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1

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

PubMed

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

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

2011-01-01

2

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

PubMed Central

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.

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

2014-01-01

3

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

Code of Federal Regulations, 2010 CFR

...appropriate conditions. (8) Clinical Biochemistry. (i) Clinical biochemistry determinations to investigate major toxic...determination of hematological and clinical biochemistry variables before dosing commences....

2009-07-01

4

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

Code of Federal Regulations, 2010 CFR

...appropriate conditions. (8) Clinical Biochemistry. (i) Clinical biochemistry determinations to investigate major toxic...determination of hematological and clinical biochemistry variables before dosing commences....

2010-07-01

5

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

Code of Federal Regulations, 2010 CFR

...appropriate conditions. (8) Clinical Biochemistry. (i) Clinical biochemistry determinations to investigate major toxic...determination of hematological and clinical biochemistry variables before dosing commences....

2012-07-01

6

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

Code of Federal Regulations, 2010 CFR

...appropriate conditions. (8) Clinical Biochemistry. (i) Clinical biochemistry determinations to investigate major toxic...determination of hematological and clinical biochemistry variables before dosing commences....

2011-07-01

7

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

Microsoft Academic Search

Interest in extracellular lipase sourced from the non conventional yeast Yarrowia lipolytica has increased over the last decade. The enzyme was recently suggested as a good candidate for pancreatic exocrine insufficiency treatment. However, there is still a lack of oral safety evaluation data. In this work, we conducted acute and 28-day repeated dose toxicity studies in rats. Both male and

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

2010-01-01

8

A 28-day oral dose toxicity study enhanced to detect endocrine effects of a purified technical pentabromodiphenyl ether (pentaBDE) mixture in Wistar rats  

Microsoft Academic Search

A 28-day subacute oral toxicity study was performed in Wistar rats with a purified preparation of the commercial pentabromodiphenyl ether (pentaBDE), DE-71. The applied OECD407 protocol was enhanced for endocrine and immune parameters, and to enable benchmark dose analysis. A vehicle control group and 7 dose groups were included, which received 0.27, 0.82, 2.47, 7.4, 22.2, 66.7 or 200mg pentaBDE\\/kg

Ton van de Kuil; Aart Verhoef; Pim E. G. Leonards; Wout Slob; Rocío F. Cantón; Silke Germer; Timo Hamers; Theo J. Visser; Sabina Litens; Helen Håkansson; Yvonne Fery; Dieter Schrenk; Martin van den Berg; Aldert H. Piersma; Josephus G. Vos

2008-01-01

9

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  

Microsoft Academic Search

A 28-day repeated oral dose toxicity study of nonylphenol (NP) was performed for an international validation of the ‘Enhanced\\u000a OECD Test Guideline 407’ paying particular attention to the sensitivity of individual endocrine-related parameters. Sprague-Dawley\\u000a rats, each group consisting of ten males and ten females, were administered NP once daily by gavage at doses of 0 (control),\\u000a 10, 50, or 250 mg\\/kg

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

2007-01-01

10

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

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. PMID:24378259

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

2014-03-01

11

Effect of 28-day oral administration of silver nanocolloid on the peripheral blood leukocytes in mice.  

PubMed

Silver nanoparticles, which have found a wide range of applications owing to their antimicrobial properties, are also recommended as dietary supplements in alternative medicine. Studies on rodents confirm that nanosilver is absorbed from the digestive tract into the bloodstream, which implies its possible interactions with leukocytes. The objective of the experiment discussed herein has been to determine the effect of 28-day oral administration of different doses (0.25, 2.5, 25 ppm) of commercial silver nanocolloid on hematological parameters, percentages of particular lymphocyte populations and activity of the peripheral blood leukocytes in mice. All the tested colloid doses decreased the counts of monocytes in the animals' blood and induced phenotypic modifications among lymphocytes: an increase in CD4+/CD8+ T cell distribution, a decrease in NK and NKT cell distribution (doses of 0.25 and 2.5 ppm) and an increased CD4+:CD8+ ratio (25 ppm). Silver nanocolloid also affected the activity of cells, depressing the proliferation of lymphocytes (0.25 ppm) and stimulating phagocytosis as well as the respiratory burst of granulocytes and monocytes (all doses). The results verify the influence of orally administered silver colloid on the peripheral blood leukocytes, at the same time implying the potential risk of developing an inappropriate immune response of an organism exposed to prolonged administration of this substance. PMID:24988852

Ma?aczewska, J

2014-01-01

12

Immunotoxic effects of imidacloprid following 28 days of oral exposure in BALB/c mice.  

PubMed

Imidacloprid, a neonicotinoid insecticide has been in use worldwide for several years in agriculture and veterinary medicine. It is possible that residue of this compound may be recycled in the food chain and thus information regarding effects from potential exposure to it is warranted. The objective of the present study was to evaluate immunotoxic effects of imidacloprid in female BALB/c mice. Imidacloprid was administered orally daily at 10, 5, or 2.5mg/kg over 28 days. Specific parameters of humoral and cellular immune response including hemagglutinating antibody (HA) titer to sheep red blood cells (SRBC; T-dependent antigen), delayed type hypersensitivity (DTH) response to SRBC, and T-lymphocyte proliferation in response to phytohemagglutinin (PHA) were evaluated. The results showed that imidacloprid at high dose, specifically suppressed cell-mediated immune response as was evident from decreased DTH response and decreased stimulation index of T-lymphocytes to PHA. At this dose, there were also prominent histopathological alterations in spleen and liver. Histopathological analysis of footpad sections of mice revealed dose-related suppression of DTH response. Imidacloprid at low dose of 2.5mg/kg/day did not produce any significant alterations in cellular and humoral immune response and it seemed to be an appropriate dose for assessment of 'no observable adverse effects level' for immunotoxicity in BALB/c mice. The results also indicated that imidacloprid has immunosuppressive effects at doses >5mg/kg, which could potentially be attributed to direct cytotoxic effects of IMD against T cells (particularly TH cells) and that long-term exposure could be detrimental to the immune system. PMID:23467117

Badgujar, Prarabdh C; Jain, S K; Singh, Ajit; Punia, J S; Gupta, R P; Chandratre, Gauri A

2013-05-01

13

28-Day oral (gavage) toxicity studies of green tea catechins prepared for beverages in rats.  

PubMed

The beneficial health effects associated with drinking green tea are widely considered to be due primarily to tea catechins. Heat treatment of marketed green tea beverages for sterilization causes epimerization and/or polymerization of tea catechins. Safety studies on heat-treated tea catechins are limited. The objective of the present study was to evaluate potential adverse effects, if any, of two standardized green tea catechin (GTC) preparations: one that underwent heat sterilization (GTC-H) and one that was not heat-sterilized (GTC-UH). A decaffeinated preparation of the GTC-H (GTC-HDC) was also evaluated to ascertain if any effects were due to caffeine. The GTC preparations were administered to rats once daily at levels up to 2000 mg/kg/day for 28 days. There were no deaths attributable to the GTC preparations. The clinical condition of the animals, functional observational battery, motor activity, clinical pathology evaluations, organ weights, and gross necropsy findings were unaffected by any of the GTC preparations. GTC-HDC or GTC-UH dosing had no effects on body weights or microscopic findings, whereas lower body weights and food consumption were observed in the 1000 and 2000 mg/kg/day GTC-H group males. The no observed-adverse-effect level (NOAEL) for localized gastric effects for GTC-H was 1000 mg/kg/day. No other target organs were identified. Thus, the NOAEL for systemic toxicity following oral administration was 2000 mg/kg/day for GTC-H, GTC HDC, and GTC-UH under the conditions of this study. PMID:18086511

Chengelis, Christopher P; Kirkpatrick, Jeannie B; Regan, Karen S; Radovsky, Ann E; Beck, Melissa J; Morita, Osamu; Tamaki, Yasushi; Suzuki, Hiroyuki

2008-03-01

14

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

PubMed Central

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 in NK satellite group. In conclusion, NK was found to be non-toxic in the tested doses and experimental conditions.

2012-01-01

15

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

PubMed Central

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

2014-01-01

16

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

PubMed Central

(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.

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

17

The splenocyte proliferative response and cytokine secretion in mice after 28-day oral administration of silver nanocolloid.  

PubMed

An increasing number of applications of silver nanoparticles in industry, medicine and everyday life means that the risk of exposure of the human organism to their potential harmful influence is growing. This study has sought to assess the effect of 28-day alimentary administration of different concentrations (0.25, 2.5 and 25 ppm) of a commercial silver nanocolloid on the proliferative activity and synthesis of cytokines by mouse splenocytes. All of the analyzed doses of the colloid had a significant, albeit different, effect on the activity of splenocytes. At the lowest dose, a significant decrease in the proliferation of T cells and more intensive synthesis of pro-inflammatory cytokines, both by non-stimulated and LPS-stimulated cells, was observed. The intermediate dose, on the other hand, stimulated proliferation of B cells while producing a pro-inflammatory effect regarding the synthesis of cytokines. Finally, the highest dose decreased the synthesis of cytokines by non-stimulated cells, but after LPS stimulation, through the strong activation of the IL-10 synthesis, it raised the proliferation of B cells and decreased the synthesis of pro-inflammatory cytokines. The results suggest that silver nanoparticles administered orally have an easy access to the peripheral organs of the immune system, such as the spleen, but the effect of long-term exposure of this organ to the effect of silver nanocolloid depends on several factors, including the dose of nanoparticles, and seems as difficult to predict. PMID:24724467

Ma?aczewska, J

2014-01-01

18

Integration of Mutation and Chromosomal Damage Endpoints into 28-Day Repeat Dose Toxicology Studies  

PubMed Central

Two endpoints of genetic toxicity, mutation at the X-linked Pig-a gene and chromosomal damage in the form of micronucleated reticulocytes (MN-RETs), were evaluated in blood samples obtained from 28-day repeat-dosing studies typical of those employed in toxicity evaluations. Male Wistar Han rats were treated at 24-h intervals on days 1 through 28 with one of five prototypical genotoxicants: N-ethyl-N-nitrosourea, 7,12-dimethyl-12-benz[a]anthracene, 4-nitroquinoline-1-oxide (4NQO), benzo(a)pyrene, and N-methyl-N-nitrosourea. Flow cytometric scoring of CD59-negative erythrocytes (indicative of glycosylphosphatidylinositol anchor deficiency and hence Pig-a mutation) was performed using blood specimens obtained on days ?1, 15, 29, and 56. Blood specimens collected on days 4 and 29 were evaluated for MN-RET frequency using flow cytometry–based MicroFlow Kits. With the exception of 4NQO, each chemical induced significant increases in the frequency of MN-RETs on days 4 and 29. All five agents increased the frequency of mutant phenotype (CD59 negative) reticulocytes (RETs) and erythrocytes. Mutation responses in RETs occurred earlier than in erythrocytes and tended to peak, or nearly peak, at day 29. In contrast, the mutant phenotype erythrocyte responses were modest on day 29 and required additional time to reach their maximal value. The observed kinetics were expected based on the known turnover of RETs and erythrocytes. The data show that RETs can serve as an appropriate indicator cell population for 28-day studies. Collectively, these data suggest that blood-based genotoxicity endpoints can be effectively incorporated into routine toxicology studies, a strategy that would reduce animal usage while providing valuable genetic toxicity information within the context of other toxicological endpoints.

Dertinger, Stephen D.; Phonethepswath, Souk; Franklin, Dean; Weller, Pamela; Torous, Dorothea K.; Bryce, Steven M.; Avlasevich, Svetlana; Bemis, Jeffrey C.; Hyrien, Ollivier; Palis, James; MacGregor, James T.

2010-01-01

19

Distribution of silver in rats following 28 days of repeated oral exposure to silver nanoparticles or silver acetate  

PubMed Central

Background The study investigated the distribution of silver after 28 days repeated oral administration of silver nanoparticles (AgNPs) and silver acetate (AgAc) to rats. Oral administration is a relevant route of exposure because of the use of silver nanoparticles in products related to food and food contact materials. Results AgNPs were synthesized with a size distribution of 14 ± 4 nm in diameter (90% of the nanoparticle volume) and stabilized in aqueous suspension by the polymer polyvinylpyrrolidone (PVP). The AgNPs remained stable throughout the duration of the 28-day oral toxicity study in rats. The organ distribution pattern of silver following administration of AgNPs and AgAc was similar. However the absolute silver concentrations in tissues were lower following oral exposure to AgNPs. This was in agreement with an indication of a higher fecal excretion following administration of AgNPs. Besides the intestinal system, the largest silver concentrations were detected in the liver and kidneys. Silver was also found in the lungs and brain. Autometallographic (AMG) staining revealed a similar cellular localization of silver in ileum, liver, and kidney tissue in rats exposed to AgNPs or AgAc. Using transmission electron microscopy (TEM), nanosized granules were detected in the ileum of animals exposed to AgNPs or AgAc and were mainly located in the basal lamina of the ileal epithelium and in lysosomes of macrophages within the lamina propria. Using energy dispersive x-ray spectroscopy it was shown that the granules in lysosomes consisted of silver, selenium, and sulfur for both AgNP and AgAc exposed rats. The diameter of the deposited granules was in the same size range as that of the administered AgNPs. No silver granules were detected by TEM in the liver. Conclusions The results of the present study demonstrate that the organ distribution of silver was similar when AgNPs or AgAc were administered orally to rats. The presence of silver granules containing selenium and sulfur in the intestinal wall of rats exposed to either of the silver forms suggests a common mechanism of their formation. Additional studies however, are needed to gain further insight into the underlying mechanisms of the granule formation, and to clarify whether AgNPs dissolve in the gastrointestinal system and/or become absorbed and translocate as intact nanoparticles to organs and tissues.

2011-01-01

20

Acute and repeated-doses (28 days) toxicity study of Hypericum polyanthemum Klotzsch ex Reichardt (Guttiferare) in mice.  

PubMed

Hypericum polyanthemum, a South Brazilian species showed antidepressant-like and antinociceptive effects in rodents. Since limited information is available on the toxicity and safety profile of the Hypericum genus, we therefore investigated whether H. polyanthemum cyclo-hexane extract (POL) treatment could be associated with toxicity in preclinical setting using mice as an experimental model. These toxicity studies were based on the guidelines of the Organization for Economic Cooperation and Development (OECD-guidelines 423 and 407). Animals received POL single dose (2000 mg/kg, p.o.) or daily for 28-days (90, 450 and 900 mg/kg, p.o.). Acute toxicity study did not detect any clinical signs, changes in behavior or mortality. In repeated dose toxicity study, POL affected the body weight gain and induced biochemical, hematological and liver histological changes at 450 and 900 mg/kg. Mice treated with POL 90 mg/kg did not show any toxicity signs. In conclusion H. polyanthemum can be classified as safe (category 5) according to OECD acute toxicity parameters. However, the alterations observed after repeated treatment with high doses suggest that the liver could be the target organ on potential H. polyanthemum toxicity and point to the need of further toxicity studies. PMID:22525862

Betti, Andresa Heemann; Stein, Ana Cristina; Dallegrave, Eliane; Wouters, Angelica Terezinha Barth; Watanabe, Tatiane Terumi Negrão; Driemeier, Davi; Buffon, Andréia; Rates, Stela Maris Kuze

2012-07-01

21

Initial Submission: Letter from (Confidential) to USEPA regarding a 28-Day Repeated Dose Inhalation Study in Rats with N-Propyl Bromide, dated 06/04/1996 (Sanitized).  

National Technical Information Service (NTIS)

A 28-day repeated dose inhalation study was conducted in Sprague Dawley rats. Nominal air concentrations were 0, 2 mg/1, 5 mg/1 and 8 mg/1. All dose groups showed decreased weight gains compared to controL Mortality was seen in the high dose group: 8 of 1...

1996-01-01

22

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

Microsoft Academic Search

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

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

2008-01-01

23

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

PubMed

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

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

2014-08-01

24

28Day dietary exposure of mice to a low total dose (7 mg\\/kg) of perfluorooctanesulfonate (PFOS) alters neither the cellular compositions of the thymus and spleen nor humoral immune responses: Does the route of administration play a pivotal role in PFOS-induced immunotoxicity?  

Microsoft Academic Search

Short-term exposure of mice to high doses of perfluorooctanesulfonate (PFOS), an ubiquitous and highly persistent environmental contaminant, induces various metabolic changes and toxic effects, including immunotoxicity. However, extrapolation of these findings to the long-term, low-dose exposures to which humans are subject is highly problematic. In this connection, recent studies have concluded that sub-chronic (28-day) exposure of mice by oral gavage

Mousumi Rahman Qazi; B. Dean Nelson; Joseph W. DePierre; Manuchehr Abedi-Valugerdi

2010-01-01

25

Oral administration of the 5HT 2C receptor agonist, m CPP, reduces body weight gain in rats over 28 days as a result of maintained hypophagia  

Microsoft Academic Search

  \\u000a \\u000a Rationale. The 5-HT2C receptor subtype has been implicated extensively in the regulation of ingestive behaviour.\\u000a \\u000a \\u000a \\u000a \\u000a Objective. To assess whether chronic administration of the preferential 5-HT2C receptor agonist, mCPP, reduces rat body weight gain and to determine if this effect is wholly or partially attributable to the effect of the\\u000a drug on daily food intake.\\u000a \\u000a \\u000a \\u000a \\u000a Methods. Animals were orally dosed

S. P. Vickers; N. Easton; L. J. Webster; A. Wyatt; M. J. Bickerdike; C. T. Dourish; G. A. Kennett

2003-01-01

26

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

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. PMID:24361408

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

2014-03-01

27

Hepatic mRNA, microRNA, and miR-34a-Target responses in mice after 28 days exposure to doses of benzo(a)pyrene that elicit DNA damage and mutation  

PubMed Central

Benzo(a)pyrene (BaP) is a mutagenic carcinogen that is ubiquitous in our environment. To better understand the toxic effects of BaP and to explore the relationship between toxicity and toxicogenomics profiles, we assessed global mRNA and microRNA (miRNA) expression in Muta™Mouse. Adult male mice were exposed by oral gavage to 25, 50, and 75 mg/kg/day BaP for 28 days. Liver tissue was collected 3 days following the last treatment. Initially, we established that exposure to BaP led to the formation of hepatic DNA adducts and mutations in the lacZ transgene of the Muta™Mouse. We then analyzed hepatic gene expression profiles. Microarray analysis of liver samples revealed 134 differentially expressed transcripts (adjusted P < 0.05; fold changes > 1.5). The mRNAs most affected were involved in xenobiotic metabolism, immune response, and the downstream targets of p53. In this study, we found a significant 2.0 and 3.6-fold increase following exposure to 50 and 75 mg/kg/day BaP, respectively, relative to controls for miR-34a. This miRNA is involved in p53 response. No other significant changes in miRNAs were observed. The protein levels of five experimentally confirmed miR-34a targets were examined, and no major down-regulation was present. The results suggest that liver miRNAs are largely unresponsive to BaP doses that cause both DNA adducts and mutations. In summary, the validated miRNA and mRNA expression profiles following 28 day BaP exposure reflect a DNA damage response and effects on the cell cycle, consistent with the observed increases in DNA adducts and mutations. Environ. Mol. Mutagen., 2012. © 2011 Crown in the right of Canada

Malik, Amal I; Williams, Andrew; Lemieux, Christine L; White, Paul A; Yauk, Carole L

2012-01-01

28

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

PubMed

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

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

2008-06-01

29

Intragastric acidity under 28-day omeprazole treatment.  

PubMed

The aim of our study was to investigate both the effect of 28-day treatment with omeprazole (30 mg orally once daily) and of repeated investigations on 24 h intragastric H+ activity. In double-blind randomized order, 10 healthy subjects received omeprazole and 5 placebo. 24 h acidity was determined before, during and after, treatment on days -8, -4, -1, 14 and 28, 32, 36, 42 and 70. A 90% reduction in the 24 h acid concentration was found after 14 and 28 days of treatment. Nocturnal H+ activity was decreased by 85%. No hyperacidity was observed after withdrawal of the drug. Control levels before, (between days -8 and -1) and after, therapy (between days 36 and 70), however, showed a significant increase in 24 h intragastric H+-activity. Summarizing, omeprazole 30 mg mane inhibits gastric acidity markedly both day and night. Repeated investigations at short intervals lead to a significant increase in intragastric acid concentration. PMID:3902602

Dammann, H G; Walter, T A; Müller, P; Simon, B

1985-08-01

30

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

Microsoft Academic Search

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

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

2007-01-01

31

[Neurobehavioral toxicity of acrylamide and IDPN (3,3'-iminodipropionitrile) in rats by 28-day oral administration--problems encountered in collaborative study and a commentary on conducting neurobehavioral testing].  

PubMed

In order to clarify technical problems in evaluating neurotoxicity of chemicals and to solve them, a collaborative study with a common protocol was conducted at 11 domestic safety research laboratories. In the collaborative study, acrylamide and IDPN (3,3'-iminodipropionitrile), which are known neurotoxicants, were used, and the chemicals were orally administered to rats for 28 days. In addition to the clinical observation done routinely, detailed clinical observation, sensory and motor function tests including grip strength and motor activity were performed to evaluate neurobehavioral toxicity with reference to Functional Observational Battery (FOB). In general, neurobehavioral toxicity of the two chemicals was detected in the collaborative study. However, we also encountered technical problems, since neurobehavioral testing was unfamiliar to us. In the present report, we describe the major problems and how to solve them, and briefly explain the neurobehavioral testing procedure. PMID:12822443

Okazaki, Shuzo; Takashima, Hiromasa; Yamaguchi, Makiko; Hamamura, Masao; Yamashita, Kotaro; Okada, Masaaki; Sunaga, Masao; Tanaka, Ryota; Sato, Shinichi; Umano, Takaaki; Tsuji, Ryozo; Yosioka, Takafumi; Fujii, Tomoko

2003-05-01

32

Differences in gene expression profiles in the liver between carcinogenic and non-carcinogenic isomers of compounds given to rats in a 28-day repeat-dose toxicity study  

SciTech Connect

Some compounds have structural isomers of which one is apparently carcinogenic, and the other not. Because of the similarity of their chemical structures, comparisons of their effects can allow gene expression elicited in response to the basic skeletons of the isomers to be disregarded. We compared the gene expression profiles of male Fischer 344 rats administered by daily oral gavage up to 28 days using an in-house oligo microarray. 2-Acetylaminofluorene (2-AAF), 2,4-diaminotoluene (2,4-DAT), 2-nitropropane (2-NP), and 2-nitro-p-phenylenediamine (2-NpP) are hepatocarcinogenic. However, their isomers, 4-acetylaminofluorene (4-AAF), 2,6-diaminotoluene (2,6-DAT), 1-nitropropane (1-NP), and 4-nitro-o-phenylenediamine (4-NoP), are non-hepatocarcinogenic. Because of the limited carcinogenicity of 2-NpP, we attempted to perform two-parametric comparison analyses with (1) a set of 4 isomers: 2-AAF, 2,4-DAT, 2-NP, and 2-NpP as 'carcinogenic', and 4-AAF, 2,6-DAT, 1-NP, and 4-NoP as 'non-carcinogenic'; and (2) a set of 3 isomers: 2-AAF, 2,4-DAT, and 2-NP, as 'carcinogenic', and 4-AAF, 2,6-DAT, and 1-NP as 'non-carcinogenic'. After ratio filtering and Welch's approximate t-test analysis, 54 and 28 genes were selected from comparisons between the sets of 3 and 4 isomers, respectively, for day 28 data. Using hierarchical clustering analysis with the 54 or 28 genes, 2-AAF, 2,4-DAT, and 2-NP clustered into a 'carcinogenic' branch. 2-NpP was in the same cluster as 4-NoP and 4-AAF. This clustering corresponded to the previous finding that 2-NpP is not carcinogenic in male Fischer 344 rats, which indicates that comparing the differences in gene expression elicited by different isomers is an effective method of developing a prediction system for carcinogenicity.

Nakayama, Koji [Research Division for Advanced Technology, Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Kamisu, Ibaraki 314-0255 (Japan)]. E-mail: k-nakayama@ankaken.co.jp; Kawano, Yukiko [Research Division for Advanced Technology, Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Kamisu, Ibaraki 314-0255 (Japan); Kawakami, Yuuki [Research Division for Advanced Technology, Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Kamisu, Ibaraki 314-0255 (Japan); Moriwaki, Norichika [Research Division for Advanced Technology, Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Kamisu, Ibaraki 314-0255 (Japan); Sekijima, Masaru [Research Division for Advanced Technology, Kashima Laboratory, Mitsubishi Chemical Safety Institute Ltd., 14 Sunayama, Kamisu, Ibaraki 314-0255 (Japan); Otsuka, Masanori [Chemical Evaluation and Research Institute, Tokyo (Japan); Yakabe, Yoshikuni [Chemical Evaluation and Research Institute, Tokyo (Japan); Miyaura, Hideki [Chemical Evaluation and Research Institute, Tokyo (Japan); Saito, Koichi [Sumitomo Chemical Co., Ltd., Osaka (Japan); Sumida, Kayo [Sumitomo Chemical Co., Ltd., Osaka (Japan); Shirai, Tomoyuki [Graduate School of Medical Sciences, Nagoya City University, Nagoya (Japan)

2006-12-15

33

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

Abstract Objectives To evaluate the impact of a 91-day extended regimen combined oral contraceptive (150 ?g levonorgestrel [LNG]/30 ?g ethinylestradiol [EE] for 84 days, followed by 10 ?g EE for seven days [Treatment 1]) compared with two traditional 21/7 regimens (21 days 150 ?g LNG/30 ?g EE [Treatment 2] or 150 ?g desogestrel [DSG]/30 ?g EE [Treatment 3], both with seven days' hormone free), on several coagulation factors and thrombin formation markers. Methods Randomised, open-label, parallel-group comparative study involving healthy women (18-40 years). The primary endpoint was change from baseline in prothrombin fragment 1 + 2 (F1 + 2) levels over six months. Results A total of 187 subjects were included in the primary analysis. In all groups, mean F1 + 2 values were elevated after six months of treatment. Changes were comparable between Treatments 1 and 2 (least squares mean change: 170 pmol/L and 158 pmol/L, respectively) but noticeably larger after Treatment 3 (least squares mean change: 592 pmol/L). The haemostatic effects of Treatment 1 were comparable to those of Treatment 2 and noninferior to those of Treatment 3 (lower limit of 95% confidence interval [- 18.3 pmol/L] > - 130 pmol/L). Conclusions The LNG/EE regimens had similar effects on F1 + 2. Noninferiority was demonstrated between extended regimen LNG/EE and DSG/EE. Chinese Abstract 91?150?g[levonorgestrel?LNG]/30?g[ethinylestradiol?EE]84?10?g EE 7[1]?21/7?21150?g LNG/30?g EE [2]150?g[desogestrel?DSG]/30?g EE [3]?7?? 18-40???6F1+2? 187?6F1+2?12?170 pmol/L158 pmol/L?3?592 pmol/L?12?3?95%[ -18.3 pmol/L] ? -130 pmol/L?? LNG/EEF1+2?LNG/EEDSG/EE? PMID:24923685

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

2014-08-01

34

Twenty-eight days repeated oral dose toxicity study of gemifloxacin in Wistar albino rats  

Microsoft Academic Search

The purpose of this study was to investigate the potential toxicity of gemifloxacin by 28-day repeated oral dose in Wistar albino rats. The test article, was administered daily by gavage to male and female rats at dose levels of 0, 50, 100, 200mg\\/kg\\/day. At the end of treatment period, 12 rats\\/sex\\/group was sacrificed, while six extra rats\\/sex in the vehicle

Bikash Roy; Amlan Kanti Sarkar; Pinaki Sengupta; Goutam Dey; Anjan Das; Tapan Kumar Pal

2010-01-01

35

Biochemical observation during 28 days of space flight  

NASA Technical Reports Server (NTRS)

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.

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

1975-01-01

36

In vivo genotoxicity evaluation of lung cells from Fischer 344 rats following 28 days of inhalation exposure to MWCNTs, plus 28 days and 90 days post-exposure.  

PubMed

Despite their useful physico-chemical properties, carbon nanotubes (CNTs) continue to cause concern over occupational and human health due to their structural similarity to asbestos. Thus, to evaluate the toxic and genotoxic effect of multi-wall carbon nanotubes (MWCNTs) on lung cells in vivo, eight-week-old rats were divided into four groups (each group?=?25 animals), a fresh air control (0?mg/m(3)), low (0.17?mg/m(3)), middle (0.49?mg/m(3)), and high (0.96?mg/m(3)) dose group, and exposed to MWCNTs via nose-only inhalation 6?h per day, 5 days per week for 28 days. The count median length and geometric standard deviation for the MWCNTs determined by TEM were 330.18 and 1.72?nm, respectively, and the MWCNT diameters ranged from 10 to 15?nm. Lung cells were isolated from five male and five female rats in each group on day 0, day 28 (only from males) and day 90 following the 28-day exposure. The total number of animals used was 15 male and 10 female rats for each concentration group. To determine the genotoxicity of the MWCNTs, a single cell gel electrophoresis assay (Comet assay) was conducted on the rat lung cells. As a result of the exposure, the olive tail moments were found to be significantly higher (p?dose exposed male and middle and high-dose exposed female rats retained DNA damage, even 90 days post-exposure (p?28 days post-exposure) dose groups (p?

Kim, Jin Sik; Sung, Jae Hyuck; Choi, Byung Gil; Ryu, Hyeon Yeol; Song, Kyung Seuk; Shin, Jae Hoon; Lee, Jong Seong; Hwang, Joo Hwan; Lee, Ji Hyun; Lee, Gun Ho; Jeon, Kisoo; Ahn, Kang Ho; Yu, Il Je

2014-03-01

37

Repeated Dosing with Oral Cocaine in Humans: Assessment of Direct Effects, Withdrawal and Pharmacokinetics  

PubMed Central

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) 2- to 3-fold 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.

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

2009-01-01

38

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

Microsoft Academic Search

A one-year-old boy with neuroblastoma (NBoma)-associated opsoclonus–myoclonus syndrome (OMS) was treated by oral high-dose dexamethasone (DEX) pulses (20mg\\/m2\\/day of DEX for three consecutive days) every 28days for 6months 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

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

39

Preclinical 28-day inhalation toxicity assessment of s-nitrosoglutathione in beagle dogs and Wistar rats.  

PubMed

To support clinical development of S-nitrosoglutathione (GSNO) as a therapeutic agent, 28-day toxicology studies in rats and dogs were conducted. Rats (21-25/sex) and dogs (3-5/sex) were exposed for 4 hours or 1 hour, respectively, to inhaled GSNO (0, 3, 9.3, 19, and 28 mg/kg per d in rats and 0, 4.6, 9.0, and 16.2 mg/kg per d in dogs) or vehicle daily via a nebulizer. Animals were monitored throughout the 28-day dosing period and during a postexposure recovery period. Complete necropsy and tissue examinations were performed. Experimental end points included clinical pathology, toxicokinetics, and immunotoxicology. No biologically significant adverse findings were noted in either species, and the no observed adverse effect levels (NOAELs) under these conditions were the highest achieved doses (28 and 16.2 mg/kg per d in rats and dogs, respectively). These data demonstrate that GSNO is well tolerated in rodents and dogs and predict a favorable toxicity profile in humans, thus supporting future clinical development of GSNO or closely related compounds. PMID:21868767

Colagiovanni, Dorothy B; Borkhataria, Daxa; Looker, Doug; Schuler, Detlef; Bachmann, Corinna; Sagelsdorff, Peter; Honarvar, Naveed; Rosenthal, Gary J

2011-10-01

40

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

Microsoft Academic Search

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

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

2009-01-01

41

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

SciTech Connect

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.

Hansen, Deborah K., E-mail: deborah.hansen@fda.hhs.gov [Division of Personalized Nutrition and Medicine, U.S. FDA/NCTR, 3900 NCTR Rd., Jefferson, AR 72079 (United States); George, Nysia I. [Division of Personalized Nutrition and Medicine, U.S. FDA/NCTR, 3900 NCTR Rd., Jefferson, AR 72079 (United States)] [Division of Personalized Nutrition and Medicine, U.S. FDA/NCTR, 3900 NCTR Rd., Jefferson, AR 72079 (United States); White, Gene E. [Toxicological Pathology Associates, 3900 NCTR Rd., Jefferson, AR 72079 (United States)] [Toxicological Pathology Associates, 3900 NCTR Rd., Jefferson, AR 72079 (United States); Pellicore, Linda S. [Office of New Drugs, U.S. FDA/Center for Drug Evaluation and Research, 10903 New Hampshire Ave., Silver Spring, MD 20903 (United States)] [Office of New Drugs, U.S. FDA/Center for Drug Evaluation and Research, 10903 New Hampshire Ave., Silver Spring, MD 20903 (United States); Abdel-Rahman, Ali; Fabricant, Daniel [Office of Nutrition, Labeling and Dietary Supplements, U.S. FDA/Center for Food Safety and Nutrition, HFS-810, College Park, MD 20740 (United States)] [Office of Nutrition, Labeling and Dietary Supplements, U.S. FDA/Center for Food Safety and Nutrition, HFS-810, College Park, MD 20740 (United States)

2012-06-15

42

Oral Artesunate Dose-Response Relationship in Acute Falciparum Malaria  

PubMed Central

The combination of an oral artemisinin derivative (usually artesunate) and mefloquine has become standard treatment for multidrug-resistant falciparum malaria in several parts of Southeast Asia. The doses of artesunate used in monotherapy and combination treatment have largely been derived empirically. In order to characterize the in vivo dose-response relationship for artesunate and thus rationalize dosing, 47 adult patients with acute uncomplicated falciparum malaria and parasitemia ?1% were randomized to receive a single oral dose of artesunate varying between 0 and 250 mg together with a curative dose of oral mefloquine. Acceleration of parasite clearance was used as the pharmacodynamic variable. An inhibitory sigmoidal maximum effect (Emax) pharmacodynamic model typical of a dose-response curve was fitted to the relationship between dose and shortening of parasite clearance time (PCT). The Emax was estimated as 28.6 oral h, and the 50% effective concentration was 1.6 mg/kg of body weight. These results imply that there is no reduction in PCTs with the use of single doses of artesunate higher than 2 mg/kg, and this therefore reflects the average lower limit of the maximally effective dose.

Angus, Brian J.; Thaiaporn, Itaporn; Chanthapadith, Kenechanh; Suputtamongkol, Yupin; White, Nicholas J.

2002-01-01

43

Effect of dose on bioavailability of oral digoxin  

Microsoft Academic Search

Nine healthy volunteers received single 0.25, 0.5, 1.0, 1.5, and 2.0 mg doses of oral digoxin tablets in random sequence on five occasions separated by at least 4 weeks. Urinary excretion of immunoassayable digoxin was determined from 8 consecutive 24 h urine samples collected after each dose. Mean values of cumulative urinary excretion of digoxin at the 5 doses were:

H. R. Ochs; G. Bodem; D. J. Greenblatt

1981-01-01

44

Oral desensitization to milk: how to choose the starting dose!  

PubMed Central

Mori F, Pucci N, Rossi ME, de Martino M, Azzari C, Novembre E. Oral desensitization to milk: how to choose the starting dose! Pediatr Allergy Immunol 2010: 21: e450–e453. © 2009 John Wiley & Sons A/S A renewed interest in oral desensitization as treatment for food allergy has been observed in the last few years. We studied a novel method based on the end point skin prick test procedure to establish the starting dose for oral desensitization in a group of 30 children higly allergic to milk. The results (in terms of reactions to the first dose administered) were compared with a group of 20 children allergic to milk as well. Such control group started to swallow the same dose of 0.015 mg/ml of milk. None reacted to the first dose when administered according to the end point skin prick test. On the other side, ten out of 20 children (50%) from the control group showed mild allergic reactions to the first dose of milk. In conclusion the end point skin prick test procedure results safe and easy to be performed in each single child in order to find out the starting dose for oral desensitization to milk, also by taking into account the individual variability.

Mori, Francesca; Pucci, Neri; Rossi, Maria Elisabetta; de Martino, Maurizio; Azzari, Chiara; Novembre, Elio

2010-01-01

45

New Short Term Prediction Method for Chemical Carcinogenicity by Hepatic Transcript Profiling Following 28-Day Toxicity Tests in Rats  

PubMed Central

We have previously shown the hepatic gene expression profiles of carcinogens in 28-day toxicity tests were clustered into three major groups (Group-1 to 3). Here, we developed a new prediction method for Group-1 carcinogens which consist mainly of genotoxic rat hepatocarcinogens. The prediction formula was generated by a support vector machine using 5 selected genes as the predictive genes and predictive score was introduced to judge carcinogenicity. It correctly predicted the carcinogenicity of all 17 Group-1 chemicals and 22 of 24 non-carcinogens regardless of genotoxicity. In the dose-response study, the prediction score was altered from negative to positive as the dose increased, indicating that the characteristic gene expression profile emerged over a range of carcinogen-specific doses. We conclude that the prediction formula can quantitatively predict the carcinogenicity of Group-1 carcinogens. The same method may be applied to other groups of carcinogens to build a total system for prediction of carcinogenicity.

Matsumoto, Hiroshi; Yakabe, Yoshikuni; Saito, Fumiyo; Saito, Koichi; Sumida, Kayo; Sekijima, Masaru; Nakayama, Koji; Miyaura, Hideki; Otsuka, Masanori; Shirai, Tomoyuki

2011-01-01

46

Pharmacokinetics and Tissue Penetration of Linezolid following Multiple Oral Doses  

Microsoft Academic Search

The pharmacokinetics of multiple-dose linezolid were determined following administration of five 600-mg oral doses given every 12 h to each of six healthy male volunteers. Concentrations of the drug were determined in plasma and inflammatory blister fluid using high-pressure liquid chromatography. A mean peak concen- tration in plasma of 18.3 mg\\/ml (standard deviation (SD), 6.0) was attained at a mean

THEKLI GEE; RICHARD ELLIS; GILLIAN MARSHALL; JENNY ANDREWS; JANET ASHBY; RICHARD WISE

2001-01-01

47

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

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. PMID:24074738

Willoughby, Darryn S; Leutholtz, Brian

2013-10-01

48

Hydralazine kinetics after single and repeated oral doses.  

PubMed

In reports on hydralazine kinetics plasma hydralazine levels have been measured with nonspecific assay techniques. The techniques used also include acid-labile hydralazine metabolites and therefore markedly overestimate hydralazine levels. We have developed specific, sensitive assay methods for the measurement of hydralazine and its major plasma metabolite, hydralazine pyruvic acid hydrazone (HPH). By these methods, we determined hydralazine and HPH kinetics after single and repeated oral doses of hydralazine in eight hypertensive patients. Hydralazine bioavailability in the fast acetylator group (9.5% single dose, 6.6% repeated doses) and in the slow acetylator group (31.3% single dose, 39.3% repeated doses) was phenotype dependent. Peak plasma levels were lower than those reported with nonspecific assays: 0.32 microM for the single dose and 0.14 microM for repeated doses in the fast acetylator group and 1.03 microM for the single dose and 0.96 microM repeated doses in the slow acetylator group. There was no alteration in kinetics and no cumulation in plasma on repeated administration. HPH plasma levels were proportional to those of hydralazine in both acetylator groups and were 2.5 to 4 times as high as those of hydralazine. Elimination half-lifes were phenotype independent, ranging from 4 to 6 hr. HPH cumulated in the rapid but not in the slow acetylator group after repeated doses of hydralazine. PMID:7438695

Shepherd, A M; Ludden, T M; McNay, J L; Lin, M S

1980-12-01

49

Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies.  

PubMed

Panobinostat is a potent oral pandeacetylase inhibitor that leads to acetylation of intracellular proteins, inhibits cellular proliferation and induces apoptosis in leukemic cell lines. A phase Ia/II study was designed to determine the maximum-tolerated dose (MTD) of daily panobinostat, administered on two schedules: three times a week every week or every other week on a 28-day treatment cycle in patients with advanced hematologic malignancies. The criteria for hematologic dose-limiting toxicities differed between patients with indications associated with severe cytopenias at baseline (leukemia and myeloid disorders) and those less commonly associated with baseline cytopenias (lymphoma and myeloma). In patients with leukemia and myeloid disorders, 60?mg was the MTD for weekly as well as biweekly panobinostat. In patients with lymphoma and myeloma, 40?mg was the recommended dose for phase II evaluation (formal MTD not determined) of weekly panobinostat, and 60 mg was the MTD for biweekly panobinostat. Overall, panobinostat-related grade 3-4 adverse events included thrombocytopenia (41.5%), fatigue (21%) and neutropenia (21%). Single-agent activity was observed in several indications, including Hodgkin lymphoma and myelofibrosis. This phase Ia/II study provided a broad analysis of the safety profile and efficacy of single-agent panobinostat in patients with hematologic malignancies. PMID:23385375

DeAngelo, D J; Spencer, A; Bhalla, K N; Prince, H M; Fischer, T; Kindler, T; Giles, F J; Scott, J W; Parker, K; Liu, A; Woo, M; Atadja, P; Mishra, K K; Ottmann, O G

2013-08-01

50

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

SciTech Connect

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.

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

1980-09-01

51

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

PubMed Central

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

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

2014-01-01

52

Differences in Regional Blood Volume During a 28-Day Period of Abstinence in Chronic Cannabis Smokers  

PubMed Central

Cerebral blood volume (CBV) studies have provided important insight into the effects of illicit substances such as cannabis. The present study examined changes in regional blood volume in the frontal and temporal lobe, and the cerebellum during 28 days of supervised abstinence from cannabis. Dynamic susceptibility contrast MRI (DSCMRI) data were collected on 15 current, long-term cannabis users between 6 and 36 hours after the subjects' last reported cannabis use (Day 0), and again after 7 and 28 days of abstinence. Resting state CBV images were also acquired on 17 healthy comparison subjects. The present findings demonstrate that at Day 7, cannabis users continued to display increased blood volumes in the right frontal region, the left and right temporal regions, and the cerebellum. However, after 28 days of abstinence, only the left temporal area and cerebellum showed significantly increased CBV values in cannabis users. These findings suggest that while CBV levels begin to normalize with continued abstinence from cannabis, specifically in frontal areas, other temporal and cerebellar brain regions show slower CBV decreases.

Sneider, Jennifer T.; Pope, Harrison G.; Silveri, Marisa M.; Simpson, Norah S.; Gruber, Staci A.; Yurgelun-Todd, Deborah A.

2008-01-01

53

Pharmacokinetics of high doses of intramuscular and oral heroin in narcotic addicts  

Microsoft Academic Search

Background: In several countries medical prescription of diacetylmorphine is currently being evaluated as a treatment option for heavily dependent narcotic addicts. Because of damaged veins, many patients administer diacetylmorphine intramuscularly or orally. Therefore we characterized the pharmacokinetics of intramuscular and oral diacetylmorphine in the high dose range usually required in narcotic addicts.Methods: Three intramuscular doses, 3 oral doses, and 1

François Girardin; Katharina M. Rentsch; Marc-André Schwab; Marco Maggiorini; Christiane Pauli-Magnus; Gerd A. Kullak-Ublick; Peter J. Meier; Karin Fattinger

2003-01-01

54

Individual dose adjustment of oral busulfan using a test dose in hematopoietic stem cell transplantation.  

