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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 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

2

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

PubMed

Human copper/zinc superoxide dismutase from recombinant Pichia pastori (RH-Cu/Zn-SOD) was orally administered, via gavage, to Sprague-Dawley rats at 500, 1,000, and 2,000?mg/kg body weight/day for 28 days. During the 28-day period, animals were examined for evidence of toxicity; there were no deaths, and in-life physical signs were normal. On day 29, the animals were exsanguinated, examined for gross pathology, and tissues were preserved for histopathology. Although statistical differences were noted in some hematology and clinical chemistry, they were of questionable biological significance. The results of the 28-day oral administration demonstrated a lack of toxicity of RH-Cu/Zn-SOD in rats. There were no treatment-related, toxicologically relevant changes in clinical signs, growth, food consumption, hematology, clinical chemistry, organ weights, or pathology. The no observed adverse effect level was greater than 2,000?mg/kg/day for RH-Cu/Zn-SOD in rats. PMID:21834671

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

2011-08-11

3

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

PubMed

Carica papaya L. leaves have been used in ethnomedicine for the treatment of fevers and cancers. Despite its benefits, very few studies on their potential toxicity have been described. The aim of the present study was to characterize the chemical composition of the leaf extract from 'Sekaki' C. papaya cultivar by UPLC-TripleTOF-ESI-MS and to investigate the sub-acute oral toxicity in Sprague Dawley rats at doses of 0.01, 0.14 and 2 g/kg by examining the general behavior, clinical signs, hematological parameters, serum biochemistry and histopathology changes. A total of twelve compounds consisting of one piperidine alkaloid, two organic acids, six malic acid derivatives, and four flavonol glycosides were characterized or tentatively identified in the C. papaya leaf extract. In the sub-acute study, the C. papaya extract did not cause mortality nor were treatment-related changes in body weight, food intake, water level, and hematological parameters observed between treatment and control groups. Some biochemical parameters such as the total protein, HDL-cholesterol, AST, ALT and ALP were elevated in a non-dose dependent manner. Histopathological examination of all organs including liver did not reveal morphological alteration. Other parameters showed non-significant differences between treatment and control groups. The present results suggest that C. papaya leaf extract at a dose up to fourteen times the levels employed in practical use in traditional medicine in Malaysia could be considered safe as a medicinal agent. PMID:22491681

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

2012-04-10

4

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

PubMed

Acute systemic toxicity is one of the areas of particular concern due to the 2009 deadline set by the 7th Amendment of the Cosmetics Directive (76/768/EEC), which introduces a testing and marketing ban of cosmetic products with ingredients tested on animals. The scientific community is putting considerable effort into developing and validating non-animal alternatives in this area. However, it is unlikely that validated and regulatory accepted alternative methods and/or strategies will be available in March 2009. Following the initiatives undertaken in the pharmaceutical industry to waive the acute oral toxicity testing before going to clinical studies by using information from other in vivo studies, we proposed an approach to identify non-toxic compounds (LD50>2000mg/kg) using information from 28 days repeated dose toxicity studies. Taking into account the high prevalence of non-toxic substances (87%) in the New Chemicals Database, it was possible to set a NOAEL threshold of 200mg/kg that allowed the correct identification of 63% of non-toxic compounds, while <1% of harmful compounds were misclassified as non-toxic. Since repeated dose toxicity studies can be performed in vivo until 2013, the proposed approach could have an immediate impact for the testing of cosmetic ingredients. PMID:18977273

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

2008-10-14

5

Acute and repeated dose (28 day) mouse oral toxicology studies with Cry34Ab1 and Cry35Ab1 Bt proteins used in coleopteran resistant DAS-59122-7 corn.  

PubMed

Expression of the Cry34Ab1 and Cry35Ab1 proteins from Bacillus thuringiensis (Bt) Berliner strain PS149B1 in genetically modified maize (event DAS-59122-7) protects the crop from damage due to feeding by Diabrotica larvae including the western corn rootworm (Diabrotica virgifera virgifera). As part of the safety assessment of this maize, mammalian toxicology studies were conducted with heterologously produced Cry34Ab1 and Cry35Ab1 proteins. No evidence of acute toxicity was observed in mice following oral exposure to either the Cry34Ab1 or Cry35Ab1 proteins individually (2700 and 1850 mg/kg, respectively) or concomitantly (482 and 1520 mg/kg, respectively; 1:1 molar ratio). Similarly, no adverse effects were observed in mice in a repeated dose (28 day) dietary toxicity study that incorporated these proteins into diets at concentrations corresponding up to 1000-fold greater than the highest estimate of human exposure based on the concentrations of these proteins expressed in 59122 maize grain. These studies demonstrate that the Cry34Ab1 and Cry35Ab1 proteins do not represent a risk to human health and support previous studies indicating that 59122 maize grain is as safe and wholesome as non-GM maize grain. PMID:19328831

Juberg, Daland R; Herman, Rod A; Thomas, Johnson; Brooks, Keith J; Delaney, Bryan

2009-03-27

6

Safety assessment of EPA-rich triglyceride oil produced from yeast: Genotoxicity and 28-day oral toxicity in rats  

Microsoft Academic Search

The 28-day repeat-dose oral and genetic toxicity of eicosapentaenoic acid triglyceride oil (EPA oil) produced from genetically modified Yarrowia lipolytica yeast were assessed. Groups of rats received 0 (olive oil), 940, 1880, or 2820mg EPA oil\\/kg\\/day, or fish oil (sardine\\/anchovy source) by oral gavage. Lower total serum cholesterol was seen in all EPA and fish oil groups. Liver weights were

Leigh A. Belcher; Susan A. MacKenzie; Maria Donner; Greg P. Sykes; Steven R. Frame; Peter J. Gillies

2011-01-01

7

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

PubMed

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

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

2013-02-04

8

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

9

Safety assessment of EPA-rich triglyceride oil produced from yeast: genotoxicity and 28-day oral toxicity in rats.  

PubMed

The 28-day repeat-dose oral and genetic toxicity of eicosapentaenoic acid triglyceride oil (EPA oil) produced from genetically modified Yarrowia lipolytica yeast were assessed. Groups of rats received 0 (olive oil), 940, 1880, or 2820 mg EPA oil/kg/day, or fish oil (sardine/anchovy source) by oral gavage. Lower total serum cholesterol was seen in all EPA and fish oil groups. Liver weights were increased in the medium and high-dose EPA (male only), and fish oil groups but were considered non-adverse physiologically adaptive responses. Increased thyroid follicular cell hypertrophy was observed in male high-dose EPA and fish oil groups, and was considered to be an adaptive response to high levels of polyunsaturated fatty acids. No adverse test substance-related effects were observed on body weight, nutritional, or other clinical or anatomic pathology parameters. The oil was not mutagenic in the in vitro Ames or mouse lymphoma assay, and was not clastogenic in the in vivo mouse micronucleus test. In conclusion, exposure for 28 days to EPA oil derived from yeast did not produce adverse effects at doses up to 2820 mg/kg/day and was not genotoxic. The safety profile of the EPA oil in these tests was comparable to a commercial fish oil. PMID:20868718

Belcher, Leigh A; MacKenzie, Susan A; Donner, Maria; Sykes, Greg P; Frame, Steven R; Gillies, Peter J

2010-09-22

10

Integration of mutation and chromosomal damage endpoints into 28-day repeat dose toxicology studies.  

PubMed

Two endpoints of genetic toxicity, mutation at the X-linked Pig-a gene and chromosomal damage in the form of micronucleated reticulocytes (MN-RETs), were evaluated in blood samples obtained from 28-day repeat-dosing studies typical of those employed in toxicity evaluations. Male Wistar Han rats were treated at 24-h intervals on days 1 through 28 with one of five prototypical genotoxicants: N-ethyl-N-nitrosourea, 7,12-dimethyl-12-benz[a]anthracene, 4-nitroquinoline-1-oxide (4NQO), benzo(a)pyrene, and N-methyl-N-nitrosourea. Flow cytometric scoring of CD59-negative erythrocytes (indicative of glycosylphosphatidylinositol anchor deficiency and hence Pig-a mutation) was performed using blood specimens obtained on days -1, 15, 29, and 56. Blood specimens collected on days 4 and 29 were evaluated for MN-RET frequency using flow cytometry-based MicroFlow Kits. With the exception of 4NQO, each chemical induced significant increases in the frequency of MN-RETs on days 4 and 29. All five agents increased the frequency of mutant phenotype (CD59 negative) reticulocytes (RETs) and erythrocytes. Mutation responses in RETs occurred earlier than in erythrocytes and tended to peak, or nearly peak, at day 29. In contrast, the mutant phenotype erythrocyte responses were modest on day 29 and required additional time to reach their maximal value. The observed kinetics were expected based on the known turnover of RETs and erythrocytes. The data show that RETs can serve as an appropriate indicator cell population for 28-day studies. Collectively, these data suggest that blood-based genotoxicity endpoints can be effectively incorporated into routine toxicology studies, a strategy that would reduce animal usage while providing valuable genetic toxicity information within the context of other toxicological endpoints. PMID:20202993

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

2010-03-04

11

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

PubMed Central

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

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

2010-01-01

12

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

PubMed Central

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

2011-01-01

13

Induction of liver preneoplastic foci in F344 rats subjected to 28-day oral administration of diheptyl phthalate and its in vivo genotoxic potential.  

PubMed

To investigate possible potential inducing preneoplastic lesions in liver and in vivo genotoxic potential of diheptyl phthalate (DHP), male F344 rats were subjected to repeated oral administration of DHP at 0, 2.5 or 5 g/kg/day for 28 days. In addition, F344 rats were subjected to once or 14 repeated oral administrations of 5 g/kg/day of DHP, and their livers were subjected to analysis in an alkaline single-cell gel electrophoresis (comet) assay. Furthermore, based on the results of these studies, partial hepatectomized male F344 rats given once, three times, and 14 repeated oral administration of 0, 2.5 or 5 g/kg body weight of DHP were examined by an in vivo liver initiation assay. In a 28-day repeated dose toxicity study, the number and area of glutathione-S-transferase placental form (GST-P) positive foci, a marker of hepatocellular preneoplastic lesions in rats, were significantly increased in DHP-treated groups compared with controls. At 24h after the 14 repeated administrations of DHP, DNA migration, a marker of DNA damage in the comet assay, was significantly induced in DHP-treated rat livers, whereas single treatment did not show such an alteration. In an in vivo liver initiation assay, a significant increase in the number and area of GST-P positive foci was observed in DHP-treated groups subjected to 14 repeated oral administrations of DHP as compared with the control group. These results indicate that DHP may induce altered hepatocellular foci in liver of rats which suggests that DHP is a genotoxic carcinogen in the liver of rats. PMID:19643158

Jin, Meilan; Dewa, Yasuaki; Kawai, Masaomi; Nishimura, Jihei; Saegusa, Yukie; Kemmochi, Sayaka; Harada, Tomoaki; Shibutani, Makoto; Mitsumori, Kunitoshi

2009-07-28

14

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

2012-11-28

15

A phase I study of oral uracil\\/ftorafur (UFT) plus leucovorin and bis-acetato-ammine-dichloro-cyclohexylamine-platinum IV (JM216) each given over 14 days every 28 days  

Microsoft Academic Search

Purpose: To determine the feasibility, maximal tolerated doses, and response rates for a combined regimen of the platinum and 5-fluorouracil\\u000a oral analogues bis-acetato-ammine-dichloro-cyclohexyl-amine platinum(IV) (JM-216) and uracil\\/ftorafur (UFT) coadministered\\u000a as a 14 consecutive-day every 28-day schedule. Methods: Of 20 patients enrolled in this investigation, 17 on the following dose escalation scheme were evaluable for toxicity and\\/or\\u000a response: I UFT 300?mg\\/day,

Mark D. DeMario; Mark J. Ratain; Nicholas J. Vogelzang; Sridhar Mani; Everett E. Vokes; Gini F. Fleming; Kimberly Melton; Sheryl Johnson; Steven Benner; David Lebwohl

1999-01-01

16

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

Code of Federal Regulations, 2013 CFR

...specific gravity, pH, protein, glucose and blood and blood cells. (iii) In addition, studies to investigate serum markers...route of administration to cover systemic effects), peripheral nerve (sciatic or tibial) preferably in close proximity to...

2013-07-01

17

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

Code of Federal Regulations, 2010 CFR

...dosage related response and NOEL...within-subject comparisons), and...posture and response to handling...e.g., auditory, visual and proprioceptive...C) Toxic response data by sex...and Stock Comparisons Using a...

2010-07-01

18

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

Code of Federal Regulations, 2010 CFR

...dosage related response and NOEL...within-subject comparisons), and...posture and response to handling...e.g., auditory, visual and proprioceptive...C) Toxic response data by sex...and Stock Comparisons Using a...

2009-07-01

19

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

PubMed

To examine the possible repeated-dose toxicity of an ultraviolet absorber, 2-(2'-hydroxy-3',5'-di-tert-butylphenyl)benzotriazole (HDBB), CD(SD)IGS rats were administered HDBB by gavage at a dose of 0 (vehicle: corn oil), 0.5, 2.5, 12.5, or 62.5 mg kg(-1) day(-1) for 28 days. At the completion of the administration period, a decrease in red blood cells, hemoglobin, and hematocrit was noted only in males at 2.5 mg/kg and more. Blood biochemical changes were noted at 0.5 mg/kg and more in males and at 62.5 mg/kg in females. Histopathologic changes were observed principally in the liver (vacuolar degeneration and hypertrophy of hepatocytes, bile duct proliferation, etc.) and in the heart (degeneration and hypertrophy of myocardium and cell infiltration). These changes were noted at 0.5 mg/kg and more in males and at 12.5 mg/kg and more in females. At higher doses, hypertrophy of tubular epithelium in the kidneys and diffuse follicular cell hyperplasia in the thyroids in both sexes and increased severity of basophilic tubules in the kidneys and extramedullary hematopoiesis in the spleen in males were also detected. After the 14-day recovery period, these changes mostly recovered in females but not in males. Based on these findings, no observed adverse effect level (NOAEL) was concluded to be less than 0.5 mg kg(-1) day(-1) in male rats and 2.5 mg kg(-1) day(-1) in female rats. PMID:17934922

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

2007-01-01

20

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

PubMed Central

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

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

2012-01-01

21

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

Microsoft Academic Search

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

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

2007-01-01

22

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.  

PubMed

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. PMID:17070881

Nakayama, Koji; Kawano, Yukiko; Kawakami, Yuuki; Moriwaki, Norichika; Sekijima, Masaru; Otsuka, Masanori; Yakabe, Yoshikuni; Miyaura, Hideki; Saito, Koichi; Sumida, Kayo; Shirai, Tomoyuki

2006-09-28

23

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

24

Immunotoxicological screening of morphine and methadone in an extended 28 day study in rats.  

PubMed

Drug addicts are prone to infection with viruses including hepatitis-B and HIV. Besides indirect effects as a consequence of lifestyle, heroin and methadone may also enhance the risk of infections by a direct immunotoxic effect affecting resistance. In addition to general toxicological screening, we therefore performed a screening for potential immunotoxicity of morphine and methadone. Rats treated orally with different dosages of morphine or methadone for 6 weeks showed only a minor effect of overt toxicity on liver and spleen at the high dose, whereas at lower doses an increase in the relative weight of the mesenteric lymph nodes and an increase in cell density in the medullary cords were observed histopathologically, indicating a specific effect on humoral immunity. This specific immunotoxic effect was corroborated by an increased IgG concentration in serum (significant for the methadone-treated group). Further immunotoxicological research is needed aimed at revealing the potential risk of opiate use with respect to immune function. In conclusion, the present paper showed the toxicological profile of morphine and methadone in an extended 28 day subchronic study. Specific immunotoxicological effects were observed at doses where no effects were seen in routine toxicological evaluation, suggesting that the immune system is sensitive to opiates. PMID:7499032

van der Laan, J W; Krajnc, E I; Krajnc-Franken, M A; van Loveren, H

1995-06-01

25

Alopecia related to low dose oral contraceptive.  

PubMed

We present a patient with diffuse baldness related to low dose oral contraceptive (LD-OC). Although LD-OC scarcely induce troublesome side effects if prescribed in accordance with Managing Contraceptive Pill Patients Guideline, this trouble might become a source of poor compliance to LD-OCs. PMID:11998965

Yokoyama, Y; Sato, S; Saito, Y

2002-01-01

26

Effects of oral prasterone (dehydroepiandrosterone) on single-dose pharmacokinetics of oral prednisone and cortisol suppression in normal women.  

PubMed

This study sought to determine effects of multiple dosing of prasterone (DHEA, dehydroepiandrosterone) on the pharmacokinetics of prednisolone and endogenous cortisol secretion. These drugs are likely to be coadministered to patients with systemic lupus erythematosus. Fourteen normal women (ages 30.1 +/- 5.4 years) received single-dose oral prednisone (20 mg) before and after 200 mg/day of oral prasterone for one menstrual cycle (approximately 28 days). Identical assessments, timed to onset of menses, were conducted pretreatment (baseline) and at days 28 and 29 of prasterone treatment and included serum total and free prednisolone, prednisone, DHEA, DHEA-S (dehydroepiandrosterone sulfate), ACTH-stimulated cortisol, and sex hormones and 24-hour urine free cortisol. Pharmacokinetic parameters of prednisolone as assessed by Cmax, t 1/2, AUC, or serum protein binding were not affected by prasterone. The ACTH-stimulated plasma cortisol concentrations were mildly reduced, but 24-hour urinefree cortisol excretion was unchanged during prasterone administration. Serum androstenedione and testosterone increased, while no changes in serum estradiol or estrone occurred. The administration of 200 mg oral prasterone produced serum concentrations of DHEA and DHEA-S significantly greater than endogenous levels. Chronic dosing with 200 mg/day of prasterone did not alter either prednisolone pharmacokinetics or inhibition of cortisol secretion by prednisolone. PMID:11697752

Meno-Tetang, G M; Blum, R A; Schwartz, K E; Jusko, W J

2001-11-01

27

Evaluation for reliability and feasibility of the draft protocol for the enhanced rat 28-day subacute study (OECD Guideline 407) using androgen antagonist flutamide.  

PubMed

As part of an international validation project to establish a test protocol for the 'Enhanced OECD Test Guideline no. 407', a 28-day repeated dose study of flutamide was performed (1) to examine which of the current and/or additional parameters can detect endocrine effects of test chemicals most reliably and sensitively, (2) to investigate whether it is actually feasible to routinely include all additional parameters into the testing routine, and (3) to assess intra-laboratory variability by performing two identical studies (experiments A and B) in parallel using groups of five animals each per dose and sex. Groups of five male and five female CD(SD)IGS rats were treated by oral gavage with 0, 1, 10 and 100 mg flutamide/kg body weight for at least 28 days. The dose level considered to be around the MTD (100 mg/kg) exerted the expected antiandrogenic effects on androgen related tissues: significant decrease of the weights of androgen dependent organs and the sperm count and increase in histopathological lesions. At the middle dose (10 mg/kg), significant decrease of prostate weight (ventral and dorso-lateral parts combined) was observed and it was suggested that weight measurement of androgen dependent organs provides the most reliable and sensitive endpoint with this protocol. As for the feasibility, because of many items in this protocol, selection should be based on the sensitivity. From our data, addition of weight measurement of androgen dependent organs to the items of the existing OECD 407 guideline might allow accurate screening for endocrine disruptors. At the dose level considered to be around the MTD, the findings achieving statistical significance in one experiment with five animals/dose/sex could be reproduced in the second experiment, and evaluation with the small groups was consistent with findings using the combined groups of 10 animals/dose/sex. The results demonstrate that the protocol can reliably detect antiandrogenic effects of flutamide. PMID:15158566

Kunimatsu, Takeshi; Yamada, Tomoya; Miyata, Kaori; Yabushita, Setsuko; Seki, Takaki; Okuno, Yasuyoshi; Matsuo, Masatoshi

2004-07-15

28

Increase of Oral Methadone Dose in Methadone Injecting Patients  

Microsoft Academic Search

A pilot study was initiated in seven methadone injecting patients to examine whether intravenous methadone use in patients in oral methadone maintenance treatment could be decreased by increased oral methadone dose. During the study, patients had a standardized methadone dose increase for three weeks, followed by a 12-week follow-up period. Mean methadone doses prior to, and at the end of

C. B. Eap; C. Felder; K. Powell Golay; C. Uehlinger

2003-01-01

29

28 day bed-rest with hypercortisolemia induces peripheral insulin resistance and increases intramuscular triglycerides  

PubMed Central

Spaceflight represents a unique physiological challenge to humans, altering hormonal profiles and tissue insulin sensitivity. Among these hormonal alterations, hypercortisolemia and insulin insensitivity are thought to negatively affect muscle mass and function with spaceflight. As insulin sensitivity influences the accumulation of muscle triglycerides, we examined this relationship during hypercortisolemia and inactivity. Six young healthy volunteers were confined to bed rest for 28 days. To mimic the stress response observed during spaceflight, hypercortisolemia (20–24mg/dL) was induced and maintained by oral ingestion of hydrocortisone. On days 1 and 28 of bed rest, insulin sensitivity across the leg was assessed with a local (femoral arterial insulin infusion) 2 stage hyperinsulinemic-euglycemic clamp (stage 1: 35 µU/min/ml leg; stage 2: 70 µU/min/ml leg). Intramuscular lipid was measured with magnetic resonance spectroscopy. Following bed rest, there was a decrease in insulin sensitivity, as assessed by glucose uptake during hyperinsulinemia (from 9.1±1.3 (mean ± SEM) mg/kg.leg/min to 5.2±0.7 mg/kg.leg/min (P=0.015)). Intramuscular triglyceride increased from 0.077±0.011 to 0.136±0.018 (signal area of fat/signal area of standard; P=0.009). Intramuscular lipid content correlated with the glucose uptake at day 28, (R= ?0.85; P=0.035). These data demonstrate that muscular inactivity and hypercortisolemia are associated with an increase in intramuscular triglyceride and skeletal muscle insulin resistance in previously healthy subjects.

Cree, Melanie G.; Paddon-Jones, Douglas; Newcomer, Bradley R.; Ronsen, Ola; Aarsland, Asle; Wolfe, Robert R.; Ferrando, Arny

2009-01-01

30

Relapsing hypocupraemic myelopathy requiring high-dose oral copper replacement  

Microsoft Academic Search

Adult-onset copper deficiency with neurological manifestations is a newly recognised syndrome. Long-term oral copper replacement therapy has been the mainstay of treatment in the literature. A case of relapsing hypocupraemic myelopathy responsive to increased doses of copper replacement is reported. Standard doses of copper may not be sufficient for all patients.

