Stewart, C. F.; Santana, V.; McGregor, L. M.

    2015-01-01

    Purpose This phase I study endeavored to estimate the maximum tolerated dose (MTD) and describe the dose-limiting toxicities (DLTs) of oral irinotecan with gefitinib in children with refractory solid tumors. Methods Oral irinotecan was administered on days 1-5 and 8-12 with oral gefitinib (fixed dose, 150mg/m2/day) on days 1-12 of a 21-day course. The Escalation with Overdose Control (EWOC) method guided irinotecan dose escalation (7 dose levels, range 5mg/m2/day to 40mg/m2/day). Results Sixteen of 19 patients were evaluable, with serial pharmacokinetic studies in 10 patients. Diagnoses included osteosarcoma (N=5), neuroblastoma (N=3), sarcoma (N=3), and others (N=5). Patients received a median of two courses (range 1-20), with at least two patients treated on dose levels 2-7. Three patients had five DLTs; the most common being metabolic (hypokalemia, N=2 and hypophosphatemia, N=1) at dose levels two (10mg/m2) and four (20mg/m2). One patient experienced grade 3 diarrhea (40mg/m2). Irinotecan bioavailability was 2.5-fold higher when co-administered with gefitinib while the conversion rate of irinotecan to SN-38 lactone was unaffected. The study closed due to poor accrual before evaluation of the next recommended irinotecan dose level (35mg/m2). Of eleven patients receiving at least two courses of therapy, three had stable disease (SD) lasting two to four courses and one patient maintained a complete response through 18 courses. Conclusions The combination of oral gefitinib and irinotecan has acceptable toxicity and anti-tumor activity in pediatric patients with refractory solid tumors. Pharmacokinetic analysis confirms that co-administration of gefitinib increases irinotecan bioavailability leading to an increased SN-38 lactone systemic exposure. PMID:25257509

  13. Subchronic Oral Dose Toxicity of Freeze-dried Powder of Allomyrina dichotoma Larvae

    PubMed Central

    Noh, Jung-Ho; Yun, Eun-Young; Park, Heejin; Jung, Kyung-Jin; Hwang, Jae Sam; Jeong, Eun Ju; Moon, Kyoung-Sik

    2015-01-01

    The objective of this study was to investigate the toxicological information of freeze-dried powder from Allomyrina dichotoma (A. dichotoma) larvae as a food ingredient. The powder, suspended in distilled water, was administered once daily by oral gavage to four groups of Sprague-Dawley (SD) rats at dose levels of 0 (vehicle control), 250, 850, and 2500 mg/kg/day. After 13 wks of repeated administration, the standard toxicological parameters such as mortality, clinical signs, body weight, food consumption, ophthalmologic examination, clinical pathology, organ weights and macro/microscopic examination were applied for assessment of general toxicity. In addition, serum IgE and histamine levels were determined to evaluate allergenicity. The freeze-dried powder from A. dichotoma larvae did not produce treatmentrelated changes or findings in any toxicological parameters in either sex of any dosed groups except for slight increases in serum histamine levels at 2500 mg/kg/day. The changes were considered not to be adverse since the magnitude was minimal. In conclusion, the NOAEL (No Observed Adverse Effect Level) of the freeze-dried powder from A. dichotoma larvae was determined to be 2500 mg/kg/day or more in both sexes of SD rats and it is considered a candidate to be edible material. PMID:25874035

  14. Evaluation of a low-dose CT protocol with oral contrast for assessment of acute appendicitis.

    PubMed

    Platon, Alexandra; Jlassi, Helmi; Rutschmann, Olivier T; Becker, Christoph D; Verdun, Francis R; Gervaz, Pascal; Poletti, Pierre-Alexandre

    2009-02-01

    The aim of this study was to evaluate a low-dose CT with oral contrast medium (LDCT) for the diagnosis of acute appendicitis and compare its performance with standard-dose i.v. contrast-enhanced CT (standard CT) according to patients' BMIs. Eighty-six consecutive patients admitted with suspicion of acute appendicitis underwent LDCT (30 mAs), followed by standard CT (180 mAs). Both examinations were reviewed by two experienced radiologists for direct and indirect signs of appendicitis. Clinical and surgical follow-up was considered as the reference standard. Appendicitis was confirmed by surgery in 37 (43%) of the 86 patients. Twenty-nine (34%) patients eventually had an alternative discharge diagnosis to explain their abdominal pain. Clinical and biological follow-up was uneventful in 20 (23%) patients. LDCT and standard CT had the same sensitivity (100%, 33/33) and specificity (98%, 45/46) to diagnose appendicitis in patients with a body mass index (BMI) >or= 18.5. In slim patients (BMI<18.5), sensitivity to diagnose appendicitis was 50% (2/4) for LDCT and 100% (4/4) for standard CT, while specificity was identical for both techniques (67%, 2/3). LDCT may play a role in the diagnostic workup of patients with a BMI >or= 18.5.

  15. Subchronic Oral Dose Toxicity of Freeze-dried Powder of Allomyrina dichotoma Larvae.

    PubMed

    Noh, Jung-Ho; Yun, Eun-Young; Park, Heejin; Jung, Kyung-Jin; Hwang, Jae Sam; Jeong, Eun Ju; Moon, Kyoung-Sik

    2015-03-01

    The objective of this study was to investigate the toxicological information of freeze-dried powder from Allomyrina dichotoma (A. dichotoma) larvae as a food ingredient. The powder, suspended in distilled water, was administered once daily by oral gavage to four groups of Sprague-Dawley (SD) rats at dose levels of 0 (vehicle control), 250, 850, and 2500 mg/kg/day. After 13 wks of repeated administration, the standard toxicological parameters such as mortality, clinical signs, body weight, food consumption, ophthalmologic examination, clinical pathology, organ weights and macro/microscopic examination were applied for assessment of general toxicity. In addition, serum IgE and histamine levels were determined to evaluate allergenicity. The freeze-dried powder from A. dichotoma larvae did not produce treatmentrelated changes or findings in any toxicological parameters in either sex of any dosed groups except for slight increases in serum histamine levels at 2500 mg/kg/day. The changes were considered not to be adverse since the magnitude was minimal. In conclusion, the NOAEL (No Observed Adverse Effect Level) of the freeze-dried powder from A. dichotoma larvae was determined to be 2500 mg/kg/day or more in both sexes of SD rats and it is considered a candidate to be edible material.

  16. Effect of low-dose oral contraceptives on androgenic markers and acne.

    PubMed

    Thorneycroft, I H; Stanczyk, F Z; Bradshaw, K D; Ballagh, S A; Nichols, M; Weber, M E

    1999-11-01

    Oral contraceptives (OC) suppress excess androgen production; however, different progestins in combination with low-dose estrogens produce divergent effects on sex hormone-binding globulin (SHBG) and testosterone that may influence clinical outcomes. This multicenter, open-label, randomized study compared biochemical androgen profiles and clinical outcomes associated with two OC containing the same amounts of ethinyl estradiol (EE, 20 micrograms) but different progestins, levonorgestrel (LNG, 100 micrograms), and norethindrone acetate (NETA, 1000 micrograms). Fifty-eight healthy women (18-28 years old) received three cycles of treatment with LNG/EE (n = 30) or NETA/EE (n = 28). The results showed that LNG reduced androgen levels in three compartments--adrenal, ovarian, and peripheral. NETA reduced only adrenal and peripheral androgens. Despite a 2.2-fold greater relative increase in SHBG with NETA than LNG, bioavailable testosterone (T) was reduced by the same amount with LNG and NETA. Both treatments improved acne and were well tolerated. Low-dose OC (EE, 20 micrograms) are effective in reducing circulating androgens and acne lesions without causing weight gain. Although LNG and NETA affected secondary markers differently, both OC formulations produced an equivalent decrease in bioavailable.

  17. Pharmacokinetics of meloxicam after intramuscular and oral administration of a single dose to American flamingos (Phoenicopertus ruber).

    PubMed

    Boonstra, Jennifer L; Cox, Sherry K; Martin-Jimenez, Tomas

    2017-03-01

    OBJECTIVE To determine pharmacokinetics after IM and oral administration of a single dose of meloxicam to American flamingos (Phoenicopertus ruber). ANIMALS 14 adult flamingos. PROCEDURES Flamingos were allocated to 2 groups. Each group received a dose of meloxicam (1 mg/kg) by the IM or oral route. After a 4-week washout period, groups received meloxicam via the other route of administration. Plasma meloxicam concentrations were measured with high-performance liquid chromatography. Data for each bird were analyzed. Estimated values of selected pharmacokinetic parameters were compared by use of a linear mixed-effects ANOVA. Pooled concentration-time profiles for each route of administration were analyzed to examine the influence of body weight on pharmacokinetics. RESULTS Mean ± SD maximum plasma concentration was 1.00 ± 0.88 μg/mL after oral administration. This was approximately 15% of the mean maximum plasma concentration of 5.50 ± 2.86 μg/mL after IM administration. Mean time to maximum plasma concentration was 1.33 ± 1.32 hours after oral administration and 0.28 ± 0.17 hours after IM administration. Mean half-life of the terminal phase after oral administration (3.83 ± 2.64 hours) was approximately twice that after IM administration (1.83 ± 1.22 hours). CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that the extent and rate of meloxicam absorption were less after oral administration than after IM administration. Intramuscular administration resulted in a short period during which mean plasma concentrations met or exceeded reported efficacious analgesic concentrations in other species, whereas oral administration did not. These results suggested that higher doses may be required for oral administration.

  18. Safety assessment of SDA soybean oil: results of a 28-day gavage study and a 90-day/one generation reproduction feeding study in rats.

    PubMed

    Hammond, Bruce G; Lemen, Joan K; Ahmed, Gulam; Miller, Kathleen D; Kirkpatrick, Jeannie; Fleeman, Tammye

    2008-12-01

    Long chain polyunsaturated fatty acids (LC-PUFAs) in the diet reduce risk of cardiac mortality. Fish oils are a dietary source of LC-PUFAs (EPA, DHA) but intake is low in Western diets. Adding beneficial amounts of LC-PUFAs to foods is limited by their instability and potential to impart off-flavors. Stearidonic acid (SDA), a precursor of EPA in man, is more stable than EPA/DHA in food matrices. SDA is present in fish oils (0.5-4%) and in nutraceuticals (echium, borage oil). Genes for Delta6, Delta15 desaturases were introduced into soybeans that convert linoleic and alpha-linolenic acid to SDA (15-30% fatty acids). Since addition of SDA soybean oil into human foods increases SDA intake, toxicology studies were undertaken to assess its safety. In a 28-day pilot study, rats were gavaged with SDA soybean oil at dosages up to 3g/kg body weight/day; no treatment-related adverse effects were observed. A 90-day/one generation rat reproduction study was subsequently conducted where SDA soybean oil was added to diets to provide daily doses of 1.5 and 4 g/kg body weight. There were no treatment-related adverse effects on parental animals or on reproductive performance and progeny development.

  19. Pharmacokinetics, safety, and hydrolysis of oral pyrroloquinazolinediamines administered in single and multiple doses in rats.

    PubMed

    Li, Qigui; Kozar, Michael P; Shearer, Todd W; Xie, Lisa H; Lin, Ai J; Smith, Kirsten S; Si, Yuanzheng; Anova, Lalaine; Zhang, Jing; Milhous, Wilbur K; Skillman, Donald R

    2007-08-01

    Pyrroloquinazolinediamine (PQD) derivatives such as tetra-acetamide PQD (PQD-A4) and bis-ethylcarbamyl PQD (PQD-BE) were much safer (with therapeutic indices of 80 and 32, respectively) than their parent compound, PQD (therapeutic index, 10). Further evaluation of PQD-A4 and PQD-BE in single and multiple pharmacokinetic (PK) studies as well as corresponding toxicity studies was conducted with rats. PQD-A4 could be converted to two intermediate metabolites (monoacetamide PQD and bisacetamide PQD) first and then to the final metabolite, PQD, while PQD-BE was directly hydrolyzed to PQD without precursor and intermediate metabolites. Maximum tolerant doses showed that PQD-A4 and PQD-BE have only 1/12 and 1/6, respectively, of the toxicity of PQD after a single oral dose. Compared to the area under the concentration-time curve for PQD alone (2,965 ng.h/ml), values measured in animals treated with PQD-A4 and PQD-BE were one-third (1,047 ng.h/ml) and one-half (1,381 ng.h/ml) as high, respectively, after an equimolar dosage, suggesting that PQD was the only agent to induce the toxicity. Similar results were also shown in multiple treatments; PQD-A4 and PQD-BE generated two-fifths and three-fifths, respectively, of PQD concentrations, with 8.8-fold and 3.8-fold safety margins, respectively, over the parent drug. PK data indicated that the bioavailability of oral PQD-A4 was greatly limited at high dose levels, that PQD-A4 was slowly converted to PQD via a sequential three-step process of conversion, and that PQD-A4 was significantly less toxic than the one-step hydrolysis drug, PQD-BE. It was concluded that the slow and smaller release of PQD was the main reason for the reduction in toxicity and that the active intermediate metabolites can still maintain antimalarial potency. Therefore, the candidate with multiple-step hydrolysis of PQD could be developed as a safer potential agent for malaria treatment.

  20. [Oral loading dose of phenytoin in the treatment of serial seizures, prevention of seizure recurrence and rapid drug substitution].

    PubMed

    Sokić, D; Janković, S M

    1994-01-01

    Over a period of nine months twenty-five epileptic patients were treated with the oral loading dose of phenytoin. The dose ranged from 12 to 23 mg/kg body weight during 1 to 12 hours. In 20 patients with serial seizures or intolerance to other antiepileptic drugs this treatment was effective. Seizures also stopped in 2 of 4 patients with serial partial motor seizures. These 2 patients required both higher loading dose and faster rate of administration than the other patients. A patient with epilepsia partialis continua failed to respond to the treatment. Patients that received phenytoin through the naso-gastric tube, in respect to oral administration, required higher doses to obtain therapeutic plasma levels of phenytoin. One patient had mild nausea, 3 mild dizziness, and 1 tinitus on the first day of the treatment. There was no correlation between a given dose and the achieved phenytoin plasma levels. In our opinion the therapy with oral loading dose of phenytoin is highly effective in the treatment of serial generalized seizures and rapid antiepileptic drug substitution, and partially effective in the prevention of partial motor seizures. It produces only mild and transient side-effects.

  1. "Zeus" a new oral anticoagulant therapy dosing algorithm: a cohort study.

    PubMed

    Cafolla, A; Melizzi, R; Baldacci, E; Pignoloni, P; Dragoni, F; Campanelli, M; Caraccini, R; Foà, R

    2011-10-01

    The demand for oral anticoagulant therapy (OAT) has constantly increased during the last ten years with an extended use of computer assistance. Many mathematical algorithms have been projected to suggest doses and time to next visit for patients on OAT. We designed a new algorithm: "Zeus". A "before-after" study was planned to compare the efficacy and safety of this algorithm dosing OAT with manual dosage decided by the same expert physicians according to the target of International Normalized Ratio (INR). The study analysed data of 1876 patients managed with each of the two modalities for eight months, with an interval of two years between them. The aim was to verify the increased quality of therapy by time spent in INR target and efficiency and safety of Zeus algorithm. Time in therapeutic range (TTR) was significantly (p < 0.0001) higher during the algorithm dosing period in comparison with the TTR during manual management period (62.3% vs 50.3%). The number of PT/INR tests above 5 was significantly (p < 0.001) reduced by algorithm suggested prescriptions in comparison with manual those (254 vs 537 times). The anticoagulant drug amount prescribed according to the algorithm suggestions was significantly (p < 0.0001) lower than that of the manual method. The number of clinical events observed in patients during the algorithm management time was significantly (p < 0.05) lower than that in those managed with the manual dosage. This study confirms the clinical utility of the computer-assisted OAT and shows the efficacy and safety of the Zeus algorithm.

  2. A repeated dose 90-day oral toxicity study of cyflumetofen,a novel acaricide, in rats.

    PubMed

    Yoshida, Toshinori; Ikemi, Naoki; Takeuchi, Yukiko; Ebino, Koichi; Kojima, Sayuri; Chiba, Yuko; Nakashima, Nobuaki; Kawakatsu, Hisao; Saka, Machiko; Harada, Takanori

    2012-02-01

    Cyflumetofen is a novel acaricide which is highly active against phytophagous mites. As a part of safety assessment, a repeated dose 90-day oral toxicity study of cyflumetofen was conducted in Fischer (F344/DuCrj) rats of both sexes. Technical grade cyflumetofen was administered in feed to groups of 10 males and 10 females at dose levels of 0, 100, 300, 1,000, and 3,000 ppm. Prothrombin time was prolonged in males at 3,000 ppm and plasma globulin levels were decreased in females at 1,000 and 3,000 ppm. At necropsy, enlarged and whitish adrenals were observed in females at 3,000 ppm. There were statistically significant increases in relative liver weight (ratio to body weight) in males and relative adrenal weight in females in the 1,000 ppm group; increased relative liver and kidney weights in both sexes at 3,000 ppm, and increased absolute and relative weights of adrenals in females at 3,000 ppm. Increased absolute liver weight was also noted in males at 3,000 ppm. Histopathologically, at 1,000 and 3,000 ppm males had diffuse vacuolation and females had diffuse hypertrophy of adrenal cortical cells. In addition, vacuolation of ovarian interstitial gland cells was noted in females at 1,000 and 3,000 ppm. There were no treatment-related changes in any parameters for either sex in other dose groups. Based on these results, the no-observed-adverse-effect level (NOAEL) of cyflumetofen was judged to be 300 ppm for both sexes (16.5 mg/kg/day for males and 19.0 mg/kg/day for females).

  3. 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.

  4. 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...

  5. Tolerance to effects of high-dose oral δ9-tetrahydrocannabinol and plasma cannabinoid concentrations in male daily cannabis smokers.

    PubMed

    Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene; Schwope, David M; Darwin, William D; Kelly, Deanna L; McMahon, Robert P; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A

    2013-01-01

    Oral cannabinoids are taken for medicinal or recreational purposes, yet little is known about tolerance to their effects after high-dose extended exposure. The development of tolerance to effects of around-the-clock oral synthetic Δ9-tetrahydrocannabinol (THC) (20 mg every 3.5-6 h) was evaluated in 13 healthy male daily cannabis smokers residing on a secure research unit: 40 mg on Day 1; 100 mg on Days 2-4; 120 mg on Days 5-6. Systolic and diastolic blood pressure (BP), heart rate, and symptoms of subjective intoxication (100 mm visual-analogue scales, VAS) were assessed the morning of Day 1 (before any oral THC), and on Days 2, 4 and 6, every 30 min for 3 h after the first morning THC dose. Morning subjective intoxication ratings increased from Days 1 to 2, and then declined on Days 4 and 6. The morning THC dose increased intoxication ratings on Day 2, but had less effect on Days 4 and 6, a pattern consistent with tolerance. THC lowered BP and increased heart rate over the six days. Plasma THC and 11-OH-THC concentrations increased significantly over the first five days of dosing. Six days of around-the-clock, oral THC produced tolerance to subjective intoxication, but not to cardiovascular effects.

  6. Novel and distinct metabolites identified following a single oral dose of alpha- or gamma-hexabromocyclododecane in mice

    Technology Transfer Automated Retrieval System (TEKTRAN)

    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 and sacrificed 3 hour...

  7. High dose and low dose Lactobacilli acidophilus exerted differential immune modulating effects on T cell immune responses induced by an oral human rotavirus vaccine in gnotobiotic pigs

    PubMed Central

    Wen, Ke; Li, Guohua; Bui, Tammy; Liu, Fangning; Li, Yanru; Kocher, Jacob; Lin, Lin; Yang, Xingdong; Yuan, Lijuan

    2011-01-01

    Background Strain-specific effects of probiotics in pro- or anti-inflammatory immune responses have been well recognized. Several proinflammatory Lactobacillus strains have been shown to act as adjuvants to enhance the immunogenicity of vaccines. However, dose effects of probiotics in modulating immune responses are not clearly understood. This study examined the dose effects of Lactobacillus acidophilus (LA) NCFM strain on T cell immune responses to rotavirus vaccination in a gnotobiotic (Gn) pig model. Methods Frequencies of IFN-γ producing CD4+ and CD8+ T cell and IL-10 and TGF-β producing CD4+CD25+ and CD4+CD25- regulatory T (Treg) cell responses were determined in the intestinal and systemic lymphoid tissues of Gn pigs vaccinated with an oral human rotavirus vaccine in conjunction with low dose (5 feedings; up to 106 colony forming units [CFU]/dose) or high dose (14 feedings; up to 109 CFU/dose) or without LA feeding. Results Low dose LA significantly promoted IFN-γ producing T cell responses and down-regulated Treg cell responses and their TGF-β and IL-10 productions in all the tissues compared to the high dose LA and control groups. To the contrary, high dose LA increased the frequencies of Treg cells in most of the tissues compared to the control groups. The dose effects of LA on IFN-γ producing T cell and CD4+CD25- Treg cell immune responses were similar in the intestinal and systemic lymphoid tissues and were independent from the vaccination. Conclusion Thus the same probiotic strain in different doses can either promote or suppress IFN-γ producing T cell or Treg cell immune responses. These findings have significant implications in the use of probiotic lactobacilli as immunostimulatory versus immunoregulatory agents. Probiotics can be ineffective or even detrimental if not used at the optimal dosage for the appropriate purposes. PMID:22178726

  8. Low-Dose Pharmacokinetics and Oral Bioavailability of Dichloroacetate in Naive and GST-zeta Depleted Rats

    SciTech Connect

    Saghir, Shakil A.; Schultz, Irv R. )

    2002-01-01

    Pharmacokinetics of dichloroacetate (DCA) in naive and glutathione-S-transferase-zeta (GSTzeta) depleted rats was studied at doses approaching human daily exposure levels. In vitro metabolism of DCA by rat and human liver cytosol was also compared. Jugular vein cannulated male Fischer-344 rats were administered (i.v or gavage) with graded doses of DCA ranging from 0.05-20 mg/kg and time-course blood samples collected from the cannula. GSTzeta was depleted by exposing rats to DCA (0.2 g/L DCA) in drinking water for 7 days. Elimination of DCA by naive rats was so rapid that only the 1-20 mg/kg i.v. and 5 and 20 mg/kg gavage doses provided plasma concentrations above the method detection limit. GSTzeta depletion slowed DCA elimination from plasma allowing kinetic analysis of doses as low as 0.05 mg/kg. DCA elimination was strongly dose-dependent in the naive rats with total body clearance declining with increasing dose. In the GSTzeta depleted rats, the pharmacokinetics became line ar at doses No.1 mg/kg. All oral doses were rapidly absorbed without any lag time. At higher oral doses (?5 mg/kg in GSTzeta depleted and?20 mg/kg in naive), secondary peaks in the plasma concentration appeared long after the completion of the initial absorption phase. Virtually all the dose was eliminated through metabolic clearance; the rate of urinary elimination of DCA was < 1 ml h-1kg-1. A maximum of 1.0?0.3% dose was recovered in urine within 24 h in the GSTzeta depleted rats dosed i.v. with 20 mg/kg. The rate of in vitro metabolism of DCA by human cytosol was statistically similar to the GSTzeta depleted rats (p > 0.3), which supported the use of GSTzeta depleted rats as a model for assessing kinetics of DCA in humans. Oral bioavailability of DCA was 0-13% in naive and 14-75% in GSTzeta depleted rats. Oral bioavailability of DCA to humans through consumption of drinking water was predicted to be a maximum of 0.05%.

  9. A 4-week Repeated dose Oral Toxicity Study of Mecasin in Sprague-Dawley Rats to Determine the Appropriate Doses for a 13-week, Repeated Toxicity Test

    PubMed Central

    Cha, Eunhye; Lee, Jongchul; Lee, Seongjin; Park, Manyong; Song, Inja; Son, Ilhong; Song, Bong-Keun; Kim, Dongwoung; Lee, Jongdeok

    2015-01-01

    Objectives: In this study, we investigated the 4-week repeated-dose oral toxicity of gami-jakyak gamcho buja decoction (Mecasin) to develop safe treatments. Methods: In order to investigate the 4-week oral toxicity of Mecasin, we administered Mecasin orally to rats. Sprague-Dawley (SD) rats were divided into four groups of five male and five female animals per group: group 1 being the control group and groups 2, 3, and 4 being the experimental groups. Doses of Mecasin of 500, 1,000, and 2,000 mg/kg of body weight were administered to the experimental groups, and a dose of normal saline solution of 10 mL/kg was administered to the control group. We examined the survival rate, weight, clinical signs, and gross findings for four weeks. This study was conducted under the approval of the Institutional Animal Ethics Committee. Results: No deaths occurred in any of the four groups. No significant changes in weights or food consumption between the control group and the experimental groups were observed. Serum biochemistry revealed that some groups showed significant decrease in inorganic phosphorus (IP) (P < 0.05). During necropsy on the rats, one abnormal macroscopic feature, a slight loss of fur, was observed in the mid dosage (1,000 mg/ kg) male group. No abnormalities were observed in any other rats. In histopathological findings, the tubular basophilia and cast of the kidney and extramedullary hematopoiesis of the spleen were found. However, those changes were minimal and had occurred naturally or sporadically. No other organ abnormalities were observed. Conclusion: During this 4-week, repeated, oral toxicity test of Mecasin in SD rats, no toxicity changes due to Mecasin were observed in any of the male or the female rats in the high dosage group. Thus, we suggest that the doses in a 13-week, repeated test should be 0, 500, 1,000, and 2,000 mg/kg respectively. PMID:26998389

  10. Miltefosine lipid nanocapsules: Intersection of drug repurposing and nanotechnology for single dose oral treatment of pre-patent schistosomiasis mansoni.

    PubMed

    El-Moslemany, Riham M; Eissa, Maha M; Ramadan, Alyaa A; El-Khordagui, Labiba K; El-Azzouni, Mervat Z

    2016-07-01

    A dual drug repurposing/nanotechnological approach was used to develop an alternative oral treatment for schistosomiasis mansoni using miltefosine (MFS), an anticancer alkylphosphocholine, and lipid nanocapsules (LNCs) as oral nanovectors. We demonstrated earlier that MFS possesses significant activity against different developmental stages of Schistosoma mansoni in the mouse model using 5 successive 20mg/kg/day oral doses. Moreover, an effective single dose (20mg/kg) oral treatment against the adult stage of S. mansoni in mice was developed using LNCs, particularly modified with CTAB, a positive charge imparting agent (MFS-LNC-CTAB(+)), or oleic acid as membrane permeabilizer (MFS-LNC-OA). Efficacy enhancement involved, at least in part, targeting of the worm tegument with MFS-LNCs as a new therapeutic entity. As the tegument surface charge and composition may differ in pre-patent stages of the parasite, it was of importance in the present study to assess the efficacy of a single oral dose of the two MFS-LNC formulations against invasive and immature stages for potential advantage relative to praziquantel. Results indicated potent schistosomicidal effects against both invasive and immature stages of S. mansoni in infected mice, efficacy being both formulation and developmental stage dependent. This was indicated by the significant reduction in the total worm burden of the invasive stage by 91.6% and 76.8% and the immature stage by 82.7% and 96.7% for MFS-LNC-CTAB+ and MFS-LNC-OA, respectively. Histopathological findings indicated amelioration of hepatic pathology with regression of the granulomatous inflammatory reaction and reduction in granulomas number and size, verifying marked improvement in architecture of hepatic lobules. From a clinical perspective, MFS-LNCs offer potential as an alternative single oral dose nanomedicine with a wide therapeutic profile for the mass chemotherapy of schistosomiasis mansoni.

  11. Clinical and microbiological effects of a subantimicrobial dose of oral doxycycline on periodontitis in dogs.

    PubMed

    Kim, S E; Hwang, S Y; Jeong, M; Lee, Y; Lee, E R; Park, Y W; Ahn, J S; Kim, S; Seo, K

    2016-02-01

    Doxycycline is regarded as an effective treatment for periodontal inflammation. In humans, it has been shown that the long-term administration of a subantimicrobial dose of doxycycline (SDD) does not induce antimicrobial effects on the subgingival microflora and furthermore does not affect antimicrobial susceptibility. The present study was designed to evaluate the influence of oral administration of SDD on normal periodontal microflora and antimicrobial susceptibility in dogs. Experimental periodontitis was induced in 12 experimental dogs using a silk and wire-twisted ligature for 60 days. After the periodontitis induction period, the ligature was removed, and dental cleaning (subgingival and supragingival ultrasonic scaling) was performed. The dogs were randomly assigned to one of two groups: an SDD group with six dogs receiving 2 mg/kg PO once daily and a control group with six dogs receiving a placebo. At weeks 0, 4 and 8, clinical periodontal parameters were evaluated. After the clinical assessments, subgingival plaque was sampled and then cultured in an anaerobic system for one week, and the total anaerobes, Porphyromonas spp., Bacteroides spp. and Pasteurella spp. counts were investigated. Using the agar dilution method, the minimum bactericidal concentration of doxycycline was evaluated and the resistance for doxycycline was monitored during this experimental phase. The clinical periodontal status of the SDD group was significantly improved compared to the control group (P <0.05). Bacterial counts were not significantly different between the two experimental groups (P > 0.05), and antibacterial resistance was not established in the SDD group during the experimental periods (P <0.05). These results suggest that the once daily oral regimen of 2 mg/kg of doxycycline could serve as a SDD in dogs.

  12. Evaluation of changes in serum chemistry in association with feed withdrawal or high dose oral gavage with Dextran Sodium Sulfate (DSS) induced gut leakage in broiler chickens

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Dextran sodium sulfate (DSS) has been shown to be effective at inducing enteric inflammation in broiler chickens, resulting in increased leakage of orally administered fluorescein isothiocyanate dextran to circulation. In a previous study, two doses of DSS (0.45g/dose) administered as oral gavage re...

  13. VO2max and ventilatory threshold of trained cyclists are not affected by 28-day L-arginine supplementation.

    PubMed

    Sunderland, Kyle L; Greer, Felicia; Morales, Jacobo

    2011-03-01

    The ergogenic effect of L-arginine on an endurance-trained population is not well studied. The few studies that have investigated L-arginine on this population have not been conducted in a laboratory setting or measured aerobic variables. The purpose of the current study is to determine if 28 days of L-arginine supplementation in trained male cyclists affects VO2max and ventilatory threshold (VT). Eighteen (18) endurance-trained male cyclists (mean ± SD, age: 36.3 ± 7.9 years; height: 182.4 ± 4.6 cm; and body mass: 79.5 ± 4.7 kg) performed a graded exercise test (GXT; 50 W + 25 W·min) before and after 28 days of supplementation with L-arginine (ARG; 2 × 6 g·d) or placebo (PLA; cornstarch). The GXT was conducted on the subject's own bicycle using the RacerMate CompuTrainer (Seattle, WA, USA). VO2 was continuously recorded using the ParvoMedics TrueOne 2400 metabolic cart (Salt Lake City, UT, USA) and VT was established by plotting the ventilatory equivalent for O2 (VE/VO2) and the ventilatory equivalent for CO2 (VE/VCO2) and identifying the point at which VE/VO2 increases with no substantial changes in VE/VCO2. L-arginine supplementation had no effect from initial VO2max (PL, 58.7 ± 7.1 ml·kg·min; ARG, 63.5 ± 7.3 ml·kg·min) to postsupplement VO2max (PL, 58.9 ± 6.0 ml·kg·min; ARG, 63.2 ± 7.2 ml·kg·min). Also, no effect was seen from initial VT (PL, 75.7 ± 4.6% VO2max; ARG, 76.0 ± 5.3% VO2max) to postsupplement VT (PL, 74.3 ± 8.1% VO2max; ARG, 74.2 ± 6.4% VO2max). These results indicate that L-arginine does not impact VO2max or VT in trained male cyclists.

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

    NASA Astrophysics Data System (ADS)

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

    2014-05-01

    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 < 0.05) compared to the control (0.51 ± 0.07). Histology of the liver, spleen and brain was found to be of similar morphology in both control and experimental groups. The kidneys of 500-mg/kg-treated rats with levodopa nanocomposite and LDH nanocomposite were found to have slight inflammatory changes, notably leukocyte infiltration around the glomeruli. The ultra-structure of the neurons from the substantia nigra of nanocomposite-exposed group was similar to those receiving only normal saline. The observed result has suggested possible liver and renal toxicity in orally administered levodopa intercalated

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

    PubMed Central

    2014-01-01

    orally administered levodopa intercalated nanocomposite; it is also dose-dependent that needs further assessment. PMID:24948886

  16. 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.

  17. Complex histopathologic response in rat kidney to oral β-myrcene: an unusual dose-related nephrosis and low-dose alpha2u-globulin nephropathy.

    PubMed

    Cesta, Mark F; Hard, Gordon C; Boyce, John T; Ryan, Michael J; Chan, Po C; Sills, Robert C

    2013-01-01

    Oral gavage studies with β-myrcene in male F344 rats showed a complex renal pathology comprising both alpha2u-globulin (α2u-g) nephropathy, an unusual nephrosis involving the outer stripe of outer medulla (OSOM), and an increased incidence of renal tubule tumors by 2 years. In the 90-day and 2-year studies, respectively, α2u-g nephropathy and linear papillary mineralization were observed in males at the two lower doses but were absent from the high dose. Nephrosis was characterized by dilation of the S3 tubules, nuclear enlargement (including karyomegaly), and luminal pyknotic cells, all in the outermost OSOM. Nephrosis was minimal at the higher doses in the 90-day study, but progressed to a severe grade in males dosed with 1,000 mg/kg for 2 years. Renal tubule tumors developed in treated groups with incidences up to 30% in the 250 and 500 mg/kg male dose groups. Tumors at the lower doses in males may have been associated with α2u-g nephropathy, while those at higher doses in both sexes may have been due to the nephrosis. Because β-myrcene induced a complex spectrum of renal pathology, the α2u-g nephropathy mechanism cannot be the sole mechanism of carcinogenesis in these rats.

  18. Aeromonas hydrophila OmpW PLGA Nanoparticle Oral Vaccine Shows a Dose-Dependent Protective Immunity in Rohu (Labeo rohita).