PubMed

Maintaining the appropriate average steady-state plasma concentrations (Css) of busulfan (BU) is critical for both successful engraftment and minimizing toxicity in hematopoietic stem cell transplantation (HST). We therefore performed a prospective trial with 50 adult Japanese patients that involved adjusting the BU dose in accordance with individual BU pharmacokinetics (PK). After administering a 0.5-mg/kg test dose of oral BU, we analyzed individual BU PK parameters and calculated an adjusted BU dose that would achieve a target BU Css of 850 ng/mL. Thirty-nine patients (78%) required a BU dose decrease, and the median adjusted BU dose was 0.81 mg/kg (range, 0.51-1.29 mg/kg). All patients who underwent allogeneic HST received the adjusted BU dose. After administering the sixth BU dose, we measured the plasma BU concentration. The actual BU concentration was significantly correlated with the expected BU concentration, and the predictability of the BU Css was 103% +/- 9%. The incidence of toxicity excluding oral mucositis was low, and there was no regimen-related toxicity-associated mortality. Engraftment was achieved in 98% of the patients. This study showed that our method for adjusting the BU dose facilitated reliable prediction of the actual BU Css and that individualized BU dose adjustment was able to improve clinical outcomes in HST recipients treated with a BU-containing conditioning regimen. PMID:17988994

Takamatsu, Yasushi; Sasaki, Noriaki; Eto, Tetsuya; Nagafuji, Koji; Abe, Yasunobu; Choi, Ilseung; Ogata, Kentaro; Hara, Shuuji; Suzumiya, Junji; Tamura, Kazuo

2007-10-01

55

Multiple dose pharmacokinetics of oral artemisinin and comparison of its efficacy with that of oral artesunate in falciparum malaria patients  

Microsoft Academic Search

The study compared the clinical efficacy and safety of oral artemisinin and oral artesunate as well as artemisinin pharmacokinetics during and after resolution of falciparum malaria. Forty adults with symptomatic falciparum malaria were allocated at random to treatment with either oral artemisinin (500 mg single dose on day 1 followed by 250 mg twice daily for 4 d and then

M. Hassan Alin; M. Ashton; C. M. Kihamia; G. J. B. Mtey; A. Björkman

1996-01-01

56

Factors Associated within 28 Days In-Hospital Mortality of Patients with Acute Respiratory Distress Syndrome  

PubMed Central

Objective. To determine the factors leading to in-hospital mortality within 28 days in hospitalized patients with ARDS. It was a prospective observational cohort study conducted in Intensive Care Unit of Aga Khan University Hospital Karachi from March to August 2011. Methodology. Data was collected from patients admitted in the intensive care unit on the basis of inclusion and exclusion criteria. The patients were followed daily for 28 days to record any in-hospital complications and the outcome of patients. Results. Total of 46 patients were included during this period out of which 56% (26) were males and 43% (20) were females. Mean age was 44 ± 19 years. There were 11 (23.9%) patients with age >65 and 35 (76%) had age <65 years. There were 21 (45.6%) patients with pulmonary ARDS and 25 (54.3%) had extrapulmonary ARDS. APACHE II score of >20 was present in 23 (50%) patients while the rest had score of <20. Regarding in-hospital complications, 23 (50%) patients developed sepsis, 31 (67.4%) had multiorgan failure, 14 (30%) had refractory shock, and 15 (32.6%) developed refractory hypoxemia. Out of 46 patients, 26 (56.5%) died within 28 days. On univariate analysis, high APACHE score, multiorgan failure, refractory shock, and refractory hypoxemia were main causes of death. Conclusion. ARDS is a syndrome of high mortality with mortality rate of 56.5% in this study. High APACHE, sepsis, multiorgan failure, refractory shock, and refractory hypoxemia are the leading causes of death in our patients.

Sharif, Nadia; Irfan, Muhammad; Hussain, Javaid; Khan, Javaid

2013-01-01

57

Phase II study of a short course of weekly high-dose cisplatin combined with long-term oral etoposide in metastatic colorectal cancer.  

PubMed Central

In a phase I study of weekly administered cisplatin combined with oral etoposide, we observed a partial response in 4 out of 11 patients with metastatic colorectal cancer. Subsequently, we performed a phase II study to investigate the activity of this combination as first-line treatment in this disease. Fourteen patients with metastatic colorectal cancer were enrolled in this study. Treatment consisted of cisplatin, administered in 3% sodium chloride, at a dose of 70 mg m-2 on days 1, 8 and 15 and days 29, 36 and 43 combined with oral etoposide 50 mg absolute dose daily on days 1-15 of both courses. Patients with stable disease or better continued treatment with etoposide 50 mg m-2 orally on days 1-21 every 28 days. A partial response was observed in two patients with liver metastases (14%; 95% confidence limits 2-42%) for 30 and 32 weeks. Five patients had stable disease. Toxicity consisted mainly of anaemia, leucocytopenia, nausea and vomiting. Tinnitus was reported by six patients. The activity of the combination cisplatin-oral etoposide in the schedule is only minimal in metastatic colorectal cancer.

Planting, A. S.; van der Burg, M. E.; van den Bent, M. J.; de Boer-Dennert, M.; Stoter, G.; Verweij, J.

1996-01-01

58

Kinetics and disposition of orally dosed sodium chlorate in sheep.  

PubMed

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 ?g/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 ?g/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 ?g/mL during the first and last collection periods, respectively. Urine contained the greatest concentration of chlorate at each time point and averaged 480 ± 268 ?g/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 elimination half-lives based on serum chlorate concentrations were about 0.4 and 2.5 h, respectively. Urine collected during the 6 h immediately following dosing contained the greatest concentrations of chlorate residues relative to subsequent collection periods. Rapid removal of chlorate from the gastrointestinal lumen suggests that effects of chlorate on colonic and fecal gastrointestinal bacteria may occur through mechanisms other than direct luminal contact between microbe and chlorate salts. PMID:22205670

Smith, D J; Taylor, J B

2012-06-01

59

[Tolerance of large doses of oral zinc sulfate].  

PubMed

The toxicity of oral zinc was investigated in patients hospitalized for chronic leg ulcers. Untoward effects were monitored by reference to clinical tolerance, hematological, hepatic and renal parameters, and serum concentrations of copper and iron. The investigation was conducted by comparing two groups of patients who initially did not differ significantly with regard to ulcer area, hemoglobin, leukocytes, copper, iron and zinc. Both groups had serum zinc concentrations in the lower normal range. One group was treated with 3 daily doses of 220 mg oral zinc sulfate and the other with placebo, and hence, untoward effects of zinc should have become manifest in the zinc-treated group. This was not the case. Therefore, oral zinc appears to be well tolerated clinically and does not cause hematological, renal or hepatic toxicity. In view of the increasing interest in and range of indications for zinc, particularly in conditions associated with cellular immunological hyporeactivity, this finding is a prerequisite for the institution of clinical zinc therapy. PMID:7031872

Tschumi, P; Floersheim, G L

1981-10-17

60

Evaluation of the Pig-a, micronucleus, and comet assay endpoints in a 28-day study with ethyl methanesulfonate.  

PubMed

Ethyl methanesulfonate (EMS) was evaluated as part of the validation effort for the rat Pig-a mutation assay and compared with other well-established in vivo genotoxicity endpoints. Male Sprague-Dawley (SD) rats were given a daily dose of 0, 6.25, 12.5, 25, 50, or 100 mg/kg/day EMS for 28 days, and evaluated for a variety of genotoxicity endpoints in peripheral blood, liver, and colon. Blood was sampled pre-dose (Day 1) and at various time points up to Day 105. Pig-a mutant frequencies were determined in total red blood cells (RBCs) and reticulocytes (RETs) as RBC(CD59-) and RET(CD59-) frequencies. The first statistically significant increases in mutant frequencies were seen in RETs on Day 15 and in RBCs on Day 29 with the maximum RET(CD59-) on Day 29 and of RBC(CD59-) on Day 55. The lowest dose producing a statistically significant increase of RET(CD59-) was 12.5 mg/kg on Day 55 and 25 mg/kg for RBC(CD59-) on Day 55. EMS also induced significant increases in % micronucleated RETs (MN-RETs) in peripheral blood on Days 3, 15, and 28. No statistically significant increases in micronuclei were seen in liver or colon. Results from the in vivo Comet assay on Day 29 showed generally weak increases in DNA damage in all tissues evaluated with little evidence for accumulation of damage seen over time. The results with EMS indicate that the assessment of RBC(CD59-) and/or RET(CD59-) in the Pig-a assay could be a useful and sensitive endpoint for a repeat dose protocol and complements other genotoxicity endpoints. Environ. Mol. Mutagen. 55:492-499, 2014. © 2014 Wiley Periodicals, Inc. PMID:24599777

Gunther, William C; Coffing, Stephanie L; Dickinson, Donna A; Engel, Maria E; Fiedler, Ronald D; O'Lone, Susan D; Sanok, Kelley E; Thiffeault, Catherine J; Shutsky, Thomas J; Schuler, Maik J; Dobo, Krista L

2014-07-01

61

Safety and Immunogenicity of a Single Oral Dose of Recombinant Double Mutant Heat-Labile Toxin Derived from Enterotoxigenic Escherichia coli  

PubMed Central

Enterotoxigenic Escherichia coli (ETEC) is a primary cause of traveler's diarrhea for which there is no licensed vaccine. This phase 1 trial determined the safety and immunogenicity of a recombinantly produced double mutant heat-labile enterotoxin (dmLT) of ETEC. It was administered as a single oral dose of dmLT in escalating doses of 5 ?g, 25 ?g, 50 ?g, and 100 ?g, followed by a 72-h inpatient observation, outpatient visits at 8, 14, and 28 days, and telephone calls at 2 and 6 months postvaccination. Safety was assessed by frequency of adverse events, and immune responses determined after immunization included dmLT-specific serum IgA and IgG, fecal IgA, antibody-secreting cells (ASC), and antibodies in lymphocyte supernatant (ALS) responses. All doses were well tolerated by the 36 healthy adults enrolled. Immune responses were limited in the 5- and 25-?g dose recipients. The 50-?g dose recipients trended toward stronger responses than the 100-?g dose recipients by serum IgA (67% versus 33%, P = 0.22), serum IgG (58% versus 33%, P = 0.41), and fecal IgA (58% versus 33%, P = 0.41). By day 14 postvaccination, there were significantly more positive responders (?4-fold increase from baseline) among the 50- versus 100-?g dose recipients for serum IgA (P = 0.036) but not serum IgG (P = 0.21). In conclusion, a single oral dose of dmLT was well tolerated and immunogenic, with immune responses plateauing at the 50-?g dose. (This clinical trial is registered at www.clinicaltrials.gov, registration number NCT01147445.)

El-Kamary, Samer S.; Cohen, Mitchell B.; Bourgeois, A. Louis; Van De Verg, Lillian; Bauers, Nicole; Reymann, Mardi; Pasetti, Marcela F.

2013-01-01

62

Disposition of 9-aminoacridine in rats dosed orally or intravenously and in monkeys dosed topically  

SciTech Connect

Following administration of ( UC)-labeled 9-aminoacridine (( UC)9AA) hydrochloride either orally or intravenously to rats, the excretion of radioactivity was similar, with 20-26% of the dose appearing in the urine and 57-68% in the feces. The pattern of tissue distribution was also similar for the two routes. This information suggests that absorption of the oral doses was extensive and that, for both routes of administration, biliary excretion accounted for most of the radioactivity in the feces. Biliary excretion of radioactivity derived from ( UC)9AA was confirmed in an experiment involving rats with inserted biliary cannulas. For these rats, 49.5% of the dose administered appeared in the bile in 4 h. The major urinary and biliary metabolite of ( UC)9AA of rats was identified as an O-beta-glucuronide of hydroxylated 9AA. Absorption of 9AA through the skin could not be conclusively demonstrated. For monkeys dosed topically with ( UC)9AA, only small amounts of radioactivity appeared in the urine and various tissues in 24 h.

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

1985-01-01

63

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

PubMed

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

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

2014-09-01

64

Effects of a novel organophosphorus pesticide (RPR-V) on extra hepatic detoxifying enzymes after repeated oral doses in rats  

Microsoft Academic Search

The effects of a novel organophosphorous pesticide, 2-butenoic acid-3-(diethoxy phosphinothionyl) ethyl ester (RPR-V) on glutathione S-transferases (GST), UDP-glucuronyl transferases (UDPGT) and the level of glutathione (GSH) were evaluated in rats after repeated oral administration at 33?gkg?1day?1 (low), 66?gkg?1day?1 (mid) and 99?gkg?1day?1 (high) for 90 days and at 28 days (withdrawal) post-treatment. GSH level and GST in kidney; GSH level in

Mohammed Mahboob; Mohammed Kaleem; Javed Siddiqui

2004-01-01

65

Applying Outpatient Protocols in Febrile Infants 1-28 Days of Age: Can the Threshold Be Lowered?  

Microsoft Academic Search

The purpose of this study was to determine the applicability of two accepted outpatient management protocols for the febrile infant 1-2 months of age (Boston and Philadelphia protocols) in febrile infants 1-28 days of age. We retrospectively reviewed charts of patients 1-28 days of age with a temperature greater than or equal to 38.00C. Criteria from each of the above-cited

Howard A. Kadish; Brian Loveridget; John Tobeyt; Robert G. Bolte; Howard M. Corneli

2000-01-01

66

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...

67

Active von Willebrand factor predicts 28-day mortality in patients with systemic inflammatory response syndrome.  

PubMed

Endothelial dysfunction contributes to the pathology of systemic inflammatory response syndrome (SIRS). However, endothelial biomarkers are not routinely evaluated in this setting. Here, 275 patients with SIRS and plasma levels of von Willebrand factor (VWF), thrombospondin-1, myeloperoxidase, ADAMTS-13, and active VWF (aVWF) were studied in relation to 28-day mortality. On admission, aVWF levels were higher in nonsurvivors vs survivors (0.69 vs 0.47 µg/mL, P = .019). Patients in the highest tertile of aVWF levels had a lower cumulative survival (86% vs 75%, P = .017) and twofold increased hazard ratio (HR). When adjusted for the Acute Physiology and Chronic Health Evaluation IV (APACHE-IV) score, this difference remained significant (HR 1.82, 95% confidence interval, 1.03-3.3). On admission, no significant differences were measured for the other proteins. These observations suggest that the stimulated release of VWF is not predictive for mortality in patients with SIRS, opposite of the processing of VWF after release. aVWF could be used with the APACHE-IV score to stratify SIRS patients at high mortality risk. PMID:24458436

Hyseni, Agon; Kemperman, Hans; de Lange, Dylan W; Kesecioglu, Jozef; de Groot, Philip G; Roest, Mark

2014-04-01

68

Disposition of firocoxib in equine plasma after an oral loading dose and a multiple dose regimen.  

PubMed

The objective of this study was to determine if a single loading dose (LD), 3× the label dose of firocoxib oral paste, followed by nine maintenance doses at the current label dose achieves and maintains near steady state concentrations. Six healthy, adult mares were administered 0.3mg/kg of firocoxib on Day 0, and 0.1 mg/kg 24 h later on Day 1, and at 24 h intervals from Day 2 to Day 9, for a total of 10 doses. Blood samples were collected throughout the study. The mean firocoxib maximum plasma concentration and standard deviation was 199±97 ng/mL, 175±44 ng/mL and 183±50 ng/mL after the LD, and first and last maintenance doses, respectively. The minimum mean concentration (C(min)) increased from 100±23 ng/mL after the LD to 132±38 ng/mL at Day 7. Then, the C(min) remained constant until Day 9. The average concentration at steady state (C(avg)) was 150±45 ng/mL, which compares well to the C(avg) (130±36 ng/mL) reported after multiple daily doses at 0.1 mg/kg. The administration of the single LD allowed achievement of the average steady state drug concentrations faster than a multi-dose regimen without a loading dose. After the LD, firocoxib at 0.1 mg/kg every 24 h was able to maintain a relatively constant average drug concentration which should produce less variability in onset of action and efficacy. PMID:24076125

Cox, S; Villarino, N; Sommardahl, C; Kvaternick, V; Zarabadipour, C; Siger, L; Yarbrough, J; Amicucci, A; Reed, K; Breeding, D; Doherty, T

2013-11-01

69

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...

70

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

PubMed

Few chronic food protein models have described the relationship between allergenicity and the molecular structure of food protein after physical processing. The effect of ?-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. PMID:23000443

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

71

Tamarind seed polysaccharide: a 28-day dietary study in Sprague-Dawley rats.  

PubMed

Forty male and 40 female Crl:SD® CD® IGS rats were fed diets containing 0, 40,000, 80,000, or 120,000 ppm tamarind seed polysaccharide (equivalent to 3450.8, 6738.9, or 10 597.1 mg/kg bw/day and 3602.1, 7190.1, or 10,690.7 mg/kg bw/day for males and females, respectively) for 28 days. Animals were observed for adverse clinical signs, body weight, feed consumption, hematology and clinical chemistry parameters, urinalysis values were recorded, and at the end of the study the rats underwent a full necropsy. Functional Observational Battery (FOB) and Motor Activity (MA) tests were performed on all animals. There were no mortalities, no clinical or ophthalmologic signs, body weight, body weight gain, food consumption and food efficiency, FOB or MA findings associated with the administration of tamarind seed polysaccharide. Initial statistically significant decreases in body weight gain and food consumption resolved after the first week and were considered the result of reduced palatability. There were no adverse changes in hematology, coagulation, clinical chemistry or urinalysis parameters in male or female rats considered the result of test substance administration. At necropsy, there were no macroscopic, histopathological findings, estrus cycle, or organ weight changes deemed related to administration of the test substance. Under the conditions of this study and based on the toxicological endpoints evaluated, the no-observed-adverse-effect level (NOAEL) for tamarind seed polysaccharide in the diet was the highest concentration tested of 120,000 ppm (equivalent to 10,597 mg/kg bw/day and 10,691 mg/kg bw/day for male and female rats, respectively). PMID:23616144

Heimbach, James T; Egawa, Hiroshi; Marone, Palma Ann; Bauter, Mark R; Kennepohl, Elke

2013-01-01

72

Effect of Carbamazepine on the Single Oral Dose Pharmacokinetics of Alprazolam  

Microsoft Academic Search

The effect of carbamazepine, an inducer of cytochrome P450 (CYP) 3A4, on the single oral dose pharmacokinetics of alprazolam was examined in a double-blind, randomized crossover study with two phases. Seven healthy male subjects took carbamazepine 300 mg\\/day or matched placebo orally for 10 days, and on the 8th day they took a single oral 0.8 mg dose of alprazolam.

Hanako Furukori; Koichi Otani; Norio Yasui; Tsuyoshi Kondo; Sunao Kaneko; Ritsuko Shimoyama; Tadashi Ohkubo; Takako Nagasaki; Kazunobu Sugawara

1998-01-01

73

Exercise thermoregulatory responses following a 28-day sleep-high train-low regimen.  

PubMed

The potentiated exercise-sweating rate observed during acute hypoxia is diminished after a sleep-high train-low (SH-TL) regimen. We tested the hypothesis that this attenuation of the sweating response after SH-TL is compensated for by an increase in heat loss via vasodilatation. Nine male subjects participated in a 28-day SH-TL regimen. Before (pre-), and after (post-) the SH-TL protocol, they performed an VO2peak test under normoxia and hypoxia. Additionally, pre- and post-SH-TL they completed three 30-min constant-work rate trials on a cycle ergometer. In one trial, the subjects inspired room air while exercising at 50% of normoxic VO2peak (CT). In the remaining trials, subjects exercised in hypoxia (F(I)O2 12.5%), either at the same absolute (HAT) or relative (50% of hypoxic VO2peak work rate (HRT) as in CT. Despite similar exercise core temperature responses between pre- and post-SH-TL trials, sweating rate was potentiated in HAT pre-SH-TL [CT: 1.97 (0.42); HRT: 1.86 (0.31); HAT: 2.55 (0.53) mg cm(-2) min(-1); p < 0.05]. Post-SH-TL exercise sweating rate was increased for CT, and remained unchanged in HRT and HAT [CT: 2.42 (0.76); HRT: 2.01 (0.33); HAT: 2.59 (0.30) mg cm(-2) min(-1)]. Pre-SH-TL, the forearm-fingertip skin temperature difference (Tsk(f-f)) was higher in HAT than in CT and HRT by ~3.5 °C (p < 0.05). The inter-condition differences in Tsk(f-f) were diminished post-SH-TL. In conclusion, the decrease in sweating rate during hypoxic exercise, following a SH-TL regimen, was countered by an increase in vasodilatation (reduced Tsk(f-f)), whereas SH-TL enhanced the sweating response during normoxic exercise. The mechanisms underlying these SH-TL-induced alterations in thermoregulatory responses remain to be settled. PMID:22407329

Kounalakis, Stylianos N; Eiken, Ola; Mekjavic, Igor B

2012-11-01

74

Single Oral Dose Escalation Pharmacokinetics of Pleconaril (VP 63843) Capsules in Adults  

Microsoft Academic Search

Pleconaril is an orally active broad-spectrum antipicornaviral agent with excellent penetration into the central nervous system and nasal epithelium. The authors report the results of a randomized, placebo-controlled, dose escalation study of pleconaril oral capsules following single-dose administration of 50 to 1000 mg. Fifty-six healthy adults (ages 19-55) participated in the study. Each subject received a single dose of pleconaril

Susan M. Abdel-Rahman; Gregory L. Kearns

1999-01-01

75

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

PubMed Central

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

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

2013-01-01

76

Oral high-dose ankaferd administration effects on gastrointestinal system.  

PubMed

Background and aims: Ankaferd Blood Stopper (ABS) is a herbal extract obtained from five different plants. It has a therapeutic potential for the management of external hemorrhage and controlling gastrointestinal bleeding. However, ABS's effects are not unknown on gastrointestinal systems. The aim of this study was to assess the effect of short- and long-term systemic exposure and gastrointestinal safety following the oral administration of high-dose ABS in rats. Methods: Eighteen healthy adult male rats were included into the study. The rats were divided into 4 groups: group A was fed with high dose ABS (2ml/Kg) for one week, group B for one month, group C for three months and group D's diet did not contain any ABS. On termination of the ABS treatment, the gastrointestinal system from the esophagus to the anus and the liver were surgically removed and histological investigated. Results: During the study period, there was no mortality; signs of intoxication in any of the studied groups. No gastrointestinal tissue fibrosis, dysplasia, or metaplasia was detectable in any of the groups. The stomach had a normal morphology in all groups. However, the other gastrointestinal tract sections showed mucosal inflammation, goblet cell decrements, and intra-epithelial lymphocyte infiltration. The most common changes were mucosal inflammation in all rats in group B and C. Frequency of inflammation was greater in groups B and C in comparison to group A (P= 0.001). Loss of goblet cell and intra-epithelial lymphocyte infiltration were not significantly different between groups A and B (P=0.308 and P=0.189, respectively). However, there was significantly higher intra-epithelial lymphocyte infiltration in group C than in group A (P=0.04). Histopathological examination of the liver showed no inflammation, fibrosis, bile duct destruction or proliferation in any of the groups. However, each groups revealed vascular dilatation and erythrocyte accumulation at the sinusoidal structures of the liver. Conclusions: ABS seems to be a safe agent and it can be used for hemorrhage originated from gastric lesions. Further work needs to be done to establish whether ABS leads to be used to stop gastrointestinal bleeding. PMID:23471574

Akbal, Erdem; Köklü, Seyfettin; Astarc?, Hesna Müzeyyen; Koçak, Erdem; Karaca, Gökhan; Beyaz?t, Yavuz; Topcu, Güler; Acar, Bilgehan; Ergün, Dilek; Haznedaro?lu, ?brahim Celalettin

2013-01-01

77

Methyl Acetate: 28 Days Inhalation Toxicity Study in Rats with Cover Letter dated 05/17/1999.  

National Technical Information Service (NTIS)

Groups of 10 male and 10 female Sprague Dawley rats received methyl acetate by nose-only inhalation exposure at concentrations of 0, 75, 350 or 2000 ppm for a period of 28 days (6 hours per day, 5 days per week). One day after the last administration all ...

1999-01-01

78

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

PubMed

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

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

2014-05-01

79

Pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of ?9-THC in cannabis users  

PubMed Central

Oral ?9-tetrahydrocannabinol (?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 behavioral effects of oral ?9-THC at acute doses higher than those tested previously. The pharmacokinetic and pharmacodynamic profile of oral ?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. ?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 ?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 ?9-THC and individual differences in sensitivity, individualized dose adjustment is needed to avoid side effects and maximize therapeutic response.

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

2013-01-01

80

Single-Dose Oral Toxicity of Fermented Scutellariae Radix Extract in Rats and Dogs  

PubMed Central

The aim of this study was to investigate the acute oral toxicity of fermented Scutellariae Radix (JKTMHGu- 100) in rats and dogs. JKTM-HGu-100 was orally administered at a dose of 2,000 mg/kg in Sprague-Dawley rats. An escalating single-dose oral toxicity test in beagle dogs was performed at doses of 500, 1000, and 2000 mg/kg with 4-day intervals. Clinical signs, changes in body weight, mortality, and necropsy findings were examined for 2 weeks following oral administration. No toxicological changes related to the test substance nor mortality was observed after administration of a single oral dose of JKTM-HGu-100 in rats or dogs. Therefore, the approximate lethal dose (LD) for oral administration of JKTMHGu-100 in rats was considered to be over 2,000 mg/kg, and the maximum tolerance doses (MTDs) in rats and dogs were also estimated to be over 2,000 mg/kg. These results indicate that JKTM-HGu-100 shows no toxicity in rodents or non-rodents at doses of 2,000 mg/kg or less.

Kim, Myoung-Seok; Ham, Seoung-Ho; Kim, Jun-Ho; Shin, Ji-Eun; Oh, Jin; Kim, Tae-Won; Yun, Hyo-In; Lim, Jong-Hwan; Jang, Beom-Su

2012-01-01

81

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

PubMed

Oral ?(9) -tetrahydrocannabinol (?(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 ?(9) -THC at acute doses higher than those tested previously. The pharmacokinetic and pharmacodynamic profile of oral ?(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. ?(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 ?(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 ?(9) -THC and individual differences in sensitivity, individualized dose adjustment is needed to avoid side effects and maximize therapeutic response. PMID:23754596

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

2013-07-01

82

Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects  

PubMed Central

Background High dose oral thiamine may have a role in treating diabetes, heart failure, and hypermetabolic states. The purpose of this study was to determine the pharmacokinetic profile of oral thiamine hydrochloride at 100 mg, 500 mg and 1500 mg doses in healthy subjects. Methods This was a randomized, double-blind, single-dose, 4-way crossover study. Pharmacokinetic measures were calculated. Results The AUC0-10 hr and Cmax values increased nonlinearly between100 mg and 1500 mg. The slope of the AUC0-10 hr vs dose, as well as the Cmax vs dose, plots are steepest at the lowest thiamine doses. Conclusion Our study demonstrates that high blood levels of thiamine can be achieved rapidly with oral thiamine hydrochloride. Thiamine is absorbed by both an active and nonsaturable passive process. Trial Registration ClinicalTrials.gov: NCT00981877

2012-01-01

83

Effect of itraconazole on the single oral dose pharmacokinetics and pharmacodynamics of alprazolam  

Microsoft Academic Search

To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP) 3A4, on the single oral dose pharmacokinetics\\u000a and pharmacodynamics of alprazolam, the study was conducted in a double-blind randomized crossover manner with two phases\\u000a of treatment with itraconazole-placebo or placebo-itraconazole. Ten healthy male subjects receiving itraconazole 200?mg\\/day\\u000a or matched placebo orally for 6 days took an oral

Norio Yasui; T. Kondo; Koichi Otani; Hanako Furukori; Sunao Kaneko; Tadashi Ohkubo; Takako Nagasaki; Kazunobu Sugawara

1998-01-01

84

Effect of Single Oral Doses of Ascorbic Acid on Body Temperaturein Healthy Guinea Pigs  

Microsoft Academic Search

A series of experiments were conducted to examine the effect of single oral doses of ascorbic acid on body temperature in healthy guinea pigs. Fifteen male guinea pigs (approximately 200 g) were fed a nonpurifled diet designed for rabbits (a scorbutogenic diet) ad libitum and received orally 2 mg L-ascorbic acid\\/100 g body wt daily. After acclimation, rectal temperatures were

CAROL S. JOHNSTON

85

Effect of Food on High-Dose Oral Ganciclovir Disposition in HIV-Positive Subjects  

Microsoft Academic Search

The effect of food on the steady-state pharmacokinetics of gan-ciclovir following high-dose oral ganciclovir in HIV- and CMV-seropositive subjects was investigated in an open-label, randomized, two-treatment crossover study. Over 2 consecu-tive weeks, subjects received in random order multiple oral doses of ganciclovir 2000 mg tid for 3 consecutive days either on an “empty stomach” (i.e., at least 1 hour before

Donald Jung; Kay Griffy; Albert Dorr

1999-01-01

86

Risk Factors and Dose–Effect Relationship for Mandibular Osteoradionecrosis in Oral and Oropharyngeal Cancer Patients  

Microsoft Academic Search

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

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

2009-01-01

87

Effects of delta-9-tetrahydrocannabinol administered subcutaneously to rabbits for 28 days.  

PubMed

Subcutaneous (s.c.) administration of delta-9-tetrahydrocannabinol (delta-9-THC) to rabbits produced dose-related cumulative toxicity. Five groups of three New Zealand albino rabbits each received 28 daily treatments with isotonic saline, sesame oil of 15.9, 45.0 or 153.4 mg/kg/day of delta-9-THC dissolved in sesame oil. Dose-related dermal responses included erythema, edema, ulceration and nodule formation. Some of the granulomatous nodules contained an oily substance and exhibited liquefactive necrosis. The severities of erythema and ulceration were generally maximal during the first week of treatment, but edema and nodule formation were most severe after days 12 and 14, respectively. All rabbits survived treatment, but body weights, liver weights and liver glycogen levels were decreased in a dose-related manner. Maximal body weight effects occurred after day 19. Hemochemical changes occurred only in rabbits treated with 153.4 mg/kg/day and included decreased blood sugar and alkaline phosphatase, and increased serum potassium. Hematology parameters were normal throughout the treatment period. No drug-related pathological lesions occurred in internal organs. The cumulative body weight changes, significantly decreased hepatic glycogen levels and reduced blood sugar and alkaline phosphatase values may have indicated drug-induced metabolic changes. PMID:1129806

Thompson, G R; Rosenkrantz, H; Fleischman, R W; Braude, M C

1975-01-01

88

Pharmacokinetics of carbamazepine in normal humans after single and repeated oral doses  

Microsoft Academic Search

The pharmacokinetic profile of carbamazepine was studied in six normal humans after single and repeated oral doses. The plasma concentrations following single dose (100, 200, 600 mg) were fitted by a one-compartment open model. Using area as a measure, availability was constant in the dose range studied. The elimination half-life ± SEafter a single dose was 37.7±5.7hr; it decreased during

André P. Gérardin; Françoise V. Abadie; Joëlle A. Campestrini; Walter Theobald

1976-01-01

89

Mouse Single Oral Dose Toxicity Study of DHU001, a Polyherbal Formula  

PubMed Central

This study was conducted to obtain acute information of the oral dose toxicity of DHU001, a polyherbal formula in male and female mice. In order to calculated 50% lethal dose (LD50) and approximate lethal dose (LD) , test material was once orally administered to male and female ICR mice at dose levels of 2000, 1000, 500, 250 and 0 (vehicle control) ml/kg (body weight) . The mortality and changes on body weight, clinical signs, gross observation, organ weight and histopathology of principle organs were monitored 14 days after treatment with DHU001. We could not find any mortalities, DHU001 treatment-related clinical signs, changes on the body and organ weights, gross and histopathological findings. The results obtained in this study suggest that LD50 and approximate LD in mice after single oral dose of DHU001 were considered over 2000 mg/kg in both female and male mice.

Roh, Seong-Soo

2010-01-01

90

Expression patterns of cell cycle proteins in the livers of rats treated with hepatocarcinogens for 28 days.  

PubMed

Some hepatocarcinogens induce cytomegaly, which reflects aberrant cell cycling and increased ploidy, from the early stages of administration to animals. To clarify the regulatory molecular mechanisms behind cell cycle aberrations related to the early stages of hepatocarcinogenesis, we performed gene expression analysis using microarrays and real-time reverse transcription polymerase chain reaction followed by immunohistochemical analysis in the livers of rats treated with the cytomegaly inducing hepatocarcinogens thioacetamide (TAA), fenbendazole, and methyleugenol, the cytomegaly non-inducing hepatocarcinogen piperonyl butoxide (PBO), or the non-carcinogenic hepatotoxicants acetaminophen and ?-naphthyl isothiocyanate, for 28 days. Gene expression profiling showed that cell cycle-related genes, especially those of G(2)/M phase, were mostly upregulated after TAA treatment. Immunohistochemical analysis was performed on cell cycle proteins that were upregulated by TAA treatment and on related proteins. All hepatocarcinogens, irrespective of their cytomegaly inducing potential, increased liver cells immunoreactive for p21(Cip1), which acts on cells arrested in G(1) phase, and for Aurora B or Incenp, which is suggestive of an increase in a cell population with chromosomal instability caused by overexpression. PBO did not induce cell proliferation after 28-day treatment. Hepatocarcinogens that induced cell proliferation after 28-day treatment also caused an increase in p53(+) cells in parallel with increased apoptotic cells, as well as increased population of cells expressing M phase-related proteins nuclear Cdc2, phospho-Histone H3, and HP1?. These results suggest that hepatocarcinogens may increase cellular populations arrested in G1 phase or showing chromosomal instability after 28-day treatment. Hepatocarcinogens that induce cell cycle facilitation may cause M phase arrest accompanied by apoptosis. PMID:23411599

Yafune, Atsunori; Taniai, Eriko; Morita, Reiko; Nakane, Fumiyuki; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

2013-06-01

91

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

PubMed

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. PMID:21546243

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

2012-01-01

92

Single daily oral dose of gemfibrozil reduces postprandial hyperlipidemia in hyperlipidemic patients  

Microsoft Academic Search

This study analyzed the effects of a single daily oral dose (900 mg) of gemfibrozil on fasting and postprandial lipids in hyperlipidemic patients. In 13 patients with hypercholesterolemia or mixed hyperlipidemia, the intake of a single daily dose (900mg) of gemfibrozil for 3 weeks reduced the plasma concentration of total cholesterol (15 ± 7%), low-density lipoprotein cholesterol (9 ± 18%),

Olivier Descamps; Jean-Claude Hondekijn; Thierry Godrie; Jean-Pierre Desager; Francis R. Heller

1998-01-01

93

Oral dose and faecal concentration of antibiotics during antibiotic decontamination in mice and in a patient.  

PubMed

In both mice and one patient, a similar correlation was found between the oral dose of a ;nonabsorbable' aminoglycoside antibiotic selected for antibiotic decontamination of the digestive tract and the resultant faecal concentration. In mice, absorption of the orally-given antibiotics could only be demonstrated in animals treated with extremely high doses of 1440 mg. per kg. body weight per day. Evidence of absorption of gentamycin was found to occur in a patient after doses as low as 70 mg. per kg. per day. PMID:4528886

van der Waaij, D; Berghuis-de Vries, J M; Korthals Altes, C

1974-10-01

94

Dietary Regulation of Glycolytic Enzymes. Viii. Dose and Time Response of Rat Jejunal Enzymes to Oral Sex Hormones.  

National Technical Information Service (NTIS)

The time and dose responses of oral 17 beta-estradiol and oral testosterone as reflected by changes in the activities of four enzymes involved in carbohydrate metabolism (phosphofructokinase, fructosediphosphatase, pyruvate kinase, and Fru-I, 6-P2 aldolas...

F. B. Stifel, N. S. Rosensweig, R. H. Herman

1970-01-01

95

Safety and Immunogenicity of Single-Dose Live Oral Cholera Vaccine Strain CVD 103-HgR, Prepared from New Master and Working Cell Banks  

PubMed Central

Currently, no cholera vaccine is available for persons traveling from the United States to areas of high cholera transmission and who for reasons of occupation or host factors are at increased risk for development of the disease. A single-dose oral cholera vaccine with a rapid onset of protection would be particularly useful for such travelers and might also be an adjunct control measure for cholera outbreaks. The attenuated Vibrio cholerae O1 vaccine strain CVD 103-HgR harbors a 94% deletion of the cholera toxin A subunit gene (ctxA) and has a mercury resistance gene inserted in the gene encoding hemolysin A. We undertook a phase I randomized placebo-controlled two-site trial to assess the safety and immunogenicity of a preliminary formulation of CVD 103-HgR prepared from new master and working cell banks. Healthy young adults were randomized (5:1 vaccinees to placebo recipients) to receive a single oral dose of ?4.4 × 108 CFU of vaccine or a placebo. Blood serum vibriocidal and cholera toxin-specific IgG antibodies were measured before and 10, 14, and 28 days following vaccination or placebo. Excretion of the vaccine strain in the stool was assessed during the first week postvaccination. A total of 66 subjects were enrolled, comprising 55 vaccinees and 11 placebo recipients. The vaccine was well tolerated. The overall vibriocidal and anti-cholera toxin seroconversion rates were 89% and 57%, respectively. CVD 103-HgR is undergoing renewed manufacture for licensure in the United States under the auspices of PaxVax. Our data mimic those from previous commercial formulations that elicited vibriocidal antibody seroconversion (a correlate of protection) in ?90% of vaccinees. (This study has been registered at ClinicalTrials.gov under registration no. NCT01585181.)

Greenberg, Richard N.; Pasetti, Marcela F.; Livio, Sofie; Lock, Michael; Gurwith, Marc; Levine, Myron M.

2014-01-01

96

Soluble receptor for advanced glycation end products predicts 28-day mortality in critically ill patients with sepsis  

PubMed Central

Objective Multiple biomarkers are used to assess sepsis severity and prognosis. Increased levels of the soluble receptor for advanced glycation end products (sRAGE) were previously observed in sepsis but also in end-organ injury without sepsis. We evaluated associations between sRAGE and (i) 28-day mortality, (ii) sepsis severity, and (iii) individual organ failure. Traditional biomarkers procalcitonin (PCT), C-reactive protein (CRP) and lactate served as controls. Methods sRAGE, PCT, CRP, and lactate levels were observed on days 1 (D1) and 3 (D3) in 54 septic patients. We also assessed the correlation between the biomarkers and acute respiratory distress syndrome (ARDS), acute kidney injury (AKI) and acute heart failure. Results There were 38 survivors and 16 non-survivors. On D1, non-survivors had higher sRAGE levels than survivors (p = 0.027). On D3, sRAGE further increased only in non-survivors (p < 0.0001) but remained unchanged in survivors. Unadjusted odds ratio (OR) for 28-day mortality was 8.2 (95% CI: 1.02–60.64) for sRAGE, p = 0.048. Receiver operating characteristic analysis determined strong correlation with outcome on D3 (AUC = 0.906, p < 0.001), superior to other studied biomarkers. sRAGE correlated with sepsis severity (p < 0.00001). sRAGE showed a significant positive correlation with PCT and CRP on D3. In patients without ARDS, sRAGE was significantly higher in non-survivors (p < 0.0001) on D3. Conclusion Increased sRAGE was associated with 28-day mortality in patients with sepsis, and was superior compared to PCT, CRP and lactate. sRAGE correlated with sepsis severity. sRAGE was increased in patients with individual organ failure. sRAGE could be used as an early biomarker in prognostication of outcome in septic patients.

BRODSKA, HELENA; MALICKOVA, KARIN; VALENTA, JIRI; FABIO, ANTHONY; DRABEK, TOMAS

2014-01-01

97

Impairment of caffeine clearance by chronic use of low-dose oestrogen-containing oral contraceptives  

Microsoft Academic Search

The effect of chronic (>3 months) administration of low-dose oestrogen-containing (<50 µg oestrogen) oral contraceptives (OCS) on the pharmacokinetics of caffeine has been examined in a treated females matched with 9 non-smoking, drug-free, healthy control females of similar age, weight and ethnic origin. Each subject received 162 mg caffeine base orally after an overnight fast. OCS subjects had a prolonged

D. R. Abernethy; E. L. Todd

1985-01-01

98

14Day Repeat-Dose Oral Toxicity Evaluation of Oxazyme in Rats and Dogs  

Microsoft Academic Search

Oxazyme (OC4) is an orally administered formulation that has as an active component a recombinant mutant form of Bacillus subtilis oxalate decarboxylase (OxDC) enzyme C383S, designed to degrade dietary oxalate in the stomach. Fourteen-day repeat-dose studies were conducted in rats and dogs to evaluate toxicity and determine a no observed adverse effect level (NOAEL). Animals were administered OC4 by oral

Aaron B. Cowley; Duane W. Poage; Robin R. Dean; Carol L. Meschter; Majid Ghoddusi; Qing-Shan Li; Harmeet Sidhu

2010-01-01

99

Comparative single-dose pharmacokinetics of rasagiline in minipigs after oral dosing or transdermal administration via a newly developed patch.  

PubMed

1. A rasagiline transdermal patch was developed for the treatment of early and advanced Parkinson's disease. Relevant pharmacokinetic parameters of rasagiline obtained after transdermal administration to minipigs were compared with those of rasagiline after oral administration. 2. A total of 18 minipigs were randomly divided into three groups (six animals for each group). A single dose of 1?mg rasagiline tablet was orally administrated to one group. Meanwhile, single dose of 1.25 and 2.5?mg (2 and 4?cm(2)) rasagiline patches were given (at the postauricular skin) to the other two groups, respectively. The pharmacokinetic parameters such as plasma half-life (t1/2), time to peak plasma-concentration (Tmax), mean residence time (MRT), area under the curve (AUC(0-t)) were significantly (p?oral administrations. 3. The plasma half-life (t1/2) of rasagiline (1.25?mg patch: 11.8?±?6.5?h, 2.5?mg patch: 12.5?±?4.7?h) in minipig following transdermal administration was significantly prolonged as compared with that following the oral administration (1?mg tablet: 4.7?±?2.5?h). The dose-normalized relative bioavailability of rasagiline patch in minipig were 178.5% and 156.4%, respectively, for 1.25 and 2.5?mg patches compared with 1?mg rasagiline tablet. The prolonged t1/2 and increased bioavailability of rasagiline patch suggested a possible longer dosing interval compared with oral tablet. PMID:23339547

Lin, Yu; Zou, Yanye; Lin, Jialiang; Zhang, Tao; Deng, Jie

2013-08-01

100

Oral/intravenous maintenance dosing of valproate following intravenous loading: a simulation.  

PubMed

Valproic acid (VPA) has a narrow therapeutic range (50-100mg/l) and exhibits nonlinear protein binding. Additionally, VPA pharmacokinetics are dependent on age, induction status, and formulation; so titration and dosing vary between individuals. The aim of these simulations was to determine optimal intravenous (i.v.) loading dose, and i.v. and oral VPA maintenance regimens. A 5-min 15mg/kg loading dose resulted in total and free plasma VPA concentrations of approximately 65 and 7.5mg/l in children, and approximately 80 and 11mg/l in adults, 1h after the infusion; induction status had little effect. For uninduced children and adults, 7.5 and 3.5mg/kg q6h i.v. valproate sodium, initiated 6h after loading dose maintains therapeutic plasma VPA concentrations. The rapid decline of plasma VPA concentrations following an i.v. loading dose in combination with the delayed initial absorption of drug from delayed-release divalproex sodium tablets warrant beginning q12h oral maintenance regimens of delayed-release divalproex sodium within 2h of a loading dose in the uninduced population. Plasma VPA concentrations can be sustained in the therapeutic range using once-daily maintenance regimens of extended-release divalproex sodium tablets if initiated concurrently with i.v. loading dose in the uninduced population. A two-fold higher i.v. and oral maintenance regimen dose may be required in induced patients. PMID:12576165

Dutta, Sandeep; Cloyd, James C; Granneman, G Richard; Collins, Stephen D

2003-02-01

101

The pharmacokinetics, pharmacodynamics, and safety of orally dosed INCB018424 phosphate in healthy volunteers.  