C I Prodan; S S Bottomley; N R Holland; S E Lind

2006-01-01

31

Relapsing hypocupraemic myelopathy requiring high-dose oral copper replacement  

PubMed Central

Adult?onset copper deficiency with neurological manifestations is a newly recognised syndrome. Long?term oral copper replacement therapy has been the mainstay of treatment in the literature. A case of relapsing hypocupraemic myelopathy responsive to increased doses of copper replacement is reported. Standard doses of copper may not be sufficient for all patients.

Prodan, C I; Bottomley, S S; Holland, N R; Lind, S E

2006-01-01

32

Perturbation of the indigenous rat oral microbiome by ciprofloxacin dosing.  

PubMed

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 of a variety of gram-positive oral commensal bacteria. We exposed the oral cavities of rats to relatively low (0.1 ?g ml(-1) ) and high (20 ?g ml(-1)) 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 the genera Rothia (74.4%) and Streptococcus (4.7%). Dosing at 0.1 ?g ml(-1) was associated with changes in Rothia and Streptococcus species that were not significant, whereas dosing at 20 ?g ml(-1) 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 regimen to selectively target a specific subset of a mucosal microbiome for elimination with minimal perturbation of the entire community. PMID:23844936

Manrique, P; Freire, M O; Chen, C; Zadeh, H H; Young, M; Suci, P

2013-07-12

33

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

34

Preoperative chemoradiotherapy with oral doxifluridine plus low-dose oral leucovorin in unresectable primary rectal cancer  

Microsoft Academic Search

Purpose: The use of oral chemotherapeutic agents in chemoradiotherapy provides several advantages. Doxifluridine, an oral 5-FU prodrug, has been shown to be effective in colorectal cancer. We attempted a Phase II trial of preoperative chemoradiotherapy with doxifluridine plus a low-dose oral leucovorin in unresectable primary rectal cancer patients. In this study, toxicity and efficacy were evaluated.Methods and Materials: There were

Jinsil Seong; Jae Ho Cho; Nam Kyu Kim; Jin Sik Min; Chang Ok Suh

2001-01-01

35

Uranyl nitrate: 28-day and 91-day toxicity studies in the Sprague-Dawley rat.  

PubMed

Although uranium (U) is a classic experimental nephrotoxin, there are few data on its potential long-term chemical toxicity. These studies were undertaken to derive a no-observed-adverse-effect level (NOAEL) in male and female Sprague-Dawley rats following 91-day exposure to uranium (as uranyl nitrate hexahydrate, UN) in drinking water. Following a 28-day range-finding study, five groups of 15 male and 15 female weanling rats were exposed for 91 days to UN in drinking water (0.96, 4.8, 24, 120, or 600 mg UN/L). A control group was given tap water (< 0.001 mg U/L). Daily clinical observations were recorded. Following the study, animals were euthanized and exsanguinated, and multiple hematological and biochemical parameters were determined. Necropsies were conducted, and multiple tissues were sampled for histopathological examination. The hematological and biochemical parameters were not affected in a significant exposure-related manner. Although there were qualitative and slight quantitative differences between males and females, histopathological lesions were observed in the kidney and liver, in both males and females, in all groups including the lowest exposure groups. Renal lesions of tubules (apical nuclear displacement and vesiculation, cytoplasmic vacuolation, and dilation), glomeruli (capsular sclerosis), and interstitium (reticulin sclerosis and lymphoid cuffing) were observed in the lowest exposure groups. A NOAEL was not achieved in this study, since adverse renal lesions were seen in the lowest exposed groups. A lowest-observed-adverse-effect level of 0.96 mg UN/L drinking water can be reported for both the male and the female rats (average dose equivalent 0.06 and 0.09 mg U/kg body wt/day, respectively). PMID:9520346

Gilman, A P; Villeneuve, D C; Secours, V E; Yagminas, A P; Tracy, B L; Quinn, J M; Valli, V E; Willes, R J; Moss, M A

1998-01-01

36

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

PubMed Central

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

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

2011-01-01

37

Low-dose oral methotrexate in refractory inflammatory bowel disease  

Microsoft Academic Search

The purpose of this study was to evaluate the efficacy and safety of low-dose weekly, oral methotrexate in patients with steroid-dependent or steroid-refractory inflammatory bowel disease (IBD). Oral methotrexate was given weekly at 15 mg\\/week. The primary criterion of response was based on steroid withdrawal. Of the 10 patients with Crohn's disease, daily prednisone dosage dropped from a mean of

Todd H. Baron; Christopher D. Truss; Charles O. Elson

1993-01-01

38

Efficacy and safety of a popular thermogenic drink after 28 days of ingestion  

Microsoft Academic Search

BACKGROUND: We have recently demonstrated that consuming a thermogenic drink (TD) acutely increases energy expenditure and serum markers of lipolysis in healthy, college-aged individuals. The purpose of this study was to determine if consuming TD over 28 days affects its acute thermogenic and lipolytic effects as well as body composition and clinical chemistry safety markers. METHODS: Sixty healthy, males (mean

Michael D Roberts; Vincent J Dalbo; Scott E Hassell; Jeffrey R Stout; Chad M Kerksick

2008-01-01

39

INTERLABORATORY COMPARISON OF A 28-DAY TOXICITY TEST WITH THE POLYCHAETE 'NEANTHES ARENACEODENTATA'  

EPA Science Inventory

An interlaboratory comparison of toxicity tests with the polychaete Neanthes arenaceodentata was conducted to determine the amount of variability expected with this test. Six laboratories each conducted two 28-day flow-through tests, one with silver nitrate (AgNO3) as the toxican...

40

Effects of oral doses of fluoride on nestling european starlings  

Microsoft Academic Search

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

W. James Fleming; Christian E. Grue; Carol A. Schuler; Christine M. Bunck

1987-01-01

41

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.

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

2012-01-01

42

“Estrophasic” dosing: A new concept in oral contraceptive therapy  

Microsoft Academic Search

The first of a new “estrophasic” type of oral contraceptive with 20 ?g ethinyl estradiol on cycle days 1 through 5, 30 ?g ethinyl estradiol on days 6 through 12, and 35 ?g ethinyl estradiol on days 13 through 21 and 1 mg norethindrone acetate throughout the cycle (Estrostep; Parke-Davis, Morris Plains, NJ) combines a continuous low progestin dose with

Jean P. Rowan

1999-01-01

43

The individual and combined metabolite profiles (metabolomics) of dibutylphthalate and di(2-ethylhexyl)phthalate following a 28-day dietary exposure in rats  

Microsoft Academic Search

Metabolite profiles (metabolomics) of plasma samples of Wistar rats dosed with di(2-ethylhexyl)phthalate (DEHP – 3000ppm) and dibutylphthalate (DBP – 150, 1000 and 7000ppm) were individually determined in 28 days dietary studies. In addition, profiles of combined exposure to 3000ppm DEHP and either 150, 1000 or 7000ppm DBP were determined.High dose levels induced more profound metabolite changes in males than in

B. van Ravenzwaay; G. Coelho-Palermo Cunha; V. Strauss; J. Wiemer; E. Leibold; H. Kamp; T. Walk; W. Mellert; R. Looser; A. Prokoudine; E. Fabian; G. Krennrich; M. Herold

2010-01-01

44

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

PubMed

It was hypothesized that d-aspartic acid (D-ASP) supplementation would not increase endogenous testosterone levels or improve muscular performance associated with resistance training. Therefore, body composition, muscle strength, and serum hormone levels associated with the hypothalamo-pituitary-gonadal axis were studied after 28 days of resistance training and D-ASP supplementation. Resistance-trained men resistance trained 4 times/wk for 28 days while orally ingesting either 3 g of placebo or 3 g of D-ASP. Data were analyzed with 2 × 2 analysis of variance (P < .05). Before and after resistance training and supplementation, body composition and muscle strength, serum gonadal hormones, and serum D-ASP and d-aspartate oxidase (DDO) were determined. Body composition and muscle strength were significantly increased in both groups in response to resistance training (P < .05) but not different from one another (P > .05). Total and free testosterone, luteinizing hormone, gonadotropin-releasing hormone, and estradiol were unchanged with resistance training and D-ASP supplementation (P > .05). For serum D-ASP and DDO, D-ASP resulted in a slight increase compared with baseline levels (P > .05). For the D-ASP group, the levels of serum DDO were significantly increased compared with placebo (P < .05). The gonadal hormones were unaffected by 28 days of D-ASP supplementation and not associated with the observed increases in muscle strength and mass. Therefore, at the dose provided, D-ASP supplementation is ineffective in up-regulating the activity of the hypothalamo-pituitary-gonadal axis and has no anabolic or ergogenic effects in skeletal muscle. PMID:24074738

Willoughby, Darryn S; Leutholtz, Brian

2013-08-15

45

"Estrophasic" dosing: A new concept in oral contraceptive therapy.  

PubMed

The first of a new "estrophasic" type of oral contraceptive with 20 microg ethinyl estradiol on cycle days 1 through 5, 30 microg ethinyl estradiol on days 6 through 12, and 35 microg ethinyl estradiol on days 13 through 21 and 1 mg norethindrone acetate throughout the cycle (Estrostep; Parke-Davis, Morris Plains, NJ) combines a continuous low progestin dose with a low, gradually increasing estrogen dose. It was developed to ensure good cycle control while conferring the benefits of low hormone content, such as minimizing estrogen-related side effects. In a double-blind, randomized, parallel-group trial, Estrostep provided acceptable cycle control and excellent tolerableness, comparable to that of the 30-microg ethinyl estradiol monophasic control drug. In a second study Estrostep demonstrated a neutral impact on serum lipids, like the triphasic control drug. This new oral contraceptive design offers a useful low-dose alternative to existing combination preparations. PMID:9988834

Rowan, J P

1999-02-01

46

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

SciTech Connect

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

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

1980-09-01

47

Uranyl Nitrate: 28Day and 91Day Toxicity Studies in the Sprague–Dawley Rat  

Microsoft Academic Search

Although uranium (U) is a classic experimental nephrotoxin, there are few data on its potential long-term chemical toxicity. These studies were undertaken to derive a no-observed-adverse-effect level (NOAEL) in male and female Sprague–Dawley rats following 91-day exposure to uranium (as uranyl nitrate hexahydrate, UN) in drinking water. Following a 28-day range-finding study, five groups of 15 male and 15 female

A. P. Gilman; D. C. Villeneuve; V. E. Secours; A. P. Yagminas; B. L. Tracy; J. M. Quinn; V. E. Valli; R. J. Willes; M. A. Moss

1998-01-01

48

Treating acne with oral contraceptives: use of lower doses.  

PubMed

Oral contraceptives (OCs) have been shown to effectively treat acne. Clinical trials of various doses of ethinyl estradiol (EE) combined with progestins such as levonorgestrel, desogestrel, norgestimate, gestodene, cyproterone acetate and drospirenone in monophasic, triphasic and combiphasic formulations used to treat acne in women are reviewed here. Open-label and comparative studies beginning in the 1980s were the first to demonstrate objective and subjective reductions in the incidence of acne, severity of existing acne and seborrhea. Placebo-controlled trials have corroborated these findings with a trend toward effective acne treatment with declining doses of EE. Significant reductions in total, inflammatory and noninflammatory lesions compared with placebo have been demonstrated with an OC containing the low dose of 20 microg of EE. Collectively, these findings support the use of low-dose OCs for the treatment of acne. PMID:16371290

Huber, Johannes; Walch, Katharina

2005-09-26

49

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

Microsoft Academic Search

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

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

2003-01-01

50

Prophylactic valacyclovir to prevent outbreaks of primary herpes gladiatorum at a 28-day wrestling camp.  

PubMed

Herpes gladiatorum (HG) plagues the sport of wrestling, especially in high school wrestlers and summer camps they attend. This study evaluated the usage of valacyclovir to prevent acquisition of primary HG, due to herpes simplex virus type 1 (HSV-1), in high school wrestlers at a 28-day wrestling camp. At the beginning and end of camp, IgM and IgG anti-HSV-1 antibodies were collected. Out of 332 male wrestlers, aged 13-20, who entered camp, 94 elected to participate in blood sampling. Sixty-four were on antiviral medication. Among the 94 wrestlers, 28 (29.8%) had positive IgG anti-HSV-1 titers. Of this group, 66 of 94, were HSV-1 IgG seronegative. At the end of camp, 55 of these original seronegative individuals elected to participate in blood sampling and none had detectable IgM anti-HSV-1 and -2 antibodies. Compared to previous years without antiviral usage, introducing prophylactic valacyclovir reduced clinical HG outbreaks by 87% at this 28-day wrestling camp. Due to the high prevalence of this virus in high school wrestlers, serological testing should be done at the beginning of each season. HSV-1 seropositive individuals should consider being on antiviral medication throughout the season to minimize the risk of transmitting the virus to other wrestlers. PMID:16495626

Anderson, B J

2006-02-01

51

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

Microsoft Academic Search

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

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

1996-01-01

52

The Dose Proportionality of Telcagepant after Administration of Single Oral and Intravenous Doses in Healthy Adult Subjects  

PubMed Central

Introduction Telcagepant (MK-0974) is a novel, orally active and selective CGRP receptor antagonist being investigated for acute treatment of migraine. Early clinical data suggested greater than dose proportional increases in exposure following oral administration. The aim of the present studies was to definitively characterize the oral and IV dose proportionality of telcagepant. Methods Healthy adult subjects were enrolled in two separate open-label randomized dose proportionality studies: 1) single oral dose crossover from 50 to 600 mg (N = 19); 2) single IV dose parallel group from 5 to 250 mg (N = 10 per dose). Blood samples were collected at time points from 0 to 48 hours postdose. Results Telcagepant was rapidly absorbed with a Tmax of approximately 1 to 2 hours after oral administration. The terminal half-life was approximately 8 to 9 hours after IV dosing and approximately 4 to 7 hours after oral dosing. Oral administration of telcagepant resulted in greater than dose proportional increases in exposure, while IV administration resulted in approximately dose proportional increases in exposure. Conclusions Telcagepant was generally well tolerated. Oral telcagepant exhibits non-linear pharmacokinetics.

Han, Tae H; Blanchard, Rebecca L; Palcza, John; Martucci, Ashley; Miller-Stein, Cynthia M; Gutierrez, Maria; Panebianco, Deborah; Rippley, Ronda K; Lines, Christopher; Murphy, M Gail

2010-01-01

53

The Dose Proportionality of Telcagepant after Administration of Single Oral and Intravenous Doses in Healthy Adult Subjects.  

PubMed

INTRODUCTION: Telcagepant (MK-0974) is a novel, orally active and selective CGRP receptor antagonist being investigated for acute treatment of migraine. Early clinical data suggested greater than dose proportional increases in exposure following oral administration. The aim of the present studies was to definitively characterize the oral and IV dose proportionality of telcagepant. METHODS: Healthy adult subjects were enrolled in two separate open-label randomized dose proportionality studies: 1) single oral dose crossover from 50 to 600 mg (N = 19); 2) single IV dose parallel group from 5 to 250 mg (N = 10 per dose). Blood samples were collected at time points from 0 to 48 hours postdose. RESULTS: Telcagepant was rapidly absorbed with a T(max) of approximately 1 to 2 hours after oral administration. The terminal half-life was approximately 8 to 9 hours after IV dosing and approximately 4 to 7 hours after oral dosing. Oral administration of telcagepant resulted in greater than dose proportional increases in exposure, while IV administration resulted in approximately dose proportional increases in exposure. CONCLUSIONS: Telcagepant was generally well tolerated. Oral telcagepant exhibits non-linear pharmacokinetics. PMID:21221171

Han, Tae H; Blanchard, Rebecca L; Palcza, John; Martucci, Ashley; Miller-Stein, Cynthia M; Gutierrez, Maria; Panebianco, Deborah; Rippley, Ronda K; Lines, Christopher; Murphy, M Gail

2010-12-01

54

Pharmacokinetics of temafloxacin in humans after single oral doses.  

PubMed Central

Temafloxacin (A-63004) is a new quinolone antibacterial agent with a broad spectrum of activity against gram-positive and gram-negative aerobes and anaerobes. The pharmacokinetics and metabolism of temafloxacin were determined in healthy volunteers after administration of single oral doses of 100, 200, 400, 600, 800, and 1,000 mg. The corresponding peak concentrations in plasma (mean +/- standard deviation) were 0.98 +/- 0.26, 1.61 +/- 0.57, 2.43 +/- 0.56, 3.87 +/- 0.64, 4.54 +/- 1.03, and 6.67 +/- 0.74 micrograms/ml. The times that elapsed to attain peak levels ranged from 1.25 to 3.5 h. Statistical analyses of parameters related to the extent of absorption and the linearity of the dispositional pharmacokinetics detected no dose-related trends. Study-wide, total clearance (223 ml/min) and renal clearance (125 ml/min) showed low intersubject variability, with coefficients of variation near 20%. The terminal-phase rate constant of 0.090 +/- 0.008 h-1 corresponds to a half-life of 7.7 h. Temafloxacin was excreted mainly in the urine, with 57 +/- 11% of the dose appearing in the urine unchanged. Conjugated temafloxacin, oxidative metabolites, and conjugates thereof were minor components in urine, collectively accounting for 5 to 8% of the dose. Since intravenously dosed dogs eliminated 50% of the dose by nonrenal processes, urinary recoveries approaching two-thirds of the dose in humans were consistent with high, if not quantitative, absorption. Reported adverse events were generally mild, were randomly distributed between temafloxacin- and placebo-treated subjects, and were not dose related.

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

1991-01-01

55

Safety and tolerability of intravenous-to-oral treatment and single-dose intravenous or oral prophylaxis with trovafloxacin  

Microsoft Academic Search

Background: The new fourth-generation fluoroquinolone, trovafloxacin, is active in vitro against gram-positive and gram-negative organisms, atypical pathogens, and anaerobes, and has pharmacokinetics permitting once-daily intravenous or oral dosing. Safety\\/tolerability data from phase II\\/III clinical trials of sequential intravenous alatrofloxacin to oral trovafloxacin and single-dose intravenous or oral prophylaxis are summarized.Methods: All trials were double-blind, randomized, and multicenter. In multidose trials

Debra J Williams; Scott Hopkins

1998-01-01

56

Evaluation of the toxicity of concentrated barley beta-glucan in a 28-day feeding study in Wistar rats.  

PubMed

Beta-glucans are water-soluble cell-wall polysaccharides consisting of (1-->3,1-->4)-linked beta-D-glucopyranosyl monomers that comprise a considerable proportion of soluble fiber from certain grains including oats and barley. Consumption of foods containing beta-glucan or beta-glucan-enriched fractions prepared from these grains lower serum cholesterol concentrations in humans and in animal models of hypercholesterolemia. The present study was conducted to evaluate the toxicity of beta-glucan-enriched soluble fiber from barley in Wistar rats on dietary administration at concentrations of 0.7, 3.5 and 7% beta-glucan for 28 days. There were no adverse effects on general condition and behavior, growth, feed and water consumption, feed conversion efficiency, red blood cell and clotting potential parameters, clinical chemistry values, and organ weights. Necropsy and histopathology findings revealed no treatment-related changes in any organ evaluated. A dose-dependent increase in full and empty cecum weight was observed. This is a common physiological response of rodents to high amounts of poorly digestible, fermentable carbohydrates, and was of no toxicological concern. The only finding of possible biological relevance was an increase in the number of circulating lymphocytes observed in males. However, the increase was not dose-dependent and was not observed in females. Results of this study demonstrated that consumption of concentrated barley beta-glucan was not associated with any obvious signs of toxicity in Wistar rats even following consumption of large quantities. PMID:12615121

Delaney, B; Carlson, T; Frazer, S; Zheng, T; Hess, R; Ostergren, K; Kierzek, K; Haworth, J; Knutson, N; Junker, K; Jonker, D

2003-04-01

57

Oral cyanocobalamin supplementation in older people with vitamin B12 deficiency: a dose-finding trial  

Microsoft Academic Search

BACKGROUND: Supplementation with high doses of oral cobalamin is as effective as cobalamin administered by intramuscular injection to correct plasma markers of vitamin B(12) deficiency, but the effects of lower oral doses of cobalamin on such markers are uncertain. METHODS: We conducted a randomized, parallel-group, double-blind, dose-finding trial to determine the lowest oral dose of cyanocobalamin required to normalize biochemical

S. J. P. M. Eussen; L. C. de Groot; R. Clarke; J. Schneede; P. M. Ueland; W. H. L. Hoefnagels; W. A. van Staveren

2005-01-01

58

Difloxacin metabolism and pharmacokinetics in humans after single oral doses.  

PubMed Central

By using high-performance liquid chromatography, the metabolism and pharmacokinetics of difloxacin were characterized in humans after single oral doses of 200, 400, and 600 mg. Group mean peak levels in plasma were obtained 4 h after administration. The means of the individual peak levels for the 200-, 400-, and 600-mg groups were 2.17, 4.09, and 6.12 micrograms/ml, respectively. The mean respective terminal-phase half-lives were 20.6, 27.1, and 28.8 h; the mean half-life for all subjects was 25.7 h. Within the dose range studied, the behavior of difloxacin could be well described by a set of linear pharmacokinetic parameters with a one-compartment open model. Levels of unconjugated metabolites in plasma were negligible. The major urinary components were difloxacin and its glucuronide, each accounting for roughly 10% of the dose. Also present were the N-desmethyl and N-oxide metabolites, accounting for 2 to 4%. Trace levels of other metabolites were observed. Group mean renal clearances ranged from 4.1 to 5.6 ml/min, indicating extensive reabsorption from the glomerular filtrate. As a result, the terminal phase half-life and the dose-normalized area under the curve were substantially greater than those of other members of the class.

Granneman, G R; Snyder, K M; Shu, V S

1986-01-01

59

Terbinafine pharmacokinetics after single dose oral administration in the dog.  

