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1

A 28-day oral dose toxicity study enhanced to detect endocrine effects of hexabromocyclododecane in Wistar rats  

Microsoft Academic Search

A 28-day repeated dose study in rats (OECD407) enhanced for endocrine and immune parameters was performed with hexabromocyclododecane (HBCD). Rats were exposed by daily gavage to HBCD dissolved in corn oil in 8 dose groups with doses ranging between 0 and 200 mg\\/kg bw per day (mkd). Evaluation consisted of dose-response analysis with calculation of a benchmark dose at the

Leo T M van der Ven; Aart Verhoef; Ton van de Kuil; Wout Slob; Pim E G Leonards; Theo J Visser; Timo Hamers; Maria Herlin; Helen Håkansson; Hanna Olausson; Aldert H Piersma; Josephus G Vos

2007-01-01

2

A 28-day oral dose toxicity study enhanced to detect endocrine effects of hexabromocyclododecane in wistar rats  

Microsoft Academic Search

A 28-day repeated dose study in rats (OECD407) enhanced for endocrine and immune parameters was performed with hexabro- mocyclododecane (HBCD). Rats were exposed by daily gavage to HBCD dissolved in corn oil in 8 dose groups with doses ranging between 0 and 200 mg\\/kg bw per day (mkd). Evaluation consisted of dose-response analysis with calculation of a benchmark dose at

Ven van der L. T. M; Aart Verhoef; Ton van de Kuil; Wout Slob; Pim E. G. Leonards; Theo J. Visser; T. H. M. Hamers; M. Herlin; H. Hakansson; H. Olausson; A. H. Piersma; J. G. Vos

2006-01-01

3

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

4

Repeated dose 28-day oral toxicity study in Wistar rats with a mixture of five pesticides often found as residues in food: alphacypermethrin, bromopropylate, carbendazim, chlorpyrifos and mancozeb  

Microsoft Academic Search

Six dose groups of 8 male and female rats respectively received a daily dose equivalent to 0, 0.15, 0.006, 0.03, 0.15 or 0.3 mg\\/kg b.w.\\/day chlorpyrifos (groups 1–6) and the last four dose groups (groups 3–6) received in addition daily doses equivalent to 18 mg\\/kg b.w.\\/day alphacypermethrin, 30 mg\\/kg b.w.\\/day bromopropylate, 45 mg\\/kg b.w.\\/day carbendazim and 12.5 mg\\/kg b.w.\\/day mancozeb

H Jacobsen; G Østergaard; H. R Lam; M. E Poulsen; H Frandsen; O Ladefoged; O Meyer

2004-01-01

5

Repeated dose (28 days) oral toxicity study of flutamide in rats, based on the draft protocol for the `Enhanced OECD Test Guideline 407' for screening for endocrine-disrupting chemicals  

Microsoft Academic Search

In association with the international validation project to establish a test protocol for the `Enhanced OECD Test Guideline\\u000a 407', we performed a preliminary 28-day, repeated-dose toxicity study of flutamide, a non-steroidal androgen antagonist, and\\u000a assessed the sensitivity of a list of parameters for detecting endocrine-related effects of endocrine-disrupting chemicals\\u000a (EDCs). Seven-week-old CD(SD)IGS rats were divided into four groups, each consisting

Kazuhiro Toyoda; Makoto Shibutani; Toru Tamura; Takatoshi Koujitani; Chikako Uneyama; Masao Hirose

2000-01-01

6

Effects of Jatropha oil on rats following 28-day oral treatment.  

PubMed

Jatropha oil is an emerging feedstock for the production of biodiesels. The increasing use of this nonedible, toxic oil will result in higher potential for accidental exposures. A repeated-dose 28-day oral toxicity study was conducted to provide data for risk assessment. Jatropha oil diluted in corn oil was administered by gavage to male and female rats at 0.5, 5, 50 and 500 mg kg(-1) body weight per day for 28 consecutive days. Control rats were administered corn oil only. The growth rates and consumption of food and water were monitored. At necropsy, organs were weighed and hematological parameters assessed. Serum clinical chemistry and C-reactive protein were measured and histological examinations of organs and tissues were performed. Markedly depressed growth rate was observed in males and females receiving Jatropha oil at 500 mg kg(-1) per day. Decreased white blood cell and lymphocyte counts were detected in females at 50 and 500 mg kg(-1) per day and in males at 500 mg kg(-1) per day. These changes were correlated to mild and reversible histological changes in male and female spleens. In the liver, a mild increase in portal hepatocytes cytoplasm density was observed in males and females, while periportal vacuolation was observed exclusively in females. Mild acinar proliferation was observed in the female mammary glands at all dose levels. It is concluded that Jatropha oil produces adverse effects on female rats starting at 50 mg kg(-1) per day with decreased white blood cell and lymphocyte counts and at 500 mg kg(-1) per day in both genders in term of depressed growth rates. PMID:23844425

Poon, Raymond; Valli, Victor E; Ratnayake, W M Nimal; Rigden, Marc; Pelletier, Guillaume

2013-07-01

7

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. PMID:22504461

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

8

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

9

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

Microsoft Academic Search

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

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

2011-01-01

10

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

PubMed

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

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

2014-11-01

11

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

PubMed

Treatment of glaucoma by intraocular pressure (IOP) reduction is typically accomplished through the administration of eye drops, the difficult and frequent nature of which contributes to extremely low adherence rates. Poor adherence to topical treatment regimens in glaucoma patients can lead to irreversible vision loss and increased treatment costs. Currently there are no approved treatments for glaucoma that address the inherent inefficiencies in drug delivery and patient adherence. Brimonidine tartrate (BT), a common glaucoma medication, requires dosing every 8-12 h, with up to 97% of patients not taking it as prescribed. This study provides proof-of-principle testing of a controlled release BT formulation. BT was encapsulated in poly(lactic-co-glycolic) acid microspheres and drug release was quantified using UV-Vis spectroscopy. For in vivo studies, rabbits were randomized to receive a single subconjunctival injection of blank (no drug) or BT-loaded microspheres or twice daily topical 0.2% BT drops. The microspheres released an average of 2.1 ± 0.37 ?g BT/mg microspheres/day in vitro. In vivo, the percent decrease in IOP from baseline was significantly greater in the treated eye for both topical drug and drug-loaded microspheres versus blank microspheres throughout the 4-week study, with no evidence of migration or foreign body response. IOP measurements in the contralateral, untreated eyes also suggested a highly localized effect from the experimental treatment. A treatment designed using the release systems described in this study would represent a vast improvement over the current clinical standard of 56-84 topical doses over 28 days. PMID:24983144

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

2014-08-01

12

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

Microsoft Academic Search

Background  The study investigated the distribution of silver after 28 days repeated oral administration of silver nanoparticles (AgNPs)\\u000a and silver acetate (AgAc) to rats. Oral administration is a relevant route of exposure because of the use of silver nanoparticles\\u000a in products related to food and food contact materials.\\u000a \\u000a \\u000a \\u000a \\u000a Results  AgNPs were synthesized with a size distribution of 14 ± 4 nm in

Katrin Loeschner; Niels Hadrup; Klaus Qvortrup; Agnete Larsen; Xueyun Gao; Ulla Vogel; Alicja Mortensen; Henrik Rye Lam; Erik H Larsen

2011-01-01

13

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. PMID:21631937

2011-01-01

14

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

PubMed

A 28-day oral gavage toxicity study in the rat with 17alpha-methyltestosterone was conducted as part of the international validation exercise on the modified Enhanced OECD Test Guideline 407 (Organisation for Economic Co-operation and Development, Paris). Special emphasis was placed on the endocrine mediated effects exerted by 17alpha-methyltestosterone, a potent androgen agonist. The test compound was administered daily by oral gavage for at least 28 days to groups of 7-week-old-Wistar rats. Dose levels were 0, 10, 40 and 200 mg/kg body weight per day for males and 0, 10, 100 and 600 mg/kg body weight per day for females. In addition, and outside the remit of the enhanced protocol, testosterone levels in males, oestradiol levels in females and luteinizing hormone (LH) levels in both sexes were measured, to provide a broader profile on the hormonally mediated effects of 17alpha-methyltestosterone. Furthermore, stage-specific quantification of Terminal deoxynucleotidyl transferase-mediated dUTP Nick-End Labeling (TUNEL)-labeled germ cells (apoptotic germ cells) in the seminiferous tubules was also performed, in an effort to demonstrate the precise stages in the spermatogenic cycle 17alpha-methyltestosterone exerts its effect. In this study, the most critical additional parameters contained in the Enhanced OECD Test Guideline 407 for the detection of endocrine disruption were considered to be the histopathological assessment and organ weight data of endocrine-related tissues. Beyond the scope of this validation exercise, an increase in apoptosis in specific germ cell types was detected using the TUNEL assay in male rats treated at 200 and 40 mg/kg. PMID:14580781

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

2003-11-01

15

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

PubMed

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

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

2013-02-01

16

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

17

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

18

Effects of cis-nonachlor, trans-nonachlor and chlordane on the immune system of Sprague–Dawley rats following a 28-day oral (gavage) treatment  

Microsoft Academic Search

The immunotoxicity of cis- and trans-nonachlor and chlordane were investigated in adult male and female Sprague–Dawley rats following a 28-day oral (gavage) treatment. Rats were randomly assigned to six experimental groups: cis-nonachlor, females; trans-nonachlor, females; technical chlordane females; cis-nonachlor, males; trans-nonachlor, males; technical chlordane, males. The immunologic endpoints included: quantification of the total serum immunoglobulin (Ig) levels and subclasses and

H. Tryphonas; G. Bondy; M. Hodgen; L. Coady; M. Parenteau; C. Armstrong; S. Hayward; V. Liston

2003-01-01

19

Category analysis of the substituted anilines studied in a 28-day repeat-dose toxicity test conducted on rats: Correlation between toxicity and chemical structure  

Microsoft Academic Search

In order to establish methods for estimating the repeat-dose toxicity of chemicals on the basis of their chemical structure, an analysis of a category formed for 14 substituted anilines was conducted. This analysis was based on the results of a 28-day repeat-dose toxicity test conducted on rats in which these 14 chemicals were studied. The intensities of the toxicological effects

Y. Sakuratani; S. Sato; S. Nishikawa; J. Yamada; A. Maekawa; M. Hayashi

2008-01-01

20

An antioxidant, N,N'-diphenyl-p-phenylenediamine (DPPD), affects labor and delivery in rats: a 28-day repeated dose test and reproduction/developmental toxicity test.  

PubMed

A 28-day repeated dose toxicity test and reproduction/developmental toxicity test for N,N'-diphenyl-p-phenylenediamine (DPPD) were conducted in [Crl:CD(SD)] SPF rats. Male and female rats were dosed with DPPD by gavage for 28 days at 0, 100, 300, or 1000 mg/kg bw/day or for a total of 42-46 days at 0, 8, 50, or 300 mg/kg bw/day. No significant adverse effects were observed in the repeated dose toxicity study up to 1000 mg/kg bw/day in both sexes. In the reproduction/developmental toxicity study, two females showed piloerection, hypothermia, and pale skin; one died and the other showed dystocia on day 23 of pregnancy at 300 mg/kg bw/day. Another female delivered only three live pups at 300 mg/kg bw/day. A significantly prolonged gestation period was observed at 50 and 300 mg/kg bw/day. The NOAELs of repeated dose toxicity and reproduction/developmental toxicity were considered to be 1000 and 8 mg/kg bw/day, respectively. PMID:23454298

Matsumoto, Mariko; Yamaguchi, Makiko; Yoshida, Yuka; Senuma, Mika; Takashima, Hiromasa; Kawamura, Tomoko; Kato, Hina; Takahashi, Mika; Hirata-Koizumi, Mutsuko; Ono, Atsushi; Yokoyama, Kazuhito; Hirose, Akihiko

2013-06-01

21

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

Code of Federal Regulations, 2010 CFR

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

2010-07-01

22

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

Code of Federal Regulations, 2012 CFR

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

2012-07-01

23

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

Code of Federal Regulations, 2011 CFR

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

2011-07-01

24

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

Code of Federal Regulations, 2013 CFR

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

2013-07-01

25

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

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

2014-07-01

26

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 PMID:21964900

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

2012-01-01

27

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

28

Acute and twenty-eight days repeated oral dose toxicity study of besifloxacin in Wistar albino rats  

Microsoft Academic Search

The purpose of this study was to investigate the potential acute and 28-day repeated oral toxicities of besifloxacin (BAF) in Wistar albino rats. In oral acute and repeated dose study, BAF was administered to both sex of rats, at dose levels of 0, 300, 600, 900mg\\/kg\\/day and 0, 100, 200, 500mg\\/kg\\/day, respectively. In the acute study, total white blood cell

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

2011-01-01

29

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

30

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

PubMed

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, 200 mg/kg/day. At the end of treatment period, 12 rats/sex/group was sacrificed, while six extra rats/sex in the vehicle control and highest dose groups sacrificed after 14 days recovery period. During the treatment and recovery periods, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, phototoxicity, hematology, serum biochemistry, synovial fluid biochemistry, electrocardiogram (ECG), gross findings, organ weights, microscopic examination of synovial fluid, and histopathology were examined. Hematological and serum biochemical investigations revealed a dose-dependent increase in the total white blood cell (WBC), total bilirubin (T-BIL), glucose (GLU), alanine aminotransferase (ALT) and significant decreases in total protein (TP) were observed in both sexes at the same dose, at the end of treatment period, but the levels returned toward normal during the recovery period. Histopathology of talar joint showed that erosion of the articular surface of that joint in both sexes at the end of treatment period at the dose level of 200 mg/kg/day. Degenerative changes in tendinocytes were observed in Achilles tendon of both sexes at the high dose level at the end of treatment period. In histopathological study shows partial effacement of liver architecture and focal ulceration in gastric mucosa at the high dose level at the end of treatment period. Based on these results, it was concluded that 28 days repeated oral dose of gemifloxacin caused increases in the liver weight, WBC count, T-BIL, glucose level, ALT, decreasing the TP, cause chronic hepatitis and acute gastritis, erosion of the articular surface of joint and histopathologic changes in Achilles tendon in rats at the dose level of 200 mg/kg/day. PMID:20580917

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

2010-11-01

31

Alternative Method of Oral Dosing for Rats  

PubMed Central

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

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

2010-01-01

32

Single dose oral lumiracoxib for postoperative pain  

PubMed Central

Background Lumiracoxib is a novel selective cyclooxygenase-2 (COX-2) inhibitor. COX-2 inhibitors have been developed to avoid COX-1 related gastrointestinal (GI) problems. Lumiracoxib has analgesic and anti-inflammatory activity comparable with traditional non-steriodal anti-inflammatory drugs (tNSAIDs) in the management of post-operative pain, but with the advantage of better GI tolerability. Objectives To review the analgesic efficacy, duration of analgesia, and adverse effects of a single oral dose of lumiracoxib for moderate to severe postoperative pain in adults and compare it with established analgesics. Search strategy We searched CENTRAL (The Cochrane Library Issue 1, 2006), MEDLINE (1966 to March 2007), EMBASE (1974 to 2006), and PubMed (February 2007). Selection criteria Single oral dose, randomised placebo controlled trials of lumiracoxib, in acute postoperative pain, in adult patients. Data collection and analysis Trials were quality scored and data extracted by two review authors independently. Summed pain relief (TOTPAR) was extracted and converted into dichotomous information yielding the number of patients with at least 50% pain relief. These derived results were used to calculate the relative benefit (RB) and number-needed-to-treat (NNT) for one patient to achieve at least 50% pain relief. Main results Three studies (737 patients) met the inclusion criteria. In total 211 patients were treated with lumiracoxib 400 mg, 51 with lumiracoxib 100 mg, and 161 with placebo. Active comparators were naproxen 500 mg (60 patients), rofecoxib 50 mg (102), celecoxib 200 mg (101), and ibuprofen 400 mg (51). One hundred patients (48%) given lumiracoxib 400 mg had at least 50% pain relief over six hours, compared with 17 (11%) given placebo; RB 4.8 (95% CI 2.9 to 7.9), NNT 2.7 (2.2 to 3.5). Weighted median time to use of rescue medication was 7.4 hours for lumiracoxib 400 mg and 1.8 hours for placebo. Patient global assessment at study endpoint was rated as “excellent” by 71 patients (34%) given lumiracoxib 400 mg and 5 (3%) given placebo. Median time to onset of analgesia was shorter for lumiracoxib 400 mg (0.6 to 1.5 hours) than placebo (>12 hours), and use of rescue medication within 12 hours occurred in 64 patients (58%) given lumiracoxib 400 mg and 100 (91%) given placebo. Adverse events reported were generally mild to moderate in severity, with one serious adverse event reported in a patient given placebo. Authors’ conclusions Lumiracoxib 400 mg given as a single oral dose, is an effective analgesic for acute postoperative pain. PMID:17943921

Roy, Yvonne M; Derry, Sheena; Moore, R Andrew

2014-01-01

33

Absence of reproductive and developmental toxicity in rats following oral dosing with nelfinavir.  

PubMed

The potential for nelfinavir mesylate (VIRACEPT) to produce reproductive toxicity was evaluated in rats administered oral doses of 200, 500, or 1000mg/kg/day. In the fertility and early embryonic development to implantation study, male rats were treated beginning 28 days prior to mating until necropsy and females for 2 weeks prior to mating and through gestation day (GD) 7. In the pre- and postnatal development study, pregnant rats were treated from GD 6 through lactation day (LD) 20. Selected F(1) pups from this study were evaluated in sensory and behavioral tests and were subsequently mated. Pregnant F(1) females were euthanized on GD 20 and their F(2) fetuses were examined. F(1) animals were not directly dosed with the drug. No treatment-related effects were observed on any male reproductive parameters. Administration of nelfinavir did not produce adverse effects on fertility, pregnancy, embryo-fetal development, parturition, or lactation in the F(0) generation. Similarly, no adverse effects of nelfinavir treatment were observed on pre- and postnatal growth, development, reproductive performance and embryo-fetal development in the F(1) offspring. Based on the results of this study, the no-observed-adverse-effect-level (NOAEL) for developmental and reproductive toxicity in rats was considered to be 1000mg/kg/day, the highest dose tested. PMID:14623481

Burns-Naas, Leigh Ann; Stump, Donald G; Webber, Stephanie; Holson, Joseph F; Masarjian, Lilit; Furman, Grace; Zorbas, Mark

2003-12-01

34

Perturbation of the indigenous rat oral microbiome by ciprofloxacin dosing  

PubMed Central

SUMMARY Mucosal surfaces such as the gut, vagina and oral cavity are colonized by microbiota that are an integral component of the healthy ecosystem. Recent molecular techniques make it feasible to correlate antimicrobial dosing levels with changes in microbiome composition. The objective of this study was to characterize the rat oral plaque microbiome composition at doses of ciprofloxacin that were considerably above and below nominal in vitro minimal inhibitory concentrations (MICs) of a variety of gram positive oral commensal bacteria. We exposed the oral cavities of rats to relatively low (0.1 µg/mL) and high (20 µg/mL) doses of ciprofloxacin in the drinking water over a 3 day period. Plaque microbiota were characterized using 454 pyrosequencing. The rat indigenous community was dominated by Rothia (74.4 %) and Streptococcus genera (4.7%). Dosing at 0.1 µg/mL was associated with changes in Rothia and Streptococcus genera which were not significant, while dosing at 20 µg/mL caused a pronounced (significant) reduction in the relative abundance of the Streptococcus genus. Taxonomic independent analysis indicated that the perturbation in the overall community structure attributed to dosing with ciprofloxacin at either the low or high dose was relatively low. The results suggest that it is feasible to use an antimicrobial dosing regime to selectively target a specific subset of a mucosal microbiome for elimination with minimal perturbation of the entire community. PMID:23844936

Manrique, Pilar; Freire, Marcelo O.; Chen, Casey; Zadeh, Homa; Young, Mark; Suci, Peter

2013-01-01

35

Rapid and Sustained Relief from the Symptoms of Carcinoid Syndrome: Results from an Open 6Month Study of the 28Day Prolonged-Release Formulation of Lanreotide  

Microsoft Academic Search

This 6-month, open, non-controlled, multicenter, dose-titration study evaluated the efficacy and safety of 28-day prolonged-release (PR) lanreotide in the treatment of carcinoid syndrome. Eligible patients had a carcinoid tumor with ?3 stools\\/day and\\/or ?1 moderate\\/severe flushing episodes\\/day. Six treatments of 28-day PR lanreotide were administered by deep subcutaneous injection. The dose for the first two injections was 90 mg. Subsequent

Philippe Ruszniewski; Sofia Ish-Shalom; Machteld Wymenga; Dermot O’Toole; Rudolf Arnold; Paola Tomassetti; Nigel Bax; Martyn Caplin; Barbro Eriksson; Benjamin Glaser; Michel Ducreux; Catherine Lombard-Bohas; Wouter W. de Herder; Gianfranco Delle Fave; Nick Reed; Jean François Seitz; Eric Van Cutsem; Ashley Grossman; Philippe Rougier; Wolfgang Schmidt; Bertram Wiedenmann

2004-01-01

36

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

PubMed Central

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

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

2014-01-01

37

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

38

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

PubMed Central

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

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

2012-01-01

39

Single dose oral meloxicam for acute postoperative pain in adults  

PubMed Central

Background Meloxicam is a non-steroidal anti-inflammatory drug (NSAID) used mainly in treating pain associated with arthritis. The usual oral dose for osteoarthritis is 15 mg daily, but lower doses of 7.5 mg are advised in older patients. This review sought to evaluate the efficacy and safety of oral meloxicam in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish that drugs have analgesic properties. Objectives To assess the efficacy of single dose oral meloxicam in acute postoperative pain, and any associated adverse events. Search methods We searched Cochrane CENTRAL (Issue 2, 2009), MEDLINE (June 2009); EMBASE (June 2009); the Oxford Pain Relief Database. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of oral meloxicam for relief of acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We planned to use area under the “pain relief versus time” curve to derive the proportion of participants with meloxicam experiencing least 50% pain relief over 4 to 6 hours, using validated equations; to use number needed to treat to benefit (NNT); the proportion of participants using rescue analgesia over a specified time period; time to use of rescue analgesia; information on adverse events and withdrawals. Main results No studies were identified by the searches that examined oral meloxicam in patients with established postoperative pain. Authors’ conclusions In the absence of evidence of efficacy, at present, for oral meloxicam in acute postoperative pain, its use in this indication is not justified. Because trials clearly demonstrating analgesic efficacy in the most basic of acute pain studies is lacking, use in other indications should be evaluated carefully. Given the large number of available drugs of this and similar classes, there is no urgent research agenda. PMID:19821429

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

2014-01-01

40

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

Microsoft Academic Search

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 30mg\\/kg-d, respectively. Ammonium perfluorooctanoate was used as a comparator at a dose of 30mg\\/kg-d in the 28-day study. Female rats were unaffected by NH4+PFBA. Effects in males included: increased liver weight, slight to minimal hepatocellular hypertrophy;

John L. Butenhoff; James A. Bjork; Shu-Ching Chang; David J. Ehresman; George A. Parker; Kaberi Das; Christopher Lau; Paul H. Lieder; François M. van Otterdijk; Kendall B. Wallace

41

Therapeutic effect of oral doxycycline on syphilis  

Microsoft Academic Search

Fifty-one patients with syphilis were treated with oral doxycycline. A course of the antibiotic treatment consisted of 200 mg of doxycycline daily in two divided doses for 28 days. The courses were repeated three to four times a year with an interval of several months. Quantitative Venereal Disease Research Laboratory (VDRL), Wassermann reaction (WR), and Treponema pallidum haemagglutination assay (TPHA)

Y Onoda

1979-01-01

42

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

43

Single dose oral piroxicam for acute postoperative pain  

PubMed Central

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

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

2014-01-01

44

Effects of oral dosing paradigms (gavage versus diet) on pharmacokinetics and pharmacodynamics  

Microsoft Academic Search

In cancer chemopreventive studies, test agents are typically administered via diet, while the preclinical safety studies normally employ oral gavage dosing. Correspondence in pharmacokinetic and pharmacodynamic profiles between the two dosing approaches cannot be assumed a priori. Sulindac, a non-steroidal anti-inflammatory agent with potential chemopreventive activity, was used to assess effects of the two oral dosing paradigms on its pharmacokinetics

I. M. Kapetanovic; R. Krishnaraj; Tomas Martin-Jimenez; L. Yuan; R. B. van Breemen; A. Lyubimov

2006-01-01

45

Single-Dose Pharmacokinetics of Oral and Intravenous Pantoprazole in Children and Adolescents  

Microsoft Academic Search

The primary objective was to determine the pharmacokinetics of single oral and intravenous doses of pantoprazole in children 2 to 16 years of age. The secondary objective was to assess the safety and tolerability of these doses. Male and female hospitalized and nonhospitalized patients from ages 5 to 16 years received single oral doses (20 mg or 40 mg), and

Gregory L. Kearns; Jeffrey Blumer; Stephen Schexnayder; Laura P. James; Kim G. Adcock; Michael D. Reed; James F. Daniel; Andrea Gaedigk; Jeffrey Paul

2008-01-01

46

Single dose oral ibuprofen for acute postoperative pain in adults  

PubMed Central

Background This review updates a 1999 Cochrane review showing that ibuprofen at various doses was effective in postoperative pain in single dose studies designed to demonstrate analgesic efficacy. New studies have since been published. Ibuprofen is one of the most widely used non-steroidal anti-inflammatory (NSAID) analgesics both by prescription and as an over-the-counter medicine. Ibuprofen is used for acute and chronic painful conditions. Objectives To assess analgesic efficacy of ibuprofen in single oral doses for moderate and severe postoperative pain in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to May 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered ibuprofen (any formulation) in adults with moderate to severe acute postoperative pain. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number-needed-to-treat-to-benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Main results Seventy-two studies compared ibuprofen and placebo (9186 participants). Studies were predominantly of high reporting quality, and the bulk of the information concerned ibuprofen 200 mg and 400 mg. For at least 50% pain relief compared with placebo the NNT for ibuprofen 200 mg (2690 participants) was 2.7 (2.5 to 3.0) and for ibuprofen 400 mg (6475 participants) it was 2.5 (2.4 to 2.6). The proportion with at least 50% pain relief was 46% with 200 mg and 54% with 400 mg. Remedication within 6 hours was less frequent with higher doses, with 48% remedicating with 200 mg and 42% with 400 mg. The median time to remedication was 4.7 hours with 200 mg and 5.4 hours with 400 mg. Sensitivity analysis indicated that pain model and ibuprofen formulation may both affect the result, with dental impaction models and soluble ibuprofen salts producing better efficacy estimates. Adverse events were uncommon, and not different from placebo. Authors’ conclusions The very substantial amount of high quality evidence demonstrates that ibuprofen is an effective analgesic in treating postoperative pain. NNTs for 200 mg and 400 mg ibuprofen did not change significantly from the previous review even when a substantial amount of new information was added. New information is provided on remedication. PMID:19588326

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

2014-01-01

47

Single dose oral tenoxicam for acute postoperative pain in adults  

PubMed Central

Background Tenoxicam is a non-steroidal anti-inflammatory drug (NSAID) licensed for use in rheumatic disease and other musculoskeletal disorders in the UK, and is widely available in other countries worldwide. This review sought to evaluate the efficacy and safety of oral tenoxicam in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish that drugs have analgesic properties. Objectives To assess the efficacy of single dose oral tenoxicam in acute postoperative pain, and any associated adverse events. Search methods We searched The Cochrane Library (Issue 1, 2009), MEDLINE (March 2009); EMBASE via Ovid (March 2009); the Oxford Pain Relief Database. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of oral tenoxicam for relief of acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. The area under the “pain relief versus time” curve was used to derive the proportion of participants with tenoxicam experiencing least 50% pain relief over 4 to 6 hours, using validated equations. The number needed to treat to benefit (NNT) was calculated using 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals was also collected. Main results Not one of sixteen studies identified by the searches and examined in detail studied oral tenoxicam in patients with established postoperative pain and therefore no results are available. Authors’ conclusions In the absence of evidence of efficacy for oral tenoxicam in acute postoperative pain, its use in this indication is not justified at present. Because trials clearly demonstrating analgesic efficacy in the most basic of acute pain studies is lacking, use in other indications should be evaluated carefully. Given the large number of available drugs of this and similar classes which are effective, there is no urgent research agenda for this particular drug. PMID:19588438

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

2014-01-01

48

Single dose oral lumiracoxib for postoperative pain in adults  

PubMed Central

Background Lumiracoxib is a selective cyclooxygenase-2 (COX-2) inhibitor. COX-2 inhibitors were developed to avoid COX-1-related gastrointestinal (GI) problems while maintaining the analgesic and anti-inflammatory activity of traditional non-steriodal anti-inflammatory drugs (NSAIDs). Objectives To review the analgesic efficacy, duration of analgesia, and adverse effects of a single oral dose of lumiracoxib for moderate to severe postoperative pain in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, and EMBASE to February 2010. Selection criteria Single oral dose, randomised, double-blind, placebo-controlled trials of lumiracoxib for relief of established moderate to severe postoperative pain in adults. Data collection and analysis Studies were assessed for methodological quality and the data extracted by two review authors independently. Summed total pain relief over six hours (TOTPAR 6) was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over six hours. Numbers of participants using rescue medication, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results In this updated review four studies met the inclusion criteria. In total 366 participants were treated with lumiracoxib 400 mg, 51 with lumiracoxib 100 mg, and 212 with placebo. Active comparators were naproxen 500 mg, rofecoxib 50 mg, celecoxib 200 mg, celecoxib 400 mg, and ibuprofen 400 mg. With lumiracoxib 400 mg 50% of participants had at least 50% pain relief over six hours, compared with 8% given placebo; RB 6.9 (95% CI 4.1 to 12), NNT 2.4 (2.1 to 2.8). Median time to onset of analgesia was shorter for lumiracoxib 400 mg (0.6 to 1.5 hours) than placebo (>12 hours). Fewer participants needed rescue medication with lumiracoxib (64%) than with placebo (91%) over 12 to 24 hours; NNT to prevent remedication 3.7 (2.9 to 5.0). The weighted median time to use of rescue medication was 9.4 hours for lumiracoxib 400 mg and 1.7 hours for placebo. Adverse events were generally mild to moderate in severity, with one serious event reported in a placebo patient. Authors’ conclusions Lumiracoxib 400 mg given as a single oral dose is an effective analgesic for acute postoperative pain, and has a relatively long duration of action. Adverse events with lumiracoxib did not differ from placebo. PMID:20614451

Roy, Yvonne M; Derry, Sheena; Moore, R Andrew

2014-01-01

49

Single dose oral pharmacokinetic profile of ?-mangostin in mice.  

PubMed

The mangosteen fruit (Garcinia mangostana) is a rich source of dietary xanthones with the most prominent being ?-mangostin. Dietary xanthones have been reported to have a variety of health promoting properties. Until now, in vivo studies on the pharmacokinetic profile of ?-mangostin are limited. For this study we employed an LC/MS/MS assay to determine the pharmacokinetic properties of ?-mangostin suspension in cottonseed oil in C57BL/6 Mice. Mice were administered 100 mg/kg of ?-mangostin by oral gavage and the plasma levels were analyzed over a 24 hour period. We observed the degree of exposure (i.e. area under the curve) of ?-mangostin to be 5,736 nmol/L/hr and the maximum plasma concentration was 1,382 nmol/L. Furthermore, we provide evidence that ?-mangostin undergoes glucuronidation into monoglucuronide and diglucuronide metabolites. Our study demonstrated that ?-mangostin when administered in cotton seed oil to mice at a dose equivalent to 615 mg in a 90kg human adult achieves an approximate maximum plasma concentration of 1,300 nmol/L and is detectable for up to 24 hours. Further research is needed to understand the relationship between the pharmacokinetic properties of ?-mangostin following oral administration and reported health benefits. PMID:23140281

Ramaiya, Atulkumar; Li, Gongbo; Petiwala, Sakina M; Johnson, Jeremy J

2012-12-01

50

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

PubMed Central

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

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

2014-01-01

51

Effects of oral doses of fluoride on nestling European starlings  

USGS Publications Warehouse

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

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

1987-01-01

52

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

Microsoft Academic Search

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

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

2008-01-01

53

Pharmacokinetics of temafloxacin in humans after multiple oral doses.  

PubMed Central

The multiple-dose pharmacokinetics and tolerance of temafloxacin, a new fluoroquinolone antibacterial agent, were evaluated in healthy volunteers. Temafloxacin was found to be well tolerated when administered orally every 12 h for 7 days at doses of 100, 200, 300, 400, 600, and 800 mg. Steady-state maximum and minimum concentrations in plasma were proportional to dose, averaging slightly over 1.0 and 0.5 microgram/ml/100 mg administered. Analyses of variance found no significant differences among the dosage groups in total apparent clearances (CLT/F), renal clearances (CLR), or nonrenal clearances, which averaged 197, 119, and 78 ml/min, respectively. The half-life increased slightly with dose, averaging 8.4 h overall. The extent of absorption of temafloxacin was quite reproducible, with day-to-day intrasubject variability in minima averaging under 10%. Renal glomerular filtration of unbound drug was the dominant elimination process; however, tubular secretion and reabsorption also appear to occur. Secretion was estimated to account for about 12% of CLT/F during a regimen of 600 mg every 12 h. CLR was relatively constant for urine flow rates above 1 ml/min, but reabsorption appeared to occur under low-flow conditions, resulting in day-versus-night differences in CLR. Intersubject variability in CLT/F over the eightfold range in dosage was only 20%, and 60% of this variance was accounted for by differences in body surface area (or lean body mass), concentration in plasma, and urine flow rate. Overall, it appears that the pharmacokinetics of temafloxacin are essentially linear, reproducible within a subject, and predictable among subjects. PMID:1318680

Granneman, G R; Carpentier, P; Morrison, P J; Pernet, A G

1992-01-01

54

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

55

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

Microsoft Academic Search

BACKGROUNDThe adverse effects of oral corticosteroids are widely recognised but there are few quantitative data on which to base advice to patients. In a two part cross sectional study we compared adverse effects in patients with lung disease taking oral corticosteroids and control subjects and related the adverse effects to corticosteroid dose in the patient group.METHODSData on oral corticosteroid use,

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

2001-01-01

56

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...

57

Pharmacokinetics of tamoxifen after intravenous and oral dosing of tamoxifen-hydroxybutenyl-beta-cyclodextrin formulations.  

PubMed

Oral and intravenous administration of tamoxifen base and tamoxifen citrate formulated with hydroxybutenyl-beta-cyclodextrin (HBenBCD) to Sprague-Dawley rats significantly increased the oral bioavailability of tamoxifen relative to that of parent drug (no HBenBCD). When formulated with HBenBCD, the form of tamoxifen (base vs. salt) made no difference in the oral bioavailability of tamoxifen. Liquid formulations (PG:PEG400:H2O) provided higher oral bioavailability than solid formulations dissolved and dosed as aqueous oral solutions. The oral bioavailability of tamoxifen was significantly influenced by both dietary status and time of dosing of the animals. Tamoxifen metabolite plasma concentrations were not affected by complexation of tamoxifen with HBenBCD. Collectively, the data indicated that dosing of fasted animals in the morning with tamoxifen:HBenBCD formulations provided a very significant increase in tamoxifen oral bioavailability (up to 10- to 14-fold). PMID:17083091

Buchanan, Charles M; Buchanan, Norma L; Edgar, Kevin J; Little, James L; Malcolm, Michael O; Ruble, Karen M; Wacher, Vincent J; Wempe, Michael F

2007-03-01

58

Stability and sterility of biosynthetic human insulin stored in plastic insulin syringes for 28 days.  

PubMed

The stability and sterility of biosynthetic human insulin products stored at refrigerator and room temperatures in two types of plastic syringes and the stability of preservatives in the products were studied. Four types of biosynthetic human insulin were used: regular, isophane, combination, and extemporaneously prepared combination. Samples (0.4 mL) were withdrawn from multiple-dose vials into 39 polypropylene and 39 propylene-ethylene copolymer syringes. Three syringes of each type were analyzed immediately; the remaining syringes were stored in plastic bags, half at room temperature (23 degrees C) and half in the refrigerator (4 degrees C). A vial of each type of insulin was maintained under similar conditions. At days 1, 3, 7, 14, 21, and 28, samples from each syringe were analyzed by high-performance liquid chromatography for insulin potency and m-cresol and phenol concentrations. Samples of each product were also tested for sterility after 1, 2, and 4 weeks of storage at 4 degrees C and 23 degrees C. The potency of insulin in each of the biosynthetic human insulin products did not change significantly during the 28-day study in both types of plastic syringes and at both temperature settings. m-Cresol concentrations decreased in all samples; greater decreases occurred in samples stored at room temperature and in samples stored in polypropylene syringes. Phenol concentrations were less affected than m-cresol concentrations; greater decreases occurred in samples stored at room temperature. No significant decreases in insulin potency or m-cresol or phenol concentrations occurred in control samples stored in vials kept under similar conditions.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:1814206

Tarr, B D; Campbell, R K; Workman, T M

1991-12-01

59

Pharmacokinetic Profile of Levofloxacin following Once-Daily 500Milligram Oral or Intravenous Doses  

Microsoft Academic Search

The pharmacokinetics of once-daily oral levofloxacin (study A) or intravenous levofloxacin (study B) in 40 healthy male volunteers were investigated in two separate randomized, double-blind, parallel-design, placebo- controlled studies. Levofloxacin at 500 mg or placebo was administered orally or intravenously as a single dose on day 1; daily oral or intravenous dosing resumed on days 4 to 10. In a

SHU-CHEAN CHIEN; MARK C. ROGGE; LEE G. GISCLON; CHRIS CURTIN; FRANK WONG; JAYA NATARAJAN; R. REX WILLIAMS; CYNTHIA L. FOWLER; WING K. CHEUNG; ANDREW T. CHOW

1997-01-01

60

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

61

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

PubMed

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

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

2014-05-20

62

Reexamination of pharmacokinetics of oral testosterone undecanoate in hypogonadal men with a new self-emulsifying formulation.  

PubMed

Many hypogonadal men prefer oral testosterone (T) treatment. Oral T undecanoate (TU) is available in many countries, but not in the United States. We aimed to assess the pharmacokinetics of oral TU in a new self-emulsifying drug delivery system formulation. Pharmacokinetics studies were conducted in 3 parts: 12 hypogonadal men were enrolled in 2 centers for a 1-day dosing study; 29 participants were enrolled from 3 centers for a 7-day dosing study; and 15 participants were enrolled from 1 center for a 28-day dosing study. Serial blood samples for serum sex hormone measurements by liquid chromatography-tandem mass spectrometry were drawn for up to 36 hours after oral TU administration. Mean serum T levels (C(avg)) after oral dosing of T 200 mg as TU twice daily with food were within the adult male range in most participants in the 1-, 7-, and 28-day dosing studies but were much lower in the fasting state. The dose-proportional increase in C(avg) of serum T after oral T 300 mg twice daily resulted in more participants with supraphysiologic serum T levels. In the 28-day study, trough serum T reached a steady state at day 7. Serum dihydrotestosterone and estradiol levels tracked serum T concentration. Dihydrotestosterone-testosterone ratios increased 3-fold after oral TU administration. Oral T 200 mg twice daily as TU in a new SEDDS formulation may be a viable therapy for hypogonadal men. PMID:21474786

Yin, Anthony Y; Htun, Michelle; Swerdloff, Ronald S; Diaz-Arjonilla, Maruja; Dudley, Robert E; Faulkner, Sandra; Bross, Rachelle; Leung, Andrew; Baravarian, Sima; Hull, Laura; Longstreth, James A; Kulback, Steven; Flippo, Gregory; Wang, Christina

2012-01-01

63

Single dose oral dihydrocodeine for acute postoperative pain  

PubMed Central

Background This is an updated version of the original Cochrane review published in Issue 2, 2000. Dihydrocodeine is a synthetic opioid analgesic developed in the early 1900s. Its structure and pharmacokinetics are similar to that of codeine and it is used for the treatment of postoperative pain or as an antitussive. It is becoming increasingly important to assess the relative efficacy and harm caused by different treatments. Relative efficacy can be determined when an analgesic is compared with control under similar clinical circumstances. Objectives To quantitatively assess the analgesic efficacy and adverse effects of single-dose dihydrocodeine compared with placebo in randomised trials in moderate to severe postoperative pain. Search methods Published reports were identified from electronic databases (MEDLINE, EMBASE, CENTRAL, the Oxford Pain Relief Database in December 2007, the original search was conducted in October 1999). Additional studies were identified from the reference lists of retrieved reports. Selection criteria Inclusion criteria: full journal publication, clinical trial, random allocation of participants to treatment groups, double blind design, adult participants, baseline pain of moderate to severe intensity, postoperative administration of study drugs, treatment arms which included dihydrocodeine and placebo and either oral or injected (intramuscular or intravenous) administration of study drugs. Data collection and analysis Data collection and analysis: summed pain intensity and pain relief data over four to six hours were extracted and converted into dichotomous information to yield the number of participants obtaining at least 50% pain relief. This was used to calculate relative benefit and number-needed-to-treat-to-benefit (NNT) for one participant to obtain at least 50% pain relief. Single-dose adverse effect data were collected and used to calculate relative risk and number-needed-to-treat-to-harm (NNH). Main results Fifty-two reports were identified in the original review as possible randomised trials which assessed dihydrocodeine in postoperative pain. Four reports met the inclusion criteria; all assessed oral dihydrocodeine. Three reports (194 participants) compared dihydrocodeine with placebo and one (120 participants) compared dihydrocodeine (30 mg or 60 mg) with ibuprofen 400 mg. For a single dose of dihydrocodeine 30 mg in moderate to severe postoperative pain the NNT for at least 50% pain relief was 8.1 (95% confidence interval 4.1 to 540) when compared with placebo over a period of four to six hours. Pooled data showed significantly more participants to have reported adverse effects with dihydrocodeine 30 mg than with placebo. When compared to ibuprofen 400 mg both dihydrocodeine 30 mg and 60 mg were significantly inferior. No additional studies were found for this update. Authors’ conclusions A single 30 mg dose of dihydrocodeine is not sufficient to provide adequate pain relief in postoperative pain. Statistical superiority of ibuprofen 400 mg over dihydrocodeine (30 mg or 60 mg) was shown. Since the last version of this review no new relevant studies have been identified. PMID:11034754

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

2014-01-01

64

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

EPA Science Inventory

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

65

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. PMID:23785463

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

66

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. PMID:24278619

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

67

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. PMID:23754596

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

2013-01-01

68

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

E-print Network

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

LeGrange, Suzanne Nauman

2012-06-07

69

A single, low dose oral antigen exposure in newborn piglets primes mucosal immunity if administered with CpG oligodeoxynucleotides and polyphosphazene adjuvants.  