PubMed

INCB018424 phosphate, a potent inhibitor of JAK enzymes with selectivity for JAK1&2, is in development for the treatment of myelofibrosis (MF). The oral dose pharmacokinetics, pharmacodynamics, safety, and tolerability of INCB018424 were evaluated in healthy volunteers in 2 double-blind, randomized, and placebo-controlled studies. The first study evaluated single ascending doses of 5 to 200 mg INCB018424 and the effect of food, whereas the second study evaluated multiple ascending doses, including both once- and twice-daily dosing for 10 days. As a Biopharma-ceutical Classification System class I drug, INCB018424 exhibited good oral bioavailability and dose-proportional systemic exposures. INCB018424 showed low oral dose clearance and a small volume of distribution, with an approximate 3-hour plasma half-life and insignificant accumulation following repeat dosing. A high-fat meal reduced INCB018424 C(max) by 24% but had little effect on INCB018424 AUC. INCB018424 was cleared primarily by metabolism with negligible renal excretion. The pharmacodynamics of INCB018424, evaluated by the inhibition of phosphorylated STAT3 following cytokine stimulation in whole blood, showed good correlation with INCB018424 plasma concentrations. INCB018424 was generally safe and well tolerated, with 25 mg bid and 100 mg qd established as the maximum tolerated doses in healthy volunteers. PMID:21257798

Shi, Jack G; Chen, Xuejun; McGee, Ryan F; Landman, Robert R; Emm, Thomas; Lo, Yvonne; Scherle, Peggy A; Punwani, Naresh G; Williams, William V; Yeleswaram, Swamy

2011-12-01

102

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

PubMed

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. PMID:21531096

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

2012-03-01

103

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

PubMed Central

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 activation associated with HIV-1 disease. Rapid reductions in markers of immune system hyperactivation and cellular proliferation were obtained despite the fact that VS411 did not attain maximal suppression of HIV RNA, suggesting this effect was due to the HALT component. Trial Registration ITEudraCT 2007-002460-98

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

104

Subchronic oral toxicity of microcystin in common carp ( Cyprinus carpio L.) exposed to Microcystis under laboratory conditions  

Microsoft Academic Search

The subchronic oral toxicity of microcystin in common carp (Cyprinus carpio L.) was investigated in this study. The fish (mean body weight of 322±36g, n=10) were orally exposed to Microcystis by feeding with bloom scum at a dose of 50?g microcystins\\/kg body weight under laboratory conditions for 28 days. Growth assay results showed that microcystin could completely inhibit the growth

Xiao-Yu Li; Ik-Kyo Chung; Jung-In Kim; Jin-Ae Lee

2004-01-01

105

Interpatient variability in bioavailability of the intravenous formulation of topotecan given orally to children with recurrent solid tumors  

Microsoft Academic Search

Purpose: Evaluation of inter- and intrapatient variability of topotecan oral bioavailability and disposition was performed in children\\u000a with malignant solid tumors. Patients and methods: Topotecan i.v. formulation was given orally on schedules of daily for 21 consecutive days (d?×?21) or daily for 5 days per\\u000a week for 3 weeks [(d?×?5)3], in both cases repeated every 28 days. Topotecan doses of

William C. Zamboni; Laura C. Bowman; Ming Tan; Victor M. Santana; Peter J. Houghton; William H. Meyer; Charles B. Pratt; Richard L. Heideman; Amar J. Gajjar; Alberto S. Pappo; Clinton F. Stewart

1999-01-01

106

Validation of two-dimensional measurements of root resorption craters on human premolars after 28 days of force application.  

PubMed

The aims of this study were to develop a three-dimensional (3D) mathematical model of a typical root resorption crater and to correlate two-dimensional (2D) surface area measurements to 3D volumetric measurements of root resorption craters created under light and heavy orthodontic forces. Data were obtained from a previous study of 36 first premolars from 16 subjects requiring extraction of these teeth as part of their orthodontic treatment. Buccal tipping forces of 25 or 225 g were applied for an experimental period of 28 days. After extraction, the samples were prepared for scanning electron microscopy (SEM) imaging, image processing and analysis. Surface area (2D) and volumetric (3D) measurements of all craters were obtained. A mathematical analysis of the 2D/3D relationship enabled the determination of an appropriate digital model for the shape, type and dimensions of resorption craters, which was also able to distinguish between a 'hemispheric' model versus a 'layered' model of craters. The results demonstrated that 2D and 3D measurements were strongly correlated (r = 0.991**). Within the light and heavy force groups, the measurements were also strongly correlated (r = 0.978** and r = 0.994**, respectively). For a 28 day experimental period, 2D measurements of root resorption craters were found to be as reliable as 3D measurements. PMID:16043475

Chan, E K M; Petocz, P; Darendeliler, M A

2005-08-01

107

Silymarin Ascending Multiple Oral Dosing Phase I Study in Noncirrhotic Patients With Chronic Hepatitis C  

PubMed Central

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg.

Hawke, Roy L.; Schrieber, Sarah J.; Soule, Tedi A.; Wen, Zhiming; Smith, Philip C.; Reddy, K. Rajender; Wahed, Abdus S.; Belle, Steven H.; Afdhal, Nezam H.; Navarro, Victor J.; Berman, Josh; Liu, Qi-Ying; Doo, Edward; Fried, Michael W.

2011-01-01

108

Randomised controlled trial of oral vitamin A supplementation in preterm infants to prevent chronic lung disease  

PubMed Central

BACKGROUND—Intramuscular supplementation with vitamin A in large doses may reduce the incidence of chronic lung disease.?AIM—To investigate whether oral supplementation with vitamin A would reduce the incidence of chronic lung disease in a group of extremely low birthweight infants.?METHODS—Infants with birth weight < 1000 g were randomised at birth to receive oral vitamin A supplementation (5000 IU/day) or placebo for 28 days. The primary outcome was oxygen dependency at 28 days of age or death.?RESULTS—A total of 154 infants were randomised; 77 received vitamin A (median birth weight (interquartile range) 806 (710-890) g), and 77 received placebo (median birth weight (interquartile range) 782 (662-880) g). Plasma vitamin A concentrations in the supplemented group were significantly higher at 24 hours of age but did not differ significantly at birth, 12 hours of age, 7 days, or 28days of life. There were no significant differences in the proportion of infants who survived, required oxygen at 28 days, required oxygen at 36 weeks postmenstrual age, survived without chronic lung disease at 36 weeks, survived without significant retinopathy, or who survived without significant intraventricular haemorrhage.?CONCLUSIONS—Oral supplementation with 5000 IU vitamin A in extremely low birthweight infants does not significantly alter the incidence of chronic lung disease. However, this dose may have been inadequate to achieve optimal serum retinol concentrations.??

Wardle, S; Hughes, A; Chen, S; Shaw, N

2001-01-01

109

Oral contraceptives and tryptophan metabolism: Effects of oestrogen in low dose combined with a progestagen and of a low-dose progestagen (megestrol acetate) given alone  

Microsoft Academic Search

The effect upon tryptophan metabolism of the use of combined oestrogen-progestagen oral contraceptives containing a low (0·05 mg) dose of oestrogen, or of the continuous administration of megestrol acetate, has been studied by determining the excretion of tryptophan metabolites in urine collected after a 2 g oral dose of the amino acid.An investigation of 10 women before being given oral

D. P. Rose; P. W. Adams

1972-01-01

110

Captopril: determination in blood and pharmacokinetics after single oral dose.  

PubMed

The study describes a specific, precise, sensitive and accurate method for determination of unchanged captopril, an angiotensin-converting enzyme inhibitor, in human plasma. Captopril was stabilized by forming an adduct with p-bromophenacyl bromide and this adduct was measured by high-performance liquid chromatography with UV detection. The standard curve was linear over a range of 30-800 ng ml-1. The average yield of derivatization of the unchanged captopril was 73.6% and the recovery of captopril-adduct reached 93.1%. The limit of detection was 15 ng ml-1, while the quantitative limit was 30 ng ml-1. Inter- and intra-assay RSD was below 9%, but inter- and intra-assay accuracy was below 8%. On the basis of elaborated method, a single-dose pharmacokinetics in 12 men, in two doses (25 and 50 mg of captopril) has been investigated. The comparison of the pharmacokinetic parameters obtained from both doses of the drug have been made. PMID:9696583

Jankowski, A; Skorek, A; Krzy?ko, K; Zarzycki, P K; Ochocka, R J; Lamparczyk, H

1995-04-01

111

High Dose Rate versus Low Dose Rate Brachytherapy for Oral Cancer - A Meta-Analysis of Clinical Trials  

PubMed Central

Objective To compare the efficacy and safety of high dose rate (HDR) and low dose rate (LDR) brachytherapy in treating early-stage oral cancer. Data Sources A systematic search of MEDLINE, EMBASE and Cochrane Library databases, restricted to English language up to June 1, 2012, was performed to identify potentially relevant studies. Study Selection Only randomized controlled trials (RCT) and controlled trials that compared HDR to LDR brachytherapy in treatment of early-stage oral cancer (stages I, II and III) were of interest. Data Extraction and Synthesis Two investigators independently extracted data from retrieved studies and controversies were solved by discussion. Meta-analysis was performed using RevMan 5.1. One RCT and five controlled trials (607 patients: 447 for LDR and 160 for HDR) met the inclusion criteria. The odds ratio showed no statistically significant difference between LDR group and HDR group in terms of local recurrence (OR?=?1.12, CI 95% 0.62–2.01), overall mortality (OR?=?1.01, CI 95% 0.61–1.66) and Grade 3/4 complications (OR?=?0.86, CI 95% 0.52–1.42). Conclusions This meta-analysis indicated that HDR brachytherapy was a comparable alternative to LDR brachytherapy in treatment of oral cancer. HDR brachytherapy might become a routine choice for early-stage oral cancer in the future.

Zhang, Dongsheng

2013-01-01

112

Pharmacokinetics and safety of firocoxib after oral administration of repeated consecutive doses to neonatal foals.  

PubMed

The purpose of this study was to determine the pharmacokinetics and safety profile of firocoxib in neonatal foals. Seven healthy foals were administered 0.1 mg/kg firocoxib orally q24 h for nine consecutive days, commencing at 36 h of age. Blood was collected for firocoxib analysis using high-pressure liquid chromatography with fluorescence detection at 0 (dose #1 only), 0.25, 0.5, 1, 2, 4, 8, 16, and 24 h after doses 1, 5, and 9. For all other doses (2, 3, 4, 6, 7, and 8), blood was collected immediately prior to the next dose (24 h trough). Elimination samples (36, 48, 72, 96, 120, and 144 h) were collected after dose 9. Safety was assessed via physical examinations, body weight measurements, gastroscopy, complete blood count, plasma biochemistry and urinalysis. Firocoxib was rapidly absorbed following oral administration with minimal accumulation after repeat dosing. After the final dose, the terminal half-life was approximately 11 h. Firocoxib was below the limit of detection (<2.5 ng/mL) in plasma 72 h after the final dose. No significant abnormalities were found on blood analyses, urinalysis, or gastroscopy. This study demonstrated that firocoxib is absorbed in neonatal foals with no demonstrable adverse effects after repeated doses of 0.1 mg/kg. PMID:24749691

Hovanessian, N; Davis, J L; McKenzie, H C; Hodgson, J L; Hodgson, D R; Crisman, M V

2014-06-01

113

A phase I and pharmacokinetic study of bi-daily dosing of oral paclitaxel in combination with cyclosporin A  

Microsoft Academic Search

Purpose: To investigate dose escalation of bi-daily (b.i.d.) oral paclitaxel in combination with cyclosporin A in order to improve and prolong the systemic exposure to paclitaxel and to explore the maximum tolerated dose and dose limiting toxicity (DLT) of this combination. Patients and methods: A total of 15 patients received during course 1 two doses of oral paclitaxel (2Ꮔ, 2Ꮲ,

Mirte M. Malingré; Jos H. Beijnen; Hilde Rosing; Franciska J. Koopman; Olaf van Tellingen; Ken Duchin; Wim W. Ten Bokkel Huinink; Martha Swart; Jan Lieverst; Jan H. M. Schellens

2001-01-01

114

Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation  

Microsoft Academic Search

We investigated optimal dose of prothrombin complex concentrate (PCC) for acute reversal of oral anticoagulation in patients with major hemorrhagic complications or who required invasive procedures. We also checked how rapidly international normalized ratio (INR) was reversed after PCC administration.INR was measured before and 10–60 min after administration of PCC with or without vitamin K in 42 patients (men 28,

Masahiro Yasaka; Toshiyuki Sakata; Hiroaki Naritomi; Kazuo Minematsu

2005-01-01

115

PROPOSED ORAL REFERENCE DOSE (RFD) FOR BARIUM AND COMPOUNDS (Final Report) 2004  

EPA Science Inventory

This document is the final report for 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 Informa...

116

A new concept for bisphosphonate therapy: a rationale for the development of monthly oral dosing of ibandronate  

Microsoft Academic Search

Oral daily and weekly bisphosphonates represent the current mainstay of treatment for postmenopausal osteoporosis (PMO). However, the inconvenience of frequent dosing is known to negatively affect adherence to therapy in the long term. This has prompted the development of convenient oral bisphosphonate regimens that feature simple, less frequent dosing schedules. Such regimens require high potency agents, which can be given

Jean-Yves Reginster; Dieter Felsenberg; Cyrus Cooper; Jacob A. Stakkestad; Paul D Miller; David L. Kendler; Silvano Adami; Michael R. McClung; Michael A. Bolognese; Roberto Civitelli; Etienne Dumont; Bernard Bonvoisin; Robert R Recker; Pierre D. Delmas

2006-01-01

117

Pharmacokinetics and pharmacodynamics of low doses of midazolam administered intravenously and orally to healthy volunteers.  

PubMed

1. Midazolam, a short-acting benzodiazepine, has been considered a probe for estimating hepatic and intestinal cytochrome P450 (CYP) 3A activity in humans. The aim of the present study was to evaluate the pharmacokinetics and pharmacodynamics of midazolam administered intravenously (i.v.) and orally (p.o.) at relatively low doses to healthy volunteers. 2. The present study was an open-label, single-sequence trial in three phases distinguished by differing doses of midazolam. Plasma concentrations of midazolam and its metabolites, as well as pharmacodynamic parameters, were measured simultaneously after administration of 5, 15 and 30 microg/kg, i.v., midazolam and 15, 50 and 100 microg/kg, p.o., midazolam. 3. The area under the concentration-time curve (AUC) of midazolam was significantly correlated with dose after both i.v. and oral administration (both P < 0.001). The AUC(0-6) of midazolam after oral administration was also well correlated with the area under the effect curve for peak saccadic velocity (PSV; P < 0.018), postural sway area (PSA; P < 0.069) and mental sedation as measured on a visual analogue scale (VAS; P < 0.054), but not for critical flicker fusion. 4. The present study has shown that the pharmacokinetics of midazolam at relatively low doses are linear for both intravenous and oral dosing regimens. In addition, PSV, PSA and VAS may be useful for the simultaneous evaluation of the pharmacokinetics and pharmacodynamics of midazolam at subtherapeutic doses. PMID:19719748

Misaka, Shingen; Uchida, Shinya; Imai, Hiromitsu; Inui, Naoki; Nishio, Shinichiro; Ohashi, Kyoichi; Watanabe, Hiroshi; Yamada, Shizuo

2010-03-01

118

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

PubMed

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 selenocompounds when orally dosed to sheep. Therefore, in cases of acute selenosis, it is important to understand the chemical form to which an intoxicated animal was exposed when determining the importance and meaning of Se concentration in serum or whole blood obtained at various times postexposure. PMID:23825349

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

2013-09-01

119

One dose of oral hexarelin protects chronic cardiac function after myocardial infarction.  

PubMed

Both hexarelin and its natural analog ghrelin exert comparable cardioprotective activities. A single dose of ghrelin administered at the very acute phase after experimental myocardial infarction positively affects cardiac function in chronic heart failure. Therefore, this study aimed to determine whether a single dose of oral hexarelin has the same effect in the chronic disease phase. Myocardial infarction or sham operation was generated by left coronary artery ligation in male C57BL/6J mice, which subsequently received one dose of hexarelin or vehicle treatment by oral gavage 30min after operation. Although the mortality within 14 days after myocardial infarction did not differ between the groups, hexarelin treatment protected cardiac function in the chronic phase as evidenced by higher ejection fraction and fractional shortening, as well as lower lung weight/body weight and lung weight/tibial length ratios, compared with vehicle treatment. Hexarelin treatment concurrently lowered plasma epinephrine and dopamine levels, and shifted the balance of autonomic nervous activity toward parasympathetic nervous activity as evidenced by a smaller low/high-frequency power ratio and larger normalized high-frequency power on heart rate variability analysis. The results first demonstrate that one dose of oral hexarelin treatment potentially protects chronic cardiac function after acute myocardial infarction, and implicate that activating growth hormone secretagogue receptor 1a might be beneficial for cardioprotection, although other mechanism may also be involved. PMID:24747279

Mao, Yuanjie; Tokudome, Takeshi; Kishimoto, Ichiro; Otani, Kentaro; Miyazato, Mikiya; Kangawa, Kenji

2014-06-01

120

28 day modulation of global lightning activity and its relation to tropical cloud coverage and solar activity  

NASA Astrophysics Data System (ADS)

In order to investigate characteristics of global lightning activity changes, we analyzed Schumann resonance (SR) spectral intensity variation using 1-100 Hz ELF magnetic field waveform data obtained at Syowa station (69.0°S, 39.6°E) for the period between February 2000 and January 2003. We calculated dynamic spectra of ELF data with the fast Fourier transform (FFT) method and extracted spectral powers at the first three resonance modes (8, 14, 20 Hz) as a function of day. Then, we calculated a power spectrum of the SR spectral intensity variation. It is found that there are steep peaks at 28 and 11, and multiple peaks around ~4-6 days. Though it is suggested that the ~10 and ~5 day periodicities are highly associated with planetary wave activity in the tropical region, clear evidence for the presence of the 28 day periodicity over three years has been found for the first time in this study. As a next step, we analyzed the composite infrared cloud images to examine the relationship between the SR spectral intensity variation and the variation of the tropical cloud coverage. From the cross-spectral analysis between these variations it is found that the cross spectrum showed a steep peak at the 24 day period and that the phase histogram showed the clear anti-phase relation. The discovered anti-phase relation may be best explained by the decrease of lightning activity, driven by the decrease of the heat flux and the convective available potential energy (CAPE) needed to induce thunderstorms. Further, we performed dynamic cross-spectral analysis between the SR spectral intensity variation and solar and geomagnetic activity parameters such as F10.7 index, sunspot number, Kp index , Dst index, cosmic ray flux, and relativistic electron and ion fluxes measured by the GOES-8 satellite. Though the cross-spectrum peaks in the period range from 20 to 30 day, the coherence values in this period range are estimated to be less than 0.6. In addition, there is no clear one-to-one phase relationship among these parameters. These facts imply that 28 day modulation of global lightning activity may not be directly controlled by these solar and geomagnetic activity parameters.

Sato, M.; Takahashi, Y.; Fukunishi, H.

2005-12-01

121

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

USGS Publications Warehouse

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.

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

1998-01-01

122

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

PubMed Central

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

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

2014-01-01

123

Toxicological assessment of ?-(1-->6)-glucan (lasiodiplodan) in mice during a 28-day feeding study by gavage.  

PubMed

Studies evaluating the toxicity caused by fungal exopolysaccharides of the ?-(1-->6)-D-glucan type are rare. In this study, the toxicological effects of sub-chronic treatments with lasiodiplodan (?-(1-->6)-D-glucan from Lasiodiplodia theobromae MMPI) were evaluated in mice through the assessment of biochemical, hematological, and histopathological alterations. Thirty-two mice (16 male, 16 female) were used in this study divided in two groups; one group received lasiodiplodan (50 mg/kg body weight) daily for 28 days via gavage, and another (control group) received saline during the same period. Blood samples were collected via cardiac puncture for hematological and biochemical analyses. Liver, heart, kidney, and spleen were collected for histopathological analysis. Statistical analysis was performed through one-way analysis of variance and only p < 0.05 F-values were presented. Significant reduction in blood glucose in the male group (35%; p < 0.01), transaminases activity in both sexes (AST and ALT; ~35%; p < 0.05), and urea (20%; p < 0.01) in the female group was observed with the lasiodiplodan treatment. The results showed that sub-chronic treatments with lasiodiplodan did not generate hematological and histopathological alterations leading to signs of toxicity in healthy mice, independent of gender. PMID:23208465

Túrmina, Janaína A; Carraro, Emerson; Alves da Cunha, Mário A; Dekker, Robert F H; Barbosa, Aneli M; Dos Santos, Fábio Seidel; Silva, Luiz A; Malfatti, Carlos R M

2012-01-01

124

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

SciTech Connect

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.

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

2009-11-15

125

Effect of Time of Meal Consumption on Bioavailability of a Single Oral 5 mg Tacrolimus Dose  

Microsoft Academic Search

Tacrolimus (FK506, Prograf ®) is marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation. This study investigated the effect of timing of a standardized breakfast meal on both the rate and extent of tacrolimus absorption following a single 5 mg oral dose. The protocol used a randomized, open-label, four-period, four-treatment, four-sequence crossover design in 16 healthy,

Ihor Bekersky; Dawna Dressler; Qais Mekki

2001-01-01

126

Colon Cleansing With Oral Sodium Phosphate in Adolescents: Dose, Efficacy, Acceptability, and Safety  

Microsoft Academic Search

BACKGROUND AND AIMS:Standardized bowel preparation in children and adolescents has not been established. Our aim was to compare two bowel preparation regimens and determine which was more effective, acceptable, and safer for children undergoing colonoscopy.METHODS:We compared the efficacy and acceptability of a 1-day regimen with oral sodium phosphate solution (NaP solution) (1 mL\\/kg\\/day, maximum 90 mL in two divided doses;

Mahmoud Sabri; Carlo Di Lorenzo; Wendy Henderson; William Thompson; Seema Khan

2008-01-01

127

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

Microsoft Academic Search

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

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

1999-01-01

128

Single oral dose toxicity test of platycodin d, a saponin from platycodin radix in mice.  

PubMed

The object of this study was to evaluate the single oral dose toxicity of platycodin D, a saponin from the root of Platycodon grandiflorum in male and female mice. Platycodin D was administered to female and male mice as an oral dose of 2000, 1000, 500, 250 and 125 mg/kg (body wt.). Animals were monitored for the mortality and changes in body weight, clinical signs and gross observation during 14 days after treatment, upon necropsy, organ weight and histopathology of 14 principle organs were examined. As the results, no platycodin D treatment related mortalities, clinical signs, changes on the body and organ weights, gross and histopathological observations against 14 principle organs were detected up to 2000 mg/kg in both female and male mice. Therefore, LD50 (50% lethal dose) and approximate LD of playtcodin D after single oral treatment in female and male mice were considered over 2000 mg/kg - the limited dosages recommended by KFDA Guidelines [2009-116, 2009], respectively. PMID:24278575

Lee, Won-Ho; Gam, Cheol-Ou; Ku, Sae-Kwang; Choi, Seong-Hun

2011-12-01

129

Phase I study of single-dose BMY-28100, a new oral cephalosporin.  

PubMed Central

The objective of this Phase I study was to evaluate the safety, tolerance, and pharmacokinetics of BMY-28100 in 36 male subjects after the administration of single oral doses of 250, 500, and 1,000 mg. The subjects were divided into groups of 12 per dose group. All subjects completed the study, and BMY-28100 was well tolerated at all doses. The maximum concentration of the drug in plasma ranged from 6.2 to 17.7 micrograms/ml for the 250- and 1,000-mg doses, respectively, and the area under the curve increased in a dose-proportional manner. The elimination half-life and renal clearance averages were 1.2 h and 200 ml/min, respectively. The values for renal clearance suggest that BMY-28100 is excreted by glomerular filtration and tubular secretion. Mean concentrations of the drug in urine were highest during the first 4 h after the doses and ranged from 175 to 658 micrograms/ml following the 250- and 1,000-mg doses, respectively. The mean urinary recovery ranged from 57 to 70% of the dose. The results from this Phase I study indicate that BMY-28100 is well tolerated and exhibits linear pharmacokinetics.

Barbhaiya, R H; Gleason, C R; Shyu, W C; Wilber, R B; Martin, R R; Pittman, K A

1990-01-01

130

Single-dose intravenous and oral pharmacokinetics of enrofloxacin in goral (Nemorrhaedus goral arnouxianus).  

PubMed

This study describes the pharmacokinetics of enrofloxacin following oral and i.v. administration to goral (Nemorrhaedus goral arnouxianus). The objective of this study was to expand upon current antimicrobial treatment options available for use in goral by measuring plasma concentrations and examining the pharmacokinetics of enrofloxacin in these animals. Two single-dose treatments of enrofloxacin were administered to four goral in a crossover design. Single-dose treatments consisted of administration of injectable enrofloxacin i.v. (5 mg/kg) and enrofloxacin tablets (136 mg chewable tablets) dissolved in a grain slurry and administered p.o. (10 mg/kg). Plasma levels of enrofloxacin and its metabolite ciprofloxacin were measured with the use of high-performance liquid chromatography with UV detection. Plasma volume of distribution for i.v. enrofloxacin was 2.15 - 1.01 L/kg, with a mean elimination half-life of 13.3 hr and total body clearance of 0.19+/-0.14 L/kg/hr. The maximum plasma concentration measured for oral enrofloxacin was 2.77 microg/ml, with a mean half-life of 5.2 hr and systemic availability of 14.6%. The area under the plasma concentration over time curve (AUC) for oral enrofloxacin was 21.06 microg/hr/ml. The area under the plasma concentration over time curve generated for oral enrofloxacin in goral yields an area under the plasma concentration over time curve to minimum inhibitory concentration ratio > 100 for many gram-positive and gram-negative bacterial pathogens common to small ruminants. Based on these results, oral enrofloxacin may be considered for further study as a treatment option for susceptible infections in goral. PMID:17312793

Gandolf, A Rae; Papich, Mark G; Bringardner, Amy B; Atkinson, Mark W

2006-06-01

131

Phase I study of oral clofarabine consolidation in adults aged 60 and older with acute myeloid leukemia.  

PubMed

Clofarabine has shown activity and tolerability in older patients with acute myeloid leukemia (AML). We investigated the safety and tolerability of an oral formulation of clofarabine for consolidation therapy of patients aged 60 and older with AML. In this phase I study, twenty-two patients older than 60 years with AML in first complete remission were treated once daily with oral clofarabine for 14 or 21 days of a 28-day cycle, for up to five cycles. Dose escalation from 1 mg to 6 mg daily using a 3?+?3 design was used to determine dose-limiting toxicities (DLT), the maximum tolerated dose (MTD), and tolerability of oral clofarabine. No DLTs or Grade 3-4 nonhematologic toxicities were observed. The primary toxicities were hematologic, including uncomplicated grade 3-4 neutropenia (50%) and thrombocytopenia (50%). Given that myelosuppression necessitating dose delays/reductions was observed more commonly at higher doses, the recommended phase II dose is 2 mg daily for 21 of 28 days. At doses equal to or greater than 2 mg, the median relapse-free survival was 28.35 months. Oral clofarabine was well-tolerated with encouraging activity in patients older than 60 years. Further investigation of oral clofarabine as a consolidation and/or maintenance therapy in AML for older individuals is warranted. (ClinicalTrials.gov:NCT00727766). PMID:24415560

Jacoby, Meagan A; Martin, Michael G; Uy, Geoffrey L; Westervelt, Peter; Dipersio, John F; Cashen, Amanda; Stockerl-Goldstein, Keith; Vij, Ravi; Luo, Jingqin; Reineck, Teresa; Bernabe, Noel; Abboud, Camille N

2014-05-01

132

Single, escalating dose pharmacokinetics, safety and food effects of a new oral androgen dimethandrolone undecanoate in man: a prototype oral male hormonal contraceptive.  

PubMed

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

Surampudi, P; Page, S T; Swerdloff, R S; Nya-Ngatchou, J J; Liu, P Y; Amory, J K; Leung, A; Hull, L; Blithe, D L; Woo, J; Bremner, W J; Wang, C

2014-07-01

133

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

PubMed

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%. PMID:23868556

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

2013-11-01

134

Pharmacokinetics of gamma-hydroxybutyric acid in alcohol dependent patients after single and repeated oral doses.  

PubMed Central

1. The pharmacokinetics of gamma-hydroxybutyric acid (GHB) were studied in 10 alcohol dependent subjects after single and repeated therapeutic oral doses (25 mg kg-1 every 12 h for 7 days). 2. GHB was readily absorbed and rapidly eliminated (tmax = 20-45 min; mean t1/2z 27 +/- 5 s.d. min). Urinary recovery of unchanged GHB was negligible (less than 1% of the dose). gamma-butyrolactone was not detected in either plasma or urine, indicating that lactonization of GHB does not occur in vivo. 3. The multiple-dose regimen resulted neither in accumulation of GHB nor in time-dependent modification of its pharmacokinetics. 4. In five subjects, the data were consistent with nonlinear elimination kinetics of GHB. Administration of a 50 mg kg-1 dose to these subjects resulted in significant increases in dose-normalized AUC, t1/2z and mean residence time. 5. Doubling of the dose also resulted in a significant increase in tmax with little change in Cmax. 6. At the administered doses, GHB did not accumulate in the plasma and caused no serious side effects.

Ferrara, S D; Zotti, S; Tedeschi, L; Frison, G; Castagna, F; Gallimberti, L; Gessa, G L; Palatini, P

1992-01-01

135

Two-Year Chronic Oral-Toxicity Study with Low-Dose-Irradiated Papayas in Swiss White Mice.  

National Technical Information Service (NTIS)

A two-year and three-generation reproduction study using Swiss white mice subjected to chronic oral administration of low-dose-irradiated papayas was conducted. There were no statistical differences in growth, body weight, food consumption, mortality, beh...

1971-01-01

136

Pharmacokinetics and Tolerability of Gemifloxacin (SB-265805) after Administration of Single Oral Doses to Healthy Volunteers  

PubMed Central

Gemifloxacin (known as SB-265805 or LB-20304) is a potent, novel fluoroquinolone compound with a broad spectrum of antibacterial activity. The pharmacokinetics and tolerability of oral gemifloxacin were characterized in healthy male volunteers after a single dose of 20, 40, 80, 160, 320, 600, or 800 mg. Multiple serum and urine samples were collected and analyzed for gemifloxacin using high-performance liquid chromatography with fluorescence detection. Safety assessments included vital signs, 12-lead electrocardiogram readings, hematology, clinical chemistry, urinalysis, and adverse-experience monitoring. Gemifloxacin was rapidly absorbed after all doses. Maximum concentrations of gemifloxacin in serum (Cmax) were achieved approximately 1 h after dosing, after which concentrations in serum declined in a biexponential manner. Values of Cmax and the area under the concentration-time curve in serum from 0 h to infinity (serum AUC0–?) increased linearly with dose. Serum AUC0–? values (mean ± standard deviation) were 0.65 ± 0.01, 1.28 ± 0.22, 2.54 ± 0.31, 5.48 ± 1.24, 9.82 ± 2.70, 24.4 ± 7.1, and 31.4 ± 7.6 ?g · h/ml following 20-, 40-, 80-, 160-, 320-, 600-, and 800-mg doses, respectively. The terminal phase elimination half-life was independent of dose, with an overall mean of 7.4 ± 2.0 h. The profiles indicated that the pharmacokinetic profile is suitable for a once-daily dosing regimen. Approximately 25 to 40% of the administered dose was excreted unchanged in the urine, and renal clearance (ca. 150 ml/min) was independent of dose. There were no significant changes in clinical chemistry, hematology, or urinalysis parameters, vital signs, or 12-lead electrocardiogram readings in subjects, irrespective of dose. The results of these studies support the further investigation of once-daily administration of gemifloxacin.

Allen, Ann; Bygate, Elizabeth; Oliver, Stuart; Johnson, Martin; Ward, Christopher; Cheon, Ae-Jin; Choo, Youn Sung; Kim, In-Chull

2000-01-01

137

Urinary corticoid:creatinine ratios in healthy pet dogs after oral low-dose dexamethasone suppression tests  

Microsoft Academic Search

Eleven dogs were used in a trial to find a suitable dose of dexamethasone for an oral dexamethasone suppression test for the diagnosis of hyperadrenocorticism. Basal urinary corticoid:creatinine ratios were established in all 11 and then groups of seven were given oral doses of 0.02, 0.01 or 0.0075 mg dexamethasone\\/kg bodyweight and urine samples were collected at two-hour intervals from

M. M. A. R. Vaessen; H. S. Kooistra; J. A. Mol; A. Rijnberk

2004-01-01

138

Kinetics of Monochloroacetic Acid at Subtoxic and Toxic Doses in Rats after Single Oral and Dermal Administrations  

Microsoft Academic Search

Rats were administered a single oral (10 (subtoxic) or 225 (toxic, LD20) mg\\/kg) or dermal (125 mg\\/kg, LD20) dose of 14 C-monochlo- roacetic acid (MCA) and the time-course (0.25, 0.75, 2, 4, 8, 16, and 32 h postadministration) of radioactivity determined in plasma, tissues, and excreta. At the subtoxic oral dose, concentra- tion of 14 C-MCA peaked at 0.1% of

Shakil A. Saghir; Karl K. Rozman

2003-01-01

139

Low-dose oral vitamin K is safe and effective for outpatient management of patients with an INR>10  

Microsoft Academic Search

Background: Low-dose oral vitamin K effectively returns an international normalized ratio (INR) between 4.5 and 10.0 to an INR of 2.0–3.0 within 24 h in about 70% of patients. However, the efficacy of oral vitamin K for the treatment of higher INR values has only been studied in one small randomized trial. Treatment of markedly prolonged INR values with low-dose

Karen E Gunther; Gladys Conway; Linda Leibach; Mark A Crowther

2004-01-01

140

Risk of Ovarian Cancer in Relation to Estrogen and Progestin Dose and Use Characteristics of Oral Contraceptives  

Microsoft Academic Search

Although past studies have shown that oral contraceptives with 50 µg or more of estrogen reduce the risk of ovarian cancer, it is not clear whether newer, lower-dose formulations do as well. We conducted a population- based, case-control study in the Delaware Valley to assess the impact of dose of oral contraception on risk of ovarian cancer. Cases aged 20-69

Roberta B. Ness; Jeane Ann Grisso; Jennifer Klapper; James J. Schlesselman; Stacey Silberzweig; Ron Vergona; Mark Morgan; James E. Wheeler

141

Kinetics of monochloroacetic acid at subtoxic and toxic doses in rats after single oral and dermal administrations.  

PubMed

Rats were administered a single oral (10 [subtoxic] or 225 [toxic, LD20] mg/kg) or dermal (125 mg/kg, LD20) dose of 14C-monochloroacetic acid (MCA) and the time-course (0.25, 0.75, 2, 4, 8, 16, and 32 h postadministration) of radioactivity determined in plasma, tissues, and excreta. At the subtoxic oral dose, concentration of 14C-MCA peaked at 0.1% of dose by 2 h. Most tissue profiles of MCA paralleled that of plasma with few exceptions. At the toxic oral dose, tissue concentrations remained initially below those seen after the subtoxic dose, because stomach retained most of the toxic dose for up to 8 h. Peak plasma concentration was reached within 0.25 h without an apparent subsequent uptake phase. Most of the dermal dose rapidly penetrated into the skin (>95% within 0.25 h) and remained sequestered there and released slowly. Concentration in plasma peaked at 0.36% of dose by 0.75 h and remained constant for up to 4 h. Peak tissue concentrations were reached between 2 and 4 h. Within 0.75 h, 9% of the dermally absorbed dose was metabolized by liver and eliminated through bile, all of which was subsequently reabsorbed. Two percent of MCA appeared in colon by 0.75 h, apparently as a result of direct transport through GI-wall in retrograde movement. About 70-80% of radioactivity recovered from the small intestine of orally dosed rats was parent compound. Fecal elimination was negligible (dose. At the toxic oral dose, urinary excretion was initially slow and accelerated after 8 h. The plasma half-life was 2 h for oral and 4 h for dermal administration. Differential oral low and high dose kinetics was due to delayed stomach emptying and not to saturation of metabolic pathways. Dose-responses were steep, with no overt toxicity (coma/death) up to 200 (oral) and 100 (dermal) mg/kg, whereas 100% mortality occurred at 450 (LD50 > 400 and < 450) and 175 (LD50 145) mg/kg after oral and dermal exposure, respectively. PMID:12915718

Saghir, Shakil A; Rozman, Karl K

2003-11-01

142

Flecainide: single and multiple oral dose kinetics, absolute bioavailability and effect of food and antacid in man.  

PubMed Central

The kinetics of flecainide after single intravenous (2 mg kg-1) and oral (200 mg) dosing, absolute bioavailability, effects of food and aluminium hydroxide on flecainide absorption and steady-state kinetics following twice daily oral dosing (200 mg) have been evaluated in ten healthy subjects. Absolute bioavailability of oral flecainide averaged 70% (range 60-86%). Rate and extent of flecainide absorption were not significantly affected by food nor by concomitantly administered aluminium hydroxide. The apparent volume of distribution of 5.5 +/- 0.3 l kg-1 indicates wide distribution of flecainide in tissues. Estimated elimination half-lives from plasma data averaged 9.3 to 12.4 h (single oral dose studies), 11.8 h (single i.v. dose), and 11.5 h (multiple oral dose). Half-lives calculated from urinary excretion data corresponded well with those calculated from plasma data. Flecainide elimination takes place both by nonrenal (metabolic) clearance and renal excretion of the intact drug involving glomerular filtration and active tubular secretion. Following i.v. dosing CLNR and CLR averaged respectively 3.24 +/- 0.80 and 2.38 +/- 0.49 ml min-1 kg-1. After 200 mg twice daily oral treatment steady state was reached within 3-4 days with trough and peak plasma levels on day 8 of 457 and 662 ng ml-1, which are well within the therapeutic range.

Tjandra-Maga, T B; Verbesselt, R; Van Hecken, A; Mullie, A; De Schepper, P J

1986-01-01

143

A 4-week Repeated Dose Oral Toxicity and Cytotoxicity Study of Gumiganghwaltang in Crl:CD (SD) Rats  

PubMed Central

Gumiganghwaltang (GGT) is a traditional oriental herbal prescription commonly used to treat colds and inflammatory diseases in Korea. This study reports the first evaluation of the oral toxicity and cytotoxicity effects of repeat doses of GGT. GGT was orally administered daily at doses of 0, 500, 1000, and 2000 mg/kg for 4 weeks. Analysis of body weight gain, mortality, clinical observations, urinalysis, blood biochemistry, hematology, organ weight, and histopathological data revealed no significant differences between the V.CONTROL and GGT-treated groups. In addition, we investigated the cytotoxicity of GGT against LNCaP, RBL-1, and BEAS-2B cell lines, and splenocytes. Based on the results, we conclude that GGT orally administered to rats is safe with no drug-related toxicity, even at the highest dose, in 4-week repeated dose studies. Thus, this concentration is considered the non-observable effect dose in rats.

Lee, Mee-Young; Shin, In-Sik; Seo, Chang-Seob; Kim, Jung-Hoon; Ha, Heykyung; Huh, Jung-Im; Shin, Hyeun-Kyoo

2011-01-01

144

Effect of low-dose oral glutamine on painful stomatitis during bone marrow transplantation.  

PubMed

Painful oral mucositis is a common complication after bone marrow transplantation (BMT). Glutamine is a nutrient for rapidly dividing cells and the major energy source for intestinal epithelium. This study tested whether an oral glutamine preparation could decrease the severity of oral mucositis in patients undergoing BMT. Glutamine or a placebo (glycine) were administered from admission until day +28 in 193 BMT patients in a randomized, double-blind, placebo-controlled study at a dose of 1.0 g amino acid/m2/dose swish and swallow four times a day. In autologous BMT patients (n = 87) glutamine was associated with significantly less mouth pain by self report and by opiate use (5.0+/-6.2 days of morphine for glutamine vs 10.3+/-9.8 days for placebo; P= 0.005). Matched sibling BMT patients had no effect by self report and an increased duration of opiate use (23.2+/-5.7 days for glutamine vs 16.3+/-8.3 days for placebo) (P = 0.002). However, day 28 survival of allogeneic patients was improved by glutamine. No significant differences in TPN use, rate of relapse or progression of malignancy, parenteral antibiotic use, acute or chronic GVHD, or days of hospitalization were observed in either autologous or allogeneic recipients. No toxicity of glutamine was observed. We conclude that oral glutamine can decrease the severity and duration of oropharyngeal mucositis in autologous BMT patients but not in allogeneic BMT patients, possibly due to interaction with methotrexate. PMID:9722068

Anderson, P M; Ramsay, N K; Shu, X O; Rydholm, N; Rogosheske, J; Nicklow, R; Weisdorf, D J; Skubitz, K M

1998-08-01

145

Acute toxicity of various oral doses of dried Nerium oleander leaves in sheep.  

PubMed

The acute toxicity of dried Nerium oleander leaves to Najdi sheep is described in 12 sheep assigned as untreated controls, N. oleander-treated once at 1 and 0.25 g/kg body weight and N. oleander-treated daily at 0.06 g/kg body weight by drench. Single oral doses of 1 or 0.25 g of dried N. oleander leaves/kg body weight caused restlessness, chewing movements of the jaws, dyspnea, ruminal bloat, incoordination of movements, limb paresis, recumbency and death 4-24 hr after dosing. Lesions were widespread congestion or hemorrhage, pulmonary cyanosis and emphysema, hepatorenal fatty change and catarrhal abomasitis and enteritis. The daily oral doses of 0.06 g dried N. oleander leaves/kg body weight caused less severe signs and death occurred between days 3 and 14. In these animals, the main lesions were hepatonephropathy and gelatinization of the renal pelvis and mesentry and were accompanied by significant increases in serum AST and LDH activities, in bilirubin, cholesterol and urea concentrations and significant decreases in total protein and albumin levels, anemia and leucopenia. PMID:11789596

Ada, S E; Al-Yahya, M A; Al-Farhan, A H

2001-01-01

146

Disposition of Posaconazole following Single-Dose Oral Administration in Healthy Subjects  

PubMed Central

Posaconazole is a potent, broad-spectrum triazole antifungal agent currently in clinical development for the treatment of refractory invasive fungal infections. Eight healthy male subjects received a single 399-mg (81.7 ?Ci) oral dose of [14C]posaconazole after consuming a high-fat breakfast. Urine, feces, and blood samples were collected for up to 336 h postdose and assayed for total radioactivity; plasma and urine samples were also assayed for parent drug. Posaconazole was orally bioavailable, with a median maximum posaconazole concentration in plasma achieved by 10 h postdose. Thereafter, posaconazole was slowly eliminated, with a mean half-life of 20 h. The greatest peak in the radioactivity profile of pooled plasma extracts was due to posaconazole, with smaller peaks due to a monoglucuronide, a diglucuronide, and a smaller fragment of the molecule. The mean total amount of radioactivity recovered was 91.1%; the cumulative excretion of radioactivity in feces and in urine was 76.9 and 14.0% of the dose, respectively. Most of the fecal radioactivity was associated with posaconazole, which accounted for 66.3% of the administered dose; however, urine contained only trace amounts of unchanged posaconazole. The radioactivity profile of pooled urine extracts included two monoglucuronide conjugates and a diglucuronide conjugate of posaconazole. These observations suggest that oxidative (phase 1) metabolism by cytochrome P450 isoforms represents only a minor route of elimination for posaconazole, and therefore cytochrome P450-mediated drug interactions should have a limited potential to impact posaconazole pharmacokinetics.