PubMed

Terbinafine is an allylamine antifungal prescribed for the treatment of mycoses in humans. It is increasingly being used in veterinary patients. The purpose of this study was to evaluate the pharmacokinetic properties of terbinafine in dogs after a single oral dose. Ten healthy adult dogs were included in the study. A single dose of terbinafine (30-35 mg/kg) was administered orally, and blood samples were periodically collected over a 24 h period during which dogs were monitored for adverse effects. Two of 10 dogs developed transient ocular changes. A high-performance liquid chromatography assay was developed and used to determine plasma terbinafine concentrations. Pharmacokinetic analysis was performed using PK Solutions(®) computer software. Area under the curve (AUC) from time 0 to 24 h was 15.4 ?g·h/mL (range 5-27), maximal plasma concentration (C(max) ) was 3.5 ?g/mL (range 3-4.9 ?g/mL) and time to C(max) (T(max) ) was 3.6 h (range 2-6 h). The time above minimal inhibitory concentration (T > MIC) as well as AUC/MIC was calculated for important invasive fungal pathogens and dermatophytes. The T > MIC was 17-18 h for Blastomyces dermatitidis, Histoplasma capsulatum and dermatophytes (Microsporum spp. and Trichophyton mentagrophytes), while the MIC for Sporothrix schenckii and Coccidioides immitis was exceeded for 9.5-11 h. The AUC/MIC values ranged from 9 to 13 ?g h/mL for these fungi. Our results provide evidence supporting the use of terbinafine as an oral therapeutic agent for treating systemic and subcutaneous mycoses in dogs. PMID:21599768

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

2011-05-20

60

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

PubMed

Enterotoxigenic Escherichia coli (ETEC) is a primary cause of traveler's diarrhea for which there is no licensed vaccine. This phase 1 trial determined the safety and immunogenicity of a recombinantly produced double mutant heat-labile enterotoxin (dmLT) of ETEC. It was administered as a single oral dose of dmLT in escalating doses of 5 ?g, 25 ?g, 50 ?g, and 100 ?g, followed by a 72-h inpatient observation, outpatient visits at 8, 14, and 28 days, and telephone calls at 2 and 6 months postvaccination. Safety was assessed by frequency of adverse events, and immune responses determined after immunization included dmLT-specific serum IgA and IgG, fecal IgA, antibody-secreting cells (ASC), and antibodies in lymphocyte supernatant (ALS) responses. All doses were well tolerated by the 36 healthy adults enrolled. Immune responses were limited in the 5- and 25-?g dose recipients. The 50-?g dose recipients trended toward stronger responses than the 100-?g dose recipients by serum IgA (67% versus 33%, P = 0.22), serum IgG (58% versus 33%, P = 0.41), and fecal IgA (58% versus 33%, P = 0.41). By day 14 postvaccination, there were significantly more positive responders (?4-fold increase from baseline) among the 50- versus 100-?g dose recipients for serum IgA (P = 0.036) but not serum IgG (P = 0.21). In conclusion, a single oral dose of dmLT was well tolerated and immunogenic, with immune responses plateauing at the 50-?g dose. (This clinical trial is registered at www.clinicaltrials.gov, registration number NCT01147445.). PMID:24049109

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

2013-09-18

61

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

62

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

63

A Phase 1 dose-escalation study of the safety and pharmacokinetics of once-daily oral foretinib, a multi-kinase inhibitor, in patients with solid tumors.  

PubMed

Foretinib is an oral multi-kinase inhibitor targeting MET, vascular endothelial growth factor receptor (VEGFR)-2, RON, KIT, and AXL kinases. In this Phase 1, open-label, non-randomized study, foretinib was administered once daily at doses of 60 mg, 80 mg, 100 mg, or 120 mg for 28 days. The primary objectives were to determine the maximum tolerated dose (MTD) and assess the safety and tolerability of the daily oral administration schedule. Secondary objectives included pharmacokinetics, pharmacodynamics, and assessment of tumor response. Patients had histologically confirmed metastatic or unresectable solid tumors for which no standard treatments existed and all received oral foretinib once daily. Dose escalation was planned as a conventional "3+3" design with an expansion at the MTD for collection of additional safety and pharmacokinetic information. Thirty-seven patients were treated across four dose levels. The MTD was established as 80 mg foretinib. Dose-limiting toxicities were hypertension, dehydration, and diarrhea. The most common adverse events included fatigue, hypertension, nausea, and diarrhea. Twenty-three of 31 patients (74 %) had a best response of stable disease. No patient had a confirmed partial or complete response. At the MTD, steady state was achieved by approximately 2 weeks, with average post-dose time to maximum concentration, peak concentration, and trough concentration of 4 h, 46 ng/mL, and 24 ng/mL, respectively. In patients treated at the MTD, soluble MET and VEGF-A plasma levels significantly increased (P<0.003) and soluble VEGFR2 plasma levels significantly decreased from baseline (P<0.03). The MTD of foretinib bisphosphate salt was determined to be 80 mg once daily. PMID:23054208

Shapiro, Geoffrey I; McCallum, Stewart; Adams, Laurel M; Sherman, Laurie; Weller, Steve; Swann, Suzanne; Keer, Harold; Miles, Dale; Müller, Thomas; Lorusso, Patricia

2012-10-06

64

Effects of Oral Prasterone (Dehydroepiandrosterone) on Single-Dose Pharmacokinetics of Oral Prednisone and Cortisol Suppression in Normal Women  

Microsoft Academic Search

This study sought to determine effects of multiple dosing of prasterone (DHEA, dehydroepiandrosterone) on the pharmacokinetics of prednisolone and endogenous cortisol secretion. These drugs are likely to be coadministered to patients with systemic lupus erythematosus. Fourteen normal women (ages 30.1 ± 5.4 years) received single-dose oral prednisone (20 mg) before and after 200 mg\\/day of oral prasterone for one menstrual

Guy M. L. Meno-Tetang; Robert A. Blum; Kenneth E. Schwartz; William J. Jusko

2001-01-01

65

The effect of low oral doses of (?)-deprenyl and its metabolites on DSP4 toxicity  

Microsoft Academic Search

Summary.   Treatment with a single oral dose of (?)-deprenyl (selegiline) before DSP-4 administration could dose-dependently decrease\\u000a the noradrenaline (NA) depleting effect of the toxin in mouse hippocampus. The maximum protective effect was achieved at as\\u000a low oral dose as 0.25 mg\\/kg. Pre-treatment with the same doses of the main metabolites of (?)-deprenyl: (?)-amphetamine and\\u000a (?)-methylamphetamine provided a weaker attenuation of

D. Haberle; É. Szökö; A. S. Halász; K. Magyar

2001-01-01

66

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

EPA Science Inventory

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

67

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...

68

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

69

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

2011-04-07

70

Learning the Dose Adjustment for the Oral Anticoagulation Treatment  

Microsoft Academic Search

\\u000a Several attempts have been recently provided to define Oral Anticoagulant (OA) guidelines. These guidelines include indications\\u000a for oral anticoagulation and suggested arrangements for the management of an oral anticoagulant service. They aim to take\\u000a care of the current practical difficulties involved in the safe monitoring of the rapidly expanding numbers of patients on\\u000a long-term anticoagulant therapy. Nowadays, a number of

Giacomo Gamberoni; Evelina Lamma; Paola Mello; Piercamillo Pavesi; Sergio Storari; Giuseppe Trocino

2004-01-01

71

Persistence of the oral probiotic Streptococcus salivarius M18 is dose dependent and megaplasmid transfer can augment their bacteriocin production and adhesion characteristics.  

PubMed

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

2013-06-13

72

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

PubMed Central

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

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

2013-01-01

73

Comparative trials of low-dose combined oral contraceptives.  

PubMed

2 studies were conducted to assess the rate of side effects among women using combined oral contraceptives (OCs). In the 1st study, women were randomly assigned to Norinyl, Norlestrin, or Ovral for 3 cycles and then switched to 1 of the other 2 OCs or stayed on the same OC. For all 3 OCs, the rates of most side effects declined significantly with the increasing duration of OC use. Cycle control appeared best for women using Ovral. There were some adverse effects due to switching from 1 OC to another. Generally, women who switched to Ovral experienced a decrease in the rate of breakthrough bleeding and those who switched from Ovral experienced an increase in the rate of breakthrough bleeding. Discontinuation rates were similar for users of all 3 OCs. In the 2nd study, women who had used Norinyl or Ovral for at least 3 cycles were randomly assigned to either Brevicon or Lo-Ovral for 6 cycles. The most noticeable effect was a large increase in the proportions of women with breakthrough bleeding; this rate remained above the preswitchover rate even after 6 cycles of either drug. In the initial cycle after crossover, there was an increase in the rate of some side effects. By the completion of the 6th cycle, the rates of side effects were generally lower than those before crossover, with the exception of breakthrough bleeding. Discontinuation rates were similar for users of Brevicon and Lo-Ovral. The results of the study indicate that although women on low-dose OCs report lower rates of certain side effects, breakthrough bleeding occurs more frequently and might adversely affect continuation rates. PMID:6854550

Edelman, D A; Kothenbeutel, R; Levinski, M J; Kelly, S E

1983-03-01

74

Pharmacokinetics of sildenafil after single oral doses in healthy male subjects: absolute bioavailability, food effects and dose proportionality  

PubMed Central

Aims To determine the absolute bioavailability, dose proportionality and the effects of food on the pharmacokinetics of single oral doses of sildenafil citrate. Methods Three open-label, randomized crossover studies were conducted in healthy male subjects. Absolute bioavailability was determined by comparing pharmacokinetic data after administration of single oral and intravenous 50-mg doses of sildenafil (n = 12 subjects). Food effects were examined by comparing pharmacokinetic data for sildenafil and its primary circulating metabolite, UK-103,320, after administration of a single oral 100-mg dose in the fasted and fed states (n = 34 subjects). Dose proportionality was assessed from pharmacokinetic data obtained after administration of four single oral doses of sildenafil (25, 50, 100 and 200 mg) to 32 subjects. The safety and tolerability of sildenafil were also assessed in all of these studies. Results The calculated absolute oral bioavailability of sildenafil was 41% (90% CI: 36–47). Food slowed the rate of absorption, delaying mean tmax by approximately 1 h and reducing Cmax by 29% (90% CI: 19–38). Systemic exposure, as assessed by the mean area under the plasma concentration–time curve (AUC), was reduced by 11% (90% CI: 6–16). These food effects were not considered to be of clinical significance. There was statistical evidence of nonproportionality in Cmax and AUC over the dose range 25–200 mg. However the degree of nonproportionality was small, with predicted increases in Cmax and AUC of 2.2- and 2.1-fold, respectively, for a doubling in dose, and was thought to be clinically nonsignificant. Sildenafil was well tolerated in the three studies; the majority of adverse events were mild and transient. Conclusions Sildenafil had a mean absolute bioavailability of 41%. Food caused small reductions in the rate and extent of systemic exposure; these reductions are unlikely to be of clinical significance. Across the dose range of 25–200 mg, systemic exposure increased in a slightly greater than dose-proportional manner.

Nichols, Donald J; Muirhead, Gary J; Harness, Jane A

2002-01-01

75

Intrapulmonary Pharmacokinetics of Azithromycin in Healthy Volunteers Given Five Oral Doses  

Microsoft Academic Search

The intrapulmonary pharmacokinetics of oral azithromycin were studied in 25 healthy volunteers, each of whom received an initial dose of 500 mg and then 250 mg once daily for four additional doses. Bronchoscopy, bronchoalveolar lavage, and venipuncture were performed 4, 28, 76, 124, 172, 244, 340, and 508 h after thefirst dose was administered. Azithromycin concentrations in epithelial lining fluid

KEITH M. OLSEN; GERARDO S. SAN PEDRO; LARRY P. GANN; PAUL O. GUBBINS

1996-01-01

76

High dose weekly oral prednisone improves strength in boys with Duchenne muscular dystrophy  

Microsoft Academic Search

Daily prednisone improves strength in boys with Duchenne muscular dystrophy, but side effects are almost universal. We used a different dosing regimen of prednisone to determine if benefit to boys with Duchenne muscular dystrophy might be maintained with fewer side effects. Twice weekly oral prednisone was given each Friday and Saturday (5mg\\/kg\\/dose). This total dose is twice as high as

Anne M. Connolly; Jeanine Schierbecker; Renee Renna; Julaine Florence

2002-01-01

77

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.

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

1995-01-01

78

Low dose oral methotrexate treatment of multiple sclerosis: a pilot study  

Microsoft Academic Search

An 18-month double-blind treatment of multiple sclerosis with low dose oral methotrexate showed it to be well tolerated and suggested effectiveness in exacerbating-remitting MS but not in the exacerbating progressive and chronic progressive stages.

R D Currier; A F Haerer; E F Meydrech

1993-01-01

79

Gastric emptying response to variable oral erythromycin dosing in diabetic gastroparesis  

Microsoft Academic Search

Intravenous erythromycin has been shown to improve gastric emptying in diabetic gastroparesis. Oral erythromycin also accelerates gastric emptying, but to a lesser degree. To determine if this is a dose-dependent phenomenon, gastric emptying was measured in 10 insulin-requiring diabetic patients with gastroparesis after administration of either 250 mg or 1000 mg of erythromycin or placebo. The drugs were orally administered

Steven G. Desautels; William R. Hutson; Paul E. Christian; John G. Moore; Fred L. Datz

1995-01-01

80

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

81

Relative validity of a semi-quantitative food frequency questionnaire versus 28 day weighed diet records in Japanese female dietitians  

Microsoft Academic Search

Objective: To assess the relative validity of a semi-quantitative food frequency questionnaire (SQFFQ) against 28 day weighed diet records (WDRs).Subjects and methods: The SQFFQ was administered to 106 (21 male and 85 female) Japanese dietitians in Aichi Prefecture in autumn, 1996 and four-season consecutive 7 day WDRs were carried out during 1996–1997. We evaluated validity of intakes of 15 foods

S Tokudome; N Imaeda; Y Tokudome; N Fujiwara; T Nagaya; J Sato; K Kuriki; M Ikeda; S Maki

2001-01-01

82

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

Microsoft Academic Search

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

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

1976-01-01

83

Pharmacokinetics of bolus intravenous and oral doses of L-carnitine in healthy subjects.  

PubMed

The pharmacokinetics of single intravenous and oral doses of L-carnitine 2 and 6 g was studied in 6 healthy subjects on a low-carnitine diet. Carnitine was more rapidly eliminated from plasma after the 6 g dose. Comparing the doses, the t1/2 beta of the elimination phase (beta) was 6.5 h vs 3.9 h, the elimination constant 0.40 vs 0.50 h-1 and the plasma carnitine clearance was 5.4 vs 6.11.h-1 for the 2 g and 6 g doses, respectively, showing dose-related elimination. Saturable kinetics were not found. The apparent volumes of distribution after the two doses were not significantly different and were of the same order as the total body water. Urinary recoveries of the 2 g and 6 g doses were 70% and 82%, respectively, during the first 24 h. Following the oral doses, there was no significant difference between the areas under the plasma carnitine concentration-time curves. Urinary recovery was 8% and 4% for the 2 g and 6 g doses during the first 24 h. Oral bioavailability was 16% for the 2 g dose and 5% for the 6 g dose. The results suggest that the mucosal absorption of carnitine was already saturated by the 2 g dose. PMID:3220097

Harper, P; Elwin, C E; Cederblad, G

1988-01-01

84

Urinary Excretion and Bactericidal Activities of a Single Oral Dose of 400 Milligrams of Fleroxacin versus a Single Oral Dose of 800 Milligrams of Pefloxacin in Healthy Volunteers  

Microsoft Academic Search

Twelve healthy volunteers participated in this randomized crossover study to compare the concentrations and recovery levels of fleroxacin and pefloxacin in urine and to assess their bactericidal activities against 12 strains of urinary pathogens with different susceptibilities over a wide range of MICs. The volunteers received a single oral dose of 400 mg of fleroxacin or 800 mg of pefloxacin.

KURT G. NABER; URSULA THEURETZBACHER; MARTINA KINZIG; ORLIN SAVOV; FRITZ SORGEL

1998-01-01

85

Noncontraceptive benefits of modern low-dose oral contraceptives  

Microsoft Academic Search

Most oral contraceptive formulations in current use contain 50 µg or less of ethinyl estradiol and 1 mg or less of the various progestins: norethindrone (0.5–1 mg), norgestrel (0.3–0.5 mg), or levonorgestrel (0.05–0.25 mg) [1].

I. H. Thorneycroft

1992-01-01

86

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

87

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

PubMed

This study compared the oral cavity dose between the routine 7-beam intensity-modulated radiotherapy (IMRT) beam arrangement and 2 other 7-beam IMRT with the conventional radiotherapy beam arrangements in the treatment of nasopharyngeal carcinoma (NPC). Ten NPC patients treated by the 7-beam routine IMRT technique (IMRT-7R) between April 2009 and June 2009 were recruited. Using the same computed tomography data, target information, and dose constraints for all the contoured structures, 2 IMRT plans with alternative beam arrangements (IMRT-7M and IMRT-7P) by avoiding the anterior facial beam and 1 conventional radiotherapy plan (CONRT) were computed using the Pinnacle treatment planning system. Dose-volume histograms were generated for the planning target volumes (PTVs) and oral cavity from which the dose parameters and the conformity index of the PTV were recorded for dosimetric comparisons among the plans with different beam arrangements. The dose distributions to the PTVs were similar among the 3 IMRT beam arrangements, whereas the differences were significant between IMRT-7R and CONRT plans. For the oral cavity dose, the 3 IMRT beam arrangements did not show significant difference. Compared with IMRT-7R, CONRT plan showed a significantly lower mean dose, V30 and V-40, whereas the V-60 was significantly higher. The 2 suggested alternative beam arrangements did not significantly reduce the oral cavity dose. The impact of varying the beam angles in IMRT of NPC did not give noticeable effect on the target and oral cavity. Compared with IMRT, the 2-D conventional radiotherapy irradiated a greater high-dose volume in the oral cavity. PMID:21546243

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

2011-05-04

88

“Zeus” a new oral anticoagulant therapy dosing algorithm : A cohort study  

Microsoft Academic Search

The demand for oral anticoagulant therapy (OAT) has constantly increased during the last ten years with an extended use of computer assistance. Many mathematical algorithms have been projected to suggest doses and time to next visit for patients on OAT. We designed a new algorithm: “Zeus”.A “before-after” study was planned to compare the efficacy and safety of this algorithm dosing

A. Cafolla; R. Melizzi; E. Baldacci; P. Pignoloni; F. Dragoni; M. Campanelli; R. Caraccini; R. Foŕ

2011-01-01

89

Alterations in prednisolone disposition as a result of oral contraceptive use and dose.  

PubMed Central

The disposition of total and free prednisolone has been studied in eight female subjects who used combined oestrogen-progestogen oral contraceptives and in eight female subjects who did not, each of whom received separate intravenous doses of 0.1 mg/kg (low) and 1.0 mg/kg (high) of prednisolone. Mean free prednisolone clearance was reduced congruent to 30% in oral contraceptive users compared to control subjects (P less than 0.001), the difference being greater for the low dose (39%) than for the high dose (24%). Pre-dose plasma cortisol concentrations were elevated two-fold (P less than 0.001) in oral contraceptive users compared to control subjects. These effects are consistent with a mechanism in which the competitive inhibition of free prednisolone clearance by cortisol contributes to the reduction of free prednisolone clearance by oral contraceptive use. Mean total prednisolone clearance and steady state distribution volume showed an approximate two-fold dose dependent increase consistent with a similar increase in plasma prednisolone free fraction (P less than 0.001). Free prednisolone clearance showed an 18% dose dependent decrease (P less than 0.001) but free steady-state distribution volume did not change with dose. At plasma prednisolone concentrations less than 400 ng/ml, prednisolone free fractions at any prednisolone concentration were greater after the low, than after the high dose. This effect is consistent with the displacement of prednisolone by cortisol from transcortin but not from albumin.

Meffin, P J; Wing, L M; Sallustio, B C; Brooks, P M

1984-01-01

90

LBNP treadmill exercise maintains spine function and muscle strength in identical twins during 28-day simulated microgravity.  

PubMed

The purpose of this study was to determine whether lower body negative pressure (LBNP) treadmill exercise maintains lumbar spinal compressive properties, curvature, and back muscle strength after 28 days of 6 degrees head-down tilt (HDT) bed rest (BR). We hypothesize that LBNP treadmill exercise will maintain lumbar spine compressibility, lumbar lordosis and back muscle strength after 28 days of 6 degrees HDT bed rest. Fifteen healthy identical twin pairs (14 women and 16 men) participated in this study. One identical twin was randomly assigned to the nonexercise control (Con) group, and their sibling was assigned to the exercise (Ex) group. The lumbar spine was significantly more compressible Post-BR compared with Pre-BR in the Con (P=0.01). Lumbar spine compressibility Post-BR was not significantly different compared with Pre-BR in the Ex group (P=0.89). In both the Con and Ex groups, there were no significant changes Post-BR in lumbar lordosis compared with Pre-BR. Back muscle strength significantly decreased in the Con group Post-BR (P=0.002), whereas in the Ex group back muscle strength was not significantly different from Pre-BR values. A significant increase in lumbar spine compressibility in the Con group suggests that spinal deconditioning to gravity occurs during 28-day bed rest. Changes in the mechanical properties of the lumbar spine may be an early indicator of lumbar intervertebral disk degeneration. Supine LBNP treadmill exercise provides axial loads to the lumbar spine and may prevent lumbar spine deconditioning associated with HDT bed rest. PMID:17395762

Macias, Brandon R; Cao, Peihong; Watenpaugh, Donald E; Hargens, Alan R

2007-03-29

91

A Dose Escalation Study of Biweekly Oral Vinorelbine and Gemcitabine in Patients with Solid Tumors  

Microsoft Academic Search

Purpose: To determine the maximum tolerated doses (MTDs) and the dose-limiting toxicities of a biweekly administration of oral vinorelbine and gemcitabine in patients with advanced solid tumors. Patients and Methods: Twenty-eight patients with advanced stage solid tumors were enrolled, and 12 (42.9%) of them were chemotherapy naive. Escalating doses of vinorelbine (50–70 mg\\/m2 per os) and gemcitabine (800–1,000 mg\\/m2 as

A. Karampeazis; L. Vamvakas; S. Agelaki; N. Kentepozidis; E. Papadimitraki; I. Gioulbasanis; N. Vardakis; M. Ignatiadis; D. Mavroudis; V. Georgoulias

2006-01-01

92

Pharmacokinetics of bolus intravenous and oral doses of L-carnitine in healthy subjects  

Microsoft Academic Search

The pharmacokinetics of single intravenous and oral doses of L-carnitine 2 and 6 g was studied in 6 healthy subjects on a low-carnitine diet. Carnitine was more rapidly eliminated from plasma after the 6 g dose. Comparing the doses, the t1\\/2ß of the elimination phase (ß) was 6.5 h vs 3.9 h, the elimination constant 0.40 vs 0.50 h-1 and

P. Harper; C.-E. Elwin; G. Cederblad

1988-01-01

93

Importance of dose selection in novel oral anticoagulants for atrial fibrillation.  

PubMed

There are several excellent alternatives to warfarin on the horizon for atrial fibrillation. Results from the trials, as well as pharmacokinetic data from the edoxaban studies, suggest that dose selection, based on pharmacokinetic and pharmacodynamic properties, is a critical component in the development of novel anticoagulants. Greater flexibility in dosing with edoxaban and the opportunity for dose adjustment throughout the ENGAGE AF-TIMI 48 trial may be advantageous in the competitive field of novel oral anticoagulants. PMID:23168295

Grip, Laura T; Giugliano, Robert P

94

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

Microsoft Academic Search

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

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

1977-01-01

95

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.