    PubMed

    Dubey, Saurabh; Avadhani, Kiran; Mutalik, Srinivas; Sivadasan, Sangeetha Madambithara; Maiti, Biswajit; Paul, Joydeb; Girisha, Shivani Kallappa; Venugopal, Moleyur Nagarajappa; Mutoloki, Stephen; Evensen, Øystein; Karunasagar, Indrani; Munang'andu, Hetron Mweemba

    2016-06-01

    Aeromonas hydrophila is a Gram-negative bacterium that causes high mortality in different fish species and at different growth stages. Although vaccination has significantly contributed to the decline of disease outbreaks in aquaculture, the use of oral vaccines has lagged behind the injectable vaccines due to lack of proven efficacy, that being from primary immunization or by use of boost protocols. In this study, the outer membrane protein W (OmpW) of A. hydrophila was cloned, purified, and encapsulated in poly d,l-lactide-co-glycolic acid (PLGA) nanoparticles (NPs) for oral vaccination of rohu (Labeo rohita Hamilton). The physical properties of PLGA NPs encapsulating the recombinant OmpW (rOmpW) was characterized as having a diameter of 370-375 nm, encapsulation efficiency of 53% and -19.3 mV zeta potential. In vitro release of rOmpW was estimated at 34% within 48 h of incubation in phosphate-buffered saline. To evaluate the efficacy of the NP-rOmpW oral vaccine, two antigen doses were orally administered in rohu with a high antigen (HiAg) dose that had twice the amount of antigens compared to the low antigen (LoAg) dose. Antibody levels obtained after vaccination showed an antigen dose dependency in which fish from the HiAg group had higher antibody levels than those from the LoAg group. The antibody levels corresponded with post challenge survival proportions (PCSPs) and relative percent survival (RPS) in which the HiAg group had a higher PCSP and RPS than the LoAg group. Likewise, the ability to inhibit A. hydrophila growth on trypticase soy agar (TSA) by sera obtained from the HiAg group was higher than that from the LoAg group. Overall, data presented here shows that OmpW orally administered using PLGA NPs is protective against A. hydrophila infection with the level of protective immunity induced by oral vaccination being antigen dose-dependent. Future studies should seek to optimize the antigen dose and duration of oral immunization in rohu in order to

  19. Aeromonas hydrophila OmpW PLGA Nanoparticle Oral Vaccine Shows a Dose-Dependent Protective Immunity in Rohu (Labeo rohita)

    PubMed Central

    Dubey, Saurabh; Avadhani, Kiran; Mutalik, Srinivas; Sivadasan, Sangeetha Madambithara; Maiti, Biswajit; Paul, Joydeb; Girisha, Shivani Kallappa; Venugopal, Moleyur Nagarajappa; Mutoloki, Stephen; Evensen, Øystein; Karunasagar, Indrani; Munang’andu, Hetron Mweemba

    2016-01-01

    Aeromonas hydrophila is a Gram-negative bacterium that causes high mortality in different fish species and at different growth stages. Although vaccination has significantly contributed to the decline of disease outbreaks in aquaculture, the use of oral vaccines has lagged behind the injectable vaccines due to lack of proven efficacy, that being from primary immunization or by use of boost protocols. In this study, the outer membrane protein W (OmpW) of A. hydrophila was cloned, purified, and encapsulated in poly d,l-lactide-co-glycolic acid (PLGA) nanoparticles (NPs) for oral vaccination of rohu (Labeo rohita Hamilton). The physical properties of PLGA NPs encapsulating the recombinant OmpW (rOmpW) was characterized as having a diameter of 370–375 nm, encapsulation efficiency of 53% and −19.3 mV zeta potential. In vitro release of rOmpW was estimated at 34% within 48 h of incubation in phosphate-buffered saline. To evaluate the efficacy of the NP-rOmpW oral vaccine, two antigen doses were orally administered in rohu with a high antigen (HiAg) dose that had twice the amount of antigens compared to the low antigen (LoAg) dose. Antibody levels obtained after vaccination showed an antigen dose dependency in which fish from the HiAg group had higher antibody levels than those from the LoAg group. The antibody levels corresponded with post challenge survival proportions (PCSPs) and relative percent survival (RPS) in which the HiAg group had a higher PCSP and RPS than the LoAg group. Likewise, the ability to inhibit A. hydrophila growth on trypticase soy agar (TSA) by sera obtained from the HiAg group was higher than that from the LoAg group. Overall, data presented here shows that OmpW orally administered using PLGA NPs is protective against A. hydrophila infection with the level of protective immunity induced by oral vaccination being antigen dose-dependent. Future studies should seek to optimize the antigen dose and duration of oral immunization in rohu in order to

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

    PubMed Central

    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

  1. Dose-response of Listeria monocytogenes after oral exposure in pregnant guinea pigs.

    PubMed

    Williams, Denita; Irvin, Elizabeth A; Chmielewski, Revis A; Frank, Joseph F; Smith, Mary A

    2007-05-01

    Listeriosis, a severe disease that results from exposure to the foodborne pathogen Listeria monocytogenes, is responsible for approximately 2500 illnesses and 500 deaths in the United States each year. Pregnant women are 20 times more likely to develop listeriosis than the general population, with adverse pregnancy outcomes that include spontaneous abortions, stillbirths, and neonatal meningitis. The objective of this study was to determine an infective dose that resulted in stillbirths and infectivity of selected tissues in pregnant guinea pigs. Pregnant guinea pigs were exposed orally on gestation day 35 to 10(4) to 10(8) L. monocytogenes CFU in sterile whipping cream. L. monocytogenes was recovered at 64, 73, 90, and 100% from the livers of animals infected with 10(5), 10(6), 10(7), and 10(8) CFU, respectively. In dams exposed to > or =10(6) CFU, L. monocytogenes was cultured from 50% of the spleen samples and 33% of the gallbladder samples. Eleven of 34 dams infected with > or =10(6) CFU delivered stillborn pups. L. monocytogenes was cultured from the placenta, liver, and brain tissue of all stillbirths. Dams that delivered nonviable fetuses after treatment with > or =10(7) L. monocytogenes CFU had fecal samples positive for L. monocytogenes at every collection posttreatment. On the basis of a log-logistic model, the dose that adversely affected 50% of the pregnancies was approximately 10(7) L. monocytogenes CFU compared with that estimated from a human outbreak of 106 CFU. Listeriosis in pregnant guinea pigs can result in stillbirths, and the overall disease is similar to that described in nonhuman primates and in humans.

  2. Psychomotor performance during a 28 day head-down tilt with and without lower body negative pressure

    NASA Astrophysics Data System (ADS)

    Traon, A. Pavy-le; de Feneyrols, A. Rous; Cornac, A.; Abdeseelam, R.; N'uygen, D.; Lazerges, M.; Güell, A.; Bes, A.

    Several factors may affect psychomotor performance in space: sensory-motor changes, sleep disturbances, psychological modifications induced by the social isolation and confinement. However, psychomotor performance is difficult to assess. A battery of standardized and computerized tests, so-called "Automated Portable Test System" (APTS) was devised to ascertain the cognitive, perceptive and motor abilities and their possible fluctuations according to environmental effects. Antiorthostatic bedrest, often used to simulate weightlessness, (particularly cardiovascular modifications) also constitutes a situation of social confinement and isolation. During two bedrest experiments (with head-down tilt of -6°) of 28 days each, we intended to assess psychomotor performance of 6 males so as to determine whether: —on the one hand, it could be altered by remaining in decubitus; —on the other, the Lower Body Negative Pressure sessions, designed to prevent orthostatic intolerance back on Earth, could improve the performance. To accomplish this, part of the APTS tests as well as an automated perceptive attention test were performed. No downgrading of psychomotor performance was observed. On the contrary, the tasks were more accurately performed over time. In order to assess the experimental conditions on the acquisition phase, the learning curves were modelled. A beneficial effect of the LBNP sessions on simple tests involving the visual-motor coordination and attention faculties can only be regarded as a mere trend. Methods used in this experiment are also discussed.

  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. Acute toxicity, twenty-eight days repeated dose toxicity and genotoxicity of vanadyl trehalose in kunming mice.

    PubMed

    Jiang, Pingzhe; Ni, Zaizhong; Wang, Bin; Ma, Baicheng; Duan, Huikun; Li, Xiaodan; Ma, Xiaofeng; Wei, Qian; Ji, Xiangzhen; Liu, Qiqi; Xing, Shuguang; Li, Minggang

    2017-04-01

    A new trend has been developed using vanadium and organic ligands to form novel compounds in order to improve the beneficial actions and reduce the toxicity of vanadium compounds. In present study, vanadyl trehalose was explored the oral acute toxicity, 28 days repeated dose toxicity and genotoxicity in Kunming mice. The Median Lethal Dose (LD50) of vanadyl trehalose was revealed to be 1000 mg/kg body weight in fasted Kunming mice. Stomach and intestine were demonstrated to be the main target organs of vanadyl trehalose through 28 days repeated dose toxicity study. And vanadyl trehalose also showed particular genotoxicity through mouse bone marrow micronucleus and mouse sperm malformation assay. In brief, vanadyl trehalose presented certain, but finite toxicity, which may provide experimental basis for the clinical application.

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

    PubMed Central

    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

  6. Comparison of plasma bismuth levels after oral dosing with basic bismuth carbonate or tripotassium dicitrato bismuthate.

    PubMed

    Madaus, S; Schulte-Frohlinde, E; Scherer, C; Kämmereit, A; Schusdziarra, V; Classen, M

    1992-04-01

    In 20 healthy subjects plasma bismuth concentration was measured after single oral doses of basic bismuth carbonate or tripotassium dicitrato bismuthate. The drugs were administered in the fasted state or immediately after ingestion of a standard breakfast. After basic bismuth carbonate, plasma bismuth rose to concentrations between 0.7 and 2.6 micrograms/L in the fasted state, while after the meal the maximal level was only 1.3 micrograms/L. In contrast to these very low levels after basic bismuth carbonate, the administration of tripotassium dicitrato bismuthate was paralleled by an increase of plasma bismuth to concentrations between 15 and 232 micrograms/L with a mean peak value of 64 +/- 15.3 (S.E.M.) micrograms/L in the fasted state. Postprandial ingestion of tripotassium dicitrato bismuthate attenuated the peak concentrations to 10.9 +/- 6.3 micrograms/L. One subject, however, had a value of 120 micrograms/L. This study demonstrates that basic bismuth carbonate leads to very low plasma bismuth concentrations, which are far below the critical range that might eventually be associated with bismuth neurotoxicity. Therefore this compound can be considered potentially useful for bismuth therapy of gastrointestinal disorders.

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

    PubMed

    Schultz, I R; Reed, S; Pratt, A; Skillman, A 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 5 min. 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 absorption with peak body levels occurring within 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.

  8. 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.

  9. Evaluation of 2-week repeated oral dose toxicity of 100 nm zinc oxide nanoparticles in rats

    PubMed Central

    Ko, Je-Won; Hong, Eun-Taek; Lee, In-Chul; Park, Sung-Hyeuk; Park, Jong-Il; Seong, Nak-Won; Hong, Jeong-Sup; Yun, Hyo-In

    2015-01-01

    The aim of this study was to verify subacute oral dose toxicity of positively charged 100 nm zinc oxide (ZnOAE100[+]) nanoparticles (NPs) in Sprague-Dawley rats. ZnOAE100[+] NPs were administered to rats of each sex by gavage at 0, 500, 1,000, and 2,000 mg/kg/day for 14 days. During the study period, clinical signs, mortality, body weight, food consumption, hematology, serum biochemistry, gross pathology, organ weight, and histopathology were examined. Increased mortality and clinical signs, decreased body weight, feed consumption, hemoglobin (HB), hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet (PT), and lymphocyte (LYM) and increased white blood cells (WBCs), neutrophils (NEUs), alkaline phosphatase (ALP), and histopathological alterations in the spleen, stomach, and pancreas were observed at 2,000 mg/kg/day. Increased clinical signs, decreased body weight, feed consumption, HB, HCT, MCV, MCH, MCHC, and LYM and increased WBCs, NEUs, ALP, and histopathological alterations in the spleen, stomach, and pancreas were seen at 1,000 mg/kg/day. Increased clinical signs, decreased MCV and MCH and increased histopathological alterations in the stomach and pancreas were found at 500 mg/kg/day. These results suggest that the target organs were the spleen, stomach, and pancreas in rats. The no-observed-adverse-effect level was <500 mg/kg for both sexes. PMID:26472967

  10. A 13-week repeated-dose oral toxicity and bioaccumulation of aluminum oxide nanoparticles in mice.

    PubMed

    Park, Eun-Jung; Sim, Jaehoon; Kim, Younghun; Han, Beom Seok; Yoon, Cheolho; Lee, Somin; Cho, Myung-Haing; Lee, Byoung-Seok; Kim, Jae-Ho

    2015-03-01

    Because of an increase in the commercial applications of manufactured nanoparticles, the issue of potential adverse health effects of nanoparticles following intended or unintended exposure is rapidly gaining attention. In this study, we evaluated the toxicity of aluminum oxide nanoparticles (AlNPs, rod-type, 1.5, 3, and 6 mg/kg) after oral administration to mice for 13 weeks. Compared with the control group, the consumption of diet and drinking water and body weight gain decreased in the group treated with AlNPs. The group treated with 6 mg/kg AlNPs also showed a marked elevation in the count of white blood cells that associated with a significant decrease and increase to the proportion of eosinophils and lymphocytes, respectively. In addition, the secretion of IL-6 and monocyte chemotactic protein-1 increased in a dose-dependent manner in the treated groups. Furthermore, AlNPs showed the highest accumulation in the liver and kidneys compared with the control group, increased the lactate dehydrogenase level in the blood, and induced the development of a pathological lesion in the liver and kidneys. Taken together, we suggest that the target organs of rod-type AlNPs may be the liver, kidneys and the immune system, and the not-observed adverse effect level may be lower than 6 mg/kg.

  11. Pharmacokinetics of Ferrous Sulphate (Tardyferon®) after Single Oral Dose Administration in Women with Iron Deficiency Anaemia.

    PubMed

    Leary, A; Barthe, L; Clavel, T; Sanchez, C; Oulmi-Castel, M; Paillard, B; Edmond, J M; Brunner, V

    2016-01-01

    Iron-containing preparations available on the market vary in dosage, salt, and chemical state of iron contained in the preparation, as well as in the iron delivery process (immediate or prolonged-release). The present study aimed at characterizing the serum pharmacokinetics of iron in non pregnant women with iron deficiency anaemia (IDA) following a single oral administration of a prolonged-release ferrous sulphate tablet. This multicenter, single dose, open-label study was conducted in 30 women aged between 18 and 45 years with IDA. A single 160 mg oral dose of ferrous sulphate was given as 2 tablets of 80 mg of Tardyferon(®) under fasting conditions. Blood samples were collected before dosing and until 24 h post-dosing. Serum iron concentrations were determined using a routine colorimetric analytical method. Pharmacokinetic parameters were determined from the serum concentration profiles using a non compartmental approach. Serum profiles showed elevated levels of iron up to 12 h after drug intake. The median time to maximum serum concentrations (Tmax) occurred 4 h post-dosing. Between 2 and 8 h post-dosing, mean serum iron concentrations fluctuated by only 20%. Additionally, C8h and C12h represented on average 78.6% and 47.5% of the Cmax, respectively. This study demonstrates that a single oral dose of 160 mg Tardyferon(®) administered under fasting condition to 30 women with IDA leads to an optimal long-lasting release of iron in the gastrointestinal tract in the targeted population. This allows the attainment and maintenance of elevated serum iron levels for up to 12 h after administration.

  12. Comparison of the single dose pharmacokinetics, pharmacodynamics, and safety of two novel oral formulations of dimethandrolone undecanoate (DMAU): a potential oral, male contraceptive.

    PubMed

    Ayoub, R; Page, S T; Swerdloff, R S; Liu, P Y; Amory, J K; Leung, A; Hull, L; Blithe, D; Christy, A; Chao, J H; Bremner, W J; Wang, C

    2017-03-01

    Dimethandrolone (DMA, 7α,11β-dimethyl-19-nortestosterone) has both androgenic and progestational activities, ideal properties for a male hormonal contraceptive. In vivo, dimethandrolone undecanoate (DMAU) is hydrolyzed to DMA. We showed previously that single oral doses of DMAU powder in capsule taken with food are well tolerated and effective at suppressing both LH and testosterone (T), but absorption was low. We compared the pharmacokinetics and pharmacodynamics of two new formulations of DMAU, in castor oil and in self-emulsifying drug delivery systems (SEDDS), with the previously tested powder formulation. DMAU was dosed orally in healthy adult male volunteers at two academic medical centers. For each formulation tested in this double-blind, placebo-controlled study, 10 men received single, escalating, oral doses of DMAU (100, 200, and 400 mg) and two subjects received placebo. All doses were evaluated for both fasting and with a high fat meal. All three formulations were well tolerated without clinically significant changes in vital signs, blood counts, or serum chemistries. For all formulations, DMA and DMAU showed higher maximum (p < 0.007) and average concentrations (p < 0.002) at the 400 mg dose, compared with the 200 mg dose. The powder formulation resulted in a lower conversion of DMAU to DMA (p = 0.027) compared with both castor oil and SEDDS formulations. DMAU in SEDDS given fasting resulted in higher serum DMA and DMAU concentrations compared to the other two formulations. Serum LH and sex hormone concentrations were suppressed by all formulations of 200 and 400 mg DMAU when administered with food, but only the SEDDS formulation was effectively suppressed serum T when given fasting. We conclude that while all three formulations of oral DMAU are effective and well tolerated when administered with food, DMAU in oil and SEDDS increased conversion to DMA, and SEDDS may have some effectiveness when given fasting. These properties might be

  13. Simulation for clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance.

    PubMed

    Ishida, Kazuya; Kayano, Yuichiro; Taguchi, Masato; Hashimoto, Yukiya

    2007-11-01

    We performed a simulation for the clinical pharmacokinetic study, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral drug administration to subjects. We estimated the approximate oral clearance (CL/F(approx)) as 2.D/(C(peak).tau+C(trough).tau), where D is the dose, and tau is the dosing interval. The CL/F(approx) value was accurate for drugs with a long-elimination half-life, and the estimation error of the CL/F value was slightly increased for drugs with a shorter elimination half-life. The accuracy of CL/F(approx) in each subject was not affected by the magnitude of the interindividual pharmacokinetic variability, but was significantly decreased by the larger measurement error of drug concentrations (or intraindividual pharmacokinetic variability). We further performed several computer simulations to mimic statistical hypothesis testing following the clinical repeated-dose pharmacokinetic trials. The statistical power to detect the difference of oral clearance between two groups was marginally dependent on the measurement error of drug concentration, but was highly dependent on the interindividual pharmacokinetic variability. These findings suggested that the peak-and-trough sampling design to estimate the CL/F(approx) value is useful for clinical repeated-dose pharmacokinetic trials, and that the study design and protocol should be evaluated carefully by computer simulation prior to a real clinical trial.

  14. Prolonged Oral Administration of Oleuropein Might Protect Heart against Aconitine-induced Arrhythmia

    PubMed Central

    Esmailidehaj, Mansour; Mirhosseini, Seyed-Jalil; Rezvani, Mohammad Ebrahim; Rasoulian, Bahram; Mosaddeghmehrjardi, Mohammad Hossein; Haghshenas, Damoon

    2012-01-01

    In this study, it was surveyed to know whether an oral single dose of oleuropein could mimic the cardiac preconditioning in rats’ hearts or whether its prolonged oral administration could protect the heart against the aconitine-induced arrhythmia in rats. Eighty male Wistar rats were divided into two series (n = 8 in each group). In the first series, all groups (except the control (Con) group) were given a single oral dose of oleuropein (20 mg/Kg) 1, 3, 24 and 48 h before the infusion of aconitine. In the second series, except the Con group, the other four groups were given oral oleuropein (20 mg/Kg/day) for 3, 7, 14 and 28 days, before the infusion of aconitine. Electrocardiogram was recorded to monitor arrhythmia. Data of the first series showed that the initiation time of arrhythmia, the initiation of ventricular tachycardia (VT), the numbers of reversible ventricular fibrillation (VF) and the death time had no significant difference compared with Con group. In the second series, a significant protection was occurred only in the 28 days group that was evident with increased initiation time of arrhythmia, increased initiation time of VT, and increased the number of reversible VF and death time in compared to the Con group. The findings of this study show that the oral administration of a single dose of oleuropein could not mimic the preconditioning effects in rat hearts, but the prolonged administration of oleuropein for about four weeks could protect the heart against aconitine-induced arrhythmia. PMID:24250560

  15. 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 μm). 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.

  16. No Increases in Biomarkers of Genetic Damage or Pathological Changes in Heart and Brain Tissues in Male Rats Administered Methylphenidate Hydrochloride (Ritalin) for 28 Days

    PubMed Central

    Witt, Kristine L.; Malarkey, David E.; Hobbs, Cheryl A.; Davis, Jeffrey P.; Kissling, Grace E.; Caspary, William; Travlos, Gregory; Recio, Leslie

    2009-01-01

    Following a 2005 report of chromosomal damage in children with attention deficit/hyperactivity disorder (ADHD) who were treated with the commonly prescribed medication methylphenidate (MPH), numerous studies have been conducted to clarify the risk for MPH-induced genetic damage. Although most of these studies reported no changes in genetic damage endpoints associated with exposure to MPH, one recent study (Andreazza et al. 2007) reported an increase in DNA damage detected by the Comet assay in blood and brain cells of Wistar rats treated by intraperitoneal injection with 1, 2, or 10 mg/kg MPH; no increases in micronucleated lymphocyte frequencies were observed in these rats. To clarify these findings, we treated adult male Wistar Han rats with 0, 2, 10, or 25 mg/kg MPH by gavage once daily for 28 consecutive days and measured micronucleated reticulocyte (MN-RET) frequencies in blood, and DNA damage in blood, brain, and liver cells 4 hr after final dosing. Flow cytometric evaluation of blood revealed no significant increases in MN-RET. Comet assay evaluations of blood leukocytes and cells of the liver, as well as of the striatum, hippocampus, and frontal cortex of the brain showed no increases in DNA damage in MPH-treated rats in any of the three treatment groups. Thus, the previously reported observations of DNA damage in blood and brain tissue of rats exposed to MPH for 28 days were not confirmed in this study. Additionally, no histopathological changes in brain or heart, or elevated serum biomarkers of cardiac injury were observed in these MPH-exposed rats. PMID:19634155

  17. No increases in biomarkers of genetic damage or pathological changes in heart and brain tissues in male rats administered methylphenidate hydrochloride (Ritalin) for 28 days.

    PubMed

    Witt, Kristine L; Malarkey, David E; Hobbs, Cheryl A; Davis, Jeffrey P; Kissling, Grace E; Caspary, William; Travlos, Gregory; Recio, Leslie

    2010-01-01

    Following a 2005 report of chromosomal damage in children with attention deficit/hyperactivity disorder (ADHD) who were treated with the commonly prescribed medication methylphenidate (MPH), numerous studies have been conducted to clarify the risk for MPH-induced genetic damage. Although most of these studies reported no changes in genetic damage endpoints associated with exposure to MPH, one recent study (Andreazza et al. [2007]: Prog Neuropsychopharmacol Biol Psychiatry 31:1282-1288) reported an increase in DNA damage detected by the Comet assay in blood and brain cells of Wistar rats treated by intraperitoneal injection with 1, 2, or 10 mg/kg MPH; no increases in micronucleated lymphocyte frequencies were observed in these rats. To clarify these findings, we treated adult male Wistar Han rats with 0, 2, 10, or 25 mg/kg MPH by gavage once daily for 28 consecutive days and measured micronucleated reticulocyte (MN-RET) frequencies in blood, and DNA damage in blood, brain, and liver cells 4 hr after final dosing. Flow cytometric evaluation of blood revealed no significant increases in MN-RET. Comet assay evaluations of blood leukocytes and cells of the liver, as well as of the striatum, hippocampus, and frontal cortex of the brain showed no increases in DNA damage in MPH-treated rats in any of the three treatment groups. Thus, the previously reported observations of DNA damage in blood and brain tissue of rats exposed to MPH for 28 days were not confirmed in this study. Additionally, no histopathological changes in brain or heart, or elevated serum biomarkers of cardiac injury were observed in these MPH-exposed rats.

  18. Cellular distribution of cell cycle-related molecules in the renal tubules of rats treated with renal carcinogens for 28 days: relationship between cell cycle aberration and carcinogenesis.

    PubMed

    Taniai, Eriko; Hayashi, Hitomi; Yafune, Atsunori; Watanabe, Maiko; Akane, Hirotoshi; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

    2012-09-01

    Some renal carcinogens can induce karyomegaly, which reflects aberrant cell division in the renal tubules, from the early stages of exposure. To clarify the cell cycle-related changes during the early stages of renal carcinogenesis, we performed immunohistochemical analysis of tubular cells in male F344 rats treated with carcinogenic doses of representative renal carcinogens for 28 days. For this purpose, the karyomegaly-inducing carcinogens ochratoxin A (OTA), ferric nitrilotriacetic acid, and monuron, and the non-karyomegaly-inducing carcinogens tris(2-chloroethyl) phosphate and potassium bromate were examined. For comparison, a karyomegaly-inducing non-carcinogen, p-nitrobenzoic acid, and a non-carcinogenic non-karyomegaly-inducing renal toxicant, acetaminophen, were also examined. The outer stripe of the outer medulla (OSOM) and the cortex + OSOM were subjected to morphometric analysis of immunoreactive proximal tubular cells. Renal carcinogens, irrespective of their karyomegaly-inducing potential, increased proximal tubular cell proliferation accompanied by an increase in topoisomerase IIα-immunoreactive cells, suggesting a reflection of cell proliferation. Karyomegaly-inducing carcinogens increased nuclear Cdc2-, γH2AX-, and phosphorylated Chk2-immunoreactive cells in both areas, the former two acting in response to DNA damage and the latter one suggestive of sustained G₂. OTA, an OSOM-targeting carcinogen, could easily be distinguished from untreated controls and non-carcinogens by evaluation of molecules responding to DNA damage and G₂/M transition in the OSOM. Thus, all renal carcinogens examined facilitated proximal tubular proliferation by repeated short-term treatment. Among these, karyomegaly-inducing carcinogens may cause DNA damage and G₂ arrest in the target tubular cells.

  19. Effects of 28-day mechanical and chewing stress on content of bound and diffusible ions in muscles of mastication.

    PubMed

    Gedrange, T; Kuhn, U D; Walter, B; Harzer, W; Bauer, R

    2001-06-01

    Type I and type II muscle fibres have different ion concentrations. Muscles adapt to chronic stress by changing of fibre types and remodelling of the myosin heavy chains in the muscle fibres. The present investigation on ionic change during muscular contraction was carried out on 10-week-old pigs (6 treated animals, 6 controls) over a 28-day period. Six pigs received acrylic build-ups to induce mechanical advancement of the lower jaw and chronic chewing stress. Muscle tissue was taken from the masseter (M1, M2, M3), temporal (TP1, TP2), medial pterygoid (PM) and geniohyoid (GH) muscles by a standardized method. Eighty-four muscle samples were used for histological fibre differentiation with mATPase. Energy-dispersive X-ray microanalysis of muscles was carried out in an environmental scanning electron microscope. Endurance stress in the stressed muscles was seen as an increase of type I fibres (P < 0.001). This histological change and ionic alterations were measured in the anterior region of the masseter (M1 and M2) and in the posterior region of the temporal muscle (TP2). Smaller changes were found in the medial pterygoid muscle. We measured in this muscles increases in potassium, sulphur, chloride (P < 0.05) and even larger increases in phosphate (up to 1.5 mmol/g to 2.3 mmol/g, P < 0.001) and sodium (3-fold, P < 0.001). The results reveal the effects of chronic stress on muscle fibres and ion concentration in the muscle. Chronic stress resulted in an increase of type I fibres and increased ion concentration in the same muscle region. These are considered to be indicators of more efficient contraction. The changes in ion concentration are an important factor in muscle contraction.

  20. Toxicologic effects of 28-day dietary exposure to the flame retardant 1,2-dibromo-4-(1,2-dibromoethyl)-cyclohexane (TBECH) in F344 rats.

    PubMed

    Curran, Ivan H A; Liston, Virginia; Nunnikhoven, Andrée; Caldwell, Don; Scuby, Matthew J S; Pantazopoulos, Peter; Rawn, Dorothea F K; Coady, Laurie; Armstrong, Cheryl; Lefebvre, David E; Bondy, Genevieve S

    2017-02-15

    The brominated flame retardant TBECH is used as an additive to delay ignition and inhibit fires in construction materials and consumer goods. Trends in human exposure are not clear, although humans may be exposed to TBECH via indoor dust and air. In birds and fish there is some evidence of disruption in endocrine and reproductive parameters due to TBECH. In vitro studies indicate that TBECH is an androgen receptor agonist. In this study rats were exposed to 0, 10, 50, 250, 1250 or 5000mg/kg technical TBECH for 28days in diet, corresponding to 0, 0.9, 4.2, 21.3, 98.0 or 328.9mg TBECH/kg bw/d in males and 0, 0.8, 3.9, 19.4, 91.7 or 321.4mg TBECH/kg bw/d in females. Dose-dependent increases in α- and β- TBECH were detected in serum, liver and adipose. Rats in the 5000mg/kg group lost weight rapidly and were euthanized after 15-18days. At study termination rats displayed dose-dependent clinical and histopathological changes consistent with mild hepatic and renal inflammation. In male rats, evidence of gender-specific alpha2u-globulin nephropathy was not considered predictive of renal toxicity in humans. Frank immunosuppression or inappropriate immunostimulation were not apparent, nor was there a primary effect of TBECH on adaptive immunity. Some evidence of hormone disruption was observed, including changes in serum testosterone levels in males and changes in serum T3 and T4 levels in females. Apparent increases in thyroid follicular cell hypertrophy and hyperplasia in male and female rats were not statistically significant. Benchmark dose (BMD) modelling indicated that clinical changes indicative of mild nephrotoxicity and increased blood monocyte numbers indicative of inflammation and tissue damage were the most sensitive outcomes of TBECH exposure that could be modelled. Preliminary evidence of hormone disruption supports the need for rodent studies using more sensitive models of growth, development and reproduction.

  1. Characterization of pulmonary protein profiles in response to zinc oxide nanoparticles in mice: a 24-hour and 28-day follow-up study

    PubMed Central

    Pan, Chih-Hong; Chuang, Kai-Jen; Chen, Jen-Kun; Hsiao, Ta-Chih; Lai, Ching-Huang; Jones, Tim P; BéruBé, Kelly A; Hong, Gui-Bing; Ho, Kin-Fai; Chuang, Hsiao-Chi

    2015-01-01

    Although zinc oxide nanoparticles (ZnONPs) are recognized to cause systemic disorders, little is known about the mechanisms that underlie the time-dependent differences that occur after exposure. The objective of this study was to investigate the mechanistic differences at 24 hours and 28 days after the exposure of BALB/c mice to ZnONPs via intratracheal instillation. An isobaric tag for the relative and absolute quantitation coupled with liquid chromatography/tandem mass spectrometry was used to identify the differential protein expression, biological processes, molecular functions, and pathways. A total of 18 and 14 proteins displayed significant changes in the lung tissues at 24 hours and 28 days after exposure, respectively, with the most striking changes being observed for S100-A9 protein. Metabolic processes and catalytic activity were the main biological processes and molecular functions, respectively, in the responses at the 24-hour and 28-day follow-up times. The glycolysis/gluconeogenesis pathway was continuously downregulated from 24 hours to 28 days, whereas detoxification pathways were activated at the 28-day time-point after exposure. A comprehensive understanding of the potential time-dependent effects of exposure to ZnONPs was provided, which highlights the metabolic mechanisms that may be important in the responses to ZnONP. PMID:26251593

  2. Characterization of pulmonary protein profiles in response to zinc oxide nanoparticles in mice: a 24-hour and 28-day follow-up study.

    PubMed

    Pan, Chih-Hong; Chuang, Kai-Jen; Chen, Jen-Kun; Hsiao, Ta-Chih; Lai, Ching-Huang; Jones, Tim P; BéruBé, Kelly A; Hong, Gui-Bing; Ho, Kin-Fai; Chuang, Hsiao-Chi

    2015-01-01

    Although zinc oxide nanoparticles (ZnONPs) are recognized to cause systemic disorders, little is known about the mechanisms that underlie the time-dependent differences that occur after exposure. The objective of this study was to investigate the mechanistic differences at 24 hours and 28 days after the exposure of BALB/c mice to ZnONPs via intratracheal instillation. An isobaric tag for the relative and absolute quantitation coupled with liquid chromatography/tandem mass spectrometry was used to identify the differential protein expression, biological processes, molecular functions, and pathways. A total of 18 and 14 proteins displayed significant changes in the lung tissues at 24 hours and 28 days after exposure, respectively, with the most striking changes being observed for S100-A9 protein. Metabolic processes and catalytic activity were the main biological processes and molecular functions, respectively, in the responses at the 24-hour and 28-day follow-up times. The glycolysis/gluconeogenesis pathway was continuously downregulated from 24 hours to 28 days, whereas detoxification pathways were activated at the 28-day time-point after exposure. A comprehensive understanding of the potential time-dependent effects of exposure to ZnONPs was provided, which highlights the metabolic mechanisms that may be important in the responses to ZnONP.

  3. Bovine spongiform encephalopathy: the effect of oral exposure dose on attack rate and incubation period in cattle.

    PubMed

    Wells, G A H; Konold, T; Arnold, M E; Austin, A R; Hawkins, S A C; Stack, M; Simmons, M M; Lee, Y H; Gavier-Widén, D; Dawson, M; Wilesmith, J W

    2007-04-01

    The dose-response of cattle exposed to the bovine spongiform encephalopathy (BSE) agent is an important component of modelling exposure risks for animals and humans and thereby, the modulation of surveillance and control strategies for BSE. In two experiments calves were dosed orally with a range of amounts of a pool of brainstems from BSE-affected cattle. Infectivity in the pool was determined by end-point titration in mice. Recipient cattle were monitored for clinical disease and, from the incidence of pathologically confirmed cases and their incubation periods (IPs), the attack rate and IP distribution according to dose were estimated. The dose at which 50 % of cattle would be clinically affected was estimated at 0.20 g brain material used in the experiment, with 95 % confidence intervals of 0.04-1.00 g. The IP was highly variable across all dose groups and followed a log-normal distribution, with decreasing mean as dose increased. There was no evidence of a threshold dose at which the probability of infection became vanishingly small, with 1/15 (7 %) of animals affected at the lowest dose (1 mg).

  4. Evaluation of 90 day repeated dose oral toxicity and reproductive/developmental toxicity of 3'-hydroxypterostilbene in experimental animals

    PubMed Central

    Majeed, Muhammed; Bani, Sarang; Natarajan, Sankaran; Pandey, Anjali; S, Naveed

    2017-01-01

    3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed. PMID:28257483

  5. Evaluation of 90 day repeated dose oral toxicity and reproductive/developmental toxicity of 3'-hydroxypterostilbene in experimental animals.

    PubMed

    Majeed, Muhammed; Bani, Sarang; Natarajan, Sankaran; Pandey, Anjali; S, Naveed

    2017-01-01

    3'-Hydroxypterostilbene (3'-HPT) is one of the active constituents of Sphaerophysa salsula and Pterocarpus marsupium. Despite many proposed therapeutic applications, the safety profile of 3'-HPT has not been established. The present work investigated 90 day repeated oral dose and reproductive (developmental) toxicity of 3'-HPT as a test substance in rats as per OECD guidelines. 90 day toxicity was conducted in sixty Sprague Dawley rats of each sex (120 rats), grouped into six dosage groups of 0 (control), 0 (control recovery), 20 (low dose), 80 (mid dose), 200 (high dose) and 200 (high dose recovery) mg/kg bwt/day (body weight/day) respectively. For the reproductive toxicity study forty Wistar rats of each sex (80 rats) divided into four dosage groups received 0 (vehicle control), 20 (low dose), 100 (mid dose) and 200 (high dose) mg/kg bwt/day of 3'-HPT respectively for a period of two weeks while pre-mating, mating, on the day before sacrifice, in females during pregnancy and four days of lactation period. Results showed no significant differences in body weight, food intake, absolute organ weight, haematology, with no adverse effects (toxicity) on biochemical values nor any abnormal clinical signs or behavioural changes were observed in any of the control/treatment groups, including reproductive and developmental parameters, gross and histopathological changes. In conclusion, the results suggested a No-Observed-Adverse-Effect-Level (NOAEL) of 200 mg/kg bwt/day in rats after oral administration, implying 3'-HPT did not exhibit any toxicity under the study conditions employed.

  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. A New Orally Active, Aminothiol Radioprotector-Free of Nausea and Hypotension Side Effects at Its Highest Radioprotective Doses

    SciTech Connect

    Soref, Cheryl M.; Hacker, Timothy A.; Fahl, William E.

    2012-04-01

    Purpose: A new aminothiol, PrC-210, was tested for orally conferred radioprotection (rats, mice; 9.0 Gy whole-body, which was otherwise lethal to 100% of the animals) and presence of the debilitating side effects (nausea/vomiting, hypotension/fainting) that restrict use of the current aminothiol, amifostine (Ethyol, WR-2721). Methods and Materials: PrC-210 in water was administered to rats and mice at times before irradiation, and percent-survival was recorded for 60 days. Subcutaneous (SC) amifostine (positive control) or SC PrC-210 was administered to ferrets (Mustela putorius furo) and retching/emesis responses were recorded. Intraperitoneal amifostine (positive control) or PrC-210 was administered to arterial cannulated rats to score drug-induced hypotension. Results: Oral PrC-210 conferred 100% survival in rat and mouse models against an otherwise 100% lethal whole-body radiation dose (9.0 Gy). Oral PrC-210, administered by gavage 30-90 min before irradiation, conferred a broad window of radioprotection. The comparison of PrC-210 and amifostine side effects was striking because there was no retching or emesis in 10 ferrets treated with PrC-210 and no induced hypotension in arterial cannulated rats treated with PrC-210. The tested PrC-210 doses were the ferret and rat equivalent doses of the 0.5 maximum tolerated dose (MTD) PrC-210 dose in mice. The human equivalent of this mouse 0.5 MTD PrC-210 dose would likely be the highest PrC-210 dose used in humans. By comparison, the mouse 0.5 MTD amifostine dose, 400 {mu}g/g body weight (equivalent to the human amifostine dose of 910 mg/m{sup 2}), when tested at equivalent ferret and rat doses in the above models produced 100% retching/vomiting in ferrets and 100% incidence of significant, progressive hypotension in rats. Conclusions: The PrC-210 aminothiol, with no detectable nausea/vomiting or hypotension side effects in these preclinical models, is a logical candidate for human drug development to use in healthy

  8. The protective effects of oral low-dose quercetin on diabetic nephropathy in hypercholesterolemic mice

    PubMed Central

    Gomes, Isabele B. S.; Porto, Marcella L.; Santos, Maria C. L. F. S.; Campagnaro, Bianca P.; Gava, Agata L.; Meyrelles, Silvana S.; Pereira, Thiago M. C.; Vasquez, Elisardo C.