Krieter, Philip; Flannery, Brian; Musick, Timothy; Gohdes, Mark; Martinho, Monika; Courtney, Rachel

2004-01-01

147

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

PubMed Central

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.

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

2012-01-01

148

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

PubMed

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. PMID:23382105

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

2013-04-01

149

Safety of fluralaner, a novel systemic antiparasitic drug, in MDR1(-/-) Collies after oral administration  

PubMed Central

Background Fluralaner is a novel systemic ectoparasiticide for dogs providing long-acting flea- and tick-control after a single oral dose. This study investigated the safety of oral administration of fluralaner at 3 times the highest expected clinical dose to Multi Drug Resistance Protein 1 (MDR1(-/-)) gene defect Collies. Methods Sixteen Collies homozygous for the MDR1 deletion mutation were included in the study. Eight Collies received fluralaner chewable tablets once at a dose of 168 mg/kg; eight sham dosed Collies served as controls. All Collies were clinically observed until 28 days following treatment. Results No adverse events were observed subsequent to fluralaner treatment of MDR1(-/-) Collies at three times the highest expected clinical dose. Conclusions Fluralaner chewable tablets are well tolerated in MDR1(-/-) Collies following oral administration.

2014-01-01

150

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

PubMed

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. PMID:22936336

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

2013-12-01

151

A randomised dose finding study of oral tacrolimus (FK506) therapy in refractory ulcerative colitis  

PubMed Central

Background and aims Immunosuppressive therapy with intravenous ciclosporin is an alternative treatment option to total colectomy for patients with ulcerative colitis (UC), while the benefits of oral administration of tacrolimus are not well defined and are based on reports of several uncontrolled studies. Methods Patients with refractory active UC were randomly assigned to a high trough concentration (10–15?ng/ml) group (HT group) (n?=?21), low trough concentration (5–10?ng/ml) group (LT group) (n?=?22), or placebo group (n?=?20). Patients received an initial oral dose of 0.05?mg/kg tacrolimus or placebo twice daily. Efficacy was evaluated in 60 patients based on a disease activity index (DAI) score. Fifty eight patients had additional treatment with tacrolimus and were evaluated for efficacy in a 10?week open label extension. Results An improvement in DAI score (?4?points, all categories improved) was observed for 68.4% of cases in the HT group compared with 10.0% in the placebo group (p<0.001). In the HT group, 20.0% of patients had clinical remission and 78.9% had mucosal healing. In the open label extension, 55.2% of all patients had an improved DAI score at week 10. Mean dose of prednisolone was reduced from 19.7?mg/day at study entry to 7.8?mg/day at week 10. The incidence of side effects in the HT group was significantly higher than that of the placebo group (p?=?0.043). The most common event was mild finger tremor. Conclusions Our findings demonstrate dose dependent efficacy and safety of oral tacrolimus for remission?induction therapy of refractory UC. The optimal target range appears to be 10–15?ng/ml in terms of efficacy with two week therapy.

Ogata, H; Matsui, T; Nakamura, M; Iida, M; Takazoe, M; Suzuki, Y; Hibi, T

2006-01-01

152

Pharmacokinetic and Pharmacodynamic Study of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir after Multiple Oral Dosing  

PubMed Central

In a dose-ranging study of amprenavir (formerly 141W94), an inhibitor of the protease enzyme of human immunodeficiency virus (HIV) type 1, single-dose and steady-state pharmacokinetic parameters were estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either a twice-daily (b.i.d.) or three-times-daily dosage schedule to 62 HIV-infected adults, 59 of whom had pharmacokinetic data. Log-log regression analysis (the power model) revealed that the steady-state area under the curve (AUCss) and the maximum, minimum, and average concentrations at steady state (Cmax,ss, Cmin,ss, and Cavg,ss, respectively) increased in a dose-proportional manner over the 300- to 1,200-mg dose range. Steady-state clearance was dose independent. AUCss/AUC0?? decreased linearly with dose and correlated significantly with treatment-associated decreases in ?1-acid glycoprotein. After 3 weeks, the dose of 1,200 mg b.i.d. provided a median amprenavir Cmin,ss (0.280 ?g/ml) that was higher than the median in vitro 50% inhibitory concentration for clinical HIV isolates (0.023 ?g/ml), even after adjustment for protein binding. The median amprenavir Cmin,ss was also greater than the estimated in vivo trough concentration calculated to yield 90% of the maximum antiviral effect (0.228 ?g/ml) over 4 weeks. A pharmacodynamic analysis of the relationship between steady-state pharmacokinetic parameters and safety revealed headache and oral numbness to be the only side effects significantly associated with Cmax. The pharmacodynamic relationship defined in this study supports the use of 1,200 mg b.i.d. as the approved dose of amprenavir.

Sadler, Brian M.; Gillotin, Catherine; Lou, Yu; Stein, Daniel S.

2001-01-01

153

Oral clonidine premedication reduces induction dose and prolongs awakening time from propofol-nitrous oxide anesthesia  

Microsoft Academic Search

Purpose  To evaluate whether oral clonidine premedication affects the induction dose of propofol and awakening time from epidural and\\u000a propofol anesthesia.\\u000a \\u000a \\u000a \\u000a Methods  Thirty-nine female patients (ASA I or II) were randomly allocated to receive 5 ?g · kg?1 clonidine po or no clonidine 90 min before induction of anesthesia. After epidural anesthesia was achieved with lidocaine,\\u000a general anesthesia was induced with continuous

Toru Goyagi; Makoto Tanaka; Toshiaki Nishikawa

1999-01-01

154

Single oral dose of epicillin combined with probenecid in the treatment of gonorrhoea.  

PubMed

Two hundred and sixty male patients with gonorrhoea, allocated to 4 unequal groups, were treated with one single oral dose of: (a) 2 g epicillin plus 1 g probenecid, (b) 2 g epicillin alone, (c) 1 g epicillin, 1 g cephradine plus 1 g probenecid, and (d) 1 g epicillin and 1 g cephradine. The last 3 groups acted as controls. Follow-up, with cultures of urethral discharge, was carried out over a 2-week period in all patients. The most satisfactory results were in the group of patients receiving epicillin plus probenecid, a 97% cure rate being achieved, with urethral discharge disappearing within 24 hours of treatment. PMID:7191790

Theodoridis, A; Marcollou-Kindi, O; Vagana, A; Sivenas, C; Capetanakis, J

1980-01-01

155

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

Microsoft Academic Search

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

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

156

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

Microsoft Academic Search

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

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

1998-01-01

157

Pharmacokinetics of oxiracetam in patients with renal impairment after a 800 mg single oral dose  

Microsoft Academic Search

Summary  The pharmacokinetics of oxiracetam in patients with renal impairment were investigated after administration of a 800 mg single\\u000a oral dose of oxiracetam. The renal insufficiency was estimated on the basis of the creatinine clearance (CLcr) which ranged\\u000a from 9 to 95 ml\\/min among the 20 patients.\\u000a \\u000a \\u000a In plasma, the terminal elimination half-life (T1\\/2) ranged from 10.6 to 68.1 h, the

J. B. Lecaillon; J. P. Dubois; H. Coppens; T. Darragon; G. Reumond; N. Pozet; J. Traeger; G. Lambrey

1990-01-01

158

Immunogenicity in Peruvian Volunteers of a Booster Dose of Oral Cholera Vaccine Consisting of Whole Cells Plus Recombinant B Subunit.  

National Technical Information Service (NTIS)

Forty-nine subjects received two doses of oral cholera vaccine consisting of whole cells plus recombinant F B subunit; this was followed by a booster dose one year later. After the primary series, a significant F (greater than twofold) increase in the lev...

R. E. Begue G. Castellares C. Cabezas J. L. Sanchez R. Meza

1995-01-01

159

Acute and 4-week repeated-dose oral toxicity studies of Cirsium setidens in rats.  

PubMed

Cirsium setidens is a wild perennial plant species found in Korea that may have anti-oxidative, anti-adipogenic, and hepatoprotective activities. However, details of the toxicology of C. setidens remain unknown. This study was performed to evaluate the toxicological effects of an acute administration and 4-week repeated dosing of a C. setidens extract in Sprague-Dawley rats to ensure the safe use of this extract. C. setidens (1250, 2500, and 5000 mg/kg body weight/day) did not induce significant toxicological changes in groups matched by gender with respect to mortality, clinical signs, body weight, urinalysis, ophthalmoscopy, necropsy findings, hematology, and histopathology. Therefore, this study demonstrates that acute administration and 4-week repeated dosing of C. setidens extract orally using this administration protocol is safe. PMID:24886940

Lee, Jong Seok; Kim, Young-Hyun; Kim, Dan-Bi; Bang, Woo-Suk; Lee, Ok-Hwan

2014-01-01

160

Efficacy of a Single Oral Dose of Oxfendazole against Fasciola hepatica in Naturally Infected Sheep  

PubMed Central

The efficacy of a single oral dose of 30 mg/kg of oxfendazole against Fasciola hepatica was evaluated in a controlled study in naturally infected sheep. Sheep were diagnosed by stool microscopy after sedimentation, and positive animals were randomized to oxfendazole (N = 20) or no treatment (N = 20). A new stool exam was performed 10 days after treatment. All stool microscopies were performed masked to the treatment group. No side effects were noticed. All sheep in the control group remained infected with similar counts of eggs per gram of stools. None of the animals in the treatment group showed Fasciola eggs in stools after 10 days of treatment. A single dose of oxfendazole is highly effective against F. hepatica, providing a new drug alternative for the control of fascioliasis or integrated zoonosis control.

Gomez-Puerta, Luis A.; Gavidia, Cesar; Lopez-Urbina, Maria T.; Garcia, Hector H.; Gonzalez, Armando E.

2012-01-01

161

Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: A dose escalation and pharmacologic study1  

PubMed Central

We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 ?M were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme–inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.

Phuphanich, Surasak; Baker, Sharyn D.; Grossman, Stuart A.; Carson, Kathryn A.; Gilbert, Mark R.; Fisher, Joy D.; Carducci, Michael A.

2005-01-01

162

The Dose Effects of Short-Term Dronabinol (Oral THC) Maintenance in Daily Cannabis Users  

PubMed Central

BACKGROUND Prior studies have separately examined the effects of dronabinol (oral THC) on cannabis withdrawal, cognitive performance, and the acute effects of smoked cannabis. A single study examining these clinically relevant domains would benefit the continued evaluation of dronabinol as a potential medication for the treatment of cannabis use disorders. METHODS Thirteen daily cannabis smokers completed a within-subject crossover study and received 0, 30, 60 and 120 mg dronabinol per day for 5 consecutive days. Vital signs and subjective ratings of cannabis withdrawal, craving and sleep were obtained daily; outcomes under active dose conditions were compared to those obtained under placebo dosing. On the 5th day of medication maintenance, participants completed a comprehensive cognitive performance battery and then smoked 5 puffs of cannabis for subjective effects evaluation. Each dronabinol maintenance period occurred in a counterbalanced order and was separated by 9 days of ad-libitum cannabis use. RESULTS Dronabinol dose-dependently attenuated cannabis withdrawal and resulted in few adverse side effects or decrements in cognitive performance. Surprisingly, dronabinol did not alter the subjective effects of smoked cannabis, but cannabis-induced increases in heart rate were attenuated by the 60 and 120 mg doses. CONCLUSIONS Dronabinol’s ability to dose-dependently suppress cannabis withdrawal may be therapeutically beneficial to individuals trying to stop cannabis use. The absence of gross cognitive impairment or side effects in this study supports safety of doses up to 120mg per day. Continued evaluation of dronabinol in targeted clinical studies of cannabis treatment, using an expanded range of doses, is warranted.

Vandrey, Ryan; Stitzer, Maxine L.; Mintzer, Miriam Z.; Huestis, Marilyn A.; Murray, Jeannie A.; Lee, Dayong

2012-01-01

163

REGULATION OF OPERANT ORAL ETHANOL SELF-ADMINISTRATION: A DOSE-RESPONSE CURVE STUDY IN RATS  

PubMed Central

Background Oral ethanol self-administration procedures in rats are useful pre-clinical tools for the evaluation of potential new pharmacotherapies as well as for the investigation of the etiology of alcohol abuse disorders and addiction. Determination of the effects of a potential treatment on a full ethanol dose-response curve should be essential to predict its clinical efficacy. Unfortunately, this approach has not been fully explored due to the aversive taste reaction to moderate to high doses of ethanol, which may interfere with consumption. In the present study, we set out to determine whether a meaningful dose-response curve for oral ethanol self-administration can be obtained in rats. Methods Long-Evans rats were trained to self-administer a 20% ethanol solution in an operant procedure following a history of excessive voluntary ethanol intake. After stabilization of ethanol self-administration the concentration of the solution was varied from 2.5 to 60% (v/v) and operant and drinking behaviors as well as blood ethanol concentration (BEC) were evaluated following the self-administration of a 20, 40 and 60% ethanol solution. Results Varying the concentration of ethanol from 2.5% to 60% after development of excessive ethanol consumption led to a typical inverted U-shape dose-response curve. Importantly, rats adapted their level and pattern of responding to changes in ethanol concentration to obtain a constant level of intake and BEC, suggesting that their operant behavior is mainly driven by the motivation to obtain a specific pharmacological effect of ethanol. Conclusion This procedure can be a useful and straightforward tool for the evaluation of the effects of new potential pharmacotherapies for the treatment of alcohol abuse disorders.

Carnicella, Sebastien; Yowell, Quinn V.; Ron, Dorit

2010-01-01

164

Bovine spongiform encephalopathy: the effect of oral exposure dose on attack rate and incubation period in cattle - an update  

PubMed Central

Background To provide information on dose–response and aid in modelling the exposure dynamics of the BSE epidemic in the United Kingdom groups of cattle were exposed orally to a range of different doses of brainstem homogenate of known infectious titre from clinical cases of classical bovine spongiform encephalopathy (BSE). Interim data from this study was published in 2007. This communication documents additional BSE cases, which occurred subsequently, examines possible influence of the bovine prion protein gene on disease incidence and revises estimates of effective oral exposure. Findings Following interim published results, two further cattle, one dosed with 100 mg and culled at 127 months post exposure and the other dosed with 10 mg and culled at 110 months post exposure, developed BSE. Both had a similar pathological phenotype to previous cases. Based on attack rate and incubation period distribution according to dose, the dose estimate at which 50% of confirmed cases would be clinically affected was revised to 0.15 g of the brain homogenate used in the experiment, with a 95% confidence interval of 0.03–0.79 g. Neither the full open reading frame nor the promoter region of the prion protein gene of dosed cattle appeared to influence susceptibility to BSE, but this may be due to the sample size. Conclusions Oral exposure of cattle to a large range of doses of a BSE brainstem homogenate produced disease in all dose groups. The pathological presentation resembled natural disease. The attack rate and incubation period were dependent on the dose.

2012-01-01

165

Pharmacokinetics of fleroxacin after multiple oral dosing in patients receiving regular hemodialysis.  

PubMed Central

The pharmacokinetic profile of fleroxacin was studied in eight noninfected patients receiving regular hemodialysis (four women and four men; mean age, 63 years; age range, 48 to 73 years). Dialysis clearances (mean +/- standard deviation) calculated from the amount of drug recovered in the dialysate exceeded those calculated from rates of extraction from plasma for fleroxacin (126 +/- 29 versus 73 +/- 11 ml/min) and its metabolite N-demethylfleroxacin (103 +/- 31 versus 72 +/- 15 ml/min) but not that for the metabolite fleroxacin N-oxide (100 +/- 25 versus 100 +/- 12 ml/min). Data were fitted to a two-compartment model over the total observation period of 8 days (six oral daily doses of 200 mg of fleroxacin on days 1 to 6 and hemodialysis treatments on day 1,3, and 6) by nonlinear mixed-effects modeling. The random variability of plasma fleroxacin concentrations was 13% about its prediction. The estimated metabolic clearance was 25 ml/min (coefficient of variation, 43%), and the calculated steady-state volume of distribution was 84 liters (coefficient of variation, 16%). The model was expanded for the two major metabolites by the addition of a two-compartment metabolite distribution. Formation clearances of N-demethylfleroxacin and fleroxacin N-oxide were estimated to be 54 and 33% of fleroxacin's metabolic clearance, respectively. The conclusions were as follows. Because of the slow metabolic clearance and intermittent dialysis treatment, steady-state conditions were not reached after 1 week of oral fleroxacin therapy, and there was relevant accumulation of fleroxacin as well as that of fleroxacin N-oxide in our patients with end-stage renal disease. We recommend that infected hemodialysis patients be treated with an initial oral dose of 400 mg of fleroxacin and then daily oral doses of 200 mg. One cannot recommend the treatment of this patient population with fleroxacin over prolonged time periods until more date about the levels of accumulation of fleroxacin and its metabolites in infected patients with renal disease are available.

Uehlinger, D E; Schaedeli, F; Kinzig, M; Sorgel, F; Frey, F J

1996-01-01

166

MRI enterography with divided dose oral preparation: Effect on bowel distension and diagnostic quality  

PubMed Central

Aim: To assess the impact of an extended oral preparation magnetic resonance (MR) enterography protocol on bowel distension, timing of imaging, and the quality of diagnostic images. Materials and Methods: An analysis of 52 patients who underwent divided oral preparation and 39 patients who underwent standard preparation for MR enterography examination was done. Distension was assessed by measuring the transverse diameters of the jejunum, ileum, and the ileocecal region. Diagnostic quality of the examination was assessed subjectively by two radiologists and graded as poor, diagnostic, and excellent (Grades 1-3). Correlation between bowel diameter and diagnostic quality was assessed using regression analysis. Results: The mean diameters of the jejunum, ileum, and colon in patients who underwent divided preparation were 1.90 ± 0.47, 2.14 ± 0.41, and 4.27 ± 0.96 cm, respectively, and the mean diameters in patients who underwent standard preparation were 1.46 ± 0.47, 2.02 ± 0.47, and 4.45 ± 0.90 cm, respectively. A total of 96.6% of patients on divided dose had diagnostic distension of the bowel (Grades 2 and 3). A total of 87.9% of the patients on standard dose had diagnostic distension of the bowel (Grades 2 and 3). A greater number of patients who underwent divided preparation had diagnostic quality examinations compared to those given standard preparation (96.6% vs. 87.9%). A greater number of patients who underwent divided preparation had Grade 3 quality examinations compared to those on standard preparation (75.5% vs. 68.5%). There was significant difference between diagnostic (Grades 2 and 3) and optimal grades (Grade 3) of the jejunal diameters in patients having divided or standard preparation (89.7% vs. 66.6%, P < 0.05; 40.8% vs. 25%, P < 0.05, respectively). Linear regression showed a positive correlation between increasing bowel diameter and diagnostic grade of the examination (? = 0.76). Conclusion: Using an extended oral preparation with divided dose resulted in the majority of patients being scanned in a single visit to the MRI suite. Dividing the oral contrast into aliquots can promote uniform distension of the entire small bowel and provide better bowel distension and improve the diagnostic quality.

Sinha, Rakesh; Rawat, Sudarshan

2013-01-01

167

Population pharmacokinetics of oral high-dose busulfan in adult patients undergoing hematopoietic stem cell transplantation  

PubMed Central

Background and the purpose of the study Many factors have been reported that contribute to the wide intra- and inter-patient variability of Busulfan (Bu) disposition. The purpose of this study was to develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics (PK) of Bu in Iranian adult patients who received oral high-dose as a conditioning regimen before Hematopoietic Stem Cell Transplantation (HSCT). Methods A population PK analysis was performed in 30 patients who received an oral Bu and cyclophosphamide regimen before HSCT. Bu was given orally according to the protocol of the institution. In order to prevent seizures caused by Bu, phenytoin was administered orally one hour before each dose of Bu.A total of 180 blood samples were analyzed by HPLC and PK parameters were estimated by the non-linear mixed effect model by MONOLIX 3.1 program. A one-compartment model with an additive error model was used to describe the concentration-time profile of Bu. Results Patients’ disease and weight was found to be the determinant factors for clearance (CL) and the volume of distribution (Vd) according to Monolix analysis. The covariate entered in final model followed by these equations:CL=13.4[1+(0.141×Disease)], Vd=42.6[1+0.010×(Weight-63.9)] In this limited study, the age (15–43 years) had no significant effect. For a patient weighting 60 kg, the typical CL and Vd were estimated to be 13.4 l/hr and 42.6 L, respectively. The interindividual variability of CL and Vd were 13.6 and 6.3%, respectively. There was no significant metabolic induction in these four days as is evident by comparing the trough levels of Bu. However it should be mentioned that, one tailed t-test p-values of the days of two and three, two and four and three and four were 0.083, 0.069 and 0.388, respectively. Major conclusions Results of this study showed that the type of disease was a determinant of CL and the weight of patient was a determinant of Vd for Bu population PK parameters. A reliable PK parameters and Css, estimated from only one plasma concentrations (5 hrs after the first dose), were validated. Since these methods require few sampling and are easy to be used, the limited sampling methods might be advantageous in the routine clinical practice.

Hadjibabaie, M.; Rahimian, S.; Jahangard-Rafsanjani, Z.; Amini, M.; Alimoghaddam, K.; Iravani, M.; Ghavamzadeh, A.

2011-01-01

168

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

PubMed Central

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

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

2006-01-01

169

Dose-response toxicity studies on tributoxyethyl phosphate orally administered to Sprague-Dawley rats  

SciTech Connect

The response of the peripheral nervous system to various dose levels of tributoxyethyl phosphate (TBOP) was investigated in Sprague-Dawley rats. Groups of randomized female and male rats (10 rats/gender/dose level) were administered a single oral dose of TBOP (1.0 to 3.2 g/kg for females;1.0 to 9.0 g/kg for males). Physiological parameters were measured in surviving rats three weeks following TBOP administration. A significant reduction (p<0.05) in caudal nerve conduction velocity (NCV) was observed in both female and male rats. Light and electron microscopic examination of sciatic nerve sections showed degenerative changes in both myelinated and unmyelinated fibers of female (2.0 g/kg) and male (6.8 g/kg) groups. Advanced degeneration was observed only in the highest dose level of both genders (3.2 g/kg for females; 8.0 and 9.0 g/kg for males). Although similar morphological changes were observed in both genders, females were more susceptible than males to the toxic effects of this compound.

Laham, S.; Szabo, J.; Long, G.; Schrader, K.

1985-08-01

170

Multiple-Dose Pharmacokinetics and Tolerability of Gemifloxacin Administered Orally to Healthy Volunteers  

PubMed Central

Gemifloxacin mesylate (SB-265805-S, LB-20304a) is a potent, novel fluoroquinolone agent with a broad spectrum of antibacterial activity. The pharmacokinetics and tolerability of oral gemifloxacin were characterized in two parallel group studies in healthy male volunteers after doses of 160, 320, 480, and 640 mg once daily for 7 days. Multiple serum or plasma and urine samples were collected on days 1 and 7 and were analyzed for gemifloxacin by high-performance liquid chromatography (HPLC)–fluorescence (study 1) or HPLC-mass spectrometry (study 2). Safety assessments included vital signs, 12-lead electrocardiogram (ECG) readings, hematology, clinical chemistry, urinalysis, and adverse experience monitoring. Gemifloxacin was rapidly absorbed, with a time to maximum concentration of approximately 1 h after dosing followed by a biexponential decline in concentration. Generally, maximum concentration and area under the concentration-time curve (AUC) increased linearly with dose after either single or repeat doses. Mean ± standard deviation values of AUC0–? on day 7 were 4.92 ± 1.08, 9.06 ± 2.20, 12.2 ± 3.69, and 20.1 ± 3.67 ?g·h/ml following 160-, 320-, 480-, and 640-mg doses, respectively. The terminal-phase half-life was approximately 7 to 8 h, independent of dose, and was similar following single and repeated administrations. There was minimal accumulation of gemifloxacin after multiple dosing. Approximately 20 to 30% of the administered dose was excreted unchanged in the urine. The renal clearance was 160 ml/min on average after single and multiple doses, which was slightly greater than the accepted glomerular filtration rate (approximately 120 ml/min). These data show that the pharmacokinetics of gemifloxacin are linear and independent of dose. Gemifloxacin was generally well tolerated, although one subject was withdrawn from the study after 6 days at 640 mg for mild, transient elevations of alanine aminotransferase and aspartate aminotransferase not associated with any clinical signs or symptoms. There were no other significant changes in clinical chemistry, hematology or urinalysis parameters, vital signs, or ECG readings. In conclusion, the results of these studies, combined with the antibacterial spectrum and potency, support the further investigation of once-daily administration of gemifloxacin for indications such as respiratory tract and urinary tract infections.

Allen, Ann; Bygate, Elizabeth; Vousden, Marika; Oliver, Stuart; Johnson, Martin; Ward, Christopher; Cheon, Ae-Jin; Choo, Youn Sung; Kim, In-Chull

2001-01-01

171

A Randomised Trial Evaluating the Safety and Immunogenicity of the Novel Single Oral Dose Typhoid Vaccine M01ZH09 in Healthy Vietnamese Children  

PubMed Central

Background The emergence of drug resistant typhoid fever is a major public health problem, especially in Asia. An oral single dose typhoid vaccine would have major advantages. M01ZH09 is a live oral single dose candidate typhoid vaccine containing Salmonella enterica serovar Typhi (Ty2 aroC? ssaV?) ZH9 with two independently attenuating deletions. Studies in healthy adults demonstrated immunogenicity and an acceptable safety profile. Objectives We conducted a randomised placebo controlled, single-blind trial to evaluate the safety and immunogenicity of M01ZH09 in healthy Vietnamese children aged 5 to 14 years. Methods Subjects were randomly assigned to receive either a nominal dose of 5×109 CFU of M01ZH09 or placebo and were followed up for 28 days. The primary safety outcome was the proportion of subjects with any adverse event attributed to M01ZH09. The primary immunogenicity endpoint was the proportion of subjects who showed a positive immune response to M01ZH09 in the Salmonella Typhi lipopolysaccharide (LPS) specific serum IgA and IgG ELISA. Principal Findings One hundred and fifty-one children were enrolled, 101 subjects received M01ZH09 and 50 subjects received placebo. An intention to treat analysis was conducted. There were no serious adverse events and no bacteraemias. In the M01ZH09 group, 26 (26%; 95% CI, 18–5%) of 101 subjects experienced adverse events compared to 11 (22%; 95% CI, 12–36%) of 50 subjects in the placebo group (odds ratio (OR) [95%CI] ?=?1.23 [0.550–2.747]; p?=?0.691). Faecal shedding of S. Typhi (Ty2 aroC? ssaV?) ZH9 was detected in 51 (51%; 95% CI, 41–61%) of 100 M01ZH09 subjects. No shedding was detected beyond day 3. A positive immune response, defined as 70% increase (1.7 fold change) in LPS specific serum IgG (day 14 or 28) and/or 50% increase (1.5 fold change) in LPS specific serum IgA (day 7 or 14) from baseline was detected in 98 (97%; 95% CI, 92–99%) of 101 M01ZH09 recipients and 8 (16%; 95% CI, 7–29%) of 50 placebo recipients. Twenty-eight (100%; 95% CI, 88–100%) of 28 vaccine recipients who were evaluated in the LPS specific IgA ELISPOT assay showed a positive response compared to none of the 14 placebo recipients tested. Conclusions This was the first phase II trial of a novel oral candidate typhoid vaccine in children in an endemic country. M01ZH09 had an appropriate safety profile and was immunogenic in children. Trial Registration Controlled-trials.comISRCTN91111837

Hien, Tran Tinh; Dung, Nguyen Thi; Truong, Nguyen Thanh; Van, Ninh Thi Thanh; Bich Chau, Tran Nguyen; Hoang, Nguyen Van Minh; Nga, Tran Thi Thu; Thuy, Cao Thu; Minh, Pham Van; Binh, Nguyen Thi Cam; Ha, Tran Thi Diem; Toi, Pham Van; Song Diep, To; Campbell, James I.; Stockwell, Elaine; Schultsz, Constance; Simmons, Cameron P.; Glover, Clare; Lam, Winnie; Marques, Filipe; May, James P.; Upton, Anthony; Budhram, Ronald; Dougan, Gordon; Farrar, Jeremy; Vinh Chau, Nguyen Van; Dolecek, Christiane

2010-01-01

172

Multiple-dose pharmacokinetics and safety of oral amifloxacin in healthy volunteers.  

PubMed

The multiple-dose pharmacokinetics and safety of amifloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy male volunteers. Amifloxacin was administered orally at 200, 400, or 600 mg every 12 h (q12h) and 400, 600, or 800 mg every 8 h (q8h) for 10 days. An additional dose was administered on day 11. Concentrations of amifloxacin in plasma and urine were measured on days 1, 5, and 11 by high-performance liquid chromatography. Steady-state amifloxacin concentrations were reached by day 5. Mean +/- standard deviation maximum observed amifloxacin concentrations in plasma were 2.52 +/- 1.12, 4.98 +/- 1.44, 5.40 +/- 2.02, 4.59 +/- 2.17, 6.53 +/- 2.44, and 8.01 +/- 3.00 micrograms/ml after the initial dose and 2.30 +/- 0.98, 5.41 +/- 0.74, 8.05 +/- 1.68, 6.87 +/- 2.81, 9.53 +/- 0.50, and 11.9 +/- 1.92 micrograms/ml on day 11 of the study for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. Amifloxacin was rapidly absorbed, as evidenced by the mean time to the maximum observed amifloxacin concentration of 0.98 h. Mean values for the terminal amifloxacin half-life in plasma ranged from 3.58 to 5.78 h. Mean amifloxacin concentrations in urine on day 11 in samples collected 0 to 2 h after dosing were 105, 417, 376, 336, 518, and 464 micrograms/ml for the 200-, 400-, and 600-mg q12h and 400-, 600-, and 800-mg q8h regimens, respectively. The mean amount of the dose excreted in the urine as amifloxacin was 53.9%. Amifloxacin was generally well tolerated, although there was a tendency for the subjects who received amifloxacin to experience more gastrointestinal, central nervous system, and cutaneous complaints than did those who received placebo. Clinically significant adverse reactions, including pruritus and transaminase elevations, occurred only at doses of 1,200 mg/day or above. Clinical and pharmacokinetic data suggest that orally administered amifloxacin may have utility in the treatment of urinary tract infections. PMID:2393295

Cook, J A; Silverman, M H; Schelling, D J; Nix, D E; Schentag, J J; Brown, R R; Stroshane, R M

1990-06-01

173

Single oral dose toxicity study of prebrewed armeniacae semen in rats.  

PubMed

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

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

2013-06-01

174

Single Oral Dose Toxicity Study of Prebrewed Armeniacae Semen in Rats  

PubMed Central

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

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

2013-01-01

175

Enhanced antithrombotic effects of unfractionated heparin in rats after repeated oral doses and its relationship to endothelial heparin concentration  

PubMed Central

Background and purpose: An oral, single dose of 7.5?mg?kg?1 of unfractionated heparin (UFH) reduces thrombosis by 50% in a rat model of venous thrombosis. As long-term use is required clinically, our objectives were to study the antithrombotic effects following repeated oral UFH administration. Experimental approach: Bovine lung UFH was administered by oral gavage to rats in 3 doses of 7.5?mg?kg?1 each 12, 24, 48, and 72?h apart; and in 3 or 15 doses of 1?mg?kg?1 every 48?h. The last dose was given immediately after thrombus initiation where 10% formalin in methanol was applied to the jugular vein. The vessel was examined for thrombosis 4?h later. Amounts of heparin in tissue and endothelium, and plasma anticoagulant activity were measured. Key results: When 3 × 7.5?mg?kg?1 heparin was given, thrombotic incidence was most reduced at 48?h dose-intervals and was significantly less than single dose treatment. There was a negative correlation between endothelial heparin content and thrombotic incidence, but not anticoagulant activity. When 3 doses of 1?mg?kg?1 every 48?h were given, thrombotic incidence was similar to single dose treatment. When 15 doses were given, total thrombotic incidence was less than for 3 doses and was similar to that after s.c. administration. Conclusions and implications: Antithrombotic activity increased with repeated doses of oral UFH, with antithrombotic effects similar to s.c. administration. Antithrombotic activity was related to heparin on endothelium.

Hiebert, L M; Ping, T; Wice, S M

2008-01-01

176

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

PubMed Central

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.

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

2012-01-01

177

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

PubMed

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

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

2012-01-01

178

Oral administration of a low dose of midazolam (75 µg) as an in vivo probe for CYP3A activity  

Microsoft Academic Search

Objective We investigated whether the oral administration of a low dose (75 µg) of midazolam, a CYP3A probe, can be used to measure the in vivo CYP3A activity. Methods Plasma concentrations of midazolam, 1'OH-midazolam and 4'OH-midazolam were measured after the oral administration of 7.5 mg and 75 µg midazolam in 13 healthy subjects without medication, in four subjects pretreated for 2 days with ketoconazole

Chin B. Eap; Thierry Buclin; Gianni Cucchia; Daniele Zullino; Elisabeth Hustert; Gabriela Bleiber; Kerry Powell Golay; Anne-Catherine Aubert; Pierre Baumann; Amalio Telenti; Reinhold Kerb

2004-01-01

179

Effect of high-dose oral rabeprazole on recurrent bleeding after endoscopic treatment of bleeding peptic ulcers.  

PubMed

Background. The aim of this study was to compare the effect of high-dose oral rabeprazole versus high-dose IV PPI on rebleeding after endoscopic treatment of bleeding peptic ulcers. Methods. This was a two-center, prospective, randomized, controlled trial. Patients with a high-risk bleeding peptic ulcer had endoscopic hemostasis and were randomly assigned to the high-dose oral rabeprazole group (20?mg twice daily for 72 hours) or the high-dose IV omeprazole group (80?mg as a bolus injection followed by continuous infusion at 8?mg/h for 72 hours). Results. The study was stopped because of slow enrollment (total n = 106). The rebleeding rates within 3 days were 3.7% (2 of 54 patients) given oral rabeprazole and 1.9% (1 of 52 patients) given IV omeprazole (P = 1.000). The rebleeding rates after 3 days were 1.9% and 0% (P = 1.000), respectively. The surgical intervention rates were 3.7% and 0% (P = 0.495), and the mortality rates were 1.9% and 0% (P = 1.000), respectively. Conclusions. The effect of high-dose oral rabeprazole did not differ significantly from that of high-dose IV omeprazole on rebleeding, surgical intervention, or mortality after endoscopic treatment of bleeding peptic ulcers, but this requires further evaluation. PMID:23049546

Kim, Hyung-Keun; Kim, Jin-Soo; Kim, Tae-Ho; Kim, Chang-Whan; Cho, Young-Seok; Kim, Sung-Soo; Chae, Hiun-Suk; Han, Sok-Won; Park, Yong-Wan; Son, Hye-Suk; Min, Jeong-Yo; Cho, Guen-Jong; Bag, Jung-Sun; Choi, Son-Ook

2012-01-01

180

Effect of High-Dose Oral Rabeprazole on Recurrent Bleeding after Endoscopic Treatment of Bleeding Peptic Ulcers  

PubMed Central

Background. The aim of this study was to compare the effect of high-dose oral rabeprazole versus high-dose IV PPI on rebleeding after endoscopic treatment of bleeding peptic ulcers. Methods. This was a two-center, prospective, randomized, controlled trial. Patients with a high-risk bleeding peptic ulcer had endoscopic hemostasis and were randomly assigned to the high-dose oral rabeprazole group (20?mg twice daily for 72 hours) or the high-dose IV omeprazole group (80?mg as a bolus injection followed by continuous infusion at 8?mg/h for 72 hours). Results. The study was stopped because of slow enrollment (total n = 106). The rebleeding rates within 3 days were 3.7% (2 of 54 patients) given oral rabeprazole and 1.9% (1 of 52 patients) given IV omeprazole (P = 1.000). The rebleeding rates after 3 days were 1.9% and 0% (P = 1.000), respectively. The surgical intervention rates were 3.7% and 0% (P = 0.495), and the mortality rates were 1.9% and 0% (P = 1.000), respectively. Conclusions. The effect of high-dose oral rabeprazole did not differ significantly from that of high-dose IV omeprazole on rebleeding, surgical intervention, or mortality after endoscopic treatment of bleeding peptic ulcers, but this requires further evaluation.

Kim, Hyung-Keun; Kim, Jin-Soo; Kim, Tae-Ho; Kim, Chang-Whan; Cho, Young-Seok; Kim, Sung-Soo; Chae, Hiun-Suk; Han, Sok-Won; Park, Yong-Wan; Son, Hye-Suk; Min, Jeong-Yo; Cho, Guen-Jong; Bag, Jung-Sun; Choi, Son-Ook

2012-01-01

181

Oral Tolerance in Myelin Basic Protein T-Cell Receptor Transgenic Mice: Suppression of Autoimmune Encephalomyelitis and Dose-Dependent Induction of Regulatory Cells  

Microsoft Academic Search

Orally administered antigens induce a state of immunologic hyporesponsiveness termed oral tolerance. Different mechanisms are involved in mediating oral tolerance depending on the dose fed. Low doses of antigen generate cytokine-secreting regulatory cells, whereas high doses induce anergy or deletion. We used mice transgenic for a T-cell receptor (TCR) derived from an encephalitogenic T-cell clone specific for the acetylated N-terminal

Youhai Chen; Jun-Ichi Inobe; Vijay K. Kuchroo; Jody L. Baron; Charles A. Janeway; Howard L. Weiner

1996-01-01

182

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

PubMed

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

Komiya, Akira; Shimbo, Masaki; Suzuki, Hiroyoshi; Imamoto, Takashi; Kato, Tomonori; Fukasawa, Satoshi; Kamiya, Naoto; Naya, Yukio; Mori, Ikuo; Ichikawa, Tomohiko

2010-01-01

183

Neurotoxicity in lymphoblastic leukaemia: comparison of oral and intramuscular methotrexate and two doses of radiation.  

PubMed Central

Serial cranial computed tomograms were carried out in 136 children with acute lymphoblastic leukaemia who were receiving 24 Gy or 18 Gy of cranial irradiation and continuing treatment with doses of methotrexate given weekly orally or intramuscularly. The findings were correlated with treatment variables, the development of fits, and the intelligence quotient (IQ). Reversible brain shrinkage, attributed to treatment with steroids, was found on 87 of 114 initial scans (76%); 14 showed changes in white matter during treatment (10%), and calcification was found in 13 either during or after treatment (10%). Eight children (6%) had fits, and in six of the eight there were changes in white matter or calcification on the scans. Comparison of the two radiotherapy dosages showed no difference in the incidence of abnormalities seen on computed tomography, fits, or serial IQ measurements, but children receiving intramuscular methotrexate had a higher incidence of calcification and a lower mean IQ at one year than those who received the drug orally, although this difference was not apparent later. Younger children were more likely to develop changes on computed tomograms and fits, and to have low IQs on completion of treatment, with changes most apparent in those less than 2 years of age. There were highly significant correlations between abnormalities on computed tomography, fits, and IQ. These findings confirm the neurological vulnerability of younger children with acute lymphoblastic leukaemia, show an association between abnormalities on computed tomography and intellectual deficit, and suggest that methotrexate is more toxic when given intramuscularly than orally. They provide no evidence that 18 Gy of cranial irradiation is less toxic than 24 Gy, and indicate the need for alternative treatment regimens.

Chessells, J M; Cox, T C; Kendall, B; Cavanagh, N P; Jannoun, L; Richards, S

1990-01-01

184

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

SciTech Connect

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.

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

2009-03-01

185

In vitro inhibition of HUVECs by low dose methotrexate - insights into oral adverse events  

PubMed Central

Background With socio-economic changes, dentists and maxillofacial surgeons are more and more faced with medically compromised patients. Especially, the admission of antirheumatic drugs has increased remarkably. So dentists and maxillofacial surgeons should be aware of related adverse reactions that affect the craniofacial region. To identify possible cellular effects of disease modifying antirheumatic drugs (DMARDs) we investigated the influence of methotrexate (MTX) on human umbilical vein endothelial cells (HUVECs). Methods HUVECs were incubated with various concentrations of MTX, corresponding to serum concentrations found in rheumatoid arthritis (RA) patients. The effect of MTX on cell proliferation, differentiation as well as mitochondrial activity was measured by use of immunostaining, cell counting and 3-(4, 5-dimethylthiazol-2-yl)- 2, 5-diphenyltetrazolium bromide (MTT) assay. Results All samples incubated with MTX (1-1000 nM) showed significantly decreased cell viability when compared to controls. Cells were less proliferating, but did not lose their ability to synthesize endothelial proteins. A slight dose dependency of inhibiting effects was demonstrated. The observed differences between control and sample groups were rising with longer duration. Conclusion Because of the crucial role of endothelial cells and their precursor cells in wound healing, a negative influence of MTX on oral health has to be supposed, correlating to clinical observations of adverse reactions in the oral cavity, such as ulcerative or erosive lesions.

2014-01-01

186

Pharmacokinetics of single-dose oral ciprofloxacin in infants and small children.  

PubMed Central

The pharmacokinetics of orally administered ciprofloxacin (CIP) was studied in seven infants aged 5 to 14 weeks and nine children aged 1 to 5 years, most of whom were Salmonella carriers. In each case, 15 mg of CIP per kg of body weight was given with water on an empty stomach, and timed serum samples were taken during the following 12 h. The elimination half-life of CIP was significantly (P less than 0.001) longer in the infants (2.73 +/- 0.28 h; mean +/- standard deviation) than it was in the children (1.28 +/- 0.52 h). The area under the serum CIP concentration-time curve (AUC) from time zero to infinity was 16.1 +/- 7.4 mg.h.liter-1 among the infants and 5.3 +/- 3.3 mg.h.liter-1 in the children (P less than 0.01). No significant differences in the maximum concentration in serum, time to maximum concentration in serum, or absorption half-life were observed between the two groups. In contrast, the mean residence time was twofold longer in the infants (4.6 h) than it was in the children (2.4 h; P less than 0.001). The findings suggest that elimination of CIP is particularly rapid in children who just have passed infancy; they may require doses at shorter time intervals than those required by infants or older children or adults. In general, an oral dose of 10 to 15 mg of CIP per kg three times daily seems appropriate for children aged 1 to 5 years.