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

2009-01-01

96

Postnatal Evaluation of Behavior and Cardiovascular Function in Rats Following Daily Oral Caffeine Dosing of Dams Throughout Gestation.  

National Technical Information Service (NTIS)

The study was designed to evaluate the teratogenic effects of caffeine given orally by gavage, and to further evaluate postnatal development and function after oral caffeine exposure. Experiment I consisted of sixty rats given daily gavage doses on days 1...

C. Kimmel J. Adams P. Sullivan

1984-01-01

97

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-naďve HIV-1-infected adults. Randomization and allocation to study arms were carried out by a central computer system. Results were analyzed by ANOVA, Kruskal-Wallis, ANCOVA, and two-tailed paired t tests. Results VS411 was well-tolerated, produced significant reductions of HIV-1 RNA levels, increased CD4+ T cell counts, and led to significant, rapid, unprecedented reductions of immune activation markers after 28 days despite incomplete viral suppression and without inhibiting HIV-1-specific immune responses. The didanosine 200 mg/HC 900 mg once-daily formulation demonstrated the greatest antiviral efficacy (HIV-1 RNA: ?1.47 log10 copies/mL; CD4+ T cell count: +135 cells/mm3) and fewest adverse events. Conclusions VS411 successfully established the Proof-of-Concept that AV-HALTs can combine antiviral efficacy with rapid, potentially beneficial reductions in the excessive immune system activation associated with HIV-1 disease. Rapid reductions in markers of immune system hyperactivation and cellular proliferation were obtained despite the fact that VS411 did not attain maximal suppression of HIV RNA, suggesting this effect was due to the HALT component. Trial Registration ITEudraCT 2007-002460-98

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

2012-01-01

98

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.

2012-01-01

99

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

100

Low-dose intranasal versus oral midazolam for routine body MRI of claustrophobic patients  

Microsoft Academic Search

The purpose of this study was to assess prospectively the potential of low-dose intranasal midazolam compared to oral midazolam\\u000a in claustrophobic patients undergoing routine body magnetic resonance imaging (MRI). Seventy-two adult claustrophobic patients\\u000a referred for body MRI were randomly assigned to one of two treatment groups (TG1 and TG2). The 36 patients of TG1 received\\u000a 7.5 mg midazolam orally 15 min before

Frank T. C. Tschirch; Kerstin Göpfert; Johannes M. Fröhlich; Genevieve Brunner; Dominik Weishaupt

2007-01-01

101

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

102

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

PubMed

Voclosporin (VCS) is a novel calcineurin (CN) inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. These studies evaluated the single ascending dose pharmacokinetics (PK) and pharmacodynamics (PD, CN activity) of VCS and the effect of food. VCS was administered orally in single doses of 0.25 through 4.5 mg/kg in 62 subjects in the single ascending dose study and as a single oral 1.5?mg/kg dose to 18 subjects after fasting, consumption of a low-fat and high-fat meal. Non-compartmental PK, PD, and PKPD correlation were evaluated. Following single oral doses, systemic exposure increased in a linear manner and demonstrated 1:1 dose-proportional, first-order linear PK above 1.5?mg/kg. VCS inhibited CN activity in a dose-related fashion with maximal inhibition peaking at 3.0 mg/kg. PKPD correlation indicated an EC50 of 78.3?±?6.8?ng/mL. Administration of VCS with a low-fat and high-fat meal decreased C(max) by 29% and 53%, respectively, and AUC(inf) by 15% and 25%, respectively. Following ascending single doses of VCS, exposure increased in a linear fashion. A food effect on exposure was demonstrated, with a more pronounced effect following a high-fat meal. VCS concentrations were also found to correlate with CN activity. PMID:23736966

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

2013-06-04

103

Crossover Dose Escalation Study to Assess Safety, Pharmacokinetics, and Pharmacodynamics of Single Doses of R1663, an Oral Factor Xa Inhibitor, in Healthy Male Volunteers  

Microsoft Academic Search

This study investigated the safety, pharmacokinetics, and pharmacodynamics of single oral doses of R1663, a factor Xa inhibitor, in healthy volunteers. It was a single-blind, randomized, crossover, placebo-controlled, dose escalation study in 33 healthy male volunteers aged 18 to 45 years. Each volunteer was dosed on 3 occasions with R1663 or placebo. Single oral doses of R1663 were safe and

Christophe Schmitt; Anne Pannier; Christine McIntyre; Hagen Zandt; Cornelia Ciorciaro; Katie Winters; Tom Pepper

2012-01-01

104

Low-dose oral caffeine induces a specific form of behavioral sensitization in rats.  

PubMed

The present study assessed the effects of a low dose of orally administered caffeine on sensitization of open-field behavior in rats. Rats had free access to untreated water every day or water containing 0.2 mg/ml of caffeine every other day of the 14-day experiment. On alternate days discrete movements (horizontal and vertical) and ambulatory distance were measured in open-field activity monitors. Although caffeine intake significantly decreased across test sessions in caffeine-treated rats, the number of discrete horizontal movements significantly increased. These findings suggest that low doses of orally administered caffeine induce a specific form of behavioral sensitization in rats. PMID:22358105

Ball, Kevin T; Poplawsky, Alex

2011-01-01

105

Relation of infarct site to 15 year prognosis in patients who survived for 28 days after a first myocardial infarction.  

PubMed Central

Six hundred and eighty four patients (629 men), all aged under 60 years, who had survived for 28 days after a first acute myocardial infarction were studied to determine the influence of the site of infarction on long term prognosis. The infarct site was not significantly related to age nor to extent of infarct at the time of the acute episode. Mechanical complications were more common in patients with anteroseptal infarctions, while atrioventricular conduction disturbances were more commonly found in those with inferior infarction. The site of infarction was not related to smoking habits or angina before the infarction or at 2 year follow up. Life table methods did not show any relation between infarction site and morbidity or mortality either two years or 15 years after the initial infarction.

Robinson, K; Conroy, R M; Mulcahy, R; Madden, B

1988-01-01

106

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

107

Dose-response relationship for oral idazoxan effects in healthy human subjects: comparison with oral yohimbine  

Microsoft Academic Search

The effects of oral administration of the ?2 adrenergic receptor antagonists idazoxan (20 mg, 40 mg, 80 mg) and yohimbine (20 mg) were compared using a placebo-controlled within-subjects design. Healthy subjects completed 5 test days during which medication effects on mood and anxiety states, physiologic indices, plasma cortisol levels, and plasma levels of the norepinephrine metabolite 3-methoxy-4-hydroxyphenylethylene glycol (MHPG) were

John H. Krystal; Christopher J. McDougle; Scott W. Woods; Lawrence H. Price; George R. Heninger; Dennis S. Charney

1992-01-01

108

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

Microsoft Academic Search

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

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

2004-01-01

109

Anti-inflammatory effects of high-dose inhaled fluticasone versus oral prednisone in asthma exacerbations  

Microsoft Academic Search

The objective of the present study was to investigate the kinetics of high doses of inhaled steroid fluticasone in comparison with oral steroid prednisone on plasma protein leakage and bronchial eosinophilia in adults with moderate asthma exacerbations. The study design was a randomised, double-blind, placebo-controlled prospective trial. In total, 45 patients treated at the emergency department for moderate asthma exacerbations

J. Belda; G. Margarit; C. Martinez; J. Bellido-Casado; P. Casan; M. Torrejon; M. Brufal; F. Rodriguez-Jerez; J. Sanchis

2007-01-01

110

Effect of single dose of oral erythromycin on gastric and gallbladder emptying  

Microsoft Academic Search

To evaluate the effects of a single oral dose of erythromycin on gastric and gallbladder emptying, 10 volunteers, without a known history of gastrointestinal disease, were investigated. Erythromycin stearate (500 mg) or placebo was given on separate mornings 30 min before a standard solid meal in a randomized, double-blind, crossover study. Gastric and gallbladder emptying rates were simultaneously evaluated by

Vincenzo Arienti; Fabio Magri; Luciana Boriani; Giovanni Maconi; Leona Bassein; Mario Baraldini; Leonardo Marzio; Giovanni Gasbarrini

1994-01-01

111

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

EPA Science Inventory

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

112

Exposure to the organophosphate diazinon: data from a human volunteer study with oral and dermal doses  

Microsoft Academic Search

Biological monitoring of occupational exposure to diazinon is possible by the determination of blood cholinesterase activity and by the measurement of metabolites in urine. However, there is little data to aid in the interpretation of results. This study gave oral (11 ?g kg?1 (36 nmol kg?1) body weight) and occluded dermal (100 mg (329 ?mol)) doses of diazinon to five

S. J. Garfitt; K. Jones; H. J. Mason; J. Cocker

2002-01-01

113

EFFECTS OF THREE COOKING METHODS ON CESIUM134 CONTENT OF BEEF FROM ORALLY DOSED STEERS  

Microsoft Academic Search

Meat front 10 steers that had been orally dosed with cesium-134 was ; cooked by 3 methods: roasting, braising, and stewing. The loss of radioactivity ; from the cooked meat was affected by the surface area exposed to liquid and the ; amount of water used for cooking. Boneless loin, oven-roasted without added ; liquid, retained 81% of the radioactivity;

B. Meyer; J. Forrester; M. C. Bell

1962-01-01

114

Effect of a single oral dose of rabeprazole on nocturnal acid breakthrough and nocturnal alkaline amplitude  

Microsoft Academic Search

AIM: To study the effect of rabeprazole (RAB) on nocturnal acid breakthrough (NAB) and nocturnal alkaline amplitude (NAKA) and to compare it with omeprazole (OME) and pantoprazole (PAN). METHODS: By an open comparative study, forty patients with active peptic ulcer were randomly assigned to receive one of the three PPIs (proton pump inhibitor) with a single oral dose. They were

Jin-Yan Luo; Chun-Yan Niu; Xue-Qin Wang; You-Ling Zhu; Jun Gong

115

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

PubMed

A single dose of 8 mg of thiocolchicoside was administered to 12 healthy volunteers according to a Latin square design, either as tablets (reference), oral solution, or intramuscular injection. Serum thiocolchicoside concentrations showed an absorption phase followed by a biexponential decay with a terminal half-life (t1/2 beta) of approximately 5 h, similar for the three formulations. The relative bioavailability of both oral formulations was approximately 25%, compared to the intramuscular formulation. There was a trend for the oral solution to have a slightly larger AUC and Cmax, as well as a slightly shorter Tmax, than the tablet formulation. However, the comparison of the two oral forms did not show statistically significant differences in the pharmacokinetic parameters Cmax, Tmax, and AUC, suggesting that the Coltramyl tablets have an adequate in vivo dissolution profile. PMID:8161719

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

1994-01-01

116

Treatment strategies to overcome end-of-dose failure with oral and transdermal opioids.  

PubMed

Extended-release oral and transdermal opioids are increasingly being used for the management of chronic pain. Although the dosing intervals for these products were established through controlled clinical trials, expanded use of extended-release and transdermal dosage forms has resulted in awareness that a significant number of patients with chronic pain experience loss of baseline pain control prior to the next scheduled dose. End-of-dose failure (EDF) is the term used to describe this type of pain manifestation. By recognizing potential causes of EDF, strategies may be developed to overcome its occurrence to improve patients' pain control. PMID:23011962

Hall, Levi M; O'Lenic, Kathleen

2011-03-24

117

28-Day Toxicity Study of 1-Methylethyl 2-Chloro-5-(((1-Methylethoxy)Thiomethyl)Amino)Benzoate (NSC-D629243) in Hamsters.  

National Technical Information Service (NTIS)

The study was conducted to determine potential target organ toxicity and its reversibility in hamsters following twice daily oral doses of NSC-D629243 for 28 consecutive days. Male and female hamsters were administered NSC-D629243 dissolved in sesame oil ...

G. E. Wilkinson M. E. Lynch M. J. Ryan M. E. Placke

1992-01-01

118

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

PubMed

Long chain polyunsaturated fatty acids (LC-PUFAs) in the diet reduce risk of cardiac mortality. Fish oils are a dietary source of LC-PUFAs (EPA, DHA) but intake is low in Western diets. Adding beneficial amounts of LC-PUFAs to foods is limited by their instability and potential to impart off-flavors. Stearidonic acid (SDA), a precursor of EPA in man, is more stable than EPA/DHA in food matrices. SDA is present in fish oils (0.5-4%) and in nutraceuticals (echium, borage oil). Genes for Delta6, Delta15 desaturases were introduced into soybeans that convert linoleic and alpha-linolenic acid to SDA (15-30% fatty acids). Since addition of SDA soybean oil into human foods increases SDA intake, toxicology studies were undertaken to assess its safety. In a 28-day pilot study, rats were gavaged with SDA soybean oil at dosages up to 3g/kg body weight/day; no treatment-related adverse effects were observed. A 90-day/one generation rat reproduction study was subsequently conducted where SDA soybean oil was added to diets to provide daily doses of 1.5 and 4 g/kg body weight. There were no treatment-related adverse effects on parental animals or on reproductive performance and progeny development. PMID:18804141

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

2008-08-31

119

Environmental Effects of Dredging. Preliminary Protocol for Conducting 28-Day Chronic Sublethal Sediment Bioassays Using the Estuarine Amphipod Leptocheirus plumulosus (Shoemaker).  

National Technical Information Service (NTIS)

This technical note describes a preliminary protocol for conducting a 28-day chronic sublethal sediment bioassay using the estuarine amphipod Leptocheirus plumulosus. End points for this test include survival, growth, and reproduction. This protocol provi...

1996-01-01

120

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

PubMed

Consumption of Se accumulator plants by livestock can result in Se intoxication. Recent research indicates that the Se forms most common in Se accumulator plants are selenate and Se-methylselenocysteine (MeSeCys). In this study the absorption, distribution, and elimination kinetics of Se in serum and whole blood of lambs dosed with a single oral dose of (1, 2, 3, or 4 mg Se/kg BW) of sodium selenate or MeSeCys were determined. The Se concentrations in serum and whole blood for both chemical forms of Se followed simple dose-dependent relationships. Se-methylselenocysteine was absorbed more quickly and to a greater extent in whole blood than sodium selenate, as observed by a greater peak Se concentration (Cmax; P < 0.0001), and faster time to peak concentration (Tmax; P < 0.0001) and rate of absorption (P < 0.0001). The rate of absorption and Tmax were also faster (P < 0.0001) in serum of lambs dosed with MeSeCys compared with those dosed sodium selenate at equimolar doses; however, Cmax in serum was greater (P < 0.0001) in lambs dosed with sodium selenate compared with those dosed MeSeCys at equimolar doses. The MeSeCys was absorbed 4 to 5 times faster into serum and 9 to 14 times faster into whole blood at equimolar Se doses. There were dose-dependent increases in the area under the curve (AUC) for Se in serum and whole blood of lambs dosed with both sodium selenate and MeSeCys. In whole blood the MeSeCys was approximately twice as bioavailable as sodium selenate at equimolar doses as observed by the AUC, whereas in serum there were no differences (P > 0.05) in AUC at the same doses. At 168 h postdosing the Se concentration in whole blood remained much greater (P < 0.0001) in lambs dosed with MeSeCys as compared with lambs dosed with sodium selenate; however, the serum Se concentrations were not different between treatments at the same time point. The results presented in this study demonstrate that there are differences between the kinetics of different selenocompounds when orally dosed to sheep. Therefore, in cases of acute selenosis, it is important to understand the chemical form to which an intoxicated animal was exposed when determining the importance and meaning of Se concentration in serum or whole blood obtained at various times postexposure. PMID:23825349

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

2013-07-03

121

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.

122

[Four-week repeated dose oral toxicity study of BMY-28100 in juvenile rats].  

PubMed

In order to investigate the repeated dose oral toxicity of BMY-28100 in juvenile rats, the drug was administered orally to 4-day-old Crj: CD(SD) rats of both sexes at daily doses of 250, 750 and 1,500 mg/kg for 4 weeks. The results obtained are summarized as follows: 1. Soiling around the anus apparently correlated to soft stool or diarrhea was observed at 750 and 1,500 mg/kg and the incidence appeared to be dose-related. Three deaths including 1 death due to cannibalization occurred at 750 and 1,500 mg/kg, but they were considered to have been caused by misadministration. 2. Slightly depressed body weight gains were noted in the 750 and 1,500 mg/kg dose groups during early dosing period. 3. Slightly increased averages of food and water consumption observed predominantly in the 1,500 mg/kg dose group at later dosing period and the recovery period were considered as incidental and unrelated to the treatment. 4. Though average values of some blood chemical parameters were slightly suppressed or elevated compared with those of controls at the completion of the dosing and recovery periods, these differences appeared to be generally within normal ranges and to be irrelevant to the drug treatment. No definitive drug-related changes were detected in hematological examinations and urinalyses. 5. The average absolute and/or relative organ weights of the brain, thymus, lungs and liver from male rats in the 1,500 mg/kg dose group were lower than those of the corresponding organs from controls. However, these findings were not considered to be toxicologically significant because no corroborative changes were detected microscopically. 6. Macroscopic and microscopic examinations demonstrated dilatation of the cecum in a dose-related fashion. This phenomenon has been reported with other antibiotics and appears to be drug-related and reversible caused by an alteration of the gut flora. There were no other microscopic changes that were considered to be related to the administration of the drug. 7. Electron microscopic examination revealed no drug-related changes in the liver and kidneys from rats of the 1,500 mg/kg dose group. Based upon these results, the no-effect dose level of BMY-28100 was estimated to be 250 mg/kg/day for both male and female juvenile rats in the 4-week repeated dose oral toxicity study if the finding of cecum dilatation was not considered.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:2232155

Kadota, T; Kondoh, H; Chikazawa, H; Kawano, S; Kuroyanagi, K; Ohta, S; Ishikawa, K; Kai, S; Kohmura, H; Takahashi, N

1990-07-01

123

Dose-finding and pharmacokinetic study of an all-oral combination regimen of oral vinorelbine and capecitabine for patients with metastatic breast cancer  

Microsoft Academic Search

Purpose: A phase I study was performed to determine the maximal tolerated dose, recommended doses (RDs), safety and efficacy of oral vinorelbine when combined with capecitabine in an all-oral chemotherapy regimen in patients with metastatic breast cancer (MBC), with pharmacokinetic blood sampling to investigate potential drug-drug interactions. Patients and methods: Forty-four patients with MBC received as first- or second-line chemotherapy,

C. Catania; G. Sanna; K. Imadalou; E. Munzone; L. Adamoli; B. Longerey; G. Blanchot; A. Goldhirsch

2005-01-01

124

Acute toxicity and cholinesterase inhibition in chicks dosed orally with organophosphate insecticides.  

PubMed

Acute toxic effects of three commonly used insecticidal preparations of the organophosphates chlorpyrifos, diazinon, and dichlorvos were examined in mixed breed broiler chicks, and cholinesterase activity in plasma and brain were measured. The acute (24 h) oral median lethal doses (LD50) of chlorpyrifos, diazinon, and dichlorvos were 10.79 mg kg(-1), 6.32 mg kg(-1), and 6.30 mg kg(-1), respectively, as determined by the up-and-down method in chicks. Signs of cholinergic toxicosis in the chicks appeared within two hours after dosing, and they included salivation, lacrimation, gasping, frequent defecation, drooping of wings, tremors, convulsions, and recumbency before death. Halving the oral LD50 of chlorpyrifos (5 mg kg(-1)), diazinon (3 mg kg(-1)), and dichlorvos (3 mg kg(-1)) caused immobility and wing drooping, but not the clinical signs of cholinergic toxicity. However, at full LD50 doses of these insecticides, chicks showed clinical signs of cholinergic toxicity similar to those seen in the LD50 experiments. Two out of six chicks died within two hours after treatment with LD50 doses of chlorpyrifos and dichlorvos, whereas LD50 dosing with diazinon caused death in three out of six chicks. Compared to control values, the insecticides reduced plasma and whole brain cholinesterase activities by 29% to 84% and 18% to 77%, respectively, depending on the dose. The decrease in plasma cholinesterase correlated well (r=0.82) with that of the brain. These data suggest that organophosphate insecticides administered orally at LD50 doses induce clinical signs of cholinergic poisoning and concurrently reduce brain and plasma cholinesterase activities in chicks. PMID:18796381

Mohammad, Fouad K; Al-Badrany, Yasser M; Al-Jobory, Mohammed M

2008-09-01

125

Differential Innate Immune Responses to Low or High Dose Oral SIV Challenge in Rhesus Macaques  

PubMed Central

Mucosal transmission of HIV predominately occurs during sexual intercourse or breast-feeding and generally results in a successful infection from just one or few founder virions. Here we assessed the impact of viral inoculum size on both viral and immune events within two groups of Rhesus macaques that were non-traumatically, orally inoculated with either multiple low (1000 to 4000 TCID50) or high (100,000 TCID50) doses of SIV. In agreement with previous studies, more diverse SIV variants were observed in macaques following infection with high dose oral SIV compared to a low dose challenge. In peripheral blood cells, the immune gene transcript levels of CXCL9, IFN?, TNF? and IL10 remained similar to uninfected macaques. In contrast, OAS and CXCL10 were upregulated following SIV infection in both the high and low dosed macaques, with a more rapid kinetics (detectable by 7 days) following the high SIV dose challenge. In peripheral lymph nodes, an increase in CXCL10 was observed irrespective of viral dose while CXCL9 and OAS were differentially regulated in the two SIV dosed groups. Magnetic bead sorting of CD3+, CD14+ and CD3?/CD14? cells from peripheral blood identified the increase in OAS expression primarily within CD14+ monocytes, whereas the CXCL10 expression was primarily in CD3+ T cells. These findings provide insights into the impact of SIV challenge dose on viral and innate immune factors, which has the potential to inform future SIV/HIV vaccine efficacy trials in which vaccinated hosts have the potential to be infected with a range of viral challenge doses.

Durudas, Andre; Chen, Hui-Ling; Gasper, Melanie A.; Sundaravaradan, Vasudha; Milush, Jeffrey M.; Silvestri, Guido; Johnson, Welkin; Giavedoni, Luis D.; Sodora, Donald L.

2012-01-01

126

Assessment of dose proportionality of muraglitazar after repeated oral dosing in rats via a sparse sampling methodology.  