PubMed

By definition, soluble antigens ingested orally trigger mucosal tolerance such that any subsequent re-exposure by a systemic route results in suppression of immunity. We propose that antigens introduced in extreme early life can readily traverse the gut wall and therefore circumvent induction of mucosal tolerance and instead induce immunity. Piglets were drenched with low-doses of ovalbumin (OVA; 5mg or 0.05mg) alone, OVA plus adjuvants (CpG oligodeoxynucleotides and PCEP polyphosphazene) or saline within 6h of birth. At 28 days of age, they were administered 10mg OVA plus 1:1 Montanide adjuvant (or saline) via the intraperitoneal (i.p.) route or via the oral route. Serum was obtained on day 28 and day 49 to measure OVA-specific antibodies titres. All piglets boosted orally with OVA plus Montanide, regardless of prior OVA exposure, failed to induce immunity. As expected, piglets drenched with saline but boosted via the i.p. route with OVA plus Montanide showed significant induction of anti-OVA IgA, IgG, IgG1 and IgG2 relative to saline control piglets. Newborn animals drenched with 5mg or 0.05mg OVA failed to induce oral immunity. A second intramuscular injection in adulthood triggered immunity in the piglets that were drenched with 0.05mg OVA and boosted initially by the i.p. route suggesting that some systemic lymphocytes were primed despite initial lack of induction of humoral immunity. In contrast, piglets orally immunized with 5mg or 0.05mg OVA plus adjuvants resulted in significant induction of anti-OVA IgA (5mg only), IgM, IgG, IgG1 and IgG2 in serum relative to saline control piglets as well as significant induction of anti-OVA IgA, IgM (5mg only) IgG, IgG1 (5mg only) or IgG2 relative to piglets drenched with OVA alone. These data clearly show that the response was sensitive to the oral vaccine components and was not simply a response to the i.p. immunization at day 28. This work demonstrates that newborn piglets respond to oral antigens with immunity if re-exposure to the antigen occurs via a systemic route and if adjuvants are included with the oral vaccine administered at birth. These results should be further explored to establish whether early life oral vaccination can be exploited to protect this susceptible population against infectious diseases. PMID:25194591

Pasternak, J Alex; Ng, Siew Hon; Wilson, Heather L

2014-10-15

70

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

SciTech Connect

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

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

1989-01-01

71

Placental transfer and pharmacokinetics of a single oral dose of [ 14 C] p -nitrophenol in rats  

Microsoft Academic Search

The pharmacokinetics and placental transfer of a single oral dose of 100 mg\\/kg (10 µCi\\/kg, 16% of acute oral LD50) of uniformly phenyl-labeled [14C]p-nitrophenol were investigated in pregnant Sprague-Dawley rats at 14-18 days of gestation. Three animals were killed on gestation day 18, at 0.5, 1, 2, 4, 12, 24, and 48 h after dosing. Radioactivity was rapidly absorbed and

Aqel W. Abu-Qare; Cecil F. Brownie; Mohamed B. Abou-Donia

2000-01-01

72

Biotransformation and pharmacokinetics of ethylmorphine after a single oral dose.  

PubMed

1. The pharmacokinetics of ethylmorphine after administration of a single dose of the cough mixture Cosylan were investigated in 10 healthy subjects. 2. The median urinary recovery of ethylmorphine and measured metabolites was 77% over 48 h. The median tmax of unchanged ethylmorphine was 45 min, and the terminal elimination t1/2 was 2 h. Ethylmorphine-6-glucuronide was found to be the major metabolite. 3. Two subjects had significantly lower urinary recovery (0.48 h) of morphine and morphine-glucuronides than the remainder. Furthermore, these two had urinary metabolic ratios (MRO) and partial metabolic clearances (CLmO) for O-deethylation of ethylmorphine tentatively classifying them phenotypically as poor metabolisers of the debrisoquine/sparteine type. 4. Genotyping for cytochrome P450 (CYP) 2D6 alleles revealed five homozygote (wt/wt) and five heterozygote subjects. Two subjects phenotypically classified as poor metabolisers were genotypically CYP2D6A/wt and CYP2D6D/wt, respectively. 5. Serum and urine samples taken more than 8 and 24 h after administration of ethyl-morphine respectively, contained morphine and morphine-glucuronides, but no ethylmorphine, ethylmorphine-6-glucuronide or (serum only) norethylmorphine. Norethylmorphine could be detected after hydrolysis of urine samples in all subjects. The urinary recovery of the active metabolites morphine and morphine-6-glucuronide after administration of ethylmorphine varied by a factor of 9 between individuals. 6. The wide variation in recovery of morphine and morphine-glucuronides after oral administration of ethylmorphine could not be explained simply by a difference in CYP2D6 genotype. Constitutional variation in other enzymatic pathways involved in ethylmorphine metabolism is probably crucial. Ratios of morphine to parent drug cannot be used to distinguish the source of morphine after administration of ethylmorphine. Norethylmorphine should be included in urine assays for opiates in forensic toxicology, and no firm conclusions about the source of morphine are possible based on serum samples obtained more than 24 h after drug administration. PMID:7654478

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

1995-06-01

73

Biotransformation and pharmacokinetics of ethylmorphine after a single oral dose.  

PubMed Central

1. The pharmacokinetics of ethylmorphine after administration of a single dose of the cough mixture Cosylan were investigated in 10 healthy subjects. 2. The median urinary recovery of ethylmorphine and measured metabolites was 77% over 48 h. The median tmax of unchanged ethylmorphine was 45 min, and the terminal elimination t1/2 was 2 h. Ethylmorphine-6-glucuronide was found to be the major metabolite. 3. Two subjects had significantly lower urinary recovery (0.48 h) of morphine and morphine-glucuronides than the remainder. Furthermore, these two had urinary metabolic ratios (MRO) and partial metabolic clearances (CLmO) for O-deethylation of ethylmorphine tentatively classifying them phenotypically as poor metabolisers of the debrisoquine/sparteine type. 4. Genotyping for cytochrome P450 (CYP) 2D6 alleles revealed five homozygote (wt/wt) and five heterozygote subjects. Two subjects phenotypically classified as poor metabolisers were genotypically CYP2D6A/wt and CYP2D6D/wt, respectively. 5. Serum and urine samples taken more than 8 and 24 h after administration of ethyl-morphine respectively, contained morphine and morphine-glucuronides, but no ethylmorphine, ethylmorphine-6-glucuronide or (serum only) norethylmorphine. Norethylmorphine could be detected after hydrolysis of urine samples in all subjects. The urinary recovery of the active metabolites morphine and morphine-6-glucuronide after administration of ethylmorphine varied by a factor of 9 between individuals. 6. The wide variation in recovery of morphine and morphine-glucuronides after oral administration of ethylmorphine could not be explained simply by a difference in CYP2D6 genotype. Constitutional variation in other enzymatic pathways involved in ethylmorphine metabolism is probably crucial. Ratios of morphine to parent drug cannot be used to distinguish the source of morphine after administration of ethylmorphine. Norethylmorphine should be included in urine assays for opiates in forensic toxicology, and no firm conclusions about the source of morphine are possible based on serum samples obtained more than 24 h after drug administration. PMID:7654478

Aasmundstad, T A; Xu, B Q; Johansson, I; Ripel, A; Bj?rneboe, A; Christophersen, A S; Bodd, E; M?rland, J

1995-01-01

74

Dose-related prolongation of tetracaine spinal anesthesia by oral clonidine in humans.  

PubMed

The prolonging effects of oral clonidine on sensory block during tetracaine spinal anesthesia were studied in 47 healthy patients scheduled for urologic or gynecologic surgery. All patients received 15 mg tetracaine intrathecally in isobaric saline. The patients were randomly allocated into four groups. Group 1 (n = 13) was administered 0.25 mg triazolam orally. Group 2 (n = 12), Group 3 (n = 12), and Group 4 (n = 10) received 75 micrograms, 150 micrograms, and 300 micrograms of oral clonidine, respectively. These drugs were administered 1 h before anesthesia. Sensory block was evaluated by pinprick. All regression times in Groups 2, 3, and 4 were significantly longer than those in Group 1. The prolonging effect of oral clonidine increased in a dose-dependent manner and reached a maximal effect at 150 micrograms. Four patients in Group 4 developed bradycardia (heart rate < 45 bpm), suggesting that the dose of 300 micrograms of oral clonidine may promote bradycardia during spinal anesthesia. PMID:7978436

Ota, K; Namiki, A; Iwasaki, H; Takahashi, I

1994-12-01

75

Pharmacokinetic profile of levofloxacin following once-daily 500-milligram oral or intravenous doses.  

PubMed

The pharmacokinetics of once-daily oral levofloxacin (study A) or intravenous levofloxacin (study B) in 40 healthy male volunteers were investigated in two separate randomized, double-blind, parallel-design, placebo-controlled studies. Levofloxacin at 500 mg or placebo was administered orally or intravenously as a single dose on day 1; daily oral or intravenous dosing resumed on days 4 to 10. In a third study (study C), the comparability of the bioavailabilities of two oral and one intravenous levofloxacin formulations were investigated with 24 healthy male subjects in an open-label, randomized, three-way crossover study. Levofloxacin at 500 mg as a single tablet or an intravenous infusion was administered on day 1; following a 1-week washout period, subjects received the second regimen (i.e., the other oral formulation or the intravenous infusion); the third and final regimen was administered following a 1-week washout period. The concentrations of drug in plasma and urine were measured by validated high-pressure liquid chromatography methods. Pharmacokinetic parameters were estimated by noncompartmental methods. In both study A (oral levofloxacin) and study B (intravenous levofloxacin), steady state was attained within 48 h after the start of the multiple dosing on day 4. Levofloxacin pharmacokinetics were linear and predictable for the single and multiple 500-mg, once-daily oral and intravenous dosing regimens, and the values of the pharmacokinetic parameters for the oral and intravenous administrations were similar. Study C indicated that levofloxacin was rapidly and completely absorbed from the oral tablets, with mean times to the maximum concentration of drug in serum of approximately 1.5 h and mean absolute bioavailability of > or =99%. These results support the interchangeability of the oral and intravenous routes of levofloxacin administration. PMID:9333057

Chien, S C; Rogge, M C; Gisclon, L G; Curtin, C; Wong, F; Natarajan, J; Williams, R R; Fowler, C L; Cheung, W K; Chow, A T

1997-10-01

76

Comparison of high-dose intermittent and low-dose continuous oral artemisinin in dogs with naturally occurring tumors.  

PubMed

To evaluate the clinical toxicity and activity of orally administered artemisinin in dogs with spontaneous tumors, 24 client-owned dogs were randomly divided into two groups and received either low-continuous dose (3 mg/kg q 24 hr) or high-dose intermittent (three doses of 45 mg/kg q 6 hr repeated q 1 wk) of artemisinin per os. Treatment was continued for 21 days. Dogs were evaluated weekly for clinical effect and at the end of the treatment for hematologic and biochemical adverse events. Whole blood concentrations of artemisinin and dihydroartemisinin were measured by liquid chromatography/tandem mass spectrometry after the first dose of artemisinin in three dogs in each group. Blood concentrations of artemisinin and dihydroartemisinin were <0.1 ?M at all time points, and there was no difference in blood concentration between the two dosing groups. The most frequent adverse event was anorexia, which was observed in 11% of the low-dose group and 29% of the high-dose group. Oral artemisinin, both in low-dose continuous and high-dose intermittent, is well tolerated in dogs but results in low bioavailability. Parenteral administration should be considered for future studies. PMID:25251432

Hosoya, Kenji; Couto, C Guillermo; London, Cheryl A; Kisseberth, William C; Phelps, Mitchell A; Dalton, James T

2014-01-01

77

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

SciTech Connect

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.

Wu, Vincent W.C. [Department of Health Technology and Informatics, Hong Kong Polytechnic University, Kowloon, Hong Kong (Hong Kong); Yang Zhining; Zhang Wuzhe; Wu Lili [Cancer Hospital, Shantou University Medical College, Shantou (China); Lin Zhixiong, E-mail: zxlin5@yahoo.com [Cancer Hospital, Shantou University Medical College, Shantou (China)

2012-07-01

78

Laboratory assessment of the speed of action on honey bees of orally dosed insecticides  

Microsoft Academic Search

A laboratory test to determine the times taken by orally dosed pesticides to affect and paralyse honey bees is described. Ten insecticides were tested at levels 1.5, 2, and 4 times that of their LDs 90. Results rre expressed as the times taken after consumption of the test doses for 50% and 90% of the bees to become affected and

P. G. Clinch; J. G. M. Ross

1970-01-01

79

Oral gavage subchronic neurotoxicity and inhalation subchronic immunotoxicity studies of ethylbenzene in the rat  

Microsoft Academic Search

The potential for neurotoxicological and immunotoxicological effects of ethylbenzene was studied in young adult Crl:CD(SD) rats following 90-day oral (neurotoxicity) or 28-day inhalation (immunotoxicity) exposures. In the neurotoxicity study, ethylbenzene was administered orally via gavage twice daily at 0, 25, 125, or 250mg\\/kg per dose (total daily dosages of 0, 50, 250, or 500mg\\/kg bwt\\/day [mg\\/kg bwt\\/day]) for 13 weeks

Abby A. Li; Jacques P. J. Maurissen; John F. Barnett Jr.; John Foss; Les Freshwater; Robert H. Garman; Vanessa L. Peachee; Sandra J. Hong; Donald G. Stump; James S. Bus

2010-01-01

80

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. PMID:23878811

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

2013-01-01

81

Hepatotoxicity of High Oral Dose (-)-Epigallocatechin-3-Gallate in Mice  

PubMed Central

The tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) has been studied for chronic disease preventive effects, and is marketed as part of many dietary supplements. However, case reports have associated the use of green tea-based supplements with liver toxicity. We studied the hepatotoxic effects of high dose EGCG in male CF-1 mice. A single dose of EGCG (1500 mg/kg, i.g.) increased plasma alanine aminotransferase (ALT) by 138-fold and reduced survival by 85%. Once-daily dosing with EGCG increased hepatotoxic response. Plasma ALT levels were increased 184-fold following two once-daily doses of 750 mg/kg, i.g. EGCG. Moderate to severe hepatic necrosis was observed following treatment with EGCG. EGCG hepatotoxicity was associated with oxidative stress including increased hepatic lipid peroxidation (5-fold increase), plasma 8-isoprostane (9.5-fold increase) and increased hepatic metallothionein and ?-histone 2AX protein expression. EGCG also increased plasma interleukin-6 and monocyte chemoattractant protein 1. Our results indicate that higher bolus doses of EGCG are hepatotoxic to mice. Further studies on the dose-dependent hepatotoxic effects of EGCG and the underlying mechanisms are important given the increasing use of green tea dietary supplements, which may deliver much higher plasma and tissue concentrations of EGCG than tea beverages. PMID:19883714

Lambert, Joshua D.; Kennett, Mary J.; Sang, Shengmin; Reuhl, Kenneth R.; Ju, Jihyeung; Yang, Chung S.

2009-01-01

82

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

NASA Astrophysics Data System (ADS)

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

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

83

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

84

Effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive  

Microsoft Academic Search

The effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive containing 30 ?g ethinyl estradiol and 75 ?g gestodene were assessed in a randomized, double-blind, placebo-controlled parallel-group study in healthy premenopausal female volunteers established in a regimen of oral contraceptive use. They received either placebo or 2400 mg\\/day felbamate from midcycle (day 15) to midcycle (day 14)

Veijo Saano; Paul Glue; Christopher R. Banfield; Pascale Reidenberg; Robert D. Colucci; Jeffrey W. Meehan; Pertti Haring; Elaine Radwanski; Amin Nomeir; Chin-Chung Lin; Peder K. Jensen; Melton B. Affrime

1995-01-01

85

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. 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

86

Effectiveness of a single dose of oral misoprostol 600 ?g for treatment in early pregnancy failure.  

PubMed

Abstract The purpose of this study was to examine the effectiveness, side-effects and acceptability of a single dose of oral misoprostol 600 ?g for treatment of 1st trimester pregnancy failure. A prospective descriptive study was conducted on pregnant women of < 13 weeks' gestation, diagnosed as 1st trimester pregnancy failure. Patients were assigned to receive a single dose of misoprostol 600 ?g orally and then evaluated 48 h after drug administration for complete abortion. A total of 55 women were recruited to the study. The complete abortion rate was 65.5%. Pain and diarrhoea were the most common side-effects. Acceptability and satisfactory rates were 70.9% and 70.9%, respectively. In conclusion, a single dose of oral misoprostol 600 ?g is a fair method for the management of 1st trimester pregnancy failure. Side-effects are tolerable and satisfaction is high. Thus, this method may be used as an alternative treatment. PMID:24988526

Benchamanon, R; Phupong, V

2014-11-01

87

Safety and immunogenicity of single-dose live oral cholera vaccine strain CVD 103-HgR, prepared from new master and working cell banks.  

PubMed

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 × 10(8) 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.). PMID:24173028

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

2014-01-01

88

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.) PMID:24173028

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

2014-01-01

89

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

PubMed Central

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

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

1977-01-01

90

Variability of serum drug level following a single oral dose of dipyridamole  

SciTech Connect

Serum dipyridamole levels were measured in 27 patients undergoing planar thallium-201 myocardial perfusion scintigraphy after receiving a 300 mg oral dose. Mean serum dipyridamole level was 2.9 +/- 1.6 mcg/ml (range 0.2-5.7). No correlation was found between serum level and symptoms, heart rate or blood pressure response, peak heart to lung thallium activity ratio, peak heart to liver thallium activity ratio, or peak myocardial thallium washout. Serum level following a single oral dose of dipyridamole is unpredictable and patients with low drug levels cannot be easily identified at the time of study.

Segall, G.M.; Davis, M.J.

1988-10-01

91

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. PMID:19841158

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

92

Single-dose pharmacokinetics of oral and intravenous pantoprazole in children and adolescents.  

PubMed

The primary objective was to determine the pharmacokinetics of single oral and intravenous doses of pantoprazole in children 2 to 16 years of age. The secondary objective was to assess the safety and tolerability of these doses. Male and female hospitalized and nonhospitalized patients from ages 5 to 16 years received single oral doses (20 mg or 40 mg), and those from ages 2 to 16 years received single intravenous doses (0.8 mg/kg or 1.6 mg/kg) of pantoprazole. The plasma concentration-time data for each patient were analyzed using noncompartmental methods. Routine safety and tolerability assessments were also obtained. The mean values for peak plasma concentration and total area under the plasma concentration-time curve increased with increasing dose. Pharmacokinetic values were similar in patients from ages 2 to 16 years and to those previously obtained in adults. Statistically significant differences were observed for dose-normalized pantoprazole area under the plasma concentration-time curve when compared between CYP2C19 extensive metabolizers with 1 versus 2 functional alleles. All adverse events were mild in severity and considered to be unrelated to study drug. The pharmacokinetic profile of oral and intravenous pantoprazole was similar in children ages 2 to 16 years. The doses used here were safe and well tolerated in this population. PMID:18664620

Kearns, Gregory L; Blumer, Jeffrey; Schexnayder, Stephen; James, Laura P; Adcock, Kim G; Reed, Michael D; Daniel, James F; Gaedigk, Andrea; Paul, Jeffrey

2008-11-01

93

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

PubMed

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

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

2014-09-01

94

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. PMID:23762369

Zhang, Dongsheng

2013-01-01

95

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

96

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

97

Vardenafil Increases Penile Rigidity and Tumescence in Men with Erectile Dysfunction after a Single Oral Dose  

Microsoft Academic Search

Objectives: To evaluate the effect of two doses of vardenafil hydrochloride on penile rigidity and tumescence while determining the pharmacokinetics.Methods: Twenty–one patients with erectile dysfunction completed three oral single–dose regimens (placebo, 20 and 40 mg vardenafil) in a randomized, placebo–controlled, 3–way cross–over study. Penile rigidity and tumescence were measured at the base and tip with a Rigiscan™ for up to

S. Stark; R. Sachse; T. Liedl; J. Hensen; G. Rohde; G. Wensing; R. Horstmann; K. M. Schrott

2001-01-01

98

Localization of lanthanum in bone of chronic renal failure rats after oral dosing with lanthanum carbonate  

Microsoft Academic Search

Localization of lanthanum in bone of chronic renal failure rats after oral dosing with lanthanum carbonate.BackgroundLanthanum carbonate has been shown to be a safe, effective phosphate-binding agent. We have shown that an impaired mineralization in chronic renal failure rats treated with high doses of lanthanum carbonate develops secondary to phosphate depletion and is therefore pharmacologically mediated rather than a direct

Geert J. Behets; Steven C. Verberckmoes; LINE OSTE; An R. Bervoets; MURIELLE SALOMÉ; Alan G. Cox; JOHN DENTON; Marc E. De Broe; Patrick C. D'Haese

2005-01-01

99

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

100

Single and repeated oral dose toxicity study of fucoxanthin (FX), a marine carotenoid, in mice.  

PubMed

Fucoxanthin (FX), a xanthophyll derivative, is an orange-colored pigment present in edible brown algae. As a part of safety evaluation, single and repeated oral dose toxicity study of FX was conducted. In a single dose study, FX purified from seaweed was orally administered to male and female ICR mice at doses of 1,000 and 2,000 mg/kg. In a repeated doses study, FX at doses of 500 and 1,000 mg/kg was orally administered for 30 days. In both studies, no mortality and no abnormalities in gross appearance were observed. In the repeated doses study, histological observation revealed no abnormal changes in liver, kidney, spleen and gonadal tissues of any of the FX-treated groups. However, significantly increased total cholesterol concentrations were shown by plasma biochemical analyses in all FX-treated groups. Although total bilirubin concentrations were increased by FX, it was established that presence of fucoxanthinol, a major metabolite of FX, interfered with bilirubin determination in plasma. To further ascertain the safety of FX, the mechanism by which FX induces hypercholesterolemia in mice and species differences in the induction of hypercholesterolemia should be elucidated. PMID:19797858

Beppu, Fumiaki; Niwano, Yoshimi; Tsukui, Takayuki; Hosokawa, Masashi; Miyashita, Kazuo

2009-10-01

101

Oral carvedilol in escalating doses in the acute treatment of atrial fibrillation  

PubMed Central

Objective: To study the efficacy of oral carvedilol in acute treatment of atrial fibrillation (AF) with fast ventricular rate. Materials and Methods: In an open-label, single-arm trial, oral carvedilol was administered to 35 patients of AF in escalating doses from 3.125 mg o.d. to 12.5 mg b.i.d. Results: A successful result was seen in 25 patients (71.4%) with 4 converting to sinus rhythm, rate control to less than 90 bpm in 16 and a 20% rate reduction in 5 patients. Two patients developed hypotension needing withdrawal of the drug. Conclusion: Escalating doses of oral carvedilol can be effectively and safely used in the acute treatment of AF with fast ventricular rate.

Chitrapu, Ravi Venkatachelam; Rao, Pentakota Ramana; Reddy, Gangireddy Venkateswara

2014-01-01

102

The Relative Potency between High Dose Oral Oxycodone and Intravenous Morphine  

Microsoft Academic Search

Oxycodone is an effective opioid analgesic for cancer pain. In the United States, it is available exclusively as an oral formulation, predominantly in fixed dose combination with acetaminophen or aspirin. The latter limits its use in cancer pain due to the potential toxicity of the nonopioid component. Oxycodone is now available as a single agent, controlled release formulation. The following

Donna S Zhukovsky; Declan Walsh; Marie Doona

1999-01-01

103

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

SciTech Connect

The influence on cobalt 60 dose distributions of typical metal parts used in oral and maxillofacial surgery was studied. Relative doses were determined by exposing x-ray films in a polystyrene phantom set-up containing samples of vitallium, titanium, and stainless steel. Optical densities were converted to doses with the aid of sensitometric curves. The results show that for normal incidence there is a 25% to 40% increase in dose at the entrance side of the metal and a 20% to 25% decrease in dose at the exit side. The enhancement effect falls off rapidly and becomes negligible at about 1 mm from the interface. The reduction effect decreases more gradually and is still evident at distances of a few centimeters. These dose perturbations should be taken into account in the planning of radiation therapy for patients in whom metal objects have been implanted.

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

1984-02-01

104

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

E-print Network

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

Paris-Sud XI, Université de

105

Immunotoxicity of sodium bromate in female B6C3F1 mice: a 28-day drinking water study.  

PubMed

Bromate is one of the water disinfection by-products (DBPs) produced during the process of ozonation. The purpose of this study was to evaluate the immunotoxic potential of sodium bromate (SB) in female B6C3F1 mice. SB was administered in the drinking water for 28 days at doses of 80-800 mg/l. There was no difference in drinking water consumption between the animals exposed to SB and the tap water controls. Exposure to SB did not produce any signs of overt toxicity. Furthermore, no significant differences were observed in body weight, body weight gain, or the weights of thymus, liver, kidneys or lungs. No gross pathological lesions were observed in SB-treated animals. However, animals exposed to SB had a significant increase in absolute (28%) and relative (26%) spleen weights. The erythrocyte count, hemoglobin, hematocrit, mean corpuscular volume (MCV), platelet count, total leukocyte count, and counts of differential leukocytes were unaffected by SB. A dose-related increase in reticulocytes was observed following exposure to SB with the greatest increase (78%) observed at the highest dose level. Overall, there were no changes in the absolute number of total T cells, CD4+CD8- T cells, CD4-CD8+ T cells, natural killer (NK) cells and macrophages. Exposure to SB did not affect the percentage of B cells, although a slight increase in absolute number of B cells at the dose of 600 mg/l was observed. There was no alteration in IgM antibody-forming cell (AFC) response, mixed leukocyte reaction (MLR) and NK cell activity after exposure to SB. When the activity of peritoneal macrophages, unstimulated or stimulated with IFN-gamma and LPS, was evaluated using the cytotoxic/cytostatic assay of B16F10 tumor cells, the suppressive effect of macrophages on the proliferation of B16F10 tumor cells was decreased after exposure to SB. In conclusion, SB, when administered in the drinking water at doses from 80 mg/l to 800 mg/l, produced minimal toxicological and immunotoxic effects in female B6C3F1 mice. PMID:11360431

Guo, T L; McCay, J A; Karrow, N A; Brown, R D; Musgrove, D L; Luebke, R W; Germolec, D R; White, K L

2001-05-01

106

The absorption of bismuth and salicylate from oral doses of Pepto-Bismol (bismuth salicylate).  

PubMed

Plasma bismuth and plasma salicylate concentrations were measured before and after three 30-ml oral doses of bismuth salicylate (Pepto-Bismol liquid) in 10 fasting healthy subjects. From 0 to 120 min following the first dose of bismuth salicylate, the plasma bismuth concentration was less than 1 ng/ml. The peak median plasma bismuth concentration was at +240 min (1.7 ng/ml; range 0.8-5.3 ng/ml). Salicylate appeared in the plasma of all subjects at +30 min, and it reached a peak at +120 min (median 61 mg/L; range 46-104 mg/L). The study demonstrates that, despite rapid and substantial absorption of salicylate, there is negligible absorption of bismuth into the bloodstream from standard oral doses of bismuth salicylate. PMID:2104082

Nwokolo, C U; Mistry, P; Pounder, R E

1990-04-01

107

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

PubMed

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

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

2012-10-01

108

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 30 min 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

109

Current profiles of astrocytes from the corpus callosum of newborn and 28-day-old rats.  

PubMed

In astrocytes, ion currents are predominantly carried by K(+) ions, and their potassium channel expression changes during development. Here, we studied ion current generated by voltage-ramp protocols in cultured astrocytes from the corpus callosum of newborn (P0) and 28-day-old (P28) rats. Inward currents measured at -140 mV and chord conductances measured from -140 to -75 mV, were smaller in P0-astrocytes than in P28-astrocytes, and in P28-astrocytes were affected by 100 ?M Ba(2+), indicating the presence of an inward rectifier K(+) (Kir) current. On the other hand, P0-astrocytes showed higher outward current measured at 80 mV and a higher chord conductance, between 0 and 80 mV, than P28-astrocytes. The outward current was more potently reduced by 2mM Ba(2+) in P0-astrocytes than in P28-astrocytes, and slightly reduced at both ages using low concentrations of Ba(2+). Moreover, outward current was partially blocked by iberiotoxin in P0-astrocytes, indicating the presence of big-conductance Ca(2+)-activated K(+) (BK) channels. In addition, 4-aminopyridine inhibited the outward current in P0- and P28-astrocytes. In summary, P0-astrocytes exhibited the BK current, a major density of delayed rectifier K(+) (K(DR)) current, and a low density of the Kir current, whereas P28-astrocytes presented a major density of Kir current, a low density of the K(DR) current, and the absence of BK current. These results could contribute to a better understanding of the role of K(+) currents in the corpus callosum. PMID:20851740

Montiel-Herrera, Marcelino; García-Colunga, Jesús

2010-11-26

110

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

111

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

E-print Network

and 10 and 21 days after drug administration. All dogs were given a single oral dose (2 mg/kg of body weight) of clorazepate. Whole blood samples were obtained at 0, 0. 5, 1, 1. 5, 2, 3, 4, 6, 8, 12, 16, and 24 hours after administration of this single... intervals previously specified. Serum nordiazepam concentrations were determined using fluorescence polarization immunoassay validated for the dog. Drug disposition data were derived using nonlinear regression as well as the trapezoidal rule method...

Forrester, Sharon Dru

2012-06-07

112

Pharmacokinetics and Safety of Voriconazole following Intravenous to Oral-Dose Escalation Regimens  

Microsoft Academic Search

In this study, the safety, tolerability, and pharmacokinetics of intravenous (i.v.)- to oral-dose regimens of voriconazole were evaluated with a group of 42 healthy men, 41 of whom completed the study. Two cohorts of subjects participated in the study. Cohort 1 (n 28) took part in two study periods, each consisting of 14 days separated by a minimum 7-day washout.

L. Purkins; N. Wood; P. Ghahramani; K. Greenhalgh; M. J. Allen; D. Kleinermans

2002-01-01

113

Pharmacokinetics of loxiglumide after single intravenous or oral doses in man.  

PubMed

Loxiglumide (D,L-4-(3,4-dichlorobenzoylamino)-5-(N-3-methoxypropyl-pentylam ino)-5-oxo-pentanoic acid, CR 1505) was given intravenously to 8 male healthy volunteers in a single dose of 2 mg/kg body weight (b.w.) or orally in a single dose of 5 mg/kg b.w. Loxiglumide was measured in plasma and in urine by HPLC during 48 h following the administration. After i.v. infusion the plasma levels were consistent with an open two-compartment pharmacokinetic model represented by the equation C (mg/l) = 43.791 x e-2.652 x h + 2.657 x e-0.139 x h. In the urine, besides loxiglumide, two metabolites were found and in the 48 h following the i.v. administration the urinary excretion of loxiglumide and of its metabolites accounted for 11.13% of the administered dose. After oral administration loxiglumide appeared in plasma with a lag time of 14 min, reached the peak 34 min after administration, being eliminated with an initial fast and a terminal slow elimination rate. The plasma levels were consistent with an open two-compartment pharmacokinetic model represented by the equation C (mg/l) = -46.72 x e-8.765 x (h-0.23) + 40.660 x e-1.383 x (h-0.23) + 6.057 x e-0.120 x (h-0.23). In the urine, besides loxiglumide, two metabolites were found and in the 48 h following the oral administration the excretion of loxiglumide and of its metabolites accounted for 7.67% of the administered dose. The absolute bioavailability of loxiglumide was calculated comparing the AUC(0-inf) found after oral and after i.v. administration and was estimated as 0.967, with p = 0.05 fiducial limit of 0.656-1.278. PMID:3415715

Setnikar, I; Chisté, R; Makovec, F; Rovati, L C; Warrington, S J

1988-05-01

114

The pharmacokinetics and safety of single escalating oral doses of eletriptan.  

PubMed

The pharmacokinetics, safety, and tolerability of the 5-HT(1B/1D) agonist eletriptan were characterized in a randomized, double-blind, placebo-controlled, dose escalation study. Healthy males received single oral doses of 10 to 120 mg. Following screening and baseline measurements, plasma and saliva eletriptan concentrations were measured at intervals over 48 hours and 24 hours, respectively. Samples were analyzed using high-performance liquid chromatography with ultraviolet detection. Both the maximum plasma concentration and the area under the plasma eletriptan concentration-time curve showed an essentially linear relationship to the administered dose. Eletriptan exhibited a median time to maximum plasma concentration of 1 to 1.25 hours and a mean elimination half-life of 3.6 to 7.0 hours. Mean salivary-plasma ratios for pharmacokinetic parameters generally remained constant across the 30 to 90 mg dose range. Eletriptan was well tolerated, with mostly mild and transient adverse events. In conclusion, oral doses of eletriptan in the therapeutic range were rapidly absorbed and exhibited essentially linear plasma and saliva pharmacokinetics. PMID:12017346

Shah, Ajit K; Harris, Stephen C; Greenhalgh, Catherine; Morganroth, Joel

2002-05-01

115

Pharmacokinetics of saquinavir after intravenous and oral dosing of saquinavir: hydroxybutenyl-beta-cyclodextrin formulations.  

PubMed

The current research evaluated the ability of hydroxybutenyl-beta-cyclodextrin (HBenBCD) to enhance saquinavir in vitro solubility and in vivo oral bioavailability; both the base and mesylate salt forms of saquinavir were investigated. HBenBCD was effective and significantly improved saquinavir solubility in aqueous media. In the presence of 10 wt % HBenBCD, saquinavir base solubility in water was increased to ca. 5.5 +/- 0.4 mg/mL and represents a 27-fold increase from that observed in water (207 +/- 5 microg/mL) in the absence of HBenBCD. Saquinavir-HBenBCD formulations were found to have rapid dissolution over a wide pH range (1.2-6.8), and saquinavir solubility in these media was maintained throughout the experiments. When saquinavir-HBenBCD formulations were administered to Wistar-Hannover rats, saquinavir was rapidly absorbed and rapidly eliminated. Rapid saquinavir elimination was particularly pronounced when saquinavir-HBenBCD formulations were given as an oral aqueous gavage. Saquinavir oral bioavailability in rats obtained from saquinavir mesylate capsules (2.0% +/- 0.7%) was increased (9 +/- 4)-fold (18.6% +/- 7.3%) when dosed with saquinavir base-HBenBCD capsules. Clearly, HBenBCD can significantly improve the solubility and oral bioavailability of saquinavir; however, further formulation studies are required to optimize saquinavir oral delivery using this technology. PMID:18072746

Buchanan, Charles M; Buchanan, Norma L; Edgar, Kevin J; Little, James L; Ramsey, Michael G; Ruble, Karen M; Wacher, Vincent J; Wempe, Michael F

2008-01-01

116

Stability of amoxicillin trihydrate-potassium clavulanate in original containers and unit dose oral syringes.  

PubMed

The stability of reconstituted amoxicillin trihydrate-potassium clavulanate oral suspension both in original containers and pre-packaged in commercially available oral syringes stored at various temperatures was determined. Amoxicillin trihydrate 125 mg/5 mL-potassium clavulanate 31.25 mg/5 mL and amoxicillin trihydrate 250 mg/5 mL-potassium clavulanate 62.5 mg/5 mL were reconstituted according to the manufacturer's instructions. The reconstituted suspensions in the original containers and in five brands of oral syringes were stored at 5 degrees C and 25 degrees C and -10 degrees C, 5 degrees C, and 25 degrees C, respectively, for 0, 2, 4, 7, and 14 days. The concentrations of amoxicillin trihydrate and potassium clavulanate remaining after storage were assayed in triplicate by reverse-phase high-performance liquid chromatography, using a stability-indicating method. An F statistic was calculated to determine whether different syringe brands had significantly different effects on drug stability. Amoxicillin trihydrate was stable for at least 10 days in the original containers and all types of oral syringes at 5 degrees C. However, potassium clavulanate was stable for 11.1 days in original containers and less than 5 days in all types of oral syringes at 5 degrees C. The effect of syringe brand on the stability of drugs over time at specific storage conditions and temperature was significant for potassium clavulanate at 5 degrees C and for both amoxicillin trihydrate and potassium clavulanate at 25 degrees C. The manufacturer's guidelines for storage of reconstituted amoxicillin trihydrate-potassium clavulanate oral suspension in the original containers should not be applied to dosages repackaged in unit dose oral syringes. PMID:3400652

Tu, Y H; Stiles, M L; Allen, L V; Olsen, K M; Barton, C I; Greenwood, R B

1988-05-01

117

Modifying a displacement pump for oral gavage dosing of solution and suspension preparations to adult and neonatal mice  

Microsoft Academic Search

To assess a drug's toxic or carcinogenic effects on neonatal and adult mice and rats, researchers often carry out oral gavage studies. Whether dosed singly or in various combinations, provided as soluble solutions or as colloidal suspensions, the drug must be delivered in accurate and precise doses. For studies that require newborn mice to receive multiple daily doses, delicately handling

Fei W. Lee; A. Afshan Ali; William T. Allaben; Constance C. Weis; Julian E. A. Leakey; Sherry M. Lewis

2010-01-01

118

International integrated database for the evaluation of severe sepsis and drotrecogin alfa (activated) therapy: 28-day survival and safety  

Microsoft Academic Search

PurposeTo enhance the understanding of severe sepsis, a database of patients from multiple clinical trials spanning a 6-year period was constructed. Initial analyses evaluated the 28-day survival in the placebo group and further assessed the treatment effect of drotrecogin alfa (activated) (DrotAA).

Pierre-Francois Laterre; David R. Nelson; William Macias; Edward Abraham; Andreas Sashegyi; Mark D. Williams; Mitchell Levy; Marcel Levi; Barbara Utterback; Jean-Louis Vincent

2007-01-01

119

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

PubMed Central

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

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

1999-01-01

120

Efficacy of oral ofloxacin for single-dose perioperative prophylaxis in general surgery - a controlled randomized clinical study  

Microsoft Academic Search

Background. Perioperative antibiotic prophylaxis surely reduces surgical infection rate. Pharmacokinetic data of oral ofloxacin in combination with its antibacterial spectrum suggest effective protection against perioperative infection. In addition, costs, adverse effects, and induction of microbial resistance are low. Therefore we performed a controlled randomized study comparing oral and intravenous single dose prophylaxis. Methods. A total of 61 patients undergoing colonic

Michael Schwarz; Rainer Isenmann; Jens Thomsen; Wilhelm Gaus; Hans G. Beger

2001-01-01

121

Daily Oral Oleoyl-Estrone Gavage Induces a Dose-Dependent Loss of Fat in Wistar Rats  

Microsoft Academic Search

Objective: To establish whether single daily oral doses of oleoyl-estrone result in dose-dependent slimming effects on normal weight rats, and to determine the changes in energy parameters induced by this treatment.Research Methods and Procedures: The effects of a daily oral gavage of oleoyl-estrone (0, 0.2, 0.5, 1, 2, 5, 10, and 20 ?mol\\/kg per day) in 0.2 ml of sunflower

Maria del Mar Grasa; Cristina Cabot; Montserrat Esteve; Pilar Yubero; Rosa Maria Masanés; Maria Teresa Blay; Ruth Vilà; Jesus López-Martí; José Antonio Fernández-López; Xavier Remesar; Marià Alemany

2001-01-01

122

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

123

Evaluation of oral and low dose intravenous prostaglandin E2 in management of ductus dependent congenital heart disease  

Microsoft Academic Search

Prostaglandin E2 was given orally to 59 infants with ductus dependent congenital heart disease, and intravenous infusions were substituted for varying periods in 27 of them. An additional three neonates received intravenous treatment alone. Mean oral maintenance dose was 27 micrograms\\/kg per hour and the mean intravenous dose was 0.005 micrograms\\/kg per minute. Mean duration of treatment was 49 days

E D Silove; D G Roberts; J V de Giovanni

1985-01-01

124

Estimates of dose to systematic organs and GI tract based on data from miniature swine orally intubated with a single dose of Am-241 citrate  

SciTech Connect

A model is presented for the internal radiation dose to the small intestine wall of miniature swine given Americium 241 citrate by oral intubation. The model incorporates the uptake of the Am-241 by the intestinal wall. About equal contributions of dose to the small intestine were observed from the intestinal contents and the wall itself. (ACR)

Bernard, S.R.; Nestor, C.W. Jr.; Eisele, G.R.; Eckerman, K.F.

1982-01-01

125

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

SciTech Connect

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

Kopp, Eva Katharina [Department of Toxicology, University of Wuerzburg, Versbacher Strasse 9, 97078 Wuerzburg (Germany); Dekant, Wolfgang [Department of Toxicology, University of Wuerzburg, Versbacher Strasse 9, 97078 Wuerzburg (Germany)], E-mail: dekant@toxi.uni-wuerzburg.de

2009-03-01

126

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

PubMed

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

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

1986-07-01

127

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

PubMed Central

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

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

1986-01-01

128

Pharmacokinetics of fluoride in man after single and multiple oral doses.  

PubMed

The doses of fluoride (F) recommended in the literature for caries prevention and for the treatment of osteoporosis vary. This partly reflects inadequate knowledge of F pharmacokinetics. In the present study various single and multiple oral doses of F were given to eight volunteers, who had a strictly controlled F intake in the diet. The resulting plasma and parotid saliva concentrations as well as urinary output of F were measured. The plasma data fitted a two-compartment open model with a beta-slope half-life ranging between 2 and 9 h. Plasma clearance was 0.15+/-0.02 (SD) liter/kg/h. Data from the highest dose (10 mg) were fitted to both two- and three-compartment models, and there was no significant difference between them. Multiple doses of F 3.0 Or 4.5 mg yielded steady state concentrations ranging from 54 to 145 ng/ml. About 50 per cent of the given dose was recovered in the urine, which is indicative of considerable accumulation in the body. The saliva F/plasma F concentration ratio was 0.64 with a coefficient of variation of 5%. PMID:590317

Ekstrand, J; Alván, G; Boréus, L O; Norlin, A

1977-12-01

129

Pharmacokinetics of pradefovir and PMEA in healthy volunteers after oral dosing of pradefovir.  