Peltola, H; Vaarala, M; Renkonen, O V; Neuvonen, P J

1992-01-01

187

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

PubMed Central

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

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

2014-01-01

188

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

PubMed

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) PMID:8533282

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

1995-10-01

189

Comparing the effects of low-dose contraceptive pills to control dysfunctional uterine bleeding by oral and vaginal methods  

PubMed Central

Background and Objective : Contraceptive pills are generally taken orally and can cause side effects such as nausea, vomiting and hypertension. The vaginal use of these pills can reduce such complications. Our objective was to compare the efficacy and side effects of low dose contraceptive pills by oral and vaginal route in the management of dysfunctional uterine bleeding-(DUB) Methods: This comparative observational study was conducted at Beheshti and Alzahra (SA) teaching hospitals, affiliated to Isfahan University of Medical Sciences in 2010-2011. One hundred women who presented with DUB were randomly assigned into two groups of equal number, receiving the low dose oral contraceptive pills by oral or vaginal route for three month. The amount and duration of bleeding were compared at the beginning and at the end of the study and side effects by these two methods compared. Results: The results of this study showed that both oral and vaginal routes effectively reduced the duration and amount of bleeding due to DUB after three courses of treatment. This effect was better in the vaginal method compared with oral administration (P = 0.03). Regarding the side effects, nausea and vomiting were significantly higher in the oral group than in the vaginal group (P = 0.03). Vulvovaginitis infection was more frequent in the vaginal group than in the oral group (P = 0.03). Conclusion: Low dose contraceptive pills are effective in reducing the amount, time, and duration of bleeding in patients with DUB. In addition, reduction of gastrointestinal side effects by vaginal route helps to use these pills by the patient with proper training of physicians, midwives and patients.

Mehrabian, Ferdous; Abbassi, Fariba

2013-01-01

190

Comparing the effects of low-dose contraceptive pills to control dysfunctional uterine bleeding by oral and vaginal methods.  

PubMed

Background and Objective : Contraceptive pills are generally taken orally and can cause side effects such as nausea, vomiting and hypertension. The vaginal use of these pills can reduce such complications. Our objective was to compare the efficacy and side effects of low dose contraceptive pills by oral and vaginal route in the management of dysfunctional uterine bleeding-(DUB) Methods: This comparative observational study was conducted at Beheshti and Alzahra (SA) teaching hospitals, affiliated to Isfahan University of Medical Sciences in 2010-2011. One hundred women who presented with DUB were randomly assigned into two groups of equal number, receiving the low dose oral contraceptive pills by oral or vaginal route for three month. The amount and duration of bleeding were compared at the beginning and at the end of the study and side effects by these two methods compared. Results: The results of this study showed that both oral and vaginal routes effectively reduced the duration and amount of bleeding due to DUB after three courses of treatment. This effect was better in the vaginal method compared with oral administration (P = 0.03). Regarding the side effects, nausea and vomiting were significantly higher in the oral group than in the vaginal group (P = 0.03). Vulvovaginitis infection was more frequent in the vaginal group than in the oral group (P = 0.03). Conclusion: Low dose contraceptive pills are effective in reducing the amount, time, and duration of bleeding in patients with DUB. In addition, reduction of gastrointestinal side effects by vaginal route helps to use these pills by the patient with proper training of physicians, midwives and patients. PMID:24353721

Mehrabian, Ferdous; Abbassi, Fariba

2013-09-01

191

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

PubMed

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

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

2014-05-01

192

A Phase I Multicenter Study of Continuous Oral Administration of Lonafarnib (SCH 66336) and Intravenous Gemcitabine in Patients with Advanced Cancer  

PubMed Central

We conducted a phase I study to assess safety, pharmacokinetics, pharmacodynamics and activity of lonafarnib plus gemcitabine. Subjects received oral lonafarnib twice daily and gemcitabine on days 1, 8 and 15 every 28 days; multiple dose levels were explored. Lonafarnib had no apparent effect on gemcitabine PK. Mean lonafarnib half-life ranged from 4 to 7 hours; median Tmax values ranged from 4 to 8 hours. Two patients had partial response; 7 patients had stable disease ?6 months. Oral lonafarnib at 150 mg AM/100 mg PM plus gemcitabine at 1000 mg/m2 is the maximum tolerated dose with acceptable safety and tolerability.

Wong, Nan Soon; Meadows, Kellen L.; Rosen, Lee S.; Adjei, Alex A.; Kaufmann, Scott H.; Morse, Michael A.; Petros, William P.; Zhu, Yali; Statkevich, Paul; Cutler, David L.; Meyers, Michael L.; Hurwitz, Herbert I.

2014-01-01

193

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

PubMed

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

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

2014-08-15

194

Reproductive toxicity in rats with crystal nephropathy following high doses of oral melamine or cyanuric acid.  

PubMed

The industrial chemical melamine was used in 2007 and 2008 to raise the apparent protein content in pet feed and watered down milk, respectively. Because humans may be exposed to melamine via several different routes into the human diet as well as deliberate contamination, this study was designed to characterize the effect of high dose melamine or cyanuric acid oral exposure on the pregnant animal and developing fetus, including placental transfer. Clear rectangular crystals formed following a single triazine exposure which is a different morphology from the golden spherulites caused by combined exposure or the calculi formed when melamine combines with endogenous uric acid. Crystal nephropathy, regardless of cause, induces renal failure which in turn has reproductive sequelae. Specifically, melamine alone-treated dams had increased numbers of early and late fetal deaths compared to controls or cyanuric acid-treated dams. As melamine was found in the amniotic fluid, this study confirms transfer of melamine from mammalian mother to fetus and our study provides evidence that cyanuric acid also appears in the amniotic fluid if mothers are exposed to high doses. PMID:24582682

Stine, Cynthia B; Reimschuessel, Renate; Keltner, Zachary; Nochetto, Cristina B; Black, Thomas; Olejnik, Nicholas; Scott, Michael; Bandele, Omari; Nemser, Sarah M; Tkachenko, Andriy; Evans, Eric R; Crosby, Tina C; Ceric, Olgica; Ferguson, Martine; Yakes, Betsy J; Sprando, Robert

2014-06-01

195

Oral Mucosal Progenitor Cells Are Potently Immunosuppressive in a Dose-Independent Manner  

PubMed Central

Oral mucosal lamina propria progenitor cells (OMLP-PCs) are a novel, clonally derived PC population of neural crest origin with the potential to differentiate down both mesenchymal and neuronal cell lineages. In this study we aimed to determine the immunological properties of OMLP-PCs and to establish whether they would be suitable candidates for allogeneic tissue engineering and in the treatment of immune-related diseases. OMLP-PCs demonstrated no inherent immunogenicity with insignificant expression of costimulatory molecules (CD40, CD80, CD86, CD154, and CD178) or human leukocyte antigen (HLA) class II. OMLP-PCs required 7 days of stimulation with interferon-? (IFN-?) to induce cell surface expression of HLA II. Mixed lymphocyte cultures and mitogen stimulation demonstrated the potent immunosuppressive capability of OMLP-PCs in a contact-independent manner. Complete inhibition of lymphocyte proliferation was seen at doses as low as 0.001% OMLP-PCs to responder lymphocytes, while annexin V staining confirmed that this immunosuppressive effect was not due to the induction of lymphocyte apoptosis. These data demonstrate, for the first time, that OMLP-PC immunomodulation, unlike that for mesenchymal stem cells, occurs via a dose- and HLA II–independent mechanism by the release of immunosuppressive soluble factors and suggests these cells may have wide ranging potential in future immune-related therapies.

Davies, Lindsay C.; Lonnies, Helena; Locke, Matthew; Sundberg, Berit; Rosendahl, Kerstin; Gotherstrom, Cecilia; Le Blanc, Katarina

2012-01-01

196

Pharmacokinetics of oxiracetam in patients with renal impairment after a 800 mg single oral dose.  

PubMed

The pharmacokinetics of oxiracetam in patients with renal impairment were investigated after administration of a 800 mg single oral dose of oxiracetam. The renal insufficiency was estimated on the basis of the creatinine clearance (CLcr) which ranged from 9 to 95 ml/min among the 20 patients. In plasma, the terminal elimination half-life (T1/2) ranged from 10.6 to 68.1 h, the highest T1/2 corresponding to the patients with a high degree of renal impairment. In urine, the amounts of oxiracetam excreted during the 48 h postdosing represented 8.3 to 82.6% of the dose. They were lower in patients with a high degree of renal impairment. The correlations between the total clearance of oxiracetam, the renal clearance, the terminal apparent elimination rate constant in plasma, and CLcr were estimated by linear regression analysis. The correlation coefficients were 0.916, 0.985 and 0.803 respectively. The apparent volume of distribution of the central compartment V(1) and the total volume of distribution at the steady-state V(SS) were not dependent on the degree of renal impairment. The mean values +/- SD were 25.9 +/- 13.0 litres and 48.3 +/- 21.5 litres respectively. Oxiracetam concentrations in plasma of patients were estimated for repeated administration of 800 mg of oxiracetam.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2253654

Lecaillon, J B; Dubois, J P; Coppens, H; Darragon, T; Reumond, G; Pozet, N; Traeger, J; Lambrey, G

1990-01-01

197

Oral contraception does not alter single dose saquinavir pharmacokinetics in women  

PubMed Central

Aims Women experience more adverse drug reactions (ADR) to antiretroviral therapy than men. This may be attributed to higher plasma concentrations of protease inhibitors due to pharmacokinetic interactions with hormonal preparations. Thus, in the present study we aimed to investigate the influence of oral contraceptives (OC) on the pharmacokinetics of the protease inhibitor saquinavir. Methods Saquinavir was administered in a hard gelatin capsule formulation (Invirase®) to rule out confounding by pharmaceutical aids of the more frequently used soft gelatin capsule. After an overnight fast, eight healthy female participants ingested a single oral dose of 600 mg saquinavir immediately before and after the 19th dose of a combined, low dose OC (0.03 mg ethinylestradiol, 0.075 mg gestodene) in a prospective, fixed sequence study design. The first saquinavir application was scheduled on day 1, 2, or 3 of the individual menstrual cycle. Plasma concentrations of saquinavir and relative concentrations of its M2&M3-hydroxy metabolites were determined by LC/MS/MS for 48 h. Results Intake of OC resulted in a significant decrease in morning serum concentrations (before intake of OC, compared to day 19 of OC therapy) of 17?-estradiol by ?23.4 pg ml?1 (57%, 95%CI: ?76% to ?37.4%); progesterone by ?0.25 ng ml?1 (33%, 95%CI: ?45.3% to ?21.5%); follicle-stimulating hormone by ?4.06 U l?1 (82%, 95%CI: ?96.5% to ?67.7%); and luteinizing hormone by ?3.49 U l?1 (74%, 95%CI: ?93 to ?54.6%). Conversely, sexual hormone binding globulin serum concentrations increased by 83.6 nmol l?1 (205%, 95%CI: 32.2% to 377%). Pharmacokinetic parameters of saquinavir (AUC, Cmax, tmax, t1/2, CLR) were not affected by OC, nor was the relative metabolic ratio of saquinavir/M2&M3-hydroxy saquinavir. Furthermore, there was no association of serum hormone concentrations or MDR1-polymorphisms (C3435T and G2677T) with pharmacokinetic parameters of saquinavir. Conclusions There was no effect of OC on saquinavir pharmacokinetics. Thus, pharmacokinetic interactions of synthetic sexual steroids with saquinavir are not likely to account for the increased ADR to antiretroviral therapy seen in women.

Frohlich, Margit; Burhenne, Jurgen; Martin-Facklam, Meret; Weiss, Johanna; von Wolff, Michael; Strowitzki, Thomas; Walter-Sack, Ingeborg; Haefeli, Walter E

2004-01-01

198

Pharmacokinetic interaction of enrofloxacin/trimethoprim combination following single-dose intraperitoneal and oral administration in rats.  

PubMed

The pharmacokinetic interaction of enrofloxacin and trimethoprim was evaluated after single-dose intraperitoneal or oral co-administration in rats. Plasma concentrations of the two drugs were determined by high-performance liquid chromatography. Following intraperitoneal combination, a significant (P < 0.05) increase in mean values of plasma half-life (t 1/2) and maximum plasma concentration (C max) was observed for enrofloxacin and trimethoprim, respectively. There was a significant (P < 0.05) increase in mean values of area under the plasma drug concentration versus time from time zero to infinity (AUC0-?) and C max between combined oral doses (10, 30 and 100 mg/kg) of both antibacterial drugs. Also, after oral conjugation a significant difference in mean values of MRT0-? was observed between lower (10 mg/kg) and higher (100 mg/kg) doses of both drugs. A significant increase in pharmacokinetic parameters of both drugs in combined intraperitoneal and oral doses indicated pharmacokinetic interaction of enrofloxacin and trimethoprim. Further study is recommended in other species of animals. PMID:23749586

Choi, Myung-Jin; Yohannes, Sileshi Belew; Lee, Seung-Jin; Damte, Dereje; Kim, Jong-Choon; Suh, Joo-Won; Park, Seung-Chun

2014-03-01

199

The pharmacokinetics and pharmacodynamics of diltiazem and its metabolites in healthy adults after a single oral dose  

Microsoft Academic Search

A potential complicating factor in the characterization of the pharmacokinetics and pharmacodynamics of diltiazem after an oral dose is the presence of two metabolites, N-demethyldiltiazem and desacetyldiltiazem, in plasma. Both N-demethyldiltiazem and desacetyldiltiazem have been shown to have pharmacologic activity in animal tissues. It is therefore possible that these metabolites contribute to the pharmacologic effect of diltiazem, but this possibility

Rebecca A Boyd; Shu K Chin; Oluta Don-Pedro; Davide Verotta; Lewis B Sheiner; Roger L Williams; Kathleen M Giacomini

1989-01-01

200

Hepatic and renal metallothionein induction by an oral equimolar dose of zinc, cadmium or mercury in mice  

Microsoft Academic Search

The hepatic and the renal subcellular distribution of zinc, cadmium or mercury and induction of tissue metallothionein (MT) at 24, 48 and 72 h following an oral equimolar dose (15 ?mol metal\\/kg) of zinc (II) chloride, cadmium (II) chloride or mercury (II) chloride in male albino mice were investigated. There was a moderate increase in hepatic and renal zinc levels

S. K Tandon; S Singh; S Prasad; N Mathur

2001-01-01

201

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

Microsoft Academic Search

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

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

1996-01-01

202

Population pharmacokinetics of artesunate and dihydroartemisinin following single- and multiple-dosing of oral artesunate in healthy subjects  

Microsoft Academic Search

BACKGROUND: The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food. METHODS: Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects

Beesan Tan; Himanshu Naik; In-Jin Jang; Kyung-Sang Yu; Lee E Kirsch; Chang-Sik Shin; J Carl Craft; Lawrence Fleckenstein

2009-01-01

203

The use of low-dose protracted oral clofarabine in a patient with myelodysplastic syndrome after failing 5-azacitidine  

PubMed Central

Patients with myelodysplastic syndrome who fail hypomethylating agents have a very short median survival and about 25% risk of disease transformation to acute myeloid leukemia. We report our experience with low-dose protracted oral clofarabine in one patient who achieved stable disease for more than two years after failing 5-azacitidine.

Al Ustwani, Omar; Greene, Jessica D.; Wetzler, Meir

2013-01-01

204

Tolerance to Effects of High-Dose Oral ?9-Tetrahydrocannabinol and Plasma Cannabinoid Concentrations in Male Daily Cannabis Smokers  

PubMed Central

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 ?9-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.

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

205

Tolerance to effects of high-dose oral ?9-tetrahydrocannabinol and plasma cannabinoid concentrations in male daily cannabis smokers.  

PubMed

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 ?9-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. PMID:23074216

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

206

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

PubMed Central

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

Weisberg, Edith

2012-01-01

207

Thesaurus for histopathological findings in publically available reports of repeated-dose oral toxicity studies in rats for 156 chemicals.  

PubMed

Because histopathological findings are often conclusive indicators of the toxicities of chemicals, standardization of nomenclature and construction of a thesaurus for histopathological findings are important for the comparative evaluation of histopathological data from repeated-dose toxicity studies (RTS). However, terms for histopathological findings have not been standardized and different technical terms are used to indicate almost the same thing in RTS. The present study was conducted to construct an easy-to-use thesaurus for histopathological findings in order to facilitate hazard assessments of untested chemicals by the category approach using knowledge of the toxicity of analogue chemicals. We used reports of 28-day RTS, conducted on rats by gavage, which were posted on the websites of the National Institute of Health Sciences (NIHS) and the National Institute of Technology and Evaluation (NITE). The histopathological data were from 156 reports on RTS conducted by 13 institutions in Japan. As a result of this study, major parts of the thesaurus were devoted to the findings in the liver, kidney, stomach, adrenal, thyroid and testis; the first three organs are known to be the main targets of chemicals. We also decided that findings such as swelling and enlargement of hepatocytes should be categorized as synonyms for terms meaning hypertrophy. Our thesaurus will be helpful in assessing or screening new untested chemicals by the category approach using knowledge of the toxicities of analogues of the new chemical. The RTS database with this thesaurus will be made publically available in 2012. PMID:20519837

Nishikawa, Satoshi; Yamashita, Tatsuhiro; Imai, Toshio; Yoshida, Midori; Sakuratani, Yuki; Yamada, Jun; Maekawa, Akihiko; Hayashi, Makoto

2010-06-01

208

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

PubMed Central

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

2014-01-01

209

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

PubMed

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

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

2014-01-01

210

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

SciTech Connect

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%.

Saghir, Shakil A. (ASSOC WESTERN UNIVERSITY); Schultz, Irv R. (BATTELLE (PACIFIC NW LAB))

2002-01-01

211

Pharmacokinetics of oxiracetam in elderly patients after 800 mg oral doses, comparison with non-geriatric healthy subjects.  

PubMed

The pharmacokinetics of oxiracetam have been studied in eighteen elderly patients and in six healthy non-geriatric adults. A 800 mg single oral dose was administered in the morning of the first day and repeatedly, every 12 h, from day 2 evening to day 10 morning, to the elderly patients. The healthy non-geriatric adults were given a 800 mg single oral dose of oxiracetam. In healthy non-geriatric subjects after a single oral administration of 800 mg, the normalized plasma levels of oxiracetam for 1 mg/kg dose were similar to those already recorded after a 2000 mg single dose of oxiracetam. Therefore, there was no tendency towards non-linear pharmacokinetics of oxiracetam between 800 and 2000 mg single doses in healthy subjects. After the single oral dose, the mean area under the plasma concentration-time curve of oxiracetam in elderly patients was increased by a factor of two as compared to that observed in non-geriatric healthy subjects whereas the maximum concentration (Cmax) was almost not modified and slightly delayed. This can be explained by a slower absorption and elimination in the elderly patients. The highest oxiracetam levels were predominantly recorded in the oldest patients. The slower elimination (mean T1/2 = 12.3 h in elderly and 7.7 h in healthy subjects) could be attributed to a physiological decrease of the renal function. The volume of distribution was not significantly modified in the elderly patients.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:2253653

Lecaillon, J B; Dubois, J P; Coppens, H; Darragon, T; Theobald, W; Reumond, G; Beck, H

1990-01-01

212

Comparison of Minimal Phototoxic Dose and Skin Type for Determining Initial UVA Dose in Oral Liquid Methoxsalen Photochemotherapy for the Treatment of Psoriasis  

Microsoft Academic Search

Twenty-five patients with extensive psoriasis were randomly assigned into one of the three groups, each receiving 0.5 mg\\/kg of oral liquid methoxsalen photochemotherapy followed 1 h later by exposure to long-wave ultraviolet light (UVA). The sole difference between the three groups was the method used to determine the initial UVA dose, which was either based on skin type, 25% of

Elyse S. Rafal; Ted A. Hamilton; Ernesto Gonzalez

1991-01-01

213

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

SciTech Connect

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.

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

2007-02-01

214

A comparative study of oral single dose of metronidazole, tinidazole, secnidazole and ornidazole in bacterial vaginosis  

PubMed Central

Objective: To compare the cure rates of oral single dose of metronidazole (2 g), tinidazole (2 g), secnidazole (2 g), and ornidazole (1.5 g) in cases of bacterial vaginosis. Materials and Methods: This was a prospective, comparative, randomized clinical trial on 344 Indian women (86 women in each group) who attended a gynecology outpatient department with complaint of abnormal vaginal discharge or who had abnormal vaginal discharge on Gynecological examination but they did not complaint of it. For diagnosis and cure rate of bacterial vaginosis, Amsel's criteria were used. Statistical analysis was done by Chi-square test of proportions. The cure rate was compared considering metronidazole cure rate as gold standard. Results: At 1 week, the cure rate of tinidazole and ornidazole was 100% and at 4 weeks, it was 97.7% for both drugs (P<0.001). Secnidazole had cure rate of 80.2% at 4 weeks (P=NS). Metronidazole showed a cure rate of 77.9% at 4 weeks, which is the lowest of all four drugs. Conclusion: Tinidazole and ornidazole have better cure rate as compared to metronidazole in cases of bacterial vaginosis.

Thulkar, Jyoti; Kriplani, Alka; Agarwal, Nutan

2012-01-01

215

Immunotoxicological profile of chloramine in female B6C3F1 mice when administered in the drinking water for 28 days.  

PubMed

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. PMID:22017662

Guo, Tai L; Germolec, Dori R; Collins, Bradley J; Luebke, Robert W; Auttachoat, Wimolnut; Smith, Matthew J; White, Kimber L

2011-01-01

216

A one-month repeated oral dose toxicity study of methotrexate in unilaterally nephrectomized rats.  

PubMed

A repeated oral dose toxicity study of methotrexate (MTX) was conducted in order to examine whether the enhancement of MTX toxicity would occur in unilaterally nephrectomized (UNX) rats. UNX rats or sham-treated (SHAM) rats received dosages of 0, 0.06, 0.2 or 0.6 mg/kg/day (control animals received physiological saline). Toxic effects of MTX observed in this study were not different from studies already conducted, i.e., myelo- and lympho-toxicity, gastrointestinal toxicity, hepatotoxicity, pulmonary toxicity and renal toxicity were evident in the animals given MTX. Toxic effects of MTX in the UNX rats were more severe than those in the SHAM rats; a higher number of dead and moribund animals was observed among the UNX rats, and abnormal clinical signs appeared a few days earlier in the UNX rats. In the hematological examination, a decreased number of the blood cells in the UNX rats was observed at the lower dose level as compared to SHAM rats. The nontoxic dose of MTX in SHAM rats and UNX rats was 0.06 mg/kg/day and below 0.06 mg/kg/day, respectively. According to the results of a toxicokinetic examination conducted in the animals receiving 0.2 mg/kg/day, AUC and T 1/2terminal of MTX in the UNX rats were higher than those of SHAM rats. It was considered that the enhancement of the MTX toxicity in UNX rats was caused by the longer exposure of MTX in UNX rats. Serum UN and Cr of the UNX rats receiving physiological saline were higher than those of the corresponding SHAM rats, which suggested a slightly decreased GFR had been induced in UNX rats in this study. However, decreased PSP excretion was not observed in the UNX rats and urine volume of the UNX rats was equivalent to that of SHAM rats. Thus, it was considered that vicarious hypertrophy occurred in the residual kidney and decreased renal function was not evident in the UNX rats. This study demonstrated that the enhancement of toxicity of MTX had occurred even though a decreased renal function was not evident. PMID:9891907

Murakami, Y; Yamazaki, K; Sakauchi, N; Ogasawara, H; Yamashita, N; Masuda, T; Tauchi, K

1998-11-01

217

Effect of time of meal consumption on bioavailability of a single oral 5 mg tacrolimus dose.  

PubMed

Tacrolimus (FK506, Prograf) is marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation. This study investigated the effect of timing of a standardized breakfast meal on both the rate and extent of tacrolimus absorption following a single 5 mg oral dose. The protocol used a randomized, open-label, four-period, four-treatment, four-sequence crossover design in 16 healthy, nonsmoking, drug-free male subjects between the ages of 22 and 45 years who were within 15% of their ideal body weight. The four treatments were the following: (A) fasting for 10 hours, (B) ingestion 1 hour before breakfast, (C) ingestion immediately following consumption of the breakfast, and (D) ingestion 1.5 hours after beginning consumption of the breakfast. The breakfast, which was consumed over 15 minutes, contained 848 kcal, with 30%, 16%, and 54% of calories derived from fat, protein, and carbohydrate, respectively. Tacrolimus absorption in the fasting state provided the greatest relative bioavailability (p < 0.05 compared with all other three treatments). AUC(0-infinity)) averaged 312, 276, 205, and 203 ng x h/mL for treatments A, B, C and D, respectively. In contradistinction to taking the drug 1 hour prior to a meal, which had a relatively minor impact on the relative extent of absorption (approximately 12%) compared to the fasting state, ingestion of tacrolimus immediately after a meal (treatment C) or 1.5 hours subsequent to a meal (treatment D) had a more pronounced influence. Mean AUC(0-infinity) ratios (fasting to either postmeal treatments) were approximately 1.5, indicating that absorption extent was considerably reduced by ingesting tacrolimus capsules immediately after eating or 1.5 hours thereafter. Absorption was also prolonged following drug ingestion after a meal, as indicated by a mean tmax value in the fasting state of 1.84 hours, relative to 3.41 hours (immediately aftermeal, p = 0.0035) and 3.22 hours (1.5 hours postmeal, p = 0.0094). The only discernable difference in parameters between treatments C and D was with Cmax, with values of 7.19 and 9.04 ng/mL, respectively, but was not statistically significantly different (p = 0.231). Based on these results and those from a prior study, it is recommended that under therapeutic conditions, oral tacrolimus be administered in a consistent manner, both with respect to the type of meal as well as timing of ingestion relative to consumption of the meal. PMID:11269569

Bekersky, I; Dressler, D; Mekki, Q

2001-03-01

218

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

PubMed

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

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

2014-06-16

219

Toxico-kinetics, recovery, and metabolism of napropamide in goats following a single high-dose oral administration.  

PubMed

Toxicokinetic behavior, recovery and metabolism of napropamide (a pre-emergent herbicide) and its effect on Cytochrome P(450) of liver microsomal pellet were studied following a single high-dose oral administration of 2.5 g kg(-1) and continuous (7 days) oral administration of 500 mg kg(-1) in black Bengal goat. Napropamide was detected in blood at 15 min and the maximum quantity was recovered at 3 h after administration. The absorption rate constant (Ka) value was low indicating poor absorption from the gastrointestinal tract. High elimination half-life (t(1/2) beta) and low body clearance (Cl(B)) values coupled with higher transfer of compound from tissue to central compartment (K(21)) suggest that napropamide persisted in the blood for a long time, i.e., after 72 h of oral administration. The recovery percentage of napropamide, including metabolites, from goats varied from 75.94 to 80.08 and excretion of the parent compound through feces varied from 18.86 to 21.59%, indicating that a major portion of the orally administered napropamide was absorbed from the gastrointestinal tract of goat. Napropamide significantly increased the Cytochrome P(450) content of liver microsomal pellet. The recovery of metabolites from feces, urine, and tissues ranged from 4.2--6.2, 40.81--49.42, and 2.7--11.6%, respectively, during a 4--7 day period. The material balance of napropamide (including metabolites) following a single high-dose oral administration at 2.5 g kg(-1) during 4--7 days after dosing was found to be in the range of 75--80%. PMID:11308331

Pahari, A K; Majumdar, S; Mandal, T K; Chakraborty, A K; Bhattacharyya, A; Chowdhury, A

2001-04-01

220

Oral anticoagulants controlled by the British comparative thromboplastin versus low-dose heparin in prophylaxis of deep vein thrombosis.  

PubMed

The British comparative thromboplastin (BCT) was used to monitor the effectiveness of oral anticoagulants in preventing deep vein thrombosis (DVT) in patients undergoing major gynaecological surgery. All patients were screened for DVT with the use of the (125)I-fibrinogen scan.One hundred and forty-five patients aged 40 years or more were randomised into three groups. Group 1 received oral anticoagulant (nicoumalone) treatment, stabilised over five days before surgery and continuing into the second postoperative week. The other patients served as two contrast groups and were managed on a double-blind basis. Group 2 received a subcutaneous low-dose regimen of heparin calcium. Group 3 received subcutaneous saline. Eleven of 48 patients in the saline group, three of 49 patients in the heparin group, and three of 48 patients in the oral anticoagulant group developed DVT as judged by (125)I-fibrinogen scanning. The incidences in groups 1 and 2 were significantly lower than in the saline group. The falls in haemoglobin concentration and incidence of haemorrhage were similar in all three groups.The study showed that oral anticoagulant prophylaxis stabilised preoperatively and low-dose heparin were equally effective in preventing deep vein thrombosis in a moderate-risk group. Immediate preoperative prothrombin ratios of 2.0-2.5 and postoperative ratios of 2.0-4.0 with the BCT gave adequate protection without increased haemorrhagic risk. PMID:340005

Taberner, D A; Poller, L; Burslem, R W; Jones, J B

1978-02-01

221

Oral anticoagulants controlled by the British comparative thromboplastin versus low-dose heparin in prophylaxis of deep vein thrombosis  

PubMed Central

The British comparative thromboplastin (BCT) was used to monitor the effectiveness of oral anticoagulants in preventing deep vein thrombosis (DVT) in patients undergoing major gynaecological surgery. All patients were screened for DVT with the use of the 125I-fibrinogen scan. One hundred and forty-five patients aged 40 years or more were randomised into three groups. Group 1 received oral anticoagulant (nicoumalone) treatment, stabilised over five days before surgery and continuing into the second postoperative week. The other patients served as two contrast groups and were managed on a double-blind basis. Group 2 received a subcutaneous low-dose regimen of heparin calcium. Group 3 received subcutaneous saline. Eleven of 48 patients in the saline group, three of 49 patients in the heparin group, and three of 48 patients in the oral anticoagulant group developed DVT as judged by 125I-fibrinogen scanning. The incidences in groups 1 and 2 were significantly lower than in the saline group. The falls in haemoglobin concentration and incidence of haemorrhage were similar in all three groups. The study showed that oral anticoagulant prophylaxis stabilised preoperatively and low-dose heparin were equally effective in preventing deep vein thrombosis in a moderate-risk group. Immediate preoperative prothrombin ratios of 2·0-2·5 and postoperative ratios of 2·0-4·0 with the BCT gave adequate protection without increased haemorrhagic risk.

Taberner, D A; Poller, L; Burslem, R W; Jones, J B

1978-01-01

222

Second-line chemotherapy with long-term low-dose oral etoposide in patients with advanced breast cancer  

Microsoft Academic Search

In a phase II study, 27 patients with metastatic breast cancer were treated with oral etoposide as second-line chemotherapy at a dose of 50 mg\\/m2\\/day for 21 days, which courses were repeated every 4 weeks. Twenty-one patients were evaluable for response, and twenty-five for toxicity. In two (10%) patients a partial response was observed with a duration of 60 and

M. Bontenbal; A. S. Th. Planting; J. Verweij; R. Wit; W. H. J. Kruit; G. Stoter; J. G. M. Klijn

1995-01-01

223

Effects of Food and Sucralfate on a Single Oral Dose of 500 Milligrams of Levofloxacin in Healthy Subjects  

Microsoft Academic Search

The effects of food and sucralfate on the pharmacokinetics of levofloxacin following the administration of a single 500-mg oral dose were investigated in a randomized, three-way crossover study with young healthy subjects (12 males and 12 females). Levofloxacin was administered under three conditions: fasting, fed (immediately after a standardized high-fat breakfast), and fasting with sucralfate given 2 h following the

LING-JAR LEE; BARRY HAFKIN; I-DER LEE; J. HOH; R. DIX; Hoechst Marion

1997-01-01

224

Metronomic oral low-dose treosulfan chemotherapy combined with cyclooxygenase-2 inhibitor in pretreated advanced melanoma: a pilot study  

Microsoft Academic Search

PurposeThe safety and efficacy of oral metronomic low-dose treosulfan chemotherapy in combination with the cyclooxygenase-2 (COX-2) inhibitor rofecoxib as a compound with antiangiogenic potential, a therapeutic regimen optimally targeting endothelial cells instead of tumor cells, were assessed in pretreated advanced melanoma patients.MethodsEndothelial cells were analyzed for proliferation, apoptosis and cytotoxicity in response to increasing concentrations of treosulfan, either in the

Konstanze Spieth; Roland Kaufmann; Jens Gille

2003-01-01

225

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,...

226

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

Microsoft Academic Search

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

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

2000-01-01

227

The Prospective Oral Mucositis Audit: relationship of severe oral mucositis with clinical and medical resource use outcomes in patients receiving high-dose melphalan or BEAM-conditioning chemotherapy and autologous SCT  

Microsoft Academic Search

The Prospective Oral Mucositis Audit was an observational study in 197 patients with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL) undergoing, respectively, high-dose melphalan or BEAM chemotherapy and autologous SCT at 25 European centres. We evaluated the relationship between severe oral mucositis (SOM; WHO Oral Toxicity Scale grade 3–4) and local and systemic clinical sequelae and medical resource use. SOM

S. McCann; M. Schwenkglenks; P. Bacon; H. Einsele; A. D'Addio; J. Maertens; D. Niederwieser; W. Rabitsch; A. Roosaar; T. Ruutu; H. Schouten; R. Stone; S. Vorkurka; B. Quinn; N. M. A. Blijlevens

2009-01-01

228

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

PubMed

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·?g/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. PMID:24745065

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

2014-04-01

229

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

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.

Poirier, Miriam C.

2012-01-01

230

Intraindividual variability of the bioavailability of low dose methotrexate after oral administration in rheumatoid arthritis  

Microsoft Academic Search

OBJECTIVES--To analyse whether the intraindividual variability of the bioavailability of oral methotrexate in rheumatoid arthritis (RA) is as high as the interindividual variability and whether the bioavailability testing can be simplified. METHODS--Fifteen mg methotrexate was given orally after an overnight fast to 10 patients with RA on two occasions, one week (n = 4) or two years (n = 6)

C Lebbe; C Beyeler; N J Gerber; J Reichen

1994-01-01

231

Comparison of the pharmacokinetics and pharmacodynamics of oral doses of perindopril in normotensive Chinese and Caucasian volunteers.  

PubMed Central

1. The pharmacokinetics of perindopril and perindoprilat and the hormonal and haemodynamic responses following a single oral dose were studied in 12 Chinese and 10 Caucasian healthy, normotensive volunteers on two occasions. Perindopril was given on the first occasion as a 4 mg dose and then after at least 10 days as a weight-adjusted dose of 4 mg/70 kg. Plasma was sampled for assay of perindopril, perindoprilat, plasma renin activity (PRA), aldosterone, angiotensin I (AI) and ACE activity. Urine was collected for perindopril and perindoprilat assay. A radioimmunoassay technique was used to measure the prodrug and its active metabolite. 2. The time to maximum concentration (tmax) for perindopril was shorter for the Chinese group after the 4 mg dose (median 0.5, range 0.5-1.5 h vs median 1.0, 0.5-1.5 h P < 0.05) and also tended to be shorter after the weight-adjusted dose (median 0.5, range 0.5-1.0 h vs median 1.0, range 0.5-3.0 h). Cmax and AUC tended to be higher after the 4 mg dose in the Chinese group who had a lower body weight than the Caucasians. 3. The tmax of perindoprilat tended to be shorter for both doses and there was a tendency towards a higher Cmax after the 4 mg dose in the Chinese group but there was no statistically significant difference between the two groups. 4. There were no differences in the levels of PRA, plasma AI, plasma aldosterone or the degree of ACE-inhibition for either dose in the two ethnic groups. 5. Blood pressure was measured at intervals up to 24 h post-dose in both the supine and standing positions. Perindopril reduced blood pressure acutely with respect to the pre-dose level with good tolerability in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Anderson, P J; Critchley, J A; Tomlinson, B; Resplandy, G

1995-01-01

232

Low-dose pharmacokinetics and oral bioavailability of dichloroacetate in naive and GST-zeta-depleted rats.  

PubMed Central

We studied the pharmacokinetics of dichloroacetate (DCA) in naive rats and rats depleted of glutathione S-transferase-zeta (GST-zeta), at doses approaching human daily exposure levels. We also compared in vitro metabolism of DCA by rat and human liver cytosol. Jugular vein-cannulated male Fischer-344 rats received graded doses of DCA ranging from 0.05 to 20 mg/kg (intravenously or by gavage), and we collected time-course blood samples from the cannulas. GST-zeta activity was depleted by exposing rats to 0.2 g/L DCA in drinking water for 7 days before initiation of pharmacokinetic studies. Elimination of DCA by naive rats was so rapid that only 1-20 mg/kg intravenous and 5 and 20 mg/kg gavage doses provided plasma concentrations above the method detection limit of 6 ng/mL. GST-zeta 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 GST-zeta-depleted rats, the pharmacokinetics became linear at doses less than or equal to 1 mg/kg. Virtually all of the dose was eliminated through metabolic clearance; the rate of urinary elimination was < 1 mL/hr/kg. At higher oral doses (less than or equal to 5 mg/kg in GST-zeta-depleted and 20 mg/kg in naive rats), secondary peaks in the plasma concentration appeared long after the completion of the initial absorption phase. Oral bioavailability of DCA was 0-13% in naive and 14-75% in GST-zeta- depleted rats. Oral bioavailability of DCA in humans through consumption of drinking water was predicted to be very low and < 1%. The use of the GST-zeta-depleted rat as a model for assessing the kinetics of DCA in humans is supported by the similarity in pharmacokinetic parameter estimates and rate of in vitro metabolism of DCA by human and GST-zeta-depleted rat liver cytosol.

Saghir, Shakil A; Schultz, Irvin R

2002-01-01

233

Dose Responsive Effects of Subcutaneous Pentosan Polysulfate Injection in Mucopolysaccharidosis Type VI Rats and Comparison to Oral Treatment  

PubMed Central

Background We previously demonstrated the benefits of daily, oral pentosan polysulfate (PPS) treatment in a rat model of mucopolysaccharidosis (MPS) type VI. Herein we compare these effects to once weekly, subcutaneous (sc) injection. The bioavailability of injected PPS is greater than oral, suggesting better delivery to difficult tissues such as bone and cartilage. Injected PPS also effectively treats osteoarthritis in animals, and has shown success in osteoarthritis patients. Methodology/Principal Findings One-month-old MPS VI rats were given once weekly sc injections of PPS (1, 2 and 4 mg/kg, human equivalent dose (HED)), or daily oral PPS (4 mg/kg HED) for 6 months. Serum inflammatory markers and total glycosaminoglycans (GAGs) were measured, as were several histological, morphological and functional endpoints. Overall, weekly sc PPS injections led to similar or greater therapeutic effects as daily oral administration. Common findings between the two treatment approaches included reduced serum inflammatory markers, improved dentition and skull lengths, reduced tracheal deformities, and improved mobility. Enhanced effects of sc treatment included GAG reduction in urine and tissues, greater endurance on a rotarod, and better improvements in articular cartilage and bone in some dose groups. Optimal therapeutic effects were observed at 2 mg/kg, sc. No drug-related increases in liver enzymes, coagulation factor abnormalities or other adverse effects were identified following 6 months of sc PPS administration. Conclusions Once weekly sc administration of PPS in MPS VI rats led to equal or better therapeutic effects than daily oral administration, including a surprising reduction in urine and tissue GAGs. No adverse effects from sc PPS administration were observed over the 6-month study period.

Frohbergh, Michael; Ge, Yi; Meng, Fanli; Karabul, Nesrin; Solyom, Alexander; Lai, Alon; Iatridis, James; Schuchman, Edward H.; Simonaro, Calogera M.

2014-01-01

234

Dosing regimens of oral ciprofloxacin for children with severe malnutrition: a population pharmacokinetic study with Monte Carlo simulation  

PubMed Central

Background Severe malnutrition is frequently complicated by sepsis, leading to high case fatality. Oral ciprofloxacin is a potential alternative to the standard parenteral ampicillin/gentamicin combination, but its pharmacokinetics in malnourished children is unknown. Methods Ciprofloxacin (10 mg/kg, 12 hourly) was administered either 2 h before or up to 2 h after feeds to Kenyan children hospitalized with severe malnutrition. Four plasma ciprofloxacin concentrations were measured over 24 h. Population analysis with NONMEM investigated factors affecting the oral clearance (CL) and the oral volume of distribution (V). Monte Carlo simulations investigated dosage regimens to achieve a target AUC0–24/MIC ratio of ?125. Results Data comprised 202 ciprofloxacin concentration measurements from 52 children aged 8–102 months. Absorption was generally rapid but variable; Cmax ranged from 0.6 to 4.5 mg/L. Data were fitted by a one-compartment model with first-order absorption and lag. The parameters were CL (L/h)?=?42.7 (L/h/70 kg)?×?[weight (kg)/70]0.75?×?[1?+?0.0368 (Na+ – 136)]?×?[1?–?0.283 (high risk)] and V (L)?=?372?×?(L/70 kg)?×?[1?+?0.0291 (Na+ – 136)]. Estimates of AUC0–24 ranged from 8 to 61 mg·h/L. The breakpoint for Gram-negative organisms was <0.06 mg/L with doses of 20 mg/kg/day and <0.125 mg/L with doses of 30 or 45 mg/kg/day. The cumulative fraction of response with 30 mg/kg/day was ?80% for Escherichia coli, Klebsiella pneumoniae and Salmonella species, but <60% for Pseudomonas aeruginosa. Conclusions An oral ciprofloxacin dose of 10 mg/kg three times daily (30 mg/kg/day) may be a suitable alternative antibiotic for the management of sepsis in severely malnourished children. Absorption was unaffected by the simultaneous administration of feeds.

Thuo, Nahashon; Ungphakorn, Wanchana; Karisa, Japhet; Muchohi, Simon; Muturi, Alex; Kokwaro, Gilbert; Thomson, Alison H.; Maitland, Kathryn

2011-01-01

235

Low-dose retinoic acid enhances in vitro invasiveness of human oral squamous-cell-carcinoma cell lines  

PubMed Central

Retinoids inhibit the proliferation of several types of tumour cells, and are used for patients with several malignant tumours. In this study, we examined the effect of retinoic acids (RAs) on the invasive potentials of the oral squamous cell carcinoma (SCC) cells, BHY and HNt. BHY cells expressed all of retinoid nuclear receptors (RAR?, ?, ?, and RXR?) and cytoplasmic retinoic acid binding proteins (CRABP1 and CRABP2). HNt cells lacked the expression of RAR?, but expressed other nuclear receptors and CRABPs. All-trans retinoic acid (ATRA) and 13-cis retinoic acid (13-cisRA) (10?6and 10?7M) inhibited the growth of the cells, but low-dose ATRA and 13-cisRA (10?8M) marginally affected the growth of the cells. Surprisingly, low-dose RAs enhanced the activity of tissue-type plasminogen activator (tPA), and activated pro-matrix metalloproteinases (proMMP2 and proMMP9). Activation of proMMP2 and proMMP9 was inhibited by aprotinin, a serine-proteinase, tPA inhibitor. Furthermore, low-dose RAs enhanced the in vitro invasiveness of BHY cells. These results indicate that low-dose RAs enhances the in vitro invasiveness of oral SCC cells via an activation of proMMP2 and proMMP9 probably mediated by the induction of tPA. © 2001 Cancer Research Campaign http://www.bjcancer.com

Uchida, D; Kawamata, H; Nakashiro, K; Omotehara, F; Hino, S; Hoque, M O; Begum, N-M; Yoshida, H; Sato, M; Fujimori, T

2001-01-01

236

Comparison of the pharmacokinetics of metronidazole in healthy female volunteers following either a single oral or intravenous dose  

PubMed Central

1 The plasma pharmacokinetics of metronidazole following a single dose (500 mg) of metronidazole have been investigated in a crossover study in healthy female volunteers, using assays specific for metronidazole and its metabolites 1-(2-hydroxyethyl)-2-hydroxymethyl-5-nitroimidazole (metabolite I) and 2-methyl-5-nitroimidazole-1-acetic acid (metabolite II). 2 No systematic differences, which could be related to the route of metronidazole administration, were observed in the area under the plasma metronidazole concentration against time curve, elimination half-life, apparent volume of distribution, or total urinary excretion of metronidazole. Following a single oral or intravenous dose, the half-life estimates were 7.0 h and 7.3 h respectively. 3 No metabolite II was detected in plasma following the administration of metronidazole by either route. Urinary elimination of this metabolite appeared to be independent of the route of administration. 4 No systematic differences, which could be related to the route of administration, were observed in the apparent half-life or total urinary excretion of metabolite I. However, the area under the plasma concentration against time curve for metabolite I was significantly greater (+27%) following oral administration than following intravenous administration. 5 A single dose of metronidazole (500 mg) produced a peak plasma concentration for the drug which was in excess of the minimum inhibitory concentration of most susceptible anaerobic bacteria, and in several of the volunteers such an inhibitory concentration of metronidazole was maintained in plasma for more than 8 h following a single dose.