PubMed

Muraglitazar is an alpha/gamma-dual peroxisome proliferator-activated receptor (PPAR) agonist. This study evaluated the single- and multiple-dose oral toxicokinetics of muraglitazar in rats at doses of 3, 30 and 300 mg/kg/day. In total, 15 rats/gender/dose group received muraglitazar every day for 1 month. On both day 1 and day 28, blood samples were obtained at 0.5, 2, 4, 6, 8 and 24 h post-dose, followed by LC/MS analysis. In order to minimize blood loss in the rats, a sparse sampling approach was used to delineate the toxicokinetics. The peak plasma concentration (C(max)) and area under the plasma concentration-time curve (TAUC(0-t)) values for muraglitazar increased in a proportion less than the increment in dose. As the dose increased in the ratio 1:10:100, the C(max) for muraglitazar in male and female rats increased in the ratio of 1:10.3:58.6 and 1:15.3:75.3 on day 1, and 1:5.9:28.1 and 1:13.3:37.3 on day 28, respectively. The corresponding TAUC(0-t) values for males and females were in the ratio of 1:10.2:131 and 1:12.4:131 on day 1, and 1:9.5:93.4 and 1:11.8:94.3 on day 28, respectively. The results indicate that muraglitazar exhibits a dose dependent toxicokinetics in rats and the systemic exposure of muraglitazar was decreased on day 28 compared with day 1. PMID:17117455

Yao, Ming; Swaminathan, Arun; Srinivas, Nuggehally

2007-01-01

127

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

128

Combination of low-dose isotretinoin and pulsed oral azithromycin for maximizing efficacy of acne treatment.  

PubMed

Acne vulgaris is one of the most common skin disorders. It mainly affects adolescent, though may present at any age. The conventionally used dose of isotretinoin in acne causes significant dose-related adverse effects. Low-dose isotretinoin has been used successfully, in mild to moderate papulopustular acne. To observe whether the addition of an antibacterial enables use of isotretinoin in low doses even in moderate to severe acne. An open-label, non-comparative study was carried out for 24 weeks. Eighty two teenagers with moderate to severe papulo-pustular acne vulgaris were enrolled. These patients were treated with a combination of low-dose isotretinoin (0.3mg/kg/day) and pulsed oral azithromycin (500mg/day over three consecutive days in each week for one month. No topical treatment was permitted. Response to treatment was assessed at monthly intervals and was recorded as a percentage decrease in overall severity of disease. Treatment was continued to complete clearance of lesions or to 24 weeks. All patients were also evaluated at six months post-treatment. Eighty (97.56%) patients had complete clearance of disease activity after treatment duration of 24 weeks. Only two (2.43%) patients had a relapse of disease during the post-treatment follow-up period. Four (4.87%) patients were observed with adverse effects. Three (3.65%) patients had initial aggravation of disease that was managed with oral betamethasone and this disappeared with continuation of treatment. A combination of low-dose isotretinoin and oral azithromycin pulse is effective in moderate to severe acne. PMID:23416807

Hasibur, M R; Meraj, Z

2013-01-01

129

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

PubMed

The effects of felbamate on the pharmacokinetics of a low-dose combination oral contraceptive containing 30 micrograms ethinyl estradiol and 75 micrograms 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) of two consecutive oral contraceptive cycles (months 1 and 2). Pharmacokinetic assessments of ethinyl estradiol and gestodene were performed on day 14 of both cycles. To determine whether ovulation occurred, plasma progesterone and urinary luteinizing hormone levels were measured, and diaries recording vaginal bleeding were kept. Felbamate treatment resulted in a significant 42% decrease in gestodene area under the plasma concentration-time curve (0 to 24 hours) (p = 0.018) compared with baseline, whereas a minor but not clinically relevant effect was observed on the pharmacokinetic parameters of ethinyl estradiol. There were no changes in the pharmacokinetics of ethinyl estradiol or gestodene after placebo treatment. No volunteer showed hormonal evidence of ovulation; however, one volunteer reported the onset of intermenstrual bleeding during felbamate treatment. Because of the effect of felbamate on the pharmacokinetics of gestodene and the report of intermenstrual bleeding, it is possible that the contraceptive efficacy of low-dose combination oral contraceptives may be adversely affected during felbamate treatment. PMID:7586946

Saano, V; Glue, P; Banfield, C R; Reidenberg, P; Colucci, R D; Meehan, J W; Haring, P; Radwanski, E; Nomeir, A; Lin, C C

1995-11-01

130

Failure of massive single oral dose of vitamin A to prevent deficiency  

PubMed Central

Preschool children maintained on low and moderate carotene diets were given a single oral dose of 50,000 ?g vitamin A palmitate. On the low carotene diet, xerosis was observed in 8 weeks' time in the control group of children, and in 10 weeks' time in the children given the load of vitamin A. Statistical differences in serum vitamin A values between the groups were not of significance after 18 weeks. Children on a moderate carotene diet did not benefit from the loading dose of vitamin A.

Pereira, Sheila M.; Begum, Almas

1971-01-01

131

High and prolonged pulmonary tissue concentrations of azithromycin following a single oral dose  

Microsoft Academic Search

Antibiotic concentrations in pulmonary tissue samples and plasma were studied in this open investigation. Twenty-nine patients scheduled for elective pulmonary surgery received a single oral dose of 500 mg azithromycin 24, 72, 96 or 120 h prior to the operation; two patients received 250 mg b.i.d. Blood samples were taken before and at the time of resection, and tissue was

D. L. Morris; A. De Souza; J. A. Jones; W. E. Morgan

1991-01-01

132

Comparative clinical efficacy of single oral doses of cefuroxime axetil and amoxicillin in uncomplicated gonococcal infections.  

PubMed

Cefuroxime axetil (1.5 g) was compared with amoxicillin (3 g), both given as a single oral dose combined with probenecid (1 g) for the treatment of uncomplicated gonorrhea. Of 60 evaluable patients receiving amoxicillin, 55 (91.7%) were cured, whereas 55 (96.5%) of the 57 patients receiving cefuroxime axetil were cured (P greater than 0.1). Both drugs were well tolerated. PMID:3094443

Fong, I W; Linton, W; Simbul, M; Hinton, N A

1986-08-01

133

Single-dose oral naproxen for acute postoperative pain: a quantitative systematic review  

Microsoft Academic Search

BACKGROUND: Naproxen and naproxen sodium are non-steroidal anti-inflammatory drugs used in a variety of painful conditions, including the treatment of postoperative pain. This review aims to assess the efficacy, safety and duration of action of a single oral dose of naproxen\\/naproxen sodium for moderate to severe acute postoperative pain in adults, compared with placebo. METHODS: The Cochrane Library (issue 4

Lorna Mason; Jayne E Edwards; R Andrew Moore; Henry J McQuay

2003-01-01

134

Influence of renal function on the pharmacokinetics of diacerein after a single oral dose  

Microsoft Academic Search

Summary  The pharmacokinetics of diacetylrhein following a single oral dose of 50 mg was studied in 12 healthy volunteers and two groups\\u000a of 8 patients with mild or severe renal insufficiency.\\u000a \\u000a \\u000a Statistical analysis using a Kruskal-Wallis rank sum test showed a significant difference between the three groups for the\\u000a following parameters. In severely uraemic patients, median AUC0?? was multiplied by a

P. DEBORDI; K. Louchahi; A. Tod; A. Cournot; G. Perret; O. Petitjean

1994-01-01

135

Serum levels of ciprofloxacin after single oral doses in patients with septicemia  

Microsoft Academic Search

Ciprofloxacin serum levels were measured after administration of the drug to 36 patients with septicemia (at least one positive blood culture) who were able to take oral medication. Patients were randomly allocated to receive ciprofloxacin 500 mg p.o. (n=21) or 200 mg i.v. over 30 min (n=15). A first dose was administered 18–30 h after the last positive blood culture

M. D'Espine; F. Bellido; J. C. Pechčre; R. Auckenthaler; P. Rohner; D. Lew; B. Hirschel

1989-01-01

136

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

Microsoft Academic Search

Oral contraceptives (OC) suppress excess androgen production; however, different progestins in combination with low-dose estrogens produce divergent effects on sex hormone-binding globulin (SHBG) and testosterone that may influence clinical outcomes. This multicenter, open-label, randomized study compared biochemical androgen profiles and clinical outcomes associated with two OC containing the same amounts of ethinyl estradiol (EE, 20 ?g) but different progestins, levonorgestrel

Ian H Thorneycroft; Frank Z Stanczyk; Karen D Bradshaw; Susan A Ballagh; Mark Nichols; Margaret E Weber

1999-01-01

137

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

138

Oral Protein Supplementation Alone Improves Anabolism in a Dose-Dependent Manner in Chronic Hemodialysis Patients  

PubMed Central

Objective We examined the protein anabolic effects of Pro-Stat 64, a high nitrogen-containing, enzyme-hydrolyzed, tryptophan-fortified, collagen protein supplement administrated during hemodialysis, at two different dosing regimens. Design This was a randomized, controlled, prospective study with 3 different groups: control, single dose of supplementation, and double dose of supplementation. Setting This study was performed at a clinical research center. Patients Six prevalent chronic hemodialysis (HD) patients were enrolled: 5 males, 1 female, 4 African Americans, and 2 Caucasians. Their mean age was 45 ± 11 years. Two patients were diabetic. Methods Protein turnover studies were performed using amino-acid (AA) balance and primed constant infusion of L-(1-13C) leucine. Main Outcome Measure Whole-body protein balance was determined according to substrate kinetics. Results There were no statistically significant difference at any time point between protocols for blood chemistries and hormonal markers, except for minor variations in plasma glucose. All plasma AA groups displayed decreases during control. Compared with the control group, plasma nonessential AA and total AA concentrations were statistically significantly higher during HD after both single and double doses of supplementation. The forearm arteriovenous AA balance was statistically significantly better for essential, nonessential, and total AA uptake after both single-dose and double-dose supplementation compared with the control group, except for nonessential AA, which was significantly better only after a double dose. Whole-body protein breakdown and net protein balance were statistically significantly better during HD with a double-dose administration in a dose-dependent manner, compared with the control and single-dose groups. Conclusions Oral AA supplementation alone improves whole-body and skeletal muscle protein anabolism in a dose-dependent manner in chronic HD patients. These data should be taken into account during clinical decision-making or when designing clinical trials of nutritional supplementation.

Sundell, Mary B.; Cavanaugh, Kerri L.; Wu, Pingsheng; Shintani, Ayumi; Hakim, Raymond M.; Ikizler, T. Alp

2009-01-01

139

Blood levels following multiple oral dosing of chlorpheniramine conventional and controlled release preparations.  

PubMed

An examination of steady-state performance of chlorpheniramine conventional versus controlled release products was conducted using 15 male subjects in a 3-way crossover study with a 2-week washout period between studies. The study was designed to determine if chlorpheniramine formulations provide consistent pharmacokinetic performance between individual units upon going from single dose to multiple dose therapy. In addition, the validity of predicting steady-state levels for these kinds of products using only single oral dose data was examined. The dosage forms evaluated were a conventional 4 mg tablet, and 8 mg barrier coated-bead capsule, and an 8 mg repeat action tablet. Multiple doses of each product were orally administered to each subject for 6 days prior to the study day to achieve steady-state levels and on the actual study day. Serum samples were collected at specific time intervals on the study day, and chlorpheniramine levels assayed by HPLC. Pharmacokinetic analysis was based on a two-compartment open model. The mean plasma elimination half-lives of the various dosage forms were in the range 24.5-25.4 h. There was no rapid release of drug from the controlled release products nor did they have drug release problems during the dosing interval. Good agreement was obtained between predicted average drug concentration at steady-state and drug concentration actually present for all the formulations studied. Based upon comparative examination of AUC, Cmax, and fraction of dose absorbed data, the controlled release products administered every 12 h were comparable in performance to a conventional release tablet administered every 6 h. Since the half-life of chlorpheniramine is approximately 1 day, therapeutic management may possibly be gained with dosing the patient once daily with a controlled release product or twice daily with a conventional tablet. PMID:7104467

Vallner, J J; Kotzan, J A; Stewart, J T; Brown, W J; Honigberg, I L; Needham, T E; Dighe, S V

140

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

PubMed

To characterize doxylamine pharmacokinetics in children. This study was conducted in 41 subjects, ages 2-17 years. Doxylamine succinate doses based on age/weight ranged from 3.125 to 12.5?mg. A single oral dose was administered with 2 to 4?oz. of water or decaffeinated beverages ?2?hours after a light breakfast. Plasma samples were obtained before and for 72?hours after dosing and analyzed for doxylamine using HPLC MS/MS. Pharmacokinetic parameters were estimated using non-compartmental methods and relationships with age were assessed using linear regression. Over the fourfold dose range, Cmax was similar while AUC increased only 60%, although not statistically significant (P-value?=?0.0517). As expected due to increasing body size, CLo and Vz /F increased with age. Due to a similar increase with age for Clo and Vz /F, no age-related differences in t1/2,z were observed (?16?hours). Allometric scaling indicated no maturation related changes in CLo ; although Vz /F remained age-dependent, the predicted range decreased ?70%. Overall, the single doses were well tolerated. Somnolence was the most common reported AE with no apparent differences in incidence noted with age. An age/weight dosing nomogram utilizing a fourfold range of doses achieves similar Cmax , whereas AUC increases only 60%. PMID:23868556

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

2013-07-18

141

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

PubMed Central

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

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

2000-01-01

142

Safety and efficacy of an extended-regimen oral contraceptive utilizing continuous low-dose ethinyl estradiol  

Microsoft Academic Search

ObjectiveTo assess the efficacy and safety of Seasonique™, a 91-day extended-regimen oral contraceptive (OC) utilizing continuous low-dose ethinyl estradiol (EE) during the typical hormone-free interval.

Freedolph D. Anderson; William Gibbons; David Portman

2006-01-01

143

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

SciTech Connect

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

de Haan, R.A.; van Aken, J. (Utrecht Univ., (The Netherlands))

1990-08-01

144

Quality of life, taste, olfactory and oral function following high-dose chemotherapy and allogeneic hematopoietic cell transplantation  

Microsoft Academic Search

Multiple oral complaints develop following high-dose chemo\\/radiotherapy and hematopoietic cell transplantation (HCT) which can influence quality of life. The purpose of this investigation was to assess quality of life, oral function, taste and smell in a cohort of patients following HCT. A general quality of life survey (the European Organization for Research and Treatment of Cancer (EORTC)) Quality of Life

JB Epstein; N Phillips; J Parry; Epstein; T Nevill; P Stevenson-Moore

2002-01-01

145

Single-dose oral naproxen for acute postoperative pain: a quantitative systematic review  

PubMed Central

Background Naproxen and naproxen sodium are non-steroidal anti-inflammatory drugs used in a variety of painful conditions, including the treatment of postoperative pain. This review aims to assess the efficacy, safety and duration of action of a single oral dose of naproxen/naproxen sodium for moderate to severe acute postoperative pain in adults, compared with placebo. Methods The Cochrane Library (issue 4 2002), EMBASE, PubMed, MEDLINE and an in-house database were searched for randomised, double blind, placebo controlled trials of a single dose of orally administered naproxen or naproxen sodium in adults with acute postoperative pain. Pain relief or pain intensity data were extracted and converted into dichotomous information to give the number of patients with at least 50% pain relief over 4 to 6 hours. Relative benefit and number-needed-to-treat were then calculated. The percentage of patients with any adverse event, number-needed-to-harm, and time to remedication were also calculated. Results Ten trials with 996 patients in met the inclusion criteria. Six trials compared naproxen sodium 550 mg (252 patients) with placebo (248 patients); the NNT for at least 50% pain relief over six hours was 2.6 (95% confidence interval 2.2 to 3.2). There was no significant difference between the number of patients experiencing any adverse event on treatment compared with placebo. Weighted mean time to remedication was 7.6 hours for naproxen sodium 550 mg (206 patients) and 2.6 hours for placebo (205 patients). Four other trials used lower doses. Conclusion A single oral dose of naproxen sodium 550 mg is an effective analgesic in the treatment of acute postoperative pain. A low incidence of adverse events was found, although these were not reported consistently.

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

2003-01-01

146

Pharmacokinetics of EDP-420 after ascending single oral doses in healthy adult volunteers.  

PubMed

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

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

2009-02-17

147

Effect of itraconazole on the pharmacokinetics and pharmacodynamics of a single oral dose of brotizolam  

PubMed Central

Aims To assess the effect of itraconazole, a potent inhibitor of cytochrome P450 (CYP)3A4, on the single oral dose pharmacokinetics and pharmacodynamics of brotizolam. Methods In this randomized, double-blind, cross-over trial 10 healthy male subjects received either itraconazole 200 mg or matched placebo once daily for 4 days. On day 4, a single 0.5 mg dose of brotizolam was administered orally. Plasma concentrations of brotizolam were followed up to 24 h, together with assessment of psychomotor function measured by the digit symbol substitution test (DSST), visual analogue scales and UKU side-effect rating scale. Results Itraconazole significantly (P < 0.001) decreased the apparent oral clearance (CL/F) (16.47 ± 4.3 vs 3.91 ± 2.1), increased the area under the concentration-time curves (AUC) from 0 h to 24 h (28.37 ± 10.8 vs 68.71 ± 24.1 ng ml h?1), and prolonged the elimination half-life (4.56 ± 1.4 vs 23.27 ± 10.3 h) of brotizolam. The AUC(0,24 h) of the DSST (P < 0.001) and the item ‘sleepiness’ of UKU (P < 0.05) were significantly decreased. Conclusions Itraconazole increases plasma concentrations of brotizolam probably via its inhibitory effect on CYP3A4 brotizolam metabolism.

Osanai, T; Ohkubo, T; Yasui, N; Kondo, T; Kaneko, S

2004-01-01

148

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 Vilŕ; Jesus López-Martí; José Antonio Fernández-López; Xavier Remesar; Mariŕ Alemany

2001-01-01

149

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

150

Pharmacokinetics of cefpodoxime in plasma and skin blister fluid following oral dosing of cefpodoxime proxetil.  

PubMed Central

The single-dose and steady-state pharmacokinetics of cefpodoxime were assessed in plasma and skin blister fluid (SBF) after oral dosing of 200 mg (n = 8) and 400 mg (n = 8) of cefpodoxime proxetil (doses are expressed as cefpodoxime equivalents) in healthy subjects in an open-label, parallel-design study. Skin blisters were formed by air suction on the midvolar forearm by a previously validated method. After single-dose administration, serial plasma and SBF samples were collected over 24 h for measurement of cefpodoxime by microbiological assays. After a 1-week washout, subjects received the same doses of antibiotic every 12 h for 5 days, with plasma and SBF sampling on day 5. After 200 mg of cefpodoxime proxetil, average peak concentrations (Cmax) in plasma and SBF were 2.18 +/- 0.52 and 1.55 +/- 0.59 micrograms/ml, respectively, after a single dose and 2.33 +/- 0.74 and 1.56 +/- 0.55 micrograms/ml, respectively, at steady state. After 400 mg of cefpodoxime proxetil, Cmax in plasma and SBF averaged 4.16 +/- 1.04 and 2.94 +/- 0.71 micrograms/ml, respectively, following a single dose and 4.10 +/- 0.95 and 2.84 +/- 0.88 micrograms/ml, respectively, at steady state. Cmax occurred 1.1 to 1.6 h later in SBF than in plasma. There was no accumulation of cefpodoxime in plasma or SBF when dosing was done every 12 h. Cefpodoxime blister fluid penetration was estimated to be 67 to 101%, consistent with the relatively low serum protein binding of the drug. Cefpodoxime levels exceeding the MIC for 90% of many skin pathogens, such as Streptococcus species (<1 microgram/ml) or Staphylococcus species (2 to 4 micrograms/ml), were achieved in plasma and SBF following the 200- and/or 400-mg dosing regimens.

Borin, M T; Hughes, G S; Spillers, C R; Patel, R K

1990-01-01

151

Intermediate-term toxicity of repeated orally administered doses of the anti-malarial ?-artemether in dogs  

Microsoft Academic Search

The artemisinin derivative ?-artemether, an anti-malarial, was evaluated for its toxicity and tolerability in a 2-week, multiple-dose study in dogs. Eight beagle dogs (4 females, 4 males) were given ?-artemether by oral gavage 3 times daily at 45mg\\/kg\\/dosing (a total daily dose-level of 135mg\\/kg) for 2 weeks. This ?-artemether dose regime was well tolerated. Body weight changes were normal although

Eric Peys; Jan Vandenkerckhove; Johan Van hemel; Benedikt Sas

2006-01-01

152

Fowl typhoid: assessment of a disinfectant oral dose to reduce horizontal spread and mortality.  

PubMed

To determine the most appropriate dose in drinking water of the disinfectant N-alkyl dimethyl benzyl ammonium chloride (TIMSEN), a fowl typhoid challenge trial was carried out using 21-day-old Salmonella-free chickens. In a pretrial, performed with six groups of 10 chickens each, it was shown that the disinfectant was atoxic and safe when administered during 15 days at doses of 0 ppm, 200 ppm, 400 ppm, 800 ppm, 1600 ppm, or 3200 ppm. Thereafter, a challenge trial was performed with 390 chickens divided into six groups of 65 birds each. Chickens were treated during 9 days with oral doses of 0 ppm, 25 ppm, 50 ppm, 100 ppm, 250 ppm, and 500 ppm (groups identified as A, B, C, D, E, and F, respectively). Twenty-four hours after the beginning of the treatment, 30 chickens of each group were orally inoculated with 10(9) colony-forming units of Salmonella Gallinarum strain INTA 91 per bird. The remaining 35 unchallenged chickens from each group were left in the same cage in close contact with the other challenged birds of their group. All surviving chickens were sacrificed 8 days after challenge. Livers from all birds were examined for the presence of Salmonella Gallinarum. Salmonella Gallinarum was isolated from all challenged chickens and from some unchallenged chickens of groups A (4/35), E (3/35), and F (6/35), but not from any unchallenged chicken from groups B, C, and D. Doses of 50 ppm (group C) significantly reduced mortality (30%) in comparison with the untreated control group A (65%). Mortality in group B (45%) was not significantly different from group C. Administration of higher doses of the disinfectant resulted in significantly higher mortality rates, 70% in group E and 85% in groups D and F. Increased infection and mortality rates of groups D, E, and F might have been caused by inhibition of the protective action of the normal gut flora. To reduce horizontal infection and mortality, the manufacturer's prescribed oral dose of 25 ppm may be increased up to 50 ppm. Nevertheless, higher doses should be avoided because they may cause horizontal increased spread of the disease and mortality. PMID:18646464

Huberman, Y D; Terzolo, H R

2008-06-01

153

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

PubMed

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 microg/kg b.w. (13)C(3)-AA in deionized water via oral gavage. Human subjects (n=3/gender) were orally administered 0.5 and 20 microg/kg b.w. (13)C(3)-AA with drinking water. Urine samples were collected in intervals for 96 and 94 h, respectively. Urinary concentrations of (13)C(3)-AAMA, (13)C(3)-GAMA and (13)C(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 microg/kg b.w. doses in rats and for 71.3% and 70.0% of the 0.5 and 20 microg/kg b.w. doses in humans. In rats, (13)C(3)-AAMA accounted for 33.6% and 38.8% of dose and 32.7% and 31.7% of dose was recovered as (13)C(3)-GAMA; (13)C(3)-AAMA-sulfoxide was not detected in rat urine. In humans, (13)C(3)-AAMA, (13)C(3)-GAMA and (13)C(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. PMID:19118568

Kopp, Eva Katharina; Dekant, Wolfgang

2008-12-11

154

A comparison of a new graduated estrogen formulation with three constant-dosed oral contraceptives.  