    2015-01-01

    Aims: Diabetic nephropathy (DN) is one of the most important causes of chronic renal disease, and the incidence of DN is increasing worldwide. Considering our previous report (Gomes et al., 2014) indicating that chronic treatment with oral low-dose quercetin (10 mg/Kg) demonstrated anti-oxidative, anti-apoptotic and renoprotective effects in the C57BL/6J model of DN, we investigated whether this flavonoid could also have beneficial effects in concurrent DN and spontaneous atherosclerosis using the apolipoprotein E-deficient mouse (apoE−/−). Methods: Streptozotocin was used to induce diabetes (100 mg/kg/day, 3 days) in male apoE−/− mice (8 week-old). After 6 weeks, the mice were randomly separated into DQ: diabetic apoE−/− mice treated with quercetin (10 mg/kg/day, 4 weeks, n = 8), DV: diabetic ApoE−/− mice treated with vehicle (n = 8) and ND: non-treated non-diabetic mice (n = 8). Results: Quercetin treatment diminished polyuria (~30%; p < 0.05), glycemia (~25%, p < 0.05), normalized the hypertriglyceridemia. Moreover, this bioflavonoid diminished creatininemia (~30%, p < 0.01) and reduced proteinuria but not to normal levels. We also observed protective effects on the renal structural changes, including normalization of the index of glomerulosclerosis and kidney weight/body weight. Conclusions: Our data revealed that quercetin treatment significantly reduced DN in hypercholesterolemic mice by inducing biochemical changes (decrease in glucose and triglycerides serum levels) and reduction of glomerulosclerosis. Thus, this study highlights the relevance of quercetin as an alternative therapeutic option for DN, including in diabetes associated with dyslipidemia. PMID:26388784

  9. Pharmacokinetics of ketorolac tromethamine in horses after intravenous, intramuscular, and oral single-dose administration.

    PubMed

    Bianco, A W; Constable, P D; Cooper, B R; Taylor, S D

    2016-04-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are an integral component of equine analgesia, yet currently available NSAIDs are both limited in their analgesic efficacy and have adverse effects. The NSAID ketorolac tromethamine (KT) is widely used in humans as a potent morphine-sparing analgesic drug but has not been fully evaluated in horses. The purpose of this study was to determine the pharmacokinetic profile of KT in horses after intravenous (i.v.), intramuscular (i.m.), and oral (p.o.) administration. Nine healthy adult horses received a single 0.5-mg/kg dose of KT via each route of administration. Plasma was collected up to 48 h postadministration and analyzed for KT concentration using HPLC/MS/MS. Noncompartmental analysis of i.v. dosage indicated a mean plasma clearance of 8.4 (mL/min)/kg and an estimated mean volume of distribution at steady-state of 0.77 L/kg. Noncompartmental analysis of i.v., i.m., and p.o. dosages indicated mean residence times of 2.0, 2.6, and 7.1 h, respectively. The drug was rapidly absorbed after i.m. and p.o. administration, and mean bioavailability was 71% and 57% for i.m. and p.o. administration, respectively. Adverse effects were not observed after i.v., i.m., and p.o. administration. More studies are needed to evaluate the analgesic and anti-inflammatory properties of KT in horses.

  10. Dose-response relationship of an environmental mixture of pyrethroids following an acute oral administration in the rat

    EPA Science Inventory

    Dose-response relationship of an environmental mixture of pyrethroids following an acute oral administration in the rat M.F. Hughes1, D.G. Ross1, J.M. Starr1, E.J. Scollon1,2, M.J. Wolansky1,3, K.M. Crofton1, M.J. DeVito1,4 1U.S. EPA, ORD, Research Triangle Park, NC, 2U.S. EPA,...

  11. Pharmacokinetics and preliminary safety data of a single oral dose of bosentan, a dual endothelin receptor antagonist, in cats.

    PubMed

    Puza, N; Papich, M G; Reinero, C; Chang, C H; Yu, D-H; Sharp, C; DeClue, A

    2014-04-01

    The objective of this study was to evaluate the pharmacokinetic properties and adverse effect profile of single-dose oral bosentan, a dual endothelin receptor antagonist, in healthy cats. Pharmacokinetic parameters were determined following a single mean ± SD oral dose of 3.2 ± 0.6 mg/kg of bosentan in 6 adult cats. Blood was collected for quantification of bosentan via high-performance liquid chromatography with ultraviolet detection. Blood and urine were evaluated for CBC, plasma biochemical profile, and urinalysis, and repeat physical examinations were performed to evaluate for adverse effects. The mean terminal half-life of bosentan was 20.4 ± 17.2 h. The mean peak plasma concentration was 0.49 ± 0.24 g/mL, and the mean time to maximum plasma concentration was 6.8 ± 8.6 h. The area under the curve was 5.14 ± 3.81 h·μg/mL. Oral bosentan tablets were absorbed in cats, and no clinically important adverse events were noted. Further evaluation of repeat dosing, investigation into the in vivo efficacy of decreasing endothelin-1 concentrations in cats, as well as safety in conjunction with other medications is warranted.

  12. Pharmacokinetics of bismuth and ranitidine following multiple doses of ranitidine bismuth citrate

    PubMed Central

    KOCH, K M; KERR, B M; GOODING, A E; DAVIS, I M

    1996-01-01

    The pharmacokinetics of bismuth and ranitidine derived from oral doses of ranitidine bismuth citrate 800 mg given twice daily for 28 days were examined in this double-blind, placebo-controlled, parallel-group study in 27 healthy subjects. Bismuth accumulation in plasma reflected its multicompartmental disposition, achieving the majority of predicted steady state within 14–28 days. Bismuth absorption from ranitidine bismuth citrate is limited (<0.5% of the dose), and bismuth elimination is predominantly renal secretion. Peak plasma concentrations did not exceed 19 ng ml−1, remaining well below those associated with bismuth toxicity. Bismuth was measurable at low concentrations in plasma and urine for up to 5 months after the last dose. Plasma bismuth concentration-time data and urinary excretion data were best described by separate multicompartmental models, with terminal half-lives averaging 21 days and 45 days, respectively. The pharmacokinetics of ranitidine derived from ranitidine bismuth citrate were similar to those of ranitidine administered alone. Ranitidine did not appreciably accumulate in plasma. Ranitidine bismuth citrate was well-tolerated during 28 days of repeated dosing. PMID:8864319

  13. Chronic invasive sinus and intracerebral aspergillosis controlled by combination therapy with micafungin and a daily dose of 400 mg itraconazole oral solution.

    PubMed

    Ogawa, Taku; Matsumoto, Kana; Tsujimoto, Kazunori; Hishiya, Naokuni; Yamada, Yutaka; Uno, Kenji; Kasahara, Kei; Maeda, Koichi; Nario, Kazuhiko; Mikasa, Keiichi; Morita, Kunihiko

    2015-02-01

    Chronic invasive aspergillosis of the sinus is frequently fatal in the absence of early surgical and chemotherapeutic intervention because of its invasion of vascular tissue. We attempted to control a case of inoperable invasive aspergillosis of the sinus with micafungin and itraconazole oral solution. We prescribed a daily oral dose of 400 mg of itraconazole, which is twice the usual dose, and monitored the serum concentration of the drug. Finally, we were able to control the spread of the lesion. This case indicates that combination therapy with micafungin and a daily dose of 400 mg itraconazole oral solution is an alternative treatment strategy for inoperable invasive aspergillosis of the sinus.

  14. The pharmacokinetics, CNS pharmacodynamics and adverse event profile of brivaracetam after multiple increasing oral doses in healthy men

    PubMed Central

    Rolan, Paul; Sargentini-Maier, Maria Laura; Pigeolet, Etienne; Stockis, Armel

    2008-01-01

    AIMS Brivaracetam is a novel synaptic vesicle protein 2A ligand that has shown potent activity in animal models of epilepsy. This study examined the pharmacokinetics, central nervous system pharmacodynamics and adverse event profile of multiple oral doses of brivaracetam in healthy male subjects. METHODS Three successive panels of 12 healthy male subjects received double-blind brivaracetam 200, 400 or 800 mg day−1 (all doses well above the expected therapeutic range) or placebo (9 : 3), in two divided doses, for 14 days. RESULTS Brivaracetam was rapidly absorbed (tmax∼2 h) and eliminated (t1/2 7–8 h). Volume of distribution was slightly lower than total body water. A small fraction of the dose (5–8%) was excreted unchanged in urine together with significant levels of metabolites, suggesting predominantly metabolic clearance. Based on 6-β-hydroxycortisol/cortisol ratios in urine, there was no evidence of induction of CYP3A4 activity. Saliva and plasma brivaracetam levels were highly correlated. Adverse events were mostly mild to moderate, central nervous system-related and resolved within the first day of treatment. No clinically relevant changes were observed in laboratory tests, vital signs, physical examinations or ECGs. Pharmacodynamic tests showed dose-related sedation and decreased alertness that only persisted at 800 mg daily. CONCLUSIONS Brivaracetam was well tolerated by healthy male volunteers at doses of 200–800 mg daily for 2 weeks, well above the expected clinically effective dose range. Brivaracetam had a favourable pharmacokinetic profile in this population, characterized by rapid absorption, volume of distribution limited to total body water, apparent single-compartment elimination and dose proportionality. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT The pharmacokinetic profile, metabolism and proof of concept of a single oral dose of brivaracetam have been reported.Previous studies have shown that it was well absorbed, had linear kinetics

  15. A comprehensive study of the association between drug hepatotoxicity and daily dose, liver metabolism, and lipophilicity using 975 oral medications.

    PubMed

    Weng, Zuquan; Wang, Kejian; Li, Haibo; Shi, Qiang

    2015-07-10

    It was recently suggested that daily dose, liver metabolism and lipophilicity were associated with an oral drug's potential to cause hepatotoxicity, but this has not been widely accepted. A likely reason is that published data lack comprehensiveness, as they were based on only about one third of all FDA approved single-active-ingredient oral prescription drugs. Here the 975 oral drugs used worldwide which have a Defined Daily Dose (DDD) designated in the World Health Organization's Anatomical Therapeutic Chemical classification system and whose hADRs potential and metabolism data are available in the Micromedex Drugdex® compendium were studied, with their lipophilicity calculated by the partition coefficient LogP. Of the 975 drugs examined, 49% (478) have the potential to induce at least one type of hepatic adverse drug reactions (hADRs) such as fatal hepatotoxicity, acute liver failure, significant ALT/AST elevation, hepatitis, and jaundice. By single factor analysis, a higher DDD (≥100 mg) was found to be associated with all types of hADRs, and extensive liver metabolism (≥50%) was associated with a subset of hADRs including fatal hADRs, hepatitis and jaundice, while LogP showed no relation to any types of hADRs. Contrary to previous reports, none of the combination, neither DDD and liver metabolism, nor DDD and LogP, was found to be more predictive of hADRs than using DDD or liver metabolism alone. These data provide convincing evidence that a higher daily dose and extensive liver metabolism, but not lipophilicity, are independent but not synergistic risk factors for oral drugs to induce hepatotoxicity.

  16. A comprehensive study of the association between drug hepatotoxicity and daily dose, liver metabolism, and lipophilicity using 975 oral medications

    PubMed Central

    Li, Haibo; Shi, Qiang

    2015-01-01

    It was recently suggested that daily dose, liver metabolism and lipophilicity were associated with an oral drug's potential to cause hepatotoxicity, but this has not been widely accepted. A likely reason is that published data lack comprehensiveness, as they were based on only about one third of all FDA approved single-active-ingredient oral prescription drugs. Here the 975 oral drugs used worldwide which have a Defined Daily Dose (DDD) designated in the World Health Organization's Anatomical Therapeutic Chemical classification system and whose hADRs potential and metabolism data are available in the Micromedex Drugdex® compendium were studied, with their lipophilicity calculated by the partition coefficient LogP. Of the 975 drugs examined, 49% (478) have the potential to induce at least one type of hepatic adverse drug reactions (hADRs) such as fatal hepatotoxicity, acute liver failure, significant ALT/AST elevation, hepatitis, and jaundice. By single factor analysis, a higher DDD (≥100 mg) was found to be associated with all types of hADRs, and extensive liver metabolism (≥50%) was associated with a subset of hADRs including fatal hADRs, hepatitis and jaundice, while LogP showed no relation to any types of hADRs. Contrary to previous reports, none of the combination, neither DDD and liver metabolism, nor DDD and LogP, was found to be more predictive of hADRs than using DDD or liver metabolism alone. These data provide convincing evidence that a higher daily dose and extensive liver metabolism, but not lipophilicity, are independent but not synergistic risk factors for oral drugs to induce hepatotoxicity. PMID:26220713

  17. Four Week Oral (Gavage) Dose Range-Finding Study of Halofantrine Hydrochloride in Mice

    DTIC Science & Technology

    1994-10-26

    Because marginal halofantrine- induced toxicity was seen in low dose females, the following dose level ranges are suggested: 1 - 2, 4 - 8 and 15-30 mg/kg...halofantrine- induced toxicity was seen in low dose females, the following dose level ranges are suggested: 1 - 2, 4 - 8 and 15-30 mg/kg/day. 2...selected on the basis of Sponsor-supplied subchronic toxicity data in rats and following discussions with the Sponsor. During the test animal selection

  18. Acute and repeated dose toxicity studies of different β-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.

  19. Retention, organ distribution, and excretory pattern of cadmium orally administered in a single dose to two monkeys

    SciTech Connect

    Suzuki, S.; Taguchi, T.

    1980-07-01

    Retention, excretion, and organ distribution of radioactive Cd were observed after a single oral dose of two monkeys. The retention rate of Cd 19 d after the administration of radiocadmium (/sup 109/CdCl/sub 2/, carrier-free) to one monkey was 5.2% of the administered dose; 73.4% of the dose was excreted in the feces and 0.7% in the urine. The largest fractions of the administered dose were found in the small intestine, liver, and kidney. The absorption rate of Cd 25 d after the administration of radiocadmium with 1.0 mg cold Cd as CdCl/sub 2/ solution to the other monkey was 6.3% of the administered dose; 75.5% of the dose was excreted in the feces and 0.9% in the urine. Setting the whole body retention equal to 100% on d 19 or 25, the largest fractions were found in the small intestines (51.5 and 36.3%), livers (21.8 and 29.6%), and kidneys (13.4 and 21.0%) of the respective monkeys). The effect of carrier Cd on absorption, excretion, and organ distribution was not pronounced. The highest concentration and greatest retention of Cd was observed in the upper small intestinal wall and the content of the small intestine, indicating the importance of enteroenteric circulation of the element; this finding was different from the results for Cd metabolism in rodents.

  20. Preclinical Study of Single-Dose Moxidectin, a New Oral Treatment for Scabies: Efficacy, Safety, and Pharmacokinetics Compared to Two-Dose Ivermectin in a Porcine Model

    PubMed Central

    Bernigaud, Charlotte; Aho, Ludwig Serge; Dreau, Dominique; Kelly, Andrew; Sutra, Jean-François; Moreau, Francis; Lilin, Thomas; Botterel, Françoise; Guillot, Jacques; Chosidow, Olivier

    2016-01-01

    Background Scabies is one of the commonest dermatological conditions globally; however it is a largely underexplored and truly neglected infectious disease. Foremost, improvement in the management of this public health burden is imperative. Current treatments with topical agents and/or oral ivermectin (IVM) are insufficient and drug resistance is emerging. Moxidectin (MOX), with more advantageous pharmacological profiles may be a promising alternative. Methodology/Principal Findings Using a porcine scabies model, 12 pigs were randomly assigned to receive orally either MOX (0.3 mg/kg once), IVM (0.2 mg/kg twice) or no treatment. We evaluated treatment efficacies by assessing mite count, clinical lesions, pruritus and ELISA-determined anti-S. scabiei IgG antibodies reductions. Plasma and skin pharmacokinetic profiles were determined. At day 14 post-treatment, all four MOX-treated but only two IVM-treated pigs were mite-free. MOX efficacy was 100% and remained unchanged until study-end (D47), compared to 62% (range 26–100%) for IVM, with one IVM-treated pig remaining infected until D47. Clinical scabies lesions, pruritus and anti-S. scabiei IgG antibodies had completely disappeared in all MOX-treated but only 75% of IVM-treated pigs. MOX persisted ~9 times longer than IVM in plasma and skin, thereby covering the mite’s entire life cycle and enabling long-lasting efficacy. Conclusions/Significance Our data demonstrate that oral single-dose MOX was more effective than two consecutive IVM-doses, supporting MOX as potential therapeutic approach for scabies. PMID:27732588

  1. Short-term repeated-dose toxicity profile of archaeosomes administered to mice via intravenous and oral routes.

    PubMed

    Omri, Abdelwahab; Agnew, Brian J; Patel, Girishchandra B

    2003-01-01

    Archaeosomes, liposomes made from polar ether lipids of archaea, show promise for vaccine and drug delivery applications. The potential toxicity of intravenously (14, 70, or 140 mg/kg/day for 5 consecutive days) and orally (gavaged at 55, 275, or 550 mg/kg/day for 10 consecutive days) administered unilamellar archaeosomes, prepared from the total polar lipids (TPLs) extracted from several species of archaea, was assessed in female BALB/c mice. Liposomes prepared from an ester phospholipid composition were included for comparative purposes. Control groups of mice were administered 0.1 ml phosphate-buffered saline (PBS) by either route. Animals were monitored at least once daily for temperature, body weight, and clinical signs of adverse reactions. One day after the last dose, the mice were sacrificed. Blood was collected for selected biochemical/enzyme analyses, and the major organs (heart, lungs, liver, spleen, kidneys) were weighed and examined macroscopically. In addition, the spleens were examined histologically. At the two lower dosages of intravenously administered vesicles, there were no significant indications of toxicity, as compared with the PBS-administered control group. At the highest intravenous dose of 140 mg/kg/day, archaeosomes prepared from the TPL of the extreme halophiles, Halobacterium salinarum and Natronobacterium magadii, indicated potential toxicity, as evidenced by clinical signs (hyperactivity and/or piloerection), drop in body temperature, and loss in body weight. Spleens from mice administered some archaeosomes types, primarily at the highest intravenous dose tested, were enlarged, had increased organ weight, and microscopic examination revealed mild to moderate expansion of the red pulp with increased numbers of hematopoietic cells, but no changes in the white pulp. There were similar clinical signs at one or more of the higher oral doses of the ester liposomes and some of the archaeosome types; however, no other apparent toxicity was

  2. A comparative study of paediatric oral premedication: midazolam, ketamine and low dose combination of midazolam and ketamine.

    PubMed

    Banerjee, Bhakti; Bose, Anjana; Pahari, Subrata; Dan, Amit Kumar

    2011-06-01

    In a prospective randomised double-blind trial, 90 patients aged 1-7 years (ASA I) undergoing elective surgery less than 90 minutes duration were allocated into three separate groups to compare the safety and effectiveness of oral midazolam, ketamine, and low dose combination of midazolam and ketamine for premedication in paediatric patients. Group M received midazolam 0.5 mg kg(-1), group K received ketamine 6mg kg(-1) and group C received combination of ketamine 2.5 mg kg(-1) and midazolam 0.25 mg kg(-1) orally in 0.2ml kg(-1) of sugar syrup to make it palatable. The sedation score and emotional state on a four -point scale, ease of parental separation, cooperation for venepuncture, ease of mask acceptance and peri-operative cardiorespiratory status were evaluated. Peri-operative incidence of vomiting, nystagmus, emergence phenomenon and postanesthetic recovery time were noted. In the present study it was found that C group was more effective in sedating the children within 10 minutes and 20 minutes, whereas, the combination and midazolam groups are comparable in sedating the children at 30 minutes. Side-effects and recovery time were more in ketamine group. The recovery time was significantly less in group C. In conclusion oral combination of low dose ketamine and midazolam produced quick onset of satisfactory conscious sedation and more rapid recovery without significant side-effects, so that more children could be separated easily from their parents and provides smooth induction than the individual drug.

  3. 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 < 0.01) and β-hydroxy-butyrate (P < 0.01) in the plasma, particularly after the third LPS challenge. Also, after the third oral LPS challenge, treatment tended to increase plasma glucose. Plasma calcium did not change, but concentrations of insulin (P < 0.01) and zinc (P < 0.01) were greater, while that of copper was lower (P < 0.01) in the plasma of treated cows. This is the first report to indicate a potential role for repeated oral administration of LPS around parturition to modulate the profile of plasma metabolites and minerals postpartum.

  4. 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 μg/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 μg/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 μg/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

  5. Dose-related immunohistochemical and ultrastructural changes after oral methylphenidate administration in cerebrum and cerebellum of the rat.

    PubMed

    Bahcelioglu, Meltem; Gozil, Rabet; Take, Gulnur; Elmas, Cigdem; Oktem, Hale; Kadioglu, Dural; Calguner, Engin; Erdogan, Deniz; Sargon, Mustafa F; Yazici, A Canan; Tas, Murat; Bardakci, Yesim; Senol, Selahattin

    2009-01-01

    Methylphenidate is a piperidine derivative and is the drug most often used to treat attention deficit/hyperactivity disorder of children and young adults. Our aim is to investigate dose-dependent dopamine-2 receptor and glial fibrillary acidic protein expression and ultrastructural changes of the rat brain, to demonstrate possible toxicity of the long-term and high dose use of the methylphenidate. In this study, 27 female prepubertal Wistar albino rats, divided into three different dose groups (5, 10 and 20 mg/kg) were treated orally with methylphenidate dissolved in saline solution for 5 days per week during 3 months. At the end of the third month, tissues were removed and sections were collected for immunohistochemical and ultrastructural studies. We believe that methylphenidate causes dose-related activation of the dopaminergic system in several brain regions especially in ventral tegmental area and also causing neuronal degeneration and capillary wall structural changes such as basal membrane thickness and augmentation of the pinostatic vesicle in the endothelial cells. Also, increased dose of Ritalin is inducing astrocytes hypertrophy especially astrogliosis in pia-glial membrane and this is the result of the degenerative changes in prefrontal cortex region due to high dose methylphenidate administration. The dose-related accumulation of the astrocytes in capillary wall might well be a consequence of the need for nutrition of the neuronal tissue, due to transport mechanism deficiency related to neuronal and vascular degeneration. Thus, we believe that the therapeutic dose of methylphenidate must be kept in minimum level to prevent ultrastructural changes.

  6. A Randomized, Double-Blind, Placebo-Controlled, Multicenter, 28-Day, Polysomnographic Study of Gabapentin in Transient Insomnia Induced by Sleep Phase Advance

    PubMed Central

    Furey, Sandy A.; Hull, Steven G.; Leibowitz, Mark T.; Jayawardena, Shyamalie; Roth, Thomas

    2014-01-01

    Study Objective: To evaluate multiple doses of gabapentin 250 mg on polysomnography (PSG) and participant-reported sleep assessments in a 5-h phase advance insomnia model. Methods: Adults reporting occasional disturbed sleep received gabapentin 250 mg (n = 128) or placebo (n = 128). On Days 1 and 28, participants received medication 30 min before bedtime and were in bed from 17:00 to 01:00, ∼5 h before their habitual bedtime. Sleep was assessed by PSG, a post sleep questionnaire, and the Karolinska Sleep Diary. Next-day residual effects and tolerability were evaluated. On Days 2-27, participants took medication at home 30 min before their habitual bedtime. Results: Treatment-group demographics were comparable. Gabapentin resulted in significantly less PSG wake after sleep onset (WASO) compared with placebo on Day 1 (primary endpoint, mean: 107.0 versus 149.1 min, p ≤ 0.001) and Day 28 (113.6 versus 152.3 min, p = 0.002), and significantly greater total sleep time (TST; Day 1: 347.6 versus 283.9 min; Day 28: 335.3 versus 289.1 min) (p ≤ 0.001). Participant-reported WASO and TST also showed significant treatment effects on both days. Gabapentin was associated with less %stage1 on Day 1, and greater %REM on Day 28, versus placebo. During home use, gabapentin resulted in significantly less participant-reported WASO and higher ratings of sleep quality. Gabapentin was well tolerated (most common adverse events: headache, somnolence) with no evidence of next-day impairment. Conclusion: Gabapentin 250 mg resulted in greater PSG and participant-reported sleep duration following a 5-h phase advance on Day 1 and Day 28 of use without evidence of next-day impairment, and greater sleep duration during at-home use. Citation: Furey SA, Hull SG, Leibowitz MT, Jayawardena S, Roth T. A randomized, double-blind, placebo-controlled, multicenter, 28-day, polysomnographic study of gabapentin in transient insomnia induced by sleep phase advance. J Clin Sleep Med 2014

  7. Dose Response of Listeria monocytogenes Invasion, Fetal Morbidity, and Fetal Mortality after Oral Challenge in Pregnant and Nonpregnant Mongolian Gerbils

    PubMed Central

    Roulo, Rebecca M.; Fishburn, Jillian D.; Amosu, Mayowa; Etchison, Ashley R.

    2014-01-01

    Listeria monocytogenes is a food-borne pathogen that can result in adverse pregnancy outcomes, such as stillbirth or premature delivery. The Mongolian gerbil was recently proposed as the most appropriate small-animal model of listeriosis due to its susceptibility to the same invasion pathways as humans. The objectives of this study were to investigate invasion and adverse pregnancy outcomes in gerbils orally exposed to L. monocytogenes, to compare the dose-response data to those of other animal models, and to investigate differences in the responses of pregnant versus nonpregnant gerbils. Gerbils were orally exposed to 0 (control), 103, 105, 107, or 109 CFU L. monocytogenes in whipping cream. L. monocytogenes was recovered in a dose-dependent manner from fecal samples, adult organs, and pregnancy-associated tissues. Dams exposed to 109 CFU had more invaded organs and higher concentrations of L. monocytogenes in almost all organs than nonpregnant animals, though no differences in fecal shedding were seen between the two groups. Adverse pregnancy outcomes occurred only in the dams treated with 109 CFU. A 50% infectivity dose (ID50) of 2.60 × 106 CFU for fetuses was calculated by fitting the data to a logistic model. Our results suggest that the 50% lethal dose (LD50) falls within the range of 5 × 106 to 5 × 108 CFU. This range includes the guinea pig and nonhuman primate LD50s, but the observation that L. monocytogenes-induced stillbirths can be seen in guinea pigs and primates exposed to lower doses than those at which stillbirths were seen in gerbils indicates that gerbils are not more sensitive to L. monocytogenes invasion. PMID:25156729

  8. Dose response of Listeria monocytogenes invasion, fetal morbidity, and fetal mortality after oral challenge in pregnant and nonpregnant Mongolian gerbils.

    PubMed

    Roulo, Rebecca M; Fishburn, Jillian D; Amosu, Mayowa; Etchison, Ashley R; Smith, Mary Alice

    2014-11-01

    Listeria monocytogenes is a food-borne pathogen that can result in adverse pregnancy outcomes, such as stillbirth or premature delivery. The Mongolian gerbil was recently proposed as the most appropriate small-animal model of listeriosis due to its susceptibility to the same invasion pathways as humans. The objectives of this study were to investigate invasion and adverse pregnancy outcomes in gerbils orally exposed to L. monocytogenes, to compare the dose-response data to those of other animal models, and to investigate differences in the responses of pregnant versus nonpregnant gerbils. Gerbils were orally exposed to 0 (control), 10(3), 10(5), 10(7), or 10(9) CFU L. monocytogenes in whipping cream. L. monocytogenes was recovered in a dose-dependent manner from fecal samples, adult organs, and pregnancy-associated tissues. Dams exposed to 10(9) CFU had more invaded organs and higher concentrations of L. monocytogenes in almost all organs than nonpregnant animals, though no differences in fecal shedding were seen between the two groups. Adverse pregnancy outcomes occurred only in the dams treated with 10(9) CFU. A 50% infectivity dose (ID50) of 2.60 × 10(6) CFU for fetuses was calculated by fitting the data to a logistic model. Our results suggest that the 50% lethal dose (LD50) falls within the range of 5 × 10(6) to 5 × 10(8) CFU. This range includes the guinea pig and nonhuman primate LD50s, but the observation that L. monocytogenes-induced stillbirths can be seen in guinea pigs and primates exposed to lower doses than those at which stillbirths were seen in gerbils indicates that gerbils are not more sensitive to L. monocytogenes invasion.

  9. Derivation of a bisphenol A oral reference dose (RfD) and drinking-water equivalent concentration.

    PubMed

    Willhite, Calvin C; Ball, Gwendolyn L; McLellan, Clifton J

    2008-02-01

    Human exposure to bisphenol A (BPA) is due to that found in the diet, and BPA and its metabolites were detected at parts per billion (or less) concentrations in human urine, milk, saliva, serum, plasma, ovarian follicular fluid, and amniotic fluid. Adverse health effects in mice and rats may be induced after parenteral injection or after massive oral doses. Controlled ingestion trials in healthy adult volunteers with 5 mg d16-BPA were unable to detect parent BPA in plasma despite exquisitely sensitive (limit of detection = 6 nM) methods, but by 96 h 100% of the administered dose was recovered in urine as the glucuronide. The extensive BPA glucuronidation following ingestion is not seen after parenteral injection; only the parent BPA binds plasma proteins and estrogen receptors (ER). The hypothesis that BPA dose-response may be described by a J- or U-shape curve was not supported by toxicogenomic data collected in fetal rat testes and epididymes (after repeated parenteral exposure at 2-400,000 microg/kg-d), where a clear monotonic dose-response both in the numbers of genes and magnitude of individual gene expression was evident. There is no clear indication from available data that the BPA doses normally consumed by humans pose an increased risk for immunologic or neurologic disease. There is no evidence that BPA poses a genotoxic or carcinogenic risk and clinical evaluations of 205 men and women with high-performance liquid chromatography (HPLC)-verified serum or urinary BPA conjugates showed (1) no objective signs, (2) no changes in reproductive hormones or clinical chemistry parameters, and (3) no alterations in the number of children or sons:daughters ratio. Results of benchmark dose (BMD10 and BMDL10) calculations and no-observed-adverse-effect level (NOAEL) inspections of all available and reproducible rodent studies with oral BPA found BMD and NOAEL values all greater than the 5 mg/kg-d NOAELs from mouse and rat multigeneration reproduction toxicity studies

  10. A Study on the Single-dose Oral Toxicity of Super Key in Sprague-Dawley Rats

    PubMed Central

    Kim, Jinhee; Lee, Jongcheol; Kim, Sungchul

    2015-01-01

    Objectives: This study was performed to analyze the single-dose oral toxicity of the super key (processed sulfur). Methods: All experiments were conducted at Medvill, an institution authorized to perform non-clinical studies, under the Good Laboratory Practice (GLP) regulations. In order to investigate the oral toxicity of super key We administered it orally to Sprague-Dawley (SD) rats. The SD rats were divided into four groups of five male and five female animals per group: group 1 being the control group and groups 2, 3, and 4 being the experimental groups. Doses of super key 500 mg/kg, 1,000 mg/kg and 2,000 mg/kg were administered to the experimental groups, and a dose of normal saline solution, 10 mL/kg, was administered to the control group. We examined the survival rates, weights, clinical signs, gross findings and necropsy findings. This study was conducted under the approval of the Institutional Animal Ethics Committee. (Approval number: A01-14018). Results: No deaths or abnormalities occurred in any of the four groups. Although slight decreases in the weights of some female rats were noted, no significant changes in weights or differences in the gross findings between the control group and the experimental groups were observed. To check for abnormalities in organs, we used microscopy to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs. Conclusion: The results of this research showed that administration of 500 ─ 2,000 mg/kg of super key did not cause any changes in the weights or in the results of necropsy examinations. Neither did it result in any mortalities. The above findings suggest that treatment with super key is relatively safe. Further studies on this subject are needed to yield more concrete evidence. PMID:26392913

  11. A randomized comparative trial of two low-dose oral isotretinoin regimens in moderate to severe acne vulgaris

    PubMed Central

    Dhaked, Daulat Ram; Meena, Ram Singh; Maheshwari, Anshul; Agarwal, Uma Shankar; Purohit, Saroj

    2016-01-01

    Background: Oral isotretinoin is highly effective in all forms and grades of acne, even in lower dosages (<0.5 mg/kg/day). There is a paucity of comparative data on the various low-dose regimens of oral isotretinoin in the Indian literature. Objectives: To assess and compare the efficacy and tolerability of two low-dose oral isotretinoin treatment regimens (20 mg daily and 20 mg alternate days) in moderate to severe acne vulgaris. Materials and Methods: A total of 240 patients with moderate to severe acne vulgaris were selected and randomized into two groups and treated with a fixed dose of 20 mg of isotretinoin (Group A - daily and Group B - alternate days) for 24 weeks and followed up for 12 weeks post therapy. Results: A total of 234 patients completed the study. At the end of therapy, decrease in the total acne loads up to 98.99% (Group A) and 97.69% (Group B) was achieved from the baseline (P < 0.01), excellent response was observed in 98.3% (Group A) and 93.96% (Group B) patients (P = 0.166). In the severe acne, Group A performed significantly better than Group B until the end of 36 weeks. While in the moderate acne, significant difference in the response between both groups was observed only up to 12 weeks. No serious side effect was observed. Conclusion: Both isotretinoin regimens were well tolerated and found to be an effective treatment for moderate to severe acne vulgaris. However, in moderate acne 20 mg alternate day regimen may be preferred. A 20 mg daily regimen is a better choice for severe acne in terms of response. Limitation: Small sample size and short follow-up period. PMID:27730033

  12. Population pharmacokinetics of a single dose of meloxicam after oral and intramuscular administration to captive lesser flamingos (Phoeniconaias minor).

    PubMed

    Zordan, Martín A; Papich, Mark G; Pich, Ashley A; Unger, Katy M; Sánchez, Carlos R

    2016-12-01

    OBJECTIVE To determine the pharmacokinetics of a single dose of meloxicam after IM and oral administration to healthy lesser flamingos (Phoeniconaias minor) by use of a population approach. ANIMALS 16 healthy captive lesser flamingos between 1 and 4 years of age. PROCEDURES A single dose of meloxicam (0.5 mg/kg) was administered IM to each bird, and blood samples were collected from birds at 3 (n = 13 birds), 2 (2), or 1 (1) selected point between 0 and 13 hours after administration, with samples collected from birds at each point. After a 15-day washout period, the same dose of meloxicam was administered PO via a red rubber tube and blood samples were collected as described for IM administration. Pharmacokinetic values were determined from plasma concentrations measured by high-performance liquid chromatography. RESULTS Plasma drug concentrations after IM administration of meloxicam reached a mean ± SD maximum value of 6.01 ± 3.38 μg/mL. Mean area under the concentration-versus-time curve was 17.78 ± 2.79 μg•h/mL, and mean elimination half-life was 1.93 ± 0.32 hours. Plasma concentrations after oral administration reached a mean maximum value of 1.79 ± 0.33 μg/mL. Mean area under the curve was 22.16 ± 7.17 μg•h/mL, and mean elimination half-life was 6.05 ± 3.53 hours. CONCLUSIONS AND CLINICAL RELEVANCE In lesser flamingos, oral administration of meloxicam resulted in higher bioavailability and a longer elimination half-life than did IM administration, but the maximum plasma concentration was low and may be insufficient to provide analgesia in flamingos. Conversely, IM administration achieved the desired plasma concentration but would require more frequent administration.