Houghton, G. W.; Thorne, P. S.; Smith, Joy; Templeton, R.; Collier, J.

1979-01-01

237

[Changes of miRNA after oral submucous fibrosis co-cultured with Salvia and low-dose prednisolone].  

PubMed

Objective: To explore and analyze the the expression change of miRNA associated with oral submucous fibrosis (OSF) treated by the Salvia combined with law-dose prednisolone. Methods: Ten pairs of tissues from patients with typical early or advanced stage clinical pathological features of OSF and their paired normal tissues (internal control), were selected respectively. The miRNA expression profiles between the OSF and its paired controls were compared by the Affymetrix analysis. The primary normal oral mucous cells were cultured in arecoline (50 ?g/mL) for 3, 6, 12 d (0 d ser ved as cont rol), and the primary OSF-fibroblast cells were cultured with Salvia (90 mg/mL) combined with low-dose prednisolone for 12, 24, 36 h (0 h served as control). The differential expression of miRNA was detected. Results: Arecoline induced the expression changes of miRNAs in normal mucosal cells. Salvia combined with low doses of prednisolone reversed the related miRNA expression. Conclusion: MiRNAs play an essential role in the occurrence and development of OSF. Salvia combined with low-dose prednisolone can reverse the expression of related miRNAs in OSF cells. PMID:24921400

Liu, Binjie; Chen, Jun; Jian, Xinchun

2014-05-01

238

Effect of vitamin K intake on the stability of oral anticoagulant treatment: dose-response relationships in healthy subjects.  

PubMed

Oral anticoagulants exert their effect by blocking the utilization of vitamin K, yet little is known about competitive aspects of their interaction with dietary vitamin K. We carried out systematic dose-response studies in healthy volunteers who had been stably anticoagulated and maintained on their individualized doses for 13 weeks. First, we studied the response to weekly incremental doses (50 microg-500 microg) of vitamin K(1) supplements (K(1)) taken daily for 7 days. The threshold K(1) dose causing a statistically significant lowering of the INR was 150 microg/day. In 25% of the participants the INR change was regarded as clinically relevant at a vitamin K intake of 150 microg/day. Circulating undercarboxylated osteocalcin did not decrease until 300 microg K(1)/day compared with 100 microg K(1)/day for undercarboxylated FII, suggesting differential antidotal effects on bone and hepatic gamma-carboxylation. Next, we tested the response to vitamin K-rich food items. The short-lived response after meals of spinach and broccoli suggested an inefficient bioavailability from these 2 sources. We conclude that short-term variability in intake of K(1) is less important to fluctuations in the international normalized ratio (INR) than has been commonly assumed and that food supplements providing 100 microg/day of vitamin K(1) do not significantly interfere with oral anticoagulant therapy. PMID:15231565

Schurgers, Leon J; Shearer, Martin J; Hamulyák, Karly; Stöcklin, Elisabeth; Vermeer, Cees

2004-11-01

239

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

PubMed

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

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

2013-06-01

240

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

Microsoft Academic Search

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

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

241

Impact of reducing dosing frequency on adherence to oral therapies: a literature review and meta-analysis  

PubMed Central

Objectives To assess the impact of reduced frequency of oral therapies from multiple-dosing schedules to a once-daily (OD) dosing schedule on adherence, compliance, persistence, and associated economic impact. Methods A meta-analysis was performed based on relevant articles identified from a comprehensive literature review using MEDLINE® and Embase®. The review included studies assessing adherence with OD, twice-daily (BID), thrice-daily (TID), and four-times daily (QID) dosing schedules and costs associated with optimal/suboptimal adherence among patients with acute and chronic diseases. Effect estimates across studies were pooled and analyzed using the DerSimonian and Laird random-effect model. Results Forty-three studies met inclusion criteria, and meta-analyzable data were available from 13 studies. The overall results indicated that OD schedules were associated with higher adherence rates (odds ratio [OR] 3.07, 95% confidence interval [CI] 1.80–5.23; P < 0.001 for OD versus > OD dosing) and compliance rates (OR 3.50, 95% CI 1.73–7.08; P < 0.001 for OD versus > OD dosing); persistence rates showed the same direction but were not statistically significant (OR 1.43, 95% CI 0.62–3.29; P = 0.405 for OD versus BID dosing). Results for each of the conditions were consistent with those observed overall with respect to showing the benefits of less frequent dosing. From a health economic perspective, higher adherence rates with OD relative to multiple dosing in a number of conditions were consistently associated with corresponding lower costs of health care resources utilization. Conclusion Current meta-analyses suggested that across acute and chronic disease states, reducing dosage frequency from multiple dosing to OD dosing may improve adherence to therapies among patients. Improving adherence may result in subsequent decreases in health care costs.

Srivastava, Kunal; Arora, Anamika; Kataria, Aditi; Cappelleri, Joseph C; Sadosky, Alesia; Peterson, Andrew M

2013-01-01

242

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

PubMed Central

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-?-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 and was well tolerated, and suggested effective doses of 10–80 mg in photoparoxysmal epilepsy. WHAT THIS STUDY ADDS We now report the pharmacokinetics, pharmacodynamics and tolerability in healthy volunteers after multiple doses.

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

2008-01-01

243

Preliminary Study of Effects of Multiple Oral Dosing of Clarithromycin on the Pharmacokinetics of Cyclosporine in Dogs  

PubMed Central

ABSTRACT Clarithromycin (CLM) has been known to increase the cyclosporine (CsA) trough level in human and feline organ transplant patients. However, the interaction of CLM with CsA has not been reported in dogs. In this study, the effects of multiple dosing of CLM on the pharmacokinetics of CsA in three healthy beagles were investigated. The treatments included CsA 10 mg/kg alone and CsA 10 mg/kg + multiple-dose of CLM 10 mg/kg. Co-administration of CLM with CsA resulted in significant increases of oral bioavailability of CsA. The results of our study suggest that administration of multiple therapeutic doses of CLM may decrease the required CsA dosage in CsA-based immunosuppressive therapy in renal transplanted dogs.

KATAYAMA, Masaaki; KAWAKAMI, Yoshiki; KATAYAMA, Rieko; SHIMAMURA, Shunsuke; OKAMURA, Yasuhiko; UZUKA, Yuji

2013-01-01

244

A Randomised Trial Evaluating the Safety and Immunogenicity of the Novel Single Oral Dose Typhoid Vaccine M01ZH09 in Healthy Vietnamese Children  

Microsoft Academic Search

Background: The emergence of drug resistant typhoid fever is a major public health problem, especially in Asia. An oral single dose typhoid vaccine would have major advantages. M01ZH09 is a live oral single dose candidate typhoid vaccine containing Salmonella enterica serovar Typhi (Ty2 aroC(-) ssaV(-)) ZH9 with two independently attenuating deletions. Studies in healthy adults demonstrated immunogenicity and an acceptable

T. H. Tran; T. D. Nguyen; Nguyen Thanh Truong; T. T. V. Ninh; N. B. C. Tran; V. M. H. Nguyen; T. T. N. Tran; Cao Thu Thuy; V. M. Pham; T. C. B. Nguyen; V. T. Pham; S. D. To; James I. Campbell; Elaine Stockwell; Constance Schultsz; Cameron P. Simmons; Clare Glover; Winnie Lam; Filipe Marques; James P. May; Anthony Upton; Ronald Budhram; Gordon Dougan; Jeremy Farrar; V. V. C. Nguyen; Christiane Dolecek

2010-01-01

245

A Randomised Trial Evaluating the Safety and Immunogenicity of the Novel Single Oral Dose Typhoid Vaccine M01ZH09 in Healthy Vietnamese Children  

Microsoft Academic Search

BackgroundThe emergence of drug resistant typhoid fever is a major public health problem, especially in Asia. An oral single dose typhoid vaccine would have major advantages. M01ZH09 is a live oral single dose candidate typhoid vaccine containing Salmonella enterica serovar Typhi (Ty2 aroC?ssaV?) ZH9 with two independently attenuating deletions. Studies in healthy adults demonstrated immunogenicity and an acceptable safety profile.ObjectivesWe

Tran Tinh Hien; Nguyen Thi Dung; Nguyen Thanh Truong; Ninh Thi Thanh van; Tran Nguyen Bich Chau; Nguyen Van Minh Hoang; Tran Thi Thu Nga; Cao Thu Thuy; Pham Van Minh; Nguyen Thi Cam Binh; Tran Thi Diem Ha; Pham Van Toi; To Song Diep; James I. Campbell; Elaine Stockwell; Constance Schultsz; Cameron P. Simmons; Clare Glover; Winnie Lam; Filipe Marques; James P. May; Anthony Upton; Ronald Budhram; Gordon Dougan; Jeremy Farrar; Nguyen Van Vinh Chau; Christiane Dolecek; J. Jaime Miranda

2010-01-01

246

A novel potent indazole carboxylic acid derivative blocks spermatogenesis and is contraceptive in rats after a single oral dose.  

PubMed

Women have historically been the focus for development of new contraceptive methods. The National Institutes of Health, World Health Organization, and Institute of Medicine have stressed the need to develop nonhormonal, nonsteroidal male contraceptive agents. We report results from initial dose-ranging studies of a new indazole carboxylic acid analogue, gamendazole. An infertility rate of 100% was achieved in seven out of seven proven-fertile male rats 3 wk after a single oral dose of 6 mg/kg of gamendazole. Fertility returned by 9 wk in four of seven animals, with typical numbers of normal-appearing conceptuses. A fertility rate of 100% returned in four of six animals that became infertile at a single oral dose of 3 mg/kg of gamendazole. No differences in mating behavior were observed in either of the gamendazole-treated groups versus the control (vehicle-only) group. In the animals that showed reversible infertility, a transient increase in circulating FSH levels coincided with an initial decline in inhibin B levels after administration of gamendazole, but no other significant changes in circulating reproductive hormones were observed. Gamendazole inhibited production of inhibin B by primary Sertoli cells in vitro with a median inhibitory concentration of 6.8 thorn+/- 3.0 (SEM) (3/4)x 10(-10) M, suggesting that Sertoli cells are a primary target. A biotinylated gamendazole analogue revealed cytoplasmic and perinuclear binding of gamendazole in primary Sertoli cells. Gamendazole represents the most potent new oral antispermatogenic indazole carboxylic acid to date. Our results, however, demonstrate that additional dose-finding studies are required to improve reversibility and widen the therapeutic window before more detailed drug development of this potential nonhormonal male contraceptive agent can occur. PMID:18218612

Tash, Joseph S; Attardi, Barbara; Hild, Sheri A; Chakrasali, Ramappa; Jakkaraj, Sudhakar R; Georg, Gunda I

2008-06-01

247

Oral Delivery of Anticoagulant Doses of Heparin A Randomized, Double-Blind, Controlled Study in Humans  

Microsoft Academic Search

Background—Parenteral heparin is the anticoagulant of choice in hospitalized patients. Continued anticoagulation is achieved by subcutaneous administration of low-molecular-weight heparin or with an orally active anticoagulant such as warfarin. An oral heparin formulation would avoid the inconvenience of subcutaneous injection and the unfavorable drug interactions and adverse events associated with warfarin. A candidate delivery agent, sodium N-(8(-2- hydroxybenzoyl)amino)caprylate (SNAC), was

Robert A. Baughman; Shiv C. Kapoor; Rajesh K. Agarwal; James Kisicki; Francesca Catella-Lawson; Garret A. FitzGerald

248

The added value of the 90-day repeated dose oral toxicity test for industrial chemicals with a low (sub)acute toxicity profile in a high quality dataset.  

PubMed

A survey conducted on the EU Notification of New Substances (NONS) database suggested that for industrial chemicals with a profile of low toxicity in (sub)acute toxicity tests there is little added value to the conduct of the 90-day repeated dose study. Avoiding unnecessary animal testing is a central aim of the EU REACH chemicals legislation; therefore we sought to verify the profile using additional data. The OECD's eChemPortal was searched for substances that had both a 28-day and a 90-day study and their robust study summaries were then examined from the ECHA CHEM database. Out of 182 substances with high quality 28-day and 90-day study results, only 18 reported no toxicity of any kind in the (sub)acute tests. However, for 16 of these there were also no reported signs of toxicity at or close to the limit dose (1000mg/kgbw/d) in the 90-day study. Restricting the 'low (sub)acute toxicity in a high quality dataset' profile to general industrial chemicals of no known biological activity, whilst allowing irritant substances, increases the data set and improves the prediction to 95% (20 substances out of 21 substances). The low toxicity profile appears to be of low prevalence within industrial chemicals (10-15%), nevertheless, avoidance of the conduct of a redundant 90-day study for this proportion of the remaining REACH phase-in substances would avoid the use of nearly 50,000 animals and save industry 50million Euros, with no impact on the assessment of human health. PMID:24768988

Taylor, Katy; Andrew, David J; Rego, Laura

2014-08-01

249

Effects of 28 days of resistance exercise and consuming a commercially available pre-workout supplement, NO-Shotgun®, on body composition, muscle strength and mass, markers of satellite cell activation, and clinical safety markers in males  

Microsoft Academic Search

PURPOSE: This study determined the effects of 28 days of heavy resistance exercise combined with the nutritional supplement, NO-Shotgun®, on body composition, muscle strength and mass, markers of satellite cell activation, and clinical safety markers. METHODS: Eighteen non-resistance-trained males participated in a resistance training program (3 × 10-RM) 4 times\\/wk for 28 days while also ingesting 27 g\\/day of placebo

Brian Shelmadine; Matt Cooke; Thomas Buford; Geoffrey Hudson; Liz Redd; Brian Leutholtz; Darryn S Willoughby

2009-01-01

250

Safety, Tolerance, and Pharmacokinetic Studies of OPT-80 in Healthy Volunteers following Single and Multiple Oral Doses?  

PubMed Central

Current therapies for Clostridium difficile infection (CDI) are encumbered by treatment failures and recurrences. Due to its high in vitro activity against C. difficile but low activity against the typical intestinal flora, minimal absorption, and durable cure in the hamster model of C. difficile infection, OPT-80 was considered for clinical development as a therapy for CDI. This trial consisted of two phases. Four single oral doses of OPT-80 (100, 200, 300, and 450 mg) were administered in a crossover manner to 16 healthy volunteers in a double-blind, placebo-controlled phase 1A study; a 1- to 2-week washout interval separated the treatments. In the double-blind phase 1B study, 24 healthy subjects were randomized to receive OPT-80 (150, 300, or 450 mg) or placebo for 10 days. In both studies, OPT-80's safety and tolerability were evaluated and the concentrations of OPT-80 and its primary metabolite (OP-1118) in plasma and feces were determined. OPT-80 levels in the urine were also analyzed for the phase 1A study. In both the single-dose and the multiple-dose studies, OPT-80 was well tolerated by all subjects in all dose groups. Maximal plasma concentrations were near or below the limit of quantification (5 ng/ml) across the dose range; urine concentrations were below the detection limit. The fecal total recovery of OPT-80 plus its major metabolite, OP-1118, approximated 100%. The tolerability, high fecal concentration, and low systemic exposure data from these studies support the further clinical development of OPT-80 as an oral therapy for CDI.

Shue, Y. K.; Sears, P. S.; Shangle, S.; Walsh, R. B.; Lee, C.; Gorbach, S. L.; Okumu, F.; Preston, R. A.

2008-01-01

251

Folate supplementation induces differential dose-dependent modulation of proliferative phenotypes among cancerous and noncancerous oral cell lines in vitro.  

PubMed

Sufficient folate intake confers positive health benefits, while deficiency is linked with many health problems. Although the US policy of dietary folic acid fortification has reduced the incidence of these deficiency-related health problems, recent evidence has demonstrated an association between folic acid supplementation and increased colorectal cancer incidence. Few studies have explored the possibility that folate affects other slowly developing cancers. This study sought to determine whether folic acid supplementation is sufficient to alter the growth and development of existing oral cancers. A series of in vitro growth, viability, and adhesion assays were performed using the well-characterized human oral squamous cell carcinoma cell lines, CAL27 and SCC25, to determine the effects of folic acid supplementation. Folic acid administration significantly stimulated CAL27 and SCC25 proliferation in a dose-dependent manner, but it was not sufficient to increase proliferation at any concentration tested in the normal control cell line, HGF-1. Neither oral cancer cell line harbored the common C677T DNA polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene, which might reduce folate bioavailability. Overexpression of p53 mRNA was observed in both cancerous cell lines, but it was differentially altered by folic acid administration in only SCC25 cells. These findings suggest folic acid administration may significantly alter growth of oral cancers in vitro via p53-dependent and p53-independent pathways. As oral cancer rates continue to rise in specific geographic areas, and among specific subsets of the US population, understanding environmental mediators, such as folic acid supplementation, becomes increasingly important for nutrition and public health scientists. PMID:22432562

McCabe, Jonathan; Chang, Sarah; Hajibandeh, Jeffrey; Tran, Michael D; Meeder, Colby A; Sharma, Kanika; Nguyen, Dieu-Hoa; Moody, Michael; Keiserman, Mark A; Bergman, Christine J; Kingsley, Karl

2010-12-01

252

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

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. PMID:24632068

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

253

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

PubMed

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. While allometric and physiologically based pharmacokinetic (PBPK) models were constructed for interspecies scaling of BPA and its interaction with ER, multigeneration feeding studies with BPA at doses spanning 5 orders of magnitude failed to identify signs of developmental toxicity or adverse changes in reproductive tract tissues; the 5-mg/kg-d NOAELs identified for systemic toxicity in rats and mice were less than the oral NOAELs for reproductive toxicity. Thus, it is the generalized systemic toxicity of ingested BPA rather than reproductive, immunologic, neurobehavioral, or genotoxic hazard that represents the point of departure. Using U.S. Environmental Protection Agency (EPA) uncertainty factor guidance and application of a threefold database uncertainty factor (to account for the fact that the carcinogenic potential of transplacental BPA exposure has yet to be fully defined and comprehensive neurobehavioral and immunotoxicologic evaluations of BPA by relevant routes and at relevant doses have yet to be completed) to the administered dose NOAEL results in an oral RfD of 0.016 mg/kg-d. Assuming the 70-kg adult consumes 2 L of water each day and adopting the default 20% U.S. EPA drinking water relative source contribution yields a 100 microg/L BPA total allowable concentration (TAC). PMID:18188738

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

2008-02-01

254

Melatonin pharmacokinetics following two different oral surge-sustained release doses in older adults.  

PubMed

Melatonin is increasingly used for the treatment of sleep disorders. Surge-sustained formulations consisting of combined immediate release and controlled release dosing may mimic the endogenous melatonin physiologic profile. However, relatively little is known about the pharmacokinetic properties of low-dose (<0.5mg) and high-dose (>2mg) melatonin in a combined immediate release/controlled release dose, especially in older adults who may also exhibit altered melatonin disposition. To assess this, we conducted a randomized, double-blind, placebo-controlled study of low-dose (0.4mg) and high-dose (4.0mg) melatonin (25% immediate release+75% controlled release) in 27 older adults with insomnia complaints and low endogenous melatonin levels to determine whether melatonin pharmacokinetic properties differ between these two doses. The time to maximum level (1.3hrs versus 1.5hrs), elimination half-life (1.8hrs versus 2.1hrs), and apparent total clearance (379L/hr versus 478L/hr) did not differ significantly between the low- and high-dose arms, respectively. The maximum concentration was 405?±93pg/mL for the low-dose arm and 3999±700pg/mL for the high-dose arm, both of which are substantially higher than physiologic melatonin levels for this age group. In addition, subjects in the high-dose arm maintained melatonin levels >50pg/mL for an average of 10hrs, which could result in elevated melatonin levels beyond the typical sleep period. Renal and liver function parameters remained stable after 6wks of treatment. The linear pharmacokinetic behavior of melatonin observed in the elderly can form the basis for future studies exploring a wider range of dosing scenarios to establish exposure-response relationships for melatonin-mediated sleep outcomes. PMID:22348451

Gooneratne, Nalaka S; Edwards, Alena Y Z; Zhou, Chen; Cuellar, Norma; Grandner, Michael A; Barrett, Jeffrey S

2012-05-01

255

POTENTIAL LONG-TERM TOXICITY OF REPEATED ORALLY ADMINISTERED DOSES OF ARTEMETHER IN RATS  

Microsoft Academic Search

Artemether, an efficacious antimalarial drug, effectively prevents patent schistosome infections and morbidity, as established in laboratory models and in clinical trials. In view of concern about the potential long-term toxicity, rats were treated orally with 80 mg\\/kg artemether once every 2 weeks for 5 months. After the final treatment, routine blood test results were normal except for reversible reductions of

XIAO SHUHUA; YANG YUANQING; JURG UTZINGER; GUO HUIFANG; JIAO PEIYING; MEI JINYING; GUO JIAN; ROBERT BERGQUIST; MARCEL TANNER

256

Comparative clinical pharmacokinetics of single doses of sumatriptan following subcutaneous, oral, rectal and intranasal administration  

Microsoft Academic Search

Sumatriptan, a 5-HT1 receptor agonist active for the acute treatment of migraine, is currently available as subcutaneous injection and oral tablets. Rectal or intranasal formulations may offer advantages over those marketed. This study compared the pharmacokinetics of sumatriptan via all four routes. Usual absorption parameters were described and the rate of absorption was assessed using deconvolution technics. There were no

C Duquesnoy; J. P Mamet; D Sumner; E Fuseau

1998-01-01

257

Efficacy and safety of oral low-dose glucocorticoids in patients with estrogen-dependent primary osteoarthritis.  

PubMed

Estrogen-dependent osteoarthritis (EDPOA) is a disease of perimenopausal-age women. Their manifestations are polyarticular pain with common co-morbidities (carpal tunnel syndrome, insomnia, fatigue, depression, and fibromyalgia). Based on dual role of glucocorticoids, its trophic action on the chondrocyte and its anti-inflammatory effect, we conducted a prospective interventional cohort study where we evaluate the efficacy and safety of oral low-dose GC in one hundred women with EDPOA. The pain intensity, number of tender joints as well as impact in co-morbidities were analyzed. We conclude that the use of low-dose GC in patients with EDPOA can be an effective and a safe therapeutic option. PMID:23334371

Cañas, Carlos A; Osorio, Carlos J; Coronel, Nicolás; Cepeda, Magda C; Izquierdo, Jorge H; Bonilla-Abadía, Fabio

2014-05-01

258

Phase I-II study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell cancer  

PubMed Central

Background For patients with metastatic renal cell cancer (mRCC) who progressed on vascular endothelial growth factor (VEGF) receptor tyrosine kinase inhibitor therapy, the orally administered mammalian target of rapamycin (mTOR) inhibitor everolimus has been shown to prolong progression free survival. Intriguingly, inhibition of mTOR also promotes expansion of immunosuppressive regulatory T cells (Tregs) that can inhibit anti-tumor immune responses in a clinically relevant way in various tumor types including RCC. This study intends to investigate whether the antitumor efficacy of everolimus can be increased by preventing the detrimental everolimus induced expansion of Tregs using a metronomic schedule of cyclophosphamide. Methods/design This phase I-II trial is a national multi-center study of different doses and schedules of low-dose oral cyclophosphamide in combination with a fixed dose of everolimus in patients with mRCC not amenable to or progressive after a VEGF-receptor tyrosine kinase inhibitor containing treatment regimen. In the phase I part of the study the optimal Treg-depleting dose and schedule of metronomic oral cyclophosphamide when given in combination with everolimus will be determined. In the phase II part of the study we will evaluate whether the percentage of patients progression free at 4 months of everolimus treatment can be increased from 50% to 70% by adding metronomic cyclophosphamide (in the dose and schedule determined in the phase I part). In addition to efficacy, we will perform extensive immune monitoring with a focus on the number, phenotype and function of Tregs, evaluate the safety and feasibility of the combination of everolimus and cyclophosphamide, perform monitoring of selected angiogenesis parameters and analyze everolimus and cyclophosphamide drug levels. Discussion This phase I-II study is designed to determine whether metronomic cyclophosphamide can be used to counter the mTOR inhibitor everolimus induced Treg expansion in patients with metastatic renal cell carcinoma and increase the antitumor efficacy of everolimus. Trial Registration ClinicalTrials.gov Identifier NCT01462214, EudraCT number 2010-024515-13, Netherlands Trial Register number NTR3085.

2011-01-01

259

Pharmacokinetics, pharmacodynamics, tolerability and safety of single ascending doses of ticagrelor, a reversibly binding oral P2Y 12 receptor antagonist, in healthy subjects  

Microsoft Academic Search

Purpose  Ticagrelor (AZD6140) is the first reversibly binding oral P2Y12 receptor antagonist in development for reduction of clinical thrombotic events in patients with acute coronary syndromes.\\u000a The purpose of our studies was to determine the effect of single-ascending doses of ticagrelor in healthy subjects.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  In two randomised, double-blind, placebo-controlled single ascending dose studies, healthy subjects received oral doses of\\u000a 0.1–100 mg or

Renli Teng; Kathleen Butler

2010-01-01

260

Effect of various oral dose levels of a trimethoprim/sulphadiazine mixture on Bordetella bronchiseptica infection and on the proliferation of trimethoprim-resistant faecal coliforms in pigs.  

PubMed Central

When a 1:5 mixture of trimethoprim (TMP) and sulphadiazine was fed to pigs intra-nasally infected with bordetella bronchiseptica, 10 mg/kg/day was shown to be highly effective in suppressing the organism. This dose level had little effect on numbers of TMP-resistant coliforms in faeces, but oral doses of 30 mg/kg/day eventually selected a resistant population. It is suggested that the proliferation of resistant coliforms would be minimized by administration of the lowest oral dose rates of antibacterial drugs compatible with efficacy.

Dassanayake, L.; White, G.

1983-01-01

261

Reduced doses of oral killed enterotoxigenic Escherichia coli plus cholera toxin B subunit vaccine is safe and immunogenic in Bangladeshi infants 6–17 months of age: Dosing studies in different age groups  

Microsoft Academic Search

The oral-formalin inactivated whole cell enterotoxigenic Escherichia coli (ETEC) vaccine needs to be further tested in developing countries in order to determine the dose at which it will be safe and immunogenic for infants who are the target population for the vaccine. To determine the immunogenicity of reduced doses, studies were first carried out in children, 2–12 years of age

Firdausi Qadri; Tanvir Ahmed; Firoz Ahmed; Yasmin Ara Begum; David A. Sack; Ann-Mari Svennerholm

2006-01-01

262

A combined single and multiple dose pharmacokinetic study of oral isosorbide-5-mononitrate in healthy volunteers.  

PubMed

Pharmacokinetics of 20 mg isosorbide-5-mononitrate (IS-5-MN) after single and multiple administration of two different tablet formulations were investigated in twelve healthy human subjects using an open, randomized, two-way crossover experimental design. Pentacard 20 mg tablets were compared with Ismo 20 mg tablets. After single-dose administration, both preparations caused a rapid increase in IS-5-MN plasma levels with the peak plasma concentration occurring between 0.5 and 1.5 h. For both formulations, the mean plasma half-life was found to be approximately 5 h after a single dose. In steady state during multiple dosing (t.i.d. at 8 h dosing intervals), a reduced elimination rate was observed. In line with this observation, the area under the plasma concentration-time curve (AUC) for one 8 h dosing interval during multiple dosing was higher than the extrapolated AUC after a single dose. Based on statistical evaluation of the various relevant pharmacokinetic parameters calculated from the plasma concentrations occurring after single and multiple dosing, the tablet formulations are judged to be bioequivalent. PMID:1790311

Storm, G; Oosterhuis, B; Bron, J; Wittebrood, A J; De Jong, A P; Jonkman, J H

1991-12-01

263

Pharmacokinetics and Safety of Single Oral Doses of Emtricitabine in Human Immunodeficiency Virus-Infected Children  

Microsoft Academic Search

Emtricitabine (FTC; Emtriva), a potent deoxycytidine nucleoside reverse transcriptase inhibitor, has re- cently been approved by the U.S. Food and Drug Administration for the treatment of human immunodeficiency virus (HIV) infection. In adults, FTC has demonstrated linear kinetics over a wide dose range, and FTC 200 mg once a day (QD) is the recommended therapeutic dose. A phase I open-label

Laurene H. Wang; Andrew A. Wiznia; Mobeen H. Rathore; Gregory E. Chittick; Saroj S. Bakshi; Patricia J. Emmanuel; Patricia M. Flynn

2004-01-01

264

Resistance training and timed essential amino acids protect against the loss of muscle mass and strength during 28 days of bed rest and energy deficit  

PubMed Central

Spaceflight and bed rest (BR) result in losses of muscle mass and strength. Resistance training (RT) and amino acid (AA) supplementation are potential countermeasures to minimize these losses. However, it is unknown if timing of supplementation with exercise can optimize benefits, particularly with energy deficit. We examined the effect of these countermeasures on body composition, strength, and insulin levels in 31 men (ages 31–55 yr) during BR (28 days) followed by active recovery (14 days). Subjects were randomly assigned to essential AA supplementation (AA group, n = 7); RT with AA given 3 h after training (RT group, n = 12); or RT with AA given 5 min before training (AART group, n = 12). Energy intake was reduced by 8 ± 6%. Midthigh muscle area declined with BR for the AA > RT > AART groups: ?11%, ?3%, ?4% (P = 0.05). Similarly, greatest losses in lower body muscle strength were seen in the AA group (?22%). These were attenuated in the exercising groups [RT (?8%) and AART (?6%; P < 0.05)]. Fat mass and midthigh intramuscular fat increased after BR in the AA group (+3% and +14%, respectively), and decreased in the RT (?5% and ?4%) and AART groups (?1 and ?5%; P = 0.05). Muscle mass and strength returned toward baseline after recovery, but the AA group showed the lowest regains. Combined resistance training with AA supplementation pre- or postexercise attenuated the losses in muscle mass and strength by approximately two-thirds compared with AA supplement alone during BR and energy deficit. These data support the efficacy of combined AA and RT as a countermeasure against muscle wasting due to low gravity.

Brooks, Naomi; Cloutier, Gregory J.; Cadena, Samuel M.; Layne, Jennifer E.; Nelsen, Carol A.; Freed, Alicia M.; Roubenoff, Ronenn; Castaneda-Sceppa, Carmen

2008-01-01

265

Oral exposure to Microcystis increases activity-augmented antioxidant enzymes in the liver of loach (Misgurnus mizolepis) and has no effect on lipid peroxidation.  

PubMed

Recently, eutrophication has induced severe cyanobacterial blooms in the Naktong River, the second largest river of Korea. In the present study, lipid peroxidation and the antioxidant enzymes superoxide dismutase, catalase, and glutathione peroxidase, were evaluated in the liver of loach (Misgurnus mizolepis) that were orally exposed to a low dose of Microcystis through dietary supplementation with bloom scum. Loach received 75 mg of dry cells/kg body weight mass (equal to 10 microg microcystin-RR/kg body mass), for 28 days under controlled conditions. Antioxidant enzymatic activity and lipid peroxidation were measured after termination of exposure. The activities of antioxidant enzyme were significantly increased in the livers of toxin-exposed loach after 28 days of exposure, as compared to control fish. However, lipid peroxidation remained stable in both groups. These results suggest that antioxidant enzymes were able to eliminate oxidative stress induced by low concentrations of microcystins and to prevent increased lipid peroxidation in the liver of loach. PMID:16055386

Li, Xiao-Yu; Chung, Ik-Kyo; Kim, Jung-In; Lee, Jin-Ae

2005-07-01

266

New Dosing Regimens for Amifostine: A Pilot Study to Compare the Relative Bioavailability of Oral and Subcutaneous Administration with Intravenous Infusion  

Microsoft Academic Search

A phase I clinical trial was conducted to assess the feasibility of a more convenient and safe dosing regime for the cytoprotective drug amifostine. Two alternative routes of administration, oral and subcutaneous (SQ), each with a dose of 500 mg, were compared to a 7.5-minute intravenous (IV) infusion, with a dose of 200 mg\\/m2, in normal, healthy volunteers (N =

H. S. Bonner; L. M. Shaw

2002-01-01

267

Pharmacokinetics and pharmacodynamics of methadone enantiomers after a single oral dose of racemate  

Microsoft Academic Search

Background: The pharmacokinetics and dynamics of methadone are characterized by high interindividual variability. This study aimed to examine a number of factors that may contribute to this variability.Methods: Eight healthy drug-free women were administered 0.2 mg\\/kg of R,S-methadone orally. The concentrations of methadone's enantiomers in plasma and urine were monitored for 96 hours. Vital signs, blood biochemical parameters, and pupillary

David W. Boulton; Philippe Arnaud; C. Lindsay DeVane

2001-01-01

268

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

PubMed

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 ApoB(tm2Sgy)/Ldlr(tm1Her/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. PMID:24962340

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

2014-08-01

269

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

PubMed

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 observed. Based on this limited mouse study, archaeosomes were generally well tolerated after intravenous or oral delivery at the dosages so indicated in this study. PMID:12573945

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

2003-01-01

270

A study of dose-response relationship between tobacco habits and oral leukoplakia.  

PubMed Central

In a house-to-house survey in Ernakulam district, Kerala, India, 12,213 tobacco users were interviewed about the details of their tobacco usage and examined for the presence of leukoplakia. The frequency of tobacco habit was associated with the prevalence of leukoplakia indicating a positive dose-response relationship. The dose-response relationship remained significant, taking age, sex, and the type of tobacco habit into account. After adjusting for all these variables jointly the association still remained significant. The dose-response relationship was stronger for the smoking habit than for the chewing habit. A weaker relationship in the chewing habit was not due to the duration of chewing habit or the habit of retaining the betel quid in the mouth while sleeping. Thus the dose-response relationship, although significant, was different for tobacco smoking and chewing habits.

Gupta, P. C.

1984-01-01

271

Bioequivalence assessment of ambroxol tablet after a single oral dose administration to healthy male volunteers  

Microsoft Academic Search

A bioequivalence study of the ambroxol hydrochloride tablets was conducted. Twenty-four healthy male Korean volunteers received each medicine at the ambroxol hydrochloride dose of 30mg in a 2×2 cross-over study. There was a 1-week washout period between the doses. Plasma concentrations of ambroxol were monitored by a high-performance liquid chromatography (HPLC) for over a period of 24h after the administration.

Hee Joo Lee; Sun Koung Joung; Yoon Gyoon Kim; Jeong-Yeon Yoo; Sang Beom Han

2004-01-01

272

Pharmacokinetic and Pharmacodynamic Study of the Human Immunodeficiency Virus Protease Inhibitor Amprenavir after Multiple Oral Dosing  

Microsoft Academic Search

In a dose-ranging study of amprenavir (formerly 141W94), an inhibitor of the protease enzyme of human immunodeficiency virus (HIV) type 1, single-dose and steady-state pharmacokinetic parameters were estimated from plasma samples collected on day 1 and during week 3, respectively. Amprenavir was administered on either a twice-daily (b.i.d.) or three-times-daily dosage schedule to 62 HIV-infected adults, 59 of whom had

BRIAN M. SADLER; CATHERINE GILLOTIN; YU LOU; DANIEL S. STEIN

2001-01-01

273

CTLA-4 is required for the induction of high dose oral tolerance  

Microsoft Academic Search

Mucosal and systemic administrations of high dose antigens induce long-lasting peripheral T cell tolerance. We and others have shown that high dose peripheral T cell tolerance is mediated by anergy or deletion and is preceded by T cell activation. Co-stimulatory molecules B7-1 (CD80)\\/B7-2 (CD86) and their counter-receptors CD28\\/CTLA-4 play pivotal roles in T cell activation and immune regulation. In the

Elena B. Samoilova; Jennifer L. Horton; Haidi Zhang; Samia J. Khoury; Howard L. Weiner; Youhai Chen

1998-01-01

274

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

PubMed

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

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

2005-10-01

275

Maternal toxicity, embryolethality and abnormal fetal development in CD-1 mice following one oral dose of T-2 toxin.  

PubMed

An experiment was undertaken to determine the teratogenic effect of oral administration of T-2 toxin, a trichothecene mycotoxin. Firstly, a dose response study using 0, 0.5, 1.0, 2.0, 3.0, 3.5 and 4.0 mg/kg T-2 toxin in propylene glycol, on day 9 of pregnancy, was undertaken. Maternal deaths and toxicity was noted in the 4.0 and 3.5 mg/kg groups post-toxin administration. These groups gained less weight throughout gestation than the rest of the groups, because no fetuses were found in the 4.0 mg/kg group and the 3.5 mg/kg group had significantly fewer fetuses than the remaining groups. The total fetal weight was similar among all groups with fetuses, and normal sex ratio of offspring was seen. More major and minor defects were seen in the 3.0 mg/kg T-2 toxin treated group than any other group. Secondly, a day response trial using a single dose of 3.0 mg/kg T-2 toxin given on either days 6, 7, 8, 10, 11 or 12 of gestation was undertaken. Maternal mortality, with placental hemorrhage, was observed. Fetal loss was greater in the T-2 toxin treated groups than in the starved controls. The greatest number of dead term fetuses was seen in mice treated on day 9 of gestation. Normal sex ratios were present in the offspring. Major skeletal defects were more numerous in mice treated on day 7 of gestation, whereas minor defects, retardations and variants were more common in mice treated on day 8. It was concluded that a single oral dose of T-2 toxin in propylene glycol is primarily maternotoxic and embryolethal, and that defective development was possibly secondary to maternal toxicity. PMID:3624788

Rousseaux, C G; Schiefer, H B

1987-08-01

276

High lipophilicity and high daily dose of oral medications are associated with significant risk for drug-induced liver injury.  

PubMed

Drug-induced liver injury (DILI) is a leading cause of drug failure in clinical trials and a major reason for drug withdrawals from the market. Although there is evidence that dosages of ?100 mg/day are associated with increased risk for hepatotoxicity, many drugs are safe at such dosages. There is an unmet need to predict risk for DILI more reliably, and lipophilicity might be a contributing factor. We analyzed the combined factors of daily dose and lipophilicity for 164 US Food and Drug Administration-approved oral medications and observed high risk for hepatotoxicity (odds ratio [OR], 14.05; P < 0.001) for drugs given at dosages ?100 mg/day and octanol-water partition coefficient (logP) ?3. This defined the "rule-of-two." Similar results were obtained for an independent set of 179 oral medications with 85% of the rule-of-two positives being associated with hepatotoxicity (OR, 3.89; P < 0.01). Using the World Health Organization's Anatomical Therapeutic Chemical classification system, the rule-of-two performed best in predicting DILI in seven therapeutic categories. Among 15 rule-of-two positives, 14 were withdrawn from hepatotoxic drugs, and one was over-the-counter medication labeled for liver injury. We additionally examined drug pairs that have similar chemical structures and act on the same molecular target but differ in their potential for DILI. Again, the rule-of-two predicted hepatotoxicity reliably. Finally, the rule-of-two was applied to clinical case studies to identify hepatotoxic drugs in complex comedication regimes to further demonstrate its use. Conclusion: Apart from dose, lipophilicity contributes significantly to risk for hepatotoxicity. Applying the rule-of-two is an appropriate means of estimating risk for DILI compared with dose alone. PMID:23258593

Chen, Minjun; Borlak, Jürgen; Tong, Weida

2013-07-01

277

Oral Contraceptives and Breast Cancer: Oral Contraceptives and Breast Cancer: Issues Related to Age, Duration of Use, Dose, and Latent Effects.  

National Technical Information Service (NTIS)

The report addresses the relative risk of breast cancer associated with prolonged use of oral contraceptives. Several studies are discussed which suggest that use of oral contraceptives may increase the risk of very early-occurring breast cancer, and that...

J. J. Schlesselman

1991-01-01

278

Bacterial Ghosts as an Oral Vaccine: a Single Dose of Escherichia coli O157:H7 Bacterial Ghosts Protects Mice against Lethal Challenge  

PubMed Central

Enterohemorrhagic Escherichia coli (EHEC) is a bacterial pathogen that is associated with several life-threatening diseases for humans. The combination of protein E-mediated cell lysis to produce EHEC ghosts and staphylococcal nuclease A to degrade DNA was used for the development of an oral EHEC vaccine. The lack of genetic material in the oral EHEC bacterial-ghost vaccine abolished any hazard of horizontal gene transfer of resistance genes or pathogenic islands to resident gut flora. Intragastric immunization of mice with EHEC ghosts without the addition of any adjuvant induced cellular and humoral immunity. Immunized mice challenged at day 55 showed 86% protection against lethal challenge with a heterologous EHEC strain after single-dose oral immunization and 93.3% protection after one booster at day 28, whereas the controls showed 26.7% and 30% survival, respectively. These results indicate that it is possible to develop an efficacious single-dose oral EHEC bacterial-ghost vaccine.

Mayr, Ulrike Beate; Haller, Christoph; Haidinger, Wolfgang; Atrasheuskaya, Alena; Bukin, Eugenij; Lubitz, Werner; Ignatyev, Georgy

2005-01-01

279

Metabolism of metamitron in goat following a single oral administration of a nontoxic dose level: a continued study.  

PubMed

Disposition kinetic behavior and metabolism studies of metamitron and its metabolite in terms of the parent compound were carried out in black Bengal goats after a single oral administration of a nontoxic oral dose at 30 mg kg(-1) of body weight. Metamitron was detected in the blood sample at 5 min (2.23 +/- 0.04 microg mL(-1)), maximum at 1 h (3.43 +/- 0.02 microg mL(-1)) and minimum at 12 h (0.41 +/- 0.01 microg mL(-1)), after a single oral administration. Metabolite [3-methyl-6-phenyl-1,2,4-triazin-5(4H)-one] in terms of the parent compound was detected in the blood sample at 5 min (0.47 +/- 0.006 microg mL(-1)), maximum at 6 h (5.12 +/- 0.02 microg mL(-1)) and minimum at 96 h (1.06 +/- 0.016 microg mL(-1)), after a single oral administration. The t(1/2 K) and Cl(B) values of metamitron were 3.63 +/- 0.05 h and 1.36 +/- 0.016 L kg(-1) h(-1), respectively, whereas the t(1/2K)(m) and Cl(B)(m) values of the metabolite were 38.15 +/- 0.37 h and 0.091 +/- 0.001 L kg(-1) h(-1), respectively, which suggested long persistence of the metabolite in blood and tissues of goat. Metamitron was excreted through feces and urine for up to 48 and 72 h, whereas the metabolite was excreted for up to 168 and 144 h, respectively. Metabolite alone contributed to 96 and 67% of combined recovery percentage of metamitron and metabolite against the administered dose in feces and urine of goat, respectively. All of the goat tissues except lung, adrenal gland, ovary, testis, and mammary gland retained the metabolite residue for up to 6 days after administration. PMID:15563222

Chanda, Debabrata; Debnath, Shiben C; Das, Shyamal K; Mandal, Tapan K; Bhattacharyya, Anjan; Choudhury, Ashim; Chakraborty, Animesh K

2004-12-01

280

Single and 90-day repeated oral dose toxicity studies of fermented Rhus verniciflua stem bark extract in Sprague-Dawley rats.  