PubMed

The pharmacokinetics of pradefovir and adefovir, 9-(2-phosphonylmethoxyethyl) adenine (PMEA), was evaluated in healthy male volunteers after oral dosing of pradefovir (10, 30, or 60 mg). Pradefovir was absorbed rapidly. The maximum serum concentration, the area under the concentration-time curve between 0 and 96 hours after dosing (AUC(0-96)), and the area under the plasma concentration versus time curve from time 0 to infinity (AUC(0-infinity)) of pradefovir and PMEA increased with the dose of pradefovir. The ratio of PMEA to pradefovir for AUC(0-96) and AUC(0-infinity) ranged from 1.4 to 1.8. Renal clearance of pradefovir (18-31 L/h) increased with the dose of pradefovir and was greater than glomerular filtration. The fraction of total body clearance due to renal clearance was low (0.045 to 0.083), suggesting that metabolic clearance played a significant role in the clearance of pradefovir in man. In addition, an evaluation of the food effect was conducted at the 30-mg dose. The results indicate that food intake has no effect on the extent of exposure of pradefovir and PMEA but may decrease the rate of systemic availability of PMEA. PMID:16239358

Lin, Chin-chung; Xu, Christine; Teng, Alice; Yeh, Li-Tain; Peterson, Janet

2005-11-01

130

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

Microsoft Academic Search

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

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

1998-01-01

131

Mathematical model for the prediction of cement compressive strength at the ages of 7 and 28 days within 24 hours  

Microsoft Academic Search

In this study 450 cement mortar cubes were cast from 50 different cement samples taken from 9 different cement factories,\\u000a to develop a mathematical model that can predict Portland cement compressive strength at ages 7 and 28 days within 24 hours\\u000a only. This is in order to save time and expense, that is lost in waiting for such a long

G. F. Kheder; A. M. Al Gabban; S. M. Abid

2003-01-01

132

Aberrant activation of M phase proteins by cell proliferation-evoking carcinogens after 28-day administration in rats.  

PubMed

We have previously reported that hepatocarcinogens increase liver cells expressing p21(Cip1), a G1 checkpoint protein and M phase proteins after 28-day treatment in rats. This study aimed to identify early prediction markers of carcinogens available in many target organs after 28-day treatment in rats. Immunohistochemical analysis was performed on Ki-67, p21(Cip1) and M phase proteins [nuclear Cdc2, phospho-Histone H3 (p-Histone H3), Aurora B and heterochromatin protein 1? (HP1?)] with carcinogens targeting different organs. Carcinogens targeting thyroid (sulfadimethoxine; SDM), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole; BHA), glandular stomach (catechol; CC), and colon (2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine and chenodeoxycholic acid) were examined using a non-carcinogenic toxicant (caprolactam) and carcinogens targeting other organs as negative controls. All carcinogens increased Ki-67(+), nuclear Cdc2(+), p-Histone H3(+) or Aurora B(+) carcinogenic target cells, except for both colon carcinogens, which did not increase cell proliferation. On the other hand, p21(Cip1+) cells increased with SDM and CC. HP1? responded only to BHA. Results revealed carcinogens evoking cell proliferation concurrently induced cell cycle arrest at M phase or showing chromosomal instability reflecting aberration in cell cycle regulation, irrespective of target organs, after 28-day treatment. Therefore, M phase proteins may be early prediction markers of carcinogens evoking cell proliferation in many target organs. PMID:23535288

Yafune, Atsunori; Taniai, Eriko; Morita, Reiko; Hayashi, Hitomi; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

2013-06-01

133

Pharmacokinetics of alfuzosin after single oral administration to healthy volunteers, of three different doses.  

PubMed

The aim of this study was to assess the linearity of pharmacokinetic of alfuzosin, administered by oral route, at the doses of 1, 2.5, and 5 mg to 12 young healthy volunteers. The pharmacokinetic parameters (tmax, Cmax, AUC, t1/2 beta) obtained from plasma alfuzosin concentrations after administration of the three doses show that pharmacokinetics of alfuzosin is linear in the range of doses 1-5 mg. Mean pharmacokinetic parameters of alfuzosin observed after 1, 2.5, and 5 mg were, respectively: tmax (h) 1.5 +/- 0.3, 1.1 +/- 0.2, 1.3 +/- 0.1; Cmax (ng ml-1) 2.6 +/- 0.3, 9.4 +/- 1.2, 13.5 +/- 1.0; AUC (ng ml-1 h) 17.7 +/- 2.9, 51.7 +/- 7.1, 99.0 +/- 14.1; t1/2 (h) 3.7 +/- 0.4, 3.9 +/- 0.2, 3.8 +/- 0.3. Cmax (corrected by the dose) obtained after 2.5 mg was significantly higher than those obtained after 1 and 5 mg. This difference seems to be due principally to the intraindividual variability. The absence of statistically significant difference on individual values of AUC corrected by the administered dose, supports the linearity of the pharmacokinetics of alfuzosin in the range of doses between 1 and 5 mg. Some postural hypotension, clinical criterion, was observed with a frequency increasing with the dose in these healthy subjects: 0 volunteers of 12 after 1 mg, 3 volunteers of 12 after 2.5 mg and 4 volunteers of 12 after 5 mg. PMID:1358243

Salva, P; Bianchetti, G; Morselli, P; Garcia-Teresa, G; Costa, J

1992-11-01

134

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

PubMed

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

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

2010-06-01

135

Treatment of Plane Warts with a Low-Dose Oral Isotretinoin  

PubMed Central

Objective. To assess the efficacy of a low-dose oral isotretinoin in the treatment of plane warts. Patients and Methods. Thirty-one patients with recalcitrant facial plane warts were enrolled. A cumulative dose of 30?mg/kg for two months of treatment was calculated; this was equal to a mean of 0.5?mg/kg/day. Each patient was seen every two weeks during the treatment period. Response to treatment was either complete or no response. Patients with complete response were followed up monthly for four months to record the relapse rate. Results. Twenty-six patients completed the study; their ages range from 5 to 35 with a mean ± SD 15.28 ± 8.51 years. Fifteen (57.69%) patients were females and eleven (42.30%) were males. Nineteen (73.07%) patients showed complete response and seven (26.92%) patients showed no response at the end of two months of therapy. The difference was statistically significant; P value <0.0001. Fifteen (78.94%) out of nineteen patients, who had complete response, were still free from warts at the end of four-month followup. Conclusion. Oral isotretinoin is effective in the treatment of recalcitrant facial plane warts. PMID:23304543

Al-Hamamy, Hayder R.; Salman, Husam Ali; Abdulsattar, Nawar A.

2012-01-01

136

Significant Increase in Salivary Substance P Level after a Single Oral Dose of Cevimeline in Humans  

PubMed Central

Cevimeline is a novel muscarinic acetylcholine receptor agonist currently being developed as a therapeutic agent for xerostomia. We examined the effects of cevimeline on salivary and plasma levels of substance-P- (SP-), calcitonin-gene-related-peptide- (CGRP-), and vasoactive-intestinal-polypeptide- (VIP-) like immunoreactive substances (ISs) in humans. An open-labeled crossover study was conducted on seven healthy volunteers. Saliva volume was measured, and saliva and venous blood samples were collected before and 30–240?min after a single oral dose of cevimeline or placebo. Salivary and plasma levels of SP-, CGRP-, and VIP-IS were measured using a highly sensitive enzyme immunoassay. A single oral dose of cevimeline resulted in significant increases in salivary but not plasma SP-IS level compared to placebo. Cevimeline administration did not alter the salivary or plasma levels of CGRP-IS or VIP-IS compared to placebo. Significant increases in salivary volume were observed after cevimeline administration compared to placebo. A significant correlation was observed between the total release of SP-IS and that of salivary volume. These findings suggest an association of SP with the enhancement of salivary secretion by cevimeline. PMID:23589717

Suzuki, Yosuke; Itoh, Hiroki; Amada, Kohei; Yamamura, Ryota; Sato, Yuhki; Takeyama, Masaharu

2013-01-01

137

Assessment of orally dosed commercial silver nanoparticles on human ex vivo platelet aggregation.  

PubMed

Enhanced in vitro human and ex vivo rat platelet aggregation from direct exposure to silver nanoparticles is previously reported. Given the increasing human use of engineered silver nanoscale products, platelet aggregation prompted by silver nanoparticles may contribute to human cardiovascular events. To understand how direct washed platelet exposure to silver nanoparticles translates to ex vivo platelet aggregation, the authors conducted a placebo-controlled, single-blind, dose-monitored, cross-over study design in 18 healthy human volunteers. After 2 weeks of daily oral silver nanoparticle ingestion, platelet aggregation was evaluated by light transmission aggregometry in response to collagen and ADP agonists, both at baseline and after silver nanoparticle or placebo diluent oral dosing. Final percent aggregation (PA) and the changes in PA were determined using a paired design (i.e., active and placebo solutions). Enhanced ex vivo platelet activation was not detectable at peak serum silver concentrations <10 µg/L. Further studies of colloidal silver nanoparticles on human platelet activities are warranted. PMID:23517080

Smock, Kristi J; Schmidt, Robert L; Hadlock, Greg; Stoddard, Greg; Grainger, David W; Munger, Mark A

2014-05-01

138

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 PMID:23094055

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

139

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

PubMed Central

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

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

2014-01-01

140

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. 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

2013-01-01

141

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. PMID:15328123

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

2004-01-01

142

Effects of Corynebacterium parvum and BCG therapy on immune parameters in patients with disseminated melanoma. A sequential study over 28 days. II. Changes in non-specific (NK, K and T cell) lymphocytoxicity and delayed hypersensitivity skin reactions.  

PubMed Central

C. parvum and BCG produced significant changes in NK, K and T cell lymphocytotoxicity using a Chang liver target cell. A consistent temporal pattern over 28 days of early depression, recovery, overshoot and then decline was described. This was particularly marked for C. parvum and 'K' cell activity. Skin test reactivity to recall antigens at 28 days was not appreciably different from the pre-immunization reactivity. The importance of using lymphocyte concentration-cytotoxicity titration curves and the linearization of such curves is discussed. An immunotherapy schedule with 3 weekly immunization intervals is proposed as the optimum schedule in patients receiving C. parvum at a dose of 2.0 mg/m2 i.v. PMID:312169

Thatcher, N; Swindell, R; Crowther, D

1979-01-01

143

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

PubMed Central

Aims The purpose of this study was to characterize the dose relationship of selegiline and desmethylselegiline pharmacokinetics within the selegiline dose range from 5 to 40 mg. Methods Eight female subjects, of whom four were using oral contraceptives, ingested a single dose of 5 mg, 10 mg, 20 mg or 40 mg of selegiline HCl in an open four-period randomized study. Concentrations of selegiline and desmethylselegiline in serum were measured by gas chromatography for 5 h. As it became evident that the use of oral steroids had a drastic effect on selegiline concentrations, the pharmacokinetic analyses were performed separately for oral contraceptive users and those not receiving any concomitant medication. Results The total AUC and Cmax of selegiline were 10-to 20-fold higher in those subjects taking oral steroids compared with subjects with no concomitant medication; this finding was consistent and statistically significant at all the four dose levels. The dose linearity of selegiline pharmacokinetics failed to be demonstrated in both groups. The AUC and Cmax of desmethylselegiline were only moderately higher (about 1.5-fold; P=NS at each dose level) in the subjects taking oral steroids than in those not receiving concomitant medication. The AUC values of desmethylselegiline increased in a dose linear manner in subjects with no concomitant medication, but not in the oral steroid group. The metabolic ratio (AUC(desmethylselegiline)/AUC(selegiline)) was several-fold lower in the group receiving oral steroids compared with the no-concomitant-medication group (P<0.005 at all the four dose levels). Conclusions Concomitant use of oral contraceptives caused a drastic (20-fold) increase in the oral bioavailability of selegiline. The highly significant difference in the metabolic ratio between the groups provides evidence that the mechanism of the interaction between selegiline and female sex steroids involves reduced N-demethylation of selegiline. The present results suggest that concomitant use of selegiline with exogenous female sex steroids should be avoided or the dosage of selegiline should be reduced in order to minimize the risks of selegiline related adverse drug reactions. PMID:10215747

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

1999-01-01

144

Effect of a single oral dose of moxifloxacin (400 mg and 800 mg) on ventricular repolarization in healthy subjects  

Microsoft Academic Search

Background: Moxifloxacin is a new fluoroquinolone. In vitro studies have suggested that it could prolong ventricular repolarization. The main objective of this study was to measure the actual effect of single oral doses of moxifloxacin on QT interval duration in healthy volunteers.Methods: Nine men and 9 women participated in a double-blind, randomized, placebo-controlled, crossover study. Each participant received single oral

Jean-Louis Démolis; Dagmar Kubitza; Laurent Tennezé; Christian Funck-Brentano

2000-01-01

145

Metabolism of an oral tryptophan load. I: Effects of dose and pretreatment with tryptophan.  

PubMed

1 The metabolism of three oral doses of L-tryptophan (50, 25 and 10 mg/kg) in healthy young males has been investigated. 2 There was a linear relationship between both peak and area under curve of the total plasma tryptophan concentrations whilst the relationship between these parameters and plasma free tryptophan was hyperbolic. 3 Before the tryptophan load about 85% of plasma tryptophan was bound to albumin. As plasma tryptophan concentrations increased there was a hyperbolic increase in free tryptophan. Scatchard analysis revealed 1.4 binding sites/molecule albumin with a dissociation constant (Kd) of 57.9 microM. Following administration of L-tryptophan (50 mg/kg) twice daily for 7 days there was no alteration in the number of binding sites but the dissociation constant (Kd) had decreased to 30.9 microM. 4 L-Tryptophan (50 mg/kg twice daily for 7 days) markedly increased both basal plasma total and free tryptophan. However following a further load the total tryptophan curve was comparable to that seen after acute administration. The plasma free tryptophan curve was lowered relative to that seen after an acute dose. 5 Increasing the tryptophan dose shortened the plasma half-life and decreased the volume of distribution and the rate of clearance. Longer term tryptophan administration had no significant effect on plasma half-life or volume of distribution but did decrease the rate of plasma clearance. 6 The plasma kynurenine concentration increased with increasing tryptophan dose and basal concentrations increased markedly after longer term tryptophan administration. 7 Tryptophan administration either acutely or chronically produced little change in urinary tryptophan or 5-hydroxyindole acetic acid excretion. Urinary kynurenine and indole acetic acid excretion increased with increasing doses of tryptophan. 8 Data are discussed in relation to the administration of L-tryptophan for the treatment of depression. PMID:6162471

Green, A R; Aronson, J K; Curzon, G; Woods, H F

1980-12-01

146

Toxicity of copper-spiked sediments to Tubifex tubifex (Oligochaeta, Tubificidae): a comparison of the 28-day reproductive bioassay with a 6-month cohort experiment  

Microsoft Academic Search

Results from a 28-day adult reproductive bioassay using the aquatic oligochaete Tubifex tubifex (Müller, 1774) are compared with life table statistics obtained from a 6-month experiment on cohorts of the same species. This was done by simultaneously performing the two tests on copper spiked sediments. Five concentrations and a control were tested. The 28-day bioassay was performed 3 times in

Andrea Pasteris; Martina Vecchi; Trefor B Reynoldson; Giuliano Bonomi

2003-01-01

147

Multiple-dose study of oral pyridostigmine in swine. Interim report, January 1986-January 1987  

SciTech Connect

The hemodynamic, metabolic, and hormonal responses to pyridostigmine treatment were evaluated in immature swine(20.7 + or - 0.5 kg). Pyridostigmine bromide was administered orally three times per day at 60 mg per dose. Animals receiving treatment (n=12) were compared to a group with no treatment (n=14). After three days of treatment, plasma and erythrocyte cholinesterase activities were reduced by 31% and 47%, respectively. Blood gases, heart rate, and blood pressure were not different. Pyridostigmine tended to increase blood glucose levels and elevated hematocrits 26 to 29%. Treatment with 60 mg of pyridostigmine three times daily for three days reduced acetylcholinesterase activity as desired in man for prophylactic treatment against possible exposure to nerve agents. In swine this degree of inhibition of acetylcholinesterase activity was associated with an index of stress, a slight increase in hematocrit. Swine appear to offer an effective animal model in which to evaluate pyridostigmine treatment.

Wade, C.E.; Waring, P.P.; Trail, D.S.; Williams, B.F.; Bonner, G.D.

1987-03-01

148

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

SciTech Connect

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

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

1985-01-01

149

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. PMID:24884884

2014-01-01

150

Orally supplemented l-arginine impairs amino acid absorption depending on dose in horses.  

PubMed

The beneficial effect of l-arginine (l-Arg) supplementation, on the physiology of several species, has generated an interest in the use of l-Arg as a nutraceutical in horses, but dosage and absorption of orally supplemented l-Arg must be inferred from other species. The study objective was to determine the effect of 2 oral l-Arg doses on plasma arginine concentrations and the effect on absorption of other amino acids in mares. In Experiment 1, mares were blocked by age and breed and were fed l-Arg supplemented (supplemented with 0.025% BW l-Arg; n = 6) or control (no supplement; n = 6) concentrate on a single day with blood samples taken at 0, 0.5, 1, 2, 3, 4, and 5 h relative to feeding. In Experiment 2, mares (n = 6) were used in a 3 × 3 Latin square design with l-Arg (0.0125% of BW), urea (0.0087% of BW), and control (no supplement) fed mixed into a grain concentrate as single meal with blood samples taken at 0, 1,2, 4, 6, 8,10, and 12 h relative to feeding. In Experiment 1, l-Arg supplementation increased (P < 0.05) plasma l-Arg and ornthine concentrations and decreased (P < 0.05) lysine and methionine concentrations compared with the control group. At 1 h post feeding, l-Arg mares had lower (P < 0.05) plasma concentrations of histidine, glutamic acid, proline, isoleucine, threonine, phenylalanine, leucine, valine, alanine, and taurine. In Experiment 2, l-Arg supplementation increased (P < 0.05) arginine and ornithine concentrations compared with urea and control; there was no difference among other amino acids. These experiments indicate that l-Argis absorbed and, dependent on the dose, alters the absorption of other amino acids in mares. PMID:25403187

Kelley, D E; Warren, L K; Mortensen, C J

2014-12-01

151

Metabolic changes in dairy cows induced by oral, low-dose interferon-alpha treatment.  

PubMed

Many apparently healthy cows show marked inflammatory conditions around calving, associated with endocrine and metabolic changes. To prevent the above conditions, a low-dose, oral interferon-alpha (IFN-alpha) treatment was carried out on periparturient, multiparous dairy cows. In the first trial, 10 cows received 10 IU of IFN-alpha/kg of BW daily during the last 2 wk of pregnancy. In a second trial, 4 cows received 0.5 IU of IFN-alpha/kg of BW daily until d 5 of lactation. In both trials, a homogenous group of untreated dairy cows was used as control. All cows were monitored, during the month before and after calving, for health status, BCS, milk yield, and inflammatory, metabolic, immune, and hematological variables. Compared with control cows, IFN-alpha-treated animals showed in both trials a larger decrease of BCS along with decreased milk yield (P < 0.05), increased haptoglobin (P < 0.05) and ceruloplasmin, and a slower increase of negative acute phase proteins (albumin, cholesterol, paraoxonase, vitamin A) after calving. Interferon-alpha-treated animals also showed a larger decrease of plasma glucose and greater values of NEFA, beta-hydroxybutyrate, and reactive oxygen metabolites. There also was evidence of IL-6 and tumor necrosis factor-alpha responses in both groups before calving with a quick decrease thereafter. The IL-6 response appeared in some animals regardless of the IFN-alpha treatment. Results indicate that low-dose IFN-alpha can sustain an inflammatory response in dairy cows and cause notable metabolic changes. This outcome might be explained by the repeated and extended interaction of IFN-alpha at low doses with the oral lymphoid tissues during rumination, as suggested by the observed stability of the cytokine in the rumen milieu; the final inflammatory effect could thus be as large as that of high doses. In addition, the antiflogistic signal of IFN-alpha might be counteracted and inverted by lymphocytes detected in the rumen liquor. PMID:19502505

Trevisi, E; Amadori, M; Bakudila, A M; Bertoni, G

2009-09-01

152

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

PubMed

Inhalation toxicity of silicon dioxide aerosol (150, 300 mg/m(3)) daily over a period of 28 days was carried out in rats. The changes in respiratory variables during the period of exposure were monitored using a computer programme that recognizes the modifications of the breathing pattern. Exposure to the aerosol caused a time dependent decrease in tidal volume, with an increase in respiratory frequency compared to the control. Biochemical variables and histopathological observation were noted at 28th day following the start of exposure. Biochemical markers of silica induced lung injury like plasma alkaline phosphatase, lactate dehydrogenase and angiotensine converting enzyme activities increased in a concentration dependent manner compared to control. Increase in the plasma enzymatic activities indicates endothelial lung damage, increased lung membrane permeability. Histopathological observation of the lungs confirmed concentration dependent granulomatous inflammation, fibrosis and proteinacious degeneration. Aggregates of mononuclear cells with entrapped silica particles circumscribed by fibroblast were observed in 300 mg/m(3) silica aerosol exposed group at higher magnification. Decrease in tidal volume and increase in respiratory frequency might be due to the thickening of the alveolar wall leading to a decreased alveolar volume and lowered elasticity of the lung tissue. The trends in histological and biochemical data are in conformity with the respiratory data in the present study. This study reports for the first time, the changes in respiratory variables during silica aerosol exposure over a period of 28 days. PMID:22974794

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

2012-11-01

153

Defining upper gastrointestinal bleeding from linked primary and secondary care data and the effect on occurrence and 28 day mortality  

PubMed Central

Background Primary care records from the UK have frequently been used to identify episodes of upper gastrointestinal bleeding in studies of drug toxicity because of their comprehensive population coverage and longitudinal recording of prescriptions and diagnoses. Recent linkage within England of primary and secondary care data has augmented this data but the timing and coding of concurrent events, and how the definition of events in linked data effects occurrence and 28 day mortality is not known. Methods We used the recently linked English Hospital Episodes Statistics and General Practice Research Database, 1997–2010, to define events by; a specific upper gastrointestinal bleed code in either dataset, a specific bleed code in both datasets, or a less specific but plausible code from the linked dataset. Results This approach resulted in 81% of secondary care defined bleeds having a corresponding plausible code within 2 months in primary care. However only 62% of primary care defined bleeds had a corresponding plausible HES admission within 2 months. The more restrictive and specific case definitions excluded severe events and almost halved the 28 day case fatality when compared to broader and more sensitive definitions. Conclusions Restrictive definitions of gastrointestinal bleeding in linked datasets fail to capture the full heterogeneity in coding possible following complex clinical events. Conversely too broad a definition in primary care introduces events not severe enough to warrant hospital admission. Ignoring these issues may unwittingly introduce selection bias into a study’s results. PMID:23148590

2012-01-01

154

Accumulation of lovastatin, but not pravastatin, in the blood of cyclosporine-treated kidney graft patients after multiple doses  

Microsoft Academic Search

Objectives: To study pravastatin and lovastatin pharmacokinetic and pharmacodynamic effects and their interactions with cyclosporine (INN, ciclosporin) in kidney transplant patients after single and multiple doses.Subjects and methods: The pharmacokinetic and pharmacodynamic effects of administration of 20 mg\\/day oral pravastatin and lovastatin for 28 days and their interactions with cyclosporine (2 to 6 mg\\/kg\\/day) were studied in a double-blind, double-dummy,

Christoph Olbricht; Christoph Wanner; Thomas Eisenhauer; Volker Kliem; Rainer Doll; Michel Boddaert; Padraig O'Grady; Michael Krekler; Bernhard Mangold; Uwe Christians

1997-01-01

155

Oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients  

Microsoft Academic Search

Goals: The purpose of this study was to evaluate the efficacy of oral cryotherapy to prevent high-dose melphalan-induced stomatitis. Patients and methods: Eighteen consecutive recipients of allogeneic hematopoietic stem cell transplant conditioned with high-dose mel- phalan (140 mg\\/m 2 ) in combination with fludarabine alone or with flu- darabine and additional chemotherapy or radiation were enrolled. The severity of stomatitis

Yoshinobu Aisa; Takehiko Mori; Masumi Kudo; Tomoko Yashima; Sakiko Kondo; Akihiro Yokoyama; Yasuo Ikeda; Shinichiro Okamoto

2005-01-01

156

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. PMID:23217206

2012-01-01

157

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. PMID:22011284

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

158

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. PMID:14998420

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

2004-01-01

159

Single dose oral gabapentin for established acute postoperative pain in adults  

PubMed Central

Background Gabapentin is an antiepileptic drug, also used in the treatment of neuropathic pain, which is the subject of a Cochrane review, currently under revision. Its efficacy in treating established acute postoperative pain has not been demonstrated. Objectives To assess the efficacy and safety of single dose oral gabapentin compared with placebo in established acute postoperative pain using methods that permit comparison with other analgesics. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE, and the Oxford Pain Relief Database. Additional studies were sought from reference lists of retrieved articles and reviews. Clinical trials databases were searched for unpublished studies; clinical trial reports of several unpublished studies have been made public following litigation in the US. Selection criteria Single oral dose, randomised, double-blind, placebo-controlled trials of gabapentin for relief of established moderate to severe postoperative pain in adults. Data collection and analysis Studies were assessed for methodological quality and data extracted by two review authors independently. Numbers of participants with at least 50% of maximum possible total pain relief (TOTPAR) or summed pain intensity difference (SPID) with gabapentin or placebo were calculated and used to derive relative benefit (RB) or risk (RR), and number-needed-to-treat-to-benefit (NNT). Numbers of participants using rescue medication, and time to its use, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results Four unpublished studies met inclusion criteria; in three, participants had pain following dental surgery, and one followed major orthopaedic surgery; 177 participants were treated with a single dose of gabapentin 250 mg, 21 with gabapentin 500 mg, and 172 with placebo. At least 50% pain relief over 6 hours was achieved by 15% with gabapentin 250 mg and 5% with placebo; giving a RB of 2.5 (95% CI 1.2 to 5.0) and an NNT of 11 (6.4 to 35). Significantly fewer participants needed rescue medication within 6 hours with gabapentin 250 mg than with placebo; NNT to prevent use 5.8. About one third of participants reported adverse events with both gabapentin 250 mg and placebo. No serious adverse events occurred with gabapentin. Authors’ conclusions Gabapentin 250 mg is statistically superior to placebo in the treatment of established acute postoperative pain, but the NNT of 11 for at least 50% pain relief over 6 hours with gabapentin 250 mg is of limited clinical value and inferior to commonly used analgesics. Gabapentin 250 mg is not clinically useful as a stand-alone analgesic in established acute postoperative pain, though this is probably the first demonstration of analgesic effect of an antiepileptic in established acute pain. PMID:20464764

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

2014-01-01

160

Dexamethasone concentration in the subretinal fluid after a subconjunctival injection, a peribulbar injection, or an oral dose  

Microsoft Academic Search

PurposeTo determine dexamethasone concentrations in the subretinal fluid of patients after a peribulbar injection, a subconjunctival injection, or an oral dose of dexamethasone and to compare the results with those of previous similar studies of dexamethasone concentrations in the vitreous.

Olga Weijtens; Rik C Schoemaker; Eef G. W. M Lentjes; Fred P. H. T. M Romijn; Adam F Cohen; Jan C van Meurs

2000-01-01

161

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

PubMed

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

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

2012-04-01

162

Urinary bactericidal activity and pharmacokinetics of enoxacin versus norfloxacin and ciprofloxacin in healthy volunteers after a single oral dose  

Microsoft Academic Search

In an open, randomised monocentric crossover study in six male and six female healthy volunteers, the urinary antibacterial activity and pharmacokinetics of enoxacin, norfloxacin and ciprofloxacin were assessed. Urine was collected up to 6 days, and venous blood samples up to 12 h, after a single oral dose of 400 mg enoxacin, 400 mg norfloxacin and 500 mg ciprofloxacin. Enoxacin

Michaela Well; Kurt G. Naber; M. Kinzig-Schippers; Fritz Sörgel

1998-01-01

163

Pharmacokinetic comparison of oral solution and tablet formulations of citalopram: a single-dose, randomized, crossover study  

Microsoft Academic Search

Background: Citalopram tablets fulfill most dosing needs in the treatment of depression, but some patients may have difficulty swallowing tablets and thus may be less likely to comply with their medication regimen. A liquid formulation of citalopram could be beneficial for such patients.Objective: This study was undertaken to compare the pharmacokinetic profiles of oral solution and tablet formulations of citalopram

Marcelo M. Gutierrez; Wattanaporn Abramowitz

2000-01-01

164

Measured and reported weight change for women using a vaginal contraceptive ring vs. a low-dose oral contraceptive  

Microsoft Academic Search

BackgroundWomen often stop hormonal contraception because of perceived weight change. We conducted a randomized trial comparing the contraceptive vaginal ring to a low-dose oral contraceptive (OC). We examined the difference between women's reported and measured baseline weights and looked at factors affecting perceived weight change.

Katharine J. O'Connell; Lauren M. Osborne; Carolyn Westhoff

2005-01-01

165

Derivation of a Bisphenol a Oral Reference Dose (RfD) and Drinking-Water Equivalent Concentration  

Microsoft Academic Search

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

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

2008-01-01

166

Single-Dose Oral Tolerance Test with Alternative Compounds for the Management of Adverse Reactions to Drugs  

Microsoft Academic Search

Background: Adverse reactions to drugs are common in the clinical practice. Many outpatients are frequently referred to allergists in order to determine which drugs they can safely take in the future. Objective: We set up an oral single-dose tolerance test procedure to find out for each patient one or more alternative drugs that can be taken when needed. Methods: 452

Giovanni Passalacqua; Manlio Milanese; Marcello Mincarini; Giorgio Ciprandi; Laura Guerra; Antonio Scordamaglia; Giorgio Walter Canonica

2002-01-01

167

Anticonvulsant effects of acute treatment with cyane-carvone at repeated oral doses in epilepsy models.  

PubMed

Epilepsy affects about 40 million people worldwide. Many drugs block seizures, but have little effect in preventing or curing this disease. So the search for new drugs for epilepsy treatment using animal models prior to testing in humans is important. Increasingly pharmaceutical industries invest in the Re?search & Drug Development area to seek safe and effective new therapeutic alternatives to the currently available epilepsy treatment. In this perspective, natural compounds have been investigated in epilepsy models, particularly the monoterpenes obtained from medicinal plants. In our study we investigated the effects of cyane-carvone (CC), a synthetic substance prepared from natural a monoterpene, carvone, against pilocarpine- (PILO), pentylenetetrazole- (PTZ) and picrotoxine (PTX)-induced seizures in mice after acute treatment with repeated oral doses (CC 25, 50 and 75 mg/kg) for 14 days. CC in all doses tested showed increase in latency to first seizure, decrease in percentages of seizuring animals as well as reduction percentages of dead animals (p<0.05) in PILO, PTZ and PTX groups when compared with vehicle. However, these effects were not reversed by flumazenil, benzodiazepine (BZD) antagonist used to investigate the CC action mechanism. Our results suggest that acute treatment with CC at the doses tested can exert anticonvulsant effects in PILO, PTZ and PTX epilepsy models. In addition, our data suggest that CC could act in an allosteric site of GABAA, which would be different from the site in which BDZ acts, since flumazenil was not able to reverse any of CC effects on the modulation of seizure parameters related with epilepsy models investigated. New studies should be conducted to investigate CC effects in other neurotransmitter systems. Nevertheless, our study reinforces the hypothesis that CC could be used, after further research, as a new pharmaceutical formulation and a promising alternative for epilepsy treatment, since it showed anticonvulsant effects. PMID:24967871

Marques, Thiago Henrique Costa; Marques, Maria Leonildes Boavista Gomes Castelo Branco; Medeiros, Jand-Venes Rolim; Lima, Tamires Cardoso; de Sousa, Damião Pergentino; de Freitas, Rivelilson Mendes

2014-09-01

168

Evaluation of safety and human tolerance of the oral probiotic Streptococcus salivarius K12: a randomized, placebo-controlled, double-blind study.  

PubMed

Streptococcus salivarius is naturally a predominant member of the human oropharynx and the commercial probiotic strain K12 has been consumed for more than a decade. The present study examines the health responses of human volunteers to oral ingestion of high doses of S. salivarius K12. A randomized group of 53 subjects received a dose of 1 × 10(10)cfu S. salivarius K12 (N=25) or placebo (N=28) for 28 days, followed by a 28-day wash out period. Blood, urine and saliva samples were collected at baseline and following treatment and analyzed, while the oral and gastrointestinal tolerance of the subjects to the dosing regimen was determined by use of questionnaires. Adverse events (AE)s were recorded for both groups. No statistically significant differences between the probiotic and placebo treated groups were detected in either the blood clinical chemistry or hematology results (P>0.05). The questionnaire responses of the subjects indicated that both treatments were well tolerated. The frequency and intensity of AEs was similar in the two groups. This data demonstrates that the daily ingestion of S. salivarius K12 over a 28-day period does not adversely affect the human host and supports the safety of its oral delivery in a food-based carrier. PMID:21722694

Burton, J P; Cowley, S; Simon, R R; McKinney, J; Wescombe, P A; Tagg, J R

2011-09-01

169

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

170

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. PMID:24948886

2014-01-01

171

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

172

Intravenous pharmacokinetics, oral bioavailability, dose proportionality and in situ permeability of anti-malarial lumefantrine in rats  

PubMed Central

Background Despite the wide spread use of lumefantrine, there is no study reporting the detailed preclinical pharmacokinetics of lumefantrine. For the development of newer anti-malarial combination(s) and selection of better partner drugs, it is long felt need to understand the detailed preclinical pharmacokinetics of lumefantrine in preclinical experimental animal species. The focus of present study is to report bioavailability, pharmacokinetics, dose linearity and permeability of lumefantrine in rats. Methods A single dose of 10, 20 or 40 mg/kg of lumefantrine was given orally to male rats (N = 5 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of lumefantrine was given to rats (N = 4) at 0.5 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of lumefantrine and its metabolite desbutyl-lumefantrine in plasma were determined by partially validated LC-MS/MS method. In-situ permeability study was carried in anaesthetized rats. The concentration of lumefantrine in permeability samples was determined using RP-HPLC. Results For nominal doses increasing in a 1:2:4 proportion, the Cmax and AUC0-? values increased in the proportions of 1:0.6:1.5 and 1:0.8:1.8, respectively. For lumefantrine nominal doses increasing in a 1:2:4 proportion, the Cmax and the AUC0-t values for desbutyl-lumefantrine increased in the proportions of 1:1.45:2.57 and 1:1.08:1.87, respectively. After intravenous administration the clearance (Cl) and volume of distribution (Vd) of lumefantrine in rats were 0.03 (± 0.02) L/h/kg and 2.40 (± 0.67) L/kg, respectively. Absolute oral bioavailability of lumefantrine across the tested doses ranged between 4.97% and 11.98%. Lumefantrine showed high permeability (4.37 × 10-5 cm/s) in permeability study. Conclusions The pharmacokinetic parameters of lumefantrine and its metabolite desbutyl-lumefantrine were successfully determined in rats for the first time. Lumefantrine displayed similar pharmacokinetics in the rat as in humans, with multiphasic disposition, low clearance, and a large volume of distribution resulting in a long terminal elimination half-life. The absolute oral bioavailability of lumefantrine was found to be dose dependent. Lumefantrine displayed high permeability in the in-situ permeability study. PMID:21985153

2011-01-01

173

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

PubMed

Oral gavage studies with ?-myrcene in male F344 rats showed a complex renal pathology comprising both alpha2u-globulin (?2u-g) nephropathy, an unusual nephrosis involving the outer stripe of outer medulla (OSOM), and an increased incidence of renal tubule tumors by 2 years. In the 90-day and 2-year studies, respectively, ?2u-g nephropathy and linear papillary mineralization were observed in males at the two lower doses but were absent from the high dose. Nephrosis was characterized by dilation of the S3 tubules, nuclear enlargement (including karyomegaly), and luminal pyknotic cells, all in the outermost OSOM. Nephrosis was minimal at the higher doses in the 90-day study, but progressed to a severe grade in males dosed with 1,000 mg/kg for 2 years. Renal tubule tumors developed in treated groups with incidences up to 30% in the 250 and 500 mg/kg male dose groups. Tumors at the lower doses in males may have been associated with ?2u-g nephropathy, while those at higher doses in both sexes may have been due to the nephrosis. Because ?-myrcene induced a complex spectrum of renal pathology, the ?2u-g nephropathy mechanism cannot be the sole mechanism of carcinogenesis in these rats. PMID:23531794

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

2013-01-01

174

Oral (gavage), in utero and post-natal exposure of Sprague–Dawley rats to low doses of tributyltin chloride  

Microsoft Academic Search

The immunotoxic effects of tributyltin chloride (TBTC) were examined in the offspring of Sprague–Dawley rats exposed in utero from day 8 of gestation, through lactation and post-weaning until pups reached the age of 30 days (male and female), 60 days (female) and 90 days (male). Daily oral (gavage) doses of 0.025, 0.25 and 2.5 mg\\/kg body weight\\/day were administered in

H Tryphonas; G Cooke; D Caldwell; G Bondy; M Parenteau; S Hayward; O Pulido

2004-01-01

175

Combination chemotherapy with low doses of weekly Carboplatin and oral Etoposide in poor risk small cell lung cancer  

Microsoft Academic Search

Sixty patients with poor prognostic features, either with extensive disease (ED) or limited disease (LD) small cell lung cancer (SCLC), were treated on an out-patient basis with Carboplatin 80 mg\\/m2 weekly for 3 weeks and oral Etoposide, at a dose of 100 mg, every other day for 21 days. The treatment was repeated every 5 weeks. Responding patients with LD

E. Samantas; D. V. Skarlos; D. Pectasides; P. Nicolaides; H. Kalofonos; N. Mylonakis; Th. Vardoulakis; P. Kosmidis; N. Pavlidis; G. Fountzilas

1999-01-01

176

The effects of single and repeated doses of oral scopolamine, cinnarizine, and placebo upon psychological performance and physiological functioning  

Microsoft Academic Search

The present study was one in a series in the Institute of Naval Medicine's Motion Illness Project. A battery of psychological performance tests (producing 26 indices of mental and hand-eye co-ordination), together with visual near fixation point, resting heart rate and a self-rated feeling state questionnaire, were used to compare the effects of thrice-daily oral doses of scopolamine (0.6mg), cinnarizine

A. C. Parrott; J. F. GOLDINGt; R. J. Pethybridge

1990-01-01

177

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

NASA Astrophysics Data System (ADS)

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

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

178

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

PubMed

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

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

2014-03-01

179

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

SciTech Connect

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

Soref, Cheryl M. [ProCertus BioPharm, Inc., Madison, WI (United States); Hacker, Timothy A. [Department of Medicine, Cardiovascular Physiology Core, University of Wisconsin-Madison, Madison, WI (United States); Fahl, William E., E-mail: fahl@oncology.wisc.edu [ProCertus BioPharm, Inc., Madison, WI (United States); McArdle Laboratory for Cancer Research, University of Wisconsin Carbone Cancer Center, Madison, WI (United States)

2012-04-01

180

Modification of radiation-induced oral mucositis (mouse) by adult stem cell therapy: single-dose irradiation.  

PubMed

Early oral mucositis occurs in response to accidental upper partial body exposure as well as to radiotherapy in the head-and-neck region. This study was initiated to define the potential of mobilization of endogenous bone marrow (BM) stem cells by rHuG-CSF or of bone marrow transplantation (BMT) to reduce the effect of single-dose irradiation on mouse oral epithelium. A 3 × 3 mm(2) area of the lower tongue surface of mice was irradiated with graded single doses (day 0). Mucosal ulceration was used as the endpoint for dose-response analyses. Stem cells were mobilized by rHuG-CSF (8 times/4 days), timed to achieve a maximum of circulating stem cells on days 0, +1, +4, +8 or +10. Alternatively, syngeneic BM was transplanted on these days. The ED50 (dose at which ulceration is expected in 50 % of the animals) for irradiation alone was 11.9 ± 3.4 Gy. Mobilization of stem cells with a maximum of circulating stem cells on days +4, +8 or +10 significantly increased the ED50 to 25.5 ± 10.1, 23.5 ± 10.1 and 26.5 ± 13.0 Gy. In contrast, a maximum of circulating stem cells on day 0 or day +1 had no effect. BMT did not result in a significant change in isoeffective doses in any of the protocols. In conclusion, the response of oral mucosal epithelium to a single-radiation exposure can be significantly reduced by post-exposure mobilization, but not by transplantation, of BM stem cells. PMID:24929346

Schmidt, Margret; Piro-Hussong, Aline; Siegemund, Annett; Gabriel, Peggy; Dörr, Wolfgang

2014-11-01

181

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

PubMed Central

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

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

1996-01-01

182

Liquid medication dispensing and dose monitoring: the CycloTech Cyclosporine Oral Solution Dispenser.  

PubMed

This liquid medication dispenser offers an easy, convenient means for accurate dispensing of medication. The ability of the device to store dose size, time to next dose, remaining available doses, and doses dispensed may allow for future analysis of patient behavior and improve compliance. PMID:10372052

Rossi, S J; McEnroe, D L; Tanner, T; Levy, R E; Pouletty, P

1999-06-01

183

Pharmacokinetics of itraconazole after intravenous and oral dosing of itraconazole-cyclodextrin formulations.  