  13. [Dose-finding for treatment with a transdermal fentanyl patch : Titration with oral transmucosal fentanyl citrate and morphine sulfate].

    PubMed

    Mücke, M; Conrad, R; Marinova, M; Cuhls, H; Elsner, F; Rolke, R; Radbruch, L

    2016-12-01

    To date, no studies investigating titration with oral transmucosal fentanyl for the dose-finding of transdermal fentanyl treatment have been published. In an open randomized study 60 patients with chronic malignant (n = 39) or nonmalignant pain (n = 21), who required opioid therapy according to step three of the guidelines of the World Health Organization (WHO), were investigated. In two groups of 30 patients each titration with immediate release morphine (IRM) or oral transmucosal fentanyl citrate (OTFC) was undertaken. For measurement purposes the Brief Pain Inventory (BPI) and Minimal Documentation System (MIDOS) were used. After a 24-h titration phase, in which patients documented the intensity of pain, nausea, and tiredness, treatment with transdermal fentanyl was evaluated over a 10-day period by means of the necessary dose adaptation (responder ≤ 1 dose adaptation; conversion formula 1:1 [OTFC group] vs 100:1 [IRM group]).The pain reduction over the first 24 h (titration phase) did not differ significantly between the groups. The number of responders (17 OTFC vs. 21 IRM) over the 10-day period did not show any difference either. In both groups there was a significant reduction in pain intensity (p < 0.001). Over the course of the study, there were significantly more drop-outs because of adverse effects in the OTFC group than in the IRM group (8 vs 1, p = 0.028).Oral transmucosal fentanyl citrate can be applied for the titration of transdermal fentanyl, but it does not show any clinically relevant advantage. For example, the risk of side effects-induced drop-outs was greater in the present study. Whether the unnecessary opioid switching to treat chronic pain and breakthrough pain is advantageous with regard to minimizing conversion errors cannot be definitively answered within the scope of this study.

  14. Δ9-Tetrahydrocannabinol (THC), 11-Hydroxy-THC, and 11-Nor-9-carboxy-THC Plasma Pharmacokinetics during and after Continuous High-Dose Oral THC

    PubMed Central

    Schwilke, Eugene W.; Schwope, David M.; Karschner, Erin L.; Lowe, Ross H.; Darwin, William D.; Kelly, Deanna L.; Goodwin, Robert S.; Gorelick, David A.; Huestis, Marilyn A.

    2011-01-01

    BACKGROUND Δ9-Tetrahydrocannabinol (THC) is the primary psychoactive constituent of cannabis and an active cannabinoid pharmacotherapy component. No plasma pharmacokinetic data after repeated oral THC administration are available. METHODS Six adult male daily cannabis smokers resided on a closed clinical research unit. Oral THC capsules (20 mg) were administered every 4–8 h in escalating total daily doses (40–120 mg) for 7 days. Free and glucuronidated plasma THC, 11-hydroxy-THC (11-OH-THC), and 11-nor-9-carboxy-THC (THC COOH) were quantified by 2-dimensional GC-MS during and after dosing. RESULTS Free plasma THC, 11-OH-THC, and THCCOOH concentrations 19.5 h after admission (before controlled oral THC dosing) were mean 4.3 (SE 1.1), 1.3 (0.5), and 34.0 (8.4) μg/L, respectively. During oral dosing, free 11-OH-THC and THCCOOH increased steadily, whereas THC did not. Mean peak plasma free THC, 11-OH-THC, and THCCOOH concentrations were 3.8 (0.5), 3.0 (0.7), and 196.9 (39.9) μg/L, respectively, 22.5 h after the last dose. Escherichia coli β-glucuronidase hydrolysis of 264 cannabinoid specimens yielded statistically significant increases in THC, 11-OH-THC, and THCCOOH concentrations (P < 0.001), but conjugated concentrations were underestimated owing to incomplete enzymatic hydrolysis. CONCLUSIONS Plasma THC concentrations remained >1 μg/L for at least 1 day after daily cannabis smoking and also after cessation of multiple oral THC doses. We report for the first time free plasma THC concentrations after multiple high-dose oral THC throughout the day and night, and after Escherichia coli β-glucuronidase hydrolysis. These data will aid in the interpretation of plasma THC concentrations after multiple oral doses. PMID:19833841

  15. Comparison of single-dose oral grepafloxacin with cefixime for treatment of uncomplicated gonorrhea in men. The STD Study Group.

    PubMed Central

    Hook, E W; McCormack, W M; Martin, D; Jones, R B; Bean, K; Maroli, A N

    1997-01-01

    In a randomized open study, 351 male patients with uncomplicated gonorrhea were given single oral doses of grepafloxacin (400 mg) or cefixime (400 mg). In the 299 microbiologically evaluable patients, urethral infections were cured in 99% (147 of 149) of those receiving grepafloxacin and 97% (145 of 150) of those given cefixime. Eradication rates for both regimens were 100% in the 16% (47 of 299) of participants who were infected with penicillin-resistant Neisseria gonorrhoeae and 97% in the 21% (62 of 299) of participants infected with tetracycline-resistant strains. Grepafloxacin is a well-tolerated alternative to cefixime for treatment of uncomplicated gonorrhea in males. PMID:9257777

  16. Comparison of single-dose oral grepafloxacin with cefixime for treatment of uncomplicated gonorrhea in men. The STD Study Group.

    PubMed

    Hook, E W; McCormack, W M; Martin, D; Jones, R B; Bean, K; Maroli, A N

    1997-08-01

    In a randomized open study, 351 male patients with uncomplicated gonorrhea were given single oral doses of grepafloxacin (400 mg) or cefixime (400 mg). In the 299 microbiologically evaluable patients, urethral infections were cured in 99% (147 of 149) of those receiving grepafloxacin and 97% (145 of 150) of those given cefixime. Eradication rates for both regimens were 100% in the 16% (47 of 299) of participants who were infected with penicillin-resistant Neisseria gonorrhoeae and 97% in the 21% (62 of 299) of participants infected with tetracycline-resistant strains. Grepafloxacin is a well-tolerated alternative to cefixime for treatment of uncomplicated gonorrhea in males.

  17. Effect of low-dose oral contraceptives on natural killer cell activity.

    PubMed

    Baker, D A; Salvatore, W; Milch, P O

    1989-01-01

    Several reports indicate an association between oral contraceptives and increased infection rates. One mechanism that could explain this increased infection rate is a decrease in immune function. A study comparing T cell subsets showed no differences in numbers between oral contraceptive users and controls. In this study, natural killer cell activity was compared in women before and 3 and 6 months after oral contraceptive use. There was a statistically significant decrease in NK cell activity after three months. There was no further decrease by six months and the differences were no longer significant due to greater variability. No infections were reported during the study period. Thus, the observed reduction in NK activity was either physiologically insignificant or the previously reported increase in infections may be the result of non-immunological factors.

  18. Absorption and elimination of bismuth from oral doses of tripotassium dicitrato bismuthate.

    PubMed

    Froomes, P R; Wan, A T; Keech, A C; McNeil, J J; McLean, A J

    1989-01-01

    The pharmacokinetics of bismuth subcitrate were studied in plasma and urine under conditions of single and multiple dosing (28-56 days) using atomic absorption technique. Single dose plasma pharmacokinetics showed peak concentrations of 5.5-57.5 micrograms.l-1 (mean = 24.7 micrograms.l-1), reached between 30 and 60 min post dosing with an apparent biphasic elimination pattern. Multiple dose studies showed a continuing rise in plasma concentration and urine excretion rate reaching apparent steady-state levels over 7-29 days (mean = 18 days). Washout studies in 6 individuals reciprocated accumulation. Maximum equilibrated plasma levels of 7.6-58.3 micrograms.l-1 (mean = 38.3 micrograms.l-1) were well below those associated with encephalopathy. The half-life of bismuth elimination was 20.7 days. Present patterns of intermittent dosing with bismuth are unlikely to be associated with bismuth accumulation despite slow accumulation and elimination.

  19. First report on the pharmacokinetics of tramadol and O-desmethyltramadol in exhaled breath compared to plasma and oral fluid after a single oral dose.

    PubMed

    Meyer, Markus R; Rosenborg, Staffan; Stenberg, Marta; Beck, Olof

    2015-12-01

    Exhaled breath (EB) is a promising matrix for bioanalysis of non-volatiles and has been routinely implemented for drugs of abuse analysis. Nothing is known regarding the pharmacokinetics of therapeutics and their metabolites in EB. Therefore, we used tramadol as a model drug. Twelve volunteers received a single oral dose of tramadol and repeated sampling of EB, plasma, and oral fluid (OF) was done for 48 h using a particle filter device for EB and the Quantisal-device for OF. Samples were analyzed with LC-MS/MS and the pharmacokinetic correlations between matrices were investigated. The initial tramadol half-life in EB was shorter than in plasma but it reappeared in EB after 8-24 h. The ratio of O-desmethyltramadol to tramadol was considerably lower in EB and OF compared to plasma. This pilot study compared for the first time the pharmacokinetics of a therapeutic drug and active metabolite in different biomatrices including EB and demonstrated its potential for bioanalysis.

  20. Acute response of rat liver microsomal lipids, lipid peroxidation, and membrane anisotropy to a single oral dose of polybrominated biphenyls.

    PubMed

    Bernert, J T; Groce, D F

    1984-01-01

    Liver microsomal lipids and lipid peroxidation activities were examined in adult male rats at intervals over a 2-mo period after the administration of a single oral dose of 0 or 500 mg/kg of FireMaster BP-6 in corn oil. Microsomal lipids were markedly altered in the polybrominated biphenyl- (PBB-) dosed animals at the earliest time examined (1 wk), and these changes persisted throughout the remainder of the study. An early decrease in the cholesterol-phospholipid ratio was noted, which probably contributed to the significant decrease in the steady-state fluorescence anisotropy demonstrable in both intact microsomes and in liposomes prepared from microsomal lipid extracts. Significant concentrations of PBBs were present in dosed rat microsomes, but the changes in anisotropy appeared to result from membrane lipid alterations rather than from a direct perturbation by PBBs. Iron ascorbate-induced peroxidation was also greatly enhanced in dosed rat microsomes, even when rats were maintained on a low-iron (25 ppm) diet. These early alterations in membrane fluidity and peroxidative capacity of microsomes may ultimately contribute to the hepatotoxicity of PBBs.

  1. Clinical improvement in feline herpesvirus 1 infected cats by oral low dose of interleukin-12 plus interferon-gamma.

    PubMed

    Fiorito, Filomena; Cantiello, Antonietta; Granato, Giovanna Elvira; Navas, Luigi; Diffidenti, Carmine; De Martino, Luisa; Maharajan, Veeramani; Olivieri, Fabio; Pagnini, Ugo; Iovane, Giuseppe

    2016-10-01

    Feline herpesvirus 1 (FHV-1) is a widespread cat pathogen inducing rhinitis, conjunctivitis and corneal ulcers. To alleviate acute FHV-1-induced disease, antiviral agents are used often with antibiotics. But sometimes, these treatments, as well as conventional doses of cytokines have moderate efficacy and/or collateral effects. Herein we have investigated the effects of low dose interleukin (IL)-12 plus interferon (IFN)-gamma, prepared by Sequential Kinetic Activated (SKA), on the treatment of FHV-1 infection. Twenty-five, unvaccinated FHV-1-positive cats were recruited into a prospective, randomized, placebo-controlled, double-blinded clinical trial. Fifteen cats were treated for 6 months with oral low doses of SKA IL-12 plus IFN-gamma and 10 cats were treated with placebo. At 1, 6 and 12 months (follow-up) after the beginning of treatment, clinical assessment, PCR assay and blood count were carried out. At follow-up, in treated group, we observed significant (p<0.05) improvements in clinical signs and PCR became negative in 12/15 cats (80%). In placebo, 10/10 cats were PCR-positive, with improvements (30%) or worsening (70%) in clinical signs. Blood values were normal in both groups. Our results show that the low dose therapy, based on activated solutions of IL-12 plus IFN-gamma, represents a novel approach to treat FHV-1 infection in cats.

  2. Efficacy of mouth rinse in preventing oral mucositis in patients receiving high-dose cytarabine for allogeneic hematopoietic stem cell transplantation.

    PubMed

    Mori, Takehiko; Hasegawa, Kaori; Okabe, Ai; Tsujimura, Natsuki; Kawata, Yusuke; Yashima, Tomoko; Kobayashi, Naoko; Kondo, Sakiko; Aisa, Yoshinobu; Kato, Jun; Tsunoda, Kazuyuki; Nagai, Tetsuo; Nakagawa, Taneaki; Shigematsu, Naoyuki; Kubo, Atsushi; Ikeda, Yasuo; Okamoto, Shinichiro

    2008-12-01

    High-dose cytarabine is one of the major components of the conditioning regimen for hematopoietic stem cell transplantation (HSCT), and frequently causes severe oral mucositis. We have recently demonstrated that cytarabine is excreted into the saliva in patients receiving high-dose cytarabine, and proposed that it might locally and directly contribute to the development of oral mucositis. Therefore, this study was performed to assess whether removing the excreted cytarabine in the saliva by intensive mouth rinse during high-dose cytarabine infusion could reduce the incidence of oral mucositis. Fifteen patients with hematologic malignancies undergoing allogeneic HSCT who received total body irradiation (12 Gy) and high-dose cytarabine at a dose of 3 g/m(2) every 12 h for 4 days as a conditioning were evaluated. Patients were instructed to rinse their mouths using ice-cold water every 10 min, starting simultaneously with the 2-h cytarabine infusion and continuing up to 1 h after completion of each infusion. Oral mucositis was graded on a daily basis according to the National Cancer Institute, Common Toxicity Criteria. Thirty-five patients who previously underwent the same conditioning without mouth rinse served as controls. The incidence of Grades 2-3 and Grade 3 oral mucositis was significantly reduced in patients who performed mouth rinse as compared with the controls (40 vs. 80%, P = 0.009; 0 vs. 25. 7%, P = 0.02). In conclusion, mouth rinse during and shortly after high-dose cytarabine infusion could be an effective and inexpensive measure in reducing the incidence of moderate to severe oral mucositis caused by high-dose cytarabine. This finding strongly suggests the role of cytarabine excretion in the saliva in the development of cytarabine-associated oral mucositis.

  3. Pharmacokinetics of clarithromycin, a new macrolide, after single ascending oral doses.

    PubMed Central

    Chu, S Y; Sennello, L T; Bunnell, S T; Varga, L L; Wilson, D S; Sonders, R C

    1992-01-01

    The pharmacokinetics and safety of single ascending doses of clarithromycin (6-0-methylerythromycin A) were assessed in a placebo-controlled, double-blind, randomized trial with 39 healthy male volunteers. Subjects were randomized to receive single doses of either placebo or 100, 200, 400, 600, 800, or 1,200 mg of clarithromycin. Blood and urine collections were performed over the 24 h following administration of the test preparation. Biological specimens were analyzed for clarithromycin and 14(R)-hydroxyclarithromycin content by a high-performance liquid chromatographic technique. The pharmacokinetics of clarithromycin appeared to be dose dependent, with terminal disposition half-life ranging from 2.3 to 6.0 h and mean +/- standard deviation area under the concentration-versus-time curve from time 0 to infinity for plasma ranging from 1.67 +/- 0.48 to 3.72 +/- 1.26 mg/liter.h per 100-mg dose over the 100- to 1,200-mg dose range. Similar dose dependency was noted in the pharmacokinetics of the 14(R)-hydroxy metabolite. Mean urinary excretion of clarithromycin and its 14(R)-hydroxy metabolite ranged from 11.5 to 17.5% and 5.3 to 8.8% of the administered dose, respectively. Urinary excretion data and plasma metabolite/parent compound concentration ratio data suggested that capacity-limited formation of the active metabolite may account, at least in part, for the nonlinear pharmacokinetics of clarithromycin. No substantive dose-related trend was observed for the renal clearance of either compound. There were no clinically significant drug-related alterations in laboratory and nonlaboratory safety parameters. In addition, there was no significant difference between placebo and clarithromycin recipients in the incidence or severity of adverse events. Clarithromycin appears to be safe and well tolerated. PMID:1489187

  4. A comparative metabolic study of two low-estrogen-dose oral contraceptives containing desogestrel or gestodene progestins.

    PubMed

    Crook, D; Godsland, I F; Worthington, M; Felton, C V; Proudler, A J; Stevenson, J C

    1993-11-01

    A comparative study of low-dose oral contraceptives (OCs) containing either desogestrel or gestodene failed to detect any major differences in metabolic risk markers for coronary heart disease. Included in the investigation were 70 women who used an OC composed of 30 mcg of ethinyl estradiol and 150 mcg of desogestrel, 43 women who took an OC containing 30 mcg of ethinyl estradiol and 75 mcg of gestodene, and 54 controls who did not use hormonal contraception. The study subjects, 18-35 years of age, were recruited from family planning clinics and general practices in England. Concentrations of serum total cholesterol, high-density lipoproteins (HDL), and apolipoproteins were higher in both groups of OC users than in controls, primarily because of increases in the protective HDL subfraction 3. Low-density lipoprotein cholesterol concentrations were unaffected, but serum triglyceride concentrations were elevated in OC users. Fasting plasma glucose, insulin, and C-peptide concentrations were similar in all three groups. The only significant differences between the two OCs were in HDL subfraction 2 concentrations (higher with desogestrel) and the late oral glucose tolerance test plasma insulin response (higher with gestodene). Further research and development, perhaps involving modification of the estrogen component, are needed to avoid the increased triglyceride concentrations and insulin responses associated with these low-dose formulations.

  5. Dose-response and time-course of neurobehavioral changes following oral chlorpyrifos in rats of different ages.

    PubMed

    Moser, V C

    2000-01-01

    Young rats have been shown in several laboratories to be more sensitive to the neurotoxic effects of acute exposure to chlorpyrifos. To examine the neurobehavioral effects of chlorpyrifos as a function of age and dose, we conducted dose-response and time-course assessments in rats of three different ages (postnatal day, or PND, 17, 27, and adults). Doses were selected to span the effective dose range in each age group: PND17 - 4, 10, 20 mg/kg; PND27 - 10, 25, 50 mg/kg; adult - 10, 50, 100 mg/kg. Rats were tested at the time of peak effect on the day of dosing, and again at 1 and 3 days, and at 1 and 2 weeks after a single oral dose. There were age- and sex-related differences in the recovery of these behavioral effects; the adult males recovered from the behavioral effects more quickly than the other age groups, and the adult females showed the slowest recovery (up to at least 3 days). Although these doses had been shown previously to produce a similar degree of cholinesterase inhibition, the neurobehavioral alterations fell into the following three patterns of effect as a function of age. (1) Some endpoints (e.g., gait abnormalities, tremor) showed a dose-response curve that was shifted to the right in the older animals. Calculated ED50 values indicated that the PND17 rats were three- to five-fold more sensitive than the adults. (2) Some measures showed less effect in the youngest rats; for example, maximal motor activity decreases were half as great as with adults. (3) A few effects that were typically observed in adults, e.g., salivation, were not seen at all in the PND17 rats. Thus, differential responses on these neurobehavioral endpoints were observed as a function of age. These data suggest that, for some endpoints, young rats are more sensitive to a range of chlorpyrifos doses; however, the magnitude of age-related differences depends on the specific endpoint and time of assessment, as well as age and sex of the test subject.

  6. Hepatic and intestine alterations in mice after prolonged exposure to low oral doses of Microcystin-LR.

    PubMed

    Sedan, Daniela; Laguens, Martín; Copparoni, Guido; Aranda, Jorge Oswaldo; Giannuzzi, Leda; Marra, Carlos Alberto; Andrinolo, Darío

    2015-09-15

    Oral intake of Microcystin-LR (MC-LR) is the principal route of exposure to this toxin, with prolonged exposure leading to liver damage of unspecific symptomatology. The aim of the present paper was therefore to investigate the liver and intestine damage generated by prolonged oral exposure to low MC-LR doses (50 and 100 μg MC-LR/kg body weight, administrated every 48 h during a month) in a murine model. We found alterations in TBARS, SOD activity and glutathione content in liver and intestine of mice exposed to both doses of MC-LR. Furthermore, the presence of MC-LR was detected in both organs. We also found hepatic steatosis (3.6 ± 0.6% and 15.3 ± 1.6%) and a decrease in intraepithelial lymphocytes (28.7 ± 5.0% and 44.2 ± 8.7%) in intestine of 50- and 100-μg MC-LR/kg treated animals, respectively. This result could have important implications for mucosal immunity, since intraepithelial lymphocytes are the principal effectors of this system. Our results indicate that prolonged oral exposure at 50 μg MC-LR/kg every 48 h generates significant damage not only in liver but also in intestine. This finding calls for a re-appraisal of the currently accepted NOAEL (No Observed Adverse Effect Level), 40 μg MC-LR/kg body weight, used to derive the guideline value for MC-LR in drinking water.

  7. A Flexible-Dose Study of Paliperidone ER in Patients With Nonacute Schizophrenia Previously Treated Unsuccessfully With Oral Olanzapine

    PubMed Central

    KOTLER, MOSHE; DILBAZ, NESRIN; ROSA, FERNANDA; PATERAKIS, PERIKLIS; MILANOVA, VIHRA; SMULEVICH, ANATOLY B.; LAHAYE, MARJOLEIN

    2016-01-01

    Objective: The goal of this study was to explore the tolerability, safety, and treatment response of switching from oral olanzapine to paliperidone extended release (ER). Methods: Adult patients with nonacute schizophrenia who had been treated unsuccessfully with oral olanzapine were switched to flexible doses of paliperidone ER (3 to 12 mg/d). The primary efficacy outcome was a ≥20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to endpoint for patients who switched medications because of lack of efficacy with olanzapine and noninferiority versus previous olanzapine treatment (mean endpoint change in PANSS total scores vs. baseline of ≤5 points) for patients who switched for reasons other than lack of efficacy. Safety and tolerability were assessed by monitoring adverse events, extrapyramidal symptoms, and weight change. Results: Of 396 patients, 65.2% were men, mean age was 40.0±12.0 years, and 75.5% had paranoid schizophrenia. Among the patients whose main reason for switching was lack of efficacy, an improvement in the PANSS total score of ≥20% occurred in 57.4% of patients. Noninferiority was confirmed for each subgroup of patients whose main reason for switching was something other than lack of efficacy. Paliperidone ER was generally well tolerated. Extrapyramidal symptoms as measured by total Extrapyramidal Symptom Rating Scale scores showed statistically significant and clinically relevant improvements at endpoint, the average weight decreased by 0.8±5.2 kg at endpoint, and a clinically relevant weight gain of ≥7% occurred in 8.0% of patients. Conclusion: Paliperidone ER flexibly-dosed over 6 months was well tolerated and associated with a meaningful clinical response in patients with nonacute schizophrenia who had previously been unsuccessfully treated with oral olanzapine. PMID:26813484

  8. Pharmacokinetics of tetracycline after single-dose oral administration in the American alligator (Alligator mississippiensis).

    PubMed

    Rivera, Sam; Nevarez, Javier G; Maxwell, Lara K; Barker, Steven A

    2012-12-01

    The major objective of the study was to assess the pharmacokinetics of tetracycline administered orally to fasted and nonfasted American alligators (Alligator mississippiensis) at 50 mg/kg. Plasma levels of tetracycline were determined using high-performance liquid chromatography with ultraviolet detection. The concentration versus time curve was analyzed using a compartmental modeling technique. A one-compartment model with first-order absorption and elimination, as well as a lag time to absorption, best described the data. The area under the curve and mean residence time values differed significantly between the fasted and nonfasted groups. Based on the results of this study, tetracycline suspension administered once orally at 50 mg/kg to American alligators is not expected to reach plasma concentrations above the breakpoint minimum inhibitory concentration of 4 microg/ml for susceptible organisms.

  9. Oral dosing with multi-antigenic construct induces atheroprotective immune tolerance to individual peptides in mice.

    PubMed

    Mundkur, Lakshmi; Ponnusamy, Thiruvelselvan; Philip, Sheena; Rao, Lakshmi Narasimha; Biradar, Suryakant; Deshpande, Vrushali; Kumar, Ramesh; Lu, Xinjie; Kakkar, Vijay V

    2014-08-01

    Inflammatory immune response to self-antigens plays an important role in the development of atherosclerosis. Restoring immune tolerance to self-proteins reduces the pro-inflammatory response. We previously showed that oral tolerance to a combination of two peptides is atheroprotective. In the present study we expressed epitopes from apolipoprotein B 100 (ApoB), human heat shock protein (HSP60) and Chlamydia pneumonia outer membrane protein (Cpn) in a single protein scaffold and used this multi-antigenic construct to induce tolerance to individual peptides by oral route in ApoBtm2Sgy/Ldlrtm1Her/J mice. Antigen specific tolerance to individual peptides was observed in treated animals as seen by an increase in regulatory T cells. Tolerance to the peptides resulted in a 46.5% (p=0.002) reduction in the development of atherosclerosis compared with control. Atheroprotection was associated with a significant (p<0.05) decrease in plaque inflammation and an increase in the expression of immune regulatory markers in the aorta. CD11c+ cells coexpressing CD11b and CD103 increased in lymphoid organs and were found to activate regulatory T cells and reduce effector T-cell response. Adoptive transfer of CD11c+ cells was atheroprotective. Our results suggest that atheroprotection by oral tolerance to a multi-antigenic construct is mediated by antigen specific regulatory T cells and CD11c+ cells with immune regulatory properties.

  10. Preventive effects of low-dose dexmedetomidine on postoperative cognitive function and recovery quality in elderly oral cancer patients

    PubMed Central

    Guo, Yong; Sun, Lulu; Zhang, Junfeng; Li, Qifang; Jiang, Hong; Jiang, Wei

    2015-01-01

    This study analyzed the preventive effects of low-dose dexmedetomidine on postoperative cognitive function and recovery quality in elderly oral cancer patients by observing the perioperative kinetics of inflammatory cytokines, cortisol and melatonin.A total of 149 elderly oral cancer patients who had undergone tumor resection surgery were selected and randomly divided into 2 groups, Group D and Group S. After surgery, Group D was assigned to take intravenous dexmedetomidine at a dose of 0.2 μg/kg/h for 12 h, while Group S was administered physiological saline in the same manner. On the day of surgery and for the first three postoperative days, the patients were assessed with the Mini-Mental State Examination (MMSE) and a 40-item quality of recovery score questionnaire (QoR40) at 7:00 am every morning. Venous blood was harvested at the same time. Then, IL-6, CRP, cortisol and melatonin levels were measured. There were no significant between-group differences in the baseline characteristics. After surgery, the MMSE and QoR40 scores in Group D were better than those in Group S. No between-group differences were observed in the incidences of severe hypotension and bradycardia. Moreover, respiratory depression was not observed in the 2 groups. The peaks of IL-6, CRP and cortisol concentrations in Group D were lower than those in Group S. However, the melatonin levels did not differ between the 2 groups. In elderly patients, intravenous dexmedetomidine administered postoperatively for 12 h at a dose of 0.2 ug/kg/h could improve postoperative cognitive function and recovery quality by decreasing excessive inflammation and stress levels. PMID:26629132

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

    PubMed

    Schnellbacher, Rodney; Beaufrère, 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 μg/mL and 95.1 μg/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.

  12. PRT062607 Achieves Complete Inhibition of the Spleen Tyrosine Kinase at Tolerated Exposures Following Oral Dosing in Healthy Volunteers

    PubMed Central

    Rani, Aradhana; Betz, Andreas; Pak, Yvonne; Haberstock‐Debic, Helena; Pandey, Anjali; Hollenbach, Stanley; Gretler, Daniel D.; Mant, Tim; Jurcevic, Stipo; Sinha, Uma

    2016-01-01

    Abstract The spleen tyrosine kinase (SYK) regulates immune cell activation in response to engagement of a variety of receptors, making it an intriguing target for the treatment of inflammatory and autoimmune disorders as well as certain B‐cell malignancies. We have previously reported on the discovery and preclinical characterization of PRT062607, a potent and highly selective inhibitor of SYK that exhibits robust anti‐inflammatory activity in a variety of animal models. Here we present data from our first human studies aimed at characterizing the pharmacokinetics (PK), pharmacodynamics (PD), and safety of PRT062607 in healthy volunteers following single and multiple oral administrations. PRT062607 demonstrated a favorable PK profile and the ability to completely inhibit SYK activity in multiple whole‐blood assays. The PD half‐life in the more sensitive assays was approximately 24 hours and returned to predose levels by 72 hours. Selectivity for SYK was observed at all dose levels tested. Analysis of the PK/PD relationship indicated an IC50 of 324 nM for inhibition of B‐cell antigen receptor‐mediated B‐cell activation and 205 nM for inhibition of FcεRI‐mediated basophil degranulation. PRT062607 was safe and well tolerated across the entire range of doses. Clinical PK/PD was related to in vivo anti‐inflammatory activity of PRT062607 in the rat collagen‐induced arthritis model, which predicts that therapeutic concentrations may be safely achieved in humans for the treatment of autoimmune disease. PRT062607 has a desirable PK profile and is capable of safely, potently, and selectively suppressing SYK kinase function in humans following once‐daily oral dosing. PMID:27406873

  13. Effect of half adult dose of oral Rifampicin (300mg) in patients with idiopathic central serous chorioretinopathy

    PubMed Central

    Khan, Muhammad Saim; Sameen, Murtaza; Lodhi, Arshad Ali; Ahmed, Munawar; Ahmed, Noman; Kamal, Mustafa; Junejo, Sameen Afzal

    2016-01-01

    Objectives: To evaluate the effect of half adult dose of oral Rifampicin on mean change in best corrected visual acuity and central macular thickness in patients with central serous chorioretinopathy. Methods: Thirty-eight eyes of 31 patients with idiopathic central serous chorioretinopathy (CSCR) were registered. Unaided Visual acuity, best corrected visual acuity was documented and detailed slit lamp examination along with dilated ophthalmoscopy was performed. All subjects were treated with oral Rifampicin 300 mg (half adult dose) daily for 03 months. Patients underwent a complete ocular and systemic examination as well as central macular thickness (CMT) measurement by optical coherence tomography (OCT) every month after starting treatment until four months. Fundus fluorescein angiography (FFA) was performed in recurrent cases. Liver function tests were carried out prior to the treatment and during follow up period. Results: A total of 38 eyes of 31 patients (24 males, 07 females) were included in the study. Mean age of patients was 36.16±3.19 years (range 30-44). Mean best corrected visual acuity (BCVA) before treatment was 0.56±0.11 and improved to 0.47±0.14 at 04 weeks (P<0.001) of treatment. The mean CMT at the time of presentation was 494.39±96.29 um and was decreased to 306.90±50.71 um after 04 weeks of treatment (P<0.001). The mean induced reduction in CMT was 187.48±122 um (P<0.001) while that in BCVA 0.41±0.16 at 04 weeks of treatment (P<0.001). Liver function tests were within normal range before and after the treatment. Conclusion: Half adult dose rifampicin (300mg) is effective and safe in treatment of central serous chorioretinopathy without causing any systemic imbalance. PMID:27882013

  14. Evaluation of the "make or buy" decision for oral solid unit-dose medications.

    PubMed

    Yeoman, A E

    1979-01-01

    Changing from one drug distribution system to another requires analysis of many standard operating procedures. Analysis of the "make or buy" decision, a form of break-even analysis, is necessary. A mathematical model is developed that considers the relevant costs and allows one to compare directly the commercially available unit-dose medication with your own repackaging process. The mathematical model is intended to aid in the decision of whether to make or buy a unit-dose form of medication. The relevant range of the model and the results are approximate but they give a good estimation of the costs involved. The information necessary to decide what form of unit-dose packaging suits your needs best and the ability to analyze the alternatives is implicit.

  15. Asian Patients with Stroke plus Atrial Fibrillation and the Dose of Non-Vitamin K Oral Anticoagulants

    PubMed Central

    Bang, Oh Young; Hong, Keun-Sik; Heo, Ji Hoe

    2016-01-01

    After recent randomized control trials (RCTs), non-vitamin K oral anticoagulants (NAOAs) are now widely being used in patients with atrial fibrillation (AF) worldwide. However, current guidelines for the use of NOACs in patients with AF are derived mostly using a Caucasian population and non-stroke patients. Relatively few Asian patients with AF and stroke are included in the recent RCTs. As a result, the optimal use of NOACs in this particular group of patients is remains to be settled. The optimal dose of NOACs and response to current dose of NOACs of Asian patients with AF and stroke may differ from those of westerners and patients without stroke. We reviewed available research on NOACs by searching PubMed and ClinicalTrials.gov published in English up to December 2015. In this review, the characteristics of Asian AF patients with prior stroke/transient ischemic attack, which might influence the efficacy and safety profiles of NOACs, are discussed. In addition, we summarize the risk factors for bleeding complications on NOACs, which are related or unrelated with the blood level of NOACs. Lastly, we provide recent data of reduced dose of NOACs from RCTs or large cohorts. The results reviewed herein call for clinical trials to test whether a reduced dose of NOACs is beneficial in Asian patients with AF and stroke. In the meantime, further researches are needed to establish the safety and efficacy of dose-adjusted NOACs considering both blood levels of NOACs and fragility of patients in Asian patients with AF and stroke. PMID:27170995

  16. Impact of peptide transporter 1 on the intestinal absorption and pharmacokinetics of valacyclovir after oral dose escalation in wild-type and PepT1 knockout mice.

    PubMed

    Yang, Bei; Hu, Yongjun; Smith, David E

    2013-10-01

    The primary objective of this study was to determine the in vivo absorption properties of valacyclovir, including the potential for saturable proton-coupled oligopeptide transporter 1 (PepT1)-mediated intestinal uptake, after escalating oral doses of prodrug within the clinical dose range. A secondary aim was to characterize the role of PepT1 on the tissue distribution of its active metabolite, acyclovir. [³H]Valacyclovir was administered to wild-type (WT) and PepT1 knockout (KO) mice by oral gavage at doses of 10, 25, 50, and 100 nmol/g. Serial blood samples were collected over 180 minutes, and tissue distribution studies were performed 20 minutes after a 25-nmol/g oral dose of valacyclovir. We found that the C(max) and area under the curve (AUC)₀₋₁₈₀ of acyclovir were 4- to 6-fold and 2- to 3-fold lower, respectively, in KO mice for all four oral doses of valacyclovir. The time to peak concentration of acyclovir was 3- to 10-fold longer in KO compared with WT mice. There was dose proportionality in the C(max) and AUC₀₋₁₈₀ of acyclovir in WT and KO mice over the valacyclovir oral dose range of 10-100 nmol/g (i.e., linear absorption kinetics). No differences were observed in the peripheral tissue distribution of acyclovir once these tissues were adjusted for differences in perfusing drug concentrations in the systemic circulation. In contrast, some differences were observed between genotypes in the concentrations of acyclovir in the distal intestine. Collectively, the findings demonstrate a critical role of intestinal PepT1 in improving the rate and extent of oral absorption for valacyclovir. Moreover, this study provides definitive evidence for the rational development of a PepT1-targeted prodrug strategy.

  17. Single Dose Pharmacokinetics of Oral Tenofovir in Plasma, Peripheral Blood Mononuclear Cells, Colonic Tissue, and Vaginal Tissue

    PubMed Central

    Louissaint, Nicolette A.; Cao, Ying-Jun; Skipper, Paul L.; Liberman, Rosa G.; Tannenbaum, Steven R.; Nimmagadda, Sridhar; Anderson, Jean R.; Everts, Stephanie; Bakshi, Rahul; Fuchs, Edward J.