PubMed

Four-hundred-twenty-six women, aged 18 to 36, completed a four-cycle comparative, randomized, single-blind (observer blind), multicenter study of a new graduated estrogen formulation with three constant-dosed combination oral contraceptives containing the same synthetic steroid compounds. The products studied were Loestrin 1/20, Loestrin 1.5/30, Norlestrin 1/50, and a new graduated estrogen product, Estrostep. A total of 1,850 cycles were completed and analyzed for efficacy, side effects, metabolic changes, and cycle control. Four pregnancies occurred during the course of the study. None of the pregnancies occurred in the group receiving Estrostep. The new formulation produced the lowest rate of breakthrough bleeding (BTB) compared with the other three products. All four combination oral contraceptives resulted in an increase in high-density lipoprotein cholesterol (HDL-C). The levels of HDL-C were greatest with Estrostep. PMID:3311619

Appel, T B; Kambi, A A; Birdsall, C; Christenson, D A; Clark, D O; DeKoning, J R; Dreisbach, L A; Frost, J F; Gustin, A E; Halikis, M

1987-06-01

155

Bioavailability and pharmacokinetics of norethisterone in women after oral doses of ethynodiol diacetate.  

PubMed

Measurement by radioimmunoassay of plasma norethisterone (NE) has been used to compare the bioavailability of tablets containing ethynodiol diacetate (EDA) with that of a standard oral solution of this progestogen in 12 normal women. The tablets investigated were from three batches which showed different in vitro dissolution rates. There were no significant differences in the bioavailability of the tablet formulations, which were essentially bioequivalent to the solution. Peak blood levels of NE were reached within 4h of EDA administration in solution or tablets. After the peak, NE plasma levels declined in two phases, with a mean terminal elimination half lives of 4 to 6.9h. The pharmacokinetics of NE after EDA administration showed some similarity to those observed by other workers after oral doses of NE itself. PMID:428229

Vose, C W; Butler, J K; Williams, B M; Stafford, J E; Shelton, J R; Rose, D A; Palmer, R F; Breckenridge, A M; Orme, M L; Serlin, M J

1979-02-01

156

Repeat oral dose toxicity studies of melamine in rats and monkeys.  

PubMed

Melamine is an important and widely used organic industrial chemical. Recently, clinical findings of renal failure and kidney stones in infants have been associated with ingestion of melamine-contaminated infant formula. To understand the toxicity and clinical outcome of melamine exposure, repeated oral dose studies in rats and monkeys were performed to characterize the subchronic toxicity of melamine. Assessment of toxicity was based on mortality, clinical signs, body weights, ophthalmic findings, clinical pathology, gross pathology, organ weights, and microscopic observations. The first rat study was intended to be a 14-day oral study followed by an 8-day recovery period. The dose levels were 140, 700, and 1,400 mg/kg/day (lowered to 1,000 mg/kg/day subsequently due to mortality). Oral administration of melamine at 700 mg/kg/day for 14 consecutive days in rats produced compound-related clinical signs (red urine), decreased body weights, and changes in clinical pathology (increased serum urea nitrogen and creatinine) and anatomical pathology (renal tubular cell debris, crystal deposition, and hyperactive regeneration of renal tubular epithelium). The kidney was identified as the target organ. Oral administration at 1,400 mg/kg/day (subsequently lowered to 1,000 mg/kg/day) resulted in animal death and moribundity. There were no treatment-related findings in the 140 mg/kg/day group. There were no compound-related findings in the high-dose recovery animals. The second rat study was a 5-day oral toxicity study with genomic biomarkers assayed in the kidney tissues. At the top dose of 1,050 mg/kg/day, similar clinical and anatomical pathology findings as described above were observed. The genes measured, Kim-1, Clu, Spp1, A2m, Lcn2, Tcfrsf12a, Gpnmb, and CD44, were significantly up-regulated (fivefold to 550-fold), while Tff3 was significantly down-regulated (fivefold). These results indicated that genomic markers could sensitively diagnose melamine-induced kidney injury. A 3-month oral study with 4-week recovery in monkeys was also conducted. In this monkey study, the animals were treated with melamine at doses of 60, 200, or 700 mg/kg/day. The administration of 700 mg/kg/day melamine by nasal-gastric gavage to monkeys resulted in test article-related clinical signs including turbid and whitish urine, urine crystals, red blood cell changes, increased serum alanine aminotransferase and kidney and/or liver weights, and microscopic findings including nephrotoxicity, pericarditis, and increased hematopoiesis. Nephrotoxicity was also noted at 200 mg/kg/day. It was concluded that the kidney is the primary target organ and the NOAEL was estimated to be 140 mg/kg/day in rats following a 14-day oral administration and 60 mg/kg/day in the monkey study. PMID:23052191

Early, Richard J; Yu, Hong; Mu, Xueyan Peter; Xu, Haiyan; Guo, Lei; Kong, Qingxue; Zhou, Junma; He, Bruce; Yang, Xiuying; Huang, Hailiang; Hu, Edward; Jiang, Ying

2012-09-28

157

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.

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

1986-01-01

158

Interstitial high-dose rate brachytherapy with iridium-192 in patients with oral squamous cell carcinoma.  

PubMed

Thirty-four patients with recurrent oral and oropharyngeal carcinomas were treated over a period of 4 years, by interstitial high-dose rate (HDR) brachytherapy (BT) using an iridium-192 source (Gammamed 2i and 12i equipment, Sauerwein, Germany) and fractionated application (1 up to 3 times, weekly recovery phases, single maximum dose 10 Gy). Pretreatment characteristics of patients in terms of irradiation (RT) and surgery differed (22 had external RT alone, with a total dose between 60.0 and 75.6 Gy; RT and surgery: 7; surgery alone: 1). The initial TNM-stages (UICC, Hermanek et al., 1987) of patients were: I = 2, II =3, III = 7, IV = 22. In the majority of cases, clinical indications for HDR-BT included tumour recurrence or progression following external RT, and second primary tumours of the oral cavity. Therapy was successful in most cases, i.e. complete remission: 11, partial remission: 16, no change: 2, progression: 5. Local control and overall survival rates, including patients surgically treated after BT, were at 6 months 58% and 62%, and 44% and 53% at 12 months, respectively. This type of treatment is recommended in patients with local recurrence or second primary tumours after previous external RT in the head and neck region. However, the benefit of interstitial HDR-BT remains questionable, particularly in patients with large tumours and lymph node metastases. PMID:7560110

Friedrich, R E; Krüll, A; Hellner, D; Schwarz, R; Heyer, D; Plambeck, K; Schmelzle, R

1995-08-01

159

Dose-proportionality of a final market image sitagliptin formulation, an oral dipeptidyl peptidase-4 inhibitor, in healthy volunteers.  

PubMed

Sitagliptin is a highly selective orally active dipeptidyl peptidase-4 inhibitor recently approved in the United States for the treatment of type 2 diabetes. Ten healthy subjects received single oral doses of 25, 50, 100, 200 and 400 mg final market image tablets in five separate treatment periods in randomized fashion to assess dose proportionality. Blood (up to 72 h post-dose) and urine (up to 24 h post-dose) samples for sitagliptin pharmacokinetic analysis were collected at pre-specified times following administration of sitagliptin. Dose-proportionality of AUC(0-infinity), C(max) and C(24 h) was assessed using a power-law model. The results of this study indicate that plasma AUC(0-infinity) increased in a dose-proportional manner over the 25-400 mg dose range. Over the same dose range, plasma C(max) increased in a greater than dose-proportional manner and C(24 h) increased in a modestly less than dose proportional manner. No clinically meaningful differences in T(max) or apparent t(1/2) were noted across the dose range. Differences in the percentage of the sitagliptin dose excreted unchanged in urine (72.5% pooled across doses) and renal clearance (344 ml/min pooled across doses) were not statistically significant. Sitagliptin was generally well tolerated at all the doses evaluated. PMID:17571284

Bergman, Arthur; Mistry, Goutam C; Luo, Wen-Lin; Liu, Q; Stone, Julie; Wang, Amy; Zeng, Wei; Chen, Li; Dilzer, Stacy; Lasseter, Kenneth; Herman, Gary A; Wagner, John A; Krishna, Rajesh

2007-09-01

160

Acute and genetic toxicity of 1-nitropyrene and its fate after single oral doses to rats  

SciTech Connect

The mammalian acute and genetic toxicity of 1-nitropyrene (NP) was studied because this and other nitroarenes are highly mutagenic toward bacteria and have been identifid in emissions from combustion processes. A suspension of NP did not cause observable signs of acute toxicity and was not lethal when administered to male and female rats at single oral doses at high as 5.0 g/kg. Histological examination of stomach, intestine, lung, heart, spleen, pancreas, adrenal, and kidney from rats euthanized at 4 and 14 d after treatment revealed no detectable differences from control rats. Urine and feces were collected for 4 d after treatment with 5.0 g/kg. About 70% of the dose was present in the feces as NP, and about 2% was present as the reduced metabolite 1-aminopyrene (AP). Sulfate and glucuronide conjugates of AP were present in small amounts (<1%) in the urine, showing that at least some of the dose was absorbed. Bone marrow cells from female rats given NP orally at 0.5, 1.5, and 5.0 g/kg showed a slight dose-related increase in the frequency of sister chromatid exchanges. Both NP and AP showed low mutagenicity in Chinese hamster ovary cells in vitro. Evidence of reductive metabolsm of NP in rats raises concern about the potential exposure of humans to this compound. However, the weak in vivo and in vitro genetic toxicity of NP at high dose level in mammalian systems suggests that the potential hazard may not be as high as predicted from bacterial mutagenicity data.

Marshall, T.C.; Royer, R.E.; Li, A.P.; Kusewitt, D.F.; Brooks, A.L.

1982-09-01

161

Acute and genetic toxicity of 1-nitropyrene and its fate after single oral doses to rats  

SciTech Connect

The mammalian acute and genetic toxicity of 1-nitropyrene (NP) was studied because this and other nitroarenes are highly mutagenic toward bacteria and have been identified in emissions from combustion processes. A suspension of NP did not cause observable signs of acute toxicity and was not lethal when administered to male and female rats at single oral doses as high as 5.0 g/kg. Histological examination of stomach, intestine, lung, heart, spleen, pancreas, adrenal, and kidney from rats euthanized at 4 and 14 d after treatment revealed no detectable differences from control rats. Urine and feces were collected for 4 d after treatment with 5.0 g/kg. About 70% of the dose was present in the feces as NP, and about 2% was present as the reduced metabolite 1-aminopyrene (AP). Sulfate and glucuronide conjugates of AP were present in small amounts (<1%) in the urine, showing that at least some of the dose was absorbed. Bone marrow cells from female rats given NP orally at 0.5, 1.5, and 5.0 g/kg showed a slight dose-related increase in the frequency of sister chromatid exchanges. Both NP and AP showed low mutagenicity in Chinese hamster ovary cells in vitro. Evidence of reductive metabolism of NP in rats raises concern about the potential exposure of humans to this compound. However, the weak in vivo and in vitro genetic toxicity of NP at high dose levels in mammalian systems suggests that the potential hazard may not be as high as predicted from bacterial mutagenicity data.

Marshall, T.C.; Royer, R.E.; Li, A.P.; Kusewitt, D.F.; Brooks, A.L.

1982-01-01

162

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  

Technology Transfer Automated Retrieval System (TEKTRAN)

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 ...

163

Disposition of chloroquine in man after single intravenous and oral doses.  

PubMed Central

1 Chloroquine was given in 300 mg single doses as an i.v. infusion, an oral solution and as tablets at intervals of at least 56 days to 11 healthy volunteers. Concentrations of chloroquine and its metabolite desethylchloroquine were measured in plasma, erythrocytes and urine using h.p.l.c. 2 Chloroquine was detectable in all plasma samples up to 23 days and occasionally up to 52 days after dosage. Urinary concentrations were monitored up to 119 days. The disposition pattern was multiexponential reflecting extensive tissue binding of the drug. 3 After i.v. dosing the volume of distribution ranged from 116 to 285 l/kg and the apparent terminal half-life from 146 to 333 h. Total plasma clearance +/- s.d. was 712 +/- 166 ml/min and renal clearance 412 +/- 139 ml/min. The mean estimated urinary recovery of chloroquine was 47%, 42% and 46% after i.v., oral solution and tablets indicating nearly complete bioavailability. The corresponding figures for the metabolite were 7%, 10% and 12%. 4 The disposition of chloroquine in erythrocytes was parallel to that in plasma. The concentrations in erythrocytes were consistently 2 to 5 times higher than in plasma. 5 Subjective side effects like difficulties with swallowing and accommodation, diplopia and fatigue occurred during intravenous infusion and were closely related to plasma concentrations. No effect was seen on the electrocardiogram, mean arterial blood pressure and pulse rate. No adverse reactions were observed after the oral doses. High frequency audiometry did not reveal any significant hearing impairment for the group as a whole.

Gustafsson, L L; Walker, O; Alvan, G; Beermann, B; Estevez, F; Gleisner, L; Lindstrom, B; Sjoqvist, F

1983-01-01

164

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

Microsoft Academic Search

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

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

1998-01-01

165

Pharmacokinetic and pharmacodynamic interaction of single oral doses of valsartan and furosemide  

Microsoft Academic Search

Objective: Pharmacokinetic and pharmacodynamic interactions between single oral doses of valsartan (160?mg) and furosemide (40?mg)\\u000a were investigated in an open, randomized, three-period crossover study in twelve healthy male subjects.\\u000a \\u000a \\u000a \\u000a Methods: A washout period of one week was observed between treatments. Pharmacokinetic measurements included plasma concentrations\\u000a of valsartan and furosemide, and urinary excretion of the latter. Plasma renin activity (PRA), plasma

M. Bindschedler; P. Degen; G. Flesch; M. de Gasparo; G. Preiswerk

1997-01-01

166

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

PubMed

Effects of chronic exposure to corticosterone in drinking water on corticosterone kinetics, blood chemistry, and concentrations of catecholamines in parts of brain were studied in Long-Evans rats. Rats were randomly grouped into 3 x 2 treatments (n=4), with three treatments of drinking water (tap water, or 2.5% ethanol, or 400 microg/mL of corticosterone in 2.5% ethanol) for 28 days and two treatments of gavage with a single dose of either corn oil or corticosterone 20 mg/kg on day 28. Blood samples were collected at 0, 15, 30, 60, 120, 240, 480, and 720 min after dosing to determine plasma corticosterone concentrations. Blood samples were collected for clinical pathology on day 42. Hippocampus, cerebral cortex, caudate-putamen, and pons were examined to determine concentrations of catecholamines and activities of esterases. Concentrations of plasma corticosterone before gavage of the corticosterone-drinking rats (47.61 +/- 1.13 ng/mL) were lower than the water (418.47 +/- 1.13 ng/mL) or the ethanol rats (383.71 +/- 1.13 ng/mL, P < 0.0001). Plasma corticosterone rose to peak concentrations by 15 min after gavage in all three groups of drinking rats. Corticosterone-drinking rats had concentrations of plasma corticosterone that returned to basal levels slower than water- and ethanol-drinking rats. Plasma sodium and chloride concentrations were lower in the corticosterone-drinking rats than the water-drinking rats (P < 0.01). Plasma albumin, globulin, and total protein were highest in the corticosterone-drinking rats when compared to the other groups of drinking rats (P < 0.001, P < 0.05, and P < 0.001, respectively). Corticosterone in drinking water did not affect activities of brain neurotoxic esterase, carboxylesterase, acetylcholinesterase, or concentrations of monoamines and their metabolites. A single oral dose of corticosterone reduced neurotoxic esterase activity in the cerebral cortex (P < 0.05) and increased norepinephrine concentrations in the hippocampus (P < 0.05). PMID:15747778

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

2003-10-01

167

Intravenous pharmacokinetics, oral bioavailability and dose proportionality of ragaglitazar, a novel PPAR-dual activator in rats.  

PubMed

Pharmacokinetics of ragaglitazar (a novel phenoxazine derivative of aryl propanoic acid), a potent insulin sensitizing and lipid-lowering compound was studied in Wistar rats. A single dose of 1, 3 or 10 mg/kg of ragaglitazar was given orally to male rats (n=4 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of ragaglitazar was given to rats (n=4) at 3 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 ragaglitazar in plasma was determined by a validated HPLC method. Plasma concentration versus time data were generated following oral and intravenous dosing and pharmacokinetic analysis was performed using non-compartmental analysis. The results revealed that Cmax and AUC(0-infinity) increased more than proportionally to the administered oral doses. As dose increased in the ratio of 1:3:10, the mean Cmax and AUC(0-infinity) increased in the ratio of 1:3.2:13 and 1:3.2:16, respectively. After intravenous administration the systemic clearance and volume of distribution of ragaglitazar in rats were 139+/-30 ml/h/kg and 463+/-51 ml/kg, respectively (mean+/-SD). Plasma concentrations declined mono-exponentially following intravenous administration and elimination half-life (t1/2) was about 2.6 h and not significantly different (p > 0.05) from the value from oral administration. Mean residence time (MRT) values for ragaglitazar were found to be 4.15+/-0.52 h (3.5 to 4.6 h). Absolute oral bioavailability of ragaglitazar across the doses tested was in the range of 68%-93%. In conclusion, ragaglitazar exhibits promising pharmacokinetic properties in rats. PMID:15386480

Jagannath, Kota; Chaluvadi, Madhusudana Rao; Mullangi, Ramesh; Mamidi, N V S Rao; Srinivas, Nuggehally R

2004-10-01

168

Coagulation profile in women on low-dose oral contraceptive pills.  

PubMed

The effect of low dose combined oral contraceptives containing 30 mcg ethinyl estradiol and either 150 mcg levonorgestrel or 150 mcg desogestrel on coagulation indices in Malaysian women was examined. 50 women who had been using the pills for 1 year or more, were compared to 75 non-users. All were attending the Maternity Clinic of the General Hospital, Kuala Lumpur. Pill users registered shorter prothrombin time, 11.5 vs. 11.1 seconds (p=0.016), and partial thromboplastin time, 40.1 vs 35.1 seconds (p=0.000). Since there were no significant differences in Factors II, V, VII, or VIII, the overall effects of low-dose pills on coagulation is probably not clinically significant. PMID:12343152

Roshidah, I; Khalid, H; Baharum, Y

1990-12-01

169

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

PubMed Central

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

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

2012-01-01

170

Efficacy of a single oral dose of oxfendazole against Fasciola hepatica in naturally infected sheep.  

PubMed

The efficacy of a single oral dose of 30 mg/kg of oxfendazole against Fasciola hepatica was evaluated in a controlled study in naturally infected sheep. Sheep were diagnosed by stool microscopy after sedimentation, and positive animals were randomized to oxfendazole (N = 20) or no treatment (N = 20). A new stool exam was performed 10 days after treatment. All stool microscopies were performed masked to the treatment group. No side effects were noticed. All sheep in the control group remained infected with similar counts of eggs per gram of stools. None of the animals in the treatment group showed Fasciola eggs in stools after 10 days of treatment. A single dose of oxfendazole is highly effective against F. hepatica, providing a new drug alternative for the control of fascioliasis or integrated zoonosis control. PMID:22403323

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

2012-03-01

171

Comparison of amoxicillin and ampicillin in single-dose oral treatment of males with gonococcal urethritis  

PubMed Central

Amoxicillin in single oral doses of 2.0 g, 2.0 g plus 1.0 g probenecid, or 3.0 g was compared with ampicillin 3.5 g plus 1.0 g probenecid in the treatment of 203 males with uncomplicated acute gonococcal urethritis. Cure rates above 95% were produced by all treatments except the 2.0-g amoxicillin dose, which cured 89% of patients. Of 198 pretreatment gonococcus isolates tested by an agar dilution technique for susceptibility to penicillin G, ampicillin and amoxicillin, over 50% showed relative resistance (MIC > 0.06 ?g/ml) to the antibiotics. However, amoxicillin was somewhat more active against isolates showing considerable resistance (MIC ? 1.0 ?g/ml) to penicillin G or ampicillin. Adverse effects of amoxicillin were few: two patients reported transient nausea and six noted short-lived diarrhea. No hypersensitivity reactions were observed.

Mitchell, Richard W.; Robson, Hugh G.

1974-01-01

172

Minimal androgenic activity of a new oral contraceptive containing norethindrone acetate and graduated doses of ethinyl estradiol  

Microsoft Academic Search

The pharmacokinetics and androgenic activity of Estrostep®, a new oral contraceptive providing low-dose estrogen in a graduated sequence with a constant dose of progestin, were characterized in an open-label, nonrandomized study in 17 normally cycling women treated for three cycles with Estrostep. Women received 1 mg of norethindrone acetate daily combined with 20 ?g of ethinyl estradiol daily for the

Rebecca A Boyd; Elizabeth A Zegarac; Edward L Posvar; Mary R Flack

2001-01-01

173

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

PubMed Central

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

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

2010-01-01

174

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

PubMed Central

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

2012-01-01

175

Pharmacokinetic analysis of two different doses of duloxetine following oral administration in dogs.  