PubMed

The current research evaluated and compared the efficacy of hydroxybutenyl-beta-cyclodextrin (HBenBCD) and hydroxypropyl-beta-cyclodextrin (HPBCD) as enhancers of itraconazole solubility and oral bioavailability. At 10 wt% cyclodextrin, 17-fold and 3.8-fold increases in itraconazole aqueous solubility were observed in the presence of HBenBCD and HPBCD, respectively. Significant differences in the dissolution of itraconazole in the presence of these two cyclodextrins were also observed. Itraconazole pharmacokinetics is known to exhibit a significant food effect. However, testing in biorelevant media indicated that no food effects should be observed after oral administration of itraconazole:HBenBCD complexes. Formulations of itraconazole with HBenBCD were prepared and these complexes, along with the commercial forms of itraconazole with and without HPBCD (Sporanox) were administered to male Sprague-Dawley rats by oral and intravenous routes. Intravenous administration of itraconazole formulated with HBenBCD resulted in a higher AUC relative to Sporanox. When administered as oral solutions, the itraconazole:HBenBCD formulation provided higher oral bioavailability than the Sporanox oral solution. When administered as solid formulations, the itraconazole:HBenBCD solid formulation provided a 2x increase in oral bioavailability relative to the Sporanox solid formulation. No food effects were observed with the itraconazole:HBenBCD solid dosage forms. Drug/metabolite ratios were dependent upon the dosage form. PMID:17712849

Buchanan, Charles M; Buchanan, Norma L; Edgar, Kevin J; Klein, Sandra; Little, James L; Ramsey, Michael G; Ruble, Karen M; Wacher, Vincent J; Wempe, Michael F

2007-11-01

184

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. PMID:508508

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

1979-01-01

185

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

186

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. PMID:23737662

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

2013-01-01

187

Brief oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis in allogeneic hematopoietic stem cell transplant recipients  

Microsoft Academic Search

We previously reported the efficacy of oral cryotherapy for the prevention of high-dose melphalan-induced stomatitis. The purpose of this study was to evaluate whether the further shortening of the duration of oral cryotherapy could minimize its side effects while sparing its efficacy. Seventeen consecutive recipients of allogeneic hematopoieic stem cell transplant conditioned with high-dose melphalan in combination with fludarabine alone

Takehiko Mori; Rie Yamazaki; Yoshinobu Aisa; Tomonori Nakazato; Masumi Kudo; Tomoko Yashima; Sakiko Kondo; Yasuo Ikeda; Shinichiro Okamoto

2006-01-01

188

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. PMID:24189617

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

2013-01-01

189

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

PubMed Central

What is already known about this subject Brivaracetam is a new chemical entity structurally related to levetiracetam, displaying a markedly higher affinity for the binding site believed to be primarily involved in the antiepileptic effect of levetiracetam. Studies to evaluate the pharmacological profile of brivaracetam demonstrate an approximately 10-fold higher potency than levetiracetam as well as a higher efficacy in models of epilepsy. If translated into therapeutic effects in humans, this would mean a greater decrease in seizure frequency and a higher number of responders and seizure-free patients in refractory epileptic patients as seen with levetiracetam. What this study adds This article reports the results of the first in human study with brivaracetam. Its pharmacokinetics and adverse events profile after single administration are evaluated, together with the effect of food on the former. Aims The objective of the study was to evaluate the pharmacokinetics (and how they are affected by food), CNS pharmacodynamics and the adverse event profile of brivaracetam after single increasing doses. Methods Healthy males (n = 27, divided into three alternating panels of nine subjects) received two different single oral doses of brivaracetam (10–1400 mg) and one dose of placebo during three periods of a randomized, double-blind, placebo-controlled study. The effect of food on its pharmacokinetics was assessed using a standard two-way crossover design in a further eight subjects who received two single oral doses of brivaracetam (150 mg) in the fasting state and after a high fat meal. Results Adverse events, none of which were serious, were mostly CNS-related and included somnolence, dizziness, and decreased attention, alertness, and motor control. Their incidence, severity and duration were dose-related. The maximum tolerated dose was established to be 1000 mg. Severe somnolence lasting 1 day occurred in one subject following 1400 mg. Brivaracetam was rapidly absorbed under fasting conditions, with a median tmax of approximately 1 h. Cmax was dose-proportional from 10 to 1400 mg, whereas AUC deviated from dose linearity above 600 mg. A high-fat meal had no effect on AUC (point estimate 0.99, 90%CI: 0.92–1.07) but delayed tmax (3 h) and decreased Cmax (point estimate 0.72, 90%CI: 0.66–0.79). Conclusions Brivaracetam was well tolerated after increasing single doses that represent up to several times the expected therapeutic dose. Brivaracetam was found to have desirable pharmacokinetic properties. The most common adverse events were somnolence and dizziness. PMID:17223857

Sargentini-Maier, Maria Laura; Rolan, Paul; Connell, John; Tytgat, Dominique; Jacobs, Tom; Pigeolet, Etienne; Riethuisen, Jean-Michel; Stockis, Armel

2007-01-01

190

Pharmacokinetics and safety of ascending single doses of DZ-2640, a new oral carbapenem antibiotic, administered to healthy Japanese subjects.  

PubMed

DZ-2640 is the ester-type oral carbapenem prodrug of an active parent compound, DU-6681. The pharmacokinetics and safety of DU-6681 were investigated in six studies after oral administration of a single dose of DZ-2640 to healthy male Japanese volunteers at doses of 25, 50, 100, 200, and 400 mg (as the equivalents of DU-6681) in the fasted state. The same volunteers received the drug at a dose of 100 mg in the fasted and fed states to examine the effect of food intake on the bioavailability of DZ-2640. The concentrations of DU-6681 in plasma and urine were determined by a validated high-performance liquid chromatography method and a bioassay. A good correlation between both methods was seen, indicating an absence of major active metabolites. The mean maximum concentrations of DU-6681 in plasma (C(max)) ranged from 0.263 microgram/ml (25-mg dose) to 2.489 microgram/ml (400-mg dose) and were reached within 1.5 h following drug administration. After reaching the C(max), plasma DU-6681 concentrations declined in a monophasic manner, with a half-life of 0.47 to 0.89 h. The area under the concentration-time curve (AUC) and C(max) increased almost linearly with the dose up to the 200-mg dose. The AUC and C(max) increased less than proportionally after administration of the 400-mg dose, suggesting a reduction in drug absorption. The plasma protein binding of DU-6681 was in the range of 23.3 to 25.6%. The cumulative urinary recoveries (0 to 24 h) were in the range of 31.9 to 44.9%. The AUC was slightly but statistically significantly reduced by food intake. However, the C(max), half-life, and recovery in urine were not affected by food intake. The renal clearance (402 to 510 ml/min) was much greater than the mean glomerular filtration rate (ca. 120 ml/min), which indicated active tubular secretion of the drug. A mild transient and moderate diarrhea was observed in two of six volunteers in the study with a single dose of 25 mg. Mild soft stools were observed in two of six volunteers who received a 400-mg dose of the drug. PMID:10681321

Tanaka, M; Kato, K; Hakusui, H; Murakami, Y; Sato, K; Ito, Y; Kawamoto, K

2000-03-01

191

Pharmacokinetics and Safety of Ascending Single Doses of DZ-2640, a New Oral Carbapenem Antibiotic, Administered to Healthy Japanese Subjects  

PubMed Central

DZ-2640 is the ester-type oral carbapenem prodrug of an active parent compound, DU-6681. The pharmacokinetics and safety of DU-6681 were investigated in six studies after oral administration of a single dose of DZ-2640 to healthy male Japanese volunteers at doses of 25, 50, 100, 200, and 400 mg (as the equivalents of DU-6681) in the fasted state. The same volunteers received the drug at a dose of 100 mg in the fasted and fed states to examine the effect of food intake on the bioavailability of DZ-2640. The concentrations of DU-6681 in plasma and urine were determined by a validated high-performance liquid chromatography method and a bioassay. A good correlation between both methods was seen, indicating an absence of major active metabolites. The mean maximum concentrations of DU-6681 in plasma (Cmax) ranged from 0.263 ?g/ml (25-mg dose) to 2.489 ?g/ml (400-mg dose) and were reached within 1.5 h following drug administration. After reaching the Cmax, plasma DU-6681 concentrations declined in a monophasic manner, with a half-life of 0.47 to 0.89 h. The area under the concentration-time curve (AUC) and Cmax increased almost linearly with the dose up to the 200-mg dose. The AUC and Cmax increased less than proportionally after administration of the 400-mg dose, suggesting a reduction in drug absorption. The plasma protein binding of DU-6681 was in the range of 23.3 to 25.6%. The cumulative urinary recoveries (0 to 24 h) were in the range of 31.9 to 44.9%. The AUC was slightly but statistically significantly reduced by food intake. However, the Cmax, half-life, and recovery in urine were not affected by food intake. The renal clearance (402 to 510 ml/min) was much greater than the mean glomerular filtration rate (ca. 120 ml/min), which indicated active tubular secretion of the drug. A mild transient and moderate diarrhea was observed in two of six volunteers in the study with a single dose of 25 mg. Mild soft stools were observed in two of six volunteers who received a 400-mg dose of the drug. PMID:10681321

Tanaka, Makoto; Kato, Kinuyo; Hakusui, Hideo; Murakami, Yoichi; Sato, Kenichi; Ito, Yasushi; Kawamoto, Keiji

2000-01-01

192

Brivaracetam Single and Multiple Rising Oral Dose Study in Healthy Japanese Participants: Influence of CYP2C19 Genotype.  

PubMed

Brivaracetam is a high-affinity synaptic vesicle protein 2A ligand, in phase 3 clinical development for epilepsy. A phase 1, single-center, randomized, double-blind, placebo-controlled, single (2.5-100 mg) and multiple (2.5-50 mg twice daily) rising oral dose study (N01209) was conducted to assess the adverse event profile and pharmacokinetics of brivaracetam in healthy Japanese men, and the influence of the cytochrome P450 (CYP) 2C19 genotype. Plasma and urine were collected serially for analysis of brivaracetam and its three main metabolites: acid, hydroxy and hydroxy acid. Overall, 79/80 randomized participants completed the study. Brivaracetam was generally well tolerated. After single- and multiple-dose administration, brivaracetam was rapidly absorbed, with dose-proportional pharmacokinetics over the dose ranges tested. Steady state was reached after 2 days of repeated dosing. Brivaracetam clearance (averaged across the five single dose levels) was reduced from 0.99 mL/min/kg in homozygous extensive metabolizers (EM; n = 10) to 0.81 mL/min/kg (-18%) in heterozygous EM (n = 17) and 0.70 mL/min/kg (-29%) in poor metabolizers (PM; n = 9). Exposure and urinary excretion of hydroxy metabolite were reduced 10-fold in PM participants, compared with EM participants. Results suggest that brivaracetam is hydroxylated by CYP2C19, but this pathway is minor compared with hydrolysis to the acid metabolite. PMID:24717838

Stockis, Armel; Watanabe, Shikiko; Rouits, Elisabeth; Matsuguma, Kyoko; Irie, Shin

2014-10-25

193

Orally inhaled fixed-dose combination products for the treatment of asthma and chronic obstructive pulmonary disease: not simple math.  

PubMed

Over the past decade, orally inhaled fixed-dose combination products (FDCs) have emerged as an important therapeutic class for the treatment of asthma and chronic obstructive pulmonary disease. However, the conceptual simplicity of inhaled FDCs belies both the complexity of their development, and the profound advantages they offer patients. The benefits of combining agents are not merely additive, and range from increased compliance via simple convenience to complex receptor-level synergies. Similarly, though, the development challenges often exceed the sum of their parts. FDC formulation and analytical method development is generally more complex than for two monotherapy products. Likewise, FDC clinical programs can easily eclipse those of their monotherapy peers and their inherent complexity is often furthered by the diverse regulatory requirements for worldwide approval. As such, the proposition of developing an orally inhaled FDC for global registration often represents a significant increase in both the potential rewards and assumed risks of drug development. PMID:24592955

Ehrick, Jason D; Wylie, Jennifer; Goodey, Adrian P; Li, Ying; Liu, Oscar; Donovan, Brent

2014-03-01

194

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

195

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

PubMed

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

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

2014-08-14

196

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

PubMed

Listeria monocytogenes is a food-borne pathogen that can result in adverse pregnancy outcomes, such as stillbirth or premature delivery. The Mongolian gerbil was recently proposed as the most appropriate small-animal model of listeriosis due to its susceptibility to the same invasion pathways as humans. The objectives of this study were to investigate invasion and adverse pregnancy outcomes in gerbils orally exposed to L. monocytogenes, to compare the dose-response data to those of other animal models, and to investigate differences in the responses of pregnant versus nonpregnant gerbils. Gerbils were orally exposed to 0 (control), 10(3), 10(5), 10(7), or 10(9) CFU L. monocytogenes in whipping cream. L. monocytogenes was recovered in a dose-dependent manner from fecal samples, adult organs, and pregnancy-associated tissues. Dams exposed to 10(9) CFU had more invaded organs and higher concentrations of L. monocytogenes in almost all organs than nonpregnant animals, though no differences in fecal shedding were seen between the two groups. Adverse pregnancy outcomes occurred only in the dams treated with 10(9) CFU. A 50% infectivity dose (ID50) of 2.60 × 10(6) CFU for fetuses was calculated by fitting the data to a logistic model. Our results suggest that the 50% lethal dose (LD50) falls within the range of 5 × 10(6) to 5 × 10(8) CFU. This range includes the guinea pig and nonhuman primate LD50s, but the observation that L. monocytogenes-induced stillbirths can be seen in guinea pigs and primates exposed to lower doses than those at which stillbirths were seen in gerbils indicates that gerbils are not more sensitive to L. monocytogenes invasion. PMID:25156729

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

2014-11-01

197

Effects of 28 day exposure to cold temperature or feed restriction on growth, body composition, and expression of genes related to muscle growth and metabolism in channel catfish  

Microsoft Academic Search

Cold temperature decreases feed intake and growth of channel catfish, but the physiological and molecular mechanisms associated with the growth depression remain unknown. Therefore, an experiment was conducted to determine the effects of a 28-day exposure to cold temperature or feed deprivation at warm temperature on growth, physiological indices, and the expression of genes involved in muscle growth and metabolism.

Thomas E. Weber; Brian G. Bosworth

2005-01-01

198

Therapeutic effect of oral doxycycline on syphilis.  

PubMed

Fifty-one patients with syphilis were treated with oral doxycycline. A course of the antibiotic treatment consisted of 200 mg of doxycycline daily in two divided doses for 28 days. The courses were repeated three to four times a year with an interval of several months. Quantitative Venereal Disease Research Laboratory (VDRL), Wassermann reaction (WR), and Treponema pallidum haemagglutination assay (TPHA) tests were performed monthly to evaluate the therapeutic effect of doxycycline treatment. The response rate was 100% for primary, 90% for early, 68% for late, and 90% for congenital syphilis in adults. No notable side effects were encountered except for epigastric fullness in one patient, which did not require the treatment to be discontinued. No abnormalities were detected in the results of laboratory tests. PMID:445120

Onoda, Y

1979-04-01

199

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

PubMed Central

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

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

2014-01-01

200

[The pharmacokinetics of the new Russian prolonged-action form of diclofenac sodium--Ortopek--in a single oral dose].  

PubMed

Ortopak tablets, 100 mg, were investigated. The pharmacokinetics of Ortopak was studied in 10 rheumatoid arthritis patients after a single oral dose of 100 mg. Ortophenum and voltaren-retard (Ciba-Geigy) were used for comparison. Diclophenac-sodium was measured in the patient's plasma by using high performance liquid chromatography. Ortopak was shown to be eliminated from the patient's body much slower than Ortophenum. The bioequivalence of Ortopak versus Ortophenum was 62.7%. The pharmacokinetic properties of Ortopak were similar to those of Voltaren-retard, which were close to those of diclophenac-sodium in the blood plasma within the therapeutic range. PMID:7787700

Kurapov, A P; Starodubtsev, A K; Rubtsova, T M; Ignat'ev, V G; Kemenova, V A

1995-01-01

201

A Multi-Compartment Single and Multiple Dose Pharmacokinetic Comparison of Rectally Applied Tenofovir 1% Gel and Oral Tenofovir Disoproxil Fumarate  

PubMed Central

This Phase 1, randomized, two-site (United States), double-blind, placebo-controlled study enrolled 18 sexually abstinent men and women. All received a single 300-mg dose of oral tenofovir disoproxil fumarate (TDF) and were then randomized 2?1 to receive single and then seven daily rectal exposures of vaginally-formulated tenofovir (TFV) 1% gel or a hydroxyethyl cellulose (HEC) placebo gel. Blood, colonic biopsies and rectal and vaginal mucosal fluids were collected after the single oral TDF, the single topical TFV gel dose, and after 7 days of topical TFV gel dosing for extracellular analysis of TFV and intracellular analysis of the active metabolite tenofovir diphosphate (TFVdp) in peripheral blood mononuclear cells (PBMCs) and isolated mucosal mononuclear cells (MMC), including CD4+ and CD4- cell subsets. With a single rectal dose, TFV plasma concentrations were 24–33 fold lower and half-life was 5 h shorter compared to a single oral dose (p?=?0.02). TFVdp concentrations were also undetectable in PBMCs with rectal dosing. Rectal tissue exposure to both TFV and TFVdp was 2 to 4-log10 higher after a single rectal dose compared to a single oral dose, and after 7 daily doses, TFVdp accumulated 4.5 fold in tissue. TFVdp in rectal tissue homogenate was predictive (residual standard error, RSE ?=?0.47) of tissue MMC intracellular TFVdp concentration, with the CD4+ cells having a 2-fold higher TFVdp concentration than CD4- cells. TFV concentrations from rectal sponges was a modest surrogate indicator for both rectal tissue TFV and TFVdp (RSE ?=?0.67, 0.66, respectively) and plasma TFV (RSE ?=?0.38). TFV penetrates into the vaginal cavity after oral and rectal dosing, with rectal dosing leading to higher vaginal TFV concentrations (p<0.01). Trial Registration ClinicalTrials.gov NCT00984971 PMID:25350119

Yang, Kuo-Hsiung; Hendrix, Craig; Bumpus, Namandje; Elliott, Julie; Tanner, Karen; Mauck, Christine; Cranston, Ross; McGowan, Ian; Richardson-Harman, Nicola; Anton, Peter A.; Kashuba, Angela D. M.

2014-01-01

202

Myoadenylate deaminase deficiency: Successful symptomatic therapy by high dose oral administration of ribose  

Microsoft Academic Search

Summary A 55 years old patient suffering from exercise-induced muscle pain and stiffness due to primary myoadenylate deaminase deficiency has been successfully treated with D-ribose since 1984: single doses of 4 grams administered at the beginning of exercise prevented the symptoms completely; on continuation of exercise this dose had to be repeated all 10–30 min. Total doses of 50–60 g

N. Zöllner; S. Reiter; M. Gross; D. Pongratz; C. D. Reimers; K. Gerbitz; I. Paetzke; T. Deufel; G. Hübner

1986-01-01

203

Single-dose oral ciprofloxacin versus placebo for prophylaxis during transrectal prostate biopsy  

Microsoft Academic Search

Objectives. To determine whether antimicrobial prophylaxis could prevent infections after transrectal needle biopsy of the prostate using automated biopsy devices.Methods. We conducted a prospective, randomized, double-blind, multicenter trial in which a total of 537 patients received either oral ciprofloxacin 500 mg or placebo before transrectal needle biopsy of the prostate. Repeated urine cultures and urinalysis were obtained at 2 to

Deepak A Kapoor; Ira W Klimberg; Gholam H Malek; John D Wegenke; Clair E Cox; A. Lynn Patterson; Evelyn Graham; Roger M Echols; Edward Whalen; Steven F Kowalsky

1998-01-01

204

Comparison of pharmacokinetic and pharmacodynamic profiles of aspirin following oral gavage and diet dosing in rats  

Microsoft Academic Search

Aspirin is one of the oldest drugs and has been purported to have multiple beneficial effects, including prevention of cardiovascular disease and cancer, in addition to its original indication for treatment of inflammation, fever and pain. In cancer chemoprevention studies using animal models, two methods of aspirin administration have been employed: oral gavage and diet. The untested assumption was that

Izet M. Kapetanovic; Kenneth S. Bauer; Daniel M. Tessier; Matthew O. Lindeblad; Alexander D. Zakharov; Ronald Lubet; Alexander Lyubimov

2009-01-01

205

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. PMID:6822727

Dassanayake, L.; White, G.

1983-01-01

206

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

207

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

208

Safety of Intravenous and Oral Bisphosphonates and Compliance With Dosing Regimens  

Microsoft Academic Search

Patients with advanced cancers—particularly breast and prostate cancers—are at high risk for bone metasta- sis, leading to accelerated bone resorption and clinically significant skeletal morbidity. Bisphosphonates are effective inhibitors of bone resorption and reduce the risk of skeletal complications in patients with bone metastases. The standard routes of administration for bisphosphonates used in clinical practice are either oral or i.v.

PIERFRANCO CONTE; VALENTINA GUARNERI

209

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 ApoBtm2Sgy/Ldlrtm1Her/J mice. Antigen specific tolerance to individual peptides was observed in treated animals as seen by an increase in regulatory T cells. Tolerance to the peptides resulted in a 46.5% (p=0.002) reduction in the development of atherosclerosis compared with control. Atheroprotection was associated with a significant (p<0.05) decrease in plaque inflammation and an increase in the expression of immune regulatory markers in the aorta. CD11c+ cells coexpressing CD11b and CD103 increased in lymphoid organs and were found to activate regulatory T cells and reduce effector T-cell response. Adoptive transfer of CD11c+ cells was atheroprotective. Our results suggest that atheroprotection by oral tolerance to a multi-antigenic construct is mediated by antigen specific regulatory T cells and CD11c+ cells with immune regulatory properties. 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

210

Onset and duration of beta-adrenergic receptor blockade following single oral dose acebutolol hydrochloride (Sectral).  

PubMed Central

1. The onset and duration of action of once daily acebutolol (400 mg) on resting and exercise heart rate and blood pressure were studied in normal subjects in a double-blind, cross-over trial against placebo. Subjects were studied 1.5, 3, 8 and 24 h after the first dose and 24 h after the fifth dose. 2. Resting and exercise heart rate and blood pressure were significantly reduced within 90 min of the first dose. 3. A significant reduction in these variables persisted throughout 24 h after the fifth daily dose. However, at 24 h the effects were considerably attenuated, the falls in resting and exercise systolic blood pressure being only 5%. 4. A linear relationship was noted between log serum drug level and percentage reduction of exercise heart rate. PMID:37868

Watson, R D; Littler, W A

1979-01-01

211

Impact of Peptide Transporter 1 on the Intestinal Absorption and Pharmacokinetics of Valacyclovir after Oral Dose Escalation in Wild-Type and PepT1 Knockout Mice  

PubMed Central

The primary objective of this study was to determine the in vivo absorption properties of valacyclovir, including the potential for saturable proton-coupled oligopeptide transporter 1 (PepT1)-mediated intestinal uptake, after escalating oral doses of prodrug within the clinical dose range. A secondary aim was to characterize the role of PepT1 on the tissue distribution of its active metabolite, acyclovir. [3H]Valacyclovir was administered to wild-type (WT) and PepT1 knockout (KO) mice by oral gavage at doses of 10, 25, 50, and 100 nmol/g. Serial blood samples were collected over 180 minutes, and tissue distribution studies were performed 20 minutes after a 25-nmol/g oral dose of valacyclovir. We found that the Cmax and area under the curve (AUC)0–180 of acyclovir were 4- to 6-fold and 2- to 3-fold lower, respectively, in KO mice for all four oral doses of valacyclovir. The time to peak concentration of acyclovir was 3- to 10-fold longer in KO compared with WT mice. There was dose proportionality in the Cmax and AUC0–180 of acyclovir in WT and KO mice over the valacyclovir oral dose range of 10–100 nmol/g (i.e., linear absorption kinetics). No differences were observed in the peripheral tissue distribution of acyclovir once these tissues were adjusted for differences in perfusing drug concentrations in the systemic circulation. In contrast, some differences were observed between genotypes in the concentrations of acyclovir in the distal intestine. Collectively, the findings demonstrate a critical role of intestinal PepT1 in improving the rate and extent of oral absorption for valacyclovir. Moreover, this study provides definitive evidence for the rational development of a PepT1-targeted prodrug strategy. PMID:23924683

Yang, Bei; Hu, Yongjun

2013-01-01

212

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

PubMed

The primary objective of this study was to determine the in vivo absorption properties of valacyclovir, including the potential for saturable proton-coupled oligopeptide transporter 1 (PepT1)-mediated intestinal uptake, after escalating oral doses of prodrug within the clinical dose range. A secondary aim was to characterize the role of PepT1 on the tissue distribution of its active metabolite, acyclovir. [³H]Valacyclovir was administered to wild-type (WT) and PepT1 knockout (KO) mice by oral gavage at doses of 10, 25, 50, and 100 nmol/g. Serial blood samples were collected over 180 minutes, and tissue distribution studies were performed 20 minutes after a 25-nmol/g oral dose of valacyclovir. We found that the C(max) and area under the curve (AUC)????? of acyclovir were 4- to 6-fold and 2- to 3-fold lower, respectively, in KO mice for all four oral doses of valacyclovir. The time to peak concentration of acyclovir was 3- to 10-fold longer in KO compared with WT mice. There was dose proportionality in the C(max) and AUC????? of acyclovir in WT and KO mice over the valacyclovir oral dose range of 10-100 nmol/g (i.e., linear absorption kinetics). No differences were observed in the peripheral tissue distribution of acyclovir once these tissues were adjusted for differences in perfusing drug concentrations in the systemic circulation. In contrast, some differences were observed between genotypes in the concentrations of acyclovir in the distal intestine. Collectively, the findings demonstrate a critical role of intestinal PepT1 in improving the rate and extent of oral absorption for valacyclovir. Moreover, this study provides definitive evidence for the rational development of a PepT1-targeted prodrug strategy. PMID:23924683

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

2013-10-01

213

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

214

DOSE DEPENDENT DISPOSITION OF SODIUM ARSENATE IN MICE FOLLOWING ACUTE ORAL EXPOSURE  

EPA Science Inventory

The effect of dose on arsenate disposition was studied in adult female B6C3F, mice, dosed po with 0.5 to 5000 ug/kg [73As]-arsenate in water. rine was collected at 1, 2, 4, 8, 12, 24 and 48 hr and feces at 24 and 48 hr postexposure. he mice were sacrificed at 48 hr and tissues we...

215

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

216

Transfusions of CPDA-1 red blood cells stored for up to 28 days decrease donor exposures in very low-birth-weight premature infants.  

PubMed

The goal of this research was to study the safety and the efficacy of transfusing citrate-phosphate-adenine anticoagulant-preservative (CPDA-1) RBC stored for up to 28 days to reduce donor exposures in premature infants. A prospective randomized two-group study was conducted with very low-birth-weight premature infants that received at least one RBC transfusion during hospital stay. Neonates randomly assigned to Group 1 (26 infants) were transfused with CPDA-1 RBC stored for up to 28 days; those assigned to Group 2 (26 infants) received CPDA-1 RBC stored for up to 3 days. Demographic and transfusion-related data were collected. Neonates from both groups showed similar demographics and clinical characteristics. The number of transfusions per infant transfused was 4.4 +/- 4.0 in Group 1 and 4.2 +/- 3.1 in Group 2, and the number of donors per infant transfused was 1.5 +/- 0.8 (Group 1) and 4.3 +/- 3.4 (Group 2), P < 0.001. RBC transfusions containing 29.7 +/- 18.3 mmol L(-1) of potassium (RBC stored for up to 28 days) did not cause clinical or biochemical changes and reduced donor exposures by 70.2%, compared to transfusions containing 19.8 +/- 12.3 mmol L(-1) of potassium (RBC stored for up to 3 days), P < 0.001. In conclusion, RBC stored for up to 28 days safely reduced donor exposures in premature infants. PMID:16359417

Fernandes da Cunha, D H; Nunes Dos Santos, A M; Kopelman, B I; Areco, K N; Guinsburg, R; de Araújo Peres, C; Chiba, A K; Kuwano, S T; Terzian, C C N; Bordin, J O

2005-12-01

217

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

PubMed Central

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

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

2013-01-01

218

Naproxen plasma levels in volunteers after single-dose administration by oral and rectal routes.  

PubMed

The bioavailability (plasma concentrations, AUC) of a rectal formulation (suppository) of naproxen was investigated in six healthy volunteers by comparison with an oral preparation (tablets). Plasma half-lives after both formulations were identical 10 hr 15 min+/-25 min (S.D.). Determined by the AUC the bioavailability of naproxen in the suppositories was 94.8%+/-6.3% of the bioavailability of naproxen in the tablets. This paper describes also a new gas-liquid chromatographic method for determining unchanged naproxen in human plasma which is quick, sensitive, and specific. PMID:1262531

Desager, J P; Vanderbist, M; Harvengt, C

1976-04-01

219

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

220

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. PMID:24049417

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

2013-01-01

221

Effects of a single oral dose of dinitrochlorobenzene on T lymphocyte distribution and migration in the gut.  

PubMed

In the present study the effects of a large oral dose of the contact allergen dinitrochlorobenzene (DNCB) on the distribution of T-cell subsets in the small intestines and the emigration pattern of lymphocytes from Peyer's patches were investigated. Apart from the inflammatory effects, DNCB administration resulted in an influx on the T-helper cells in the villi. Precise quantification of T lymphocytes showed a decrease in Peyer's patches and an increase in mesenteric lymph node cell suspensions. However, no differences could be found in the emigration rate of T-cell subsets from Peyer's patches into mesenteric lymph nodes, suggesting that the increase of T cells in mesenteric lymph nodes results from T-helper cells directly immigrating from the villi. PMID:3160666

Jeurissen, S H; Schmidt, E D; Sminia, T; Kraal, G

1985-01-01

222

Characterization of anxiety-related responses in male rats following prolonged exposure to therapeutic doses of oral methylphenidate.  

PubMed

Increases in the rates of attention-deficit/hyperactivity disorder (ADHD) diagnosis and the prescribed use of methylphenidate (MPH) in recent years have raised concerns over the potential effects of early MPH exposure on brain structure and function in adulthood. Animal studies have shown that long-term MPH exposure can modify anxiety-related behaviors and related neural circuitry in adulthood. The present study employed a battery of behavioral tests and repeated testing to assess the long-term effects of MPH exposure on anxious responding. Male Wistar rats beginning on post-natal day 27 were exposed to 4 or 7 weeks of twice daily MPH administration at doses of 2, 3, or 5 mg/kg. MPH was administered orally and on weekdays only in order to approximate drug treatment in clinical populations. Behavioral testing began 18 days following the last drug administration. Our results indicate that prolonged oral MPH treatment at therapeutic doses has little or no enduring effects on anxious behaviors. However, a comparison of MPH groups that received treatment for 4 or 7 weeks suggests that the two treatment periods influenced anxious behaviors in observably different manners in adulthood; namely, a more prolonged period of exposure produced less anxiety relative to the shorter period of MPH exposure as indicated by behaviors in the light-dark transition, elevated plus-maze, and fear conditioning tests. These findings were interpreted as evidence of the importance of considering length of drug exposure in pre-clinical studies aimed at investigating the effects of MPH exposure in ADHD populations. PMID:19540871

Britton, Gabrielle B; Bethancourt, José A

2009-10-01

223

Detection of Toxoplasma gondii in tissues of sheep orally challenged with different doses of oocysts.  

PubMed

The presence of Toxoplasma gondii in blood, brain, cardiac muscle and skeletal muscle (gracillis and psoas) of sheep 6 weeks after experimental infection with 10(5), 10(4) and 10(3) T. gondii oocysts was determined using the PCR technique. The study demonstrates that oral infection of sheep with T. gondii oocysts of the M3 isolate results in parasites being detectable in tissues 6 weeks p.i. The PCR detection was much more sensitive than histological detection. Parasite DNA was detected more frequently and consistently in the group of sheep given 10(5) oocysts compared with those given 10(3) oocysts. The brain and heart were most frequently infected compared with the other tissues. PMID:9770633

Esteban-Redondo, I; Innes, E A

1998-09-01

224

HPLC determination of chondrosine in mouse blood plasma after intravenous or oral dose.  

PubMed

The bioavailability of chondrosine was evaluated by its direct measurement as found in the blood plasma following removal of plasma proteins by perchloric acid. The postcolumn HPLC determination of chondrosine was performed on an SCX column (6 mm i.d.x 150 mm), 0.35 mol/l boric acid (pH 5.2 adjusted by 0.1 mol/l NaOH) as an eluent (0.9 ml/min), 0.5% 2-cyanoacetamide and 1.0 M NaOH as fluorogenic reagents (0.25 ml/min each) with a fluorescence detector (ex. 331nm, em. 383nm). Two separate animal studies were conducted. In study 1, adult male ddY mice (n=6) received i.v. chondrosine (1.0 mg/kg body weight) and the plasma samples were collected. In the second study, 6 adult male ddY mice received p.o. chondrosine (400 mg/kg body weight) and the plasma samples were collected. Blood plasma samples were deproteinized by perchloric acid, analyzed and the bioavailability of chondrosine was determined. Twenty five to fifty microliters of blood plasma were required for the assay. Chondrosine was absorbed after oral administration with two phases having two maximum values, 7.8+/-5.4 and 4.0+/-1.9 at 15 microg/ml and 120 min, respectively; it disappeared from the blood flow very quickly after intravenous administration. This study provides the first report of the bioavailability of orally administered chondrosine in mice. PMID:17666786

Kusano, Shuichi; Ootani, Atsuko; Sakai, Shinobu; Igarashi, Naoko; Takeguchi, Atsuko; Toyoda, Hidenao; Toida, Toshihiko

2007-08-01

225

Effects of various oral doses of salinomycin on serum biochemical parameters in calves  

Microsoft Academic Search

Salinomycin is a monocarboxylic polyether antibiotic with antimicrobial and anticoccidial properties. Although it has proved\\u000a to be safe at therapeutic doses, toxic effects can result from overdosage or misuse. In addition to clinical signs and pathologic\\u000a lesions, confirmatory diagnosis of toxicosis needs consideration of laboratory assays. The present study describes changes\\u000a in biochemical parameters over an extended period of 35 days

H. Rajaian; S. Nazifi; M. Fazeli; S. L. Poorbaghi; M. Sepehrimanesh; A. Ghezelbash

2009-01-01

226

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

227

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

228

An Escalating Dose Oral Gavage Study of 3?-Acetoxyandrost-5-ene-7,17-dione (7-oxo-DHEA-acetate) in Rhesus Monkeys  

Microsoft Academic Search

To test the effects of 7-oxo-dehydroepiandrosterone-3 acetate (hereafter 7-ODA) in Rhesus macaques the steroid was administered by oral gavage to two male and two female monkeys. Dose levels of 250, 500, and 1,000 mg\\/kg body weight (BW)\\/day were administered on days 1, 3, and 5 respectively, and 1,000 mg\\/kg on days 7 through 11. Each group received the dose in

Susan M. Henwood; Henry Lardy

1999-01-01

229

Dose–response for glycaemic and metabolic changes 28 days after single injection of long-acting release exenatide in diabetic fatty Zucker rats  

Microsoft Academic Search

Aims\\/hypothesis  Exenatide (exendin-4) injected subcutaneously twice daily reduces glycaemic deterioration in diabetic fatty Zucker (ZDF) rats and reduces HbA1c in humans with type 2 diabetes. Because tachyphylaxis may develop with continuous peptide exposure, we examined the activity of a long-acting-release (LAR) formulation of exenatide on HbA1c, insulin sensitivity and beta cell secretion in ZDF rats.Methods  Single subcutaneous injections of a poly-lactide-glycolide microsphere

B. R. Gedulin; P. Smith; K. S. Prickett; M. Tryon; S. Barnhill; J. Reynolds; L. L. Nielsen; D. G. Parkes; A. A. Young

2005-01-01

230

Comparisons of metabolic and physiological changes in rats following short term oral dosing with pesticides commonly found in food.  

PubMed

¹H Nuclear Magnetic Resonance spectroscopy has been used to profile urinary metabolites in male Fischer F344 rats in order to assess the metabolic changes induced by oral exposure to two benzimidazole fungicides (carbendazim and thiabendazole) and two bipyridyllium herbicides (chlormequat and mepiquat). Exposure levels were selected to be lower than those expected to cause overt signs of toxicity. We then compared the sensitivity of the metabolomics approach to more traditional methods of toxicity assessment such as the measurement of growth and organ weights. Separate, acute exposure experiments were conducted for each pesticide to identify potential metabolic markers of exposure across four doses (and a control). Growth, organ weights and feeding/drinking rates were not significantly affected by any compounds at any dose levels tested. In contrast, metabolic responses were detected within 8 and 24h for chlormequat and mepiquat, and after 24h for carbendazim and thiabendazole. These results demonstrate the potential for the use of metabolomics in food toxicity testing. PMID:23822974

Jones, Oliver A H; Murfitt, Steven; Svendsen, Claus; Turk, Anthony; Turk, Hazel; Spurgeon, David J; Walker, Lee A; Shore, Richard F; Long, Sara M; Griffin, Julian L

2013-09-01

231

Enhancement mu opioid antinociception by oral delta9-tetrahydrocannabinol: dose-response analysis and receptor identification.  

PubMed

The antinociceptive effects of various mu opioids given p.o. alone and in combination with Delta-9-tetrahydrocannabinol (Delta9-THC) were evaluated using the tail-flick test. Morphine preceded by Delta9-THC treatment (20 mg/kg) was significantly more potent than morphine alone, with an ED50 shift from 28.8 to 13.1 mg/kg. Codeine showed the greatest shift in ED50 value when administered after Delta9-THC (139.9 to 5.9 mg/kg). The dose-response curves for oxymorphone and hydromorphone were shifted 5- and 12.6-fold, respectively. Methadone was enhanced 4-fold, whereas its derivative, l-alpha-acetylmethadol, was enhanced 3-fold. The potency ratios after pretreatment with Delta9-THC for heroin and meperidine indicated significant enhancement (4.1 and 8.9, respectively). Pentazocine did not show a parallel shift in its dose-response curve with Delta9-THC. Naloxone administration (1 mg/kg s.c.) completely blocked the antinociceptive effects of morphine p.o. and codeine p.o. The Delta9-THC-induced enhancement of morphine and codeine was also significantly decreased by naloxone administration. Naltrindole (2 mg/kg s.c.) did not affect morphine or codeine antinociception but did block the enhancement of these two opioids by Delta9-THC. No effect was seen when nor-binaltorphimine was administered 2 mg/kg s.c. before morphine or codeine. Furthermore, the enhancements of morphine and codeine were not blocked by nor-binaltorphimine. We find that many mu opioids are enhanced by an inactive dose of Delta9-THC p.o. The exact nature of this enhancement is unknown. We show evidence of involvement of mu and possibly delta opioid receptors as a portion of this signaling pathway that leads to a decrease in pain perception. PMID:10215664

Cichewicz, D L; Martin, Z L; Smith, F L; Welch, S P

1999-05-01

232

Selenium absorption, distribution, and excretion in white sturgeon orally dosed with l-selenomethionine.  

PubMed

The usefulness of a newly developed, combined technique consisting of esophageal intubation, dorsal aortic cannulation, and urinary catheterization to deliver Se orally and to monitor Se uptake, accumulation, and excretion in white sturgeon (Acipenser transmontanus) was explored. Groups of five yearling sturgeon (1-2 kg) each were intubated with 0 (sham), 250, 500, or 1,000 microg Se/kg body weight in the form of L-selenomethionine, an ecologically relevant organic form of Se. Selenium concentrations in whole blood, plasma, and red blood cells did not change in the sham group but began to rise within 2 h postintubation in the other groups, and levels remained near maximum concentrations throughout the 48-h sampling period. Average urinary Se excretion rates over the entire 48-h period were 0.05, 0.46, 0.61, and 2.15 microg Se/kg/h in sturgeon intubated with 0, 250, 500, and 1,000 microg Se/kg, respectively. Selenium excretion rates were highest within the first 6 h in all treatment groups except the sham group. Selenium concentrations in the liver were positively correlated with the intubated Se dosage. PMID:17022401

Tashjian, Diran H; Hung, Silas S O

2006-10-01

233

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

PubMed

Chemical stability and in vitro bactericidal efficacy of 0.9% enrofloxacin-compounded solutions were evaluated following storage at room temperature for 28 days. Chemical stability of enrofloxacin was determined by high-performance liquid chromatography (HPLC) in five compounded solutions, including sterile water. Bactericidal efficacy was determined by spiral plating serial 10-fold dilutions of bacteria and solutions followed by colony counts. Tris-EDTA [TrizEDTA(®) (TE)], Tris-EDTA and 0.15% chlorhexidine [TrizChlor(®) (TC)], 2.5% lactic acid, 0.1% salicylic acid and 0.1% parachlorometaxylenol [Epi-Otic (EO)], and 0.1% free salicylic acid, 0.1% parachlorometaxylenol and 0.5% EDTA [Epi-Otic Advanced (EA)] were used. High-performance liquid chromatography was carried out with one-step liquid/liquid extraction to detect and quantify enrofloxacin stability. Mean recoveries for compounded samples run in triplicate at 28 days were 97.7% (TE), 99.9% (TC), 98.1% (EO) and 97.8% (EA). Kruskal-Wallis analysis showed no significant difference in the percentage recovery (H=0.0539, df=3, P=0.9967). American Type Culture Collection strains of Staphylococcus pseudintermedius and Pseudomonas aeruginosa were used to evaluate in vitro efficacy following 30 min incubation on days 0, 14 and 28. Consistent in vitro bactericidal efficacy of all compounded solutions, indicated by killing >2.3×10(7) colony-forming units/mL, was seen; however, bactericidal efficacy decreased for compounded TC on day 14. Pseudomonas aeruginosa was more sensitive to the ear cleaners and enrofloxacin than S. pseudintermedius. The HPLC and in vitro data suggest that 0.9% enrofloxacin compounded with sterile water, TE, EO and EA maintains chemical stability and bactericidal efficacy for 28 days. PMID:21777310

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

2012-02-01

234

ABSTRACT: The consequences of baclofen intake on voluntary motor behaviors remain unclear. We studied the effects of single oral doses of  

E-print Network

studied the effects of single oral doses of baclofen on voluntary, isometric knee extension torques duration performed pre- and post-baclofen ingestion revealed significant decreases in maximal knee torques to reduced motoneuronal excitability, although use of MU discharge patterns to assess these effects

235

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

Microsoft Academic Search

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

Kelly S Parsey; Annpey Pong

2000-01-01

236

Comparison of the urinary excretion of arsenic metabolites after a single oral dose of sodium arsenite, monomethylarsonate, or dimethylarsinate in man  

Microsoft Academic Search

The urinary elimination of the metabolites of arsenic has been followed up as a function of time in volunteers who ingested a single oral dose of arsenic (500 µg As) either as sodium arsenite (Asi), monomethylarsonate (MMA), or cacodylate (DMA). The excretion rate increased in the order Asi i, MMA and DMA, respectively. With regard to the in vivo biotransformations,

J. P. Buchet; R. Lauwerys; H. Roels

1981-01-01

237

Risk for ovulation in women taking a low-dose oral contraceptive (Microgynon) when receiving antibacterial treatment with a fluoroquinolone (ofloxacin)  

Microsoft Academic Search

The possibility of escape ovulation in women using a fluoroquinolone ofloxacin for antibacterial treatment at a dose of 200 mg twice daily for 7 days when taking a combined oral contraceptive (Microgynon, 150 µg levonorgestrel and 30 µg ethinyl estradiol) was studied in 20 women. By using a placebocontrolled, rendomized, cross-over design 6 contraceptive pill cycles were followed. Follicle-stimulating hormone

G. Csemiczky; C. Alvendal; B.-M. Landgren

1996-01-01

238

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

Microsoft Academic Search

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

Lawrence C Hookey; William T Depew; Stephen J Vanner

2004-01-01

239

Oral Repeated Dose Toxicity Studies of Coenzyme Q10 in Beagle Dogs  

PubMed Central

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

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

2011-01-01

240

Oral repeated-dose toxicity studies of coenzyme Q10 in beagle dogs.  