    2013-01-01

    Abstract HIV seroconversion outcomes in preexposure prophylaxis (PrEP) trials of oral tenofovir (TFV)-containing regimens are highly sensitive to drug concentration, yet less-than-daily dosing regimens are under study. Description of TFV and its active moiety, TFV diphosphate (TFV-DP), in blood, vaginal tissue, and colon tissue may guide the design and interpretation of PrEP clinical trials. Six healthy women were administered a single oral dose of 300 mg tenofovir disoproxil fumarate (TDF) and 4.3 mg (12.31 MBq, 333 μCi) 14C-TDF slurry. Blood was collected every 4 h for the first 24 h, then at 4, 8, 11, and 15 days postdosing. Colonic and vaginal samples (tissue, total and CD4+ cells, luminal fluid and cells) were collected 1, 8 and 15 days postdose. Samples were analyzed for TFV and TFV-DP. Plasma TFV demonstrated triphasic decay with terminal elimination half-life median [interquartile range (IQR)] 69 h (58–77). Peripheral blood mononuclear cell (PBMC) TFV-DP demonstrated biphasic peaks (median 12 h and 96 h) followed by a terminal 48 h (38–76) half-life; Cmax was 20 fmol/million cells (2–63). One day postdose, the TFV-DP paired colon:vaginal tissue concentration ratio was 1 or greater in all subjects' tissue homogenates, median 124 (range 1–281), but was not sustained. The ratio was lower and more variable in cells extracted from tissue. Among all sample types, TFV and TFV-DP half-life ranged from 23 to 139 h. PBMC TFV-DP rose slowly in the hours after dosing indicating that success with exposure-driven dosing regimens may be sensitive to timing of the dose prior to exposure. Colonic tissue homogenate TFV-DP concentrations were greater than in vaginal homogenate at 24 h, but not in cells extracted from tissue. These and the other pharmacokinetic findings will guide the interpretation and design of future PrEP trials. PMID:23600365

  18. A single-blind, placebo-controlled, dose-ranging trial of oral hepatic-directed vesicle insulin add-on to oral antidiabetic treatment in patients with type 2 diabetes mellitus.

    PubMed

    Geho, W Blair; Rosenberg, Len N; Schwartz, Sherwyn L; Lau, John R; Gana, Theophilus J

    2014-05-01

    The dose response of postprandial plasma glucose (PPG) to add-on, premeal oral hepatic-directed vesicle-insulin (HDV-I), an investigational lipid bio-nanoparticle hepatocyte-targeted insulin delivery system, was evaluated in a 3-test-meal/day model in type 2 diabetes patients. The single-blind, placebo-controlled, dose-escalating trial enrolled 6 patients with HbA(1c) 8.6 ± 2.0% (70.0 ± 21.9 mmol/mol) and on stable metformin therapy. Patients received oral HDV-I capsules daily 30 minutes before breakfast, lunch, and dinner as follows: placebo capsules, 0.05, 0.1, 0.2, and 0.4 U/kg on days 1, 2, 3, 4, and 5, respectively. Outcome measures were PPG and incremental PPG area under the concentration-time curve (AUC). All 4 doses of oral HDV-I statistically significantly lowered mean PPG (P ≤ .0110 each) and incremental PPG (P ≤ .0352 each) AUC compared to placebo. A linear dose response was not observed. The 0.05 U/kg dose was the minimum effective dose in the dosage range studied. Three adverse events unrelated to treatment were observed. Add-on oral HDV-I 0.05-0.4 U/kg significantly lowered PPG excursions and the dose response curve was flat. These results are consistent with the lack of a linear dose response between portal and systemic plasma insulin concentrations in previous animal and human studies. Oral HDV-I was safe and well tolerated.

  19. Oral Reference Dose for ethylene glycol based on oxalate crystal-induced renal tubule degeneration as the critical effect

    SciTech Connect

    Snellings, William M.; Corley, Richard A.; McMartin, K. E.; Kirman, Christopher R.; Bobst, Sol M.

    2013-03-31

    Several risk assessments have been conducted for ethylene glycol (EG). These assessments identified the kidney as the primary target organ for chronic effects. None of these assessments have incorporated the robust database of species-specific toxicokinetic and toxicodynamic studies with EG and its metabolites in defining uncertainty factors used in reference value derivation. Pertinent in vitro and in vivo studies related to one of these metabolites, calcium oxalate, and its role in crystal-induced nephropathy are summarized, and the weight of evidence to establish the mode of action for renal toxicity is reviewed. Previous risk assessments were based on chronic rat studies using a strain of rat that was later determined to be less sensitive to the toxic effects of EG. A recently published 12-month rat study using the more sensitive strain (Wistar) was selected to determine the point of departure for a new risk assessment. This approach incorporated toxicokinetic and toxicodynamic data and used Benchmark Dose methods to calculate a Human Equivalent Dose. Uncertainty factors were chosen, depending on the quality of the studies available, the extent of the database, and scientific judgment. The Reference Dose for long-term repeat oral exposure to EG was determined to be 15 mg/kg bw/d.

  20. Oxidative stress in rat brain but not in liver following oral administration of a low dose of nanoparticulate silver.

    PubMed

    Skalska, Joanna; Dąbrowska-Bouta, Beata; Strużyńska, Lidia

    2016-11-01

    While it is known that silver nanoparticles (AgNPs) can enter the brain, our knowledge of AgNP-induced neurotoxicity remains incomplete. We investigated the ability of 10 nm citrate-stabilized AgNPs to generate oxidative stress in brain and liver of adult male Wistar rats after repeated oral exposure for 14 days, using a low dose of 0.2 mg/kg b.w. as compared with the same dose of ionic silver (silver citrate). In AgNP-exposed animals, the level of reactive oxygen species (ROS), lipid peroxidation (MDA) and glutathione peroxidase (GPx) activity were found to be significantly higher in brain relative to the control group receiving saline. Administration of ionic silver (silver citrate) increased ROS and MDA levels in both tissues. Activities of GPx in brain so as superoxide dismutase (SOD) and catalase (CAT) in liver of exposed animals were also elevated. Besides, AgNPs and silver ions were both found to cause statistically significant decrease in the reduced-to-oxidized glutathione ratio (GSH/GSSG) in brain. The results show that exposure to a very low dose of particulate silver generates mild oxidative stress in the brain but not in the liver of rats, indicating a role of oxidative stress in AgNP-induced neurotoxicity.

  1. 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.

  2. Treatment of permanent chemotherapy-induced alopecia with low dose oral minoxidil.

    PubMed

    Yang, Xinyi; Thai, Keng-Ee

    2015-05-13

    Chemotherapy-induced alopecia is a well-established cause of major distress to patients. Permanent chemotherapy-induced alopecia (PCIA) is the absence of or incomplete hair regrowth lasting longer than 6 months after the cessation of chemotherapy and it does not respond to standard treatments of scalp cooling or topical minoxidil. The increasing numbers of reports of PCIA highlight the need for research into an effective treatment. We report a case of a 39 year-old woman with cosmetically significant regrowth after continuous therapy with oral minoxidil.

  3. Four Week Oral Dose Range-Finding Study of WR242511 in Dogs

    DTIC Science & Technology

    1994-03-09

    Laboratory, Model No. 282). The assay was performed within one-hour of sample collection. The specimens were kept on wet ice prior to analysis...this protein, which is synthesized by hepatocytes, is indicative of an inflammatory response, i.e. an acute phase reaction . Dose-dependent anemia, as...apparent decreases in the A/G ratio, and increases in serum haptoglobin levels, indicative of an acute phase reaction . In the lung, WR242511 resulted in

  4. 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 < 0.05, respectively). Factor VIII activity declined at 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial thromboplastin time prolonged significantly at 2 and 4 hours following NK administration (p < 0.05 and p < 0.01, respectively). All the changes, however, were within the normal range. In conclusion, thus, a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously. PMID:26109079

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

    PubMed

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

    2015-06-25

    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 < 0.05, respectively). Factor VIII activity declined at 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial thromboplastin time prolonged significantly at 2 and 4 hours following NK administration (p < 0.05 and p < 0.01, respectively). All the changes, however, were within the normal range. In conclusion, thus, a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously.

  6. 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

    Δ(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.

  7. Prognostic factors of 28 days survival rate in patients with a first acute myocardial infarction based on gender in Isfahan, Iran (2000-2009)

    PubMed Central

    Mohammadian, Mahdi; Hosseini, Shidokht; Salehiniya, Hamid; Sadeghi, Masoumeh; Sarrafzadegan, Nizal; Roohafza, Hamid Reza; Khazaei, Salman; Soltani, Shahin; Sarrafkia, Ali; Golshahi, Jafar; Mohammadian-Hafshejani, Abdollah

    2015-01-01

    BACKGROUND Determinant prognostic factors of 28 days survival rate in patients with a first acute myocardial infarction (AMI) based on gender in teen year’s period in Isfahan, Iran, was the aim of this study. METHODS This study is a prospective hospital-based study that consisted, all patients with AMI admitted to all hospitals (private and universal hospitals) in Isfahan and Najafabad (Iran) during 2000-2009. To determinant the prognostic factors of 28 days survival rate in patients based on gender, analysis conducted separately for male and female. In analysis, we use of t-test, log Rank tests, Kaplan-Meier method, and univariate and multivariate Cox regression model. RESULTS Short-term (28 days) survival rate was 92.5% in male and 86.7% in female (P < 0.001). The adjusted hazard ratio (HR) of death for age group 80 years and older was 12.7 [95% confidence interval (CI): 5.14-31.3] in male and 8.78 (95% CI: 1.2-63.1) in female. HR for acute transmural MI of the unspecified site in male was 8.9 (95% CI: 4.68-16.97) and in female 9.33 (95% CI: 4.42-19.7). HR for receive of streptokinase in male was 1.11 (95% CI: 0.94-1.31) and in female was 0.69 (95% CI: 0.56-0.84). CONCLUSION Short-term survival rate in male was a higher than female. In male age, anatomic location of MI and hospital status and in female streptokinase use and anatomic location of MI was the most important prognostic factors of survival in-patient with AMI in Isfahan. PMID:26862341

  8. Determination of enrofloxacin stability and in vitro efficacy against Staphylococcus pseudintermedius and Pseudomonas aeruginosa in four ear cleaner solutions over a 28 day period.

    PubMed

    Metry, Catherine A; Maddox, Carol W; Dirikolu, Levent; Johnson, Yvette J; Campbell, Karen L

    2012-02-01

    Chemical stability and in vitro bactericidal efficacy of 0.9% enrofloxacin-compounded solutions were evaluated following storage at room temperature for 28 days. Chemical stability of enrofloxacin was determined by high-performance liquid chromatography (HPLC) in five compounded solutions, including sterile water. Bactericidal efficacy was determined by spiral plating serial 10-fold dilutions of bacteria and solutions followed by colony counts. Tris-EDTA [TrizEDTA(®) (TE)], Tris-EDTA and 0.15% chlorhexidine [TrizChlor(®) (TC)], 2.5% lactic acid, 0.1% salicylic acid and 0.1% parachlorometaxylenol [Epi-Otic (EO)], and 0.1% free salicylic acid, 0.1% parachlorometaxylenol and 0.5% EDTA [Epi-Otic Advanced (EA)] were used. High-performance liquid chromatography was carried out with one-step liquid/liquid extraction to detect and quantify enrofloxacin stability. Mean recoveries for compounded samples run in triplicate at 28 days were 97.7% (TE), 99.9% (TC), 98.1% (EO) and 97.8% (EA). Kruskal-Wallis analysis showed no significant difference in the percentage recovery (H=0.0539, df=3, P=0.9967). American Type Culture Collection strains of Staphylococcus pseudintermedius and Pseudomonas aeruginosa were used to evaluate in vitro efficacy following 30 min incubation on days 0, 14 and 28. Consistent in vitro bactericidal efficacy of all compounded solutions, indicated by killing >2.3×10(7) colony-forming units/mL, was seen; however, bactericidal efficacy decreased for compounded TC on day 14. Pseudomonas aeruginosa was more sensitive to the ear cleaners and enrofloxacin than S. pseudintermedius. The HPLC and in vitro data suggest that 0.9% enrofloxacin compounded with sterile water, TE, EO and EA maintains chemical stability and bactericidal efficacy for 28 days.

  9. Malaria-Infected Mice Are Cured by a Single Oral Dose of New Dimeric Trioxane Sulfones Which Are Also Selectively and Powerfully Cytotoxic to Cancer Cells

    PubMed Central

    Rosenthal, Andrew S.; Chen, Xiaochun; Liu, Jun O.; West, Diana C.; Hergenrother, Paul J.; Shapiro, Theresa A.; Posner, Gary H.

    2009-01-01

    A new series of 6 dimeric trioxane sulfones has been prepared from the natural trioxane artemisinin in 5 or 6 chemical steps. One of these thermally and hydrolytically stable new chemical entities (4c) completely cured malaria-infected mice via a single oral dose of 144 mg/kg. At a much lower single oral dose of only 54 mg/kg combined with 13 mg/kg of mefloquine hydrochloride, this trioxane dimer 4c as well as its parent trioxane dimer 4b also completely cured malaria-infected mice. Both dimers 4c and 4b were potently and selectively cytotoxic toward five cancer cell lines. PMID:19186946

  10. Water intoxication induced by low-dose oral cyclophosphamide in a patient with anti-neutrophil cytoplasmic antibody-related glomerulonephritis.

    PubMed

    Kato, Akihiko; Sugiura, Takeshi; Yamamoto, Tatsuo; Misaki, Taro; Tsuji, Takayuki; Sakao, Yukitoshi; Sakakima, Masaaki; Yasuda, Hideo; Fujigaki, Yoshihide; Hishida, Akira

    2008-10-01

    We reported the case of a 70-year-old woman with moderate renal failure due to anti-neutrophil cytoplasmic antibody-related glomerulonephritis who developed symptomatic water intoxication (serum Na: 108 mEq/L) following treatment with oral low-dose cyclophosphamide (CY) (50mg/day). Estimated glomerular filtration rate was 29.5 mL/min/1.73 m(2). She had drunk >2 L of fluid in 12 h prior to the development of cerebral oedema. This rare case suggests that oral low-dose CY could be an occult cause of water intoxication in patients with chronic kidney disease taking large fluid volumes.

  11. An acute oral dose of caffeine does not alter glucose kinetics during prolonged dynamic exercise in trained endurance athletes.

    PubMed

    Roy, B D; Bosman, M J; Tarnopolsky, M A

    2001-08-01

    This study investigated the possible influence of oral caffeine administration on endogenous glucose production and energy substrate metabolism during prolonged endurance exercise. Twelve trained endurance athletes [seven male, five female; peak oxygen consumption (VO2peak) = 65.5 ml.kg-1.min-1] performed 60 min of cycle ergometry at 65% VO2peak twice, once after oral caffeine administration (6 mg.kg-1) (CAF) and once following consumption of a placebo (PLA). CAF and PLA were administered in a randomized double-blind manner 75 min prior to exercise. Plasma glucose kinetics were determined with a primed-continuous infusion of [6,6-2H]glucose. No differences in oxygen consumption (VO2), and carbon dioxide production (VCO2) were observed between CAF and PLA, at rest or during exercise. Blood glucose concentrations were similar between the two conditions at rest and also during exercise. Exercise did lead to an increase in serum free fatty acid (FFA) concentrations for both conditions; however, no differences were observed between CAF and PLA. Both the plasma glucose rate of appearance (Ra) and disappearance (Rd) increased at the onset of exercise (P < 0.05), but were not affected by CAF, as compared to PLA. CAF did lead to a higher plasma lactate concentration during exercise (P < 0.05). It was concluded that an acute oral dose of caffeine does not influence plasma glucose kinetics or energy substrate oxidation during prolonged exercise in trained endurance athletes. However, CAF did lead to elevated plasma lactate concentrations. The exact mechanism of the increase in plasma lactate concentrations remains to be determined.

  12. A single dose of sodium nitrate does not improve oral glucose tolerance in patients with type 2 diabetes mellitus.

    PubMed

    Cermak, Naomi M; Hansen, Dominique; Kouw, Imre W K; van Dijk, Jan-Willem; Blackwell, Jamie R; Jones, Andrew M; Gibala, Martin J; van Loon, Luc J C

    2015-08-01

    Dietary nitrate (NO3(-)) supplementation has been proposed as an emerging treatment strategy for type 2 diabetes. We hypothesized that ingestion of a single bolus of dietary NO3(-) ingestion improves oral glucose tolerance in patients with type 2 diabetes. Seventeen men with type 2 diabetes (glycated hemoglobin, 7.3% ± 0.2%) participated in a randomized crossover experiment. The subjects ingested a glucose beverage 2.5 hours after consumption of either sodium NO3(-) (0.15 mmol NaNO3(-) · kg(-1)) or a placebo solution. Venous blood samples were collected before ingestion of the glucose beverage and every 30 minutes thereafter during a 2-hour period to assess postprandial plasma glucose and insulin concentrations. The results show that plasma NO3(-) and nitrite levels were increased after NaNO3(-) as opposed to placebo ingestion (treatment-effect, P = .001). Despite the elevated plasma NO3(-) and nitrite levels, ingestion of NaNO3(-) did not attenuate the postprandial rise in plasma glucose and insulin concentrations (time × treatment interaction, P = .41 for glucose, P = .93 for insulin). Despite the lack of effect on oral glucose tolerance, basal plasma glucose concentrations measured 2.5 hours after NaNO3(-) ingestion were lower when compared with the placebo treatment (7.5 ± 0.4 vs 8.3 ± 0.4 mmol/L, respectively; P = .04). We conclude that ingestion of a single dose of dietary NO3(-) does not improve subsequent oral glucose tolerance in patients with type 2 diabetes.

  13. 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

  14. Characterization of anxiety-related responses in male rats following prolonged exposure to therapeutic doses of oral methylphenidate.

    PubMed

    Britton, Gabrielle B; Bethancourt, José A

    2009-10-01

    Increases in the rates of attention-deficit/hyperactivity disorder (ADHD) diagnosis and the prescribed use of methylphenidate (MPH) in recent years have raised concerns over the potential effects of early MPH exposure on brain structure and function in adulthood. Animal studies have shown that long-term MPH exposure can modify anxiety-related behaviors and related neural circuitry in adulthood. The present study employed a battery of behavioral tests and repeated testing to assess the long-term effects of MPH exposure on anxious responding. Male Wistar rats beginning on post-natal day 27 were exposed to 4 or 7 weeks of twice daily MPH administration at doses of 2, 3, or 5 mg/kg. MPH was administered orally and on weekdays only in order to approximate drug treatment in clinical populations. Behavioral testing began 18 days following the last drug administration. Our results indicate that prolonged oral MPH treatment at therapeutic doses has little or no enduring effects on anxious behaviors. However, a comparison of MPH groups that received treatment for 4 or 7 weeks suggests that the two treatment periods influenced anxious behaviors in observably different manners in adulthood; namely, a more prolonged period of exposure produced less anxiety relative to the shorter period of MPH exposure as indicated by behaviors in the light-dark transition, elevated plus-maze, and fear conditioning tests. These findings were interpreted as evidence of the importance of considering length of drug exposure in pre-clinical studies aimed at investigating the effects of MPH exposure in ADHD populations.

  15. Combined LRRK2 mutation, aging and chronic low dose oral rotenone as a model of Parkinson’s disease

    PubMed Central

    Liu, Hui-Fang; Ho, Philip Wing-Lok; Leung, Gideon Chi-Ting; Lam, Colin Siu-Chi; Pang, Shirley Yin-Yu; Li, Lingfei; Kung, Michelle Hiu-Wai; Ramsden, David Boyer; Ho, Shu-Leong

    2017-01-01

    Aging, genetics and environmental toxicity are important etiological factors in Parkinson’s disease (PD). However, its pathogenesis remains unclear. A major obstacle is the lack of an appropriate experimental model which incorporates genetic susceptibility, aging and prolonged environmental toxicity. Here, we explored the interplay amongst these factors using mutant LRRK2R1441G (leucine-rich-repeat-kinase-2) knockin mice. We found that mutant primary cortical and mesencephalic dopaminergic neurons were more susceptible to rotenone-induced ATP deficiency and cell death. Compared with wild-type controls, striatal synaptosomes isolated from young mutant mice exhibited significantly lower dopamine uptake after rotenone toxicity, due to reduced striatal synaptosomal mitochondria and synaptic vesicular proton pump protein (V-ATPase H) levels. Mutant mice developed greater locomotor deficits in open-field tests than wild-type mice following low oral rotenone doses given twice weekly over 50 weeks (half their lifespan). The increased locomotor deficit was associated with specific reduction in striatal mitochondrial Complex-I (NDUFS4) in rotenone-treated mutant but not in similarly treated wild-type mice. Our unique experimental model which incorporates genetic effect, natural aging and prolonged oral environmental toxicity administered to mutant knockin LRRK2 mice over half their life span, with observable and measurable phenotype, is invaluable in further studies of the pathogenic process and therapeutics of PD. PMID:28098219

  16. 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

  17. Comparative pharmacokinetics and bile transformation of R-enantiomer and racemic bambuterol after single-dose intravenous, oral administration in rats and beagle dogs.

    PubMed

    Guan, Su; Hu, Chun-Yun; He, Meng-Ying; Yang, Ying-Ying; Tang, Yu-Xin; Chen, Jie-di; Huang, Li-Jie; Tan, Wen

    2015-12-01

    This study was to compare pharmacokinetics and bile transformation of R-enantiomer bambuterol with its racemate. Pharmacokinetics of R-enantiomer was investigated after single-dose intravenous and three doses of oral administration to rats and beagle dogs. To compare the pharmacokinetics with racemic bambuterol, the same oral doses of racemic bambuterol were also administrated; the blood and bile samples were collected by cannulation. A validated LC-MS/MS method was used to assess the level of bambuterol in plasma and bile. After single intravenous administration, no significant differences were observed between the two drugs in pharmacokinetic data. After oral dosing of R-bambuterol, the AUCs of R-enantiomer presented linear correlation. After same oral dosing of R-enantiomer and its racemate, all the pharmacokinetic parameters were equivalent. However, the clearance and apparent distribution had different results due to species and administration route difference. The bile transformation of these two compounds was similar and implicated that liver transformation accounted for the major metabolism of them. The bioavailability of R-enantiomer and racemate were comparative and relatively high in beagle dogs. Thus, R-enantiomer had a comparative pharmacokinetic profile and bile transformation with racemic bambuterol in rats and beagle dogs. These findings provided references for further clinical study.

  18. Oral dosing with papaya latex is an effective anthelmintic treatment for sheep infected with Haemonchus contortus

    PubMed Central

    2011-01-01

    Background The cysteine proteinases in papaya latex have been shown to have potent anthelmintic properties in monogastric hosts such as rodents, pigs and humans, but this has not been demonstrated in ruminants. Methods In two experiments, sheep were infected concurrently with 5,000 infective larvae of Haemonchus contortus and 10,000 infective larvae of Trichostrongylus colubriformis and were then treated with the supernatant from a suspension of papaya latex from day 28 to day 32 post-infection. Faecal egg counts were monitored from a week before treatment until the end of the experiment and worm burdens were assessed on day 35 post-infection. Results We found that the soluble fraction of papaya latex had a potent in vivo effect on the abomasal nematode H. contortus, but not on the small intestinal nematode T. colubriformis. This effect was dose-dependent and at tolerated levels of gavage with papaya latex (117 μmol of active papaya latex supernatant for 4 days), the H. contortus worm burdens were reduced by 98%. Repeated treatment, daily for 4 days, was more effective than a single dose, but efficacy was not enhanced by concurrent treatment with the antacid cimetidine. Conclusions Our results provide support for the idea that cysteine proteinases derived from papaya latex may be developed into novel anthelmintics for the treatment of lumenal stages of gastro-intestinal nematode infections in sheep, particularly those parasitizing the abomasum. PMID:21406090

  19. Sexual behavior of women taking low-dose oral contraceptive containing 15 microg ethinylestradiol/60 microg gestodene.

    PubMed

    Caruso, Salvatore; Agnello, Carmela; Intelisano, Giorgia; Farina, Marco; Di Mari, Lucia; Cianci, Antonio

    2004-03-01

    The objective of this prospective study was to assess the effects of a low-dose oral contraceptive (OC) containing 15 microg ethinylestradiol and 60 microg gestodene on sexuality. Forty-eight healthy volunteers (age range, 18-35 years), having regular menstrual cycles with ovulation, participated in the study. Sexual behavior was assessed using the self-administered Personal Experience Questionnaire, at baseline, and at 3, 6 and 9 months of pill use. Women reported decreased sexual desire (p < 0.005) and sexual activity (p < 0.05) at the 9th month of pill use, and diminished sexual arousal at the 3rd month of pill intake (p < 0.05), with respect to baseline. The frequency of orgasm did not change during OC use (p = NS). Moreover, sexual enjoyment was worse at the 3rd, 6th and 9th month with respect to baseline (p < 0.001). The low dose of ethinylestradiol could cause decreased vaginal lubrication, and diminished sexual arousal could be due to hypoandrogenism. Women may expect increased sexual performance when they take the pill, as compared to before starting contraception. Consequently, they could have an unexpected effect with pill use, though sexuality may remain the same.

  20. Thirteen-week oral dose toxicity study of Oligonol containing oligomerized polyphenols extracted from lychee and green tea.

    PubMed

    Kitadate, Kentaro; Homma, Kohei; Roberts, Ashley; Maeda, Takahiro

    2014-02-01

    Oligonol is a functional food containing catechin-type monomers and proanthocyanidin oligomer converted from polymer forms via a novel manufacturing process. The catechin component of green tea extract has been associated with nasal toxicity in rats following subchronic exposure. To assess the potential for Oligonol to induce nasal toxicity a 13-week repeated oral dose toxicity study was conducted in rats using doses of 100, 300, and 1000 mg/kg/d. Clinical signs and mortality were not affected by Oligonol treatment. Compound-colored stools and an increase in food consumption were observed in some treated groups; however, there were no treatment-related differences in terminal body weights or with respect to the results of the gross postmortem examinations. Histopathological evaluation of the nasal cavity tissues revealed no treatment-related lesions. The results from this toxicity study indicate that Oligonol does not induce nasal toxicity and further supports the results of previous studies demonstrating the safety of Oligonol for human consumption.

  1. Performance properties of the population bioequivalence approach for in vitro delivered dose for orally inhaled respiratory products.

    PubMed

    Morgan, Beth; Strickland, Helen

    2014-01-01

    Regulatory agencies, industry, and academia have acknowledged that in vitro assessments serve a role in establishing bioequivalence for second-entry drug product approvals as well as innovator post-approval drug product changes. For orally inhaled respiratory products (OIPs), the issues of correctly analyzing in vitro data and interpreting the results within the broader context of therapeutic equivalence have garnered significant attention. One of the recommended statistical tests for in vitro data is the population bioequivalence method (PBE). The current literature for assessing the PBE statistical approach for in vitro data assumes a log normal distribution. This paper focuses on an assessment of that assumption for in vitro delivered dose. Concepts in development of a statistical model are presented. The PBE criterion and hypotheses are written for the case when data follows a normal distribution, rather than log normal. Results of a simulation study are reported, characterizing the performance of the PBE approach when data are expected to be normally distributed, rather than log normal. In these cases, decisions using the PBE approach are not consistent for the same absolute mean difference that the test product is from the reference product. A conclusion of inequivalency will occur more often if the test product dose is lower than the reference product for the same deviation from target. These features suggest that more research is needed for statistical equivalency approaches for in vitro data.

  2. Immunotoxicological profile of chloramine in female B6C3F1 mice when administered in the drinking water for 28 days.

    PubMed

    Guo, Tai L; Germolec, Dori R; Collins, Bradley J; Luebke, Robert W; Auttachoat, Wimolnut; Smith, Matthew J; White, Kimber L

    2011-01-01

    Monochloramine has been used to provide a disinfecting residual in water distribution systems where it is difficult to maintain an adequate free-chlorine residual or where disinfection by-product formation is of concern. The goal of this study was to characterize the immunotoxic effects of chloramine in female B(6)C(3)F(1) mice when administered via the drinking water. Mice were exposed to chloramine-containing deionized tap water at 2, 10, 20, 100, or 200 ppm for 28 days. No statistically significant differences in drinking water consumption, body weight, body weight gain, organ weights, or hematological parameters between the exposed and control animals were noted during the experimental period. There were no changes in the percentages and numbers of total B-lymphocytes, T-lymphocytes, CD4(+) and CD8(+) T-lymphocytes, natural killer (NK) cells, and macrophages in the spleen. Exposure to chloramine did not affect the IgM antibody-forming cell response to sheep red blood cells (SRBC) or anti-SRBC IgM antibody production. Minimal effects, judged to be biologically insignificant, were observed in the mixed-leukocyte response and NK activity. In conclusion, chloramine produced no toxicological and immunotoxic effects in female B(6)C(3)F(1) mice when administered for 28 days in the drinking water at concentrations ranging from 2-200 ppm.

  3. Evaluating the enantioselective degradation and novel metabolites following a single oral dose of metalaxyl in mice.

    PubMed

    Zhang, Ping; Zhu, Wentao; Qiu, Jing; Wang, Dezhen; Wang, Xinru; Wang, Yao; Zhou, Zhiqiang

    2014-11-01

    Metalaxyl [N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D,L-alaninemethylester] is a systemic fungicide widely used in agriculture. In this study, the enantioselective distribution, degradation and excretion of metalaxyl were investigated after oral gavage administration of rac-metalaxyl to mice. Concentration of metalaxyl and its enantiomers was determined by HPLC-MS/MS. The results showed that R-metalaxyl was much higher than S-metalaxyl in heart, liver, lung, urine and feces. As for the strong first pass effect, concentrations of metalaxyl in liver were much higher than those in other tissues. The total body clearance (CL) of metalaxyl in mice was 1.77 L h(-1 )kg(-1) and degradation half-lives of (t1/2) of S-metalaxyl and R-metalaxyl in liver were 2.2 h and 3.0 h, respectively. Such results indicated the enantioselectivity of metalaxyl lies in distribution, degradation and excretion processes in mice. Main metabolites were also determined and biotransformation reactions were hydroxylation, demethylation and didemethylation. Furthermore, metabolite concentrations in urine and feces were much higher than those in tissues. These results may have potential implications to predict toxicity and provide additional information associated with adverse health effects for risk assessment of metalaxyl.

  4. Selenium absorption, distribution, and excretion in white sturgeon orally dosed with l-selenomethionine.

    PubMed

    Tashjian, Diran H; Hung, Silas S O

    2006-10-01

    The usefulness of a newly developed, combined technique consisting of esophageal intubation, dorsal aortic cannulation, and urinary catheterization to deliver Se orally and to monitor Se uptake, accumulation, and excretion in white sturgeon (Acipenser transmontanus) was explored. Groups of five yearling sturgeon (1-2 kg) each were intubated with 0 (sham), 250, 500, or 1,000 microg Se/kg body weight in the form of L-selenomethionine, an ecologically relevant organic form of Se. Selenium concentrations in whole blood, plasma, and red blood cells did not change in the sham group but began to rise within 2 h postintubation in the other groups, and levels remained near maximum concentrations throughout the 48-h sampling period. Average urinary Se excretion rates over the entire 48-h period were 0.05, 0.46, 0.61, and 2.15 microg Se/kg/h in sturgeon intubated with 0, 250, 500, and 1,000 microg Se/kg, respectively. Selenium excretion rates were highest within the first 6 h in all treatment groups except the sham group. Selenium concentrations in the liver were positively correlated with the intubated Se dosage.

  5. Analysis of clinical efficacy, side effects, and laboratory changes among patients with acne vulgaris receiving single versus twice daily dose of oral isotretinoin.

    PubMed

    Ahmad, Hesham M

    2015-01-01

    Acne vulgaris is a debilitating disorder and requires proper treatment. This work evaluates the clinical efficacy, side effects, and laboratory changes of serum lipids and liver function during oral isotretinoin therapy for acne vulgaris, comparing single versus twice daily dose. Fifty-eight patients with acne vulgaris were included and randomized into group I (26 patients), who received once daily dose, and group II (32 patients), who received twice daily dose of oral isotretinoin. Global acne scoring system was used to evaluate acne severity and post-treatment improvement. Both regimens resulted in highly significant clinical improvement of acne with no significant difference. However, side effects were significantly more common among patients of group I. Both regimens caused mild rise of serum cholesterol, alanine transaminase (ALT), and aspartate aminotransferase (AST) with more prominent rise of triglycerides especially with twice daily dose. Oral isotretinoin is a very effective treatment for acne vulgaris with no statistically significant difference in clinical efficacy between once and twice daily doses. However, dividing dose to twice per day might cause fewer incidence of side effects without reducing clinical efficacy. The drug causes mild clinically insignificant rise of serum cholesterol, triglycerides, AST, and ALT.

  6. Single-dose oral pharmacokinetics of pergolide mesylate in healthy adult mares.

    PubMed

    Gehring, Ronette; Beard, Laurie; Wright, Abra; Coetzee, Johann; Havel, James; Apley, Michael

    2010-01-01

    Pituitary pars intermedia dysfunction (PPID) is probably the most common disease of geriatric horses. Affected horses show a variety of clinical signs, including hirsutism, polyuria/polydipsia, immunosuppression, muscle wasting, and laminitis. The most common treatment for PPID is pergolide, a dopamine agonist; however, there are no pharmacokinetic data about the use of this drug in horses. This article describes a study designed to address this complete lack of pharmacokinetic information. The pharmacokinetics of pergolide are described in a small group of relatively young, healthy mares (n = 6), with the objective of generating data on which to base larger studies in the future. To make definitive dosing recommendations to clinicians, more studies will be needed to investigate the relationship between plasma pergolide concentrations and clinical outcomes, as well as the effect of gender, age, and concomitant disease on the absorption and disposition of this drug.

  7. Toxicity studies with dieldrin: teratological studies in mice dosed orally with HEOD.

    PubMed

    Dix, K M; van der Pauw, C L; McCarthy, W V

    1977-08-01

    Dose of 1.5 and 4.0 mg/kg/day of HEOD in corn oil and 0.25, 0.5 and 1.0 mg/kg/day of HEOD in dimethyl sulphoxide (DMSO) were administered to pregnant CF1 mice on days 6 to 14 (inclusive) of gestation. Some maternal and foetal toxicity was seen in the HEOD in DMSO and DMSO control groups compared with the untreated controls, such as reduced body weight gains, some maternal deaths, lower foetal body weights and increased incidence of delayed ossification of the foetal bones. No maternal or foetal toxicity was seen in the HEOD in corn oil or the corn oil control groups. No compound-related teratogenic effects were observed.

  8. 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.

  9. Metabolism of omeprazole after two oral doses in children 1 to 9 months old.

    PubMed

    Hoyo-Vadillo, Carlos; Venturelli, Caterina R; González, Hector; Romero, Elba; Cervantes, Roberto; Mata, Norberto; Ortiz, Ana Carolina; Rincón, Victor; Zarate, Flora; Sosa, Cristina; Ramírez-Mayans, Jaime

    2005-01-01

    Proton pump inhibitors (PPIs) have been used recently for gastrointestinal esophageal reflux disease (GERD) in children older than one year with good results. However, the pharmacokinetics of PPIs have not been studied in children less than two years old. The aim of our study was to evaluate the frequency of the main phenotypes of the metabolizing enzymes CYP2C19 and CYP3A4 in Mexican infants. Our results indicate no significant difference between the 0.5 and the 1.5 mg/kg doses. The percentage of CYP2C19-poor metabolizers was 17% in babies below 4 months and was not detected in children above 3 months. When a combined CYP2C19- and CYP3A4- phenotype was estimated, omeprazole levels were significantly higher in poor metabolizers than in extended metabolizers. The percentage of ultra-extensive metabolizers in children older than 3 months were 20% and 33% for CYP2C19 and CYP3A4 respectively, compared to only 6% and 9% respectively, in babies between 1 and 3 months old. In general children, under 4 months had higher omeprazole levels and an immature metabolism. Studies in children older than 2 years old have showed similar pharmacokinetics to adults. For children between 1 month old and up to 9 months, we suggest the use of the 0.5 mg/kg dose, since it prevents accumulation in poor metabolizers, caution is recommended to identify ultra-fast metabolizers, but this would require new studies.

  10. Multiple-dose escalation study of the safety, pharmacokinetics, and biologic activity of oral AMD070, a selective CXCR4 receptor inhibitor, in human subjects.