PubMed

Duloxetine is a potent and balanced dual inhibitor of serotonin and norepinephrine reuptake that is being investigated for the treatment of depression and urinary incontinence. The purpose of this study was to investigate the pharmacokinetic properties of duloxetine in 20 beagle dogs following a single oral administration of a 30- or 60-mg enteric-coated pellet in a capsule (Cymbalta).Following the administration of 30 or 60 mg of Cymbalta to 20 beagle dogs, the plasma concentration of duloxetine was measured using LC-MS/MS. Pharmacokinetic parameters were analyzed using both noncompartmental and compartmental approaches.The values of C max and AUC increased in proportion to the dose of duloxetine. The one compartment model with first-order absorption and a lag time was used successfully for pharmacokinetic analysis of duloxetine following a single oral administration of Cymbalta 30 mg or 60 mg.The studies described here are the first to report the pharmacokinetics of oral duloxetine in dogs, and these findings provide important information for pharmaceutical formulation research of duloxetine using dogs. PMID:23599035

Baek, I-H; Lee, B-Y; Kang, W; Kwon, K-I

2013-04-18

176

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

PubMed Central

The effect upon tryptophan metabolism of the use of combined oestrogen-progestagen oral contraceptives containing a low (0·05 mg) dose of oestrogen, or of the continuous administration of megestrol acetate, has been studied by determining the excretion of tryptophan metabolites in urine collected after a 2 g oral dose of the amino acid. An investigation of 10 women before being given oral contraceptives and after 21 days and three months of their use showed that xanthurenic acid excretion is increased within 21 days and that by three months the urinary levels of xanthurenic acid, kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid may all be elevated. Ten other women studied after taking a combined type of oral contraceptive for six months or longer excreted significantly higher levels of all four metabolites than did those who had been treated with these steroids for only three months. The abnormal urinary excretion of tryptophan metabolites was completely reversed by treatment with pyridoxine hydrochloride, 20 mg daily for one month. Studies of four women when they were taking an oestrogen-containing oral contraceptive and at intervals after they had discontinued its use showed that abnormal tryptophan metabolism may persist for three months or longer. Megestrol acetate, a progestagen used as an oral contraceptive, was found to have no significant effect upon tryptophan metabolism. The possible clinical significance of the effects of oral contraceptives upon tryptophan metabolism is discussed.

Rose, D. P.; Adams, P. W.

1972-01-01

177

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

PubMed Central

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

Sinha, Rakesh; Rawat, Sudarshan

2013-01-01

178

Effect of seven low-dose combined oral contraceptive preparations on carbohydrate metabolism.  

PubMed

The effect of seven low-dose oral contraceptive preparations on carbohydrate metabolism was investigated in groups of 10 healthy volunteers. All preparations contained a similar amount of ethinyl estradiol but differed in the content and type of progestogen. The following progestogens were used: levonorgestrel (monophasic and triphasic), norethisterone (monophasic), cyproterone acetate (monophasic), desogestrel (monophasic and biphasic) and gestodene (triphasic). An oral glucose tolerance test was performed before and after 6 months of treatment; glucose disappearance and insulin response curve were determined. Long-term glucose homeostasis was assessed by the estimation of the extent of glycosylation of plasma proteins and hemoglobin A1. The area under the curve for insulin and glucose did not change during treatment with any of the preparations. In addition the representative variables for long-term glucose control did not increase for any of the preparations during treatment. We conclude from these results that the low-dose pills investigated in this study do not have any adverse effects on glucose metabolism after treatment for 6 months. PMID:3578401

van der Vange, N; Kloosterboer, H J; Haspels, A A

1987-04-01

179

Patient compliance with prolonged low-dose oral etoposide for small cell lung cancer.  

PubMed Central

Using an 'intelligent' tablet bottle which, unknown to the patient, electronically records the times of opening we have assessed the compliance of patients with prescribed oral medication. The compliance pattern of 12 patients receiving low dose etoposide for small cell lung cancer was monitored over 25 treatment periods, representing a total of 298 days. The data were expressed as overall compliance (OC), defined as the observed number of bottle openings as a percentage of the prescribed number of doses, and as two indices representing daily and hourly irregularities in the times of opening. The OC had a mean (+/- s.d.) value of 93.2% (+/- 12%) over the 25 treatment periods, and is similar to that which we have reported in a group of lymphoma patients (Lee et al., 1992). By means of a self assessed diary card we monitored the physical and mental state of the patients. Although we found significant associations between the compliance measures and some of the diary card measures, the magnitude of the observed effects would be of little practical consequence. We conclude that, in our group of patients, inadequate compliance with oral chemotherapy would not account for any significant lack of clinical response.

Lee, C. R.; Nicholson, P. W.; Souhami, R. L.; Slevin, M. L.; Hall, M. R.; Deshmukh, A. A.

1993-01-01

180

Stimulation of insulin secretion by large-dose oral arginine administration in healthy adults  

PubMed Central

The effects of large-dose oral arginine administration on the secretion of insulin by islet ?-cells in healthy adults were determined. Eight non-obese healthy volunteers with normal glucose tolerance participated randomly in tests with four stages (with an interval of at least 3 days): the 300 ml purified water stage (PWS), the 75 g glucose stage (GSS), the 30 g arginine stage (ARS) and the 75 g glucose with 30 g arginine stage (GAS). Venous blood samples were collected to detect the concentrations of glucose and insulin at baseline (0) and at 15, 30, 45, 60 and 120 min after drug administration. The glucose and insulin levels were steady in the PWS. The remaining three stages had similarly shaped insulin concentration-time curves, which differed from that of the PWS. The peak concentration of blood insulin and the net incremental area under the curve of blood insulin in the GSS, ARS and GAS were significantly higher compared with those in the PWS (P<0.05). In the ARS, the glucose levels remained stable; however, the net incremental area under the curve for blood insulin in the ARS was much lower compared with that in the GSS or GAS (P<0.05). Large-dose oral arginine administration may slightly stimulate insulin secretion by islet ?-cells in healthy adults with normal glucose tolerance in a manner that is independent of glucose concentration.

TANG, ZHU-QI; WU, TAO; CUI, SHI-WEI; ZHU, XIAO-HUI; YIN, TONG; WANG, CUI-FANG; ZHU, JING-YI; WU, AI-JUAN

2013-01-01

181

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

PubMed Central

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

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

2006-01-01

182

Single dose pharmacokinetics and pharmacodynamics of oral loprazolam in the elderly.  

PubMed Central

The pharmacokinetics of the benzodiazepine hypnotic, loprazolam (1.0 mg orally), and the pharmacodynamic response to single oral doses (0.5 mg and 1.0 mg) have been compared in young and elderly healthy volunteers. No difference between the groups in peak plasma concentration (Cmax) or in the time to peak (tmax) was found, but the elimination half-life t1/2,z and area under the plasma concentration-time curve (AUC) were significantly greater in the elderly group. The immediate effects of loprazolam on all three performance tests used (postural sway, critical flicker fusion threshold (CFFT) and choice reaction time (CRT] and on subjective sedation tended to be more pronounced in the elderly subjects, though intersubject variability in response was high in both groups. The corresponding plasma concentrations did not differ significantly between the two groups. The higher (1.0 mg) dosage was associated with significant residual (11 h) impairment of standing steadiness in the elderly subjects. No other hangover effects were observed. The results are compatible with previous evidence of increased 'sensitivity' to benzodiazepines in the elderly and suggest that a lower (0.5 mg) starting dose of loprazolam would be appropriate for older recipients. Further investigation would be necessary to establish whether clinically relevant accumulation of loprazolam occurs in the elderly following repeated dosage.

Swift, C G; Swift, M R; Ankier, S I; Pidgen, A; Robinson, J

1985-01-01

183

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

PubMed Central

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

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

2001-01-01

184

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

SciTech Connect

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

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

1985-08-01

185

Dialyzability and pharmacokinetics of sitafloxacin following multiple oral dosing in infected hemodialysis patients.  

PubMed

The pharmacokinetics and dialyzability of oral sitafloxacin, a newly available quinolone, in infected intermittent hemodialysis patients have not been reported previously. Seven infected maintenance hemodialysis patients lacking residual renal function were enrolled. Sitafloxacin (50 mg after hemodialysis on the first day, on the next day and 4 h before scheduled hemodialysis session on the 3rd day) was orally administered. On the 3rd day, blood was taken from arterial and venous sides before and 2 and 4 h after session initiation. Another sampling was performed 1 h after the session and on the 5(th) day of the study. Pharmacokinetic parameters and dialyzability of sitafloxacin were evaluated. All patients exhibited improved symptoms without major problems. Drug concentrations in all arterial samples were above the MIC of targeted bacteria. Dialyzer clearance and elimination fraction were 49.9 ± 0.9 mL/min per m(2) and 53.3 ± 2.1%, respectively. Apparent half-life during dialysis session was significantly shorter than that after the session (4.0 ± 0.4 and 46.5 ± 3.6 h, during and after the session, respectively). Dialyzer clearance was positively correlated with urea reduction ratio and negatively correlated with serum albumin concentration. About 23% of the drug in the body was removed by dialysis. Rebound of the drug concentration after the dialysis was not seen. Oral dosing of this drug at 50 mg daily in maintenance hemodialysis patients provides a safe drug concentration compatible with that of healthy subjects orally receiving 100 mg daily. Because a significant amount of the drug was removed, administration might be undertaken after the dialysis session. PMID:23735148

Tsuruoka, Shuichi; Yokota, Noritsugu; Hayasaka, Tokie; Saito, Tetsuo; Yamagata, Kunihiro

2012-12-07

186

EEG and blood level of the potential antidepressant paroxetine after a single oral dose to normal volunteers  

Microsoft Academic Search

The quantitative electroencephalogram (EEG) and plasma concentration of the antidepressant paroxetine were monitored in five normal volunteers after a single oral dose of 70 mg paroxetine and placebo. Peak plasma concentration occurred 4–6 h post-dose. Placebo had little effect on the EEG but the effects of paroxetine were statistically significant at 6 h post-dose. The EEG changes after treatment consisted

G. R. McClelland; P. Raptopoulos

1984-01-01

187

Pharmacokinetics of desmethylimipramine and nortriptyline in man after single and multiple oral doses — A cross-over study  

Microsoft Academic Search

Eight healthy volunteers received single oral doses (1 mg\\/kg) and 6 received multiple doses (0.4 mg\\/kg t.i.d. for 2 weeks) of desmethylimipramine (DMI) and nortriptyline (NT) on different occasions. Kinetic analysis of plasma levels of the drugs showed that the ratios between single-dose peak-levels, plasma half-lives and apparent mean “steady-state” plasma levels of the two drugs were constant in all

B. Alexanderson

1972-01-01

188

Urinary excretion of nortriptyline and five of its metabolites in man after single and multiple oral doses  

Microsoft Academic Search

The urinary excretion of nortriptyline (NT) and five of its metabolites was studied by quantitative gas chromatography in 22 twins and 7 unrelated healthy subjects after single (1 mg\\/kg) and multiple oral doses (0.4 mg\\/kg t.i.d.) of NT hydrochloride. A mean recovery of 62% of the dose was found after both single and multiple doses. The metabolite pattern in the

B. Alexanderson; O. Borgĺ

1973-01-01

189

Crossover dose escalation study to assess safety, pharmacokinetics, and pharmacodynamics of single doses of R1663, an oral factor Xa inhibitor, in healthy male volunteers.  

PubMed

This study investigated the safety, pharmacokinetics, and pharmacodynamics of single oral doses of R1663, a factor Xa inhibitor, in healthy volunteers. It was a single-blind, randomized, crossover, placebo-controlled, dose escalation study in 33 healthy male volunteers aged 18 to 45 years. Each volunteer was dosed on 3 occasions with R1663 or placebo. Single oral doses of R1663 were safe and well tolerated. R1663 did not affect bleeding time. Pharmacodynamic effects (prothrombin time [PT], activated partial thromboplastin time [aPTT]), parameters of thrombogram, and anti-factor Xa activity) and plasma concentrations of R1663 were dose-dependent and showed low to moderate (<40%) intersubject and intrasubject variability. Maximum factor Xa inhibition was achieved 3 hours post dose (time to maximum concentration of R1663): clotting times were prolonged up to 2.5-fold, whereas endogenous thrombin potential (ETP) and peak height were decreased by 48% and 85% from their baseline values, respectively. Pharmacodynamic parameters were strongly correlated to R1663 plasma concentrations, with IC50 values of 182 and 2680 ng/mL for peak height and ETP, respectively. Oral doses of R1663 up to 480 mg were well tolerated, with predictable pharmacodynamics and pharmacokinetics. R1663 prolonged clotting times (PT, aPTT) and inhibited thrombin generation without increasing bleeding time. PMID:21566199

Schmitt, Christophe; Pannier, Anne; McIntyre, Christine; Zandt, Hagen; Ciorciaro, Cornelia; Winters, Katie; Pepper, Tom

2011-05-12

190

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

PubMed Central

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

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

2010-01-01

191

Pharmacokinetics of nortriptyline in man after single and multiple oral doses: The predictability of steady-state plasma concentrations from single-dose plasma-level data  

Microsoft Academic Search

Six healthy volunteers were given nortriptyline (NT) in single (1 mg\\/kg) and multiple (0.4 mg\\/kg) oral doses with the purpose to study the pharmacokinetics of NT in plasma. The single-dose plasma levels in 3 subjects were applied to a two-compartment open model (Model II) which might be suitable for the disposition kinetics of NT. There were significant (PC-0304;, of NT

B. Alexanderson

1972-01-01

192

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.

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

1999-01-01

193

Regional differences in micro-structural and biochemical characteristics of growth and metabolism in semitendinosus muscle of 28-day old piglets  

Microsoft Academic Search

Micro-structural and biochemical characteristics of myofibre growth and metabolism were compared among three regions (dark [near bone], central, and superficial bright) of the semitendinosus muscle mid-belly of 28-day old piglets. The total fibre number as estimated from the dark, central, and bright region, as well as mean fibre area did not differ among regions. Compared with the bright region, the

D. Lösel; G. Nürnberg; C. Rehfeldt

2011-01-01

194

TISSUE DEPLETION RESIDUES IN FATTENING RABBITS FED DURING 28 DAYS WITH FEED SUPPLEMENTED WITH 40 PPM OF TIAMULIN HYDROGEN FUMARATE (TIAMUTIN® PREMIX 100)  

Microsoft Academic Search

Thirty rabbits were medicated with feed supplemented with 39 ppm of tiamulin, equivalent to 3.21±0.50 mg of tiamulin hydrogen fumarate per kg body weight and day, during 28 days, and tiamulin-derived residues (measured as 8-?-hydroxymutilin) in the muscle and liver of rabbits were evaluated at 0, 3, 6, 12 and 24 hours after the end of the medication period. A

195

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

196

Influence of Vehicles Used for Oral Dosing of Test Molecules on the Progression of Mycobacterium tuberculosis Infection in Mice  

PubMed Central

Preclinical evaluation of drug-like molecules requires their oral administration to experimental animals using suitable vehicles. We studied the effect of oral dosing with corn oil, carboxymethyl cellulose, dimethyl sulfoxide, and polysorbate-80 on the progression of Mycobacterium tuberculosis infection in mice. Infection was monitored by physical (survival time and body weight) and bacteriological (viable counts in lungs) parameters. Compared with water, corn oil significantly improved both sets of parameters, whereas the other vehicles affected only physical parameters.

Singh, Shubhra; Dwivedi, Richa

2012-01-01

197

Oral nitroglycerin in angina pectoris—Evaluation of effect by computerized exercise testing using two different doses  

Microsoft Academic Search

The antianginal effects of sustained-released oral nitroglycerin were evaluated in patients with chronic stable angina using a double-blind randomized protocol. Nineteen patients were inducted into the trial and 17 of these completed the study. Two doses of oral nitroglycerin were used; 2.6 mg and 6.5 mg given three times daily for a period of 2 weeks, the patients crossing over

Ravinder S. Kohli; Nardev S. Khurmi; Mohamed M. Kardash; Avijit Lahiri; Edward B. Raftery

1988-01-01

198

The Pharmacokinetics of Escitalopram After Oral and Intravenous Administration of Single and Multiple Doses to Healthy Subjects  

Microsoft Academic Search

The pharmacokinetics of escitalopram (S-citalopram) and its principal metabolite, S-demethylcitalopram (S-DCT), were investigated after intravenous and oral administration to healthy subjects. After intravenous infusion of escitalopram, the mean systemic clearance and volume of distribution were 31 L\\/h and 1100 L, respectively. After oral administration of single or multiple doses, the absorption was relatively fast, with the maximum observed plasma or

B. Sřgaard; H. Mengel; N. Rao; F. Larsen

2005-01-01

199

Comparative assessment of two low-dose oral contraceptives, Lo-Femenal and Lo-Estrin, in Mexican women  

Microsoft Academic Search

This trial was designed to determine the differences in effectiveness, clinical acceptability, and one-year discontinuation rates of two low-dose oral contraceptives: Lo-Estrin (norethindrone acetate 1.5 mg plus ethinyl estradiol 0.030 mg) and Lo-Femenal (norgestrel 0.30 mg plus ethinyl estradiol 0.030 mg) in 148 Mexican women. In addition, the effects of both oral contraceptive preparations on blood lipids were prospectively evaluated

J. Garza-Flores; M. Martínez; V. Valles de Bourges; L. Vázquez-Estrada; S. McMullen; R. Dunson; G. Pérez-Palacios

1992-01-01

200

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

PubMed

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

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

1995-11-01

201

Relative reinforcing effects of different oral ethanol doses in rhesus monkeys.  

PubMed

The relative reinforcing effects of different doses of orally delivered ethanol were evaluated. Mouth-contact responding by rhesus monkeys was measured under concurrent fixed-ratio fixed-ratio schedules of liquid delivery (0.67 ml/delivery) from each of two spouts during daily 3-hr sessions. Experiment 1 examined persistence of responding with ethanol (2%, 8%, and 32% wt/vol) and water available. When fixed-ratio values from 8 to 128 were tested, the number of ethanol deliveries obtained per session decreased as the response requirement increased. The decrease in deliveries was less at higher than at lower ethanol concentrations, however. Experiment 2 examined choice between two ethanol concentrations under concurrent fixed-ratio 16 schedules (4% vs. 8%, 4% vs. 16%, 8% vs. 16%, 2% vs. 8%, 2% vs. 32%, 8% vs. 32%). Higher concentrations (16%, 32%) generally maintained more responding than concurrently available concentrations of 8% or less. An exception was the observation of a preference for 8% over 32% ethanol. When the fixed-ratio value was increased, however, the relative preference for these two doses was reversed so that 32% ethanol maintained more responding than 8% ethanol. Thus, the direction of the preference depended on the size of the response requirement. These results indicate that the reinforcing effects of ethanol increase with dose. PMID:11831783

Stewart, Robert B; Wang, Nian-Sheng; Bass, April A; Meisch, Richard A

2002-01-01

202

Efficacy of oral single dose therapy with artemisinin-naphthoquine phosphate in uncomplicated falciparum malaria.  

PubMed

All artemisinin-based combination therapies (ACTs), recommended by the World Health Organization, are 3-day regimens. A considerable level of non-compliance on ACTs has been reported from some countries. The study aimed to assess the therapeutic efficacy of single dose treatment with new generation ACT containing artemisinin plus naphthoquine. An oral single dose of eight tablets (400 mg of naphthoquine+1000 mg artemisinin) of the combination drug was administered to adult uncomplicated falciparum malaria patients. Observations of fever, parasite clearance and reappearance, and other clinical manifestations were made on Days 0, 1, 2, 3, 7, 14, 21 and 28. Fifty-three adult falciparum positive cases, with fever or history of fever within the previous 24 h, were included in the final evaluation of the study. Mean fever clearance time, parasite clearance time were 18.2+/-8.6 h and 34.6+/-14.3 h, respectively. Adequate clinical and parasitological response was achieved in 52 cases, the rate being 98.1% (95% CI, 91.1-99.9). One patient was classified as late parasitological failure because of the reappearance of falciparum parasite on Day 14. The drug was well tolerated and no adverse reactions were detected in the patients. Since it is a single dose therapy, health workers can administer the drug as directly observed treatment. PMID:19464245

Tun, Thein; Tint, Hla Soe; Lin, Khin; Kyaw, Thar Tun; Myint, Moe Kyaw; Khaing, Win; Tun, Zaw Win

2009-05-21

203

Levels of itraconazole in skin blister fluid after a single oral dose and during repetitive administration.  

PubMed

Oral itraconazole is effective in the treatment of mycoses. To measure its concentrations in the tissue, levels of total and non-protein-bound itraconazole were determined in serum, suction-induced blister fluid, and cantharides-induced blister fluid. Six healthy subjects received 200 mg as a single dose, followed by 100 mg/day for 10 days. Itraconazole binding in suction-induced blister fluid (99.54%) and cantharides-induced blister fluid (99.77%) was calculated from plasma protein binding (99.8%). The single-dose study showed the drug levels in blister fluid to increase more slowly than those in serum. The terminal half-life of itraconazole in serum was 22.5 +/- 3.2 hours. Suction- and cantharides-induced blister fluid levels declined in parallel. After the final dose, itraconazole penetration into cantharides-induced blister fluid was only 70%. Moreover, trough levels of unbound itraconazole in suction- and cantharides-induced blister fluid were 0.239 +/- 0.115 and 0.334 +/- 0.101 ng/ml and thus were significantly lower than free itraconazole levels in serum (0.422 +/- 0.125 ng/ml). Thus a distribution equilibrium between serum and blister fluids was not obtained. Free drug concentrations in suction- and cantharides-induced blister fluid were far lower than the minimal inhibitory concentration values for Candida ssp. and dermatophytes. PMID:2155951

Schäfer-Korting, M; Korting, H C; Lukacs, A; Heykants, J; Behrendt, H

1990-02-01

204

Oral beclomethasone dipropionate in patients with mild to moderate ulcerative colitis: a dose-finding study.  

PubMed

Systemic glucocorticosteroids have demonstrated efficacy in ulcerative colitis (UC) but cause undesired systemic side effects. Beclomethasone dipropionate (BDP) has potent topical activity and is extensively metabolized. This randomized double-blind study investigated an oral gastroresistant controlled-release preparation of BDP in 57 patients with mild to moderately severe extensive or left-sided UC. Patients were assigned to receive BDP 5 or 10 mg/d; a third group took a clinically inactive dose (1.6 g/d) of 5-aminosalicylic acid (5-ASA). Both BDP doses displayed excellent efficacy confirmed by results of endoscopy, biopsy, and clinical evaluation. Significant improvement from baseline occurred in most signs and symptoms of UC, particularly stool frequency, rectal bleeding, and mucus in the stool (P<.01). Tolerability was good in both BDP groups. Morning plasma cortisol levels decreased significantly from baseline with BDP 10 mg, but no significant changes in vital signs were observed at the end of treatment. Despite a small sample size and the open comparison with 5-ASA, this multicenter study showed the therapeutic equivalence of BDP 5 and 10 mg/d in alleviating clinical symptoms and improving endoscopic and biopsy scores in patients with mild to moderate UC. BDP 5 mg/d displayed better general tolerability and less reduction of plasma cortisol levels, however, and may be preferable to the higher dose in this indication. PMID:11841196

Rizzello, F; Gionchetti, P; Galeazzi, R; Novelli, G; Valpiani, D; D'Arienzo, A; Manguso, F; Castiglione, G; Varoli, G; Campieri, M

205

Relapsing insulin-induced lipoatrophy, cured by prolonged low-dose oral prednisone: a case report  

PubMed Central

Introduction Circumscript, progressing lipoatrophy at the insulin injection sites is an unexplained, however rare condition in diabetes mellitus. Case presentation We report a case of severe localised lipoatrophy developing during insulin pump-treatment (continuous subcutaneous insulin infusion) with the insulin analogue lispro (Humalog®) in a woman with type-1 diabetes mellitus. After 11 months of progressing lipoatrophy at two spots on the abdomen, low-dose prednisone (5-10 mg) p.o. was given at breakfast for 8 months, whereby the atrophic lesions centripetally re-filled with subcutaneous fat tissue (confirmed by MRI) despite ongoing use of insulin lispro. However, 4 weeks after cessation of prednisone, lipoatrophy relapsed, but resolved after another 2 months of low-dose prednisone. No further relapse was noted during 12 months of follow-up on insulin-pump therapy with Humalog®. Conclusion Consistent with an assumed inflammatory nature of the condition, low-dose oral prednisone appeared to have cured the lipoatrophic reaction in our patient. Our observation suggests a temporary intolerance of the subcutaneous fat tissue to insulin lispro (Humalog®), triggered by an unknown endogenous mechanism.