PubMed

To support phase III testing of coenzyme Q10 (CoQ??) in humans, we conducted pharmacokinetic and toxicology studies in beagle dogs. Following single gavage administration of CoQ?? at 600, 1200, 1800, or 2400 mg/kg per d no obvious dose response was observed in maximum concentration (C(max)) or area under the curve (AUC) versus time curve at the 3 highest dosages. In a repeated-dose study of CoQ?? at 600, 1200, 1800, or 2400 mg/kg per d for 4 weeks, CoQ?? reached steady state in plasma by 2 weeks at all dosages. Both C (max) and AUC increased with increasing dosage of CoQ??. The highest plasma levels were recorded at 1800 mg/kg per d. In a 39-week chronic toxicity study of CoQ?? at 1200 and 1800 mg/kg per d or placebo, CoQ?? reached steady state in plasma by 13 weeks. Behaviors, blood chemistries, and detailed histopathology were normal. No deaths occurred. These results support the use of a 2400 mg/d dosage of CoQ?? in human clinical trials. PMID:22267890

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

2012-01-01

241

Comparison of oral 5-HT3-receptor antagonists and low-dose oral metoclopramide plus i.m. dexamethasone for the prevention of delayed emesis in head and neck cancer patients receiving high-dose cisplatin.  

PubMed

A phase III, single-institution, open, prospective, randomized, parallel study was carried out on head and neck cancer patients to compare a combination of low-dose (20 mg q.i.d.) oral metoclopramide (M) + i.m. Dexamethasone (D) with an oral 5-HT3-Receptor Antagonist (5-HT3-RA) alone in the prevention of high-dose (HD > or = 80 mg/m2) cisplatin-induced delayed emesis. 51 consecutive patients, all but two with advanced stage of disease, were treated for a total of 198 chemotherapic cycles: 23 patients entered Group A (5-HT3-RA) receiving a total of 108 cycles, 28 patients entered Group B (M + D) receiving a total of 90 cycles. The treatment groups were well matched for age, sex (almost all patients were males), ECOG PSR, stage of disease and alcohol intake. The efficacy of M + D was significantly higher than that of 5-HT3-RA in achieving complete protection (CR 88.9% vs 72.2%, chi2 9.9, p = 0.002) and major efficacy (ME: CR + MR) (94.5% vs 85.2%, chi2 5.6, p = 0.02). Generally, for both treatments (5-HT3-RA and M + D) a good control of delayed emesis was achieved in patients who had complete protection on acute emesis. A good control of acute emesis had a highly positive predictive value of delayed emesis for both treatments without significant difference between them (CR 85% for M + D and 82% for 5-HT3-RA; ME 88% for M + D and 92% for 5-HT3-RA). The failure (F) on acute emesis had a significantly higher negative predictive value of delayed emesis for M + D (98%) than 5-HT3-RA (67%). Our study is, to our knowledge, the first comparing M + D vs one 5-HT3-RA alone in the prevention of HD cisplatin-induced delayed emesis in a properly designed clinical trial. Our results show that M + D are more effective than 5-HT3-RA alone in the prevention of HD cisplatin induced delayed emesis, whereas 5-HT3-RA may be the treatment of choice in patients who had acute vomiting. Our study demonstrated not only the persistence of antiemetic efficacy but also increasing efficacy, during subsequent courses. Our results confirm that protection from acute emesis plays a major role in the appearance and control of delayed emesis. PMID:9458381

Mantovani, G; Macciò, A; Curreli, L; Lampis, B; Ghiani, M; Bianchi, A; Contu, P

1998-01-01

242

Pharmacokinetics of the Protease Inhibitor KNI-272 in Plasma and Cerebrospinal Fluid in Nonhuman Primates after Intravenous Dosing and in Human Immunodeficiency Virus-Infected Children after Intravenous and Oral Dosing  

Microsoft Academic Search

KNI-272 is a human immunodeficiency virus (HIV) protease inhibitor with potent activity in vitro. We stud- ied the pharmacokinetics of KNI-272 in the plasma and cerebrospinal fluid (CSF) of a nonhuman primate model and after intravenous and oral administration to children with HIV infection. Plasma and CSF were sampled over 24 h after the administration of an intravenous dose of

BRIGITTA U. MUELLER; BARRY D. ANDERSON; MAUREEN Q. FARLEY; ROBERT MURPHY; JUDY ZUCKERMAN; PAUL JAROSINSKI; KAREN GODWIN; CINDY L. MCCULLY; HIROAKI MITSUYA; PHILIP A. PIZZO; FRANK M. BALIS; Pediatric Branch

1998-01-01

243

Florfenicol residues in Rainbow Trout after oral dosing in recirculating and flow-through culture systems  

USGS Publications Warehouse

Aquaflor is a feed premix for fish containing the broad spectrum antibacterial agent florfenicol (FFC) incorporated at a ratio of 50% (w/w). To enhance the effectiveness of FFC for salmonids infected with certain isolates of Flavobacterium psychrophilum causing coldwater disease, the FFC dose must be increased from the standard 10 mg·kg?1 body weight (BW)·d?1 for 10 consecutive days. A residue depletion study was conducted to determine whether FFC residues remaining in the fillet tissue after treating fish at an increased dose would be safe for human consumption. Groups of Rainbow Trout Oncorhynchus mykiss (total n = 144; weight range, 126–617 g) were treated with FFC at 20 mg·kg?1 BW·d?1 for 10 d in a flow-through system (FTS) and a recirculating aquaculture system (RAS) each with a water temperature of ?13°C. The two-tank RAS included a nontreated tank containing 77 fish. Fish were taken from each tank (treated tank, n = 16; nontreated tank, n = 8) at 6, 12, 24, 48, 72, 120, 240, 360, and 480 h posttreatment. Florfenicol amine (FFA) concentrations (the FFC marker residue) in skin-on fillets from treated fish were greatest at 12 h posttreatment (11.58 ?g/g) in the RAS and were greatest at 6 h posttreatment (11.09 ?g/g) in the FTS. The half-lives for FFA in skin-on fillets from the RAS and FTS were 20.3 and 19.7 h, respectively. Assimilation of FFC residues in the fillets of nontreated fish sharing the RAS with FFC-treated fish was minimal. Florfenicol water concentrations peaked in the RAS-treated tank and nontreated tanks at 10 h (453 ?g/L) and 11 h (442 ?g/L) posttreatment, respectively. Monitoring of nitrite concentrations throughout the study indicated the nitrogen oxidation efficiency of the RAS biofilter was minimally impacted by the FFC treatment.

Meinertz, Jeffery R.; Hess, Karina R.; Bernady, Jeffry A.; Gaikowski, M. P.; Whitsel, Melissa; Endris, R. G.

2014-01-01

244

[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

245

In Vivo Absorption and Disposition of Cefadroxil after Escalating Oral Doses in Wild-Type and PepT1 Knockout Mice  

PubMed Central

Purpose To determine the effect of PepT1 on the absorption and disposition of cefadroxil, including the potential for saturable intestinal uptake, after escalating oral doses of drug. Methods The absorption and disposition kinetics of [3H]cefadroxil was determined in wild-type and PepT1 knockout mice after 44.5, 89.1, 178, and 356 nmol/g oral doses of drug. The pharmacokinetics of [3H]cefadroxil was also determined in both genotypes after 44.5 nmol/g intravenous bolus doses. Results PepT1 deletion reduced the area under the plasma concentration-time profile (AUC0-120) of cefadroxil by 10-fold, the maximum plasma concentration (Cmax) by 17.5-fold, and increased the time to reach a maximum plasma concentration (Tmax) by 3-fold. There was no evidence of nonlinear intestinal absorption since AUC0-120 and Cmax values changed in a dose-proportional manner. Moreover, the pharmacokinetics of cefadroxil was not different between genotypes after intravenous bolus doses, indicating that PepT1 did not affect drug disposition. Finally, no differences were observed in the peripheral tissue distribution of cefadroxil (i.e., outside gastrointestinal tract) once these tissues were corrected for differences in perfusing blood concentrations. Conclusions The findings demonstrate convincingly the critical role of intestinal PepT1 in both the rate and extent of oral administration for cefadroxil and potentially other aminocephalosporin drugs. PMID:23959853

Posada, Maria M.; Smith, David E.

2013-01-01

246

Florfenicol Residues in Rainbow Trout after Oral Dosing in Recirculating and Flow-through Culture Systems.  

PubMed

Abstract Aquaflor is a feed premix for fish containing the broad spectrum antibacterial agent florfenicol (FFC) incorporated at a ratio of 50% (w/w). To enhance the effectiveness of FFC for salmonids infected with certain isolates of Flavobacterium psychrophilum causing coldwater disease, the FFC dose must be increased from the standard 10 mg·kg(-1) body weight (BW)·d(-1) for 10 consecutive days. A residue depletion study was conducted to determine whether FFC residues remaining in the fillet tissue after treating fish at an increased dose would be safe for human consumption. Groups of Rainbow Trout Oncorhynchus mykiss (total n = 144; weight range, 126-617 g) were treated with FFC at 20 mg·kg(-1) BW·d(-1) for 10 d in a flow-through system (FTS) and a recirculating aquaculture system (RAS) each with a water temperature of ?13°C. The two-tank RAS included a nontreated tank containing 77 fish. Fish were taken from each tank (treated tank, n = 16; nontreated tank, n = 8) at 6, 12, 24, 48, 72, 120, 240, 360, and 480 h posttreatment. Florfenicol amine (FFA) concentrations (the FFC marker residue) in skin-on fillets from treated fish were greatest at 12 h posttreatment (11.58 ?g/g) in the RAS and were greatest at 6 h posttreatment (11.09 ?g/g) in the FTS. The half-lives for FFA in skin-on fillets from the RAS and FTS were 20.3 and 19.7 h, respectively. Assimilation of FFC residues in the fillets of nontreated fish sharing the RAS with FFC-treated fish was minimal. Florfenicol water concentrations peaked in the RAS-treated tank and nontreated tanks at 10 h (453 ?g/L) and 11 h (442 ?g/L) posttreatment, respectively. Monitoring of nitrite concentrations throughout the study indicated the nitrogen oxidation efficiency of the RAS biofilter was minimally impacted by the FFC treatment. Received January 8, 2014; accepted July 7, 2014. PMID:25321636

Meinertz, J R; Hess, K R; Bernardy, J A; Gaikowski, M P; Whitsel, M; Endris, R G

2014-12-01

247

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. PMID:22828138

Poirier, Miriam C.

2012-01-01

248

Evaluation of amitrole (aminotriazole) for potential carcinogenicity in orally dosed rats, mice, and golden hamsters  

SciTech Connect

Amitrole was evaluated for carcinogenic potential in lifespan studies on Wistar rats, NMRI mice, and golden hamsters. At the start of the studies the animals were 6 weeks old. Amitrole was administered, mixed with pulverized chow, at dietary concentrations of 0, 1, 10, and 100 micrograms/g (ppm). Each treated group and control group consisted of 75 male and 75 female rats and mice and of 76 male and 76 female golden hamsters. Additional animals were used to evaluate the functional state of the thyroid. Somewhat lower body weights, slightly reduced survival times, and transient effects on thyroid function were observed in golden hamsters at 100 ppm. In mice, a slight increase in pituitary gland hyperemias was seen at 100 ppm; also an effect on thyroid function usually occurred at the same concentration. In rats, a very large number of cystic dilatations of follicles in the thyroid at 100 ppm and a dose-unrelated increase in hemorrhages and hyperemias in the pituitary gland were indicative of an effect of amitrole on these organs. The strongest effect of amitrole on thyroid function, as compared to golden hamsters and mice, was seen in rats at 100 ppm. At this concentration a highly increased number of thyroid and pituitary gland tumors was observed in rats. In golden hamsters and mice, no tumor induction was seen.

Steinhoff, D.; Weber, H.; Mohr, U.; Boehme, K.

1983-06-30

249

In a randomized, double-blinded, placebo-controlled trial, the single oral dose typhoid vaccine, M01ZH09, is safe and immunogenic at doses up to 1.7 × 10 10 colony-forming units  

Microsoft Academic Search

M01ZH09, S. Typhi (Ty2?aroC?ssaV) ZH9, is a single oral dose typhoid vaccine with independently attenuating deletions. A phase II randomized, double-blind, placebo-controlled, dose-escalating trial evaluated the safety and immunogenicity of M01ZH09 to 1.7×1010 colony-forming units (CFU). 187 Healthy adults received vaccine or placebo in four cohorts. Serologic responses and IgA ELISPOT were measured. At all doses, the vaccine was well

C. E. Lyon; K. S. Sadigh; M. P. Carmolli; C. Harro; E. Sheldon; J. C. Lindow; C. J. Larsson; T. Martinez; A. Feller; C. H. Ventrone; D. A. Sack; B. DeNearing; A. Fingar; K. Pierce; E. A. Dill; H. I. Schwartz; E. E. Beardsworth; B. Kilonzo; J. P. May; W. Lam; A. Upton; R. Budhram; B. D. Kirkpatrick

2010-01-01

250

[Therapeutic effect of oral doxycycline on syphilis (author's transl].  

PubMed

Eighty-one patients with syphilis were treated with oral doxycycline. A course of the antibiotic treatment consisted of 200 mg of doxycycline daily in two divided doses for 28 days. The course was repeated three to four times a year with an interval of several months. Quantitative Venereal Disease Research Laboratory (VDRL), Wassermann reaction (WR), and Treponema pallidum hemagglutination assay (TPHA) tests were performed monthly to evaluate the therapeutic effect of doxycycline treatment. The response rate was 100% for primary, 91.7% for early, 63.0% for late, and 61.8% for congenital syphilis in adults. No notable side effects were encountered except for epigastric fullness in four patients, which did not require the treatment to be discontinued. No abnormalities were detected in the results of laboratory tests. PMID:7373850

Onoda, Y

1980-01-01

251

Vaginal Impact of the Oral Administration of Total Freeze-Dried Culture of LCR 35 in Healthy Women  

PubMed Central

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

Bohbot, J. M.; Cardot, J. M.

2012-01-01

252

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

PubMed Central

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

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

2014-01-01

253

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

254

Derivation of an oral reference dose (RfD) for the plasticizer, di-(2-propylheptyl)phthalate (Palatinol® 10-P).  

PubMed

Di-(2-propylheptyl) phthalate (DPHP) is a high molecular weight polyvinyl chloride plasticizer. Since increasing production volume and broad utility may result in human exposure, an oral reference dose (RfD) was derived from laboratory animal data due to the lack of human data. In addition to liver and kidney, target organs were the thyroid, pituitary and adrenal glands in rats, recognizing that reproductive performance was not altered in two successive generations of DPHP-exposed rats. DPHP caused a reduction in pup and maternal body weights but not developmental or testicular effects typical of "phthalate syndrome." DPHP was not genotoxic. Due to the lack of carcinogenicity data, there is inadequate information to assess carcinogenic potential. The RfD of 0.1mg/kg-day was derived from the human equivalent BMDL10 of 10mg/kg-day for thyroid hypertrophy/hyperplasia in male F1 adults from the two-generation study. While in utero exposure did not alter sensitivity to thyroid lesions compared to subchronic exposures beginning at 6weeks of age, F1 adult males were the longest-term exposed population. The total uncertainty factor of 100x was comprised of intraspecies (10x), study duration (3x), and database (3x) factors but not an interspecies factor since rodents are more sensitive than humans to thyroid gland effects. PMID:24925829

Bhat, Virunya S; Durham, Jennifer L; English, J Caroline

2014-10-01

255

Single-dose oral fluconazole versus topical clotrimazole in patients with pityriasis versicolor: A double-blind randomized controlled trial.  

PubMed

This study was designed to compare the therapeutic effects of topical clotrimazole and systemic fluconazole in pityriasis versicolor. A double-blind randomized controlled trial was carried out in the dermatological clinic of Gorgan, northern Iran, between April 2006 and May 2007. All consecutive patients with pityriasis versicolor were included and randomly divided into two groups. In the first group (G1), patients underwent treatment with a single dose of fluconazole capsule (400 mg) and placebo cream. In the second group (G2), patients underwent treatment with clotrimazole cream (twice daily) and placebo capsule. The course of treatment was 2 weeks. All subjects were re-evaluated 2, 4 and 12 weeks after the end of the therapeutic course. After 2 weeks, the rate of complete resolution of disease was significantly higher in G2 than G1 (49.1% vs 30%). After 4 weeks, 41 patients (81.2%) of G1 and 52 patients (94.9%) of G2 showed complete resolution. After 12 weeks, 46 patients (92%) in G1 and 45 patients (81.8%) in G2 showed complete resolution. Recurrence rate in G1 and G2 were 6% and 18.2%, respectively. No complications were seen in either group. In this study, clinical response at week 4 was greater in the clotrimazole group than the fluconazole group. Recurrence at week 12 after treatment was less with oral fluconazole than clotrimazole cream. So, for better evaluation, more studies need to be done. PMID:20649710

Dehghan, Mohammad; Akbari, Negin; Alborzi, Nazila; Sadani, Somayeh; Keshtkar, Abas A

2010-08-01

256

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

PubMed

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

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

2009-05-01

257

Oral Delivery of Highly Lipophilic Poorly Water-Soluble Drugs: Spray-Dried Dispersions to Improve Oral Absorption and Enable High-Dose Toxicology Studies of a P2Y1 Antagonist.  

PubMed

BMS-B is a highly lipophilic compound (clog P 7.72) with poor aqueous solubility (<10 ng/mL at pH 1 and 6.5). The compound exhibits low bioavailability in preclinical species when dosed as cosolvent solution formulations, with reduced exposure upon dose escalation. The purpose of this study was to evaluate spray-dried dispersions (SDDs) for enhancing oral exposure and enabling toxicology studies of BMS-B. SDD solids of BMS-B were prepared with 10%-25% drug in hydroxypropyl methylcellulose acetate succinate and showed an enhanced dissolution profile relative to the neat form of the compound. When dosed in rats and monkeys at 5 mg/kg, the SDD exhibited comparable exposure relative to the solution formulation. The SDD was also dosed in rats at 200 and 400 mg/kg and showed dose-proportional exposure compared to the solution formulation. Based on in vitro and in vivo data, the SDD formulation was selected for the toxicology study of BMS-B in rats. In summary, although the SDD approach could be quite challenging for highly lipophilic compounds because of the limitation on wetting and dissolution, the present study demonstrated that SDD can be applied in drug discovery to enhance oral exposure and enable preclinical toxicology studies of highly lipophilic poorly water-soluble compounds. © 2014 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 103:3924-3931, 2014. PMID:25308627

Chen, Xue-Qing; Stefanski, Kevin; Shen, Hong; Huang, Christine; Caporuscio, Christian; Yang, Wu; Lam, Patrick; Su, Ching; Gudmundsson, Olafur; Hageman, Michael

2014-12-01

258

The absorption and metabolism in rats of small oral doses of dimethylnitrosamine. Implication for the possible hazard of dimethylnitrosamine in human food.  

PubMed Central

1. Groups of rats were given one dose of the carcinogen dimethylnitrosamine by gastric intubation. The dose was varied between 10mg/kg body wt. and 1 microgram/kg body wt. 2. The dose was rapidly absorbed. 3. The methylation of liver DNA resulting from the administration of this carcinogen was proportional to dose. This suggests that small doses are absorbed from the gut with no more loss than large doses. 4. As the dose was decreased there was a disproportionately greater decrease in the alkylation of kidney DNA, and when the dose was less than 40 microgram/kg body wt. the methylation of kidney DNA was no longer detectable. This possibly explains why small amounts of dimethylnitrosamine in the diet do not induce kidney tumours. 5. Comparison of the relative alkylation of liver DNA and kidney DNA resulting from an oral and from an intravenous dose of dimethylnitrosamine suggest that small amounts of dimethylnitrosamine absorbed into the portal blood from the gut are completely metabolized by the liver and do not enter the general circulation. 6. The implications of these results for the possible hazard of dimethylnitrosamine in human food is discussed. PMID:883948

Gomez, M I; Swann, P F; Magee, P N

1977-01-01

259

Activity of the pituitary-ovarian axis in the pill-free interval during use of low-dose combined oral contraceptives  

Microsoft Academic Search

This study was performed to evaluate pituitary-ovarian recovery in the pill-free interval during use of three low-dose combined oral contraceptives (COC). Either the estrogen component or the progestin component was comparable in the study groups, to evaluate their relative influence. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), and estradiol (E2) levels were measured and follicle number and size estimated by

A. M van Heusden; B. C. J. M Fauser

1999-01-01

260

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

261

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

262

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. PMID:24911432

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

2014-01-01

263

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. PMID:24223391

Iraji, Fariba; Asilian, Ali; Saeidi, Ahmad; Siadat, Amir Hossein; Saeidi, Ali Reza; Hassanzadeh, Akbar

2013-01-01

264

Single-dose oral quercetin improves redox status but does not affect heat shock response in mice.  

PubMed

Inflammation and oxidative stress are considered as likely contributors to heat injury. However, their roles in regulating the heat shock response in vivo remain unclear. We tested the hypothesis that acute quercetin treatment would improve redox status and reduce heat shock responses in mice. Mice underwent two heat tests before and after single oral administration of either quercetin (15 mg/kg) or vehicle. We measured physiologic and biochemical responses in mice during and 18 to 22 hours after heat tests, respectively. There were no significant differences in core temperature, heart rate, or blood pressure between quercetin and vehicle groups during heat exposure. Mice with relatively severe hyperthermia during the pretreatment heat test showed a significant trend toward a lower peak core temperature during the heat test after quercetin treatment. Compared with mice not exposed to heat, quercetin-treated mice had significantly lower interleukin 6 (P < .01) and higher superoxide dismutase levels (P < .01), whereas vehicle-treated mice had significantly lower total glutathione and higher 8-isoprostane levels in the circulation after heat exposure. Heat exposure significantly elevated heat shock proteins (HSPs) 72 and 90 and heat shock factor 1 levels in mouse liver, heart, and skeletal muscles, but no significant differences in tissue HSPs and heat shock factor 1 were found between quercetin- and vehicle-treated mice. These results suggest that a single moderate dose of quercetin is sufficient to alter redox status but not heat stress response in mice. Acute adaptations of peripheral tissues to heat stress may not be mediated by systemic inflammatory and redox state in vivo. PMID:25150121

Chen, Yifan; Islam, Aminul; Abraham, Preetha; Deuster, Patricia

2014-07-01

265

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. PMID:20430063

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

2010-01-01

266

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

267

Opioid switch from low dose of oral oxycodone to transdermal fentanyl matrix patch for patients with stable thoracic malignancy-related pain  

PubMed Central

Background The effectiveness and safety of switch from oral oxycodone to fentanyl patch is little known. Here, we investigated if early phase opioid switch from low dose of oral oxycodone to transdermal fentanyl matrix patch provided any benefits for patients with thoracic malignancy and stable cancer-related pain. Methods This open-label two-centered prospective study enrolled patients with thoracic malignancy suffering persistent malignancy-related pain with numeric rating scale of pain intensity???3 which had been controlled by oral oxycodone???20 mg/day. Eligible patients switched from oral oxycodone to 12.5 ?g/h of transdermal fentanyl matrix patch. The dose was allowed to be titrated upwards every 3 day by 25-50%, except for the first increase from 12.5 ?g/hr to 25 ?g/hr,until achieving adequate pain control. The data on patients’ global assessment scores measured on a five-step scale, an 11-point numeric rating scale of pain intensity, the severity of adverse effects using a four-point categorical rating scale, and the Epworth sleepiness scale questionnaire were collected for 15 days. Results Forty-nine eligible patients were analyzed. Overall patients’ satisfaction score significantly improved from day 1 (2.7?±?0.9) to day 15 (2.3?±?0.9) (p?dose of fentanyl patch on day 8 and 15 from the opioid switch. There was a significant difference in sleepiness throughout the study period, though no difference was detected in pain intensity and other adverse effects. Conclusion Transdermal fentanyl matrix patch is an alternative analgesic option for a stable cancer pain in patients with thoracic malignancies.

2014-01-01

268

Influence of Exercise on the Metabolic Profile Caused by 28 days of Bed Rest with Energy Deficit and Amino Acid Supplementation in Healthy Men  

PubMed Central

Objective Muscle loss and metabolic changes occur with disuse [i.e. bed rest (BR)]. We hypothesized that BR would lead to a metabolically unhealthy profile defined by: increased circulating tumor necrosis factor (TNF)-?, decreased circulating insulin-like-growth-factor (IGF)-1, decreased HDL-cholesterol, and decreased muscle density (MD; measured by mid-thigh computerized tomography). Methods We investigated the metabolic profile after 28 days of BR with 8±6% energy deficit in male individuals (30-55 years) randomized to resistance exercise with amino acid supplementation (RT, n=24) or amino acid supplementation alone (EAA, n=7). Upper and lower body exercises were performed in the horizontal position. Blood samples were taken at baseline, after 28 days of BR and 14 days of recovery. Results We found a shift toward a metabolically unfavourable profile after BR [compared to baseline (BLN)] in both groups as shown by decreased HDL-cholesterol levels (EAA: BLN: 39±4 vs. BR: 32±2 mg/dL, RT: BLN: 39±1 vs. BR: 32±1 mg/dL; p<0.001) and Low MD (EAA: BLN: 27±4 vs. BR: 22±3 cm2, RT: BLN: 28±2 vs. BR: 23±2 cm2; p<0.001). A healthier metabolic profile was maintained with exercise, including NormalMD (EAA: BLN: 124±6 vs. BR: 110±5 cm2, RT: BLN: 132±3 vs. BR: 131±4 cm2; p<0.001, time-by-group); although, exercise did not completely alleviate the unfavourable metabolic changes seen with BR. Interestingly, both groups had increased plasma IGF-1 levels (EAA: BLN:168±22 vs. BR 213±20 ng/mL, RT: BLN:180±10 vs. BR: 219±13 ng/mL; p<0.001) and neither group showed TNF? changes (p>0.05). Conclusions We conclude that RT can be incorporated to potentially offset the metabolic complications of BR.

Brooks, Naomi E.; Cadena, Samuel M.; Cloutier, Gregory; Vega-Lopez, Sonia; Roubenoff, Ronenn; Castaneda-Sceppa, Carmen

2014-01-01

269

Safety, pharmacokinetics, and pharmacodynamics of CHF 3381, a novel N-methyl-D-aspartate antagonist, after single oral doses in healthy subjects.  

PubMed

A double-blind, randomized, placebo-controlled study was performed to assess the safety, tolerability, and pharmacokinetics of single oral doses of CHF 3381 in 56 young healthy male volunteers. The central nervous system effects of CHF 3381 were also evaluated, as well as the effect of food on the rate and extent of CHF 3381 absorption. Seven doses of CHF 3381 (25, 50, 100, 200, 300, 450, and 600 mg) were evaluated in an escalating order. At each dose level, 6 subjects were given CHF 3381, and 2 subjects were given placebo. Safety and tolerability evaluation included adverse events, physical examination, vital functions, electrocardiogram, laboratory tests, and 24-hour Holter (100-mg and 450-mg dose panels). Plasma and urinary concentrations of CHF 3381 and its two main metabolites (CHF 3567 and 2-aminoindane) were measured with a validated high-performance liquid chromatography method. Central nervous system effects were evaluated with the simple reaction time (SRT); learning memory task (LMT); Bond & Lader Visual Analog Scale for alertness, contentedness, and calmness; Addiction Research Center Inventory (ARCI); and electroencephalogram. There were no serious adverse events; the most frequent adverse events were dizziness, abnormal thinking, and asthenia. The number of adverse events with moderate intensity increased sharply with the dose, with no or few events up to 450 mg and 17 events with 600 mg. Therefore, 600 mg was defined as the maximum tolerated dose. There were no significant treatment effects on cardiovascular function and electrocardiogram parameters at any CHF 3381 dose or on oral temperature or laboratory tests. There were no clinically significant changes in laboratory variables. CHF 3381 was absorbed rapidly (tmax = 0.5-2 h) and cleared from plasma with a half-life of 3 to 4 hours. Plasma levels of CHF 3381 and its two major metabolites were found to be proportional to the dose. 2-Aminoindane formed slowly and reached much lower concentrations compared to the parent compound and the other metabolite (CHF 3567). Within 48 hours after dosing, 2% to 6% of the administered dose was found in the urine as unchanged drug, about 50% to 55% as the acid derivative (CHF 3567), and 2% to 3% as 2-aminoindane. Ingestion of food did not affect the extent of absorption of the drug, while the rate of absorption was considerably reduced (tmax = 4 h). No significant effects of CHF 3381 were observed on attention (SRT) or memory (LMT). Visual analog scales revealed a decreasing effect of CHF 3381 on alertness at 1 hour that reached statistical significance at 300 and 600 mg. EEG spectral analysis revealed minor decreasing effects of the 200-mg dose on total electric power measured at 2 hours. A stimulant effect was detected by the ARCI scale 24 hours after the 300-mg dose and might be related to the slow formation of the 2-aminoindane metabolite. In conclusion, this study has shown that the maximum tolerated dose of CHF 3381 after single oral administration in young healthy male volunteers is 600 mg. CHF 3381 displays linear pharmacokinetics in the dose range of 25 to 600 mg. The compound is rapidly absorbed and cleared from plasma with a half-life of 3 to 4 hours. The ingestion of food seems to not affect the extent of absorption of the drug. Minor effects on the central nervous system were detected at doses equal to or greater than 300 mg. PMID:12953347

Tarral, Antoine; Dostert, Philippe; Guillevic, Yann; Fabbri, Laura; Rondelli, Ivano; Mariotti, Fabrizia; Imbimbo, Bruno P

2003-08-01

270

[Evaluation by exercise test of effects of a single oral dose of atenolol in patients with stable angina (author's transl)].  

PubMed

Thirty patients with stable angina have been undergone a multistage treadmill test, after a single oral dose of 100 mg of Atenolol, a beta 1 . selective blocking agent, in comparison to a previous test carried out after an identical looking placebo tablet. After placebo all the patients showed ischemic ST segment response (ST depression greater than 1 mm), 25 of them interrupting the test because of anginal pain (20 patients), or of ST depression greater than 3 mm (3 patients), or of ventricular ectopics (one patient), or of fatigue (one patient). After Atenolol 10 patients completed the planned test, 7 of them without ischemic changes of ST. 27 patients (90%) showed increased working capacity with significant reduction of heart-rate (FC), systolic blood pressure (PAS) and their product and of ST depression, either before and during and at the end of exercise. The recovery time of ischemic ECG change has been significantly reduced. The observed increased working capacity is attributed to the reduced myocardial O2 consumption expressed from the reduction of the product FC x PAS. Nevertheless at the end of exercise test after beta-blocking drug this product didn't reach the threshold value at which the test was interrupted in the first test after placebo. The authors discuss the possible cause of this effect of beta-blocking drugs, which could be attributed to a reduction of coronary blood flow and/or to an increased myocardial tension because of increased end diastolic ventricular volume. However the Authors outline that the per cent increases of FC, PAS, and FC x PAS have not been reduced by the Atenolol, unlike their absolute values, at the threshold of angina: the ischemic reveals itself at same levels of per cent increase of the factors of O2 myocardial consumption, the later reaching of threshold values depending on the lower starting values. The advantages of Atenolol as regards the other beta-blocking drugs (better acceptability, stability and duration of action) are outlined too. PMID:7049818

de Divitiis, O; de Simone, G; Maddalena, G; Castaldo, M; Ruggiano, A

1981-01-01

271

Comparison of Azithromycin Pharmacokinetics following Single Oral Doses of Extended-Release and Immediate-Release Formulations in Children with Acute Otitis Media?  

PubMed Central

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 (AUC0-72) was calculated based on a noncompartmental method. One-way analysis of variance (ANOVA) was used to compare exposure parameters (e.g., AUC0-72 and peak concentration) as well as concentrations at each time point. The adjusted geometric mean ratio of the ER/IR AUC0-72 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.

2011-01-01

272

Effect of brivaracetam (400 mg/day) on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive in healthy women.  

PubMed

Brivaracetam is a high-affinity synaptic vesicle protein 2A ligand, in Phase III clinical development for epilepsy. This study assessed the effect of brivaracetam 400?mg/day on the pharmacokinetics and pharmacodynamics of a combination oral contraceptive (OC) containing 30?µg ethinylestradiol and 150?µg levonorgestrel, in healthy pre-menopausal women. This open-label, single-center, randomized, two-way crossover, multiple oral dose study (N01080) included two consecutive 28-day cycles without (control) or with brivaracetam (test), and a 28-day follow-up. OC was taken on Days 1–21 of every cycle and brivaracetam 200?mg twice daily was administered on Days 1–20 of the test cycle. Ethinylestradiol and levonorgestrel pharmacokinetics were determined on Day 20 and endogenous hormones were measured frequently during both control and test cycles. Overall, 23/24 participants (age: 19–39 years) completed the study. AUC ratio (90% confidence interval) for brivaracetam versus control was 0.73 (0.69, 0.78) for ethinylestradiol and 0.78 (0.72, 0.83) for levonorgestrel, outside pre-defined bioequivalence limits (0.80–1.25). Levels of endogenous hormones were similar and normal during brivaracetam and control cycles. Brivaracetam in combination with OC was well tolerated. Brivaracetam 400?mg/day co-administered with a combination OC in healthy women reduced ethinylestradiol and levonorgestrel plasma levels but did not result in ovulation. PMID:24386664

Stockis, Armel; Rolan, Paul

2013-12-01

273

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

PubMed Central

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

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

2012-01-01

274

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 spectrometry analytical method. Pharmacokinetic parameters were calculated using non-compartmental analysis and bioequivalence was assessed using a mixed effect ANOVA model. The ratio of the least-square means (FDC to individual products) and 90% confidence intervals (CIs) of AUC(0-t), AUC(0-infinity) and C(max) for lamivudine and stavudine were all within 80.00-125.00%, suggesting a similar rate and extent of ARVs exposure in the bloodstream. The FDC and individual products were equally safe and well tolerated. The current FDC of lamivudine and stavudine is expected to provide a similar efficacy/safety profile as co-administration of the individual products, a better adherence to treatment, and considerable cost savings in the treatment of HIV in children. PMID:19338141

Monif, Tausif; Reyar, Simrit; Tiwari, Hari Krishan; Tippabhotla, Sudhakar Koundinya; Khuroo, Arshad; Thudi, Nageshwar Rao; Ahmed, Sarfaraz; Raghuvanshi, Rajeev

2009-01-01

275

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

PubMed

Possible toxic effects of perfluorohexanoic acid (PFHxA) were evaluated when administered orally by gavage to rats at levels up to 200mg/kg/day for 90 days. Lower body weight gains were noted in the 10, 50 and 200mg/kg/day group males (not dose-responsive) throughout dosing. Other changes included lower red blood cell parameters, higher reticulocyte counts and lower globulin in the 200mg/kg/day group males and females, higher liver enzymes in males at 50 and 200mg/kg/day, lower total protein and higher albumin/globulin ratio, and lower cholesterol, calcium in males at 200mg/kg/day. Minimal centrilobular hepatocellular hypertrophy was present in 200mg/kg/day group males and correlated with higher liver weights and slightly higher peroxisome beta oxidation activity at the end of the dosing period. Based on liver histopathology and liver weight changes, the no-observed-adverse-effect level (NOAEL) for oral administration was 50mg/kg/day for males and 200mg/kg/day for females. PMID:19429405

Chengelis, Christopher P; Kirkpatrick, Jeannie B; Radovsky, Ann; Shinohara, Motoki

2009-06-01

276

Soluble receptor for advanced glycation end products in critically ill patients and its associations with other clinical markers and 28-day mortality  

PubMed Central

Purpose To investigate the possible associations between serum levels of soluble receptor for advanced glycation end products (sRAGE) and specific clinical markers and prognosis in critically ill patients diagnosed with stress hyperglycemia. Patients and methods A total of 70 critically ill patients and 25 normal controls were recruited for this study. Serum levels of sRAGE and advanced glycation end products (AGEs) were determined using enzyme-linked immunosorbent assay. Additional data on other clinical markers were obtained from patient records in the intensive care unit. Comparisons of sRAGE and AGEs levels between groups were assessed by t-test. The relationships between sRAGE and other clinical markers were assessed by Pearson’s correlation analyses and multiple linear regression analyses. Risk factors for prognosis, such as 28-day mortality were analyzed using logistic regression analysis. Results Serum sRAGE and AGEs levels were significantly higher in critically ill patients, compared to normal controls (P<0.05). The increase in serum sRAGE levels was significantly correlated with AGEs levels, interleukin-6 levels, and the sequential organ failure assessment score (P<0.01). Using multiple linear regression analysis, the association between AGEs and sRAGE remained significant after adjustment of other clinical factors. However, there were no significant correlations between sRAGE levels and patient outcome in these critically ill patients. Conclusion Serum sRAGE levels were significantly elevated in critically ill patients and positively correlated with higher AGEs levels, but sRAGE levels were not associated with increased mortality, suggesting sRAGE levels are not a predictor of prognosis in critically ill patients.

Cheng, Yanzi; Zhong, Jiwen; Xiang, Yang; Zeng, Fan; Cai, Dehong; Zhao, Ling

2014-01-01

277

Tacrolimus-based immunosuppression after liver transplantation: a randomised study comparing dual versus triple low-dose oral regimens  

Microsoft Academic Search

To evaluate the efficacy and safety of oral tacrolimus-based immunosuppressive induction therapy, 130 primary orthotopic\\u000a liver transplant (OLT) recipients were randomised to treatment in an open, parallel-group, European multicentre trial. Following\\u000a OLT, patients were immediately administered either tacrolimus (0.10 mg\\/kg) and prednisolone (dual therapy group) or tacrolimus\\u000a (0.06 mg\\/kg) in conjunction with prednisolone and azathioprine (triple therapy group) both orally.

Peter Neuhaus; Jan M. Langrehr; Roger Williams; Roy Y. Calne; Rudolf Pichlmayr; Paul McMaster

1997-01-01

278

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

PubMed

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

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

2014-08-01

279

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

PubMed Central

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

2014-01-01

280

Microvascular reactivity after ischemia/reperfusion in the hamster cheek pouch: beneficial effects of different oral doses of S-5682 (Daflon 500 mg).  

PubMed

Daflon 500 mg (S-5682) is a purified, micronized flavonoid fraction containing 90% diosmin and 10% hesperidin that is currently used to treat chronic venous insufficiency and hemorrhoidal disease. Thus, it seemed of interest to evaluate the effects of S-5682 on ischemia/reperfusion, ie, the changes in mean internal diameter and blood flow of arterioles and venules and the functional capillary density (FCD) during reperfusion after ninety minutes of total ischemia in the hamster cheek pouch microvasculature. Different doses of S-5682 (5, 20, 80, and 160 mg/kg body weight/day), suspended in 10% lactose solution or vehicle (10% lactose) were administered orally to male hamsters for ten days twice a day. The cheek pouch preparation was placed under an intravital microscope coupled to a closed-circuit TV system. A ninety-minute local ischemia was obtained by a cuff mounted around the neck of the everted pouch where it left the mouth of the hamster. Mean arteriolar and venular internal diameters were determined by means of an image-shearing device, IPM model 907; red blood cell (RBC) velocity was measured by the dual-slit photometric technique; microvessel volume flow was calculated from diameters and RBC velocities; and FCD was defined as the number of red-cell-perfused capillaries per observation field. During reperfusion, placebo-treated animals showed significant vasodilatation concomitant with a decrease in blood flow and FCD compared with preischemic values and an impairment of the myogenic response. In S-5682-treated animals, there was a significant dose-dependent improvement in all these parameters including the myogenic tonus. These results clearly demonstrated that oral administration of different doses of S-5682 for ten days improved the microvascular reactivity and FCD after ischemia/reperfusion in a dose-dependent fashion in the hamster cheek pouch microvasculature. PMID:8995341

Bouskela, E; Cyrino, F Z; Lerond, L

1997-01-01

281

In a high-dose melphalan setting, palifermin compared with placebo had no effect on oral mucositis or related patient's burden.  

PubMed

This randomized-controlled trial studied the efficacy of palifermin in a chemotherapy-only, high-dose Melphalan (HDM) transplant setting, to reduce oral mucositis (OM) and its sequelae measured by patient-reported outcomes (PRO) and medical resource use. Palifermin, relative to placebo was given either pre-/post-HDM or pre-HDM in patients with multiple myeloma (MM) undergoing auto-SCT at 39 European centers. Oral cavity assessment (WHO) and PRO questionnaires (oral mucositis daily questionnaire (OMDQ) and EQ 5D) were used in 281 patients (mean age 56, ± s.d.=8 years). 57 patients received placebo. One hundred and fifteen subjects were randomized to pre-/post-HDM receiving palifermin on 3 consecutive days before HDM and after auto-SCT and 109 patients were randomized to pre-HDM, receiving palifermin (60 ?g/kg/day) i.v. for 3 consecutive days before HDM. There was no statistically significant difference in maximum OM severity. Severe OM occurred in 37% (placebo), 38% (pre-/post-HDM) and 24% (pre-HDM) of patients. No significant difference was observed with respect to PRO assessments or medical resource use, but more infections and fever during neutropenia were reported in pre-/post-HDM vs placebo (for example, 51 and 26%). To conclude, palifermin was unable to reduce OM or OM-related patient's burden in MM transplant patients. PMID:23241739

Blijlevens, N; de Château, M; Krivan, G; Rabitsch, W; Szomor, A; Pytlik, R; Lissmats, A; Johnsen, H E; de Witte, T; Einsele, H; Ruutu, T; Niederwieser, D

2013-07-01

282

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

PubMed Central

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

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

2013-01-01

283

Short-term oral 3-hydroxypyridin-4-one dosing increases aluminum excretion and partially reverses aluminum-induced toxicity in the rabbit independent of chelator lipophilicity.  