    PubMed

    Stone, Nimalie D; Dunaway, Shelia B; Flexner, Charles; Tierney, Camlin; Calandra, Gary B; Becker, Stephen; Cao, Ying-Jun; Wiggins, Ilene P; Conley, Jeanne; MacFarland, Ron T; Park, Jeong-Gun; Lalama, Christina; Snyder, Sally; Kallungal, Beatrice; Klingman, Karin L; Hendrix, Craig W

    2007-07-01

    AMD070 is an oral CXCR4 antagonist with in vitro activity against X4-tropic human immunodeficiency virus type 1. Thirty fasting healthy male volunteers received oral doses of AMD070 ranging from a single 50-mg dose to seven 400-mg doses given every 12 h (q12h). Nine subjects received a 200-mg dose during fasting and prior to a meal. Subjects were monitored for safety and pharmacokinetics. AMD070 was well tolerated, without serious adverse events. Transient headaches (13 subjects) and neurocognitive (8 subjects) and gastrointestinal (7 subjects) symptoms were the most common complaints. Seven subjects had sinus tachycardia, and two were symptomatic. AMD070 plasma concentrations peaked 1 to 2 h after patient dosing. The estimated terminal half-life ranged from 11.2 to 15.9 h among cohorts. Dose proportionality was not demonstrated. Less than 1% of the drug appeared unchanged in the urine. Food reduced the maximum concentration of drug in serum and the area under the concentration-time curve from 0 to 24 h by 70% and 56%, respectively (P < or = 0.01). A dose-dependent elevation of white blood cells (WBC) demonstrated a maximum twofold increase over baseline (95% confidence interval, 2.0- to 2.1-fold) in an E(max) model. In healthy volunteers, AMD070 was well tolerated and demonstrated mixed-order pharmacokinetics, and food reduced drug exposure. AMD070 induced a dose-related elevation of WBC which was attributed to CXCR4 blockade. Using leukocytosis as a surrogate marker for CXCR4 inhibition, this dose-response relationship suggests that the doses used in this study were active in vivo, though not maximal, throughout the dosing interval. Trough concentrations with the 400-mg dose q12h exceeded the antiviral in vitro 90% effective concentration of AMD070.

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

    PubMed

    Guzman, David Sanchez-Migallon; Beaufrère, Hugues; KuKanich, Butch; Barker, Steven A; Brandão, João; 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.

  12. Comparative assessment of efficacy of two different pretreatment single oral doses of betamethasone on inter-appointment and postoperative discomfort: An in vivo clinical evaluation

    PubMed Central

    Gyanani, Hitesh; Chhabra, Naveen; Parmar, Ghanshyam R.

    2016-01-01

    Aim: Study aimed to evaluate the efficacy of two different pretreatment single oral doses of betamethasone on the incidence of inter-appointment flare up and postoperative discomfort. Materials and Methods: Fifty-four patients aged 18–59 years requiring endodontic treatment were selected and randomly assigned to three groups; single pretreatment oral dose of placebo or betamethasone in two different oral doses of 0.5 mg and 1 mg, respectively. Endodontic therapy was completed in two visits using triple antibiotic paste as intracanal medicament. Patients were given a questionnaire to record their pain at 1, 2, 3, and 7 days after treatment. In the second visit, obturation was done, and the patients were again instructed to record their pain scores after treatment and discharged. The verbal rating scale was used for recording the pain scores. Statistical analysis was done using ANOVA and the Friedman test. Results: 0.5 mg betamethasone group showed least mean pain scores among all experimental groups; however, there was no statistically significant difference between any of the groups (P > 0.05). Conclusion: Pretreatment single oral dose of betamethasone is an effective in managing endodontic flare-ups; however, the results were statistically insignificant. PMID:27994320

  13. Florfenicol residues in Rainbow Trout after oral dosing in recirculating and flow-through culture systems

    USGS Publications Warehouse

    Meinertz, Jeffery R.; Hess, Karina R.; Bernady, Jeffry A.; Gaikowski, M. P.; Whitsel, Melissa; Endris, R. G.

    2014-01-01

    Aquaflor is a feed premix for fish containing the broad spectrum antibacterial agent florfenicol (FFC) incorporated at a ratio of 50% (w/w). To enhance the effectiveness of FFC for salmonids infected with certain isolates of Flavobacterium psychrophilum causing coldwater disease, the FFC dose must be increased from the standard 10 mg·kg−1 body weight (BW)·d−1 for 10 consecutive days. A residue depletion study was conducted to determine whether FFC residues remaining in the fillet tissue after treating fish at an increased dose would be safe for human consumption. Groups of Rainbow Trout Oncorhynchus mykiss (total n = 144; weight range, 126–617 g) were treated with FFC at 20 mg·kg−1 BW·d−1 for 10 d in a flow-through system (FTS) and a recirculating aquaculture system (RAS) each with a water temperature of ∼13°C. The two-tank RAS included a nontreated tank containing 77 fish. Fish were taken from each tank (treated tank, n = 16; nontreated tank, n = 8) at 6, 12, 24, 48, 72, 120, 240, 360, and 480 h posttreatment. Florfenicol amine (FFA) concentrations (the FFC marker residue) in skin-on fillets from treated fish were greatest at 12 h posttreatment (11.58 μg/g) in the RAS and were greatest at 6 h posttreatment (11.09 μg/g) in the FTS. The half-lives for FFA in skin-on fillets from the RAS and FTS were 20.3 and 19.7 h, respectively. Assimilation of FFC residues in the fillets of nontreated fish sharing the RAS with FFC-treated fish was minimal. Florfenicol water concentrations peaked in the RAS-treated tank and nontreated tanks at 10 h (453 μg/L) and 11 h (442 μg/L) posttreatment, respectively. Monitoring of nitrite concentrations throughout the study indicated the nitrogen oxidation efficiency of the RAS biofilter was minimally impacted by the FFC treatment.

  14. Effects of acute and repeated oral doses of D-tagatose on plasma uric acid in normal and diabetic humans.

    PubMed

    Saunders, J P; Donner, T W; Sadler, J H; Levin, G V; Makris, N G

    1999-04-01

    D-tagatose, a stereoisomer of D-fructose, is a naturally occurring ketohexose proposed for use as a low-calorie bulk sweetener. Ingested D-tagatose appears to be poorly absorbed. The absorbed portion is metabolized in the liver by a pathway similar to that of D-fructose. The main purpose of this study was to determine if acute or repeated oral doses of D-tagatose would cause elevations in plasma uric acid (as is seen with fructose) in normal humans and Type 2 diabetics. In addition, effects of subchronic D-tagatose ingestion on fasting plasma phosphorus, magnesium, lipids, and glucose homeostasis were studied. Eight normal subjects and eight subjects with Type 2 diabetes participated in this two-phase study. Each group was comprised of four males and four females. In the first phase, all subjects were given separate 75 g 3-h oral glucose and D-tagatose tolerance tests. Uric acid, phosphorus, and magnesium were determined in blood samples collected from each subject at 0, 30, 60, 120, and 180 min after dose. In the 8-week phase of the study, the normals were randomly placed into two groups which received 75 g of either D-tagatose or sucrose (25 g with each meal) daily for 8 weeks. The diabetics were randomized into two groups which received either 75 g D-tagatose or no supplements of sugar daily for 8 weeks. Uric acid, phosphorus, magnesium, lipids, glycosylated hemoglobin, glucose, and insulin were determined in fasting blood plasma of all subjects at baseline (time zero) and biweekly over the 8 weeks. The 8-week test did not demonstrate an increase in fasting plasma uric acid in response to the daily intake of D-tagatose. However, a transient increase of plasma uric acid levels was observed after single doses of 75 g of D-tagatose in the tolerance test. Plasma uric acid levels were found to rise and peak at 60 min after such dosing. No clinical relevance was attributed to this treatment-related effect because excursions of plasma uric acid levels above the normal

  15. Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 2 mg and placebo.

    PubMed Central

    Bensimon, G; Foret, J; Warot, D; Lacomblez, L; Thiercelin, J F; Simon, P

    1990-01-01

    1. The effects of zolpidem 20 mg, flunitrazepam 2 mg and placebo, administered at bed time, were studied in 12 healthy young male volunteers. 2. The assessments included, at awakening, subjective ratings of overnight sleep, cognitive function, psychomotor performance (digit symbol substitution, choice reaction time, flicker fusion threshold), subjective ratings of alertness, and plasma assay of residual drug concentration. Daytime sleep propensity during the day after dosing was evaluated with the multiple sleep latency test. 3. Compared with placebo, both active drugs improved subjective assessment of the ease of getting to sleep. At awakening, under flunitrazepam treatment, the reduction of performance, on memory and psychomotor tests, paralleled an increased subjective rating of sleepiness, but zolpidem treatment left subjects unimpaired compared with placebo. Similarly, daytime sleep propensity was enhanced throughout the following day under flunitrazepam treatment, but not under zolpidem treatment. Plasma assay for residual drug concentration at awakening found significant amounts of flunitrazepam and marginal amounts of zolpidem. 4. Results indicate that zolpidem 20 mg is devoid of residual effects in a range of tasks that were sensitive enough to demonstrate a prolonged wakefulness impairment following flunitrzepam 2 mg in healthy volunteers. PMID:2223425

  16. Evaluation of amitrole (aminotriazole) for potential carcinogenicity in orally dosed rats, mice, and golden hamsters

    SciTech Connect

    Steinhoff, D.; Weber, H.; Mohr, U.; Boehme, K.

    1983-06-30

    Amitrole was evaluated for carcinogenic potential in lifespan studies on Wistar rats, NMRI mice, and golden hamsters. At the start of the studies the animals were 6 weeks old. Amitrole was administered, mixed with pulverized chow, at dietary concentrations of 0, 1, 10, and 100 micrograms/g (ppm). Each treated group and control group consisted of 75 male and 75 female rats and mice and of 76 male and 76 female golden hamsters. Additional animals were used to evaluate the functional state of the thyroid. Somewhat lower body weights, slightly reduced survival times, and transient effects on thyroid function were observed in golden hamsters at 100 ppm. In mice, a slight increase in pituitary gland hyperemias was seen at 100 ppm; also an effect on thyroid function usually occurred at the same concentration. In rats, a very large number of cystic dilatations of follicles in the thyroid at 100 ppm and a dose-unrelated increase in hemorrhages and hyperemias in the pituitary gland were indicative of an effect of amitrole on these organs. The strongest effect of amitrole on thyroid function, as compared to golden hamsters and mice, was seen in rats at 100 ppm. At this concentration a highly increased number of thyroid and pituitary gland tumors was observed in rats. In golden hamsters and mice, no tumor induction was seen.

  17. Benzo[a]pyrene (BP) DNA adduct formation in DNA repair–deficient p53 haploinsufficient [Xpa(−/−)p53(+/−)] and wild-type mice fed BP and BP plus chlorophyllin for 28 days

    PubMed Central

    Poirier, Miriam C.

    2012-01-01

    We have evaluated DNA damage (DNA adduct formation) after feeding benzo[a]pyrene (BP) to wild-type (WT) and cancer-susceptible Xpa(−/−)p53(+/−) mice deficient in nucleotide excision repair and haploinsufficient for the tumor suppressor p53. DNA damage was evaluated by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ES-MS/MS), which measures r7,t8,t9-trihydroxy-c-10-(N 2-deoxyguanosyl)-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG), and a chemiluminescence immunoassay (CIA), using anti-r7,t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)–DNA antiserum, which measures both BPdG and the other stable BP-DNA adducts. When mice were fed 100 ppm BP for 28 days, BP-induced DNA damage measured in esophagus, liver and lung was typically higher in Xpa(−/−)p53(+/−) mice, compared with WT mice. This result is consistent with the previously observed tumor susceptibility of Xpa(−/−)p53(+/−) mice. BPdG, the major DNA adduct associated with tumorigenicity, was the primary DNA adduct formed in esophagus (a target tissue in the mouse), whereas total BP-DNA adducts predominated in higher levels in the liver (a non-target tissue in the mouse). In an attempt to lower BP-induced DNA damage, we fed the WT and Xpa(−/−)p53(+/−) mice 0.3% chlorophyllin (CHL) in the BP-containing diet for 28 days. The addition of CHL resulted in an increase of BP–DNA adducts in esophagus, liver and lung of WT mice, a lowering of BPdG in esophagi of WT mice and livers of Xpa(−/−)p53(+/−) mice and an increase of BPdG in livers of WT mice. Therefore, the addition of CHL to a BP-containing diet showed a lack of consistent chemoprotective effect, indicating that oral CHL administration may not reduce PAH–DNA adduct levels consistently in human organs. PMID:22828138

  18. Benzo[a]pyrene (BP) DNA adduct formation in DNA repair-deficient p53 haploinsufficient [Xpa(-/-)p53(+/-)] and wild-type mice fed BP and BP plus chlorophyllin for 28 days.

    PubMed

    John, Kaarthik; Pratt, M Margaret; Beland, Frederick A; Churchwell, Mona I; McMullen, Gail; Olivero, Ofelia A; Pogribny, Igor P; Poirier, Miriam C

    2012-11-01

    We have evaluated DNA damage (DNA adduct formation) after feeding benzo[a]pyrene (BP) to wild-type (WT) and cancer-susceptible Xpa(-/-)p53(+/-) mice deficient in nucleotide excision repair and haploinsufficient for the tumor suppressor p53. DNA damage was evaluated by high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC/ES-MS/MS), which measures r7,t8,t9-trihydroxy-c-10-(N (2)-deoxyguanosyl)-7,8,9,10-tetrahydrobenzo[a]pyrene (BPdG), and a chemiluminescence immunoassay (CIA), using anti-r7,t8-dihydroxy-t-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene (BPDE)-DNA antiserum, which measures both BPdG and the other stable BP-DNA adducts. When mice were fed 100 ppm BP for 28 days, BP-induced DNA damage measured in esophagus, liver and lung was typically higher in Xpa(-/-)p53(+/-) mice, compared with WT mice. This result is consistent with the previously observed tumor susceptibility of Xpa(-/-)p53(+/-) mice. BPdG, the major DNA adduct associated with tumorigenicity, was the primary DNA adduct formed in esophagus (a target tissue in the mouse), whereas total BP-DNA adducts predominated in higher levels in the liver (a non-target tissue in the mouse). In an attempt to lower BP-induced DNA damage, we fed the WT and Xpa(-/-)p53(+/-) mice 0.3% chlorophyllin (CHL) in the BP-containing diet for 28 days. The addition of CHL resulted in an increase of BP-DNA adducts in esophagus, liver and lung of WT mice, a lowering of BPdG in esophagi of WT mice and livers of Xpa(-/-)p53(+/-) mice and an increase of BPdG in livers of WT mice. Therefore, the addition of CHL to a BP-containing diet showed a lack of consistent chemoprotective effect, indicating that oral CHL administration may not reduce PAH-DNA adduct levels consistently in human organs.

  19. Folic Acid Supplementation Is Suboptimal in a National Cohort of Older Veterans Receiving Low Dose Oral Methotrexate

    PubMed Central

    Tonner, Chris; Miao, Yinghui; Yazdany, Jinoos; Gannon, Jacqueline; Boscardin, W. John; Daikh, David I.; Steinman, Michael A.

    2016-01-01

    Objectives Co-prescription of folic acid in patients receiving low dose oral methotrexate is recommended because it reduces adverse events and prolongs the use of methotrexate (MTX). However, little is known about how often new users of methotrexate are co-prescribed folic acid, and what factors are associated with its use. We aimed to determine the prevalence, predictors of, and persistence of folic acid use in a population-based cohort of MTX users with rheumatic diseases. Methods Using a national, administrative database of patients seen through the Veterans Health Administration (VHA) that included pharmacy and laboratory data, we performed an observational cohort study of veterans over 65 years old who were new users of MTX. We used log-binomial regression to identify independent predictors of folic acid use and Kaplan Meyer survival analysis to examine persistence of folic acid over time. Results We studied 2467 incident users of MTX. 27% of patients were not prescribed folic acid through the VHA pharmacy within 30 days of MTX initiation. Patients who did not see a rheumatologist were 23% less likely to receive folic acid compared to patients who did have a rheumatologist visit during the baseline period (RR (95% CI) 0.77 (0.72, 0.82). These results remained unchanged even after adjusting for demographic, clinical, and other factors (adjusted RR (95% CI) 0.78 (0.74, 0.85)). After 20 months, only 50% of patients continued to receive folic acid. Conclusions In a nationwide VHA cohort of new users of oral MTX, many patients did not receive folic acid or discontinued it over time. Rheumatologists were more likely to prescribe folic acid than other providers. These data highlight the need to improve patient safety for users of methotrexate by standardizing workflows for folic acid supplementation. PMID:27977768

  20. Single-dose oral pharmacokinetics of three formulations of thalidomide in healthy male volunteers.

    PubMed

    Teo, S K; Colburn, W A; Thomas, S D

    1999-11-01

    Thalidomide was recently approved in the United States for the treatment of erythema nodosum leprosum, a complication of leprosy. The present study determined the bioequivalence and pharmacokinetics of Celgene's commercial and clinical trial thalidomide formulations and the Brazilian Tortuga formulation in an open-label, single-dose, three-way crossover design. Seventeen healthy subjects were given 200 mg of thalidomide on three occasions, and blood samples were collected over 48 hours. Pharmacokinetic parameters were determined using compartmental methods for the two Celgene formulations and using noncompartmental methods for all three formulations. All subjects reported adverse events, none of which was serious or unexpected. Celgene formulations were bioequivalent when comparing Cmax, tmax, and AUC. There was significant variability in plasma levels from the Tortuga formulation, giving a mean profile that was distinctly different from the two Celgene formulations with a lower Cmax value and a longer terminal phase. The lower Cmax was probably due to slower absorption. The terminal rate constant for the Tortuga formulation was significantly less, giving rise to a terminal half-life of 15 hours compared to about 5 to 6 hours for the Celgene formulations. Confidence intervals for Cmax between the Tortuga and the Celgene formulations were outside the 80% to 125% range, indicating a lack of bioequivalence. Extent of absorption, as measured by AUC0-infinity, was approximately equal for all three formulations. Terminal half-life for Tortuga was two to three times longer compared to the Celgene formulations and is clear evidence for absorption rate limitations. The two Celgene formulations showed similar pharmacokinetic parameters with profiles that were best described by a one-compartment model with first-order absorption and elimination. The authors conclude that Celgene's clinical trial and commercial thalidomide formulations are similar to each other and distinctly

  1. Nutrition Composition and Single, 14-Day and 13-Week Repeated Oral Dose Toxicity Studies of the Leaves and Stems of Rubus coreanus Miquel.

    PubMed

    Om, Ae-Son; Song, Yu-Na; Noh, GeonMin; Kim, HaengRan; Choe, JeongSook

    2016-01-08

    The leaves and stems of the plant Rubus coreanus Miquel (RCMLS) are rich in vitamins, minerals and phytochemicals which have antioxidant, anti-hemolytic, anti-inflammatory, anti-fatigue and anti-cancer effects. However, RCMLS is not included in the Korean Food Standards Codex due to the lack of safety assurance concerning RCMLS. We evaluated single and repeated oral dose toxicity of RCMLS in Sprague-Dawley rats. RCMLS did not induce any significant toxicological changes in both male and female rats at a single doses of 2500 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects in clinical signs, body weight, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at doses of 625, 1250, and 2500 mg/kg/day. The LD50 and LOAEL of RCMLS might be over 2500 mg/kg body weight/day and no target organs were identified. Therefore, this study revealed that single and repeated oral doses of RCMLS are safe.

  2. Normal tissue complication probability (NTCP) modelling using spatial dose metrics and machine learning methods for severe acute oral mucositis resulting from head and neck radiotherapy

    PubMed Central

    Dean, Jamie A; Wong, Kee H; Welsh, Liam C; Jones, Ann-Britt; Schick, Ulrike; Newbold, Kate L; Bhide, Shreerang A; Harrington, Kevin J; Nutting, Christopher M; Gulliford, Sarah L

    2016-01-01

    Background and Purpose Severe acute mucositis commonly results from head and neck (chemo)radiotherapy. A predictive model of mucositis could guide clinical decision-making and inform treatment planning. We aimed to generate such a model using spatial dose metrics and machine learning. Material and Methods Predictive models of severe acute mucositis were generated using radiotherapy dose (dose-volume and spatial dose metrics) and clinical data. Penalised logistic regression, support vector classification and random forest classification (RFC) models were generated and compared. Internal validation was performed (with 100-iteration cross-validation), using multiple metrics, including area under the receiver operating characteristic curve (AUC) and calibration slope, to assess performance. Associations between covariates and severe mucositis were explored using the models. Results The dose-volume-based models (standard) performed equally to those incorporating spatial information. Discrimination was similar between models, but the RFCstandard had the best calibration. The mean AUC and calibration slope for this model were 0.71 (s.d.=0.09) and 3.9 (s.d.=2.2), respectively. The volumes of oral cavity receiving intermediate and high doses were associated with severe mucositis. Conclusions The RFCstandard model performance is modest-to-good, but should be improved, and requires external validation. Reducing the volumes of oral cavity receiving intermediate and high doses may reduce mucositis incidence. PMID:27240717

  3. [Pharmacokinetics and relative bioavailability of THC and THC-solid dispersion orally to mice at single dose].

    PubMed

    Liao, Li; Hua, Hua; Zhao, Jun-Ning; Luo, Heng; Yang, An-Dong

    2014-03-01

    To establish a fast sensitive, reproducible LC-MS/MS method to study pharmacokinetic properties of THC, and compare relative bioavailability of THC and its solid dispersion in mice. 200 mice were divided randomly into two groups, and administered orally with THC and THC-solid dispersion after fasting (calculate on THC:400 mg x kg(-1)), used HPLC-MS/MS method to determine the THC concentration of each period at the following times: baseline ( predose ), 15, 30, 45 min, 1, 1.5, 2, 3, 4, 6, 24 h after dosing. Calculating the pharmacokinetic parameters according to the C-t curv, and then use the Phoenix WinNonlin software for data analysis. The calibration curves were linear over the range 9.06-972 microg x L(-1) for THC (R2 = 0.999). The limit of detection (LOD) was 0.7 microg x L(-1), respectively. The average extraction recoveries for THC was above 75%, The methodology recoveries were between 79% and 108%. The intra-day and inter-day RSD were less than 13%, the stability test showed that the plasma samples was stable under different conditions (RSD < 15%). The precision, accuracy, recovery and applicability were found to be adequate for pharmacokinetic studies. Pharmacokinetic parameters of THC and THC-solid dispersion orally to mice shows as fllows: T(max), were 60 and 15 min, AUC(0-t) were 44 500.43 and 57 497.81 mg x L(-1) x min, AUC(0-infinity) were 51 226.00 and 68 031.48 mg x L(-1) x min, MRT(0-infinity) were 596.915 6, 661.747 7 min, CL(z)/F were 0.007 809 and 0.005 88 L x min(-1) x kg(-1). Compared with THC, the MRT and t1/2 of the THC-solid dispersion were all slightly extended, the t(max) was significantly reduced, AUC(0-24 h), AUC(0-infinity) and C(max) were all significantly higher, the relative bioavailability of THC-solid dispersion is 1.34 times of THC. The results of the experiment shows that the precision, accuracy, recovery and applicability were found to be adequate for the pharmacokinetic studies. After oral administration to mice, the relative

  4. Open Study of the Safety and Efficacy of a Single Oral Dose of Cefixime for the Treatment of Gonorrhea in Pregnancy

    PubMed Central

    1997-01-01

    Objective: The intent of this study was to determine the efficacy and tolerance of single dose oral cefixime use in the treatment of pregnant women with endocervical gonococcal carriage. Methods: A retrospective review of clinic records over a 3 year period identified patients treated with a single 400 mg dose of cefixime for gonorrhea during pregnancy. Side effects and subsequent gonococcal carriage were noted. Results: Pregnant women (n = 102) treated with cefixime were reviewed. A cure rate of 95.2% was found. Side effects were reported in three patients: two had nausea and vomiting and one had diarrhea. Conclusions: A single 400 mg oral dose of cefixime was effective for the treatment of gonorrhea and was well tolerated by the pregnant women. PMID:18476147

  5. Failed heart rate control with oral metoprolol prior to coronary CT angiography: effect of additional intravenous metoprolol on heart rate, image quality and radiation dose.

    PubMed

    Jiménez-Juan, Laura; Nguyen, Elsie T; Wintersperger, Bernd J; Moshonov, Hadas; Crean, Andrew M; Deva, Djeven P; Paul, Narinder S; Torres, Felipe S

    2013-01-01

    The purpose of this study was to evaluate the effect of intravenous (i.v.) metoprolol after a suboptimal heart rate (HR) response to oral metoprolol (75-150 mg) on HR control, image quality (IQ) and radiation dose during coronary CTA using 320-MDCT. Fifty-three consecutive patients who failed to achieve a target HR of < 60 bpm after an oral dose of metoprolol and required supplementary i.v. metoprolol (5-20 mg) prior to coronary CTA were evaluated. Patients with HR < 60 bpm during image acquisition were defined as responders (R) and those with HR ≥ 60 bpm as non-responders (NR). Two observers assessed IQ using a 3-point scale (1-2, diagnostic and 3, non-diagnostic). Effective dose (ED) was estimated using dose-length product and a 0.014 mSV/mGy.cm conversion factor. Baseline characteristics and HR on arrival were similar in the two groups. 58% of patients didn't achieve the target HR after receiving i.v. metoprolol (NR). R had a significantly higher HR reduction after oral (mean HR 63.9 ± 4.5 bpm vs. 69.6 ± 5.6 bpm) (p < 0.005) and i.v. (mean HR 55.4 ± 3.9 bpm vs. 67.4 ± 5.3 bpm) (p < 0.005) doses of metoprolol. Studies from NR showed a significantly higher ED in comparison to R (8.0 ± 2.9 vs. 6.1 ± 2.2 mSv) (p = 0.016) and a significantly higher proportion of non-diagnostic coronary segments (9.2 vs. 2.5%) (p < 0.001). 58% of patients who do not achieve a HR of <60 bpm prior to coronary CTA with oral fail to respond to additional i.v. metoprolol and have studies with higher radiation dose and worse image quality.

  6. SU-D-16A-02: A Novel Methodology for Accurate, Semi-Automated Delineation of Oral Mucosa for Radiation Therapy Dose-Response Studies

    SciTech Connect

    Dean, J; Welsh, L; Gulliford, S; Harrington, K; Nutting, C

    2014-06-01

    Purpose: The significant morbidity caused by radiation-induced acute oral mucositis means that studies aiming to elucidate dose-response relationships in this tissue are a high priority. However, there is currently no standardized method for delineating the mucosal structures within the oral cavity. This report describes the development of a methodology to delineate the oral mucosa accurately on CT scans in a semi-automated manner. Methods: An oral mucosa atlas for automated segmentation was constructed using the RayStation Atlas-Based Segmentation (ABS) module. A radiation oncologist manually delineated the full surface of the oral mucosa on a planning CT scan of a patient receiving radiotherapy (RT) to the head and neck region. A 3mm fixed annulus was added to incorporate the mucosal wall thickness. This structure was saved as an atlas template. ABS followed by model-based segmentation was performed on four further patients sequentially, adding each patient to the atlas. Manual editing of the automatically segmented structure was performed. A dose comparison between these contours and previously used oral cavity volume contours was performed. Results: The new approach was successful in delineating the mucosa, as assessed by an experienced radiation oncologist, when applied to a new series of patients receiving head and neck RT. Reductions in the mean doses obtained when using the new delineation approach, compared with the previously used technique, were demonstrated for all patients (median: 36.0%, range: 25.6% – 39.6%) and were of a magnitude that might be expected to be clinically significant. Differences in the maximum dose that might reasonably be expected to be clinically significant were observed for two patients. Conclusion: The method developed provides a means of obtaining the dose distribution delivered to the oral mucosa more accurately than has previously been achieved. This will enable the acquisition of high quality dosimetric data for use in

  7. Renal hemodynamic and morphological changes after 7 and 28 days of leptin treatment: the participation of angiotensin II via the AT1 receptor.

    PubMed

    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-α 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-α 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.

  8. Effects of age and controlled oral dosing of Enterococcus faecium on epithelial properties in the piglet small intestine.

    PubMed

    Lodemann, U; Dillenseger, A; Aschenbach, J R; Martens, H

    2013-12-01

    Enterococcus faecium NCIMB 10415 is a licensed probiotic for piglets that has been shown to positively affect diarrhoea incidence and to act on transport properties and immunological parameters in the porcine intestine. The aim of the present study was to examine its effects on jejunal absorptive and secretory capacities around weaning. Furthermore, the possible involvement of heat shock proteins in the effects of probiotics on epithelial functions was investigated. A significant part of the probiotic was dosed orally to reduce the variability of intake of the probiotic. The piglets were randomly assigned to a control and a probiotic feeding group, the latter receiving 4.5×109 cfu/day of E. faecium directly into the mouth for 34 days starting after birth. Additionally, their feed was supplemented with the probiotic strain. Piglets were weaned at day 29 after birth. Ussing chamber studies were conducted with the mid-jejunum of piglets aged 14, 28, 31, 35 and 56 days. Changes in short-circuit current (ΔIsc) were measured after stimulation of Na+-coupled absorption with L-glutamine or glucose or with the secretagogue prostaglandin E2 (PGE2). The mRNA expression for SGLT1, CFTR and various heat shock proteins was determined. The transport properties changed significantly with age. The glucose-, L-glutamine- and PGE2-induced changes in Isc were highest at day 31 after birth. No significant differences between the feeding groups were observed. The mRNA of HSP60, HSC70, HSP70 and HSP90 was expressed in the jejunal tissues. The mRNA expression of HSC70 was higher and that of HSP60 was lower in the probiotic group. HSC70 expression increased with age. In conclusion, whereas age effects were observed on absorptive and secretory functions, controlled E. faecium dosing had no measurable effects on these functional parameters in this experimental setup. The possible role of heat shock proteins should be further evaluated.

  9. A dose-response study of orally administered clonidine as premedication in the elderly: evaluating hemodynamic safety.

    PubMed

    Filos, K S; Patroni, O; Goudas, L C; Bosas, O; Kassaras, A; Gartaganis, S

    1993-12-01

    Clonidine premedication in a dose of 5 micrograms/kg may be particularly well suited for elderly patients. To pursue this approach, sedation, intraocular pressure (IOP), and the hemodynamic profile of two doses of oral clonidine premedication were compared in 60 elderly patients, aged 65-82 yr, who underwent elective ophthalmic surgery under local anesthesia. Group 1 (n = 20) received placebo, Group 2 (n = 20) 150 micrograms of clonidine (2-2.5 micrograms/kg), and Group 3 (n = 20) 300 micrograms of clonidine (4-4.5 micrograms/kg) in a randomized, double-blind fashion. Decreases in mean arterial blood pressure were more pronounced and occurred earlier after 300 micrograms of clonidine (31.4 +/- 12.1%, P < 0.001) as compared to 150 micrograms of clonidine (18.1 +/- 10.9%, P < 0.001). Throughout the study, six patients (30%) in Group 3 (300 micrograms clonidine-treated group), but no patient in Groups 1 or 2, were treated at least once for hypotension (P < 0.05). Heart rate decreased significantly 18.5 +/- 8.1% (P < 0.001) only after 300 micrograms of clonidine. Clonidine 150 micrograms and 300 micrograms decreased IOP 32.1 +/- 14.3% (P < 0.001) and 47.8 +/- 17.2% (P < 0.001), respectively. After 150 micrograms of clonidine patients were significantly more sedated as compared to those given placebo (P < 0.01) but significantly less sedated than after 300 micrograms of clonidine (P < 0.01), where sedation persisted more than 6 h postoperatively.(ABSTRACT TRUNCATED AT 250 WORDS)

  10. Effect of single oral dose of azithromycin, clarithromycin, and roxithromycin on polymorphonuclear leukocyte function assessed ex vivo by flow cytometry.

    PubMed Central

    Wenisch, C; Parschalk, B; Zedtwitz-Liebenstein, K; Weihs, A; el Menyawi, I; Graninger, W

    1996-01-01

    Azithromycin was given as a single oral dose (20 mg/kg of body weight) to 12 volunteers in a crossover study with roxithromycin (8 to 12 mg/kg) and clarithromycin (8 to 12 mg/kg). Flow cytometry was used to study the phagocytic functions and the release of reactive oxygen products following phagocytosis by neutrophil granulocytes prior to administration of the three drugs, 16 h after azithromycin administration, and 3 h after clarithromycin and roxithromycin administration. Phagocytic capacity was assessed by measuring the uptake of fluorescein isothiocyanate-labeled bacteria. Reactive oxygen generation after phagocytosis of unlabeled bacteria was estimated by the amount of dihydrorhodamine 123 converted to rhodamine 123 intracellularly. Azithromycin resulted in decreased capacities of the cells to phagocytize Escherichia coli (median [range], 62% [27 to 91%] of the control values; P < 0.01) and generate reactive oxygen products (75% [34 to 26%] of the control values; P < 0.01). Clarithromycin resulted in reduced phagocytosis (82% [75 to 98%] of control values; P < 0.01) but did not alter reactive oxygen production (84% [63 to 113%] of the control values; P > 0.05). Roxithromycin treatment did not affect granulocyte phagocytosis (92% [62 to 118%] of the control values; P > 0.05) or reactive oxygen production (94% [66 to 128%] of the control value; P > 0.05). No relation between intra- and/or extracellular concentrations of azithromycin and/or roxithromycin and the polymorphonuclear phagocyte function and/or reactive oxygen production existed (P > 0.05 for all comparisons). These results demonstrate that the accumulation of macrolides in neutrophils can suppress the response of phagocytic cells to bacterial pathogens after a therapeutic dose. PMID:8878577

  11. Additional notes on clinical repeated-dose pharmacokinetic trials applying a peak-and-trough sampling design to estimate oral clearance.

    PubMed

    Takaai, Mari; Kayano, Yuichiro; Shimizu, Takako; Taguchi, Masato; Hashimoto, Yukiya

    2008-01-01

    In the previous study, we performed a simulation of a clinical pharmacokinetic trial, in which blood was sampled at two time points corresponding to the peak concentration (C(peak)) and trough concentration (C(trough)) following repetitive oral administration at the dose, D, and dosing interval, tau. The approximate oral clearance (CL/F(approx)), estimated as 2 x D/(C(peak) x tau+C(trough) x tau), is accurate for drugs with an elimination half-life comparative to or longer than tau; however, it was suggested that we might not use CL/F(approx) for drugs with a considerably short elimination half-life relative to tau. In the present study, we evaluated the accuracy of the alternative oral clearance (CL/F(exp)) estimated by the simple monoexponential model. In contrast to CL/F(approx), CL/F(exp) was accurate for drugs with a short elimination half-life relative to tau. The present finding in conjunction with our previous study suggested that the peak-and-trough sampling design is promising for the clinical repeated-dose pharmacokinetic trial for drugs with not only slow but also rapid elimination from the body. We think that the accuracy and precision of the two analysis methods to estimate oral clearance (CL/F(approx) and CL/F(exp)) for a target drug should be evaluated carefully before and after a real clinical trial.

  12. Effect of vitamin B6 on the side effects of a low-dose combined oral contraceptive.

    PubMed

    Villegas-Salas, E; Ponce de León, R; Juárez-Perez, M A; Grubb, G S

    1997-04-01

    Analogous to recommendations for treatment of side effects of early pregnancy and premenstrual syndrome, use of vitamin B6 has been recommended for the treatment of side effects of oral contraceptive (OC) use. A randomized, triple-blinded controlled trial of 124 women was done to evaluate the effect of taking 150 mg of vitamin B6 daily for 30 days on the severity of nausea, headache, vomiting, dizziness, depression, and irritability associated with the initiation of low-dose (30 micrograms norgestrel and 30 micrograms ethinyl estradiol) OG use. The severity of the symptoms was measured on a scale from 0 to 3 (not present to severe), and was evaluated at one month after admission. The two treatment groups (vitamin B, and placebo) had comparable baseline characteristics. From admission to follow up, there was a decrease in the severity of all symptoms in both groups. There was no statistically significant difference in the reductions found in the vitamin B6 and the placebo groups, although reductions in the severity of headache and dizziness were greater in the B6 group. The decrease in the severity of all OC side effects can be explained more by a placebo effect than by a marginal pharmacological effect of the vitamin B6.

  13. Threshold dose for peanut: Risk characterization based upon diagnostic oral challenge of a series of 286 peanut-allergic individuals.