PubMed

Fermented Rhus verniciflua stem bark (FRVSB) extract, an urushiol-free extract of Rhus verniciflua Stokes (RVS) fermented with Fomitella fraxinea, has various biological activities. The present study was carried out to investigate the potential toxicity of the FRVSB extract following single and repeated oral administration to Sprague-Dawley rats. In the single dose toxicity study, the FRVSB extract was administered orally to male and female rats at single doses of 0, 2500, 5000, and 10,000mg/kg. No animals died and no toxic changes were observed in clinical signs, body weight, and necropsy findings during the 15-day period following administration. In the repeated dose toxicity study, the FRVSB extract was administered orally to male and female rats for 90days at doses of 0, 556, 1667, and 5000mg/kg/day. There were no treatment-related adverse effects in clinical signs, body weight, food and water consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at any dose tested. The approximate lethal dose of the FRVSB extract was >10,000mg/kg in both genders, the oral no-observed-adverse-effect level of the FRVSB extract was >5000mg/kg/day in both genders, and no target organs were identified. PMID:23416650

Shin, Seo-Ho; Koo, Kyo-Hwan; Bae, Jin-Sook; Cha, Seung-Bum; Kang, In-Soo; Kang, Min-Soo; Kim, Hak-Soo; Heo, Hyun-Suk; Park, Min-Su; Gil, Gi-Hyun; Lee, Joo-Young; Kim, Kap-Ho; Li, Yinghua; Lee, Hyun-Kul; Song, Si-Whan; Choi, Han-Seok; Kang, Boo-Hyon; Kim, Jong-Choon

2013-05-01

281

Clinical pharmacokinetics of tonapofylline: evaluation of dose proportionality, oral bioavailability, and gender and food effects in healthy human subjects.  

PubMed

Tonapofylline is an antagonist of adenosine A1 receptor being developed for heart failure. In the present studies, pharmacokinetic characteristics, including dose proportionality, bioavailability, and effects of gender and food, were evaluated in healthy subjects receiving single-dose tonapofylline (0.2-375 mg) in a parallel or crossover design. Following oral administration, tonapofylline concentrations mostly peaked within 3 hours and declined over time in a multiple phasic manner. Based on a power model, dose proportionality of peak concentration (C(max)), area under the time-concentration curve for all values (AUC(all)), and area under the time-concentration curve to infinity (AUC(inf)) was concluded in a clinical setting. The bioavailability of tonapofylline was 81.2% (90% confidence interval, 70.6%-93.5%). Following intravenous administration, the steady-state volume of distribution of tonapofylline was estimated to be 756 mL/kg. The total clearance of tonapofylline was low (64.8 mL/h/kg), approximately 5% of hepatic blood flow. The terminal half-life was variable within groups and ranged from 11.2 to 24.2 hours across the dose range. Female subjects showed significantly higher C(max), AUC(all), and AUC(inf) than male subjects (P < .05). Food decreased C(max) by approximately 39%, whereas it did not appear to affect AUC(all) and AUC(inf). The intersubject variability of the pharmacokinetic parameters of tonapofylline was generally less than 30%. In these studies, a single dose of tonapofylline was safe and well tolerated. PMID:20926751

Li, Zhaoyang; TenHoor, Christopher; Marbury, Thomas; Swan, Suzanne; Ticho, Barry; Rogge, Mark; Nestorov, Ivan

2011-07-01

282

Single dose pharmacokinetics of oral tenofovir in plasma, peripheral blood mononuclear cells, colonic tissue, and vaginal tissue.  

PubMed

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??Ci) (14)C-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

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; Hendrix, Craig W

2013-11-01

283

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

PubMed Central

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

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

2012-01-01

284

Lead poisoning in cattle: reassessment of the minimum toxic oral dose  

SciTech Connect

After feeding male Holstein calves Pb acetate by nurse bottle it was found that daily Pb intakes of 2.7 mg Pb/kg can kill calves on milk diets in 20 days or less while 5.0 mg Pb/kg/day consistently caused signs of intoxication and death in 7 days. Absorption rate of Pb was rapid and tissue depositions were high in calves on milk replacer diet. Tissues were analyzed by atomic absorption spectrophotometry. Data suggest that diet, dosing method, and dosing time must be carefully considered in evaluations of minimum toxic dose. The consistent production of seizures at these low daily Pb intakes suggests that this calf model may be valuable in the study of Pb encephalopathy. (JMT)

Zmudski, J. (Texas A and M Univ., College Station); Bratton, G.R.; Womac, C.; Rowe, L.

1983-04-01

285

Very low oral doses of vitamin B-12 increase serum concentrations in elderly subjects with food-bound vitamin B-12 malabsorption.  

PubMed

The BOSSANOVA study, a randomized double-blind trial, was designed to test the ability of very low oral doses of vitamin B-12 to increase the serum vitamin B-12 concentration in elderly subjects with food-bound vitamin B-12 malabsorption, and to determine whether there was a dose response. We also aimed to quantitatively assess the most efficient dose to be added to flour in addition to folic acid (flour cofortification with vitamin B-12 and folic acid). Sixty-seven patients were randomly assigned to 1 of 6 groups receiving various daily oral doses of vitamin B-12 (i.e., 2.5, 5, 10, 20, 40, or 80 microg/d) for 30 d. The dose-response was tested for different biological variables using a mixed model, taking into account the variable's initial value (between-subject effect), a linear log-dose effect, and a linear log (dosextime) interaction, where time was d 15 or d 30. We planned to determine the amount of oral vitamin B-12 that would increase the serum vitamin B-12 concentration by 37 pmol/L (50 ng/L). Significant between-subject effects were found for serum vitamin B-12, plasma homocysteine, and methylmalonic acid concentrations, but a log-dose effect was found only for vitamin B-12 (P<0.001). The slope of the line tended to be higher (P=0.07) at d 30 than at d 15. For a mean serum vitamin B-12 increase of 37 pmol/L, a dose of 5.9 (95% CI, 0.9-12.1) microg/d was needed. We concluded that very low oral doses of vitamin B-12 increased serum vitamin B-12 concentrations in elderly subjects with subclinical vitamin B-12 deficiency, following a log-dose pattern. Our results could be beneficial in the design of a public health program for safe flour cofortification with folic acid. PMID:17237314

Blacher, Jacques; Czernichow, Sébastien; Raphaël, Mathilde; Roussel, Christophe; Chadefaux-Vekemans, Bernadette; Morineau, Gilles; Giraudier, Stéphane; Tibi, Annick; Henry, Olivier; Vayssière, Michel; Oudjhani, Moussa; Nadaï, Sophie; Vincent, Jean-Pierre; Bodak, Alexandre; Di Menza, Claude; Ménard, Joël; Zittoun, Jacqueline; Ducimetière, Pierre

2007-02-01

286

Chronic effects in mice caused by oral administration of sublethal doses of azaspiracid, a new marine toxin isolated from mussels.  

PubMed

Toxicological effects of orally administered azaspiracid (AZA), a new toxin isolated from mussels, were investigated. First, a total of 25 mice were administered AZA twice at 300-450 microg/kg doses and observed for recovery processes from severe injuries. Slow recoveries from injuries were revealed: erosion and shortened villi persisted in the stomach and small intestine for more than 3 months: edema, bleeding, and infiltration of cells in the alveolar wall of the lung for 56 days; fatty changes in the liver for 20 days; and necrosis of lymphocytes in the thymus and spleen for 10 days. Secondly, low doses of AZA (50, 20, 5 and 1 microg/kg) were administered twice a week up to 40 times to four groups of mice. Many mice, nine out of ten at 50 microg/kg and three out of ten at 20 microg/kg, became so weak that they were sacrificed before completion of 40 injections. All these mice showed interstitial pneumonia and shortened small intestinal villi. Most importantly, lung tumor were observed in four mice, one out of ten (10%) at 50 microg/kg and three out of ten (30%) at 20 microg/kg. Tumors were not observed in 11 mice treated at lower doses and in 19 control mice. Hyperplasia of epithelial cells was also observed in the stomach of six mice out of ten administered at 20 microg/kg. PMID:11689241

Ito, Emiko; Satake, Masayuki; Ofuji, Katsuya; Higashi, Morihiro; Harigaya, Kenichi; McMahon, Terry; Yasumoto, Takeshi

2002-02-01

287

Risk of ovarian cancer in relation to estrogen and progestin dose and use characteristics of oral contraceptives. SHARE Study Group. Steroid Hormones and Reproductions.  

PubMed

Although past studies have shown that oral contraceptives with 50 microg or more of estrogen reduce the risk of ovarian cancer, it is not clear whether newer, lower-dose formulations do as well. We conducted a population-based, case-control study in the Delaware Valley to assess the impact of dose of oral contraception on risk of ovarian cancer. Cases aged 20-69 years with a diagnosis of epithelial ovarian cancer ascertained between May 1994 and July 1999 (n = 767) were compared with community controls (n = 1,367). Compared with never users, the adjusted risk of ovarian cancer was reduced by 40% for oral contraceptive users overall, with longer duration of use affording greater protection. The ovarian cancer risk reduction was similar for women who initiated oral contraception before 1972, when high-dose pills dominated the market; between 1972 and 1980; and after 1980, when newer, lower-dose pills dominated. Oral contraceptive estrogen and progestin content were compared for cases and controls after adjustment for current age, number of pregnancies, race, and family history of ovarian cancer. Use of low-estrogen/low-progestin pills afforded an estimated risk reduction (odds ratio = 0.5, 95% confidence interval: 0.3, 0.6) that was identical to that for high-estrogen/high-progestin pills (odds ratio = 0.5, 95% confidence interval: 0.3, 0.7). PMID:10933270

Ness, R B; Grisso, J A; Klapper, J; Schlesselman, J J; Silberzweig, S; Vergona, R; Morgan, M; Wheeler, J E

2000-08-01

288

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

PubMed

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

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

2013-01-01

289

Repeated dose oral toxicity of Trivanga Bhasma in Swiss albino mice  

PubMed Central

Trivanga Bhasma, a metallic preparation containing Bhasmas of Naga (lead), Vanga (tin) and Yashada (zinc), was studied for repeated dose toxicity in Swiss albino mice to estimate No Observed Effect Level (NOEL) or No Observed Adverse Effect Level (NOAEL). A total of 80 Swiss albino mice of either sex with an average body weight of 28-30 g were equally divided into four groups (Group I, II, III, and IV). Group I served as control and was given vehicle (honey: water in 2:3 ratio) Group II, III, and IV received Trivanga Bhasma @ 7.8, 39.5,and 78 mg/kg body weight for 90 consecutive days. The effect of drug was assessed on body weight, feed and water consumption changes, hematological, and histopathological parameters. At the end of the study, all animals were sacrificed and examined for gross pathological changes. Histopathological evaluation was performed for control and high dose group. Trivanga Bhasma was found to be safe. No significant clinical signs were noted in all groups studied. No major alterations were observed during histopathological evaluation. Hence, dose rate of 78 mg/kg body weight was established as NOAEL. It is suggested to carry out a toxicity study at possible higher doses and in a different species so as to establish target organ of toxicity.

Jamadagni, Pallavi S.; Jamadagni, Shrirang B.; Singh, Rajendrakumar; Gaidhani, Sudesh N.; Upadhyay, Sachchidanand; Hazra, Jayram

2013-01-01

290

High Doses Intravenous Immunoglobulin versus Oral Cyclosporine in the Treatment of Severe Atopic Dermatitis  

Microsoft Academic Search

Atopic dermatitis is one of the most common allergic diseases that almost always respond to conventional therapies with topical emollient, topical corticosteroids, systemic antihistamines and allergic abstinence. However few cases of atopic dermatitis with severe course do not respond to conventional therapies and high dose of intravenous immunoglobulin or cyclosporine are recommended for them. This clinical trial study has been

Mohammad Hassan Bemanian; Masoud Movahedi; Abolhassan Farhoudi; Mohammad Gharagozlou; Mehran Heidari Seraj; Zahra Pourpak; Mohammad Nabavi; Asghar Aghamohammadi; Zahra Shirkhoda

291

Vitamin A status of Filipino preschool children given a massive oral dose.  

PubMed

The protection period of a 200,000 IU of vitamin A on Filipino children was determined. Subjects were 105 children aged 1-5 years given a single massive dose during the "Araw ng Sangkap Pinoy" (ASAP) in March 1995. Serum retinol was measured by HPLC at baseline, one, two, four and six months after the administration of the dose. Results showed that baseline serum retinol levels were significantly lower than all follow-up values. Serum retinol values were maintained at levels higher than pre-supplementation values although the values decreased on the second month after supplementation. The proportions of deficient and low (< 20 microg/dl) levels were significantly lower one and six months after supplementation. All follow-up serum retinol levels of children with deficient and low values at baseline were significantly lower (p < 0.001) than those with normal values. The WHO recommendation of 200,000 IU was effective in increasing serum retinol concentrations and maintaining it above pre-supplementation levels up to 6 months after administration of the dose. It also replenished organic vitamin A reserves as shown by the dose response (S30DR) approach. Incidence of infection also decreased among the children. Supplementation with vitamin A has likewise resulted in an increase in hemoglobin values and a decrease in the proportion of anemics (Hb < 11.0 g/dl) among the children. PMID:9253886

Perlas, L A; Florentino, R F; Fuertes, R T; Madriaga, J R; Cheong, R L; Desnacido, J A; Marcos, J M; Cabrera, M I

1996-12-01

292

Effect of CYP2C19 genotypes on the pharmacokinetic\\/pharmacodynamic relationship of rabeprazole after a single oral dose in healthy Chinese volunteers  

Microsoft Academic Search

Aims  To explore the pharmacokinetic\\/pharmacodynamic relationship of rabeprazole and the role of CYP2C19 genotypes after a single\\u000a oral dose in healthy Chinese volunteers by a population approach.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Plasma concentration time profile data and intragastric pH values of 19 genotyped healthy male adults after a single oral\\u000a dose of rabeprazole in an open label randomized fashion were used for this population analysis.

Yu-Cheng Sheng; Kun Wang; Ying-Chun He; Juan Yang; Qing-Shan Zheng

2010-01-01

293

The effects of age on the pharmacokinetics and pharmacodynamics of single oral doses of benazepril and enalapril.  

PubMed

1. Eighteen healthy, normotensive subjects (nine young and nine elderly) participated in a double-blind, 3-way, crossover study to compare aspects of the pharmacokinetics and pharmacodynamics of single oral doses of 10 mg benazepril, 10 mg enalapril and placebo. 2. The hypotensive effect was similar after both drugs but the absolute reductions were greater in the elderly who had higher initial levels of blood pressure. 3. The AUCs for both benazeprilat and enalaprilat were higher in the elderly but by a significantly greater amount for enalaprilat (+ 113% vs 40%; P < 0.01). 4. The AUCs for both drugs tended to be highest in subjects with the lowest creatinine clearance. 5. The changes in kinetics and dynamics observed in the elderly after benazepril are qualitatively similar to those with other ACE inhibitors. The clinical significance of the quantitative differences requires further investigation. PMID:9114905

Macdonald, N J; Sioufi, A; Howie, C A; Wade, J R; Elliott, H L

1993-09-01

294

Pharmacokinetics of the individual enantiomer S-(+)-ketoprofen after intravenous and oral administration in dogs at two dose levels.  

PubMed

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??g/ml, at two dose levels, respectively. The absolute bioavailability after PO route was 88.66?±?12.95% and 85.36?±?13.90%, respectively. PMID:24746290

Serrano-Rodríguez, J M; Serrano, J M; Rodríguez, J Morgaz; Machuca, M M Granados; Gómez-Villamandos, R J; Navarrete-Calvo, R

2014-06-01

295

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

PubMed Central

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

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

2014-01-01

296

Medroxyprogesterone acetate pharmacokinetics following oral high-dose administration in humans: a bioavailability evaluation of a new MPA tablet formulation.  

PubMed

The pharmacokinetics of medroxyprogesterone acetate (MPA) in healthy female volunteers have been investigated following oral administration of single doses of six different high-dose MPA tablet formulations. Blood samples were obtained over 96 hrs following administration. The plasma was separated and analyzed in duplicate for MPA by radioimmunoassay (RIA) after extraction with petroleum ether. A two compartment open model with first order absorption was computer-fitted to the plasma concentration of MPA. Following oral administration MPA is rapidly transferred from the gastrointestinal tract to the blood circulation with a half-life of the absorption process of 15-30 min. The peak plasma concentration is reached 1-3 hrs after administration, and the biological half-life of MPA is 40-60 hrs. Following administration of 1000 mg MPA the areas under the plasma concentration-time curves (AUC 0-infinity) were calculated to (mean and S.E.): 3357 (438) nmol/l and 2403 (245) nmol/l for Leo formulation A and Farlutal, respectively (P less than 0.02). Following administration of 500 mg the areas were: 2325 (389) nmol/l, 1793 (312) nmol/l, 1778 (239) nmol/l, 1178 (209) nmol/l, and 556 (89) nmol/l for Gestapuran, Leo formulation A (P = n.s.), Leo formulation B (P = n.s.), Provera (P less than 0.001), and Lutopolar (P less than 0.001), respectively. The in vitro dissolution rates of MPA from the tablet formulations were determined and compared with the results of the bioavailability studies, indicating that a rapid dissolution rate as well as the particle size of MPA are two important factors to ensure optimal absorption of MPA from the gastrointestinal tract. PMID:2943134

Johansson, E D; Johansen, P B; Rasmussen, S N

1986-05-01

297

Acquisition of oral phencyclidine (PCP) self-administration in rhesus monkeys: effects of dose and an alternative non-drug reinforcer  

Microsoft Academic Search

The effects of drug dose and a non-drug alternative reinforcer on acquisition of oral PCP self-administration in rhesus monkeys\\u000a were examined. Acquisition was studied using three groups of monkeys (seven subjects per group). One group received a low\\u000a PCP dose (0.0375?mg\\/delivery) and the other two received a high PCP dose (0.15?mg\\/delivery). One of the high dose groups had\\u000a concurrent access

U. C. Campbell; Sherry S. Thompson; Marilyn E. Carroll

1998-01-01

298

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

Microsoft Academic Search

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

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

2011-01-01

299

Recombinant human endostatin administered as a 28-day continuous intravenous infusion, followed by daily subcutaneous injections: a phase I and pharmacokinetic study in patients with advanced cancer  

Microsoft Academic Search

BACKGROUND: Endostatin is an endogenous collagen XVIII-fragment with anti-angiogenic properties and remarkable antitumor activity in mice. Preclinical data suggest that continuous low dose administration of endostatin is much more potent than intermittent dosing. The feasibility of this approach is tested in a phase I study. PATIENTS AND METHODS: We determined the safety and pharmacokinetic profile of 4-week continuous intravenous infusion

A. H. G. Hansma; H. J. Broxterman; Horst van der I; Y. Yuana; E. Boven; G. Giaccone; H. M. Pinedo; K. Hoekman

2005-01-01

300

Phase I Dose Escalation Trial Evaluating the Pharmacokinetics, Anti-Human Cytomegalovirus (HCMV) Activity, and Safety of 1263W94 in Human Immunodeficiency Virus-Infected Men with Asymptomatic HCMV Shedding  

PubMed Central

1263W94 [maribavir; 5,6-dichloro-2-(isopropylamino)-1,?-l-ribofuranosyl-1-H-benzimidazole] is a novel benzimidazole compound for treatment of human cytomegalovirus (HCMV) infection and disease, with potent in vitro activity against HCMV and good oral bioavailability. A phase I study was conducted to determine the pharmacokinetics (PK), anti-HCMV activity, and safety of 1263W94 administered as multiple oral doses to human immunodeficiency virus type 1-infected adult male subjects with asymptomatic HCMV shedding. Subjects received one of six dosage regimens (100, 200, or 400 mg three times a day, or 600, 900, or 1,200 mg twice a day) or a placebo for 28 days. 1263W94 demonstrated linear PK, with steady-state plasma 1263W94 profiles predictable based on single-dose data. 1263W94 was rapidly absorbed following oral dosing, and values for the maximum concentration of the drug in plasma and the area under the concentration-time curve increased in proportion to the dose. 1263W94 demonstrated in vivo anti-HCMV activity in semen at all of the dosage regimens tested, with mean reductions in semen HCMV titers of 2.9 to 3.7 log10 PFU/ml among the four regimens evaluated for anti-HCMV activity. 1263W94 was generally well tolerated; taste disturbance was the most frequently reported adverse event over the 28-day dosing period.

Lalezari, Jacob P.; Aberg, Judith A.; Wang, Laurene H.; Wire, Mary Beth; Miner, Richard; Snowden, Wendy; Talarico, Christine L.; Shaw, Shuching; Jacobson, Mark A.; Drew, W. Lawrence

2002-01-01

301

Pharmacokinetics of Aprepitant After Single and Multiple Oral Doses in Healthy Volunteers  

Microsoft Academic Search

Aprepitant is the first NK1 receptor antagonist approved for use with corticosteroids and 5HT3 receptor antagonists to prevent chemotherapy-induced nausea and vomiting (CINV). The effective dose to prevent CINV is a 125-mg capsule on day 1 followed by an 80-mg capsule on days 2 and 3. Study 1 evaluated the bioavailability of the capsules and estimated the effect of food.

Anup K. Majumdar; Laura Howard; Michael R. Goldberg; Lisa Hickey; Marvin Constanzer; Paul L. Rothenberg; Tami M. Crumley; Deborah Panebianco; Thomas E. Bradstreet; Arthur J. Bergman; Scott A. Waldman; Howard E. Greenberg; Kathleen Butler; A. Knops; Inge De Lepeleire; Nicole Michiels; Kevin J. Petty

2006-01-01

302

Evaluation of oral therapy on Mansonial Schistosomiasis using single dose of Balanites aegyptiaca fruits and praziquantel  

Microsoft Academic Search

The efficacy of Balanites aegyptiaca fruit mesocarp was compared with praziquantel in mice infected with Sudanese strain of Schistosoma mansoni. Infected mice were given a single dose of 200 mg\\/kg body weight of B. aegyptiaca fruit mesocarp and 200 mg\\/kg b.w. of praziquantel after 6 weeks from the onset of the infection.A significant reduction was observed in EPG (egg count

W. S. Koko; H. S. Abdalla; M. Galal; H. S. Khalid

2005-01-01

303

The influence of food on the absorption of diclofenac after single and multiple oral doses  

Microsoft Academic Search

A single dose of enteric-coated diclofenac sodium was taken fasting and immediately after a standard breakfast by twelve healthy volunteers. A considerable delay in the onset of absorption was observed, non-fasting, varying from 2.5 to 12 h compared with 1.5 to 2.75 h when fasting. Peak plasma concentrations were reduced after food but areas under plasma concentration-time curves were comparable.

J. V. Willis; M. J. Kendall; D. B. Jack

1981-01-01

304

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

Microsoft Academic Search

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

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

1998-01-01

305

Low-dose oral anticoagulation in patients with mechanical heart valve prostheses: final report from the early self-management anticoagulation trial II  

Microsoft Academic Search

Aims In mechanical heart valve recipients, low-dose international normalized ratio (INR) self- management of oral anticoagulants can reduce the risk of developing thrombo-embolic events and improve long-term survival compared with INR control by a general practitioner. Here, we present data on the safety of low-dose INR self-management. Methods and results In a prospective, randomized multi-centre trial, 1346 patients with a

Heinrich Koertke; Armin Zittermann; Gero Tenderich; Otto Wagner; Mahmoud El-Arousy; Arno Krian; Juergen Ennker; Uwe Taborski; Wolf Peter Klovekorn; Rainer Moosdorf; Werner Saggau; Reiner Koerfer

2007-01-01

306

Single-Dose Oral Toxicity Study of a Cross-linked Sodium Polyacrylate\\/Polyvinyl Alcohol Copolymer in Chickens ( Gallus domesticus)  

Microsoft Academic Search

A single-dose oral toxicity study of a grafted copolymer of cross-linked sodium polyacrylate with polyvinyl alcohol was conducted in chickens (Gallus domesticus) to demonstrate this copolymer's safety for use as a hydration medium in recently hatched poultry chicks. Three experimental groups, each composed of 25 male and 25 female 1-day-old chicks, were administered a one-time dose of 0, 3, or

Joachim Haselbach; Ted Berner; Harris Wright; Elizabeth Dunlap

2000-01-01

307

Twice- or Once-Daily Dosing of Novel Oral Anticoagulants for Stroke Prevention: A Fixed-Effects Meta-Analysis with Predefined Heterogeneity Quality Criteria  

PubMed Central

Background A number of novel oral anticoagulants (direct thrombin inhibitors or factor Xa inhibitors) are in clinical use for various indications. The dosing regimens differ between twice-daily and once-daily dosing for the prevention of stroke in patients with atrial fibrillation. With the availability of the results from four phase 3 studies (>70,000 patients), we explored whether twice-daily or once-daily dosing provides better risk-benefit balance among novel oral anticoagulants. Methods We conducted a strict, stepwise, fixed-effects meta-analysis with predefined heterogeneity quality criteria to generate the most appropriate common estimates for twice-daily (BID) or once-daily (QD) dosing regimens. An indirect comparison of these dosing regimens with fixed-effects meta-analysis common estimates (where available), or individual compound results, was done respectively. Results Comparing indirectly BID vs QD dosing regimens resulted in hazard ratios (HR [95% confidence interval]) for stroke and systemic embolism of 0.75 (0.58–0.96) for dabigatran 150 mg BID, and 0.91 (0.73–1.13) for apixaban BID vs the QD dosing regimen. For ischemic stroke, the HR of BID vs QD was 0.85 (0.69–1.05). For intracranial hemorrhage, BID vs rivaroxaban QD was 0.57 (0.37–0.88) and, vs edoxaban QD, 0.81 (0.54–1.22). Due to heterogeneity, common estimates for major bleeding QD or BID were not justified, therefore indirect comparison of regimens were not possible. All non-vitamin K antagonist oral anticoagulants reduced all-cause mortality vs warfarin with a HR of 0.90 (0.86–0.96) without differences between regimen. Conclusions Based on the available phase 3 study evidence, the twice-daily dosing regimen of non-vitamin K antagonist oral anticoagulants appears to offer a more balanced risk-benefit profile with respect to stroke prevention and intracranial hemorrhage.

Clemens, Andreas; Noack, Herbert; Brueckmann, Martina; Lip, Gregory Y. H.

2014-01-01

308

A 90-day repeated dose oral (gavage) toxicity study of perfluorohexanoic acid (PFHxA) in rats (with functional observational battery and motor activity determinations)  

Microsoft Academic Search

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

Christopher P. Chengelis; Jeannie B. Kirkpatrick; Ann Radovsky; Motoki Shinohara

2009-01-01

309

Oral high dose ascorbic acid treatment for one year in young CMT1A patients: a randomised, double-blind, placebo-controlled phase II trial  

Microsoft Academic Search

BACKGROUND: High dose oral ascorbic acid substantially improved myelination and locomotor function in a Charcot-Marie-Tooth type 1A mouse model. A phase II study was warranted to investigate whether high dose ascorbic acid also has such a substantial effect on myelination in Charcot-Marie-Tooth type 1A patients and whether this treatment is safe. METHODS: Patients below age 25 years were randomly assigned

Camiel Verhamme; Rob J de Haan; Marinus Vermeulen; Frank Baas; Marianne de Visser; Ivo N van Schaik

2009-01-01

310

The effect of two different doses comprising the simultaneous administration of intravenous B-complex vitamins and oral folic acid on serum homocysteine levels in hemodialysis patients  

Microsoft Academic Search

Background: Several regimens using different doses of folic acid (FA) alone or supplemented with B-complex vitamins (BCVs) have been\\u000a tested for their ability to reduce total homocysteine (tHcy) serum levels in hemodialysis (HD) patients. In the present study,\\u000a we assessed the effect of two different doses comprising the simultaneous administration of intravenous (IV) BCVs and an oral\\u000a FA supplementation on

Kostas Sombolos; Anna Papaioannou; Fotini Christidou; Taisir Natse; Gerasimos Bamichas; Lazaros Gionanlis; George Katsaris; Evagelia Progia

2006-01-01

311

Cardiovascular safety of sublingual apomorphine in patients on stable doses of oral antihypertensive agents and nitrates.  

PubMed

Sublingual (SL) apomorphine (2 to 6 mg) has been shown to be effective for treatment of male erectile dysfunction. Many patients with erectile dysfunction are also being treated for systemic hypertension and/or cardiovascular disease. In a double-blind, randomized, placebo-controlled, crossover trial, SL apomorphine 5 mg and placebo were administered on alternate days to 162 men who were on long-term therapy (> or =4 weeks) with angiotensin-converting enzyme inhibitors, beta blockers, diuretics, calcium channel blockers, alpha(1) blockers, or short- or long-acting nitrates. Blood pressure and heart rate were measured before and after dosing; cardiac rhythm was recorded by 4-hour Holter monitoring. The only potentially clinically significant interactions between SL apomorphine and the antihypertensive agents or short-acting nitrates were greater orthostatic decreases in systolic blood pressure in the alpha-blocker and calcium channel blocker groups (-10 and -6 mm Hg vs placebo, respectively). Administration of SL apomorphine after dosing with long-acting nitrates resulted in significant decreases in blood pressure when patients were standing (mean systolic change, -5 to -9 mm Hg 30 to 60 minutes postdose, p <0.05; mean diastolic change, -3 to -4 mm Hg 50 to 60 minutes postdose, p <0.05). The most common adverse events with SL apomorphine were dizziness, nausea, and headache. Syncope occurred in 1 patient in the beta-blocker group; symptomatic hypotension occurred in 2 patients each in the short- and long-acting nitrate groups. Thus, in patients receiving common antihypertensive agents and short-acting nitrates, as well as in most patients receiving long-acting nitrates, SL apomorphine at higher than recommended doses produced no clinically significant changes in heart rate or blood pressure greater than changes seen with SL apomorphine alone. PMID:11589843

Fagan, T C; Buttler, S; Marbury, T; Taylor, A; Edmonds, A

2001-10-01

312

Oral low dose and topical tamoxifen for breast cancer prevention: modern approaches for an old drug  

PubMed Central

Tamoxifen is a drug that has been in worldwide use for the treatment of estrogen receptor (ER)-positive breast cancer for over 30 years; it has been used in both the metastatic and adjuvant settings. Tamoxifen's approval for breast cancer risk reduction dates back to 1998, after results from the Breast Cancer Prevention Trial, co-sponsored by the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project, showed a 49% reduction in the incidence of invasive, ER-positive breast cancer in high-risk women. Despite these positive findings, however, the public's attitude toward breast cancer chemoprevention remains ambivalent, and the toxicities associated with tamoxifen, particularly endometrial cancer and thromboembolic events, have hampered the drug's uptake by high-risk women who should benefit from its preventive effects. Among the strategies to overcome such obstacles to preventive tamoxifen, two novel and potentially safer modes of delivery of this agent are discussed in this paper. Low-dose tamoxifen, expected to confer fewer adverse events, is being investigated in both clinical biomarker-based trials and observational studies. A series of systemic biomarkers (including lipid and insulin-like growth factor levels) and tissue biomarkers (including Ki-67) are known to be favorably affected by conventional tamoxifen dosing and have been shown to be modulated in a direction consistent with a putative anti-cancer effect. These findings suggest possible beneficial clinical preventive effects by low-dose tamoxifen regimens and they are supported by observational studies. An alternative approach is topical administration of active tamoxifen metabolites directly onto the breast, the site where the cancer is to be prevented. Avoidance of systemic administration is expected to reduce the distribution of drug to tissues susceptible to tamoxifen-induced toxicity. Clinical trials of topical tamoxifen with biological endpoints are still ongoing whereas pharmacokinetic studies have already shown that appropriate formulations of drug successfully penetrate the skin to reach breast tissue, where a preventive effect is sought.

2012-01-01

313

Performance properties of the population bioequivalence approach for in vitro delivered dose for orally inhaled respiratory products.  

PubMed

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. PMID:24249218

Morgan, Beth; Strickland, Helen

2014-01-01

314

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

PubMed

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

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

2014-04-01

315

Making the leap from daily oral dosing to long-acting injectables: lessons from the antipsychotics.  

PubMed

There are now long-acting versions of six antipsychotic drugs on the U.S. market, and with them, five unique combinations of molecular form and delivery strategy long-acting-injectable-antipsychotics (LAIAs) show evidence of reduced relapses of schizophrenia, but their introduction has been slow, taking at least nine years after the approval of each oral drug. Oily solutions of lipophilic prodrugs were the first to enter the LAIA market, but they relied on esterification of a hydroxyl handle that was lost with the emergence of the atypical antipsychotics. A review of the literature and patents shows that companies tested many different approaches before reaching the currently marketed versions, including aqueous suspensions of poorly soluble salts, polymeric microspheres, and new approaches to making prodrugs. Yet, very little has been published to support faster development of safe long-acting injectables (LAIs). This review introduces some of the critical considerations in creating an LAI; then it analyzes the existing products and discusses areas where further research is needed. The available literature suggests that lipophilic prodrugs may be inherently safer than poorly soluble salts as LAIs. Other areas needing additional study include (1) the range of physical properties acceptable for LAIs and the effect of prodrug tail length in achieving them, and (2) the role of physiological responses at the injection site in the release of drug from a depot. PMID:24679167

Remenar, Julius F

2014-06-01

316

Evaluation of oral therapy on Mansonial Schistosomiasis using single dose of Balanites aegyptiaca fruits and praziquantel.  

PubMed

The efficacy of Balanites aegyptiaca fruit mesocarp was compared with praziquantel in mice infected with Sudanese strain of Schistosoma mansoni. Infected mice were given a single dose of 200 mg/kg body weight of B. aegyptiaca fruit mesocarp and 200 mg/kg b.w. of praziquantel after 6 weeks from the onset of the infection. A significant reduction was observed in EPG (egg count per gram of faeces), eggs burden in tissues and recovery of adult worms (P<0.05) for both the plant and the drug-treated animals. PMID:15664459

Koko, W S; Abdalla, H S; Galal, M; Khalid, H S

2005-01-01

317

Phase I Study of Oral Azacitidine in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia  

PubMed Central

Purpose To determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). Patients and Methods Patients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m2) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received ? 6 cycles of oral azacitidine. Results Overall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (ie, complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients. Conclusion Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML.

Garcia-Manero, Guillermo; Gore, Steven D.; Cogle, Christopher; Ward, Renee; Shi, Tao; MacBeth, Kyle J.; Laille, Eric; Giordano, Heidi; Sakoian, Sarah; Jabbour, Elias; Kantarjian, Hagop; Skikne, Barry

2011-01-01

318

Oral dosing with papaya latex is an effective anthelmintic treatment for sheep infected with Haemonchus contortus  

PubMed Central

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 ?mol 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.

2011-01-01

319

Equivocal Effects of Threshold Doses of E. Coli II L-Asparaginase on the Liver and Bsp Clearances of Rhesus Monkeys Given Oral Dosages of L-Asparagine.  

National Technical Information Service (NTIS)

These studies were initiated to determine whether oral treatment with 1 g/kg T.I.D. of L-Asparagine would prevent the fatty liver produced by EC II L-Asparaginase. Dose levels of 10 and 40 I.U./kg/day x 5, I.V., were used since two animals previously trea...

N. Rakieten

1971-01-01

320

Toxicity of Single Oral and Intravenous Doses of 3-Tritylthio-L-Alanine (Trityl-Cysteine) NSC 83265 in Dogs and Rats.  

National Technical Information Service (NTIS)

The toxicity of single oral and intravenous doses of 3-tritylthio-L-alanine, (NSC 83265) was evaluated in dogs (at Levels between 500 and 60,000 mg/sq m), and rats (at levels between 150 and 10,800 mg/sq m). Criteria evaluated for toxic effect were mortal...

D. R. Patterson W. L. Fezio A. M. Guarino D. A. Cooney R. D. Davis

1980-01-01

321

Interstitial Brachytherapy with Ir192 Low-Dose-Rate in the Treatment of Primary and Recurrent Cancer the Oral Cavity and Oropharynx  

Microsoft Academic Search

Aim: To evaluate the impact of postoperative interstitial brachytherapy with and without external radiotherapy in the treatment of primary and recurrent squamous cell carcinoma of the oral cavity and oropharynx. Patients and Methods: Between 1985 and 1997, a total of 318 patients were treated by interstitial Ir-192 low-dose-rate brachytherapy as part of their primary (n = 236) or recurrent treatment

Gerhard G. Grabenbauer; Claus Rödel; Thomas Brunner; Stefan Schulze-Mosgau; Vratislav Strnad; Reinhold G. Müller; Heiner Iro; Rolf Sauer

2001-01-01

322

Circadian Variation in Urinary Excretion of Ciprofloxacin after a Single-Dose Oral Administration at 1000 and 2200 Hours in Human Subjects  

Microsoft Academic Search

Ciprofloxacin is routinely prescribed to treat a variety of infections, including those of the urinary tract. To achieve optimum therapeutic benefits of the drug, all of the factors which influence its pharmacokinetics and effectiveness need to be determined. This study investigated the urinary excretion kinetics of ciprofloxacin upon oral administration of a single dose of 250 mg at 1000 or

V. V. SARVESHWER RAO; D. RAMBHAU; B. RAMESH RAO; P. SRINIVASU

1997-01-01

323

Comparison of Serum Ethinyl Estradiol, Sex-Hormone-Binding Globulin, Corticoid-Binding Globulin and Cortisol Levels in Women Using Two Low-Dose Combined Oral Contraceptives  

Microsoft Academic Search

The study included 69 women taking a desogestrel (n = 30)- or gestodene (n = 39)-containing low-dose combined oral contraceptive for at least 3 months. Group size was calculated to detect a difference in mean values of 80% of 1 standard deviation (? = 0.05, ? = 0.1). Seven serum samples were obtained up to 4 h, and 1 sample

M. Hümpel; U. Täuber; W. Kuhnz; M. Pfeffer; K. Brill; R. Heithecker; T. Louton; B. Steinberg

1990-01-01

324

Osteonecrosis Following Short-term, Low-dose Oral Corticosteroids: A Population-based Study of 24 Million Patients.  

PubMed

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

Dilisio, Matthew F

2014-07-01

325

Dose-related effects of a neonatal 6-OHDA lesion on SKF 38393- and m-chlorophenylpiperazine-induced oral activity responses of rats.  

PubMed

Neonatal 6-hydroxydopamine (6-OHDA) treatment of rats is associated with concurrent supersensitization of dopamine (DA) D1 and serotonin 5-HT1C receptors, for agonist-induced oral activity. The present study was conducted to determine if graded reduction of striatal DA content and/or graded elevation of striatal 5-HT content by 6-OHDA would alter sensitivity of either receptor type, and thereby influence oral activity responses to DA and 5-HT agonists. At 3 days after birth, groups of rats were pretreated with desipramine (20 mg/kg i.p.), 1 h before administration of a range of doses of 6-OHDA HBr (15, 30, 60, 100, 150 and 200 micrograms, i.c.v., salt form; half in each lateral ventricle) or the vehicle, saline (0.85%)-ascorbic acid (0.1%). Between 2 and 4 months, a series of challenge doses of SKF 38393 HCl (0.30 to 3.0 mg/kg i.p.) and m-chlorophenylpiperazine 2HCl (0.30 to 6.0 mg/kg i.p.; m-CPP 2HCl) were administered to each group of rats and oral activity was observed. Oral activity was determined for 1 min every 10 min during a 60-min period, starting 10 min after injection of agonist or vehicle. SKF 38393 dose-response curves demonstrated enhanced oral activity responses in rats lesioned neonatally with 150 or 200 micrograms of 6-OHDA. m-CPP dose-response curves demonstrated enhanced oral activity responses in these 2 groups of rats, as well as those lesioned neonatally with 100 micrograms of 6-OHDA. Striatal DA content was reduced by > 97% in these 3 groups of rats.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:8149589

Gong, L; Kostrzewa, R M; Perry, K W; Fuller, R W

1993-12-17

326

Erratum : Thesaurus for histopathological findings in publically available reports of repeated-dose oral toxicity studies in rats for 156 chemicals.  

PubMed

Because histopathological findings are often conclusive indicators of the toxicities of chemicals, standardization of nomenclature and construction of a thesaurus for histopathological findings are important for the comparative evaluation of histopathological data from repeated-dose toxicity studies (RTS). however, terms for histopathological findings have not been standardized and different technical terms are used to indicate almost the same things in RTS. The present study was conducted to construct and easy-to-use thesaurus for histopathological findings in order to facilitate hazard assessments of untested chemicals by the category approach using knowledge of the toxicity of analogue chemicals. We used reports of 28-day RTS, conducted on rats by gavage, which were posted on the websites of the National Institute of health Sciences (NIHS) and the National Institute of Technology and Evaluation (NITE). The histopathological data were from 156 reports on RTS conducted by 13 institutions in Japan. As a result of this study, major parts of the thesaurus were devoted to the findings in the liver, kidney, stomach, adrenal, thyroid and testis; the first three organs are known to be the main targets of chemicals. We also decided that findings such as swelling and enlargement of hepatocytes should be categorized as synonyms for terms meaning hypertrophy. Our thesaurus will be helpful in assessing or screening new untested chemical by the category approach using knowledge of the toxicities of analogues of the new chemical. The RTS database with this thesaurus will be made publically available in 2010. PMID:20571254

Nishikawa, Satoshi; Yamashita, Tatsuhiro; Imai, Toshio; Yoshida, Midori; Sakuratani, Yuki; Yamada, Jun; Maekawa, Akihiko; Hayashi, Makoto

2010-08-01

327

Bioequivalence assessment of ambroxol tablet after a single oral dose administration to healthy male volunteers.  