PubMed

The objectives of the present study were to determine the efficacy and toxicity of repeated oral administration of 3-hydroxypyridin-4-one (HP) chelators in a rabbit model of aluminum (Al) accumulation and toxicity, and the influence of chelator lipophilicity on these effects. Efficacy was assessed as chelator-induced Al mobilization and excretion and reversal of Al accumulation and Al-induced toxicity. Chelator-induced toxicity was assessed by multiple measures. Six HPs were given orally 12 times over 1 month to Al-loaded rabbits, which had significant elevation of Al in most tissues and evidence of Al-induced nephrotoxicity, osteomalacia, and anemia. Intravenous desferrioxamine (DFO), the current chelator of choice for the treatment of Al-overload and toxicity, was included as a positive control. All six HPs and DFO demonstrated efficacy evidenced by significantly greater urinary and biliary Al elimination after the twelfth dose than seen in saline-treated controls. All of the HPs were more effective than DFO. Chelator-induced urinary Al excretion accounted for 58-98% of total (urinary plus biliary) Al excretion. Chelator-facilitated Al excretion was nearly complete within 12 hr, demonstrating a fairly short duration of action in rabbits with intact renal function. HP treatments did not consistently affect tissue concentrations of Al or other metals. However, there was a trend toward chelator-induced reduction of Al-induced nephrotoxicity. The influence of HP lipophilicity was limited to a positive correlation between HP x Al lipophilicity and biliary Al output and a negative correlation between HP and HP x Al lipophilicity and reduction of Kupffer cell Al. Little toxicity was evident after repeated oral HP dosing. Adrenal weight increased after treatment with several HPs. There was a decrease in testes weight after several HPs, which is consistent with an antiproliferative effect. More frequent dosing and/or a longer duration of HP treatment might produce greater reversal of the Al-induced toxicity and perhaps reveal more adverse effects than seen in this study. There was a lack of profound toxicity during this short-term study. The 1,2-dimethyl (CP20) and 1,2-diethyl (CP94) HPs, which have been the most extensively studied HPs, were the least effective of the HPs examined. These results encourage the further investigation of other HPs as oral alternatives to DFO for the treatment of Al accumulation and toxicity. PMID:9029049

Yokel, R A; Meurer, K A; Hong, C B; Dickey, K M; Skinner, T L; Fredenburg, A M

1997-02-01

284

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamic Properties of Taranabant, a Novel Selective Cannabinoid1 Receptor Inverse Agonist, for the Treatment of Obesity: Results From a Double-Blind, Placebo-Controlled, Single Oral Dose Study in Healthy Volunteers  

Microsoft Academic Search

Taranabant is a novel cannabinoid CB-1 receptor (CB1R) inverse agonist in clinical development for the treatment of obesity. This double-blind, randomized, placebo-controlled, single oral dose study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of taranabant (0.5-600 mg) in 24 healthy male volunteers. Single-dose AUC0-?and C max values for taranabant increased approximately linearly with dose up to 200 mg, with slightly

Carol Addy; Susie Li; Nancy Agrawal; Julie Stone; Anup Majumdar; Ling Zhong; Hankun Li; Jinyu Yuan; Andrea Maes; Paul Rothenberg; Josee Cote; Kim Rosko; Corinne Cummings; Steven Warrington; Malcolm Boyce; Keith Gottesdiener; Aubrey Stoch; John Wagner

2008-01-01

285

ORAL BISPHENOL A (BPA) GIVEN TO RATS AT MODERATE DOSES IS ASSOCIATED WITH ERECTILE DYSFUNCTION, CAVERNOSAL LIPOFIBROSIS, AND ALTERATIONS OF GLOBAL GENE TRANSCRIPTION  

PubMed Central

Introduction Bisphenol A (BPA), a suspected reproductive biohazard and endocrine disruptor released from plastics is associated with erectile dysfunction (ED) in occupationally exposed workers. However, in rats, despite the induction of hypogonadism, apoptosis of the penile corporal smooth muscle, fat infiltration into the cavernosal tissue, and changes in global gene expression with the intraperitoneal administration of high dose BPA, ED was not observed. Aims We investigated whether BPA administered orally rather than intraperitoneally to rats for longer periods and lower doses will lead to ED. Main Outcomes Measures ED, histological, and biochemical markers in rat penile tissues. Methods 2.5-month old rats were given drinking water daily without and with BPA at 1 and 0.1 mg/kg/day. Two months later, erectile function was determined by cavernosometry (DIC) and electrical field stimulation (EFS) and serum levels of testosterone (T), estradiol (E2), and BPA were measured. Penile tissue sections were assayed by Masson (smooth muscle (SM)/collagen), Oil Red O (fat), TUNEL (apoptosis), immunohistochemistry for Oct 4 (stem cells), and ?-SM actin/ calponin (SM and myofibroblasts), applying quantitative image analysis. Other markers were assayed by western blots. DNA microarrays/microRNA assays defined transcription profiles. Results Orally administered BPA did not affect body weight, but: 1) decreased serum T and E2; 2) reduced the EFS response and increased the DIC drop rate; 3) increased within the corporal tissue the presence of fat, myofibroblasts and apoptosis; 4) lowered the contents of SM and stem cells, but not nerve terminals; and 5) caused alterations of the transcriptional profiles for both mRNA and microRNAs within the penile shaft. Conclusions Long-term exposure of rats to oral BPA,caused a moderate corporal veno-occlusive dysfunction (CVOD), possibly due to alterations within the corporal tissue that pose gene transcriptional changes related to inflammation, fibrosis and epithelial/ mesenchymal transition (EMT). PMID:24305612

Kovanecz, I; Gelfand, R; Masouminia, M; Gharib, S; Segura, D; Vernet, D; Rajfer, J; Li, DK; Kannan, K; Gonzalez-Cadavid, NF

2013-01-01

286

Oral Bisphenol A (BPA) given to rats at moderate doses is associated with erectile dysfunction, cavernosal lipofibrosis and alterations of global gene transcription.  

PubMed

Bisphenol A (BPA), a suspected reproductive biohazard and endocrine disruptor, released from plastics is associated with ED in occupationally exposed workers. However, in rats, despite the induction of hypogonadism, apoptosis of the penile corporal smooth muscle (SM), fat infiltration into the cavernosal tissue and changes in global gene expression with the intraperitoneal administration of high dose BPA, ED was not observed. We investigated whether BPA administered orally rather than intraperitoneally to rats for longer periods and lower doses will lead to ED. Main outcome measures are ED, histological, and biochemical markers in rat penile tissues. In all, 2.5-month-old rats were given drinking water daily without and with BPA at 1 and 0.1 mg kg(-1) per day. Two months later, erectile function was determined by cavernosometry and electrical field stimulation (EFS) and serum levels of testosterone (T), estradiol (E2) and BPA were measured. Penile tissue sections were assayed by Masson (SM/collagen), Oil Red O (fat), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) (apoptosis), immunohistochemistry for Oct4 (stem cells), and ?-SM actin/calponin (SM and myofibroblasts), applying quantitative image analysis. Other markers were assayed by western blotting. DNA microarrays/microRNA (miR) assays defined transcription profiles. Orally administered BPA did not affect body weight, but (1) decreased serum T and E2; (2) reduced the EFS response and increased the drop rate; (3) increased within the corporal tissue the presence of fat, myofibroblasts and apoptosis; (4) lowered the contents of SM and stem cells, but not nerve terminals; and (5) caused alterations in the transcriptional profiles for both mRNA and miRs within the penile shaft. Long-term exposure of rats to oral BPA caused a moderate corporal veno-occlusive dysfunction (CVOD), possibly due to alterations within the corporal tissue that pose gene transcriptional changes related to inflammation, fibrosis and epithelial/mesenchymal transition (EMT). PMID:24305612

Kovanecz, I; Gelfand, R; Masouminia, M; Gharib, S; Segura, D; Vernet, D; Rajfer, J; Li, D K; Kannan, K; Gonzalez-Cadavid, N F

2014-01-01

287

In-vivo kinetics of ALA-induced fluorescence in the canine oral cavity: influence of drug dose and tissue type  

NASA Astrophysics Data System (ADS)

Fluorescence spectroscopic detection and photodynamic therapy may provide an effective approach for early detection and treatment of oral cancer. Thus the development of a safe photosensitizer that could enhance the spectroscopic contrast between normal and neoplastic tissue, while allowing for selective photosensitization and treatment of pre-malignant and malignant lesions in the oral cavity, is highly desired. In this study, the pharmacokinetics and a safety of 5-aminolevulinic acid (ALA) that could induce an endogenous precursor of protoporphyrin IX and heme in the biosynthetic pathway was investigated. Two doses of ALA:25 and 75 mg/kg were administered intravenously to 4 and 3 dogs, respectively. A 'wash-out' period of 1 week between administration of each does was allowed to ensure against PpIX build-up. Using an optical multichannel analyzer, the fluorescence from the oral cavity was recorded at 3 sites: buccal mucosa, gums, and the tongue, and also from a remote site, the skin. A fiber optic probe was used to deliver excitation and collect the emitted fluorescence. Results showed that the ALA-induced fluorescence reached a peak at 2-4 hours, and returned to baseline in 24-31 hours. The dogs were stable during the course of the study, minimal vomiting was noted. In conclusion, the study showed that higher doses result in a higher peak at a later time.It was observed that different tissues have different pharmacokinetic response, the tongue and the gums have the highest peak fluorescence values, followed by the buccal mucosa and skin.

Vaidyanathan, Vijay; Rastegar, Sohi; Fossum, Theresa W.; Flores, P.; van der Breggen, E. W. J.; Egger, N. G.; Jacques, Steven L.; Motamedi, Massoud

1997-06-01

288

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

PubMed

1,4-Dioxane is found in consumer products and is used as a solvent in manufacturing. Studies in rodents show liver tumors to be consistently reported after chronic oral exposure. However, there were differences in the reporting of non-neoplastic lesions in the livers of rats and mice. In order to clarify these differences, a reread of mouse liver slides from the 1978 NCI bioassay on 1,4-dioxane in drinking water was conducted. This reread clearly identified dose-related non-neoplastic changes in the liver; specifically, a dose-related increase in the hypertrophic response of hepatocytes, followed by necrosis, inflammation and hyperplastic hepatocellular foci. 1,4-Dioxane does not cause point mutations, DNA repair, or initiation. However, it appears to promote tumors and stimulate DNA synthesis. Using EPA Guidelines (2005), the weight of the evidence suggests that 1,4-dioxane causes liver tumors in rats and mice through cytotoxicity followed by regenerative hyperplasia. Specific key events in this mode of action are identified. A Reference Dose (RfD) of 0.05mg/kgday is proposed to protect against regenerative liver hyperplasia based on a benchmark dose (BMD) approach. Based on this RfD, a maximum contaminant level goal of 350?g/L is proposed using a default relative source contribution for water of 20%. PMID:24491968

Dourson, Michael; Reichard, John; Nance, Patricia; Burleigh-Flayer, Heather; Parker, Ann; Vincent, Melissa; McConnell, Ernest E

2014-04-01

289

Strong Relationship between Oral Dose and Tenofovir Hair Levels in a Randomized Trial: Hair as a Potential Adherence Measure for Pre-Exposure Prophylaxis (PrEP)  

PubMed Central

Background Pre-exposure prophylaxis (PrEP) trials using tenofovir-based regimens have demonstrated that high levels of adherence are required to evaluate efficacy; the incorporation of objective biomarkers of adherence in trial design has been essential to interpretation, given the inaccuracy of self-report. Antiretroviral measurements in scalp hair have been useful as a marker of long-term exposure in the HIV treatment setting, and hair samples are relatively easy and inexpensive to collect, transport, and store for analysis. To evaluate the relationship between dose and tenofovir concentrations in hair, we examined the dose proportionality of tenofovir in hair in healthy, HIV-uninfected adults. Methods A phase I, crossover pharmacokinetic study was performed in 24 HIV-negative adults receiving directly-observed oral tenofovir tablets administered 2, 4, and 7 doses/week for 6 weeks, with a ?3-week break between periods. Small samples of hair were collected after each six-week period and analyzed for tenofovir concentrations. Geometric-mean-ratios compared levels between each pair of dosing conditions. Intensive plasma pharmacokinetic studies were performed during the daily-dosing period to calculate areas-under-the-time-concentration curves (AUCs). Results Over 90% of doses were observed per protocol. Median tenofovir concentrations in hair increased monotonically with dose. A log-linear relationship was seen between dose and hair levels, with an estimated 76% (95% CI 60–93%) increase in hair level per 2-fold dose increase. Tenofovir plasma AUCs modestly predicted drug concentrations in hair. Conclusions This study found a strong linear relationship between frequency of dosing and tenofovir levels in scalp hair. The analysis of quantitative drug levels in hair has the potential to improve adherence measurement in the PrEP field and may be helpful in determining exposure thresholds for protection and explaining failures in PrEP trials. Hair measures for adherence monitoring may also facilitate adherence measurement in real-world settings and merit further investigation in upcoming PrEP implementation studies and programs. Trial Registration ClinicalTrials.gov +NCT00903084. PMID:24421901

Liu, Albert Y.; Yang, Qiyun; Huang, Yong; Bacchetti, Peter; Anderson, Peter L.; Jin, Chengshi; Goggin, Kathy; Stojanovski, Kristefer; Grant, Robert; Buchbinder, Susan P.; Greenblatt, Ruth M.; Gandhi, Monica

2014-01-01

290

The influence of oral contraceptives on athletic performance in female athletes.  

PubMed

It is now estimated that the prevalence of oral contraceptive use in athletic women matches that of women in the general population. The oral contraceptive pill (OCP) reduces cycle-length variability and provides a consistent 28-day cycle by controlling concentrations of endogenous sex hormones. The OCP is administered in three different forms that differ widely in chemical constitution and concomitant effects on the human body. As fluctuation in sex steroids are believed to be a possible causal factor in performance and exercise capacity, it is imperative to understand the effect of administering the various types of OCP on women. However, the research into oral contraceptives and exercise performance is not consistent. The type of OCP administered (monophasic, biphasic or triphasic), as well as the type and dose of estrogen and progestogen within, will have varying effects on exercise. To date, research in the area of oral contraceptives and exercise capacity is sparse and much has been plagued by poor research design, methodology and small sample size. It is clear from the research to date that more randomised clinical trials are urgently required to assess the array of OCP formulations currently available to women and their concomitant effect on health and exercise capacity. Therefore, the purpose of this article is to critically appraise the literature to date and to provide a current review of the physiological scientific knowledge base in relation to the OCP and exercise performance. In addition, methodological control, design and conduct will be considered with future areas of research highlighted. PMID:17595152

Burrows, Melonie; Peters, Charlotte E

2007-01-01

291

Alternative Methods for the Median Lethal Dose (LD50) Test: The Up-and-Down Procedure for Acute Oral Toxicity  

Microsoft Academic Search

The authors have developed an improved version of the up-and-down procedure (UDP) as one of the replacements for the traditional acute oral toxicity test formerly used by the Organisation for Economic Co-operation and Develop- ment member nations to characterize industrial chemicals, pesticides, and their mixtures. This method improves the performance of acute testing for applications that use the median lethal

Amy Rispin; David Farrar; Elizabeth Margosches; Kailash Gupta; Katherine Stitzel; Gregory Carr; Michael Greene; William Meyer; Deborah McCall

2002-01-01

292

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

PubMed

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

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

2014-02-26

293

Hypericin Levels in Human Serum and Interstitial Skin Blister Fluid after Oral Single-Dose and Steady-State Administration of Hypericum perforatum Extract (St. John’s Wort)  

Microsoft Academic Search

The photodynamically active plant pigment hypericin, a characteristic metabolite of Hypericum perforatum (St. John’s wort), is widely used as an antidepressant. When administered orally, phototoxic symptoms may limit the therapeutic use of hypericin-containing drugs. Here we describe the high-performance liquid chromatographic (HPLC) detection of hypericin and semiquantitative detection of pseudohypericin in human serum and skin blister fluid after oral single-dose

Christoph M. Schempp; Barbara Winghofer; Martin Langheinrich; Erwin Schöpf; Jan C. Simon

1999-01-01

294

B Cell-Deficient (mMT) Mice Have Alterations in the Cytokine Microenvironment of the Gut-Associated Lymphoid Tissue (GALT) and a Defect in the Low Dose Mechanism of Oral Tolerance1  

Microsoft Academic Search

Peripheral immune tolerance following i.v. administration of Ag has been shown to occur in the absence of B cells. Because different mechanisms have been identified for i.v. vs low dose oral tolerance and B cells are a predominant component of the gut-associated lymphoid tissue (GALT) they may play a role in tolerance induction following oral Ag. To examine the role

Patricia A. Gonnella; Hans Peter Waldner; Howard L. Weiner

295

Effect of two different doses of oral cholecalciferol supplementation on serum 25-hydroxy-vitamin D levels in healthy Indian postmenopausal women: A randomized controlled trial  

PubMed Central

Aim: To compare the effect of two different doses (500 and 1000 IU/day) of oral vitamin D3 (cholecalciferol) on serum 25-hydroxy vitamin D [25(OH)D] levels in apparently healthy postmenopausal Indian women. Materials and Methods: Serum 25(OH)D, calcium with albumin, phosphorus, and alkaline phosphatase were measured in 92 apparently healthy postmenopausal women. The subjects were randomly assigned to one of the three groups and received supplementation for 3 months each. Each group received 1000 mg calcium carbonate daily while groups B and C received 500 and 1000 IU of cholecalciferol in addition, respectively. The tests were repeated after 3 months. Results: At baseline, 83.7% subjects had vitamin D deficiency (?20 ng/mL). The difference in the percentage change in mean serum 25(OH)D levels from baseline in group A (–30.5 ± 5.3%), group B (+8.9 ± 19.7%), and in group C (+97.8 ± 53.3%) was statistically significant (P < 0.001) between the three groups. Serum 25(OH)D level >20 ng/mL was achieved in 4.7% (1/21), 16% (4/25), and 66.67% (12/18) subjects in groups A, B, and C, respectively. No significant change was found in serum calcium, phosphorus, and alkaline phosphatase levels at 3 months in either of the groups from baseline. Conclusions: Standard dose of cholecalciferol available in “calcium tablets” (250 IU per 500 mg calcium carbonate) is not adequate for achieving optimum serum 25(OH)D levels in Indian postmenopausal women. Higher dose of vitamin D supplementation with 1000 IU/day (500 IU per 500 mg calcium carbonate) daily is superior to the standard dose therapy. For achievement of optimum serum 25(OH)D levels (>30 ng/mL) in Indian postmenopausal women, still higher doses of vitamin D are likely to be required. PMID:24083171

Agarwal, Niti; Mithal, Ambrish; Dhingra, Vibha; Kaur, Parjeet; Godbole, Madan Mohan; Shukla, Manoj

2013-01-01

296

A comparison of the pharmacokinetic profile of an ascending-dose, extended-regimen combined oral contraceptive to those of other extended regimens.  

PubMed

Quartette (levonorgestrel [LNG]/ethinyl estradiol [EE] and EE) is an ascending-dose, extended-regimen combined oral contraceptive (COC) that consists of a constant dose of LNG 150 µg on days 1 to 84 with EE 20 µg on days 1 to 42, 25 µg on days 43 to 63, 30 µg on days 64 to 84, and 10 µg of EE monotherapy on days 85 to 91. A population pharmacokinetic (PK) model for EE was developed using nonlinear mixed-effects modeling to characterize the PK profile of EE administered in Quartette and other extended-regimen LNG/EE COCs. Model-predicted plasma concentration-time profiles demonstrated a stepwise increase in systemic exposure to EE during the first 84 days of the cycle following each EE dose change. Lower concentrations of EE were noted during the final 7-day period of EE 10 µg. Gradual increases in EE seen with Quartette may decrease the incidence of unscheduled bleeding frequently observed during early cycles of extended-regimen COCs. PMID:24647707

Darwish, Mona; Bond, Mary; Ricciotti, Nancy; Hsieh, Jennifer; Fiedler-Kelly, Jill; Grasela, Thaddeus

2014-11-01

297

A Phase I Study of Oral Paclitaxel with a Novel P-Glycoprotein Inhibitor, HM30181A, in Patients with Advanced Solid Cancer  

PubMed Central

Purpose The purpose of this study is to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, and recommended phase II dose of an oral drug composed of paclitaxel and HM30181A, which is an inhibitor of P-glycoprotein, in patients with advanced cancers. Materials and Methods Patients with advanced solid tumors received standard therapy were given the study drug at escalating doses, using a 3+3 design. The study drug was orally administered on days 1, 8, and 15, with a 28-day cycle of administration. The dose of paclitaxel was escalated from 60 to 420 mg/m2, and the dose of HM30181A was escalated from 30-210 mg/m2. Results A total of twenty-four patients were enrolled. Only one patient experienced a doselimiting toxicity—a grade 3 neutropenia that persisted for more than 2 weeks, at 240 mg/m2 of paclitaxel. MTD was not reached. The maximum plasma concentration was obtained at a dose level of 300 mg/m2 and the area under the curve of plasma concentration- time from 0 to the most recent plasma concentration measurement of paclitaxel was reached at a dose level of 420 mg/m2. The absorption of paclitaxel tends to be limited at doses that exceed 300 mg/m2. The effective plasma concentration of paclitaxel was achieved at a dose of 120 mg/m2. Responses of 23 patients were evaluated; 8 (34.8%) had stable disease and 15 (65.2%) had progressive disease. Conclusion The study drug appears to be well tolerated, and the effective plasma concentration of paclitaxel was achieved. The recommended phase II dose for oral paclitaxel is 300 mg/m2. PMID:25038758

Lee, Hyun Jung; Heo, Dae-Seog; Cho, Joo-Youn; Han, Sae-Won; Chang, Hye-Jung; Yi, Hyeon-Gyu; Kim, Tae-Eun; Lee, Se-Hoon; Oh, Do-Youn; Im, Seock-Ah; Jang, In-Jin; Bang, Yung-Jue

2014-01-01

298

Safety Evaluation of Multiple Strains of Lactobacillus plantarum and Pediococcus pentosaceus in Wistar Rats Based on the Ames Test and a 28-Day Feeding Study  

PubMed Central

Three lactic acid bacterial strains, Lactobacillus plantarum, HK006, and HK109, and Pediococcus pentosaceus PP31 exhibit probiotic potential as antiallergy agents, both in vitro and in vivo. However, the safety of these new strains requires evaluation when isolated from infant faeces or pickled cabbage. Multiple strains (HK006, HK109, and PP31) were subject to a bacterial reverse mutation assay and a short-term oral toxicity study. The powder product exhibited mutagenic potential in Salmonella Typhimurium strains TA98 and TA1535 (with or without metabolic activation). In the short-term oral toxicity study, rats received a normal dosage of 390?mg/kg/d (approximately 9 × 109?CFU/kg/d) or a high dosage of 1950?mg/kg/d (approximately 4.5 × 1010?CFU/kg/d) for 28?d. No adverse effects were observed regarding the general condition, behaviour, growth, feed and water consumption, haematology, clinical chemistry indices, organ weights, or histopathologic analysis of the rats. These studies have demonstrated that the consumption of multiple bacterial strains is not associated with any signs of mutagenicity of S. Typhimurium or toxicity in Wistar rats, even after consuming large quantities of bacteria. PMID:25379552

Leu, Sew-Fen; Huang, Quan-Rong; Chou, Lan-Chun; Huang, Chun-Chih

2014-01-01

299

Effects of short-term oral dosing of polychlorotrifluoroethylene (polyCTFE) on the rhesus monkey. (Reannouncement with new availability information). Final report, March 1989-March 1990  

SciTech Connect

Polychlorotrifluoroethylene (polyCTFE-primarily oligomers with 3-4 monomer units), a nonflammable hydraulic fluid for aircraft, was given daily for 15 days by oral gavage to four Rhesus monkeys at a concentration of 0.725 g kg-1. The administered dose was at a level that had caused toxicity in rats. Steady-state blood and liver concentrations reached were the same in both species. In monkeys, polyCTFE did not cause the electrolyte, serum protein, liver enzyme and anemic disturbances previously seen in rats. Liver sections taken at 15 days, analyzed for palmitoyl Co-A beta-oxidation rates or by electron microscopy, showed no significant indication of peroxisomal proliferation. An increased blood urea nitrogen (BUN) at 15 days was the only clinical pathological abnormality seen in both monkeys and rats. Previously unobserved effects were increased triglycerides and glycogen depletion. polyGTFE; aircraft hydraulic fluid; toxicity; peroxisome proliferation.

Jones, C.E.; Ballinger, M.B.; Seckel, C.; Vinegar, A.; Mattie, D.R.

1991-12-31

300

Randomized, Crossover and Single-Dose Bioquivalence Study of Two Oral Desogestrel Formulations (Film-Coated Tablets of 75 ?g) in Healthy Female Volunteers.  

PubMed

Despite the increase in the substitution of branded medicinal product with generic drugs, this is a controversial issue for some pharmacological groups (such as contraceptives).The aim of the present clinical trial was to assess the bioequivalence and tolerability of two oral formulations of desogestrel.Thirty-three healthy female volunteers participated in this randomized and two-way crossover study. During two separate experimental periods, with at least four weeks of washout period, women received a single oral dose of 75 ?g of desogestrel from each of the formulations (test formulation and reference formulation). Desogestrel bioavailability was determined by the measurement of 3-ketodesogestrel plasma concentration.Pharmacokinetic parameters were comparable and the 90% CI for the ratio of C(max) (96.14-114.53%) and AUC(0-t) (105.73-123.83%) values for the test and reference formulations fell within the established regulatory interval (80-125%). Both formulations were also comparable in terms of tolerability.From the results of this study it can be concluded that test formulation (desogestrel 75 ?g, Cyndea PHARMA S.L.) is bioequivalent to the reference formulation (Cerazet® 75 ?g, Organon Española S.A.). PMID:22896827

Pena, María Ángeles; Sanz, Emilio; Francisco, Silvia; Alonso, Ainhara; Abajo, Zurine; Felipe, Izaskun; Pascual, Jaume; Tost, Digna; Bailac, Sandra

2012-06-01

301

Subchronic oral toxicity study of decitabine in combination with tetrahydrouridine in CD-1 mice.  

PubMed

Decitabine (5-aza-2'-deoxycytidine; DAC) in combination with tetrahydrouridine (THU) is a potential oral therapy for sickle cell disease and ?-thalassemia. A study was conducted in mice to assess safety of this combination therapy using oral gavage of DAC and THU administered 1 hour prior to DAC on 2 consecutive days/week for up to 9 weeks followed by a 28-day recovery to support its clinical trials up to 9-week duration. Tetrahydrouridine, a competitive inhibitor of cytidine deaminase, was used in the combination to improve oral bioavailability of DAC. Doses were 167 mg/kg THU followed by 0, 0.2, 0.4, or 1.0 mg/kg DAC; THU vehicle followed by 1.0 mg/kg DAC; or vehicle alone. End points evaluated were clinical observations, body weights, food consumption, clinical pathology, gross/histopathology, bone marrow micronuclei, and toxicokinetics. There were no treatment-related effects noticed on body weight, food consumption, serum chemistry, or urinalysis parameters. Dose- and gender-dependent changes in plasma DAC levels were observed with a Cmax within 1 hour. At the 1 mg/kg dose tested, THU increased DAC plasma concentration (? 10-fold) as compared to DAC alone. Severe toxicity occurred in females receiving high-dose 1 mg/kg DAC + THU, requiring treatment discontinuation at week 5. Severity and incidence of microscopic findings increased in a dose-dependent fashion; findings included bone marrow hypocellularity (with corresponding hematologic changes and decreases in white blood cells, red blood cells, hemoglobin, hematocrit, reticulocytes, neutrophils, and lymphocytes), thymic/lymphoid depletion, intestinal epithelial apoptosis, and testicular degeneration. Bone marrow micronucleus analysis confirmed bone marrow cytotoxicity, suppression of erythropoiesis, and genotoxicity. Following the recovery period, a complete or trend toward resolution of these effects was observed. In conclusion, the combination therapy resulted in an increased sensitivity to DAC toxicity correlating with DAC plasma levels, and females are more sensitive compared to their male counterparts. PMID:24639139

Terse, Pramod; Engelke, Kory; Chan, Kenneth; Ling, Yonghua; Sharpnack, Douglas; Saunthararajah, Yogen; Covey, Joseph M

2014-01-01

302

Absorption and elimination of an oral dose of sup 3 H-deoxynivalenol in colostomized and intact chickens  

SciTech Connect

Deoxynivalenol (DON or 3, 7, 15-trihydroxy-12, 13-epoxy-trichothec-9-en-8-one) is a mycotoxin produced by Fusarium graminearum that can contaminate grain. Domestic fowl are particularly tolerant to DON ingestion. Prelusky et al. orally administered {sup 14}C-DON to chickens and observed high radioactivity in the liver and bile with over 90% of the original label accruing in the excreta before 48 h. DON cannot be detected in portal blood concurrent to its disappearance from the gastrointestinal tract. Presumably, DON was structurally modified upon absorption then hepatically retrieved and excreted in bile. In the present experimentation, {sup 3}H-DON was intubated into colostomized and intact hens. The objective was to measure the progressive changes in distribution of radioactivity along the gastrointestinal tract, among body tissues and between urine and feces.

Lun, A.K.; Moran, E.T. Jr.; Young, L.G.; McMillan, E.G. (Univ. of Guelph, Ontario (Canada))

1989-06-01

303

Repeated oral dosing of TAS-102 confers high trifluridine incorporation into DNA and sustained antitumor activity in mouse models.  

PubMed

TAS-102 is a novel oral nucleoside antitumor agent containing trifluridine (FTD) and tipiracil hydrochloride (TPI). The compound improves overall survival of colorectal cancer (CRC) patients who are insensitive to standard chemotherapies. FTD possesses direct antitumor activity since it inhibits thymidylate synthase (TS) and is itself incorporated into DNA. However, the precise mechanisms underlying the incorporation into DNA and the inhibition of TS remain unclear. We found that FTD-dependent inhibition of TS was similar to that elicited by fluorodeoxyuridine (FdUrd), another clinically used nucleoside analog. However, washout experiments revealed that FTD-dependent inhibition of TS declined rapidly, whereas FdUrd activity persisted. The incorporation of FTD into DNA was significantly higher than that of other antitumor nucleosides. Additionally, orally administered FTD had increased antitumor activity and was incorporated into DNA more effectively than continuously infused FTD. When TAS-102 was administered, FTD gradually accumulated in tumor cell DNA, in a TPI-independent manner, and significantly delayed tumor growth and prolonged survival, compared to treatment with 5-FU derivatives. TAS-102 reduced the Ki-67-positive cell fraction, and swollen nuclei were observed in treated tumor tissue. The amount of FTD incorporation in DNA and the antitumor activity of TAS-102 in xenograft models were positively and significantly correlated. These results suggest that TAS-102 exerts its antitumor activity predominantly due to its DNA incorporation, rather than as a result of TS inhibition. The persistence of FTD in the DNA of tumor cells treated with TAS-102 may underlie its ability to prolong survival in cancer patients. PMID:25230742

Tanaka, Nozomu; Sakamoto, Kazuki; Okabe, Hiroyuki; Fujioka, Akio; Yamamura, Keisuke; Nakagawa, Fumio; Nagase, Hideki; Yokogawa, Tatsushi; Oguchi, Kei; Ishida, Keiji; Osada, Akiko; Kazuno, Hiromi; Yamada, Yukari; Matsuo, Kenichi

2014-12-01

304

Impact of oral bisphenol A at reference doses on intestinal barrier function and sex differences after perinatal exposure in rats  

Microsoft Academic Search

Bisphenol A (BPA), a chemical estrogen widely used in the food-packaging industry and baby bottles, is recovered in human fluids (0.1-10 nM). Recent studies have reported that BPA is hormonally active at low doses, emphasizing the debate of a risk for human health. Estrogen receptors are expressed in the colon, and although the major route of BPA exposure is food,

V. Braniste; A. Jouault; E. Gaultier; A. Polizzi; C. Buisson-Brenac; M. Leveque; P. G. Martin; V. Theodorou; J. Fioramonti; E. Houdeau

2010-01-01

305

Single dose oral dexamethasone versus multi-dose prednisolone in the treatment of acute exacerbations of asthma in children who attend the emergency department: study protocol for a randomized controlled trial  

PubMed Central

Background Asthma is a major cause of pediatric morbidity and mortality. In acute exacerbations of asthma, corticosteroids reduce relapses, subsequent hospital admission and the need for ß2-agonist therapy. Prednisolone is relatively short-acting with a half-life of 12 to 36?hours, thereby requiring daily dosing. Prolonged treatment course, vomiting and a bitter taste may reduce patient compliance with prednisolone. Dexamethasone is a long-acting corticosteroid with a half-life of 36 to 72?hours. It is used frequently in children with croup and bacterial meningitis, and is well absorbed orally. The purpose of this trial is to examine whether a single dose of oral dexamethasone (0.3?mg/kg) is clinically non-inferior to prednisolone (1?mg/kg/day for three days) in the treatment of exacerbations of asthma in children who attend the Emergency Department. Methods/design This is a randomized, non-inferiority, open-label clinical trial. After informed consent with or without assent, patients will be randomized to either oral dexamethasone 0.3?mg/kg stat or prednisolone 1?mg/kg/day for three days. The primary outcome measure is the comparison between the Pediatric Respiratory Assessment Measure (PRAM) across both groups on Day 4. The PRAM score, a validated, responsive and reliable tool to determine asthma severity in children aged 2 to 16?years, will be performed by a clinician blinded to treatment allocation. Secondary outcomes include relapse, hospital admission and requirement for further steroid therapy. Data will be analyzed on an intention-to-treat and a per protocol basis. With a sample size of 232 subjects (105 in each group with an estimated 10% loss to follow-up), we will be able to reject the null hypothesis - that the population means of the experimental and control groups are equal with a probability (power) of 0.9. The Type I error probability associated with this test (of the null hypothesis) is 0.05. Discussion This clinical trial may provide evidence that a shorter steroid course using dexamethasone can be used in the treatment of acute pediatric asthma, thus eliminating the issue of compliance to treatment. Registration ISRCTN26944158 and EudraCT Number 2010-022001-18 PMID:22909281

2012-01-01

306

Efficacy and safety of rituximab plus low-dose oral fludarabine and cyclophosphamide as first-line treatment of elderly patients with indolent non-Hodgkin lymphomas.  

PubMed

Indolent non-Hodgkin lymphomas (iNHLs) are B-cell neoplasms for which no consensus is available about optimal first-line therapy. Chemoimmunotherapy with fludarabine, cyclophospamide and rituximab is very effective, but may give severe hematological and non-hematological toxicity at standard doses, especially in elderly patients. In this phase II study, 25 untreated elderly patients with iNHL received rituximab (375 mg/m(2)) plus low-dose oral fludarabine (25 mg/m(2) for 4 consecutive days) and cyclophosphamide (150 mg/m(2) for 4 consecutive days) for four monthly cycles. Twenty-three patients were responsive (92%) and 12 patients achieved a complete remission (48%). Twenty-one patients (84%) were alive, median follow-up was 30 months and median event-free survival (EFS) was not reached. Patients who we previously treated with chemotherapy alone had a shorter EFS (median 20 months). Compliance was good, with mild toxicity. This regimen is effective for elderly patients with iNHL. The addition of rituximab results in long EFS without affecting toxicity. PMID:23876098

Fabbri, Alberto; Cencini, Emanuele; Rigacci, Luigi; Bartalucci, Giulia; Puccini, Benedetta; Dottori, Roberto; Gozzetti, Alessandro; Bosi, Alberto; Bocchia, Monica

2014-04-01

307

Computational investigation of potential dosing schedules for a switch of medication from warfarin to rivaroxaban—an oral, direct Factor Xa inhibitor  

PubMed Central

The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy. The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin. Our simulations were based on the recommended anticoagulant dosing regimen for stroke prevention in patients with atrial fibrillation. The effects of the combination of discontinued warfarin plus rivaroxaban were simulated using an extended version of a previously validated blood coagulation computer model. A strong synergistic effect of the two distinct mechanisms of action was observed in the first 2–3 days after warfarin discontinuation; thereafter, the effect was close to additive. Nomograms for the introduction of rivaroxaban therapy after warfarin discontinuation were derived for Caucasian and Japanese patients using safety and efficacy criteria described previously, together with the coagulation model. The findings of our study provide a mechanistic pharmacologic rationale for dosing schedules during the therapy switch from warfarin to rivaroxaban and support the switching strategies as outlined in the Summary of Product Characteristics and Prescribing Information for rivaroxaban.

Burghaus, Rolf; Coboeken, Katrin; Gaub, Thomas; Niederalt, Christoph; Sensse, Anke; Siegmund, Hans-Ulrich; Weiss, Wolfgang; Mueck, Wolfgang; Tanigawa, Takahiko; Lippert, Jörg

2014-01-01

308

Herpes - oral  

MedlinePLUS

... HSV-2 is spread to the mouth during oral sex, causing oral herpes. Herpes viruses spread easily. You ... if someone has oral herpes. Do not have oral sex if you have oral herpes, especially if you ...

309

[Directions for use of corticosteroids and calcineurin inhibitors against generalized myasthenia gravis: therapeutic strategies that can lead to early improvements and veer away from high-dose oral corticosteroids].  

PubMed

The advent of effective immune treatment has meant that myasthenia gravis (MG) is most often not lethal. However, many MG patients still find it difficult to maintain daily activities due to chronic residual fatigability and long-term side effects of medication, since full remission without immune treatment is not common. Our analysis demonstrated that disease severity, dose of oral corticosteroids, and depressive state are the major independent factors negatively associated with self-reported QOL (MG-QOL15-J score). It is noteworthy that oral corticosteroid, the first-line agent for MG, is negatively associated with patients' QOL. When the analysis took into account MGFA postintervention status and dose of oral prednisolne (PSL), the MG-QOL15-J score of MM status patients taking ? 5 mg PSL per day is identically low (i.e., just as good QOL) as that seen in CSR and is a target of treatment. In order to veer away from high-dose oral corticosteroids and to achieve early MM or better status with PSL ? 5 mg/day, we advocate the early aggressive treatment strategy that can achieve early improvement by performing an aggressive therapy using combined treatment with plasmapheresis and high-dose intravenous methylprednisolone and then maintain an improved clinical status using low-dose oral corticosteroids and calcineurin inhibitors (cyclosporine microemulsion and tacrolimus). The early stages of MG are susceptible to treatment with calcineurin inhibitors. When using cyclosporine microemulsion for MG, blood concentrations 2 h after administration (C2) correlate with clinical improvement and immediately before administration (C0) with side effects (increased serum creatinine and/or hypertension). Monitoring of C2 and C0 levels is useful to estimate efficacy and safety of the drug. PMID:23196511

Utsugisawa, Kimiaki; Nagane, Yuriko; Suzuki, Shigeaki; Suzuki, Norihiro

2012-01-01

310

Effects of food and gender on the pharmacokinetics of ginkgolides A, B, C and bilobalide in rats after oral dosing with ginkgo terpene lactones extract.  

PubMed

The ginkgo terpene lactones (GTL), mainly including bilobalide (BB), ginkgolide A (GA), ginkgolide B (GB) and ginkgolide C (GC) possess different biological activities such as peripheral vasoregulation, platelet-activating factor (PAF) receptor antagonism, neuroprotective properties and prevention of membrane damage caused by free radicals. To investigate the effects of food and gender on the bioavailability of BB, GA, GB and GC after oral administration of GTL extract, a rapid UPLC-MS/MS method was developed and validated. A reversed phase C18 column (100mm×2.1mm, i.d., 1.7?m) and a mobile phase consisted of methanol and 1mM ammonium acetate (70/30, v/v) were employed. Compared with the fasted group, the t1/2 values for BB, GA, GB and GC in fed were all increased (p<0.05), AUC0-t and AUC0-? values of BB, GA, GB and GC were all significantly increased (p<0.05), but the Cmax values of BB, GA, GB and GC were significantly decreased (p<0.05). In comparison with the male group, all of the t1/2 values and AUC0-t values for BB, GA, GB and GC in female were higher (p<0.05), but no statistical difference in Tmax values for BB, GA, GB and GC between these two groups. Food and gender factor showed significant effects on the pharmacokinetics of BB, GA, GB, and GC. The results suggested that oral doses of GTL should be lowered for fasted and female subjects, compared with the fed and male subjects, respectively. PMID:25165009

Huang, Ping; Zhang, Liang; Chai, Chuan; Qian, Xiao-Cui; Li, Wen; Li, Jun-Song; Di, Liu-Qing; Cai, Bao-Chang

2014-11-01

311

Subacute toxicity and maximum tolerable dose of sertaconazole in repeated administration studies.  