    PubMed

    Taylor, Steve L; Moneret-Vautrin, D A; Crevel, Rene W R; Sheffield, David; Morisset, Martine; Dumont, P; Remington, Benjamin C; Baumert, Joseph L

    2010-03-01

    Clinical records of 286 consecutive patients reacting positively with objective symptoms to double-blind, placebo-controlled oral peanut challenges at University Hospital, Nancy, France were examined for individual No Observed Adverse Effect Levels (NOAELs) and Lowest Observed Adverse Effect Levels (LOAELs). After fitting to a log-normal probability distribution model, the ED(10) and ED(05) were 14.4 and 7.3mg (expressed as whole peanut), respectively, with 95% lower confidence intervals of 10.7 and 5.2mg, respectively. Compared to results from a previous study where the ED(10) was based upon individual peanut thresholds gleaned from 12 publications, a statistically significant difference was observed between the ED(50)'s, but not the ED(10)'s of the two probability distribution curves. The Nancy patient group contains more sensitive subjects than the group from the published literature thus contributing to the observed differences. Minimum eliciting dose-distributions for patients with histories of more severe reactions (grade 4 or 5; 40 subjects) did not differ significantly from those of patients with histories of less severe reactions (grades 1-3; 123 subjects). These data and this modeling approach could be used to establish population thresholds for peanut-allergic consumers and thereby provide a sound basis for allergen control measures in the food industry.

  14. Pharmacokinetics of the individual enantiomer S-(+)-ketoprofen after intravenous and oral administration in dogs at two dose levels.

    PubMed

    Serrano-Rodríguez, J M; Serrano, J M; Rodríguez, J Morgaz; Machuca, M M Granados; Gómez-Villamandos, R J; Navarrete-Calvo, R

    2014-06-01

    The pharmacokinetic of the individual S-(+)-enantiomer of ketoprofen, S-(+)-ketoprofen, after intravenous (IV) and oral (PO) administration was determined in six dogs at 1 and 3 mg/kg. Plasma concentrations were determined by high performance liquid chromatography with ultraviolet detection. The concentration-time curves were analyzed by non-compartmental methods. Steady-state volume of distribution (Vss) and clearance (Cl) of S-(+)-ketoprofen after IV administration were 0.22 ± 0.07 and 0.19 ± 0.03 L/kg, and 0.10 ± 0.02 and 0.09 ± 0.01 L/h/kg, at 1 and 3 mg/kg, respectively. Following PO administration, S-(+)-ketoprofen achieved maximum plasma concentrations of 4.91 ± 0.76 and 12.47 ± 0.62 μg/ml, at two dose levels, respectively. The absolute bioavailability after PO route was 88.66 ± 12.95% and 85.36 ± 13.90%, respectively.

  15. Novel and Distinct Metabolites Identified Following a Single Oral Dose of α- or γ-Hexabromocyclododecane in Mice

    PubMed Central

    Szabo, David T.; Huwe, Janice; Diliberto, Janet; Birnbaum, Linda S.

    2013-01-01

    The metabolism of α- and γ-hexabromocyclododecane (HBCD) was investigated in adult C57BL/6 female mice. α- or γ-[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 and sacrificed 3 hours post-exposure to investigate tissue metabolite levels. Extractable and non-extractable HBCD metabolites were quantitated in liver, blood, fat, brain, bile, urine and feces and characterized by LC/MS (ESI-). Metabolites identified were distinct between the two stereoisomers. In mice exposed to α-HBCD, four hydroxylated metabolites were detected in fecal extracts, and one of these metabolite isomers was consistently characterized in liver, brain, and adipose tissue extracts. In contrast, mice exposed to γ-HBCD contained multiple isomers of monohydroxy-pentabromocyclododecene, dihydroxy-pentabromocyclododecene, and dihydroxy-pentabromocyclododecadiene in the feces while only a single monohydroxy-pentabromocyclododecane metabolite was measured in liver and adipose tissue. Both stereoisomers were transformed to metabolites which formed covalent bonds to proteins and/or lipids in the gut as evidenced by high fecal non-extractables. Although the potential toxicity of these free and bound metabolites remains to be determined, the presence of distinct metabolic products from the two main HBCD stereoisomers should allow biomarkers to be selected that may aid in characterizing sources of HBCD exposure. PMID:23171393

  16. The efficacy of a single-oral-dose administration of ivermectin and diethylcarbamazine on the treatment of feline Brugia malayi.

    PubMed

    Chansiri, Gaysorn; Khawsak, Phaisan; Phantana, Sirichai; Sarataphan, Nopporn; Chansiri, Kosum

    2005-09-01

    The combination of ivermectin and diethylcarbamazine (DEC) have been shown to be superior to either drug alone for the suppression of Brugia malayi in humans, but their efficacy against infection with B. malayi in cats has never been investigated. Fourteen asymptomatic microfilaremic (1-200 microfilariae/20 microl blood) cats received oral doses of ivermectin (400 microg/kg body weight) and DEC (6 mg/kg body weight) as a single treatment. A two-month post-treatment examination revealed that 87-100% of the microfilariae in each subject had been cleared, with two of the subjects being amicrofilaremic. A further reduction in microfilarial levels was observed until the final follow-up, at 8 months post-treatment, when the mean clearance rate was 99% and 12 out of the 14 subjects (86%) were amicrofilaremic. The combination of ivermectin and DEC demonstrated a microfilaricidal effect superior to that of either drug used alone, both in the initial rapid clearance of microfilariae, and in sustaining the effect for 8 months. This finding has important implications for the control of brugian lymphatic filariasis in the cat reservoir.

  17. The short- and long-term effects of orally administered high-dose reduced graphene oxide nanosheets on mouse behaviors.

    PubMed

    Zhang, Ding; Zhang, Zheyu; Liu, Yayun; Chu, Maoquan; Yang, Chengyu; Li, Wenhao; Shao, Yuxiang; Yue, Yan; Xu, Rujiao

    2015-11-01

    Reduced graphene oxide (rGO), a carbon-based nanomaterial, has enormous potential in biomedical research, including in vivo cancer therapeutics. Concerns over the toxicity remain outstanding and must be investigated before clinical application. The effect of rGO exposure on animal behaviors, such as learning and memory abilities, has not been clarified. Herein, we explored the short- and long-term effects of orally administered rGO on mouse behaviors, including general locomotor activity level, balance and neuromuscular coordination, exploratory and anxiety behaviors, and learning and memory abilities using open-field, rotarod, and Morris water maze tests. Compared with mice administered buffer-dispersed mouse chow or buffer alone, mice receiving a high dose of small or large rGO nanosheets showed little change in exploratory, anxiety-like, or learning and memory behaviors, although general locomotor activity, balance, and neuromuscular coordination were initially affected, which the mechanisms (e.g. the influence of rGO exposure on the activity of superoxide dismutase in mouse serum) were discussed. The results presented in this work look to provide a deep understanding of the in vivo toxicity of rGO to animals, especially its effect on learning and memory and other behaviors.

  18. Single- and multiple-dose pharmacokinetics of an oral once-a-day osmotic controlled-release OROS (methylphenidate HCl) formulation.

    PubMed

    Modi, N B; Lindemulder, B; Gupta, S K

    2000-04-01

    Methylphenidate is used for the treatment of attention deficit hyperactivity disorder (ADHD). OROS (methylphenidate HCl) is an osmotic controlled-release delivery system designed for once-daily oral dosing. The pharmacokinetics of OROS (methylphenidate HCl) 18 mg qd, sustained-release (SR) methylphenidate 20 mg qd, and the immediate-release (IR) formulation given as three 5 mg doses every 4 hours (tid) were compared in adults. In addition, the single- and multiple-dose pharmacokinetics of the OROS formulation were studied. Following OROS (methylphenidate HCl), there was a gradual increase in the mean methylphenidate plasma concentrations with peak concentrations noted at 6 to 8 hours. With the SR formulation, peak plasma concentrations were noted at approximately 4 hours. Following the IR regimen, methylphenidate plasma concentrations fluctuated in tandem with oral dosing; peak concentrations were noted at 6.5 hours. The terminal half-life of methylphenidate was similar for the three formulations. The dose-normalized methylphenidate Cmax for OROS (methylphenidate HCl) was significantly lower than for IR and SR methylphenidate. The bioavailability of methylphenidate and PPA from OROS (methylphenidate HCl) relative to the IR and SR formulations was complete. Mean methylphenidate AUC and terminal half-life were similar after single (32.9 ng.h/mL and 3.9 hours) and multiple doses (35.2 ng.h/mL and 3.9 hours) of OROS (methylphenidate HCl).

  19. Optimal initial dose of oral cyclosporine in relation to its toxicities for graft-versus-host disease prophylaxis following reduced-intensity stem cell transplantation in Japanese patients.

    PubMed

    Kishi, Y; Murashige, N; Kami, M; Miyakoshi, S; Shibagaki, Y; Hamaki, T; Takaue, Y; Taniguchi, S

    2005-06-01

    Since the introduction of reduced-intensity stem-cell transplantation (RIST), allogeneic stem-cell transplantation has become available for elderly patients. While pharmacokinetics of cyclosporine might differ according to age or other factors, cyclosporine is uniformly started at an oral dose of 6 mg/kg/day. We retrospectively reviewed medical records of 35 patients aged between 32 and 65 (median 52) years who had undergone RIST. Doses of cyclosporine were adjusted to the target blood trough level of 150-250 ng/ml. Cyclosporine dosages were changed in 33 patients (94%). Dose reduction was required in 32 patients because of high blood levels (n=25), renal dysfunction (n=3), hepatic dysfunction (n=2), and hypertension (n=2). Cyclosporine doses were increased in one because of the suboptimal level. The median of the achieved stable doses was 3.1 mg/kg/day (range, 1.0-7.4). Five patients sustained Grade III toxicities according to NCI-CTC version 2.0: renal dysfunction (n=4), hyperbilirubinemia (n=2), and hypertension (n=2). No patients developed grade IV toxicity. There was no statistically significant difference in the frequency and severity of cyclosporine toxicities between patients aged 50 years and above and those below 50 years. The initial oral cyclosporine dose of 6 mg/kg/day was unnecessarily high irrespective of age. The possible overdose of cyclosporine might have aggravated regimen-related toxicities.

  20. Acute Oral Toxicity of Tetrodotoxin in Mice: Determination of Lethal Dose 50 (LD50) and No Observed Adverse Effect Level (NOAEL)

    PubMed Central

    Abal, Paula; Louzao, M. Carmen; Antelo, Alvaro; Alvarez, Mercedes; Cagide, Eva; Vilariño, Natalia; Vieytes, Mercedes R.; Botana, Luis M.

    2017-01-01

    Tetrodotoxin (TTX) is starting to appear in molluscs from the European waters and is a hazard to seafood consumers. This toxin blocks sodium channels resulting in neuromuscular paralysis and even death. As a part of the risk assessment process leading to a safe seafood level for TTX, oral toxicity data are required. In this study, a 4-level Up and Down Procedure was designed in order to determine for the first time the oral lethal dose 50 (LD50) and the No Observed Adverse Effect Level (NOAEL) in mice by using an accurate well-characterized TTX standard. PMID:28245573

  1. Acute Oral Toxicity of Tetrodotoxin in Mice: Determination of Lethal Dose 50 (LD50) and No Observed Adverse Effect Level (NOAEL).

    PubMed

    Abal, Paula; Louzao, M Carmen; Antelo, Alvaro; Alvarez, Mercedes; Cagide, Eva; Vilariño, Natalia; Vieytes, Mercedes R; Botana, Luis M

    2017-02-24

    Tetrodotoxin (TTX) is starting to appear in molluscs from the European waters and is a hazard to seafood consumers. This toxin blocks sodium channels resulting in neuromuscular paralysis and even death. As a part of the risk assessment process leading to a safe seafood level for TTX, oral toxicity data are required. In this study, a 4-level Up and Down Procedure was designed in order to determine for the first time the oral lethal dose 50 (LD50) and the No Observed Adverse Effect Level (NOAEL) in mice by using an accurate well-characterized TTX standard.

  2. Subchronic oral toxicity of a standardized white kidney bean (Phaseolus vulgaris) extract in rats.

    PubMed

    Chokshi, Dilip

    2007-01-01

    Dietary supplements containing "starch blockers" are believed to reduce carbohydrate-derived calories by interfering with alpha-amylase, the digestive enzyme responsible for conversion of complex carbohydrates to simple, absorbable sugars. The present paper reports the findings of a 28-day oral toxicity study in rats of Phase 2, a standardized extract derived from the common white kidney bean (Phaseolus vulgaris), which has been shown to have alpha-amylase-inhibiting activity. In order to establish safety, eighty male and female Sprague-Dawley rats (10 animals/sex/group) received Phase 2 via oral gavage at doses of 0, 625, 1250, and 2500 mg/kg (7 days/wk) for a period of 31 (males) or 32 (females) days. There were no mortalities, clinical signs, body weight or nutritional effects, gross alterations, clinical or histopathological alterations that were considered attributable to test substance administration. Under conditions of this study and based on toxicological endpoints evaluated, the no-observed-adverse-effect level (NOAEL) of Phase 2 was judged to be 2500 mg/kg/day in each sex for administration by oral gavage of a standardized white kidney bean extract, Phase 2 for 28 days.

  3. 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.

  4. 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 μg 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 μg) 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

  5. 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)-α, 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 TNFα changes (p>0.05). Conclusions We conclude that RT can be incorporated to potentially offset the metabolic complications of BR. PMID:25317071

  6. A comparison of the effect of two doses of oral melatonin with oral midazolam and placebo on pre-operative anxiety, cognition and psychomotor function in children: A randomised double-blind study

    PubMed Central

    Kurdi, Madhuri S; Muthukalai, Sindhu Priya

    2016-01-01

    Background and Aims: Melatonin (MT), a naturally occurring pituitary hormone has a sleep promoting effect. There are very few studies on pre-operative oral MT (0.2–0.5 mg/kg) in children. We planned a study to assess the efficacy of oral MT in two doses and compare it with oral midazolam and placebo for pre-operative anxiolysis, sedation, maintenance of cognition and psychomotor skills, parental separation behaviour and venepuncture compliance. Methods: This prospective double-blind randomised study was conducted after ethical committee approval on 100 children aged 5–15 years, American Society of Anaesthesiologists physical status I and II undergoing elective surgery at our hospital from January 1, 2014, to December 31, 2014. Mentally disordered children were excluded from the study. They were randomised into four groups of 25 each (A, B, C, D) to receive either oral MT 0.5 mg/kg or 0.75 mg/kg or oral midazolam 0.5 mg/kg or placebo 45–60 min, respectively, before induction. The child's anxiety, cognition and psychomotor function before and after pre-medication, behaviour during the parental separation and venepuncture were appropriately scored. Kruskal–Wallis analysis of variance for intergroup and Wilcoxon matched pairs tests for intragroup comparisons of data were applied. Results: The four groups were comparable regarding mean age, weight and sex. The anxiety score reductions in the three groups when compared to placebo were statistically significant. Children receiving MT 0.75 mg/kg had maximum anxiolysis and venepuncture compliance (P < 0.05). Cognition was decreased with maximum sedation, successful parental separation and psychomotor impairment in the midazolam group (P < 0.05). Conclusion: Oral MT (0.5 mg/kg and 0.75 mg/kg) in children decreases pre-operative anxiety without impairing cognitive and psychomotor functions, the 0.75 mg/kg dose being most effective. PMID:27761038

  7. Water intoxication induced by low-dose oral cyclophosphamide in a patient with anti-neutrophil cytoplasmic antibody-related glomerulonephritis

    PubMed Central

    Kato, Akihiko; Sugiura, Takeshi; Yamamoto, Tatsuo; Misaki, Taro; Tsuji, Takayuki; Sakao, Yukitoshi; Sakakima, Masaaki; Yasuda, Hideo; Fujigaki, Yoshihide; Hishida, Akira

    2008-01-01

    We reported the case of a 70-year-old woman with moderate renal failure due to anti-neutrophil cytoplasmic antibody-related glomerulonephritis who developed symptomatic water intoxication (serum Na: 108 mEq/L) following treatment with oral low-dose cyclophosphamide (CY) (50mg/day). Estimated glomerular filtration rate was 29.5 mL/min/1.73 m2. She had drunk >2 L of fluid in 12 h prior to the development of cerebral oedema. This rare case suggests that oral low-dose CY could be an occult cause of water intoxication in patients with chronic kidney disease taking large fluid volumes. PMID:18795141

  8. Oral supplementation with physiological doses of leptin during lactation in rats improves insulin sensitivity and affects food preferences later in life.

    PubMed

    Sánchez, Juana; Priego, Teresa; Palou, Mariona; Tobaruela, Aixa; Palou, Andreu; Picó, Catalina

    2008-02-01

    We have previously described that neonate rats supplemented with physiological doses of oral leptin during lactation become more protected against overweight in adulthood. The purpose of this study was to characterize further the long-term effects on glucose and leptin homeostasis and on food preferences. Neonate rats were supplemented during lactation with a daily oral dose of leptin or the vehicle. We followed body weight and food intake of animals until the age of 15 months, and measured glucose, insulin, and leptin levels under different feeding conditions: ad libitum feeding, 14-h fasting, and 3-h refeeding after fasting. An oral glucose tolerance test and a leptin resistance test were performed. Food preferences were also measured. Leptin-treated animals were found to have lower body weight in adulthood and to eat fewer calories than their controls. Plasma insulin levels were lower in leptin-treated animals than in their controls under the different feeding conditions, as was the increase in insulin levels after food intake. The homeostatic model assessment for insulin resistance index was significantly lower in leptin-treated animals, and the oral glucose tolerance test also indicated higher insulin sensitivity in leptin-treated animals. In addition, these animals displayed lower plasma leptin levels under the different feeding conditions and were also more responsive to exogenous leptin administration. Leptin-treated animals also showed a lower preference for fat-rich food than their controls. These observations indicate that animals supplemented with physiological doses of oral leptin during lactation were more protected against obesity and metabolic features of the metabolic syndrome.

  9. Determination of the effective dose of a novel oral formulation of sarolaner (Simparica™) for the treatment and month-long control of fleas and ticks on dogs.

    PubMed

    McTier, Tom L; Six, Robert H; Fourie, Josephus J; Pullins, Aleah; Hedges, Laura; Mahabir, Sean P; Myers, Melanie R

    2016-05-30

    Three laboratory studies were conducted to determine the appropriate dose of sarolaner, a novel isoxazoline, for the treatment and month-long control of infestations of fleas and ticks on dogs. In the first study, dogs were treated orally with sarolaner suspension formulations at 1.25, 2.5 or 5.0mg/kg, and infested with Dermacentor reticulatus, Rhipicephalus sanguineus ticks and with Ctenocephalides felis felis (cat flea) prior to treatment and then weekly for up to 8 weeks. Fleas and ticks were counted 48h after treatment and after each subsequent infestation at 24h for fleas and 48h for ticks. The lowest dose of sarolaner (1.25mg/kg) provided 100% efficacy against fleas from treatment through Day 35 and 98.4% at Day 56. This dose of sarolaner resulted in 99.7-100% control of both species of ticks through Day 28. In Study 2, dogs were dosed orally with placebo or sarolaner suspension formulations at 0.625, 1.25 or 2.5mg/kg and infested with Ixodes scapularis prior to treatment and weekly for 6 weeks, Amblyomma americanum (pretreatment and Day 26), Dermacentor variabilis (Day 33) and A. maculatum (Day 41). Ixodes scapularis was the most susceptible; the lowest dose (0.625mg/kg) providing>95% efficacy through Day 43. Efficacy against D. variabilis on Day 35 was>95% at 1.25 and 2.5mg/kg, whereas the 0.625mg/kg dose gave only 61.4% efficacy. Amblyomma spp. were the least susceptible ticks; efficacy of the 1.25mg/kg dose at Day 28 for A. americanum was markedly lower (88.5%) than achieved for D. reticulatus (100%) at Day 28 and also lower than for D. variabilis at Day 35 (96.2%). In Study 3, dogs were dosed orally with placebo or sarolaner in the proposed commercial tablet (Simparica™) at 1.0, 2.0 or 4.0mg/kg, and infested with A. maculatum, one of the ticks determined to be dose limiting, prior to treatment and then weekly for 5 weeks. All doses gave 100% control of the existing infestation. The two highest dosages resulted in >93% control of subsequent challenges

  10. Comparative bioavailability of two oral formulations of clozapine in steady state administered in schizophrenic volunteers under individualized dose regime.

    PubMed

    do Carmo Borges, Ney C; Astigarraga, Rafael B; Sverdloff, Carlos E; Galvinas, Paulo R; Borges, Bruno C; Moreno, Ronilson A

    2012-11-01

    In the present study, a novel, fast, sensitive and robust method to quantify clozapine in human plasma using quetiapine as the internal standard (IS) is described. The analyte and the IS were extracted from plasma using a single protein precipitation extraction technique with methanol and analyzed by high performance liquid chromatography coupled to the electrospray ionization tandem mass spectrometric (HPLC-ESI-MS/MS). The method was linear over the range 20 to 1500 ng.mL-1. The intra-assay precisions ranged from 3.8 to 5.9%, while inter-assay precisions ranged from 4.2 to 6.0%. The intra-assay accuracies ranged from 99.3 to 107.5%, while the inter-assay accuracies ranged from 98.9 to 101.7%. This method agrees with the requirements proposed by the US Food and Drug Administration of high sensitivity, specificity and high sample throughput and was used to evaluate the pharmacokinetic profiles and bioequivalence of the two clozapine formulations in twenty six schizophrenic patients affected by refractory schizophrenia under steady-state conditions. During the hospitalization period the patients received the 100 mg clozapine formulation tablets corresponding to the same dose they were using 14 days before hospitalization. The clozapine pharmacokinetic did not differ significantly after administration of both test and the reference formulations. The Tmax and T1/2 for the test formulation were 2.26 and 10.92 h, respectively. In addition, the Tmax and T1/2 for the reference formulation were 2.44 and 11.08 h, respectively. The 90% confidence interval of the mean ratio of lnAUC0-t was within 0.80-1.25 range which indicates that the test formulation was bioequivalent to the reference formulation when orally administered to schizophrenic patients regarding both the rate and extent of absorption.

  11. Single-dose oral quercetin improves redox status but does not affect heat shock response in mice.

    PubMed

    Chen, Yifan; Islam, Aminul; Abraham, Preetha; Deuster, Patricia

    2014-07-01

    Inflammation and oxidative stress are considered as likely contributors to heat injury. However, their roles in regulating the heat shock response in vivo remain unclear. We tested the hypothesis that acute quercetin treatment would improve redox status and reduce heat shock responses in mice. Mice underwent two heat tests before and after single oral administration of either quercetin (15 mg/kg) or vehicle. We measured physiologic and biochemical responses in mice during and 18 to 22 hours after heat tests, respectively. There were no significant differences in core temperature, heart rate, or blood pressure between quercetin and vehicle groups during heat exposure. Mice with relatively severe hyperthermia during the pretreatment heat test showed a significant trend toward a lower peak core temperature during the heat test after quercetin treatment. Compared with mice not exposed to heat, quercetin-treated mice had significantly lower interleukin 6 (P < .01) and higher superoxide dismutase levels (P < .01), whereas vehicle-treated mice had significantly lower total glutathione and higher 8-isoprostane levels in the circulation after heat exposure. Heat exposure significantly elevated heat shock proteins (HSPs) 72 and 90 and heat shock factor 1 levels in mouse liver, heart, and skeletal muscles, but no significant differences in tissue HSPs and heat shock factor 1 were found between quercetin- and vehicle-treated mice. These results suggest that a single moderate dose of quercetin is sufficient to alter redox status but not heat stress response in mice. Acute adaptations of peripheral tissues to heat stress may not be mediated by systemic inflammatory and redox state in vivo.

  12. Single dose of diclofenac or meloxicam for control of pain, facial swelling, and trismus in oral surgery

    PubMed Central

    Orozco-Solís, Mariana; García-Ávalos, Yazmín; Pichardo-Ramírez, Celeste; Tobías-Azúa, Francisco; Zapata-Morales, Juan-Ramón; Aragon-Martínez, Othoniel-Hugo

    2016-01-01

    Background Postoperative pain associated with removal of mandibular third molars has been documented from moderate to severe during the first 24 hours after surgery, with pain peaking between 6 and 8 hours when a conventional local anesthetic is used. Dental pain is largely inflammatory, and evidence-based medicine has shown that nonsteroidal anti-inflammatory drugs are the best analgesics for dental pain. The aim of this study was to compare the analgesic, anti-inflammatory and anti-trismus effect of a single dose of diclofenac and meloxicam after mandibular third molar extraction. Material and Methods A total of 36 patients were randomized into two treatment groups, each with 18 patients, using a series of random numbers: Group A, was administered 100 mg of diclofenac; and Group B, 15 mg of meloxicam. Drugs were administered orally 1 hour prior to surgery. We evaluated pain intensity, analgesic consumption, swelling, as well as trismus. Results The results of this study showed that patients receiving 15 mg of meloxicam had less postoperative pain (P=0.04) and better aperture than those receiving 100 mg of diclofenac (P=0.03). The meloxicam group presented less swelling than diclofenac group; however, significant statistical differences were not observed. Conclusions Data of this double-blind, randomized, parallel-group clinical trial demonstrated that patients receiving 15 mg of preoperative meloxicam had a better postoperative analgesia and anti-trismus effect compared with who were given 100 mg of diclofenac after third molar extractions. Key words:Diclofenac, meloxicam, dental pain, trismus, third molar surgery. PMID:26615509

  13. Comparative biodistribution and safety profiling of olmesartan medoxomil oil-in-water oral nanoemulsion.

    PubMed

    Gorain, Bapi; Choudhury, Hira; Tekade, Rakesh Kumar; Karan, Saumen; Jaisankar, P; Pal, Tapan Kumar

    2016-12-01

    Poor aqueous solubility and unfavourable de-esterification of olmesartan medoxomil (a selective angiotensin II receptor blocker), results in low oral bioavailability of less than 26%. Improvement of oral bioavailability with prolonged pharmacodynamics activity of olmesartan in Wistar rats had been approached by nanoemulsification strategy in our previous article [Colloid Surface B, 115, 2014: 286]. In continuation to that work, we herewith report the biodistribution behaviour and 28-day repeated dose sub-chronic toxicity of olmesartan medoxomil nanoemulsion in Wistar rats following oral administration. The levels of olmesartan in collected biological samples were estimated using our validated LC-MS/MS technique. Our biodistribution study showed significantly higher brain concentrations of olmesartan (0.290 ± 0.089 μg/mL, 0.333 ± 0.071 μg/mL and 0.217 ± 0.062 μg/mL at 0.5, 2.0 and 8.0 h post dosing, respectively) when administered orally as nanoemulsion formulation as compared to the aqueous suspension. In addition, the olmesartan nanoemulsion was found to be safe and non-toxic, as it neither produced any lethality nor remarkable haematological, biochemical and structural adverse effects as observed during the 28-days sub-chronic toxicity studies in experimental Wistar rats. It is herewith envisaged that the developed nanoemulsion formulation approach for the delivery of olmesartan medoxomil via oral route can further be explored in memory dysfunction and brain ischemia, for better brain penetration and improved clinical application in stroke patients.

  14. Evaluation of changes in serum chemistry in association with feed withdrawal or high dose oral gavage with dextran sodium sulfate- (DSS-) induced gut leakage in broiler chickens.

    PubMed

    Kuttappan, V A; Vicuña, E A; Faulkner, O B; Huff, G R; Freeman, K A; Latorre, J D; Menconi, A; Tellez, G I; Hargis, B M; Bielke, L R

    2016-11-01

    Dextran sodium sulfate ( DSS: ) has been shown to be effective at inducing enteric inflammation in broiler chickens, resulting in increased leakage of orally administered fluorescein isothiocyanate dextran to circulation. In a previous study, 2 doses of DSS (0.45 g/dose) administered as oral gavage resulted in increased mucosal permeability. The main objective of the present study was to compare serum turbidity in control and DSS treated birds plus with feed restriction ( FR: ), and evaluate the associated serum chemistry. Three independent experiments were conducted with different combinations of treatment groups. In Experiment 1, control full-fed ( CON: ) and DSS full-fed ( FFD: ) with n = 15 birds/group were evaluated, Experiment 2 had groups (n = 15/group) CON, FFD, feed restriction ( FRS: for 34 h), and DSS with feed restriction ( FRD: ), and Experiment 3 (n = 15/group) had CON, FFD, and FRS (29 h FRS). All DSS treated birds received one or 2 doses of DSS by oral gavage (0.45 g/dose/bird). Results showed that, compared to CON group, there was an increase (P < 0.05) in serum turbidity in FFD birds, even though the difference between FRS and FRD was not apparent (P > 0.05). Administration of DSS did not result in increase of serum enzymes such as alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase ( LDH: ), nonetheless, the FFD showed lower (P < 0.05) LDH level compared to CON in Experiment 2. Among the various serum chemistry parameters evaluated triglycerides had the highest positive correlation (r(2) = 0.85; P < 0.05) with serum turbidity. DSS administration resulted in decreased serum protein levels, especially albumin. These results suggest that oral gavage with DSS in broiler chicks could result in changes to serum chemistry parameters which could be developed as potential marker/s for gut leakage.

  15. Single oral dose toxicity test of polycalcium, a mixed composition of polycan and calcium lactate-gluconate 1:9 (G/G) in SD rat.

    PubMed

    Kim, Joo-Wan; Choi, Jae-Suk; Ha, Yu-Mi; Choi, In Soon; Kim, Ki-Young; Cho, Hyung-rae; Rha, Chae-hun; Ku, Sae-Kwang

    2013-11-01

    The object of this study was to obtain acute oral toxicity information of Polycalcium, a mixed composition of Polycan and Calcium lactate-gluconate 1:9 (g/g), in Sprague-Dawely (SD) rats. In order to investigate the toxicity and identify target organs, Polycalcium were once orally administered to female and male SD rats at dose levels of 2000, 1000, 500 and 0 (control) mg/kg body weights. The mortality, changes on body weight and clinical signs were monitored during 14 days after treatment with gross observation, changes on the organ weights and histopathology of principle organs and treatment sites based on the recommendation of KFDA Guidelines [2009-116, 2009]. As the results of single oral treatment of Polycalcium, no treatment related mortalities were observed within 14 days after end of treatment up to 2000 mg/kg, the limited dosage of rodents in the both genders. In addition, no Polycalcium treatment related changes on the body and organ weights, clinical signs, necropsy and histopathological findings were detected. The results obtained in this study suggest that the Polycalcium is non-toxic in rats. The LD50 and approximate LD in rats after single oral dose of Polycalcium were considered over 2000 mg/kg in both female and male, respectively.

  16. A 28-day rat inhalation study with an integrated molecular toxicology endpoint demonstrates reduced exposure effects for a prototypic modified risk tobacco product compared with conventional cigarettes.

    PubMed

    Kogel, Ulrike; Schlage, Walter K; Martin, Florian; Xiang, Yang; Ansari, Sam; Leroy, Patrice; Vanscheeuwijck, Patrick; Gebel, Stephan; Buettner, Ansgar; Wyss, Christoph; Esposito, Marco; Hoeng, Julia; Peitsch, Manuel C

    2014-06-01

    Towards a systems toxicology-based risk assessment, we investigated molecular perturbations accompanying histopathological changes in a 28-day rat inhalation study combining transcriptomics with classical histopathology. We demonstrated reduced biological activity of a prototypic modified risk tobacco product (pMRTP) compared with the reference research cigarette 3R4F. Rats were exposed to filtered air or to three concentrations of mainstream smoke (MS) from 3R4F, or to a high concentration of MS from a pMRTP. Histopathology revealed concentration-dependent changes in response to 3R4F that were irritative stress-related in nasal and bronchial epithelium, and inflammation-related in the lung parenchyma. For pMRTP, significant changes were seen in the nasal epithelium only. Transcriptomics data were obtained from nasal and bronchial epithelium and lung parenchyma. Concentration-dependent gene expression changes were observed following 3R4F exposure, with much smaller changes for pMRTP. A computational-modeling approach based on causal models of tissue-specific biological networks identified cell stress, inflammation, proliferation, and senescence as the most perturbed molecular mechanisms. These perturbations correlated with histopathological observations. Only weak perturbations were observed for pMRTP. In conclusion, a correlative evaluation of classical histopathology together with gene expression-based computational network models may facilitate a systems toxicology-based risk assessment, as shown for a pMRTP.

  17. 26-week repeated oral dose toxicity study of UP446, a combination of defined extracts of Scutellaria baicalensis and Acacia catechu, in beagle dogs.

    PubMed

    Yimam, Mesfin; Lee, Young Chul; Jia, Qi

    2016-07-01

    The needs for relatively safe botanical alternatives to relieve symptoms associated to arthritis have continued to grow in parallel with the ageing population. UP446, a standardized bioflavonoid composition from the roots of Scutellaria baicalensis and the heartwoods of Acacia catechu, has been used as over the counter joint care dietary supplements and a prescription medical food. Significant safety data have been documented in rodents and human for this composition. Here we evaluated the potential adverse effects of orally administered UP446 in beagle dogs following a 26-week repeated oral dose toxicity study. UP446 at doses of 250, 500 and 1000 mg/kg/day were administered orally to beagle dogs for 26 weeks. A 4-week recovery group from the high dose (1000 mg/kg) and vehicle treated groups were included. No morbidity or mortality was observed for the duration of the study. No significant differences between groups in body weights, food consumption, ophthalmological examinations, electrocardiograms, urinalysis, hematology, clinical chemistry, organ weights, gross pathology and histopathology were documented. Emesis, loose feces and diarrhea were noted in both genders at the 1000 mg/kg treatment groups. These clinical signs were considered to be reversible as they were not evident in the recovery period. In conclusion, the no-observed-adverse-effect-level (NOAEL) of UP446 was considered to be 500 mg/kg/day both in male and female beagle dogs.

  18. Efficacy of a supersaturated calcium phosphate oral rinse for the prevention and treatment of oral mucositis in patients receiving high-dose cancer therapy: a review of current data.

    PubMed

    Quinn, B

    2013-09-01

    Oral mucositis (OM) is a painful and debilitating complication of cancer therapy that can adversely affect patients' treatment regimens and quality of life. It is also considered to be a substantial burden on the financial and human resources of health services. Despite progress in the understanding of the pathophysiology of OM and the number of new treatments that have been developed, there remains an unmet need for effective preventative measures in clinical practice. Literature on oral healthcare management in oncology patients suggests that a preventative approach consisting of a supersaturated Ca2+ / PO4(3-) oral rinse (Caphosol(®)) aimed at maintaining oral hygiene, moistening and lubricating the oral cavity, effectively reduces the incidence and severity of OM. This review looked at data from all known adult and paediatric studies investigating the use of Caphosol(®) in patients receiving high-dose cancer therapy in order to evaluate its efficacy for both the prevention and treatment of OM. Thirty studies were identified. The majority of these studies (n = 24) found Caphosol(®) to be efficacious at reducing the grade and/or duration, as well as pain associated with OM. Despite important limitations, these data warrant serious consideration for the inclusion of Caphosol(®) in regimens for preventing or reducing the debilitating effects of OM.

  19. Accumulation and effects of nodularin from a single and repeated oral doses of cyanobacterium Nodularia spumigena on flounder (Platichthys flesus L.).

    PubMed

    Vuorinen, Pekka J; Sipiä, Vesa O; Karlsson, Krister; Keinänen, Marja; Furey, Ambrose; Allis, Orla; James, Kevin; Perttilä, Ulla; Rimaila-Pärnänen, Eija; Meriluoto, Jussi A O

    2009-07-01

    Nodularin (NODLN) is a cyclic pentapeptide hepatotoxin produced by the cyanobacterium Nodularia spumigena, which occurs regularly in the Baltic Sea during the summer season. In this study flounder (Platichthys flesus L.) was orally exposed to NODLN either as a single dose or as three repeated doses 3 days apart. Liver and bile samples of the fish were taken 4 days after the last dose. Liver glutathione-S-transferase (GST) activity was also measured and the histopathology of the liver was investigated. The liver of the exposed fish was analyzed by liquid chromatography-mass spectrometry for NODLN concentration. The content of NODLN-like compounds in the bile was analyzed by enzyme-linked immunosorbent assay. NODLN exposure caused slightly incoherent liver architecture and degenerative cell changes in both groups. The mean liver GST activity was significantly higher in the repeatedly dosed flounders than in the singly dosed flounders or in the control. In conclusion, the significantly lower NODLN concentration and the increased GST activity in the liver of the repeatedly dosed flounders compared to the singly dosed flounders suggest that NODLN is rapidly detoxificated. The absence of NODLN glutathione conjugates and the low concentrations of NODLN-like compounds in the bile indicate that detoxification products disintegrate or they are rapidly excreted.