PubMed

A bioequivalence study of the ambroxol hydrochloride tablets was conducted. Twenty-four healthy male Korean volunteers received each medicine at the ambroxol hydrochloride dose of 30 mg in a 2 x 2 cross-over study. There was a 1-week washout period between the doses. Plasma concentrations of ambroxol were monitored by a high-performance liquid chromatography (HPLC) for over a period of 24h after the administration. AUC(t) (the area under the plasma concentration-time curve from time 0 to last sampling time, 24h) was calculated by the linear-log trapezoidal rule method. C(max) (maximum plasma drug concentration) and T(max) (time to reach C(max)) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUC(t) and C(max), and untransformed T(max). The geometric mean of AUC(t) was 495.8 ng ml(-1)h(-1) (test medication) and 468.3 ng ml(-1)h(-1) (reference medication). C(max) of 61.5 and 57.3 ng ml(-1) were achieved for the test and the reference medication, respectively. The point estimates and 90% confidence intervals for AUC(t) (parametric) and C(max) (parametric) were, in point estimate (90% confidence interval), 1.058 (0.989-1.134) and 1.073 (1.007-1.142), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value of T(max) was 0.229 (0.015-0.444). These results indicate that the two medications of ambroxol hydrochloride are bioequivalent and, thus, may be prescribed interchangeably. PMID:14597158

Lee, Hee Joo; Joung, Sun Koung; Kim, Yoon Gyoon; Yoo, Jeong-Yeon; Han, Sang Beom

2004-01-01

328

Protective effect of an acute oral loading dose of trimetazidine on myocardial injury following percutaneous coronary intervention  

PubMed Central

Objective To evaluate the effect of pre?procedural acute oral administration of trimetazidine (TMZ) on percutaneous coronary intervention (PCI)?induced myocardial injury. Design Single?centre, prospective, randomised evaluation study. Setting Patients with stable angina pectoris and single?vessel disease undergoing PCI. Patients 582 patients were prospectively randomised. Patients who underwent more than one inflation during PCI were excluded, resulting in 266 patients randomly assigned to 2 groups. Interventions Patients were randomly assigned to receive or not an acute loading dose of 60?mg of TMZ prior to intervention. Main outcome The frequency and the increase in the level of cardiac troponin Ic (cTnI) after successful PCI. cTnI levels were measured before and 6, 12, 18 and 24?h after PCI. Results 136 patients were assigned to the TMZ group and 130 to the control group. Although no statistically significant difference was observed in the frequency of cTnI increase between the two groups, post?procedural cTnI levels were significantly reduced in the TMZ group at all time points (6?h: mean (SD) 4.2 (0.8) vs 1.7 (0.2), p<0.001; 12?h: 5.5 (1.5) vs 2.3 (0.4), p<0.001; 18?h: 9 (2.3) vs 3 (0.5), p<0.001; and 24?h: 3.2 (1.2) vs 1 (0.5), p<0.001). Moreover, the total amount of cTnI released after PCI, as assessed by the area under the curve of serial measurement, was significantly reduced in the TMZ group (p<0.05). Conclusion Pre?procedural acute oral TMZ administration significantly reduces PCI?induced myocardial infarction.

Bonello, Laurent; Sbragia, Pascal; Amabile, Nicolas; Com, Olivier; Pierre, Sandrine V; Levy, Samuel; Paganelli, Franck

2007-01-01

329

[Pharmacokinetics and relative bioavailability of THC and THC-solid dispersion orally to mice at single dose].  

PubMed

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 bioavailability of THC-solid dispersion show significant improvement compared to THC. PMID:24956859

Liao, Li; Hua, Hua; Zhao, Jun-Ning; Luo, Heng; Yang, An-Dong

2014-03-01

330

The phenomenon and cause of the dose-dependent oral absorption of chlorothiazide in rats: Extrapolation to human data based on the body surface area concept  

Microsoft Academic Search

The reported incomplete and dose-dependent absorption of chlorothiazide in humans was demonstrated in six rats after five oral solutions at doses of 0.93, 2.55, 9.23, 25.6, and 70.2 mg\\/kg. Mean 48-hr urinary recoveries of intact drug were 57.3, 50.4, 36.7, 22.8, and 15.3%, respectively. A similar degree of dose dependency in absorption was found in rat, dog, and human when

Fung-Hwa Hsu; Thomayant Prueksaritanont; Myung G. Lee; Win L. Chiou

1987-01-01

331

High doses intravenous immunoglobulin versus oral cyclosporine in the treatment of severe atopic dermatitis.  

PubMed

Atopic dermatitis is one of the most common allergic diseases that almost always respond to conventional therapies with topical emollient, topical corticosteroids, systemic antihistamines and allergic abstinence. However few cases of atopic dermatitis with severe course do not respond to conventional therapies and high dose of intravenous immunoglobulin or cyclosporine are recommended for them. This clinical trial study has been done to compare the last two regimens in patients with severe atopic dermatitis, Scoring Atopic Dermatitis (SCORAD) greater than 70. We included 14 patients in two groups. In group 1, eight patients were randomly selected and received 4mg/kg cyclosporine daily for 3 months and in group 2, six patients received 2g/kg Intravenous Immunoglobulin (IVIG) as stat infusion. All patients were followed on days 15, 30, 60 and 90 after starting the therapy. About 75% and 62.5% of patients had positive skin tests to egg and to milk respectively. Six patients out of 14 patients did not have skin test, so specific IgE by Radioallergosobent tests (RAST) was used for them. All of these patients had positive RAST to egg and 66.6% against cow's milk. There was a significant difference in the clinical outcomes of these two groups with a marked reduction in SCORAD of day 90th in group 1 in comparison to group 2 (P-value = 0.005). No significant adverse drug reaction was seen in these two groups. PMID:17301437

Bemanian, Mohammad Hassan; Movahedi, Masoud; Farhoudi, Abolhassan; Gharagozlou, Mohammad; Seraj, Mehran Heidari; Pourpak, Zahra; Nabavi, Mohammad; Aghamohammadi, Asghar; Shirkhoda, Zahra

2005-09-01

332

Traumatic chemical oral ulceration: a case report and review of the literature  

Microsoft Academic Search

A 34-year-old man experienced extensive oral ulceration as a consequence of attempted ingestion of sulphuric acid as part of an act of deliberate self harm. All oral lesions healed within 28 days after local and systemic therapy. Oral ulceration has many potential causes ranging from physical trauma to malignancy. Chemicals are a less common cause of traumatic ulceration. Most chemical

S. R. Porter; S. Fedele; C. Gilvetti

2010-01-01

333

A phase 1 dose-escalation study: safety, tolerability, and pharmacokinetics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload  

PubMed Central

Background There is still a clinical need for a well-tolerated and safe iron chelator for the treatment of transfusional iron overload. We describe the pharmacokinetic properties and safety data after 7 days of dosing of FBS0701, a novel oral, once-daily iron chelator. Design and Methods This phase 1b dose-escalation study to assess the safety, tolerability, pharmacokinetics and pharmacodynamics of FBS0701, a novel oral iron chelator for the treatment of transfusional iron overload, was conducted in 16 adult patients with iron overloaded consequent to transfusions. FBS0701 was given daily for 7 days at doses up to 32 mg/kg and was well tolerated at all dose levels. Results Pharmacokinetics showed dose-proportionality. The maxium plasma concentration (Cmax) was reached within 60–90 minutes of dosing and the drug was rapidly distributed at the predicted therapeutic doses. The plasma elimination half-life (t1/2) was approximately 19 hours. There were no serious adverse events associated with the drug. Conclusions On the basis of these safety and pharmacokinetic data, FBS0701 warrants further clinical evaluation in patients with transfusional iron overload. (Clinicaltrials.gov identifier: NCT01186419)

Rienhoff, Hugh Young; Viprakasit, Vip; Tay, Lay; Harmatz, Paul; Vichinsky, Elliott; Chirnomas, Deborah; Kwiatkowski, Janet L.; Tapper, Amy; Kramer, William; Porter, John B.; Neufeld, Ellis J.

2011-01-01

334

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

PubMed

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

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

2013-10-01

335

Effect of single oral dose of azithromycin, clarithromycin, and roxithromycin on polymorphonuclear leukocyte function assessed ex vivo by flow cytometry.  

PubMed Central

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.

Wenisch, C; Parschalk, B; Zedtwitz-Liebenstein, K; Weihs, A; el Menyawi, I; Graninger, W

1996-01-01

336

Effects of age and controlled oral dosing of Enterococcus faecium on epithelial properties in the piglet small intestine.  

PubMed

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 (?Isc) 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. PMID:24311317

Lodemann, U; Dillenseger, A; Aschenbach, J R; Martens, H

2013-12-01

337

Pharmacokinetics and bioequivalence study of irbesartan tablets after a single oral dose of 300 mg in healthy Thai volunteers.  

PubMed

Objective: Pharmacokinetics and bioequivalence of 300 mg irbesartan tablets were studied in 26 healthy Thai male volunteers. Methods: A single oral dose of one 300 mg tablet of the test product and the reference product was given to each volunteer according to a randomized two-way crossover design with 1-week wash out period. Blood samples were collected at predetermined time intervals until 72 hours post dose and irbesartan concentration was quantified with a validated HPLC method. Individual plasma irbesartan concentration-time profile was analyzed for pharmacokinetic parameters. Results: Maximum plasma concentrations (Cmax) of 3,617.19 and 3,295.77 ng/mL for test and reference, respectively, were achieved. Areas under the plasma concentration-time curve; AUC0-t and AUC0-? were 15,304.65 and 15,638.90 ng×h/mL for test and 15,389.21 and 15,730.34 ng×h/mL for reference. The median tmax was 1.50 hours and 1.25 hours for test and reference, respectively. Plasma elimination half-lives (t1/2) were 7.35 hours and 8.09 hours for test and reference, respectively. Primary pharmacokinetic parameters Cmax, AUC0-t, and AUC0-? were tested parametrically by analysis of variance (ANOVA), and it revealed no statistically significant difference (defined as p < 0.05) between the corresponding Cmax, AUC0-t, and AUC0-? with respect to sequence, volunteers, period and formulation. The 90% confidence intervals for the ratio of test and reference product of the parameters Cmax, AUC0-t, and AUC0-? were within 80 - 125% (100.13 - 121.40% for Cmax, 90.83 - 106.86% for AUC0-t and 91.11 - 106.55% for AUC0-?). Conclusion: The two products were bioequivalent in terms of both rate and extent of drug absorption into systemic circulation. PMID:24725445

Wittayalertpanya, Supeecha; Chariyavilaskul, Pajaree; Prompila, Nantaporn; Sayankuldilok, Nonlanee; Eiamart, Wanna

2014-05-01

338

Oral contraceptive pretreatment and half dose of ganirelix does not excessively suppress LH and may be an excellent choice for scheduling IUI cycles  

Microsoft Academic Search

Purpose  To assess the effects of using a reduced dose of ganirelix with oral contraceptive pretreatment in a pilot study of COH using\\u000a pure FSH for intrauterine insemination (IUI)\\u000a \\u000a \\u000a \\u000a Methods  Patients received oral contraceptive (OC; 30 ?g ethinyl estradiol\\/150 ?g desogestrel) for 14–21 days and rFSH (50–225 IU\\/day\\u000a SC) was started on day 4 after OC discontinuation. Ganirelix acetate (125 ?g\\/day) was started with a lead follicle diameter

David R. Meldrum; Denise L. Cassidenti; Gregory F. Rosen; Bill Yee; Arthur L. Wisot

2008-01-01

339

Low-dose metronomic oral dosing of a prodrug of Gemcitabine (LY2334737) causes anti-tumor effects in the absence of inhibition of systemic vasculogenesis  

PubMed Central

Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at relatively low minimally toxic doses with no prolonged break periods; it is now showing encouraging results in various phase II clinical trials, and is currently undergoing phase III trial evaluation. It is thought to cause anti-tumor effects primarily by antiangiogenic mechanisms, both locally by targeting endothelial cells of the tumor neovasculature and systemically by effects on bone marrow derived cells, including circulating endothelial progenitor cells (CEPs). Previous studies have shown reduction of CEPs by metronomic administration of a number of different chemotherapeutic drugs, including vinblastine, cyclophosphamide, paclitaxel, topotecan, and tegafur plus uracil (UFT). However in addition to, or even instead of, anti angiogenic effects, metronomic chemotherapy may cause suppression of tumor growth by other mechanisms such as stimulating cytotoxic T cell responses, or by direct anti-tumor effects. Here we report results evaluating the properties of metronomic administration of an oral prodrug of gemcitabine LY2334737 (LY) in non tumor-bearing mice, and in preclinical models of human ovarian (SKOV3-13) and breast cancer (LM2-4) xenografts. Through daily gavage (at 6mg/kg/day) the schedules tested were devoid of toxicity and caused anti-tumor effects; however, a suppressive effect on CEPs was not detected. Unexpectedly metronomic LY administration caused increased blood flow in luciferase-tagged LM2-4 tumor xenografts; and this effect coincided with a relative increase in tumor bioluminescence. These results highlight the possibility of significant anti-tumor effects mediated by metronomic administration of some chemotherapy drugs without a concomitant inhibition of systemic angiogenesis.

Francia, Giulio; Shaked, Yuval; Hashimoto, Kae; Sun, John; Yin, Melissa; Cesta, Carolyn; Xu, Ping; Man, Shan; Hackl, Christina; Stewart, Julie; Uhlik, Mark; Dantzig, Anne H.; Foster, Stuart; Kerbel, Robert S.

2012-01-01

340

Oral Administration of OKT3 Monoclonal Antibody to Human Subjects Induces a Dose-Dependent Immunologic Effect in T Cells and Dendritic Cells  

PubMed Central

Introduction Parenteral OKT3 is used to treat transplant rejection and a humanized anti-CD3 Mab has shown positive clinical effects in new onset diabetes. Oral administration of anti-CD3 has not been tested in humans, but suppresses autoimmunity in animal models. Beta-glucosylceramide enhances NKT cell and regulatory T cell activity and enhances the effects of oral anti-CD3 in animals. Materials and methods Fifteen healthy volunteers (three per group) received orally administered OKT3 over a dose range of 0.2 to 5.0 mg daily with or without beta-glucosylceramide 7.5 mg for 5 days. Safety and immune parameters were measured on days 5, 10, and 30. Results and discussion Oral OKT3 enhanced T cell proliferation, suppressed Th1 and Th17 responses by 43% and 41%, respectively, increased TGF-?/IL-10 expression and decreased IL-23/IL-6 expression by dendritic cells, and affected the IgG repertoire as measured by antigen arrays. Co-administration of oral beta-glucosylceramide induced similar effects. No side effects were observed and no subjects developed human anti-mouse antibodies. Conclusion These findings demonstrate that oral anti-CD3 monoclonal antibody is safe and biologically active in humans and presents a new avenue for the treatment of autoimmune diseases.

Ilan, Yaron; Zigmond, Ehud; Lalazar, Gadi; Dembinsky, Adi; Ya'acov, Ami Ben; Hemed, Nila; Kasis, Ibrahim; Axelrod, Elizabeth; Zolotarov, Lidya; Klein, Athalia; El Haj, Madi; Gandhi, Roopali; Baecher-Allan, Claire; Wu, Henry; Murugaiyan, Gopal; Kivisakk, Pia; Farez, Mauricio F.; Quintana, Francisco J.; Khoury, Samia J.; Weiner, Howard L.

2009-01-01

341

Hypoglycemic activity and oral bioavailability of insulin-loaded liposomes containing bile salts in rats: the effect of cholate type, particle size and administered dose.  

PubMed

Oral delivery of protein or polypeptide drugs remains a challenge due to gastric and enzymatic degradation as well as poor permeation across the intestinal epithelia. In this study, liposomes containing bile salts were developed as a new oral insulin delivery system. The primary goal was to investigate the effect of cholate type, particle size and dosage of the liposomes on the hypoglycemic activity and oral bioavailability. Liposomes containing sodium glycocholate (SGC), sodium taurocholate (STC) or sodium deoxycholate (SDC) were prepared by a reversed-phase evaporation method. After oral administration, all liposomes elicited a certain degree of hypoglycemic effect in parallel with an increase in blood insulin level. The highest oral bioavailability of approximately 8.5% and 11.0% could be observed with subcutaneous insulin as reference for SGC-liposomes in non-diabetic and diabetic rats, respectively. Insulin-loaded liposomes showed slower and sustained action over a period of over 20 h with peak time around 8-12h. SGC-liposomes showed higher oral bioavailability than liposomes containing STC or SDC and conventional liposomes. The hypoglycemic effect was size-dependent with the highest at 150 nm or 400 nm and was proportionally correlated to the administered dose. The results supported the hypothesis of insulin absorption as intact liposomes. PMID:22369880

Niu, Mengmeng; Lu, Yi; Hovgaard, Lars; Guan, Peipei; Tan, Yanan; Lian, Ruyue; Qi, Jianping; Wu, Wei

2012-06-01

342

A high performance liquid chromatographic assay of Mefloquine in saliva after a single oral dose in healthy adult Africans  

PubMed Central

Background Mefloquine-artesunate is a formulation of artemisinin based combination therapy (ACT) recommended by the World Health Organization and historically the first ACT used clinically. The use of ACT demands constant monitoring of therapeutic efficacies and drug levels, in order to ensure that optimum drug exposure is achieved and detect reduced susceptibility to these drugs. Quantification of anti-malarial drugs in biological fluids other than blood would provide a more readily applicable method of therapeutic drug monitoring in developing endemic countries. Efforts in this study were devoted to the development of a simple, field applicable, non-invasive method for assay of mefloquine in saliva. Methods A high performance liquid chromatographic method with UV detection at 220 nm for assaying mefloquine in saliva was developed and validated by comparing mefloquine concentrations in saliva and plasma samples from four healthy volunteers who received single oral dose of mefloquine. Verapamil was used as internal standard. Chromatographic separation was achieved using a Hypersil ODS column. Results Extraction recoveries of mefloquine in plasma or saliva were 76-86% or 83-93% respectively. Limit of quantification of mefloquine was 20 ng/ml. Agreement between salivary and plasma mefloquine concentrations was satisfactory (r = 0.88, p < 0.001). Saliva:plasma concentrations ratio was 0.42. Conclusion Disposition of mefloquine in saliva paralleled that in plasma, making salivary quantification of mefloquine potentially useful in therapeutic drug monitoring.

2012-01-01

343

Automation of an in vitro cytotoxicity assay used to estimate starting doses in acute oral systemic toxicity tests.  

PubMed

Application of High Throughput Screening (HTS) to the regulatory safety assessment of chemicals is still in its infancy but shows great promise in terms of facilitating better understanding of toxicological modes-of-action, reducing the reliance on animal testing, and allowing more data-poor chemicals to be assessed at a reasonable cost. To promote the uptake and acceptance of HTS approaches, we describe in a stepwise manner how a well known cytotoxicity assay can be automated to increase throughput while maintaining reliability. Results generated with selected reference chemicals compared very favourably with data obtained from a previous international validation study concerning the prediction of acute systemic toxicity in rodents. The automated assay was then included in a formal ECVAM validation study to determine if the assay could be used for binary classification of chemicals with respect to their acute oral toxicity, using a threshold equivalent to a dose of 2000 mg/kg b.w. in a rodent bioassay (LD50). This involved the blind-testing of 56 reference chemicals on the HTS platform to produce concentration-response and IC50 data. Finally, the assay was adapted to a format more suited to higher throughput testing without compromising the quality of the data obtained. PMID:22465836

Bouhifd, Mounir; Bories, Gilles; Casado, Juan; Coecke, Sandra; Norlén, Hedvig; Parissis, Nicholaos; Rodrigues, Robim M; Whelan, Maurice P

2012-06-01

344

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

PubMed

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

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

2008-09-10

345

Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42-5892) in hypertensive patients.  

PubMed Central

1 Three double-blind, randomized, placebo controlled, multiple oral dose studies in patients with mild to moderate hypertension were performed to study tolerability, pharmacodynamics and pharmacokinetics of remikiren. Doses of 100-800 mg remikiren or placebo were given over 8 days to altogether 144 patient volunteers. In some cases (n = 46) single i.v. doses of 100 mg were administered 4 h after the last oral dose. Plasma remikiren concentrations, plasma renin activity and immunoreactive renin concentrations were measured. Pharmacokinetic parameters were estimated using model independent techniques and the concentration-effect relationship was evaluated using population pharmacometric methods. 2 In most patients no distinct absorption and disposition phase could be identified, since plasma concentrations fluctuated widely over a period of approximately 10 h. Peak plasma concentrations (Cmax) were achieved within 0.25-2 h postdose. Mean Cmax values (on the first and last day of oral treatment) were in the magnitude of 4-6 ng ml(-1) (200 mg), 23-27 ng ml(-1) (300 mg), 65-83 ng ml(-1) (600 mg) and 47-48 ng ml(-1) (800 mg). Cmax and AUC0-t values were clearly different for different doses within single studies. Intersubject variability in pharmacokinetic parameters was much higher than intrasubject variability. No drug accumulation in plasma was apparent. 3 Inhibition of the angiotensin I production rate correlated well with plasma drug concentrations according to the Emax-model. An IC50 value of 0.5 ng ml(-1) (0.8 nM) was estimated. No correlation between blood pressure changes on the last day of oral treatment and either plasma remikiren concentrations or plasma renin inhibition was found.

Weber, C; Birnbock, H; Leube, J; Kobrin, I; Kleinbloesem, C H; Van Brummelen, P

1993-01-01

346

Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42-5892) in hypertensive patients.  

PubMed

1 Three double-blind, randomized, placebo controlled, multiple oral dose studies in patients with mild to moderate hypertension were performed to study tolerability, pharmacodynamics and pharmacokinetics of remikiren. Doses of 100-800 mg remikiren or placebo were given over 8 days to altogether 144 patient volunteers. In some cases (n = 46) single i.v. doses of 100 mg were administered 4 h after the last oral dose. Plasma remikiren concentrations, plasma renin activity and immunoreactive renin concentrations were measured. Pharmacokinetic parameters were estimated using model independent techniques and the concentration-effect relationship was evaluated using population pharmacometric methods. 2 In most patients no distinct absorption and disposition phase could be identified, since plasma concentrations fluctuated widely over a period of approximately 10 h. Peak plasma concentrations (Cmax) were achieved within 0.25-2 h postdose. Mean Cmax values (on the first and last day of oral treatment) were in the magnitude of 4-6 ng ml(-1) (200 mg), 23-27 ng ml(-1) (300 mg), 65-83 ng ml(-1) (600 mg) and 47-48 ng ml(-1) (800 mg). Cmax and AUC0-t values were clearly different for different doses within single studies. Intersubject variability in pharmacokinetic parameters was much higher than intrasubject variability. No drug accumulation in plasma was apparent. 3 Inhibition of the angiotensin I production rate correlated well with plasma drug concentrations according to the Emax-model. An IC50 value of 0.5 ng ml(-1) (0.8 nM) was estimated. No correlation between blood pressure changes on the last day of oral treatment and either plasma remikiren concentrations or plasma renin inhibition was found. PMID:12959271

Weber, C; Birnböck, H; Leube, J; Kobrin, I; Kleinbloesem, C H; Van Brummelen, P

1993-12-01

347

Oral tolerance.  

PubMed

Multiple mechanisms of tolerance are induced by oral antigen. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral antigen induces T-helper 2 [interleukin (IL)-4/IL-10] and Th3 [transforming growth factor (TGF)-beta] T cells plus CD4+CD25+ regulatory cells and latency-associated peptide+ T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-beta, cholera toxin B subunit, Flt-3 ligand, and anti-CD40 ligand. Oral (and nasal) antigen administration suppresses animal models of autoimmune diseases including experimental autoimmune encephalitis, uveitis, thyroiditis, myasthenia, arthritis, and diabetes in the non-obese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, graft rejection, allergy, colitis, stroke, and models of Alzheimer's disease. Oral tolerance has been tested in human autoimmune diseases including multiple sclerosis (MS), arthritis, uveitis, and diabetes and in allergy, contact sensitivity to dinitrochlorobenzene (DNCB), and nickel allergy. Although positive results have been observed in phase II trials, no effect was observed in phase III trials of CII in rheumatoid arthritis or oral myelin and glatiramer acetate (GA) in MS. Large placebo effects were observed, and new trials of oral GA are underway. Oral insulin has recently been shown to delay onset of diabetes in at-risk populations, and confirmatory trials of oral insulin are being planned. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time, and antigen-specific mechanisms of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy, and early therapy. PMID:16048553

Faria, Ana M C; Weiner, Howard L

2005-08-01

348

Nomegestrol acetate/estradiol: in oral contraception.  

PubMed

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

Yang, Lily P H; Plosker, Greg L

2012-10-01

349

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

PubMed Central

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

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

2010-01-01

350

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

PubMed

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

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

2014-04-01

351

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

PubMed Central

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

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

2014-01-01

352

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

PubMed Central

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

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

2014-01-01

353

Efficacy and Safety of Fixed-Dose Oral Sildenafil in the Treatment of Sexual Dysfunction in Depressed Patients with Idiopathic Parkinson’s Disease  

Microsoft Academic Search

Objective and Methods: The efficacy and safety of oral Sildenafil, a potent inhibitor of phosphodiesterase type 5, were evaluated in depressed men with idiopathic Parkinson’s disease and erectile dysfunction. Thirty-three men were enrolled in a 4-month prospective, open-label, fixed-dose study, and received 50mg of Sildenafil in the home setting approximately 1 hour before sexual activity, not more than once daily.

R. Raffaele; I. Vecchio; B. Giammusso; G. Morgia; M. B. Brunetto; L. Rampello

2002-01-01

354

Relative concentrations of 14 C-DDT and of two polychlorinated biphenyls in the lipids of cod tissues after a single oral dose  

Microsoft Academic Search

From 2 hr to 14 days after a single oral dose of 5 µCi (55 µg) of14C-DDT, tissues of cod(Gadus morhua) were analysed for14C-DDT, total lipid, triglyceride, phospholipid, and total cholesterol. The absolute concentrations of DDT on a total lipid basis varied from fish to fish and from tissue to tissue, but the values for liver were highest for most

A. I. Mitchell; P. A. Plack; I. M. Thomson

1977-01-01

355

Antibiotic Prophylaxis for Transrectal Biopsy of the Prostate: A Prospective Randomized Study of the Prophylactic Use of Single Dose Oral Fluoroquinolone Versus Trimethoprim-Sulfamethoxazole  

Microsoft Academic Search

We investigated the efficacy of prophylactic use of single dose oral ofloxacin and trimethoprim-sulfamethoxazole regimens for transrectal prostate biopsy in 110 men. In the ofloxacin, trimethoprim-sulfamethoxazole and control groups, urinary infection was found in 2 (4.76%), 3 (6.66%) and 6 (26.08%) patients, respectively. Both of these antibiotic regimens produced a statistically significant reduction in urinary infection (p<0.02, p<0.05).

K. Isen; B. Küpeli; Z. Sinik; S. Sözen; I. Bozkirli

1999-01-01

356

Ambulatory Treatment of Multidrug-Resistant Staphylococcus Infected Orthopedic Implants with High-Dose Oral Co-trimoxazole (Trimethoprim-Sulfamethoxazole)  

Microsoft Academic Search

We examined the effectiveness and safety of high-dose oral co-trimoxazole (trimethoprim-sulfamethoxazole) for the treatment of orthopedic implants infected with multidrug-resistant Staphylococcus species. The pro- spective study was conducted between 1989 and 1997 in a university medical center with ambulatory-care services. Patients eligible for the study consisted of those from whom multidrug-resistant Staphylococcus spp. organisms susceptible only to glycopeptides and co-trimoxazole

ANDREAS STEIN; JEAN FRANCOIS BATAILLE; MICHEL DRANCOURT; GEORGES CURVALE; JEAN NOEL ARGENSON; PIERRE GROULIER; DIDIER RAOULT

1998-01-01

357

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

Microsoft Academic Search

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

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

2005-01-01

358

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

Microsoft Academic Search

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

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

2004-01-01

359

Comparison of therapeutic effect of low-dose low-molecular-weight heparin (enoxaparin) vs. oral prednisone in treatment of patients with lichen planus; A clinical trial  

PubMed Central

Background: The aim of this study was to evaluate and compare the therapeutic efficacy of subcutaneous enoxaparin versus oral prednisone (as a standard treatment) in patients with disseminated lichen planus. Materials and Methods: In this parallel randomized clinical trial study, overall 48 patients completed the study. 25 patients were treated with subcutaneous enoxaparin 5 mg weekly and 23 patients with 0.5 mg/kg prednisone orally daily until complete remission or a maximum of 8 weeks. The results of itching severity, extent of active lesions and drug side effects were compared. In remission, patients were followed for 6 months for recurrent lesions. Results: In enoxaparin group, 8 patients (32%) had complete remission and 10 patients (40%) had partial improvement. In the oral prednisone group, 16 patients (69.6%) had complete remission and 6 patients (26.1%) had partial improvement (P = 0.005). Average size of active lesions in both groups decreased significantly after treatment, but analysis of covariance showed that the mean lesion size after treatment in the oral prednisone group was significantly lower than the enoxaparin group (P = 0.005). The relapse rate from improved patients in the enoxaparin group was 6 (33%) and in oral prednisone group was 9 (40.9%, P = 0.083). In the enoxaparin group no serious complications was seen. But 22% in the oral prednisone group show side effect, the most common complications were dyspepsia. Conclusion: Low dose enoxaparin on lichen Planus have therapeutic effect and is important for the least side effects but not as much as oral prednisone. But it could be accepted as an alternative treatment.

Iraji, Fariba; Asilian, Ali; Saeidi, Ahmad; Siadat, Amir Hossein; Saeidi, Ali Reza; Hassanzadeh, Akbar

2013-01-01

360

Effect of Admission Oral Diuretic Dose on Response to Continuous versus Bolus Intravenous Diuretics in Acute Heart Failure: An Analysis from DOSE-AHF  

PubMed Central

Background Results from the Diuretic Optimization Strategies in Acute Heart Failure (DOSE-AHF) study suggest that an initial continuous infusion of loop diuretics is not superior to bolus dosing with regard to clinical endpoints in AHF. We hypothesized that outpatient furosemide dose was associated with congestion and poorer renal function, and explored the hypothesis that a continuous infusion may be more effective in patients on higher outpatient diuretic doses. Methods DOSE-AHF randomized 308 patients within 24 hours of admission to high vs. low initial intravenous diuretic dose given as either a continuous infusion or bolus. We compared baseline characteristics and assessed associations between mode of administration (bolus vs. continuous) and outcomes in patients receiving high-dose (?120 mg furosemide equivalent, n=177) versus low-dose (<120 mg furosemide equivalent, n=131) outpatient diuretics. Results Patients on higher doses of furosemide were less frequently on renin-angiotensin system inhibitors (P=.01), and had worse renal function and more advanced symptoms. There was a significant interaction between outpatient dose and mode of therapy (P=0.01) with respect to net fluid loss at 72 hours after adjusting for creatinine and intensification strategy. Admission diuretic dose was associated with an increased risk of death or rehospitalization at 60 days (adjusted HR=1.08 per 20-mg increment in dose, 95% CI 1.01–1.16, P=.03). Conclusions In acute HF, patients on higher diuretic doses have greater disease severity, and may benefit from an initial bolus strategy.

Shah, Ravi V.; McNulty, Steven; O'Connor, Christopher M.; Felker, G. Michael; Braunwald, Eugene; Givertz, Michael M.

2014-01-01

361

Fosfomycin tromethamine. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy as a single-dose oral treatment for acute uncomplicated lower urinary tract infections.  

PubMed

Fosfomycin tromethamine is a phosphonic acid bactericidal agent with in vitro activity against most urinary tract pathogens. It is particularly active against Escherichia coli, and Citrobacter, Enterobacter, Klebsiella, Serratia and Enterococcus spp. There appears to be little cross-resistance between fosfomycin and other antibacterial agents, possibly because it differs from other agents in its general chemical structure and site of action. In its new formulation as the oral tromethamine salt, fosfomycin has 34 to 41% oral bioavailability, has a mean elimination half-life of 5.7 hours, and is primarily excreted unchanged in the urine. Following a single 3 g oral dose, peak urinary concentrations occur within 4 hours and remain high (> 128 mg/L) for 24 to 48 hours, which is sufficient to inhibit most urinary tract pathogens. In clinical trials in patients with acute uncomplicated lower urinary tract infection, single-dose fosfomycin tromethamine therapy was effective, and comparable with several other antibacterial agents given either as single-dose or multiple-dose treatments [e.g. beta-lactam and fluoroquinolone agents, cotrimoxazole (trimethoprim-sulfamethoxazole), nitrofurantoin and pipemidic acid]. Bacteriological eradication rates of 75 to 90% were achieved 5 to 11 days after therapy, with eradication rates of 62 to 93% 4 to 6 weeks after therapy. In 3 large double-blind comparisons with ciprofloxacin, cotrimoxazole and nitrofurantoin, 99% of fosfomycin tromethamine recipients and 100% of patients receiving comparator agents were considered clinically cured or improved after therapy. Fosfomycin tromethamine is well tolerated, with a low incidence of adverse events. These comprise mainly gastrointestinal symptoms that are transient, mild and self-limiting. Thus, fosfomycin tromethamine achieves high clinical and bacteriological cure rates in patients with acute uncomplicated lower urinary tract infection and is well tolerated. The single-dose administration regimen and favourable US pregnancy category rating of fosfomycin tromethamine should also encourage its use in this indication. PMID:9098664

Patel, S S; Balfour, J A; Bryson, H M

1997-04-01

362

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

PubMed

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

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

2013-09-01

363

Acute and Repeated Dose Toxicity Studies on Nsc 94100 Following Daily Oral Administration to Dogs and Monkeys and Acute Toxicity Following Oral Administration to Mice and Rats.  

National Technical Information Service (NTIS)

Compound NSC 94100, D-Mannitol, 1,6-dibromo-1,6-dideoxy- was studied following daily oral administration in beagle dogs in dosages of 200 mg/kg x 6, 100 mg/kg x 5, 50 mg/kg x 10, 35 mg/kg x 12, 25 mg/kg x 14, and 13 mg/kg x 90, the dosages being administe...

N. Rakieten

1967-01-01

364

Acute and Repeated Dose Toxicity Studies on Nsc 94100 Following Daily Oral Administration to Dogs and Monkeys and Acute Toxicity Following Oral Administration to Mice and Monkeys.  

National Technical Information Service (NTIS)

Compound NSC 94100, D-Mannitol, 1,6-dibromo- 1,6-dideoxy- was studied following daily oral administration in beagle dogs in dosages of 200 mg/kg x 6, 100 mg/kg x 5, 50 mg/kg x 10, 35 mg/kg x 12, 25 mg/kg x 14, and 13 mg/kg x 90, the dosages being administ...

N. Rakieten P. S. Schein R. D. Davis

1967-01-01

365

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

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.

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

1975-01-01

366

Pharmacokinetics and Pharmacodynamics of Oral Testosterone Enanthate Plus Dutasteride for 4 Weeks in Normal Men: Implications for Male Hormonal Contraception  

PubMed Central

Oral administration of testosterone enanthate (TE) and dutasteride increases serum testosterone and might be useful for male hormonal contraception. To ascertain the contraceptive potential of oral TE and dutasteride by determining the degree of gonadotropin suppression mediated by 4 weeks of oral TE plus dutasteride, 20 healthy young men were randomly assigned to 4 weeks of either 400 mg oral TE twice daily or 800 mg oral TE once daily in a double-blinded, controlled fashion at a single site. All men received 0.5 mg dutasteride daily. Blood for measurement of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, dihydrotesterone (DHT), and estradiol was obtained prior to treatment, weekly during treatment, and 1, 2, 4, 8, 12, 13, 14, 16, 20, and 24 hours after the morning dose on the last day of treatment. FSH was significantly suppressed throughout treatment with 800 mg TE once daily and after 4 weeks of treatment with 400 mg TE twice daily. LH was significantly suppressed after 2 weeks of treatment with 800 mg TE, but not with 400 mg TE. Serum DHT was suppressed and serum estradiol increased during treatment in both groups. High-density lipoprotein cholesterol was suppresed during treatment, but liver function tests, hematocrit, creatinine, mood, and sexual function were unaffected. The administration of 800 mg oral TE daily combined with dutasteride for 28 days significantly suppresses gonadotropins without untoward side effects and might have utility as part of a male hormonal contraceptive regimen.

AMORY, JOHN K.; KALHORN, THOMAS F.; PAGE, STEPHANIE T.

2009-01-01

367

The use of methotrexate alone or in combination with low doses of oral corticosteroids in the treatment of alopecia totalis or universalis.  

PubMed

Treatment of severe alopecia areata (AA) remains difficult. To assess the tolerance and efficacy of methotrexate (MTX) in the treatment of severe long-term AA, we retrospectively evaluated 22 patients with AA totalis or universalis with a mean duration of 11.0 +/- 8.8 years who were treated with MTX either alone (n = 6) or associated with low doses of oral prednisone (n = 16). MTX was given at an initial weekly dosage of 15 mg (n = 3), 20 mg (n = 9), or 25 mg (n = 10). Oral prednisone was given at an initial dosage of 10 mg/d in one patient and 20 mg/d in 15 patients. In all, 14 patients (64%) achieved a total recovery including 3 of 6 patients treated by MTX alone and 11 of 16 who had received the combined treatment. Of the 14 patients who had total hair regrowth, 6 stopped MTX. In all, 3 patients maintained hair regrowth and 3 relapsed. Retreatment of these 3 patients by MTX resulted again in hair regrowth. No severe side effect was observed. Although limited by its uncontrolled character, this study shows that MTX and low doses of oral corticosteroids may be an effective and well-tolerated treatment for severe types of AA. PMID:17010743

Joly, Pascal

2006-10-01

368

Low-dose oral immunization with lyophilized tissue of herbicide-resistant lettuce expressing hepatitis B surface antigen for prototype plant-derived vaccine tablet formulation.  

PubMed

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. PMID:21107787

Pniewski, Tomasz; Kapusta, Józef; Boci?g, Piotr; Wojciechowicz, Jacek; Kostrzak, Anna; Gdula, Micha?; Fedorowicz-Stro?ska, Olga; Wójcik, Piotr; Otta, Halina; Samardakiewicz, S?awomir; Wolko, Bogdan; P?ucienniczak, Andrzej

2011-05-01

369

A Randomized Controlled Trial on Safety and Efficacy of Single Intramuscular versus Staggered Oral Dose of 600 000IU Vitamin D in Treatment of Nutritional Rickets.  

PubMed

Objective: Comparison of efficacy and safety of two different regimens of vitamin D-600 000 IU as a single intramuscular dose, and 60 000IU orally once a week for 10 weeks-in treatment of nutritional rickets. Methods: Children with nutritional rickets (age: 0.5-5 years, n = 61) were randomized to receive either 60 000IU vitamin D orally once a week for 10 weeks or 600 000IU single intramuscular injection. Serum calcium, phosphate, alkaline phosphatase, urinary calcium/creatinine ratio, serum 25 hydroxy vitamin D and radiological score were compared at 12-week follow-up. Results: No difference was found in efficacy of the two regimens on comparing biochemical and radiological parameters. Serum 25 hydroxy vitamin D >100 ng/ml was found in two children in the oral group and one child in the intramuscular group. No child developed hypercalcemia or hypercalciuria after starting treatment. Conclusion: Staggered oral and one-time intramuscular administrations of 600 000IU vitamin D are equally effective and safe in treatment of nutritional rickets. PMID:24401754

Mondal, Krishanu; Seth, Anju; Marwaha, Raman K; Dhanwal, Dinesh; Aneja, Satinder; Singh, Ritu; Sonkar, Pitambar

2014-06-01

370

Comparison of azithromycin pharmacokinetics following single oral doses of extended-release and immediate-release formulations in children with acute otitis media.  

PubMed

An azithromycin extended-release (ER) oral suspension was developed to improve the gastrointestinal tolerability profile without substantially compromising systemic exposure. A single dose of 30 mg/kg azithromycin immediate-release (IR) oral suspension has been used in children to treat acute otitis media (AOM). This study was conducted to compare the pharmacokinetics of a 60-mg/kg azithromycin ER single dose with a 30-mg/kg azithromycin IR single dose in children with AOM aged 6 months to 6 years (n = 19 per treatment). Serum samples were collected at 1, 2, 3, 4, 8, 24, 48, and 72 h after dosing. The area under the curve from time zero to 72 h postdosing (AUC(0-72)) was calculated based on a noncompartmental method. One-way analysis of variance (ANOVA) was used to compare exposure parameters (e.g., AUC(0-72) and peak concentration) as well as concentrations at each time point. The adjusted geometric mean ratio of the ER/IR AUC(0-72) was 157.98% (90% confidence interval [CI], 98.87%, 252.44%), which met the predefined criterion of the lower boundary of the 90% CI of ? 80%. As expected, due to the slower-release profile of the ER formulation, the concentrations of the ER formulation during the first 3 h were lower than those of the IR formulation. After 3 h postdosing, the lower boundaries of the 90% CI for the ER/IR concentration ratios were greater than 100%. These results indicated that a 60-mg/kg single dose of ER azithromycin provides similar or greater systemic exposure in children than the 30-mg/kg single dose of IR azithromycin. PMID:21859932

Liu, Ping; Fang, Annie F; LaBadie, Robert R; Crownover, Penelope H; Arguedas, Adriano G

2011-11-01

371

Case Study: What Happened to 28 Days?  

NSDL National Science Digital Library

This is a case study for undergraduate students in anatomy and/or physiology. In particular this case study explores female reproductive physiology. Users of the National Center for Case Study Teaching in Science will be required to register (free) to gain access to the answer key (and must be of teaching status to receive the key). Included in the resource are the case overview, objectives, case study, teaching notes and answer key.

Tamar Goulet (University of Mississippi Biology)

2011-08-29

372

Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors.  

PubMed

Buparlisib (BKM120) is an oral pan-phosphatidylinositol 3-kinase inhibitor, targeting all four isoforms of class I PI3K (?, ?, ? and ?). This open-label Phase I dose-escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day (n = 3), 50 mg/day (n = 3) and 100 mg/day (n = 9) dose levels. One dose-limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first-in-man study of buparlisib in non-Japanese patients, further dose escalation was stopped and 100 mg/day was declared the recommended dose. The most common treatment-related adverse events were rash, abnormal hepatic function (including increased transaminase levels), increased blood insulin levels and increased eosinophil count. Hyperglycemia was experienced by two patients, one Grade 1 and one Grade 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose-proportional manner. Best overall response was stable disease for six patients, including one unconfirmed partial response. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non-Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients. PMID:24405565

Ando, Yuichi; Inada-Inoue, Megumi; Mitsuma, Ayako; Yoshino, Takayuki; Ohtsu, Atsushi; Suenaga, Naoko; Sato, Masahiko; Kakizume, Tomoyuki; Robson, Matthew; Quadt, Cornelia; Doi, Toshihiko

2014-03-01

373

A single-dose, randomized, open-label, two-period crossover bioequivalence study comparing a fixed-dose pediatric combination of lamivudine and stavudine tablet for oral suspension with individual liquid formulations in healthy adult male volunteers.  

PubMed

Lamivudine (CAS 134678-17-4) is a synthetic nucleoside analogue with activity against HIV-1 and HBV. Stavudine (CAS 3056-17-5) is a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus (HIV). Lamivudine and stavudine in combination with other antiretroviral (ARV) agents are indicated for the treatment of HIV infection. As there are no suitable pediatric ARVs, adult fixed-dose ARVs are commonly used in children. This practice poses concerns about dose inaccuracy, which may lead to resistance or toxicity. A new fixed-dose combination (FDC) tablet for oral suspension, containing lamivudine 40 mg and stavudine 10 mg has been developed. An open-label, balanced, randomised, two-treatment, two-period, two-sequence, single-dose, crossover bioequivalence study was conducted following administration of a fixed-dose combination of lamivudine and stavudine tablet for oral suspension (test formulation) and innovator products (reference formulations) in healthy, adult, male human subjects under fasting condition. Multiple blood samples were collected up to 36 h post dose. Plasma concentrations of lamivudine and stavudine were assayed using validated high-performance liquid chromatography with mass s