PubMed

28-Day oral and dermal subacute toxicity studies of 7-chloro-3-[1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl) ethoxy-methyl] benzo [b] thiophene (sertaconazole, FI-7045, CAS 99592-32-2), were carried out. The oral studies included the evaluation of subacute toxicity in rat (dose levels of 50, 150 and 300 mg/kg) and maximum tolerable dose in repeated administration in ferrets (consecutive dose levels in accordance with a geometric progression of 50, 75, 112.5, 168 and 250 mg/kg), which were the animal species intended for chronic toxicity studies. The dermal studies included the evaluation of subacute toxicity in rats and rabbits (1 ml/kg of a 2% cream). The results, in general, have shown low toxic effects, which can be summarized as a slight non-significant hepatomegalia in the rat with increased gamma-GTP and alkaline phosphatase values and a high urinary pH value; no histopathological changes were observed. These effects are characteristic of azole derivatives and are therefore common to other antifungals with this chemical group. PMID:1627193

Romero, A; Villamayor, F; Grau, M T; Sacristán, A; Ortíz, J A

1992-05-01

312

Oral calcitonin  

PubMed Central

Calcitonin is a hormone secreted by the C-cells of the thyroid gland in response to elevations of the plasma calcium level. It reduces bone resorption by inhibiting mature active osteoclasts and increases renal calcium excretion. It is used in the management of postmenopausal osteoporosis, Paget’s disease of bone, and malignancy-associated hypercalcemia. Synthetic and recombinant calcitonin preparations are available; both have similar pharmacokinetic and pharmacodynamic profiles. As calcitonin is a peptide, the traditional method of administration has been parenteral or intranasal. This hinders its clinical use: adherence with therapy is notoriously low, and withdrawal from clinical trials has been problematic. An oral formulation would be more attractive, practical, and convenient to patients. In addition to its effect on active osteoclasts and renal tubules, calcitonin has an analgesic action, possibly mediated through ?-endorphins and the central modulation of pain perception. It also exerts a protective action on cartilage and may be useful in the management of osteoarthritis and possibly rheumatoid arthritis. Oral formulations of calcitonin have been developed using different techniques. The most studied involves drug-delivery carriers such as Eligen® 8-(N-2hydroxy-5-chloro-benzoyl)-amino-caprylic acid (5-CNAC) (Emisphere Technologies, Cedar Knolls, NJ). Several factors affect the bioavailability and efficacy of orally administered calcitonin, including amount of water used to take the tablet, time of day the tablet is taken, and proximity to intake of a meal. Preliminary results looked promising. Unfortunately, in two Phase III studies, oral calcitonin (0.8 mg with 200 mg 5-CNAC, once a day for postmenopausal osteoporosis and twice a day for osteoarthritis) failed to meet key end points, and in December 2011, Novartis Pharma AG announced that it would not pursue further clinical development of oral calcitonin for postmenopausal osteoporosis or osteoarthritis. A unique feature of calcitonin is that it is able to uncouple bone turnover, reducing bone resorption without affecting bone formation and therefore increasing bone mass and improving bone quality. This effect, however, may be dose-dependent, with higher doses inhibiting both resorption and formation. Because so many factors affect the pharmacokinetics and pharmacodynamics of calcitonin, especially orally administered calcitonin, much work remains to be done to explore the full pharmacologic spectrum and potential of calcitonin and determine the optimum dose and timing of administration, as well as water and food intake. PMID:23071417

Hamdy, Ronald C; Daley, Dane N

2012-01-01

313

A randomized placebo-controlled study on high-dose oral algal docosahexaenoic acid supplementation in children with cystic fibrosis.  

PubMed

Low plasma concentrations of docosahexaenoic acid (DHA) are reported in unsupplemented cystic fibrosis (CF) patients. Forty-one CF patients aged from 6 to 12 years were randomized to receive high-dose DHA (100 mg/kg/day in the first month and 1g per day thereafter through a 12-month supplementation) or placebo (germ oil). Primary outcome was percentage change in plasma AA:DHA ratio. Secondary outcomes were changes in the number of pulmonary exacerbations compared to previous year, lung function, BMI, skinfold thicknesses, and body composition assessed by DXA and in serum concentrations of C-reactive protein, cytokines and vitamin (?-tocopherol and retinol). Compared to the control group plasma AA:DHA ratio decreased in the intervention group after 6 months (median percentage changes: -73% in the intervention group vs. -10% in the control group, P=0.001). No differences were detected between groups for secondary outcomes. Despite a decrease of the AA/DHA ratio, DHA supplementation for one year did not induce any significant biochemical and clinical improvement in CF patients. PMID:23266209

Alicandro, G; Faelli, N; Gagliardini, R; Santini, B; Magazzù, G; Biffi, A; Risé, P; Galli, C; Tirelli, A S; Loi, S; Valmarana, L; Cirilli, N; Palmas, T; Vieni, G; Bianchi, M L; Agostoni, C; Colombo, C

2013-02-01

314

Effect of feeding rate on biochemical measures and fate of a single oral dose of PCB in Arctic char  

SciTech Connect

This study was done to determine the effects of reducing lipid stores and the resulting mobilization of associated contaminants. Individually tagged Arctic char (Saivelinus alpinus) were treated with single gavage doses of 6.1 ng/g {sup 14}C-3,3{prime}4,4{prime},5-pentachlorobiphenyl (PCB 126) in gelatin or vehicle (controls). Following treatment, the PCB was allowed 3 weeks to reach equilibrium distribution within the fish. After this 3 week period, treated and control groups of fish were fed one of three rations, (1.5%, 0.75% or 0.25% body wt/d). Fish were sampled at 0, 8, 24 and 48 weeks following the initiation of the different rations. PCB concentrations and lipid levels were measured in 5 tissues (muscle, liver, intestine, spleen and kidney). Biochemical response measured included hepatic EROD, retinoids and tocopherol. Growth was reduced in both treated and control groups fed the lowest ration. EROD activity was negatively correlated with growth and positively correlated with liver concentrations of PCB 126. Declines in mean lipid content were ration dependent. Changes in hepatic retinoids were related to both ration and treatment. The results indicate that a low ration resulted in greater utilization of stored lipids and higher tissue concentrations of contaminants compared to the other rations. These changes altered biochemical measures which are responsive to planar chlorinated aromatic hydrocarbons.

Delorme, P.D. [Univ. of Manitoba, Winnipeg, Manitoba (Canada). Dept. of Zoology; Brown, S.B.; Lockhart, W.L.; Metner, D.A.; Vandenbyllaardt, L. [Dept. of Fisheries and Oceans, Winnipeg, Manitoba (Canada)

1995-12-31

315

Effects of oral administration of different doses of purified micronized flavonoid fraction on microvascular reactivity after ischaemia/reperfusion in the hamster cheek pouch.  

PubMed

1. The effects of a purified micronized flavonoid fraction (S5682) on mean internal diameter and blood flow of arterioles and venules, as well as the functional capillary density (FCD) were evaluated in the hamster cheek pouch microvasculature before and after 90 min of total ischaemia. 2. Male hamsters were treated for ten days, twice a day, with oral doses of S5682 (5, 20, 80 and 160 mg kg-1 day-1) or placebo (10% lactose solution). The cheek pouch preparation was placed under an intravital microscope coupled to a closed circuit TV system. Local ischaemia was obtained by a cuff mounted around the neck of the everted pouch where it leaves the mouth of the hamster. 3. Measurements were performed before ischaemia, at the onset of reperfusion and 10, 20, 30, 45 and 60 min thereafter. Diameters were measured by means of an image shearing device. Red blood cell (RBC) velocity was analysed by use of the dual-slit photometric technique. Blood flow was calculated from diameters and RBC velocities. FCD, defined as the number of capillaries with flowing blood per field of observation, was also assessed. 4. During reperfusion, placebo-treated animals showed a significant vasodilatation, a decrease in blood flow and FCD and S5682-treated animals showed a clear trend, dose-dependent, towards maintaining these parameters closer to the value found before ischaemia. 5. In conclusion, our results indicate that S5682 improves the microvascular reactivity and FCD after ischaemia/reperfusion. These data suggest that S5682 could function as an antioxidant, which may explain its beneficial therapeutic effect in chronic venous insufficiency where oxidative stress is involved in the pathological mechanism. PMID:9422805

Bouskela, E; Cyrino, F Z; Lerond, L

1997-12-01

316

Effects of oral administration of different doses of purified micronized flavonoid fraction on microvascular reactivity after ischaemia/reperfusion in the hamster cheek pouch  

PubMed Central

The effects of a purified micronized flavonoid fraction (S5682) on mean internal diameter and blood flow of arterioles and venules, as well as the functional capillary density (FCD) were evaluated in the hamster cheek pouch microvasculature before and after 90?min of total ischaemia. Male hamsters were treated for ten days, twice a day, with oral doses of S5682 (5, 20, 80 and 160?mg?kg?1?day?1) or placebo (10% lactose solution). The cheek pouch preparation was placed under an intravital microscope coupled to a closed circuit TV system. Local ischaemia was obtained by a cuff mounted around the neck of the everted pouch where it leaves the mouth of the hamster. Measurements were performed before ischaemia, at the onset of reperfusion and 10, 20, 30, 45 and 60?min thereafter. Diameters were measured by means of an image shearing device. Red blood cell (RBC) velocity was analysed by use of the dual-slit photometric technique. Blood flow was calculated from diameters and RBC velocities. FCD, defined as the number of capillaries with flowing blood per field of observation, was also assessed. During reperfusion, placebo-treated animals showed a significant vasodilatation, a decrease in blood flow and FCD and S5682-treated animals showed a clear trend, dose-dependent, towards maintaining these parameters closer to the value found before ischaemia. In conclusion, our results indicate that S5682 improves the microvascular reactivity and FCD after ischaemia/reperfusion. These data suggest that S5682 could function as an antioxidant, which may explain its beneficial therapeutic effect in chronic venous insufficiency where oxidative stress is involved in the pathological mechanism. PMID:9422805

Bouskela, E; Cyrino, F Z G A; Lerond, L

1997-01-01

317

Effect of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban, an oral, direct Factor Xa inhibitor  

PubMed Central

Aim This study investigated the effects of hepatic impairment on the pharmacokinetics and pharmacodynamics of a single dose of rivaroxaban (10 mg), an oral, direct Factor Xa inhibitor. Method This single centre, non-randomized, non-blinded study included subjects with mild (n = 8) or moderate hepatic impairment (n = 8), according to the Child–Pugh classification, and gender-matched healthy subjects (n = 16). Results Rivaroxaban was well tolerated irrespective of hepatic function. Mild hepatic impairment did not significantly affect the pharmacokinetics or pharmacodynamics of rivaroxaban, compared with healthy subjects. However, in subjects with moderate hepatic impairment, total body clearance was decreased, leading to a significant increase in the area under the plasma concentration–time curve (AUC). The least-squares (LS)-mean values for AUC were 1.15-fold [90% confidence interval (CI) 0.85, 1.57] and 2.27-fold (90% CI 1.68, 3.07) higher in subjects with mild and moderate hepatic impairment, respectively, than in healthy subjects. Consequently, the pharmacodynamic responses were significantly enhanced in subjects with moderate hepatic impairment. For inhibition of Factor Xa, increases in the area under the effect–time curve and the maximum effect were observed, with LS-mean ratios of 2.59 and 1.24, respectively, vs. healthy subjects. Prolongation of prothrombin time was similar in healthy subjects and those with mild hepatic impairment, but was significantly enhanced in those with moderate hepatic impairment. Conclusion Moderate (but not mild) hepatic impairment reduced total body clearance of rivaroxaban after a single 10 mg dose, leading to increased rivaroxaban exposure and pharmacodynamic effects. PMID:23294275

Kubitza, Dagmar; Roth, Angelika; Becka, Michael; Alatrach, Abir; Halabi, Atef; Hinrichsen, Holger; Mueck, Wolfgang

2013-01-01

318

Albuterol extended-release products: effect of food on the pharmacokinetics of single oral doses of Volmax and Proventil Repetabs in healthy male volunteers.  

PubMed

The absorption of albuterol from a single 4-mg oral dose of Volmax and Proventil Repetabs was investigated under both fasting and fed conditions in an open-label, randomized, four-period, crossover study in 24 healthy male volunteers. Blood was collected for determination of albuterol plasma concentrations by HPLC over 30 hours postdose. Twenty subjects were evaluable for data analysis. The mean Cmax for Volmax; administered after a meal was 19% lower than that of the drug administered in a fasting state (3.9 ng/mL vs. 4.8 ng/mL; P less than .01). An almost equivalent lowering of the mean Cmax (by 21%) was observed for Proventil Repetabs after administration with a meal versus fasting (4.2 ng/mL vs. 5.3 ng/mL; P less than .01). There were no significant differences between the two formulations in the degree of Cmax reduction due to the presence of food. The tmax occurred significantly later during the fed treatment for Volmax only (4.9 hours fasted vs. 6.4 hours fed; P less than .01). The lag time was significantly greater during the fed treatments for Volmax. No differences were observed in the area under the plasma concentration-time curve (AUC) for either formulation under fasting versus fed conditions, suggesting that the extent of absortion was not altered by food. Overall, food caused a more sustained release of albuterol from both Volmax and Proventil Repetabs. PMID:1880222

Hussey, E K; Donn, K H; Powell, J R; Lahey, A P; Pakes, G E

1991-06-01

319

A randomised controlled trial to compare intravenous iron sucrose and oral iron in treatment of iron deficiency anemia in pregnancy.  

PubMed

The aim of this study was to compare the efficacy and safety of intravenous iron sucrose with oral iron therapy in pregnant patients with anemia. The primary outcome of the study was increase in haemoglobin on day 7, 14 & 28 and rise of serum ferritin over 28 days. The study population consisted of 100 patients with singleton pregnancy between 24 and 34 weeks, hemoglobin levels between 7.0-9.0 gm/dL and serum ferritin levels less than 15 ng/mL. The participants in the oral group were given daily 180 mg elemental iron in three divided oral doses for 4 weeks. Total calculated dose of iron sucrose with a target hemoglobin of 11 gm %, was given in 200 mg dose on alternate days. Mean haemoglobin rise was 0.58 gm/dL in the IV group as compared to 0.23 gm/dL in the oral group on day 14 and 1.9 gm/dL in the IV group & 1.3 gm/dL in the oral group on day 28, (p <0.05). In the IV group, 76% of the subjects achieved haemoglobin levels of ?11 gm% at the time of delivery, as compared to only 54% of the subjects in the oral group who achieved these levels. Serum ferritin value was significantly higher in the IV group, 37.45 ± 5.73 ng/mL as compared to 13.96 ± 1.88 ng/mL in the oral group at 4th week (p <0.001). There was no major side effect in the IV group. 36% subjects in the oral group developed gastrointestinal side effects & 10% of the subjects were non compliant. The rate of hemoglobin rise is faster with intravenous iron sucrose therapy as compared to oral iron therapy which can be beneficial in pregnant women presenting with anemia at a later period of gestation. Intravenous iron sucrose is very well tolerated during pregnancy. PMID:24839366

Gupta, Avantika; Manaktala, Usha; Rathore, Asmita Muthal

2014-06-01

320

Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study  

PubMed Central

Background NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK1) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-hydroxytryptamine type 3 (5-HT3) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program. Patients and methods This randomized, double-blind, parallel group study in 694 chemotherapy naïve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300 mg) + PALO 0.50 mg with oral PALO 0.50 mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1–4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0–120 h) phase. Results All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA100, NEPA200, and NEPA300, respectively versus 76.5% PALO; P < 0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0–24 h), delayed (25–120 h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable. Conclusions Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND. PMID:24608196

Hesketh, P. J.; Rossi, G.; Rizzi, G.; Palmas, M.; Alyasova, A.; Bondarenko, I.; Lisyanskaya, A.; Gralla, R. J.

2014-01-01

321

Neurodegeneration of mouse nigrostriatal dopaminergic system induced by repeated oral administration of rotenone is prevented by 4-phenylbutyrate, a chemical chaperone.  

PubMed

Parkinson's disease (PD) is a progressive neurodegenerative disorder that is primarily characterized by the degeneration of dopaminergic neurons in the nigrostriatal pathway. Previous studies have demonstrated that chronic systemic exposure of Lewis rats to rotenone produced many features of PD, and cerebral tauopathy was also detected in the case of severe weight loss. The present study was designed to assess the neurotoxicity of rotenone after daily oral administration for 28 days at several doses in C57BL/6 mice. In addition, we examined the protective effects of 4-phenylbutyrate (4-PBA) on nigral dopamine (DA) neurons in rotenone-treated mice. 4-PBA was injected intraperitoneally daily 30 min before each oral administration of rotenone. Chronic oral administration of rotenone at high doses induced specific nigrostriatal DA neurodegeneration, motor deficits and the up-regulation of alpha-synuclein in the surviving DA neurons. In contrast to the Lewis rat model, cerebral tauopathy was not detected in this mouse model. 4-PBA inhibited rotenone-induced neuronal death and decreased the protein level of alpha-synuclein. These results suggest that this rotenone mouse model may be useful for understanding the mechanism of DA neurodegeneration in PD, and that 4-PBA has a neuroprotective effect in the treatment of PD. PMID:17459145

Inden, Masatoshi; Kitamura, Yoshihisa; Takeuchi, Hiroki; Yanagida, Takashi; Takata, Kazuyuki; Kobayashi, Yuka; Taniguchi, Takashi; Yoshimoto, Kanji; Kaneko, Masahiko; Okuma, Yasunobu; Taira, Takahiro; Ariga, Hiroyoshi; Shimohama, Shun

2007-06-01

322

Acute and sub-acute oral toxicity assessment of the hydroalcoholic extract of Withania somnifera roots in Wistar rats.  

PubMed

Withania somnifera is a widely used medicinal plant for several disorders. Toxicity studies on Withania somnifera are not available. Acute and sub-acute oral toxicities of Withania somnifera root extract in Wistar rats were evaluated in the present study. In the acute toxicity study, WSR extract was administered to five rats at 2000 mg/kg, once orally and were observed for 14 days. No toxic signs/mortality were observed. In the sub-acute study, WSR extract was administered once daily for 28 days to rats at 500, 1000 and 2000 mg/kg, orally. No toxic signs/mortality were observed. There were no significant changes (P < 0.05) in the body weights, organ weights and haemato-biochemical parameters in any of the dose levels. No treatment related gross/histopathological lesions were observed. The present investigation demonstrated that the no observed adverse effect level was 2000 mg/kg body weight per day of hydroalcoholic extract of W. somnifera in rats and hence may be considered as non-toxic. PMID:22996349

Prabu, P C; Panchapakesan, S; Raj, C David

2013-08-01

323

Reversed phase-high performance liquid chromatographic method for simultaneous estimation of tolperisone hydrochloride and etodolac in a combined fixed dose oral formulations.  

PubMed

A reversed-phase liquid chromatographic (RP-HPLC) method was developed for the simultaneous determination of tolperisone hydrochloride (TOLP) and etodolac (ETD) in a combined fixed dose oral formulation. The analysis was carried out using a phenomenax C-18, pre-packed column. A mobile phase containing a phosphate buffer (pH 5.5) : Methanol : Acetonitrile : Tri-ethylamine (40 : 40 : 20 : 1.5), with the pH adjusted to orthophosphoric acid, was pumped at a flow rate of 1.0 ml min(1) with a UV-detector and PDA detection at 257 nm. Retention time was 3.91 minutes and 6.89 minutes for TOLP and ETD, respectively. The method was validated for linearity, accuracy, precision, sensitivity, and specificity. The method showed good linearity in the range of 3 - 21 ?g ml for TOLP ?g / ml and 8 - 56 ?g / ml for ETD. The detection limit of the proposed method was 0.16 ?g / ml and 0.58 ?g / ml for TOLP and ETD, respectively. The quantification limit of the proposed method was 0.51 ?g / ml and 1.7 ?g / ml for TOLP and ETD, respectively. The % recovery was within the range of 99.42 - 101.15 for TOLP and 98.63 - 100.94 for ETD. The percentage RSD for precision of the method was found to be less than 2%. The method was validated as per the International Conference on Harmonization (ICH) guidelines. The developed method could be applied for routine analysis of TOLP and ETD in tablet dosage form. PMID:23781442

Patel, Mit J; Badmanaban, R; Patel, C N

2011-04-01

324

Reversed phase-high performance liquid chromatographic method for simultaneous estimation of tolperisone hydrochloride and etodolac in a combined fixed dose oral formulations  

PubMed Central

A reversed-phase liquid chromatographic (RP-HPLC) method was developed for the simultaneous determination of tolperisone hydrochloride (TOLP) and etodolac (ETD) in a combined fixed dose oral formulation. The analysis was carried out using a phenomenax C-18, pre-packed column. A mobile phase containing a phosphate buffer (pH 5.5) : Methanol : Acetonitrile : Tri-ethylamine (40 : 40 : 20 : 1.5), with the pH adjusted to orthophosphoric acid, was pumped at a flow rate of 1.0 ml min1 with a UV-detector and PDA detection at 257 nm. Retention time was 3.91 minutes and 6.89 minutes for TOLP and ETD, respectively. The method was validated for linearity, accuracy, precision, sensitivity, and specificity. The method showed good linearity in the range of 3 – 21 ?g ml for TOLP ?g / ml and 8 – 56 ?g / ml for ETD. The detection limit of the proposed method was 0.16 ?g / ml and 0.58 ?g / ml for TOLP and ETD, respectively. The quantification limit of the proposed method was 0.51 ?g / ml and 1.7 ?g / ml for TOLP and ETD, respectively. The % recovery was within the range of 99.42 – 101.15 for TOLP and 98.63 – 100.94 for ETD. The percentage RSD for precision of the method was found to be less than 2%. The method was validated as per the International Conference on Harmonization (ICH) guidelines. The developed method could be applied for routine analysis of TOLP and ETD in tablet dosage form. PMID:23781442

Patel, Mit J.; Badmanaban, R.; Patel, C. N.

2011-01-01

325

The absorption, distribution, excretion, and metabolism of a single oral dose of O-ethyl O-4-nitrophenyl phenylphosphonothioate in hens  

SciTech Connect

The disposition and metabolism of a single oral 10 mg/kg (LD50) of uniformly phenyl-labeled (/sup 14/C)EPN (O-ethyl O-4-nitrophenyl (/sup 14/C)phenylphosphonothioate) were studied in adult hens. The birds were protected from acute toxicity with atropine sulfate. Three treated hens were killed at each time interval (days): 0.5, 2, 4, 8, 12. Radioactivity was adsorbed from the gastrointestinal tract and distributed in all tissues. Most of the dose was excreted in the combined urinary-fecal excreta (74%). Only traces of the radioactivity (0.2%) were detected in expired CO/sub 2/. Most of the excreted radioactive materials were identified as phenylphosphonic acid (PPA), O-ethyl phenylphosphonic acid (EPPA), and O-ethyl phenylphosphonothioc acid (EPPTA). Radioactivity in tissues reached a peak of 11.8% in 12 days. The highest concentration of radioactivity was present in the liver followed by bile, kidney, adipose tissue, and muscle. EPN was the major compound identified in brain, spinal cord, sciatic nerve, kidney, and plasma. Most of the radioactivity in the liver was identified as EPPA followed by EPPTA and PPA. Kinetic studies showed that EPN disappeared exponentially from tissues. The half-life of the elimination of EPN from plasma was 16.5 days corresponding to a constant rate value of 0.04 day-1. Relative residence (RR) of EPN relative to plasma was shortest in liver and longest in adipose tissue followed by sciatic nerve and spinal cord.

Abou-Donia, M.B.; Reichert, B.L.; Ashry, M.A.

1983-08-01

326

Derivation of an oral reference dose (RfD) for the nonphthalate alternative plasticizer 1,2-cyclohexane dicarboxylic acid, di-isononyl ester (DINCH).  

PubMed

1,2-Cyclohexanedicarboxylic acid, 1,2-diisononylester (DINCH), a polyvinyl chloride plasticizer, has food, beverage, and medical device applications that may result in general population exposure. Although no apparent toxicity information in humans was identified, there is a substantial data set in lab animals to serve as the basis of hazard identification for DINCH. Target tissues associated with repeated dietary DINCH exposure in lab animals included liver, kidney, and thyroid and mammary glands. In contrast to some phthalate ester plasticizers, DINCH did not show evidence of hepatic peroxisomal proliferation, testicular toxicity, or liver tumors in rats. Liver and thyroid effects associated with DINCH exposure were attributed to compensatory thyroid stimulation secondary to prolonged metabolic enzyme induction. The toxicological significance of mammary fibroadenomas in female rats is unclear, given that this common benign and spontaneously occurring tumor type is unique to rats. The weight of evidence suggests DINCH is not genotoxic and the proposed mode of action (MOA) for thyroid gland lesions was considered to have a threshold. No adverse reproductive effects were seen in a two-generation study. An oral reference dose (RfD) of 0.7 mg/kg-d was derived from a human equivalent BMDL?? of 21 mg/kg-d for thyroid hypertrophy/hyperplasia seen in adult F? rats also exposed in utero. The total uncertainty factor of 30x was comprised of intraspecies (10×) and database (3×) factors. An interspecies extrapolation factor was not applied since rodents are more sensitive than humans with respect to the proposed indirect MOA for thyroid gland lesions. PMID:24627975

Bhat, Virunya S; Durham, Jennifer L; Ball, Gwendolyn L; English, J Caroline

2014-01-01

327

Changes in androgen-mediated reproductive development in male rat offspring following exposure to a single oral dose of flutamide at different gestational ages.  

PubMed

Previous studies have indicated that the androgen receptor antagonist, flutamide, can produce a suite of reproductive malformations in the male rat when orally administered daily on gestation days (GD) 12-21. The objective of this study was to investigate the gestation time dependence for the induction of these malformations to establish a robust animal model for future studies of gene expression related to specific malformations. Groups of timed-pregnant Sprague-Dawley rats (GD 0 = day of mating) were administered flutamide as a single gavage dose (50 mg/kg) on GD 16, 17, 18, or 19 with 10 dams per group. Control animals (5 dams per time per group) were administered corn oil vehicle (2 ml/kg). Dams were allowed to litter, and their adult male offspring were killed at postnatal day (PND) 100 +/- 10. Anogenital distance was measured at PND 1 and 100. Areolae were scored at PND 13, and permanent nipples evaluated at PND 100. No reproductive tract malformations were found in control male offspring. In the treated groups, malformations were noted following exposure at every GD, although the incidence of specific malformations varied by GD. At GD 16, the highest incidence was noted for permanent nipples (46% pups, 60% litters), epispadias (12% pups, 30% litters), and missing epididymal components (5% pups, 20% litters). The highest incidences for hypospadias (58% pups, 80% litters), vaginal pouch (49% pups, 70% litters), cleft prepuce (29% pups, 60% litters), and missing prostate lobes (12% pups, 60% litters) were noted at GD 17. At GD 18 the highest incidence of malformations noted were epispadias (5% pups, 30% litters), reduced prostate size (32% pups, 90% litters), and abnormal kidneys (3% pups, 30% litters) and bladders (7% pups, 30% litters), while on GD 19 70% of the litters had animals with abnormal seminal vesicles. Testicular and epididymal morphological changes were noted at all GDs and were consistent with the gross observations and peaked in incidence and severity on GD17. The major discrepancy between this study and previous multiple-dose studies was in the very few numbers of animals presenting with cryptorchidism (only one each on GDs 16 and 17), suggesting that exposure over multiple days may be required to induce this malformation. Thus, a single gestational exposure of flutamide induced numerous reproductive tract malformations consistent with previously reports following multiple exposures, with the timing of the exposure producing marked tissue selectivity in the response noted in adult offspring. PMID:15788718

Foster, Paul M D; Harris, Martha W

2005-06-01

328

Effect of physiological doses of oral vitamin B12 on plasma homocysteine - A randomized, placebo-controlled, double-blind trial in India  

PubMed Central

Background: Vitamin B12 (B12) deficiency is common in Indians and a major contributor to hyperhomocysteinemia, which may influence fetal growth, risk of type 2 diabetes and cardiovascular disease. Objective: To study the effect of physiological doses of B12 and folic acid on plasma total homocysteine (tHcy). Design: A cluster randomized, placebo-controlled, double-blind, 2x3 factorial trial, using the family as the randomization unit. Vitamin B12 was given as 2 or 10 ?g capsules, with or without 200 ?g folic acid, forming six groups (B0F0, B2F0, B10F0, B0F200, B2F200, B10F200). Plasma tHcy was measured before and after 4 and 12 mo of supplementation. Results: Three hundred individuals from 119 families in the Pune Maternal Nutrition Study were randomised. There was no interaction between B12 and folic acid (P=0.14) in relation to tHcy change and their effects were analyzed separately: B0 vs. B2 vs. B10; and F0 vs. F200. At 12 mo, tHcy fell by a mean 5.9 (95% CI: ?7.8, ?4.1) ?mol/L in B2, and by 7.1 (95% CI: ?8.9, ?5.4) ?mol/L in B10, compared to non-significant rise of 1.2 (95% CI: ?0.5, 2.9) ?mol/L in B0. B2 and B10 did not differ significantly. In F200, tHcy fell by 4.8 (95% CI: ?6.3, ?3.3) ?mol/L compared to 2.8 (95% CI: ?4.3, ?1.2) ?mol/L in F0. Conclusion: Daily oral supplementation with physiological doses of B12 is an effective community intervention to reduce tHcy. Folic acid (200 ?g/d) showed no additional benefit, neither had any unfavourable effects. PMID:20216560

Deshmukh, Urmila S; Joglekar, Charudatta V; Lubree, Himangi G; Ramdas, Lalita V; Bhat, Dattatray S; Naik, Sadanand S; Hardikar, Pallavi S; Raut, Deepa A; Konde, Trupti B; Wills, Andrew K; Jackson, Alan A; Refsum, Helga; Nanivadekar, Arun S; Fall, Caroline H; Yajnik, Chittaranjan S

2010-01-01

329

Efficacy of two low-dose oral tylosin regimens in controlling the relapse of diarrhea in dogs with tylosin-responsive diarrhea: a prospective, single-blinded, two-arm parallel, clinical field trial  

PubMed Central

Background Despite its wide acceptance as a treatment for canine chronic enteropathies, the macrolide antibiotic tylosin lacks official oral dosage recommendations. Not even textbooks share consensus about the dose; daily recommendations vary from 25 to 80 mg/kg and dosing intervals from one to three times daily. The objective of this prospective, single-blinded, two-arm parallel, clinical field trial was to determine whether doses of 5 mg/kg or 15 mg/kg tylosin administered orally once daily for seven days would have a similar effect on fecal consistency in diarrhea relapses to that of a 25 mg/kg dose of tylosin administered once daily for seven days, a dosage that has proved effective in controlling canine tylosin-responsive diarrhea (TRD). A further objective was to compare the efficacy of the 5 mg/kg and 15 mg/kg tylosin dosages. Fifteen client-owned dogs diagnosed with TRD that had responded to a dose of 25 mg/kg tylosin once daily for seven days were enrolled in the study. After a relapse of diarrhea the dogs were allocated into two groups receiving tylosin orally in doses of either 5 mg/kg or 15 mg/kg once daily for seven days. The owners were blinded to the dosage. The elimination of diarrhea was the main criterion in assessing treatment success. The mean fecal consistency score of the last three treatment days for all dosages, including 25 mg/kg, as evaluated by the owners according to a standardized fecal scoring system, served as the primary outcome measures. Results All eight dogs responded to the 5 mg/kg dose, and six of seven dogs responded to the 15 mg/kg dose. The mean fecal consistency scores at the 25 mg/kg tylosin dosage were no significantly different from scores at the 5 mg/kg or 15 mg/kg tylosin dosages (P?=?0.672, P?=?0.345). Conclusions Interestingly, 14/15 (93%) of the dogs responding to a dose of 25 mg/kg tylosin once daily for seven days also responded to the lower dosages at diarrhea relapse. The data indicate that a suitable dose of tylosin for treating diarrhea relapse in canine TRD could be as low as 5 mg/kg once daily for seven days. PMID:25096196

2014-01-01

330

A phase I study of extended dosing with lomeguatrib with temozolomide in patients with advanced melanoma  

PubMed Central

Lomeguatrib, an O6-methylguanine-DNA methyltransferase inactivator, was evaluated in an extended dosing regimen with temozolomide, designed according to pharmacodynamic data from previous studies. Patients with unresectable stage 3 or 4 cutaneous or unknown primary melanoma metastases were treated with lomeguatrib 40?mg, b.i.d. for 10 or 14 days and temozolomide 75–100?mg?m?2 on days 1–5. Drugs were administered orally with cycles repeated every 28 days, for up to six cycles. A total of 32 patients were recruited to the study. Lomeguatrib for 10 days with temozolomide 75?mg?m?2 was established as the optimal extended lomeguatrib dosing schedule, with haematological toxicity being dose limiting. There were two partial responses to treatment giving an overall response rate of 6.25%. Extending lomeguatrib administration beyond that of temozolomide requires a reduced dose of the latter agent. Only limited clinical activity was seen, suggesting no advantage for this regimen over conventional temozolomide administration in the treatment of melanoma. PMID:19367282

Kefford, R F; Thomas, N P B; Corrie, P G; Palmer, C; Abdi, E; Kotasek, D; Beith, J; Ranson, M; Mortimer, P; Watson, A J; Margison, G P; Middleton, M R

2009-01-01

331

“Sequential” Boron Neutron Capture Therapy (BNCT): A Novel Approach to BNCT for the Treatment of Oral Cancer in the Hamster Cheek Pouch Model  

SciTech Connect

In the present study we evaluated the therapeutic effect and/or potential radiotoxicity of the novel “Tandem” Boron Neutron Capture Therapy (T-BNCT) for the treatment of oral cancer in the hamster cheek pouch model at RA-3 Nuclear Reactor. Two groups of animals were treated with “Tandem BNCT”, i.e. BNCT mediated by boronophenylalanine (BPA) followed by BNCT mediated by sodium decahydrodecaborate (GB-10) either 24 h (T-24h-BNCT) or 48 h (T-48h-BNCT) later. A total tumor dose-matched single application of BNCT mediated by BPA and GB-10 administered jointly [(BPA + GB-10)-BNCT] was administered to an additional group of animals. At 28 days post-treatment, T-24h-BNCT and T-48h-BNCT induced, respectively, overall tumor control (OTC) of 95% and 91%, with no statistically significant differences between protocols. Tumor response for the single application of (BPA + GB-10)-BNCT was 75%, significantly lower than for T-BNCT. The T-BNCT protocols and (BPA + GB-10)-BNCT induced reversible mucositis in dose-limiting precancerous tissue around treated tumors, reaching Grade 3/4 mucositis in 47% and 60% of the animals respectively. No normal tissue radiotoxicity was associated to tumor control for any of the protocols. “Tandem” BNCT enhances tumor control in oral cancer and reduces or, at worst, does not increase, mucositis in dose-limiting precancerous tissue.

Ana J. Molinari; Emiliano C. C. Pozzi; Andrea Monti Hughes; Elisa M. Heber; Marcela A. Garabalino; Silvia I. Thorp; Marcelo Miller; Maria E. Itoiz; Romina F. Aromando; David W. Nigg; Jorge Quintana; Gustavo A. Santa Cruz; Veronica A. Trivillin; Amanda E. Schwint

2011-04-01

332

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

333

Effects of Corynebacterium parvum and BCG therapy on immune parameters in patients with disseminated melanoma a sequential study over 28 days. I. Changes in blood counts, serum immunoglobulins and lymphoid cell populations.  

PubMed Central

The effects of a single immunization of melanoma patients with BCG or C. parvum on the blood counts, serum immunoglobulin levels and lymphoid subpopulations were followed by multiple assays over 28 days. C. parvum produced a decrease in the white cell count, lymphocyte count and lymphoid T and sIg+ cell numbers, which recovered within 1 week; BCG did not produce such a marked depression. Both agents were associated with increases in T cell numbers and lymphocyte PHA blastogenesis after the first week; these declined to pre-immunization values by 3-4 weeks. The sIg-bearing cell subpopulation also increased after BCG. Different methods of expression the results were compared and the difficulties of immunological monitoring are discussed. PMID:428146

Thatcher, N; Swindell, R; Crowther, D

1979-01-01

334

Efficiency and effectiveness of the use of an acenocoumarol pharmacogenetic dosing algorithm versus usual care in patients with venous thromboembolic disease initiating oral anticoagulation: study protocol for a randomized controlled trial  

PubMed Central

Background Hemorrhagic events are frequent in patients on treatment with antivitamin-K oral anticoagulants due to their narrow therapeutic margin. Studies performed with acenocoumarol have shown the relationship between demographic, clinical and genotypic variants and the response to these drugs. Once the influence of these genetic and clinical factors on the dose of acenocoumarol needed to maintain a stable international normalized ratio (INR) has been demonstrated, new strategies need to be developed to predict the appropriate doses of this drug. Several pharmacogenetic algorithms have been developed for warfarin, but only three have been developed for acenocoumarol. After the development of a pharmacogenetic algorithm, the obvious next step is to demonstrate its effectiveness and utility by means of a randomized controlled trial. The aim of this study is to evaluate the effectiveness and efficiency of an acenocoumarol dosing algorithm developed by our group which includes demographic, clinical and pharmacogenetic variables (VKORC1, CYP2C9, CYP4F2 and ApoE) in patients with venous thromboembolism (VTE). Methods and design This is a multicenter, single blind, randomized controlled clinical trial. The protocol has been approved by La Paz University Hospital Research Ethics Committee and by the Spanish Drug Agency. Two hundred and forty patients with VTE in which oral anticoagulant therapy is indicated will be included. Randomization (case/control 1:1) will be stratified by center. Acenocoumarol dose in the control group will be scheduled and adjusted following common clinical practice; in the experimental arm dosing will be following an individualized algorithm developed and validated by our group. Patients will be followed for three months. The main endpoints are: 1) Percentage of patients with INR within the therapeutic range on day seven after initiation of oral anticoagulant therapy; 2) Time from the start of oral anticoagulant treatment to achievement of a stable INR within the therapeutic range; 3) Number of INR determinations within the therapeutic range in the first six weeks of treatment. Discussion To date, there are no clinical trials comparing pharmacogenetic acenocoumarol dosing algorithm versus routine clinical practice in VTE. Implementation of this pharmacogenetic algorithm in the clinical practice routine could reduce side effects and improve patient safety. Trial registration Eudra CT. Identifier: 2009-016643-18. PMID:23237631

2012-01-01

335

Dose-escalation study of rivaroxaban (BAY 59-7939) – an oral, direct Factor Xa inhibitor – for the prevention of venous thromboembolism in patients undergoing total hip replacement  

Microsoft Academic Search

IntroductionRivaroxaban (BAY 59-7939) is a novel, oral, direct Factor Xa inhibitor in clinical development for the prevention of thromboembolic disorders. The aim of this study was to demonstrate proof-of-principle for rivaroxaban.

Bengt I. Eriksson; Lars C. Borris; Ola E. Dahl; Sylvia Haas; Menno V. Huisman; Ajay K. Kakkar; Frank Misselwitz; Eva Muehlhofer; Peter Kälebo

2007-01-01

336

Oral Medication  

MedlinePLUS

... Size: A A A Listen En Español Oral Medication The first treatment for type 2 diabetes blood ... new — even over-the-counter items. Explore: Oral Medication How Much Do Oral Medications Cost? Save money ...

337

Isolation of orally attenuated Salmonella typhimurium following TnphoA mutagenesis.  

PubMed Central

One hundred fifty Tn5 IS50L::phoA (TnphoA) mutants of a mouse-virulent, nalidixic acid-resistant (Nalr), prototrophic Salmonella typhimurium strain, C5 Nalr, were isolated. None of the mutants were auxotrophs. Groups of 8 to 10 BALB/c mice were infected orally with each of 95 mutants with a dose equivalent to 20-fold the 50% lethal dose of the wild-type C5 Nalr strain, and deaths were counted over the next 28 days. Fifteen of the mutants failed to kill any mice, whereas all mice died following challenge with the other mutants. Nine of the 15 attenuated mutants exhibited a defect in lipopolysaccharide biosynthesis. The remaining six mutants were smooth. The TnphoA transposon of each of the smooth attenuated mutants was moved, using P22-mediated transduction, into a fresh C5 background, and all retransductants were still attenuated. Analysis of the membrane proteins of the attenuated mutants failed to reveal any alterations in detectable major outer membrane proteins, although colonies of two of the mutants exhibited a mucoid phenotype following growth on L-agar plates. Individual attenuated mutants differed in their abilities to translocate to livers and spleens of mice following oral infection. All of the smooth TnphoA mutants exhibited increased 50% lethal doses with respect to the wild type following intravenous infection of BALB/c mice. Southern analysis of DNA prepared from each of the mutants suggested that TnphoA had inserted into a number of different sites in the S. typhimurium genome. None of the TnphoA mutants had inserts in the virulence-associated plasmid. Images PMID:2668186

Miller, I; Maskell, D; Hormaeche, C; Johnson, K; Pickard, D; Dougan, G

1989-01-01

338

Sub-chronic toxicity study in rats orally exposed to nanostructured silica  

PubMed Central

Background Synthetic Amorphous Silica (SAS) is commonly used in food and drugs. Recently, a consumer intake of silica from food was estimated at 9.4 mg/kg bw/day, of which 1.8 mg/kg bw/day was estimated to be in the nano-size range. Food products containing SAS have been shown to contain silica in the nanometer size range (i.e. 5 – 200 nm) up to 43% of the total silica content. Concerns have been raised about the possible adverse effects of chronic exposure to nanostructured silica. Methods Rats were orally exposed to 100, 1000 or 2500 mg/kg bw/day of SAS, or to 100, 500 or 1000 mg/kg bw/day of NM-202 (a representative nanostructured silica for OECD testing) for 28 days, or to the highest dose of SAS or NM-202 for 84 days. Results SAS and NM-202 were extensively characterized as pristine materials, but also in the feed matrix and gut content of the animals, and after in vitro digestion. The latter indicated that the intestinal content of the mid/high-dose groups had stronger gel-like properties than the low-dose groups, implying low gelation and high bioaccessibility of silica in the human intestine at realistic consumer exposure levels. Exposure to SAS or NM-202 did not result in clearly elevated tissue silica levels after 28-days of exposure. However, after 84-days of exposure to SAS, but not to NM-202, silica accumulated in the spleen. Biochemical and immunological markers in blood and isolated cells did not indicate toxicity, but histopathological analysis, showed an increased incidence of liver fibrosis after 84-days of exposure, which only reached significance in the NM-202 treated animals. This observation was accompanied by a moderate, but significant increase in the expression of fibrosis-related genes in liver samples. Conclusions Although only few adverse effects were observed, additional studies are warranted to further evaluate the biological relevance of observed fibrosis in liver and possible accumulation of silica in the spleen in the NM-202 and SAS exposed animals respectively. In these studies, dose-effect relations should be studied at lower dosages, more representative of the current exposure of consumers, since only the highest dosages were used for the present 84-day exposure study. PMID:24507464

2014-01-01

339

Stability of cilazapril in pediatric oral suspensions prepared from commercially available tablet dosage forms.  