  20. 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.

  1. A phase 1 dose-escalation and expansion study of binimetinib (MEK162), a potent and selective oral MEK1/2 inhibitor

    PubMed Central

    Bendell, Johanna C; Javle, Milind; Bekaii-Saab, Tanios S; Finn, Richard S; Wainberg, Zev A; Laheru, Daniel A; Weekes, Colin D; Tan, Benjamin R; Khan, Gazala N; Zalupski, Mark M; Infante, Jeffrey R; Jones, Suzanne; Papadopoulos, Kyriakos P; Tolcher, Anthony W; Chavira, Renae E; Christy-Bittel, Janna L; Barrett, Emma; Patnaik, Amita

    2017-01-01

    Background: Binimetinib (MEK162; ARRY-438162) is a potent and selective oral MEK 1/2 inhibitor. This phase 1 study determined the maximum tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and preliminary anti-tumour activity of binimetinib in patients with advanced solid tumours, with expansion cohorts of patients with biliary cancer or KRAS- or BRAF-mutant colorectal cancer. Methods: Binimetinib was administered twice daily. Expansion cohorts were enroled after MTD determination following a 3+3 dose-escalation design. Pharmacokinetic properties were determined from plasma samples. Tumour samples were assessed for mutations in RAS, RAF, and other relevant genes. Pharmacodynamic properties were evaluated in serum and skin punch biopsy samples. Results: Ninety-three patients received binimetinib (dose-escalation phase, 19; expansion, 74). The MTD was 60 mg twice daily, with dose-limiting adverse events (AEs) of dermatitis acneiform and chorioretinopathy. The dose for expansion patients was subsequently decreased to 45 mg twice daily because of the frequency of treatment-related ocular toxicity at the MTD. Common AEs across all dose levels included rash (81%), nausea (56%), vomiting (52%), diarrhoea (51%), peripheral oedema (46%), and fatigue (43%); most were grade 1/2. Dose-proportional increases in binimetinib exposure were observed and target inhibition was demonstrated in serum and skin punch biopsy samples. Three patients with biliary cancer had objective responses (one complete and two partial). Conclusions: Binimetinib demonstrated a manageable safety profile, target inhibition, and dose-proportional exposure. The 45 mg twice daily dose was identified as the recommended phase 2 dose. The three objective responses in biliary cancer patients are encouraging and support further evaluation in this population. PMID:28152546

  2. A Single Dose Oral Azithromycin versus Intramuscular Benzathine Penicillin for the Treatment of Yaws-A Randomized Non Inferiority Trial in Ghana

    PubMed Central

    2017-01-01

    Background Yaws is a treponemal infection that was almost eradicated fifty years ago; however, the disease has re-emerged in a number of countries including Ghana. A single-dose of intramuscular benzathine penicillin has been the mainstay of treatment for yaws. However, intramuscular injections are painful and pose safety and logistical constraints in the poor areas where yaws occurs. A single center randomized control trial (RCT) carried out in Papua New Guinea in 2012 demonstrated the efficacy of a single-dose of oral azithromycin for the treatment of yaws. In this study, we also compared the efficacy of a single oral dose of azithromycin as an alternative to intramuscular benzathine penicillin for the treatment of the disease in another geographic setting. Methodology We conducted an open-label, randomized non-inferiority trial in three neighboring yaws-endemic districts in Southern Ghana. Children aged 1–15 years with yaws lesions were assigned to receive either 30mg/kg of oral azithromycin or 50,000 units/kg of intramuscular benzathine penicillin. The primary end point was clinical cure rate, defined as a complete or partial resolution of lesions 3 weeks after treatment. The secondary endpoint was serological cure, defined as at least a 4-fold decline in baseline RPR titre 6 months after treatment. Non- inferiority of azithromycin treatment was determined if the upper bound limit of a 2 sided 95% CI was less than 10%. Findings The mean age of participants was 9.5 years (S.D.3.1, range: 1–15 years), 247(70%) were males. The clinical cure rates were 98.2% (95% CI: 96.2–100) in the azithromycin group and 96.9% (95% CI: 94.1–99.6) in the benzathine penicillin group. The serological cure rates at 6 months were 57.4% (95% CI: 49.9–64.9) in the azithromycin group and 49.1% (95% CI: 41.2–56.9) in the benzathine penicillin group, thus achieving the specified criteria for non-inferiority. Conclusions A single oral dose of azithromycin, at a dosage of 30mg

  3. Sublinear response in lacZ mutant frequency of Muta™ Mouse spermatogonial stem cells after low dose subchronic exposure to N-ethyl-N-nitrosourea.

    PubMed

    O'Brien, Jason M; Walker, Mike; Sivathayalan, Ahalya; Douglas, George R; Yauk, Carole L; Marchetti, Francesco

    2015-05-01

    The transgenic rodent mutation assay was used to compare the dose-response relationship of lacZ mutant frequency (MF) in spermatogonial stem cells exposed acutely or subchronically to N-ethyl-N-nitrosourea (ENU). Muta(™) Mouse males were exposed orally to 0, 25, 50, or 100 mg/kg ENU for acute exposures and 0, 1, 2, or 5 mg/(kg day) for 28-day subchronic exposures. LacZ MF was measured in sperm collected 70 days post-exposure to target spermatogonial stem cells. Dose-response data were fit to linear, quadratic, exponential, or power models. Acute exposure resulted in a dose-dependent increase in MF that was significant (P < 0.05) at all doses tested and was best described by a quadratic dose-response model that was linear in the low dose range. In contrast, similar total doses fragmented over a 28-day subchronic exposure only resulted in a significant increase in lacZ MF at the highest dose tested. Therefore, the subchronic no observable genotoxic effect level (NOGEL) was 2 mg/(kg day) (or 56 mg/kg total dose). The subchronic dose-response was best described by the exponential and power models, which were sublinear in the low dose range. Benchmark dose lower confidence limits (BMDLs) for acute and subchronic exposure were 3.0 and 1.0 mg/(kg day) (or 27.4 mg/kg total dose), respectively. These findings are supportive of a saturable DNA repair mechanism as the mutagenic mode of action for ENU in spermatogonia and imply that sufficiently low exposures would not cause appreciable genotoxic effects over background. This may have important implications for the quantitative risk assessment of germ cell mutagens.

  4. 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.

  5. Effects on hemostasis after two-year use of low dose combined oral contraceptives with gestodene or levonorgestrel.

    PubMed

    Prasad, R N; Koh, S C; Viegas, O A; Ratnam, S S

    1999-01-01

    We studied 67 healthy women who were randomly allocated to receive third generation gestodene (Gynera) or second generation levonorgestrel (Microgynon 30) combination of low-dose estrogen oral contraceptives (OCs) for their hemostatic effects over 2 years. Hemostatic changes were apparent within 3 months of OC use. Hematocrit (Hct) was not affected, but hemoglobin (Hb) concentration decreased by 18 months. Shortened prothrombin time (PT) and activated plasma thromboplastin time (APTT) were associated with elevated fibrinogen within the 12-month use of both OCs. Factor VII was reduced only in Micro 30 during the 18 months of use. Enhanced thrombin-antithrombin (TAT)-complex level was seen at 18 months of Gynera use. Prothrombin fragment1+2 (F1+2) rise was seen at 3 months with Micro 30. Reduced antithrombin III (ATIII) activity was seen at 18 months with Gynera and at 24 months with Micro 30. Increased protein C activity was seen at 3 months and reduced protein S occurred at 18 months of Gynera use. Tissue plasminogen activator (t-PA) activity was enhanced for 6 months in both OCs with raised D-dimer levels for 12 months with Gynera and 6 months with Micro 30. Decreased t-PA antigen was seen at 18 months and decreased urokinaselike plasminogen activator (u-PA) antigen occurred throughout the 24 months of both OCs use. Enhanced u-PA activity was only seen in Gynera users. Elevated plasminogen levels were apparent throughout both OCs use. PAI-1 levels were significantly decreased with Micro 30. With Gynera, the decreased PAI-1 activity was seen only at 18 months and PAI-1 antigen at 12 months. No change in platelets and von Willebrand factor (vWF) were seen in long-term OC use except that beta-thromboglobulin (beta-TG) showed decreased trends reaching statistical significance by 18 and 24 months of Micro 30 use and by 24 months of Gynera use. A further significant decrease in beta-TG, u-PA antigen, ATIII, and protein S levels were seen 3 months after pill stoppage

  6. Shielding effect of a customized intraoral mold including lead material in high-dose-rate 192-Ir brachytherapy for oral cavity cancer.

    PubMed

    Kudoh, Takaharu; Ikushima, Hitoshi; Honda, Eiichi

    2012-01-01

    A high-dose-rate (HDR) 192-Ir brachytherapy using a customized intraoral mold is effective for superficial oral cavity cancer, and the surrounding normal tissue is kept away from the radioactive source with gauze pads and/or mouth piece for reducing the dose on the normal tissues. In the Tokushima university hospital, the mold has a lead shield which utilizes the space prepared with sufficient border-molding by a specific dental technique using modeling compound. In HDR 192-Ir brachytherapy using a lead shielded customized intraoral mold, there are no reports measuring the absorbed dose. The purpose of the present study is to measure the absorbed dose and discuss the optimum thickness of lead in HDR 192-Ir brachytherapy using a customized intraoral mold with lead shield using a 1 cm thickness mimic mold. The thickness of lead in the mold could be changed by varying the arrangement of 0.1 cm thickness sheet of the acrylic resin plate and lead. The measured doses at the lateral surface of the mold with thermo-luminescence dosimeter were reduced to 1.12, 0.79, 0.57, 0.41, 0.31, 0.24 and 0.19 Gy and the ratios to the prescription dose were reduced to 56, 40, 29, 21, 16, 12 and 10 percent as lead thickness increased from 0 to 0.6 cm in 0.1 cm increments, respectively. A 0.3 cm thickness lead was considered to be required for a 1 cm thickness mold, and it was necessary to thicken the lead as much as possible with the constraint of limited space in the oral cavity, especially at the fornix vestibule.

  7. Pharmacokinetics of single-dose intravenous, oral, and intraperitoneal pefloxacin in patients on chronic ambulatory peritoneal dialysis.

    PubMed Central

    Schmit, J L; Hary, L; Bou, P; Renaud, H; Westeel, P F; Andrejak, M; Fournier, A

    1991-01-01

    Comparison of plasma and dialysate concentrations of pefloxacin after intravenous, oral, or intraperitoneal administration shows excellent bidirectional diffusion of the quinolone through the peritoneal membrane, demonstrating that therapeutical concentrations can be achieved in the dialysate after intravenous or oral administration. In this study, the half-life of the drug was 18.8 +/- 1.4 h, i.e., apparently longer than that reported for normal controls or uremic patients on hemodialysis. PMID:1929314

  8. Low-dose oral immunization with lyophilized tissue of herbicide-resistant lettuce expressing hepatitis B surface antigen for prototype plant-derived vaccine tablet formulation.

    PubMed

    Pniewski, Tomasz; Kapusta, Józef; Bociąg, Piotr; Wojciechowicz, Jacek; Kostrzak, Anna; Gdula, Michał; Fedorowicz-Strońska, Olga; Wójcik, Piotr; Otta, Halina; Samardakiewicz, Sławomir; Wolko, Bogdan; Płucienniczak, Andrzej

    2011-05-01

    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 containing the antigen, supplemented with an adjuvant, and coming from plants conferring resistance to kanamycin. The objective of this study was to develop a prototype oral vaccine formula suitable for human immunization. Herbicide-resistant lettuce was engineered, stably expressing through progeny generation micrograms of S-HBsAg per g of fresh weight and formed into virus-like particles (VLPs). Lyophilized tissue containing a relatively low, 100-ng VLP-assembled antigen dose, administered only orally to mice with a long, 60-day interval between prime and boost immunizations and without exogenous adjuvant, elicited mucosal and systemic humoral anti-HBs responses at the nominally protective level. Lyophilized tissue was converted into tablets, which preserved S-HBsAg content for at least one year of room temperature storage. The results of the study provide indications on immunization methodology using a durable, efficacious, and convenient plant-derived prototype oral vaccine against hepatitis B.

  9. 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

  10. A 90-day repeated dose oral (gavage) toxicity study of perfluorohexanoic acid (PFHxA) in rats (with functional observational battery and motor activity determinations).

    PubMed

    Chengelis, Christopher P; Kirkpatrick, Jeannie B; Radovsky, Ann; Shinohara, Motoki

    2009-06-01

    Possible toxic effects of perfluorohexanoic acid (PFHxA) were evaluated when administered orally by gavage to rats at levels up to 200mg/kg/day for 90 days. Lower body weight gains were noted in the 10, 50 and 200mg/kg/day group males (not dose-responsive) throughout dosing. Other changes included lower red blood cell parameters, higher reticulocyte counts and lower globulin in the 200mg/kg/day group males and females, higher liver enzymes in males at 50 and 200mg/kg/day, lower total protein and higher albumin/globulin ratio, and lower cholesterol, calcium in males at 200mg/kg/day. Minimal centrilobular hepatocellular hypertrophy was present in 200mg/kg/day group males and correlated with higher liver weights and slightly higher peroxisome beta oxidation activity at the end of the dosing period. Based on liver histopathology and liver weight changes, the no-observed-adverse-effect level (NOAEL) for oral administration was 50mg/kg/day for males and 200mg/kg/day for females.

  11. Effects of oral cyclosporine on canine T-cell expression of IL-2 and IFN-gamma across a 12-h dosing interval

    PubMed Central

    FELLMAN, C. L.; ARCHER, T. M.; STOKES, J. V.; WILLS, R. W.; LUNSFORD, K. V.; MACKIN, A. J.

    2016-01-01

    The duration of immunosuppressive effects following oral cyclosporine in dogs is unknown. This study used flow cytometry and quantitative reverse transcription–polymerase chain reaction (qRT-PCR) to evaluate the effects of high-dose oral cyclosporine across a 12-h dosing interval. Expression of interleukin-2 (IL-2) and interferon-gamma (IFN-γ) was compared before and after 8 days of cyclosporine at 10 mg/kg every 12 h in six healthy dogs. Samples were collected at 0, 2, 4, and 8 h postdosing for analysis of unactivated and activated T-cell and whole blood cytokine expression using flow cytometry and qRT-PCR, respectively, and at 0, 2, 4, 6, 8, and 10 h postdosing for measurement of cyclosporine concentrations. Flow cytometry and qRT-PCR both demonstrated significant marked reductions in IL-2 and IFN-γ levels at 0, 2, 4, and 8 h after dosing compared to pretreatment levels (P < 0.05) for activated samples, with less consistent effects observed for unactivated samples. Both flow cytometry and qRT-PCR are viable techniques for measuring cyclosporine pharmacodynamics in dogs, yielding comparable results with activated samples. Two hours postdrug administration is the preferred time for concurrent assessment of peak drug concentration and cytokine expression, and T-cell activation is needed for optimal results. PMID:26676223

  12. Efficacy and safety of desmopressin orally disintegrating tablet in patients with central diabetes insipidus: results of a multicenter open-label dose-titration study.

    PubMed

    Arima, Hiroshi; Oiso, Yutaka; Juul, Kristian Vinter; Nørgaard, Jens Peter

    2013-01-01

    Central diabetes insipidus (CDI) is associated with arginine vasopressin (AVP) deficiency with resultant polyuria and polydipsia. Intranasal desmopressin provides physiological replacement but oral formulations are preferred for their ease of administration. This study aimed to demonstrate the efficacy and safety of desmopressin orally disintegrating tablet (ODT) in the treatment of Japanese patients with CDI, and confirm that antidiuresis is maintained on switching from intranasal desmopressin to desmopressin ODT. A total of 20 patients aged 6-75 years with CDI were included in this 4-week multicenter, open-label study. Following observation, patients switched from intranasal desmopressin to desmopressin ODT with titration to optimal dose over ≤5 days at the study site. Following three consecutive doses with stable patient fluid balance, patients were discharged with visits at Weeks 2 and 4. Following titration from intranasal desmopressin to ODT, the mean 24-hour urine volume was unchanged, indicating similar antidiuresis with both formulations. The proportion of patients with endpoint measurements (urine osmolality, 24-hour urine volume, hourly diuresis rate and urine-specific gravity) within normal range at Days 1-2 (intranasal desmopressin) and Week 4 (desmopressin ODT) was similar. The mean daily dose ratio of intranasal desmopressin to desmopressin ODT (Week 4) was 1:24 but a wide range was observed across individuals to maintain adequate antidiuretic effect. Hyponatraemia was generally mild and managed by dose titration. Desmopressin ODT achieved sufficient antidiuretic control compared to intranasal therapy and was well tolerated over long-term treatment. The wide range of intranasal:ODT dose ratios underline the importance of individual titration.

  13. Effects of 14-day oral low dose selenium nanoparticles and selenite in rat-as determined by metabolite pattern determination.

    PubMed

    Hadrup, Niels; Loeschner, Katrin; Skov, Kasper; Ravn-Haren, Gitte; Larsen, Erik H; Mortensen, Alicja; Lam, Henrik R; Frandsen, Henrik L

    2016-01-01

    Selenium (Se) is an essential element with a small difference between physiological and toxic doses. To provide more effective and safe Se dosing regimens, as compared to dosing with ionic selenium, nanoparticle formulations have been developed. However, due to the nano-formulation, unexpected toxic effects may occur. We used metabolite pattern determination in urine to investigate biological and/or toxic effects in rats administered nanoparticles and for comparison included ionic selenium at an equimolar dose in the form of sodium selenite. Low doses of 10 and 100 fold the recommended human high level were employed to study the effects at borderline toxicity. Evaluations of all significantly changed putative metabolites, showed that Se nanoparticles and sodium selenite induced similar dose dependent changes of the metabolite pattern. Putative identified metabolites included increased decenedioic acid and hydroxydecanedioic acid for both Se formulations whereas dipeptides were only increased for selenite. These effects could reflect altered fatty acid and protein metabolism, respectively.

  14. Effects of 14-day oral low dose selenium nanoparticles and selenite in rat—as determined by metabolite pattern determination

    PubMed Central

    Loeschner, Katrin; Skov, Kasper; Ravn-Haren, Gitte; Larsen, Erik H.; Mortensen, Alicja; Lam, Henrik R.; Frandsen, Henrik L.

    2016-01-01

    Selenium (Se) is an essential element with a small difference between physiological and toxic doses. To provide more effective and safe Se dosing regimens, as compared to dosing with ionic selenium, nanoparticle formulations have been developed. However, due to the nano-formulation, unexpected toxic effects may occur. We used metabolite pattern determination in urine to investigate biological and/or toxic effects in rats administered nanoparticles and for comparison included ionic selenium at an equimolar dose in the form of sodium selenite. Low doses of 10 and 100 fold the recommended human high level were employed to study the effects at borderline toxicity. Evaluations of all significantly changed putative metabolites, showed that Se nanoparticles and sodium selenite induced similar dose dependent changes of the metabolite pattern. Putative identified metabolites included increased decenedioic acid and hydroxydecanedioic acid for both Se formulations whereas dipeptides were only increased for selenite. These effects could reflect altered fatty acid and protein metabolism, respectively. PMID:27781177

  15. Toxicokinetics of short-chain chlorinated paraffins in Sprague-Dawley rats following single oral administration.

    PubMed

    Geng, Ningbo; Zhang, Haijun; Xing, Liguo; Gao, Yuan; Zhang, Baoqin; Wang, Feidi; Ren, Xiaoqian; Chen, Jiping

    2016-02-01

    Short-chain chlorinated paraffins (SCCPs) have attracted considerable attention for their characteristic of persistent organic pollutants. However, very limited information is available for their toxicokinetic characteristics, limiting the evaluation of their health risks. In this study, we performed a toxicokinetics study to explore the absorption and excretion processes of SCCPs (a mixture of C10-, C11-, C12- and C13-CPs) after a single oral administration to the Sprague-Dawley rats. The toxicokinetic results showed that peak blood concentration of total SCCPs was attained at 2.8 day with Cmax value of 2.3 mg L(-1). The half-lives of total SCCPs in blood for the absorption t1/2 (ka), distribution t1/2 (α) and elimination phases t1/2 (β) were calculated to be 1.0, 1.7 and 6.6 days, respectively. During the 28 days post-dosing, about 27.9% and 3.5% of orally administrated SCCPs were excreted through feces and urine without metabolism, respectively. Congener group abundance profiles indicate a relative increase of Cl5-SCCPs in blood and urine in the elimination stage, and a higher accumulation of Cl8-10-SCCPs in feces. The distribution discrepancies of SCCPs congener groups in blood and excreta were more dependent on chlorine contents than on carbon chain lengths.

  16. Nitrogen removal and mass balance in newly-formed Myriophyllum aquaticum mesocosm during a single 28-day incubation with swine wastewater treatment.

    PubMed

    Liu, Feng; Zhang, Shunan; Wang, Yi; Li, Yong; Xiao, Runlin; Li, Hongfang; He, Yang; Zhang, Miaomiao; Wang, Di; Li, Xi; Wu, Jinshui

    2016-01-15

    The aim of this research was to assess the applicability of Myriophyllum (M.) aquaticum for swine wastewater treatment. Nitrogen (N) removal processes were investigated in M. aquaticum mesocosms with swine wastewater (SW), 50% diluted swine wastewater (50% SW), and two strengths of synthetic wastewater, 200 mg [Formula: see text] L(-1) (200 [Formula: see text] ) and 400 mg [Formula: see text] L(-1) (400 [Formula: see text] ). During a 28-day incubation period, the average [Formula: see text] and TN removal rates were 99.8% and 94.2% for 50% SW and 99.8% and 93.8% for SW, which were greater than 86.5% and 83.7% for 200 [Formula: see text] , and 73.7% and 74.1% for 400 [Formula: see text] , respectively. A maximum areal total nitrogen (TN) removal rate of 157.8 mg N m(-2) d(-1) was found in M. aquaticum mesocosms with SW. During the incubation period, the observed dynamics of [Formula: see text] concentrations in water and gene copy numbers of ammonia-oxidizing archaea (AOA), ammonia-oxidizing bacteria (AOB), nirK and nirS in soil unraveled strong nitrification and denitrification processes occurring in M. aquaticum mesocosms with swine wastewater. The N mass balance analysis indicated that plant uptake and soil N accumulation accounted for 17.9-42.2% and 18.0-43.8% of the initial TN load, respectively. The coupled nitrification and denitrification process was calculated to account for, on average, 36.8% and 62.8% of TN removal for 50% SW and SW, respectively. These findings demonstrated that the N uptake by M. aquaticum contributed to a considerable proportion of N removal. In particular, the activities of ammonia-oxidizing and denitrification microbes responsible for nitrification and denitrification processes in M. aquaticum mesocosm accelerated [Formula: see text] and TN removal from swine wastewater.

  17. 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

  18. Fosfomycin trometamol: a review of its use as a single-dose oral treatment for patients with acute lower urinary tract infections and pregnant women with asymptomatic bacteriuria.

    PubMed

    Keating, Gillian M

    2013-11-01

    Fosfomycin trometamol (fosfomycin tromethamine) [Monuril(®), Monurol(®), Monural(®)] is approved in numerous countries worldwide, mainly for the treatment of uncomplicated urinary tract infections (UTIs). Fosfomycin has good in vitro activity against common uropathogens, such as Escherichia coli (including extended-spectrum β-lactamase-producing E. coli), Proteus mirabilis, Klebsiella pneumoniae and Staphylococcus saprophyticus, and the susceptibility of uropathogens to fosfomycin has remained relatively stable over time. A single oral dose of fosfomycin trometamol 3 g (the approved dosage) achieves high concentrations in urine. Results of recent randomized trials indicate that single-dose fosfomycin trometamol had similar clinical and/or bacteriological efficacy to 3- to 7-day regimens of ciprofloxacin, norfloxacin, cotrimoxazole or nitrofurantoin in women with uncomplicated lower UTIs. In addition, single-dose fosfomycin trometamol had similar bacteriological efficacy to a 5-day course of cefuroxime axetil or a 7-day course of amoxicillin/clavulanic acid in pregnant women with asymptomatic bacteriuria, and similar clinical and/or bacteriological efficacy to a 5-day course of cefuroxime axetil or amoxicillin/clavulanic acid or a 3-day course of ceftibuten in pregnant women with a lower UTI. Single-dose fosfomycin trometamol was generally well tolerated, with gastrointestinal adverse events (e.g. diarrhoea, nausea) reported most commonly. In conclusion, single-dose fosfomycin trometamol is an important option for the first-line empirical treatment of uncomplicated lower UTIs.

  19. Short-term effects of treatment with 300 mg oral-dose diethylcarbamazine on nocturnally periodic Wuchereria bancrofti microfilaremia and antigenemia.

    PubMed

    Siriaut, Chumsin; Bhumiratana, Adisak; Koyadun, Surachart; Anurat, Kowit; Satitvipawee, Pratana

    2005-07-01

    Seven microfilaremic Myanmar patients were treated with a single 300 mg dose of diethylcarbamazine (DEC) orally, as part of a case-finding survey in Ranong Province, Southern Thailand. This was conducted in order to evaluate the short-term effects of single-dose DEC on Wuchereria bancrofti microfilaremia and antigenemia during a 12-week course of treatment. Analysis of microfilarial periodicity on initial treatment revealed the microfilarial peak density (k) was at 52 minutes after midnight (0052). The periodicity index was then 103.26%. Single-dose DEC treatment did not affect the k values. A linear model of W. bancrofti microfilarial density reduction predicts a sharp decrease in the mean microfilarial density 2 weeks after DEC intake (Z = -2.197, p = 0.028). Over a longer period, a non-linear model predicts an increase in the mean microfilarial density to pre-treatment levels, having little or no macrofilaricidal effects. We reconfirmed the existence of nocturnally periodic W. bancrofti infection in Myanmar migrants in Ranong Province, and the short-term microfilaricidal activity of 300 mg single-dose DEC treatment used for biannual mass treatment and the DEC provocative test. Without an adequate DEC treatment dose, recrudescence can occur. A rational approach to the management of introduced nocturnally periodic W. bancrofti in Myanmar migrants, who came for short periods of stay in transmission-prone areas, is needed.

  20. Sex specific impact of perinatal bisphenol A (BPA) exposure over a range of orally administered doses on rat hypothalamic sexual differentiation.

    PubMed

    McCaffrey, Katherine A; Jones, Brian; Mabrey, Natalie; Weiss, Bernard; Swan, Shanna H; Patisaul, Heather B

    2013-05-01

    Bisphenol A (BPA) is a high volume production chemical used in polycarbonate plastics, epoxy resins, thermal paper receipts, and other household products. The neural effects of early life BPA exposure, particularly to low doses administered orally, remain unclear. Thus, to better characterize the dose range over which BPA alters sex specific neuroanatomy, we examined the impact of perinatal BPA exposure on two sexually dimorphic regions in the anterior hypothalamus, the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the anterioventral periventricular (AVPV) nucleus. Both are sexually differentiated by estradiol and play a role in sex specific reproductive physiology and behavior. Long Evans rats were prenatally exposed to 10, 100, 1000, 10,000μg/kg bw/day BPA through daily, non-invasive oral administration of dosed-cookies to the dams. Offspring were reared to adulthood. Their brains were collected and immunolabeled for tyrosine hydroxylase (TH) in the AVPV and calbindin (CALB) in the SDN-POA. We observed decreased TH-ir cell numbers in the female AVPV across all exposure groups, an effect indicative of masculinization. In males, AVPV TH-ir cell numbers were significantly reduced in only the BPA 10 and BPA 10,000 groups. SDN-POA endpoints were unaltered in females but in males SDN-POA volume was significantly lower in all BPA exposure groups. CALB-ir was significantly lower in all but the BPA 1000 group. These effects are consistent with demasculinization. Collectively these data demonstrate that early life oral exposure to BPA at levels well below the current No Observed Adverse Effect Level (NOAEL) of 50mg/kg/day can alter sex specific hypothalamic morphology in the rat.

  1. Sex specific impact of perinatal bisphenol A (BPA) exposure over a range of orally administered doses on rat hypothalamic sexual differentiation

    PubMed Central

    McCaffrey, Katherine A.; Jones, Brian; Mabrey, Natalie; Weiss, Bernard; Swan, Shanna H.; Patisaul, Heather B.

    2013-01-01

    Bisphenol A (BPA) is a high volume production chemical used in polycarbonate plastics, epoxy resins, thermal paper receipts, and other household products. The neural effects of early life BPA exposure, particularly to low doses administered orally, remain unclear. Thus, to better characterize the dose range over which BPA alters sex specific neuroanatomy, we examined the impact of perinatal BPA exposure on two sexually dimorphic regions in the anterior hypothalamus, the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the anterioventral periventricular (AVPV) nucleus. Both are sexually differentiated by estradiol and play a role in sex specific reproductive physiology and behavior. Long Evans rats were prenatally exposed to 10, 100, 1000, 10,000 mg/kg bw/day BPA through daily, noninvasive oral administration of dosed-cookies to the dams. Offspring were reared to adulthood. Their brains were collected and immunolabeled for tyrosine hydroxylase (TH) in the AVPV and calbindin (CALB) in the SDN-POA. We observed decreased TH-ir cell numbers in the female AVPV across all exposure groups, an effect indicative of masculinization. In males, AVPV TH-ir cell numbers were significantly reduced in only the BPA 10 and BPA 10,000 groups. SDN-POA endpoints were unaltered in females but in males SDN-POA volume was significantly lower in all BPA exposure groups. CALB-ir was significantly lower in all but the BPA 1000 group. These effects are consistent with demasculinization. Collectively these data demonstrate that early life oral exposure to BPA at levels well below the current No Observed Adverse Effect Level (NOAEL) of 50 mg/kg/day can alter sex specific hypothalamic morphology in the rat. PMID:23500335

  2. Treatment of oral leukoplakia with a low-dose of beta-carotene and vitamin C supplements: a randomized controlled trial.

    PubMed

    Nagao, Toru; Warnakulasuriya, Saman; Nakamura, Tomoyasu; Kato, Shinichiro; Yamamoto, Keiichi; Fukano, Hideo; Suzuki, Koji; Shimozato, Kazuo; Hashimoto, Shuji

    2015-04-01

    Management of oral leukoplakia-a potentially malignant disorder-is currently not evidence-based. Of the few randomized trials that have been reported, most have negative data. Therefore, a multi-centre, randomized, double-blind controlled trial (RCT) was undertaken to evaluate the use of low-dose beta-carotene combined with vitamin C supplements for the treatment and to prevent malignant transformation of oral leukoplakia. 46 Japanese participants with oral leukoplakia were allocated randomly either to an experimental arm (10 mg day(-1) of beta-carotene and 500 mg day(-1) of vitamin C) or placebo arm (50 mg day(-1) of vitamin C). Current or ex-smokers within 3 months of cessation were excluded. The supplements were continued over a period of 1 year. The primary endpoint was clinical remission at 1-year and the likelihood of malignant transformation during a 5-year follow-up period as a secondary endpoint. The overall clinical response rate in the experimental arm was 17.4% (4/23) and 4.3% (1/23) in the placebo arm (p = 0.346). During the median 60-month follow-up period, two subjects in the experimental arm and three in the control arm developed oral cancer. Under the intention-to-treat principle, relative risk by supplementing with beta-carotene and vitamin C was 0.77 (95%CI: 0.28-1.89) (p = 0.580) by the Cox proportional hazards model. No unfavorable side-effects were noted. Beta-carotene (10 mg day(-1) ) and vitamin C were neither effective for clinical remission, nor for protection against the development of cancer. Data from this RCT does not support the hypothesis that chemoprevention with this treatment is effective for oral leukoplakia.

  3. Significance of higher drug concentration in erythrocytes of mice infected with Schistosoma japonicum and treated orally with mefloquine at single doses.

    PubMed

    Tao, Yi; Xue, Jian; Jiang, Bin; Zhang, Hao-Bing; Xiao, Shu-Hua

    2015-12-01

    The purpose of the present study is to understand the pharmacokinetic feature of mefloquine measured by erythrocytes and plasma in Schistosoma japonicum (S. j.)-infected mice and non-infected mice after oral administration of the drug at single doses. A high-performance liquid chromatography (HPLC) method was used to measure the plasma and erythrocyte concentrations of mefloquine at varying intervals posttreatment. Our results demonstrated that in non-infected mice treated orally with mefloquine at an ineffective dose of 50 mg/kg or effective dose of 200 mg/kg for 2-72 h, the erythrocyte-to-plasma ratios of mefloquine were 5.8-11.2 or 2-14.2. On the other hand, in S. j.-infected mice treated with the same single doses of the drug, the erythrocyte and plasma drug concentration ratios were 3.1-4.6 or 2.9-8.5, manifesting that either in infected mice or in non-infected mice that received oral mefloquine resulted in higher concentration of mefloquine in erythrocytes than that in plasma. Unexpectedly, under oral administration of mefloquine at a higher single dose of 200 mg/kg, the pharmacokinetic parameter C max values for plasma from S. j.-infected and non-infected mice were 1.6 ± 0.3 and 2.0 ± 0.4 μg/mL, respectively, which were below the determined in vitro LC50 (50 % lethal concentration) value of 4.93 μg/mL. Therefore, the plasma concentration of mefloquine may display a little effect against schistosomes during the treatment. Although the values of T 1/2 and AUC0-∞ for erythrocytes were significantly longer and higher in infected mice than those of corresponding non-infect mice that received the same single mefloqine dose of 50 mg/kg, the C max value was only 2.6 ± 0.4 μg/mL lower than the determined in vitro LC50, which may explain why this low single dose is ineffective against schistosomes in vivo. After administration of higher mefloquine dose of 200 mg/kg, the C max value for erythrocytes in infected mice was 30 % (7.4 ± 0

  4. A pharmacokinetic and residual study of sulfadiazine/trimethoprim in mandarin fish (Siniperca chuatsi) with single- and multiple-dose oral administrations.

    PubMed

    Wang, W; Luo, L; Xiao, H; Zhang, R; Deng, Y; Tan, A; Jiang, L

    2016-06-01

    A pharmacokinetic and tissue residue study of sulfadiazine combined with trimethoprim (SDZ/TMP = 5/1) was conducted in Siniperca chuatsi after single- (120 mg/kg) or multiple-dose (an initial dose of 120 mg/kg followed by a 5-day consecutive dose of 60 mg/kg) oral administrations at 28 °C. The absorption half-life (t1/2α ), elimination half-life (t1/2β ), volume of distribution (Vd /F), and the total body clearance (ClB /F) for SDZ and TMP were 4.3 ± 1.7 to 6.3 ± 1.8 h and 2.4 ± 1.0 to 3.9 ± 0.9 h, 25.9 ± 4.5 to 53.0 ± 5.6 h and 11.8 ± 3.5 to 17.1 ± 3.4 h, 2.34 ± 0.78 to 3.67 ± 0.99 L/kg and 0.39 ± 0.01 to 1.33 ± 0.57 L/kg, and 0.03 ± 0.01 to 0.06 ± 0.01 L/kg·h and 0.02 ± 0.01 to 0.05 ± 0.01 L/kg·h, respectively, after the single dose. The elimination half-life (t1/2β ) and mean residue time (MRT) for SDZ and TMP were 68.8 ± 7.8 to 139.8 ± 12.3 h and 34.0 ± 5.5 to 56.1 ± 6.8 h, and 99.3 ± 6.1 to 201.7 ± 11.5 h and 49.1 ± 3.5 to 81.0 ± 5.1 h, respectively, after the multiple-dose administration. The daily oral SDZ/TMP administration might cause a high tissue concentration and long t1/2β , thereby affecting antibacterial activity. The withdrawal time for this oral SDZ/TMP formulation (according to the accepted guidelines in Europe for maximum residue limits, <0.1 mg/kg of tissues for sulfonamides, and <0.05 mg/kg for TMP) should not be <36 days for fish.