PubMed

Abstract: Cilazapril is a drug commonly used in management of heart failure in pediatric population. On pharmaceutical market it is available only in inconvenient for pediatric use tablet dosage forms. Until now, no oral liquid formulation containing cilazapril has been evaluated. Therefore, the aim of this study was to prepare easy to made and palatable 1 mg/mL oral liquid formulation with cilazapril (with consideration of original and generic cilazapril tablet and different packages) and subsequent investigation of physicochemical stability of these suspensions. Formulations were compounded using cilazapril obtained from original or generic cilazapril marketed tablet formulations and Ora-Blend" suspending agent. Stability of prepared suspensions stored in closed amber glass or amber plastic PET bottles in the temperature of 298 K was estimated throughout 28 day shelf-life period. Chemical stability was assessed by HPLC cilazapril stability indicating method. Physical stability was evaluated by appearance, taste, smell, pH and theological assessments. Cilazapril oral suspensions at concentration of 1 mg/mL demonstrated satisfactory stability over 28 day long storage at room temperature. Cilazapril concentrations remained within acceptable limit (+/- 10%) stored in closed amber bottles made of glass or PET material. Moreover, suspensions physical properties remained unaffected. Cilazapril - Ora-Blend* pediatric oral liquid is easy to made, palatable and stable when stored at room temperature for 28 days. Stability of cilazapril oral liquid remains unchanged while using cilazapril tablets produced by different manufacturers and bottles made of amber glass or PET material. PMID:25272892

Stanisz, Beata J; Paszun, Sylwia K; Zalewska, Anna

2014-01-01

340

Efficacy and safety of maribavir dosed at 100 mg orally twice daily for the prevention of cytomegalovirus disease in liver transplant recipients: a randomized, double-blind, multicenter controlled trial.  

PubMed

Maribavir is an oral benzimidazole riboside with potent in vitro activity against cytomegalovirus (CMV), including some CMV strains resistant to ganciclovir. In a randomized, double-blind, multicenter trial, the efficacy and safety of prophylactic oral maribavir (100 mg twice daily) for prevention of CMV disease were compared with oral ganciclovir (1000 mg three times daily) in 303 CMV-seronegative liver transplant recipients with CMV-seropositive donors (147 maribavir; 156 ganciclovir). Patients received study drug for up to 14 weeks and were monitored for CMV infection by blood surveillance tests and also for the development of CMV disease. The primary endpoint was Endpoint Committee (EC)-confirmed CMV disease within 6 months of transplantation. In a modified intent-to-treat analysis, the noninferiority of maribavir compared to oral ganciclovir for prevention of CMV disease was not established (12% with maribavir vs. 8% with ganciclovir: event rate difference of 0.041; 95% CI: -0.038, 0.119). Furthermore, significantly fewer ganciclovir patients had EC-confirmed CMV disease or CMV infection by pp65 antigenemia or CMV DNA PCR compared to maribavir patients at both 100 days (20% vs. 60%; p < 0.0001) and at 6 months (53% vs. 72%; p = 0.0053) after transplantation. Graft rejection, patient survival, and non-CMV infections were similar for maribavir and ganciclovir patients. Maribavir was well-tolerated and associated with fewer hematological adverse events than oral ganciclovir. At a dose of 100 mg twice daily, maribavir is safe but not adequate for prevention of CMV disease in liver transplant recipients at high risk for CMV disease. PMID:22947426

Winston, D J; Saliba, F; Blumberg, E; Abouljoud, M; Garcia-Diaz, J B; Goss, J A; Clough, L; Avery, R; Limaye, A P; Ericzon, B G; Navasa, M; Troisi, R I; Chen, H; Villano, S A; Uknis, M E

2012-11-01

341

Different Acute Tolerance Development to EEG, Psychomotor Performance and Subjective Assessment Effects after Two Intermittent Oral Doses of Alprazolam in Healthy Volunteers  

Microsoft Academic Search

Background\\/Aims: Benzodiazepines (BZDs) are the most effective of the psychotropic drugs in the treatment of anxiety disorders. Tolerance has been reported for the majority of BZDs after chronic administration. However, little attention has been paid to the possibility that tolerance might be present after the intermittent oral administration of BZDs. The objectives of the present study were to assess tolerance

M. J. Barbanoj; G. Urbano; R. Antonijoan; M. R. Ballester; M. Valle

2007-01-01

342

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

E-print Network

excluded. They were trained with two iterations of a standard tapping speed test. [7] They also practiced of response, dose failures, dyskinesia, and motor fluctuations within five years in the majority of patients

Lichtarge, Olivier

343

A First-in-Human Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study of Novel Imidazolopiperazine KAF156 To Assess Its Safety, Tolerability, and Pharmacokinetics in Healthy Adult Volunteers.  

PubMed

KAF156 belongs to a new class of antimalarial, the imidazolopiperazines, and is currently in clinical development for the treatment of uncomplicated malaria. This first-in-human, single- and multiple-ascending-dose study in 70 healthy male volunteers determined the maximum oral dose of KAF156 tolerated by healthy adults and derived pharmacokinetic data (including preliminary food effect) to enable dose calculations for malaria patients. KAF156 was studied in single-dose cohorts (10 to 1,200 mg, including one 400-mg food effect cohort (4 to 10 subjects/cohort), and in multiple-dose cohorts (60 to 600 mg once daily for 3 days; 8 subjects/cohort). The follow-up period was 6 to 14 days after the last dose. KAF156 was tolerated, with self-limited mild to moderate gastrointestinal and neurological adverse events. In treated subjects after single doses, headache (n = 4; 11.1%), diarrhea (n = 3; 8.3%), dizziness (n = 3; 8.3%), and abdominal pain (n = 2; 5.6%) were the most common adverse events. Headache (n = 4; 16.7%), nausea (n = 3; 12.5%), upper respiratory tract infection (n = 3; 12.5%), and dizziness (n = 2; 8.3%) were the most common adverse events following multiple doses. KAF156 time to maximum concentration (Tmax) was between 1.0 and 6.0 h. Both the area under the concentration-time curve (AUC) and maximum concentration (Cmax) increased more than dose-proportionally in both single- and multiple-ascending-dose cohorts (terminal half-life, 42.5 to 70.7 h). There was no significant accumulation over 3-day repeated administration. The extent of absorption was not significantly affected by food at a single dose of 400 mg, while mean Cmax decreased from 778 ng/ml to 627 ng/ml and Tmax was delayed from a median of 3.0 h under fasting conditions to 6.0 h under fed conditions. Renal elimination is a minor route. PMID:25136017

Leong, F Joel; Zhao, Rong; Zeng, Shuqi; Magnusson, Baldur; Diagana, Thierry T; Pertel, Peter

2014-11-01

344

Phase II Study of Oral S-1 and Concurrent Radiotherapy in Patients With Unresectable Locally Advanced Pancreatic Cancer  

SciTech Connect

Purpose: S-1 is an oral fluoropyrimidine derivative that has demonstrated favorable antitumor activity in patients with metastatic pancreatic cancer. The aim of this study was to evaluate safety and efficacy of S-1 and concurrent radiotherapy in patients with unresectable locally advanced pancreatic cancer. Methods and Materials: Patients with histopathologically proven, unresectable, locally advanced pancreatic cancer were eligible. Radiotherapy was delivered in 1.8 Gy daily fractions to a total dose of 50.4 Gy over 5.5 weeks. S-1 was administered orally twice a day at a dose of 80 mg/m{sup 2}/day from day 1 to 14 and 22 to 35. Two weeks after the completion of chemoradiotherapy, maintenance chemotherapy with S-1 was administered for 28 days every 6 weeks until progression. Results: Thirty-four patients were enrolled in this study. The most common Grade 3 toxicities during chemoradiotherapy were anorexia (24%) and nausea (12%). The overall response rate was 41% (95% confidence interval, 25%-58%) and overall disease control rate (partial response plus stable disease) was 97%. More than 50% decrease in serum CA 19-9 was seen in 27 of 29 evaluable patients (93%). The median progression-free survival was 8.7 months. The median overall survival and 1-year survival rate were 16.8 months and 70.6%, respectively. Conclusions: Oral S-1 and concurrent radiotherapy exerted a promising antitumor activity with acceptable toxicity in patients with locally advanced pancreatic cancer. This combination therapy seems to be an attractive alternative to conventional chemoradiotherapy using 5-fluorouracil infusion.

Sudo, Kentaro, E-mail: kentarosudo9@yahoo.co.j [Department of Gastroenterology, Chiba Cancer Center, Chiba (Japan); Yamaguchi, Taketo [Department of Gastroenterology, Chiba Cancer Center, Chiba (Japan); Ishihara, Takeshi [Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba (Japan); Nakamura, Kazuyoshi; Hara, Taro; Denda, Tadamichi; Tawada, Katsunobu [Department of Gastroenterology, Chiba Cancer Center, Chiba (Japan); Imagumbai, Toshiyuki; Araki, Hitoshi; Sakai, Mitsuhiro; Hatano, Kazuo [Department of Radiation Oncology, Chiba Cancer Center, Chiba (Japan); Kawakami, Hiroyuki; Uno, Takashi; Ito, Hisao [Department of Radiation Oncology, Graduate School of Medicine, Chiba University, Chiba (Japan); Yokosuka, Osamu [Department of Medicine and Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba (Japan)

2011-05-01

345

A dose-ranging study evaluating once-daily oral administration of the factor Xa inhibitor Rivaroxaban in the treatment of patients with acute symptomatic deep vein thrombosis. The EINSTEIN-DVT Dose-Ranging Study  

Microsoft Academic Search

We performed a randomized dose- ranging study, double-blind for rivaroxa- ban doses and open-label for the comparator (low-molecular-weight hepa- rin followed by vitamin K antagonists) to assess the optimal dose of rivaroxaban for the treatment of deep vein thrombo- sis. A total of 543 patients with acute deep-venous thrombosis received rivar- oxaban 20, 30, or 40 mg once daily or

Harry R. Buller; Anthonie W. A. Lensing; Martin H. Prins; Giancarlo Agnelli; Alexander Cohen; Alexander S. Gallus; Frank Misselwitz; Gary Raskob; Sebastian Schellong; Annelise Segers

346

[Oral ulcers].  

PubMed

Ulcers commonly occur in the oral cavity, their main symptom being pain. There are different ways to classify oral ulcers. The most widely accepted form divides them into acute ulcers--sudden onset and short lasting--and chronic ulcers--insidious onset and long lasting. Commonest acute oral ulcers include traumatic ulcer, recurrent aphthous stomatitis, viral and bacterial infections and necrotizing sialometaplasia. On the other hand, oral lichen planus, oral cancer, benign mucous membrane pemphigoid, pemphigus and drug-induced ulcers belong to the group of chronic oral ulcers. It is very important to make a proper differential diagnosis in order to establish the appropriate treatment for each pathology. PMID:16277953

Bascones-Martínez, Antonio; Figuero-Ruiz, Elena; Esparza-Gómez, Germán Carlos

2005-10-29

347

Absorption, Metabolization, and Antiplatelet Effects of 300-, 600-, and 900-mg Loading Doses of Clopidogrel Results of the ISAR-CHOICE (Intracoronary Stenting and Antithrombotic Regimen: Choose Between 3 High Oral Doses for Immediate Clopidogrel Effect) Trial  

Microsoft Academic Search

Background—For patients undergoing percutaneous coronary intervention, the administration of a clopidogrel loading dose ranging from 300 to 600 mg is currently recommended. It is unknown, though, whether loading doses higher than 600 mg exert additional suppression of platelet function. Methods and Results—Sixty patients with suspected or documented coronary artery disease admitted to our hospital for coronary angiography were included in

Nicolas von Beckerath; Dirk Taubert; Gisela Pogatsa-Murray; Edgar Schömig; Adnan Kastrati; Albert Schömig

2011-01-01

348

Dexamethasone versus prednisone and daily oral versus weekly intravenous mercaptopurine for patients with standard-risk acute lymphoblastic leukemia: a report from the Children's Cancer Group.  

PubMed

Conventional therapy for childhood acute lymphoblastic leukemia (ALL) includes prednisone and oral 6-mercaptopurine. Prior observations suggested potential advantages for dexamethasone over prednisone and for intravenous (IV) over oral 6-mercaptopurine, which remain to be validated. We report the results of a randomized trial of more than 1000 subjects that examined the efficacy of dexamethasone and IV 6-mercaptopurine. Children with National Cancer Institute standard-risk ALL were randomly assigned in a 2 x 2 factorial design to receive dexamethasone (6 mg/m(2)/d) for 28 days in induction, plus taper, compared with prednisone (40 mg/m(2)/d). The second randomized assignment was for daily oral or weekly IV 6-mercaptopurine during consolidation. During maintenance, 5 days of the randomized steroid was given monthly, at the same dose, and all patients received daily oral 6-mercaptopurine. During delayed intensification, all patients received a dexamethasone dosage of 10 mg/m(2)/d for 21 days, with taper. Intrathecal (IT) methotrexate was the sole central nervous system-directed therapy. Patients randomly assigned to receive dexamethasone had a 6-year isolated central nervous system-relapse rate of 3.7% +/- 0.8%, compared with 7.1% +/- 1.1% for prednisone (P =.01). There was also a trend toward fewer isolated bone marrow relapses with dexamethasone. The 6-year event-free survival (EFS) was 85% +/- 2% for dexamethasone and 77% +/- 2% for prednisone (P =.002). EFS was similar with oral or IV 6-mercaptopurine; however, patients assigned to IV 6-mercaptopurine had decreased survival after relapse. PMID:12531809

Bostrom, Bruce C; Sensel, Martha R; Sather, Harland N; Gaynon, Paul S; La, Mei K; Johnston, Katherine; Erdmann, Gary R; Gold, Stuart; Heerema, Nyla A; Hutchinson, Raymond J; Provisor, Arthur J; Trigg, Michael E

2003-05-15

349

Low-dose oral immunization with lyophilized tissue of herbicide-resistant lettuce expressing hepatitis B surface antigen for prototype plant-derived vaccine tablet formulation  

Microsoft Academic Search

Efficient immunization against hepatitis B virus (HBV) and other pathogens with plant-based oral vaccines requires appropriate plant expressors and the optimization of vaccine compositions and administration protocols. Previous immunization studies were mainly based on a combination of the injection of a small surface antigen of HBV (S-HBsAg) and the feeding with raw tissue contain- ing the antigen, supplemented with an

Tomasz Pniewski; Józef Kapusta; Piotr Boci?g; Jacek Wojciechowicz; Anna Kostrzak; Micha? Gdula; Olga Fedorowicz-Stro?ska; Piotr Wójcik; Halina Otta; S?awomir Samardakiewicz; Bogdan Wolko; Andrzej P?ucienniczak

2011-01-01

350

Oral diuretic activity of hot water infusion of Sri Lankan black tea (Camellia sinensis L.) in rats  

PubMed Central

Background: Black tea [Camellia sinensis (L.) O. Kuntze (family: Theaceae)] has been used by Sri Lankan traditional practitioners to promote diuresis. However, the type and grade of tea is not specified. Materials and Methods: This study investigates the diuretic activity of black tea infusion (BTI) in rats using Broken Orange Pekoe Fannings (BOPF) grade from major agroclimatic elevations: high-, mid-, and low-grown. Different concentrations of BTI, furosemide (positive control), and water (vehicle) were orally administered to starved (18 h) male rats (n = 9/group), then hydrated. Acute and chronic (28 days) diuretic activities were assessed by measuring cumulative urine output at hourly intervals for 6 h. Electrolyte levels (Na+, K+, Ca2+, H+, Cl?, HCO3?), pH, osmolarity of urine, and glomerular filtration rate (GFR) of treated rats were determined. Results: Administration of BTI induced a significant (P < 0.05) and dose-dependent diuretic activity, which varied with the tea produced in different agroclimatic elevations. Diuretic activity had a rapid onset (1st h), peaked at 2nd h and maintained up to 4th h (except the low dose). Furthermore, there was a dose-dependent increase in micturition frequency, which peaked at 2nd h. A close association between the caffeine content of tea and diuretic activity was evident. BTI-induced diuresis was accompanied with an increased urine Na+ level and GFR. The diuretic activity of BTI was mediated via multiple mechanisms: inhibition of both aldosterone secretion (with increased Na+/K+ ratio) and carbonic anhydrase [with decreased Cl?/(Na+ + K+) ratio] and via thiazide type of diuretic action (evaluated with increased Na+/Cl? ratio). Conclusion: The Sri Lankan BOPF grade black tea possesses mild oral diuretic activity whose efficacy differs with the agroclimatic elevation of production. Furthermore, it supports the traditional claim that the black tea acts as a diuretic. PMID:21120027

Abeywickrama, K. R. W.; Ratnasooriya, W. D.; Amarakoon, A. M. T.

2010-01-01

351

Dose-response effect of black maca (Lepidium meyenii) in mice with memory impairment induced by ethanol.  

PubMed

Previous studies have shown that black variety of maca has beneficial effects on learning and memory in experimental animal models. The present study aimed to determine whether the hydroalcoholic extract of black maca (BM) showed a dose-response effect in mice treated with ethanol 20% (EtOH) as a model of memory impairment. Mice were divided in the following groups: control, EtOH, ascorbic acid (AA) and 0.125, 0.25, 0.50 and 1.00?g/kg of BM plus EtOH. All treatments were orally administered for 28 days. Open field test was performed to determine locomotor activity and water Morris maze was done to determine spatial memory. Also, total polyphenol content in the hydroalcoholic extract of BM was determined (0.65?g pyrogallol/100?g). Mice treated with EtOH took more time to find the hidden platform than control during escape acquisition trials; meanwhile, AA and BM reversed the effect of EtOH. In addition, AA and BM ameliorated the deleterious effect of EtOH during the probe trial. Correlation analyses showed that the effect of BM a dose-dependent behavior. Finally, BM improved experimental memory impairment induced by ethanol in a dose-response manner due, in part, to its content of polyphenolic compounds. PMID:21780878

Rubio, Julio; Yucra, Sandra; Gasco, Manuel; Gonzales, Gustavo F

2011-10-01

352

Does Oral Ingestion of Piper sarmentosum Cause Toxicity in Experimental Animals?  

PubMed Central

The prevalence of diabetes mellitus has reached epidemic proportion in Malaysia and worldwide. Scientific studies have shown that herbal plant Piper sarmentosum exhibits an antidiabetic property. Despite the extensive usage and studies of this herb as alternative medicine, there is paucity of the literature on the safety information of this plant. Thus, the present study aimed to observe the subacute toxic effects of Piper sarmentosum aqueous extract (PSAE) on the haematological profile, liver, and kidney in rats. The extract was administered by oral gavage to 6 male and female Sprague Dawley rats in daily dose of 50?mg/kg, 300?mg/kg, and 2000?mg/kg for 28 consecutive days. The control group received normal saline. General behavior of the rats, adverse effects, and mortality were observed for 28 days. The haematological and biochemical parameters were determined at baseline and after the treatment. PSAE did not show abnormality on the body weight and gross observation of internal organs. The haematological, biochemical and histopathological profiles showed minimal changes and variation within normal clinical range except for significant increase in serum potassium level that suggests the need of regular monitoring. Nevertheless, these findings suggested that PSAE up to 2000?mg/kg/day did not show subacute toxicity in Sprague Dawley rats. PMID:24228062

Zakaria, Zaiton; Megat Mohd Nordin, Nor Anita; Othman, Faizah

2013-01-01

353

A First-in-Human Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study of Novel Antimalarial Spiroindolone KAE609 (Cipargamin) To Assess Its Safety, Tolerability, and Pharmacokinetics in Healthy Adult Volunteers  

PubMed Central

This first-in-human randomized, double-blind, placebo-controlled, ascending-single and -multiple oral dose study was designed to evaluate the safety, tolerability, and pharmacokinetics in healthy volunteers of KAE609 (cipargamin; formerly NITD609), a spiroindolone now in trials for malaria treatment. It was studied in single-dose cohorts (1 to 300 mg, including one 30-mg food effect cohort) with 4 to 10 subjects in each cohort and in multiple-dose cohorts (10 to 150 mg once daily for 3 days) with 8 subjects in each cohort. The follow-up period was 6 to 8 days post-last dose. Safety and pharmacokinetics were assessed at scheduled time points during the study. Systemic exposure in terms of the area under the concentration-time curve from 0 h extrapolated to infinity (AUC0–?) increased in a dose-proportional manner over the dose range of 1 to 300 mg. The AUC from time zero to the time of the last quantifiable concentration (AUClast) and the maximum concentration of drug in plasma (Cmax) also increased in an approximately dose-proportional manner. When administered daily for 3 days, the accumulation ratio on day 3 (the AUC from time zero to 24 h postdosing [AUC0–24] on day 3/AUC0–24 on day 1) was in the range of 1.5 to 2 in the studied dose range (10 to 150 mg) and was consistent with an elimination half-life of around 24 h. Urine analysis for unchanged KAE609 revealed negligible amounts (?0.01%) were excreted renally. The high fat food intake did not affect the extent of KAE609 absorption (AUC); however, the Cmax was reduced by around 27%. KAE609 was tolerated in this study, with transient gastrointestinal and genitourinary adverse events of mild to moderate intensity (semen discoloration, diarrhea, nausea and abdominal discomfort, dizziness and headache, catheter site hematoma). Gastrointestinal and genitourinary adverse events increased with rising doses. PMID:25114127

Li, Ruobing; Jain, Jay Prakash; Lefevre, Gilbert; Magnusson, Baldur; Diagana, Thierry T.; Pertel, Peter

2014-01-01

354

"Sequential" boron neutron capture therapy (BNCT): a novel approach to BNCT for the treatment of oral cancer in the hamster cheek pouch model.  

PubMed

In the present study the therapeutic effect and potential toxicity of the novel "Sequential" boron neutron capture therapy (Seq-BNCT) for the treatment of oral cancer was evaluated in the hamster cheek pouch model at the RA-3 Nuclear Reactor. Two groups of animals were treated with "Sequential" BNCT, i.e., BNCT mediated by boronophenylalanine (BPA) followed by BNCT mediated by sodium decahydrodecaborate (GB-10) either 24 h (Seq-24h-BNCT) or 48 h (Seq-48h-BNCT) later. In an additional group of animals, BPA and GB-10 were administered concomitantly [(BPA + GB-10)-BNCT]. The single-application BNCT was to the same total physical tumor dose as the "Sequential" BNCT treatments. At 28 days post-treatment, Seq-24h-BNCT and Seq-48h-BNCT induced, respectively, overall tumor responses of 95 ± 2% and 91 ± 3%, with no statistically significant differences between protocols. Overall response for the single treatment with (BPA + GB-10)-BNCT was 75 ± 5%, significantly lower than for Seq-BNCT. Both Seq-BNCT protocols and (BPA + GB-10)-BNCT induced reversible mucositis in the dose-limiting precancerous tissue around treated tumors, reaching Grade 3/4 mucositis in 47 ± 12% and 60 ± 22% of the animals, respectively. No normal tissue toxicity was associated with tumor response for any of the protocols. "Sequential" BNCT enhanced tumor response without an increase in mucositis in dose-limiting precancerous tissue. PMID:21294607

Molinari, Ana J; Pozzi, Emiliano C C; Monti Hughes, Andrea; Heber, Elisa M; Garabalino, Marcela A; Thorp, Silvia I; Miller, Marcelo; Itoiz, Maria E; Aromando, Romina F; Nigg, David W; Quintana, Jorge; Santa Cruz, Gustavo A; Trivillin, Verónica A; Schwint, Amanda E

2011-04-01

355

Safety assessment of the butyrate-producing Butyricicoccus pullicaecorum strain 25-3(T), a potential probiotic for patients with inflammatory bowel disease, based on oral toxicity tests and whole genome sequencing.  

PubMed

Inflammatory bowel disease (IBD) is a chronic inflammation of the digestive tract, characterized by dysbiosis of the intestinal microbiota. Probiotics have been suggested as a strategy to reduce active disease or extend remission. We isolated and characterized the butyrate-producing strain Butyricicoccus pullicaecorum 25-3(T) and identified it as a potential probiotic for patients with IBD. To evaluate the safety of 25-3(T) for use in humans, we conducted a standard acute oral toxicity test and a 28-day repeated oral dose toxicity test. The complete genome of B. pullicaecorum 25-3(T) was sequenced to search for virulence factors and antibiotic resistance determinants. The minimum inhibitory concentration (MIC) of 21 antimicrobials was determined. Results showed no adverse effects in the oral toxicity tests. B. pullicaecorum 25-3(T) is resistant against aminoglycosides and trimethoprim. The genome of 25-3(T) contains no virulence factors, one gene related to harmful metabolites and 52 sequences with high similarity to antimicrobial and toxic compound resistance genes, that did not correspond with a resistant phenotype. This first report of a safety assessment of a butyrate-producing strain from Clostridium cluster IV shows that B. pullicaecorum 25-3(T) is a non-pathogenic strain, but carries antibiotic resistance genes with the risk of transfer, that need further investigation. PMID:25007784

Steppe, Marjan; Van Nieuwerburgh, Filip; Vercauteren, Griet; Boyen, Filip; Eeckhaut, Venessa; Deforce, Dieter; Haesebrouck, Freddy; Ducatelle, Richard; Van Immerseel, Filip

2014-10-01

356

Oral (po) dosing with RSU 1069 or RB 6145 maintains their potency as hypoxic cell radiosensitizers and cytotoxins but reduces systemic toxicity compared with parenteral (ip) administration in mice  

SciTech Connect

RB 6145 is a pro-drug of the hypoxic cell radiosensitizer RSU 1069 with reduced systemic toxicity. The maximum tolerated dose (MTD) of RSU 1069 for C3H/He mice was 80 mg/kg (0.38 mmol/kg) ip but 320 mg/kg (1.5 mmol/kg) following po administration. The MTD values of RB 6145 were 350 mg/kg (0.94 mmol/kg) ip and 1 g/kg (2.67 mmol/kg) po. Toxicity of RSU 1069 toward bone marrow stem cells was also less after po administration than after ip administration; 0.1 mmol/kg ip RSU 1069 and 0.38 mmol/kg po RSU 1069 both reduced the surviving fraction of clonogenic CFU-A cells by 50%. Oral administration of RSU 1069 resulted in lower spermatogenic toxicity. No loss of intestinal crypts was detected after ip or po administration of RSU 1069. Some nephrotoxicity was observed in half of the mice given the highest po dose of 1.5 mmol/kg of RSU 1069; this was not observed following the highest ip dose of drug. For RSU 1069 and RB 6145, administered by either route, the maximum hypoxic cell radiosensitization in murine KHT sarcomas, occurred when the drugs were given 45-60 min before 10 Gy of X rays. The degree of radiosensitization produced by a particular dose of either compound was largely independent of the route of administration. Preliminary pharmacokinetic studies, using 3H-RSU 1069, suggested that anti-tumor efficacy correlated with peak blood level of label and concentration in the tumor at the time of irradiation, which were not reduced by po compared with ip administration. Normal tissue toxicity tended to correlate with total exposure over time, which was reduced approximately two-fold by po administration. Oral administration of RSU 1069 or RB 6145, as well as being convenient, may give therapeutic benefit since dose-limiting toxicity in mice was reduced compared with parenteral administration, whereas radiosensitizing activity was less affected.

Cole, S.; Stratford, I.J.; Bowler, J.; Nolan, J.; Wright, E.G.; Lorimore, S.A.; Adams, G.E. (Medical Research Council, Radiobiology Unit, Didcot, Oxon (England))

1991-07-01

357

Persistent increase of blood lead level and suppression of ?-ALAD activity in northern bobwhite quail orally dosed with even a single 2-mm spent lead shot.  

PubMed

Birds that display grit ingestion behavior are potentially at risk of lead (Pb) poisoning from mistaken ingestion of spent Pb shot pellets. The majority of available studies designed to assess such risk have used unspent shot pellets rather than field-obtained spent shot, which is oxidized and otherwise changed by weathering. Available studies also often administered more or heavier shot pellets to a bird than it might be expected to ingest. The current study dosed northern bobwhite quail (Colinus virginianus) weighing 194.6 ± 23.1 g (female birds) and 199.3 ± 12.2 g (male birds) with one to three spent no. 9 Pb shot collected from a skeet range, with particular interest in the toxicity that may occur from ingestion of a single 2-mm, 50 mg shot. An 8 week post-dosing clinical observation period was employed, over which feed consumption, body weight, blood Pb levels, and a battery of blood physiological parameters were made. Weight loss occurred in the birds, including male birds dosed with one Pb pellet. Erythrocyte delta aminolevulinic acid dehydratase (?-ALAD) levels were decreased for the duration of the study across exposures and to levels associated with injury in wild bird populations. Decreased ALAD was particularly severe in female birds dosed with one Pb pellet and was still 92 % decreased at 8 weeks after dosing. Together, these results suggest that inadvertent ingestion of a single no. 9 Pb shot pellet can adversely affect the health of northern bobwhite quail. PMID:22562752

Holladay, S D; Kerr, R; Holladay, J P; Meldrum, B; Williams, S M; Gogal, R M

2012-10-01

358

Simultaneous detection of deoxyadenosine and deoxyguanosine adducts in the tongue and other oral tissues of mice treated with Dibenzo[a,l]pyrene.  

PubMed

We were the first to demonstrate that direct application of the environmental pollutant and tobacco smoke constituent dibenzo[a,l]pyrene (DB[a,l]P) into the oral cavity of mice induced squamous cell carcinoma (SCC) in oral tissues but not in the tongue; however, the mechanisms that can account for the varied carcinogenicity remain to be determined. Furthermore, we also showed that not only dA adducts, but also dG adducts can account for the mutagenic activity of DB[a,l]P in the oral tissues in vivo. In this study, we initially focused on DB[a,l]P-induced genotoxic effects in both oral and tongue tissues. Therefore, to fully assess the contribution of these DNA adducts in the initiation stage of carcinogenesis induced by DB[a,l]P, an LC-MS/MS method to simultaneously detect and quantify DB[a,l]PDE-dG and -dA adducts was developed. Mice were orally administered with DB[a,l]P (24 nmole, 3 times per week for 5 weeks) or its fjord region diol epoxide, (±)-anti-11,12-dihydroxy-13,14-epoxy-11,12,13,14-tetrahydrodibenzo[a,l]pyrene (DB[a,l]PDE, 12 nmole, single application); animals were sacrificed at 2, 7, 14, and 28 days after the last dose of carcinogen administration. Oral and tongue tissues were obtained and DNA were isolated followed by enzymatic hydrolysis. Following the development of an isotope dilution LC-MS/MS method, we successfully detected (-)-anti-cis- and (-)-anti-trans-DB[a,l]PDE-N(2)-dG, as well as (-)-anti-cis- and (-)-anti-trans-DB[a,l]PDE-N(6)-dA in oral and tongue tissues of mice treated with DB[a,l]P. Levels of (-)-anti-trans-DB[a,l]PDE-N(6)-dA were ?2 folds higher than (-)-anti-cis-DB[a,l]PDE-N(6)-dA adduct and those of dG adducts in the oral tissues and tongue at all time points selected after the cessation of DB[a,l]P treatment. Levels of dG adducts were comparable in both tissues. Collectively, our results support that DB[a,l]P is predominantly metabolized to (-)-anti-DB[a,l]PDE, and the levels and persistence of (-)-anti-trans-DB[a,l]PDE-N(6)-dA may, in part, explain the carcinogenicity of DB[a,l]P in the oral tissues but not in the tongue. PMID:24911113

Zhang, Shang-Min; Chen, Kun-Ming; Sun, Yuan-Wan; Aliaga, Cesar; Lin, Jyh-Ming; Sharma, Arun K; Amin, Shantu; El-Bayoumy, Karam

2014-07-21

359

Subchronic 90-day oral (Gavage) toxicity study of a Luo Han Guo mogroside extract in dogs  

Microsoft Academic Search

A combined 28-day and 90-day oral (Gavage) study was conducted in male and female dogs to investigate the safety of PureLo®, a non-caloric sweetener derived from the Chinese fruit Luo Han Guo, which achieves its sweetness from the presence of triterpene glycosides known as mogrosides. Three dogs of each sex were administered 10mL\\/kg bw\\/day of either an aqueous solution providing

X. Qin; S. Xiaojian; L. Ronggan; W. Yuxian; T. Zhunian; G. Shouji; J. Heimbach

2006-01-01

360

Di-n-butyl Phthalate (DNBP) and Diisobutyl Phthalate (DiBP) Metabolism in a Human Volunteer after Single Oral Doses [Journal Article  

EPA Science Inventory

An individual (male, 36 years, 87 kg) ingested two separate doses of di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) at a rate of ~60 µg/kg. Key monoester and oxidized metabolites were identified and quantified in urine continuously collected until 48 hours post dos...

361

Quantification of absorption, retention and elimination of two different oral doses of vitamin A in Zambian boys using accelerator mass spectrometry  

SciTech Connect

A recent survey indicated that high-dose vitamin A supplements (HD-VAS) had no apparent effect on vitamin A (VA) status of Zambian children <5 y of age. To explore possible reasons for the lack of response to HD-VAS among Zambian children, we quantified the absorption, retention, and urinary elimination of either a single HDVAS (60 mg) or a smaller dose of stable isotope (SI)-labeled VA (5 mg), which was used to estimate VA pool size, in 3-4 y old Zambian boys (n = 4 for each VA dose). A 25 nCi tracer dose of [{sup 14}C{sub 2}]-labeled VA was co-administered with the HD-VAS or SI-labeled VA, and 24-hr stool and urine samples were collected for 3 and 7 consecutive days, respectively, and 24-hr urine samples at 4 later time points. Accelerator Mass Spectrometry (AMS) was used to measure the cumulative excretion of {sup 14}C in stool and urine 3d after dosing to estimate, respectively, absorption and retention of the VAS and SI-labeled VA. The urinary elimination rate (UER) was estimated by plotting {sup 14}C in urine vs. time, and fitting an exponential equation to the data. Estimates of mean absorption, retention and the UER were 83.8 {+-} 7.1%, 76.3 {+-} 6.7%, and 1.9 {+-} 0.6%/d, respectively, for the HD-VAS and 76.5 {+-} 9.5%, 71.1 {+-} 9.4%, and 1.8 {+-} 1.2%/d, respectively for the smaller dose of SI-labeled VA. Estimates of absorption, retention and the UER did not differ by size of the VA dose administered (P=0.26, 0.40, 0.88, respectively). Estimated absorption and retention were negatively associated with reported fever (P=0.011) and malaria (P =0.010). HD-VAS and SI-labeled VA were adequately absorbed, retained and utilized in apparently healthy Zambian preschool-age boys, although absorption and retention may be affected by recent infections.

Aklamati, E K; Mulenga, M; Dueker, S R; Buchholz, B A; Peerson, J M; Kafwembe, E; Brown, K H; Haskell, M J

2009-10-12

362

Malaria-Infected Mice Live Until At Least Day 30 After A New Artemisinin-Derived Thioacetal Thiocarbonate Combined with Mefloquine Are Administered Together In A Single, Low, Oral Dose  

PubMed Central

In only three steps and in 21–67% overall yields from the natural trioxane artemisinin, a series of 21 new trioxane C-10 thioacetals was prepared. Upon receiving a single oral dose of only 6 mg/kg of the monomeric trioxane 12c combined with 18 mg/kg of mefloquine hydrochloride, Plasmodium berghei-infected mice survived on average 29.8 days after infection. Two of the four mice in this group had no parasites detectable in their blood on day 30 after infection and they behaved normally and appeared healthy. One of the mice had 11% blood parasitemia on day 30, and one mouse in this group died on day 29. Of high medicinal importance, the efficacy of this ACT chemotherapy is much better than (almost double) the efficacy under the same conditions using as a positive control the popular trioxane drug artemether plus mefloquine hydrochloride (average survival time of only 16.5 days). PMID:22891714

Jacobine, Alexander M.; Mazzone, Jennifer R.; Slack, Rachel D.; Tripathi, Abhai K.; Sullivan, David J.; Posner, Gary H.

2012-01-01

363

Tumor blood vessel "normalization" improves the therapeutic efficacy of boron neutron capture therapy (BNCT) in experimental oral cancer.  

PubMed

We previously demonstrated the efficacy of BNCT mediated by boronophenylalanine (BPA) to treat tumors in a hamster cheek pouch model of oral cancer with no normal tissue radiotoxicity and moderate, albeit reversible, mucositis in precancerous tissue around treated tumors. It is known that boron targeting of the largest possible proportion of tumor cells contributes to the success of BNCT and that tumor blood vessel normalization improves drug delivery to the tumor. Within this context, the aim of the present study was to evaluate the effect of blood vessel normalization on the therapeutic efficacy and potential radiotoxicity of BNCT in the hamster cheek pouch model of oral cancer. Blood vessel normalization was induced by two doses of thalidomide in tumor-bearing hamsters on 2 consecutive days. All studies in thalidomide-treated animals were performed 48 h after the first dose of thalidomide, previously established as the window of normalization. Biodistribution studies were performed with BPA at a dose of 15.5 mg (10)B/kg in thalidomide-treated (Th+) and untreated (Th-) tumor-bearing hamsters. The effect of blood vessel normalization prior to BPA administration on the efficacy of BNCT was assessed in in vivo BNCT studies at the RA-3 Nuclear Reactor in tumor-bearing hamsters. Group I was treated with BPA-BNCT after treatment with thalidomide (Th+ BPA-BNCT). Group II was treated with BPA-BNCT alone (Th- BPA-BNCT). Group III was treated with the beam only after treatment with thalidomide (Th+ BO), and Group IV was treated with the beam only (Th- BO). Groups I and II were given the same dose of BPA (15.5 mg (10)B/kg), and all groups (I-IV) were exposed to the same neutron fluence. Two additional groups were treated with the beam only at a higher dose to exacerbate mucositis in precancerous tissue and to explore the potential direct protective effect of thalidomide on radiation-induced mucositis in a scenario of more severe toxicity, i.e. Group V (Th+ hdBO) and Group VI (Th- hdBO). The animals were followed for 28 days. Biodistribution studies revealed no statistically significant differences in gross boron content between Th+ and Th- animals. Overall tumor control (complete response + partial response) at 28 days post-treatment was significantly higher for Group I (Th+ BPA-BNCT) than for Group II (Th- BPA-BNCT): 84 ± 3% compared to 67 ± 5%. Pretreatment with thalidomide did not induce statistically significant changes in overall tumor control induced by the beam only, i.e. 15 ± 5% in Group III (Th+ BO) and 18 ± 5% in Group IV (Th- BO), or in overall tumor control induced by the high-dose beam only, i.e. 60 ± 7% in Group V (Th+ hdBO) and 47 ± 10% in Group VI (Th- hdBO). BPA-BNCT alone (Group II) induced mucositis in precancerous tissue that reached Grades 3-4 in 80% of the animals, whereas pretreatment with thalidomide (Group I) prevented mucositis Grades 3 and 4 completely. Beam-only Group III (Th+ BO) exhibited only Grade 1 mucositis in precancerous tissue, whereas 17% of the animals in beam-only Group IV (Th- BO) reached Grade 2 mucositis. High-dose beam-only group V (Th+ hdBO) exhibited only Grade 2 mucositis, whereas high-dose beam-only group VI (Th- hdBO) reached Grade 3 mucositis in 83% of the animals. In all cases mucositis in precancerous tissue was reversible. No normal tissue radiotoxicity was observed with any of the protocols. Pretreatment with thalidomide enhanced the therapeutic efficacy of BNCT and reduced precancerous tissue toxicity. PMID:21980958

Molinari, Ana J; Pozzi, Emiliano C C; Monti Hughes, Andrea; Heber, Elisa M; Garabalino, Marcela A; Thorp, Silvia I; Miller, Marcelo; Itoiz, Maria E; Aromando, Romina F; Nigg, David W; Trivillin, Verónica A; Schwint, Amanda E

2012-01-01

364

Oral tolerance: immune mechanisms and treatment of autoimmune diseases  

Microsoft Academic Search

Orally administered proteins induce systemic hyporesponsiveness to the fed protein. The mechanism underlying such ‘oral tolerance’ depends on the amount of antigen fed. with higher doses inducing deletion and anergy, and lower doses inducing regulatory cells. Orally administered autoantigens suppress many experimental autoimmune diseases, as discussed here by Howard Weiner.

Howard L. Weiner

1997-01-01

365

Subchronic Oral Exposure to Benzo(a)pyrene Leads to Distinct Transcriptomic Changes in the Lungs That Are Related to Carcinogenesis  

PubMed Central

We have previously shown that acute oral exposure to the environmental carcinogen benzo(a)pyrene (BaP) elicits comparable levels of DNA adducts, but distinct transcriptomic changes, in mouse lungs and livers, the two main BaP bioactivating organs. Oral BaP exposure is predominantly associated with lung cancer and not hepatic cancer in some animal models, suggesting that gene expression differences may provide insight into the drivers of tissue-specific carcinogenesis. In the present study, we examine pulmonary DNA adduct formation, lacZ mutant frequency, and mRNA profiles in adult male MutaMouse following subchronic (28 day) oral exposure to BaP (0, 25, 50, and 75mg/kg/day) and sacrificed 3 days postexposure. The results are compared with those obtained from livers of the same mice (previously published). Although there was a 1.8- to 3.3-fold increase in the levels of DNA adducts in lung compared with liver, the lacZ transgene mutant frequency was similar in both tissues. At the transcriptomic level, a transition from activation of the DNA damage response p53 pathway at the low dose to the induction of genes involved in angiogenesis, evasion of apoptosis and growth signals at the high doses was evident only in the lungs. These results suggest that tissue DNA adducts and mutant frequency are sensitive markers of target tissue exposure and mode of action, whereas early changes in gene expression may provide a better indication of the likelihood of carcinogenic transformation in selected tissues. Moreover, the study provides new information on the underlying mecha- nisms that contribute to tissue-specific responses to BaP. PMID:22610609

Halappanavar, Sabina

2012-01-01

366

Oral (gavage), in utero and postnatal exposure of Sprague–Dawley rats to low doses of tributyltin chloride. Part 1: Toxicology, histopathology and clinical chemistry  

Microsoft Academic Search

Tributyltin (TBT) is a biocide that contaminates foods, especially shellfish. TBT is an endocrine disrupter in several marine species and is neurotoxic and immunotoxic in mammals. We have examined the effects of exposure to low doses of tributyltin chloride (TBTC) from day 8 of gestation until adulthood. Pregnant rats were gavaged daily with 0, 0.025, 0.25 or 2.5 mg TBTC\\/kg

G. M Cooke; H Tryphonas; O Pulido; D Caldwell; G. S Bondy; D Forsyth

2004-01-01

367

Di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) metabolism in a human volunteer after single oral doses.  

PubMed

An individual (male, 36 years, 87 kg) ingested two separate doses of di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) at a rate of ~60 ?g/kg. Key monoester and oxidized metabolites were identified and quantified in urine continuously collected until 48 h post-dose. For both DnBP and DiBP, the majority of the dose was excreted in the first 24 h (92.2 % of DnBP, 90.3 % of DiBP), while only <1 % of the dose was excreted in urine on day 2. In each case, the simple monoesters were the major metabolites (MnBP, 84 %; MiBP, 71 %). For DnBP, ~8 % was excreted as var