2011-01-01

206

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

PubMed Central

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

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

1990-01-01

207

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

SciTech Connect

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

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

2009-03-01

208

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

PubMed

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

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

2012-06-01

209

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

PubMed

Mercury (Hg) is toxic and is released into the environment from a wide variety of anthropogenic sources. Methylmercury (MeHg), a product of microbial methylation, enables rapid Hg bioaccumulation and biomagnification in the biota. Methylmercury is sequestered and made available to the rest of the biota through the benthic-detrital component leading to the high risk of exposure to benthic fish species, such as white sturgeon (Acipenser transmontanus). In the present study, a combined technique of stomach intubation, dorsal aorta cannulation, and urinary catheterization was utilized to characterize the absorption, distribution, and elimination of Hg in white sturgeon over a 48h exposure. Mercury, as methylmercury chloride, at either 0, 250, 500, or 1000 ?g Hg/kg body weight, was orally intubated into white sturgeon, in groups of five. The blood was repeatedly sampled and urine collected from the fish over the 48h post intubation period, and at 48h, the fish were sacrificed for Hg tissue concentration and distribution determinations. The fractional rate of absorption (K), blood Hg concentration (?g/ml), tissue concentration (?g/g dry weight) and distribution (%), and urinary Hg elimination flux (?g/kg/h) are significantly different (p<0.05) among the MeHg doses. Complete blood uptake of Hg was observed in all MeHg treated fish by 12h. The maximal observed blood Hg concentration peaks are 0.56±0.02, 0.70±0.02, and 2.19±0.07 ?g/ml (mean±SEM) for the 250, 500, and 1000 ?gHg/kg body weight dose groups, respectively. Changes in blood Hg profiles can be described by a monomolecular function in all of the MeHg treated fish. The Hg concentration asymptote (A) and K are dose dependent. The relationship between A and the intubation dose, however, is nonlinear. Mercury levels in certain tissues are comparable to field data and longer-term study, indicating that the lower doses used in the current study are ecologically relevant for the species. Tissue Hg concentrations are in the following decreasing order: gastro-intestinal tract>kidney>spleen>gill>heart>liver>brain>white muscle and remaining whole body. At 48h, Hg was found to be preferentially distributed to metabolically active tissues. Digestibility is highest at the lowest MeHg dose. Measurable urinary Hg was observed in the fish treated with the highest MeHg dose, and a significant increase in the elimination flux was observed between 3 and 12h post intubation. PMID:22819805

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

2012-06-26

210

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

211

Ampicillin trihydrate in foals: serum concentrations and clearance after a single oral dose.  

PubMed

Five foals from two to three days old were given a single oral dose of ampicillin trihydrate (20 mg/kg bodyweight [bwt]). Serum ampicillin concentrations were measured serially over a 24 h period. The study was repeated in the same foals at 16 to 21 days old. The mean peak serum ampicillin concentration at two to three days old was 5.0 micrograms/ml at 1 h after treatment; the mean peak serum concentration at 16 to 21 days old was 2.7 micrograms/ml at 2 h. The concentrations steadily declined and ampicillin was not detected in the serum from any of the foals by 24 h. Serum clearance averaged 17.7 ml/min/kg at two to three days and 35.8 ml/min/kg at 16 to 21 days. PMID:6479137

Brown, M P; Gronwall, R; Kroll, W R; Beal, C

1984-07-01

212

Low dose, oral lorazepam: a safe and effective adjuvant to antiemetic therapy.  

PubMed

Twenty-five patients with acute nonlymphoblastic leukemia undergoing 41 cycles of chemotherapy with daunorubicin/cytosine arabinoside (ara-C) or with etoposide/ara-C received metoclopramide (MCP; 0.5 mg/kg 6 hourly i.v.) or MCP (same dose) plus oral lorazepam (1 mg/d) during and 24 hours following the chemotherapy as antiemetic medication. Control of vomiting was achieved is 55% (complete 5%, partial 50%) of the patients receiving MCP alone and in 100 percent (complete 76.1%; partial 23.8%) of those receiving MCP plus lorazepam (p less than 0.001). Eighteen of the 21 patients (85.7%) receiving MCP plus lorazepam opted for the same antiemetic regimen as compared to six of the 20 (30%) receiving MCP alone (p less than 0.01). One patient in each group developed mild sedation during the treatment. It is concluded that oral lorazepam is an effective and safe adjuvant to MCP for the control of vomiting during cancer chemotherapy. PMID:1937545

Charak, B S; Banavali, S D; Iyer, R S; Saikia, T K; Gopal, R; Advani, S H

1991-06-01

213

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

214

Cerebrospinal fluid and blood concentrations of toltrazuril 5% suspension in the horse after oral dosing.  

PubMed

Toltrazuril 5% suspension (Baycox, Bayer Canada, Ontario, Canada) was administered to six adult horses followed by blood collection and assay to determine the concentration of toltrazuril and its principal metabolites, toltrazuril sulfone and toltrazuril sulfoxide. From this data, the maximum concentration (C(max)), elimination half-life (T 1/2), and mean residence times of the plasma were determined from standard pharmacokinetic formulas. After a single oral dose of 10 mg/kg body weight a rapid absorption was found, with a mean peak serum concentration of 11.17 mg/L at 18 hours. Elimination was prolonged, with a mean T 1/2 for elimination of 61.4 hours. In addition, toltrazuril was administered to nine horses, and blood serum and cerebrospinal fluid (CSF) concentrations of toltrazuril and its principal metabolites were determined. Horses were randomly assigned to one of three treatment groups and received either 2.5 mg/kg body weight (Group A), 5.0 mg/kg body weight (Group B), or 7.5 mg/kg body weight (Group C) orally, once daily, for 10 days. Jugular venous blood was collected routinely on treatment days 2, 6, and 10, and CSF was collected on treatment day 10. Assay of toltrazuril and its metabolites revealed a dose-dependent effect within both the blood and CSF compartments. Mean concentrations within the CSF after 10 days of treatment were 0.146 mg/L in Group A, 0.190 mg/L in Group B, and 0.386 mg/L in Group C. Toltrazuril sulfone was the primary metabolite after 10 days of treatment, with concentrations that ranged from 39% to 116% of the parent drug in individual animals. Toltrazuril sulfone was also the predominant metabolite in the serum at treatment day 10; however, it did not always exceed the concentration of toltrazuril sulfoxide in the serum on treatment day 2. In the serum, drug concentrations at treatment day 2 were variable in the low-dose group (Group A), ranging from 4.0 to 11.61 mg/L; less variable in the high-dose group (Group C), ranging from 9.9 to 10.46 mg/L; and intermediate in Group B. This study confirms that toltrazuril is absorbed in the horse after oral administration and reaches effective in vitro concentrations within the CSF of the horse after once-daily dosing of 5 or 7.5 mg/kg. Although these data suggest that toltrazuril may have clinical value in the treatment of equine protozoal myeloencephalitis, clinical efficacy remains to be confirmed using appropriate methods. Effective in vitro concentrations are known; however, therapeutic concentrations in vivo have not been established. Further research in this area is needed to determine various drug values in the CSF (e.g., half-life, C(max), time to reach steady state). PMID:19757559

Furr, M; Kennedy, T

2000-01-01

215

Pharmacokinetics, bioavailability, and hemodynamic effects of trazodone after intravenous and oral administration of a single dose to dogs.  

PubMed

Objective-To determine the pharmacokinetics and hemodynamic effects of trazodone after IV and oral administration in dogs and bioavailability after oral administration. Animals-6 adult Beagles. Procedures-Dogs received trazodone HCl (8 mg/kg) orally and IV in a randomized controlled crossover design. Blood samples were collected at various times after administration. Heart rates and indirectly measured blood pressures of dogs and plasma concentrations and pharmacokinetics of trazodone were determined. Results-Following IV administration, the mean ± SD elimination half-life, apparent volume of distribution, and plasma total body clearance were 169 ± 53 minutes, 2.53 ± 0.47 L/kg, and 11.15 ± 3.56 mL/min/kg, respectively. Following oral administration, the mean ± SD elimination half-life and absolute bioavailability were 166 ± 47 minutes and 84.6 ± 13.2%, respectively. Maximum plasma concentration following oral administration was 1.3 ± 0.5 ?/mL, and time to maximum plasma concentration was 445 ± 271 minutes. After IV administration, all dogs immediately developed transient tachycardia (184.3 ± 8.0 beats/min), and 3 of 6 dogs developed aggression. Increase in heart rate was significantly associated with increase in plasma drug concentration following IV administration. Conclusions and Clinical Relevance-Results of this study indicated oral administration of trazodone resulted in acceptable absolute bioavailability, with substantial variability in time to maximum plasma concentration. Individualized approaches in dosing intervals may be necessary for dogs receiving oral trazodone. An orally administered dose of 8 mg/kg was well tolerated in dogs; IV administration of a dose of 8 mg/kg caused substantial adverse effects, including tachycardia and behavior disinhibition. PMID:24168312

Jay, Ariane R; Krotscheck, Ursula; Parsley, Elizabeth; Benson, Lisa; Kravitz, Ariel; Mulligan, Abby; Silva, Jharon; Mohammed, Hussni; Schwark, Wayne S

2013-11-01

216

Pharmacokinetics, tolerability, and safety of ACP-103 following single or multiple oral dose administration in healthy volunteers.  

PubMed

The pharmacokinetics, safety, and tolerability of ACP-103, a selective serotonin 5-HT(2A) receptor inverse agonist, were evaluated in 2 double-blind, placebo-controlled, dose escalation studies in healthy male volunteers. Pharmacokinetic sampling was measured up to 216 hours after single oral/nasogastric doses of ACP-103 and after the last dose of once-daily oral administration of ACP-103 for 14 days. Single doses of ACP-103 (20-300 mg) resulted in dose-proportionate mean C(max) values (9-152 ng/mL) and AUC(0-infinity) (706-10 798 h x ng/mL), and multiple doses (50-150 mg) resulted in dose-proportionate mean C(max,ss) (93-248 ng/mL) and AUC(0-infinity,ss) (1839-4680 h x ng/mL). The half-life of ACP-103 was approximately 55 hours, with a t(max) at 6 hours. ACP-103 was well tolerated at single doses up to and including 300 mg and multiple doses up to 100 mg once daily for 14 days. PMID:17473118

Vanover, Kimberly E; Robbins-Weilert, Doris; Wilbraham, Darren G; Mant, Timothy G K; van Kammen, Daniel P; Davis, Robert E; Weiner, David M

2007-05-01

217

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

PubMed

Oral contraceptives (OC) suppress excess androgen production; however, different progestins in combination with low-dose estrogens produce divergent effects on sex hormone-binding globulin (SHBG) and testosterone that may influence clinical outcomes. This multicenter, open-label, randomized study compared biochemical androgen profiles and clinical outcomes associated with two OC containing the same amounts of ethinyl estradiol (EE, 20 micrograms) but different progestins, levonorgestrel (LNG, 100 micrograms), and norethindrone acetate (NETA, 1000 micrograms). Fifty-eight healthy women (18-28 years old) received three cycles of treatment with LNG/EE (n = 30) or NETA/EE (n = 28). The results showed that LNG reduced androgen levels in three compartments--adrenal, ovarian, and peripheral. NETA reduced only adrenal and peripheral androgens. Despite a 2.2-fold greater relative increase in SHBG with NETA than LNG, bioavailable testosterone (T) was reduced by the same amount with LNG and NETA. Both treatments improved acne and were well tolerated. Low-dose OC (EE, 20 micrograms) are effective in reducing circulating androgens and acne lesions without causing weight gain. Although LNG and NETA affected secondary markers differently, both OC formulations produced an equivalent decrease in bioavailable. PMID:10717776

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

1999-11-01

218

Randomized Controlled Trial of a High Dose of Oral Erythromycin for the Treatment of Feeding Intolerance in Preterm Infants  

Microsoft Academic Search

Objectives: To evaluate the effectiveness of high-dose erythromycin to treat feeding intolerance in preterm infants predominantly fed milk formula. Design: This study is a prospective randomized controlled trial on 60 premature infants suffering from feeding intolerance. Thirty infants were given oral erythromycin ethylsuccinate at a dose of 50 mg\\/kg\\/day for 10 days or until they reached full enteral feeds. Randomization

Yasmeen Mansi; Nabil Abdelaziz; Zahraa Ezzeldin; Rania Ibrahim

2011-01-01

219

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

Microsoft Academic Search

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

Donald A. Tyndall; David B. Washburn

1987-01-01

220

Oral Mucositis and Outcomes of Autologous Hematopoietic Stem-Cell Transplantation Following High-Dose Melphalan Conditioning for Multiple Myeloma  

Microsoft Academic Search

The purpose of this study was to assess the relationship be- tween oral mucositis (OM) and adverse clinical and economic outcomes of autologous hematopoietic stem-cell transplantation (HSCT) following high-dose melphalan (Alkeran) conditioning in patients with multiple myeloma. A retrospective study of 115 consecutive autologous HSCT recipients with multiple myeloma who received high-dose melphalan conditioning before transplantation was undertaken at a

Montserrat Vera-Llonch; Gerry Oster; Colleen M. Ford; John Lu; Stephen Sonis

2007-01-01

221

Clinical Pharmacokinetics of Tonapofylline: Evaluation of Dose Proportionality, Oral Bioavailability, and Gender and Food Effects in Healthy Human Subjects  

Microsoft Academic Search

Tonapofylline is an antagonist of adenosine A1 receptor being developed for heart failure. In the present studies, pharmacokinetic characteristics, including dose proportionality, bioavailability, and effects of gender and food, were evaluated in healthy subjects receiving single-dose tonapofylline (0.2-375 mg) in a parallel or crossover design. Following oral administration, tonapofylline concentrations mostly peaked within 3 hours and declined over time in

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

2011-01-01

222

Metabolism and kinetics of bisphenol a in humans at low doses following oral administration.  

PubMed

Bisphenol A is a widely used industrial chemical with many potential sources of human exposure. Bisphenol A is a weak estrogen and has been implicated as an "endocrine disruptor". This term is used for a variety of chemicals encountered in the environment which have estrogenic activity. It has been postulated that human exposure to these chemicals may elicit unwanted estrogenic effects in humans such as reduced fertility, altered development and cancer. Up to now the body burden of bisphenol A in humans is unknown. Therefore, we investigated the metabolism and toxicokinetics of bisphenol A in humans exposed to low doses since systemic bioavailability has a major influence on possible estrogenic effects in vivo. Human subjects (three males and three females, and four males for detailed description of blood kinetics) were administered d(16)-bisphenol A (5 mg). Blood and urine samples were taken in intervals (up to 96 h), metabolites formed were identified by GC/MS and LC-MS/MS and quantified by GC/MS-NCI and LC-MS/MS. d(16)-Bisphenol A glucuronide was the only metabolite of d(16)-bisphenol A detected in urine and blood samples, and concentrations of free d(16)-bisphenol A were below the limit of detection both in urine (6 nM) and blood samples (10 nM). d(16)-Bisphenol A glucuronide was cleared from human blood and excreted with urine with terminal half-lives of less than 6 h; the applied doses were completely recovered in urine as d(16)-bisphenol A glucuronide. Maximum blood levels of d(16)-bisphenol A glucuronide (approximately 800 nM) were measured 80 min after oral administration of d(16)-bisphenol A (5 mg). The obtained data indicate major species differences in the disposition of bisphenol A. Enterohepatic circulation of bisphenol A glucuronide in rats results in a slow rate of excretion, whereas bisphenol A is rapidly conjugated and excreted by humans due to the absence of enterohepatic circulation. The efficient glucuronidation of bisphenol A and the rapid excretion of the formed glucuronide result in a low body burden of the estrogenic bisphenol A in humans following oral absorption of low doses. PMID:12387626

Völkel, Wolfgang; Colnot, Thomas; Csanády, György A; Filser, Johannes G; Dekant, Wolfgang

2002-10-01

223

Oral contraception does not alter single dose saquinavir pharmacokinetics in women  

PubMed Central

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

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

2004-01-01

224

Pharmacokinetics, Safety, and Hydrolysis of Oral Pyrroloquinazolinediamines Administered in Single and Multiple Doses in Rats?  

PubMed Central

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

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

2007-01-01

225

Integration of Pig-a, micronucleus, chromosome aberration, and Comet assay endpoints in a 28-day rodent toxicity study with 4-nitroquinoline-1-oxide.  

PubMed

As part of the Stage III Pig-a multilaboratory validation trial, we examined the induction of CD59-negative reticulocytes and total red blood cells (RET(CD59-) and RBC(CD59-) , respectively) in male Sprague Dawley(®) rats treated with 4-nitroquinoline-1-oxide (4NQO), for 28 consecutive days by oral gavage, at doses of 1.25, 2.50, 3.75, 5.00, and 7.50 mg kg(-1) day(-1) (the high dose group was sacrificed on Day 15 due to excessive morbidity/mortality). Animals also were evaluated for: micronucleated reticulocytes (mnRET) by flow cytometry; DNA damage in peripheral blood, liver, and stomach using the Comet assay; and chromosome aberrations (CAb) in peripheral blood lymphocytes (PBL). All endpoints were analyzed at two or more timepoints where possible. Mortality, body and organ weights, food consumption, and clinical pathology also were evaluated, and demonstrated that the maximum tolerated dose was achieved at 5.00 mg kg(-1) day(-1) . The largest increases observed for the genetic toxicology endpoints (fold-increase compared to control, where significant; all at 5.00 mg kg(-1) day(-1) on Day 29) were: RET(CD59-) (21X), RBC(CD59-) (9.0X), and mnRET (2.0X). In contrast, no significant increases were observed for the CAb or Comet response, in any tissue analyzed, at any timepoint. Because 4NQO is a well known mutagen, clastogen, and carcinogen, the lack of response for these latter endpoints was unexpected. These results emphasize the extreme care that must betaken in dose and endpoint selection when incorporating genotoxicity endpoints into routine toxicity studies as has been recommended or is under consideration by various regulatory and industrial bodies. PMID:22020836

Stankowski, Leon F; Roberts, Daniel J; Chen, Hepei; Lawlor, Timothy; McKeon, Marie; Murli, Hemalatha; Thakur, Ajit; Xu, Yong

2011-10-21

226

Longevity of SLE-prone mice increased by dietary 2-mercaptoethanol via a mechanism imprinted within the first 28 days of life  

PubMed Central

In the preceding report, moderately lived mice fed dietary 2-mercaptoethanol (2-Me) had their life extended, whereas long-lived mice were found to have the quality of life improved, but not extended, and did not develop high fat-diet obesity. In the present report, alteration of longevity of mice prone to develop spontaneous, systemic lupus erythematosus (SLE) by dietary 2-Me was determined. NZB, NZW, (NZW × NZB) F1-hybrid, BXSB/MpJ, BXSB-Yaa+/J, MRL/MpJ and MRL/MpJ-Faslpr mice received drinking water, without or with 2-Me at concentrations of 10?3 or 10?2 M. Therapeutic benefit was assessed by changes in longevity. The median survival of MRL/MpJ males was increased from 443 to 615 days and those of (NZW × NZB) F1 and NZB males and females were increased approximately two-fold. The most unexpected finding was that longevity of F1 males was significantly extended irrespective of whether dietary exposure to 2-Me was initiated at 28 days of age, at 50 days of age or initiated during gestation (and then terminated at weaning, 28 days of age). Survival of F1-hybrids in which treatment was initiated in utero or at 28 days of age was not significantly different, whereas if initiation was delayed until 50 days of age, survival was >200 days shorter. Survival of male MRL/MpJ-Faslpr and BXSB/MpJ (Yaa?), two strains with genetically controlled accelerated SLE, was not altered by 2-Me when started at 50 days. Various alternatives are discussed regarding potential long-lasting mechanisms imprinted early in life. Even though present day treatments of rodent SLE are generally aimed at controlling specific immunological events, with or without survival benefits or are procedures presently unsuitable for therapeutic use in humans, the findings presented herein seem worthy of clinical evaluation.

2010-01-01

227

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

228

Prediction of steady-state plasma levels of nortriptyline from single oral dose kinetics: A study in twins  

Microsoft Academic Search

Five identical (monozygotic) and 6 fraternal (dizygotic) sets of healthy twins between 47 and 53 years of age were given a single oral dose of nortriptyline (NT) hydrochloride 1 mg\\/kg. The plasma half-life, the apparent volume of distribution, and the plasma clearance of NT were estimated for each subject as well as the urinary excretion rate of conjugated and unconjugated

B. Alexanderson

1973-01-01

229

Haematic concentrations versus oral doses of methadone. Com parative assessment of two reference systems during substitute therapy in opiate addiction  

Microsoft Academic Search

Therapeutic failures in MMP patients may be due to an inadequate oppioidergic replacement effect of the drug on specific receptors for endogenous opiates. Even with oral doses considered adequate in the current literature, haematic levels may be low, due to genetic or induced over-metabolization of the drug; in addition, even when haematic levels are high, the results may be poor,

Scarlata Salvatore; Marcello Chiarotti; Nadia Fucci; Nadia De Giovanni

230

[Functional state of the cardiovascular system system during combined exposure to 28-day immersion, rotation in a short radius centrifuge, and physical loading on a bicycle ergometer].  

PubMed

The cardiovascular function of four test subjects exposed to 28-day "dry" immersion was examined before and after 6-day cycles of rotation in a short-arm centrifuge to provide 1-2 Gz, bicycle ergometer exercise, and their combination. An exposure to acceleration of 3 Gz in a 7.25 m arm centrifuge was used as a provocative test. The above countermeasures reduced but not eliminated entirely immersion-induced cardiovascular deconditioning. From this study a combined use of acceleration of 1-2 Gz in a short-arm centrifuge and bicycle ergometer exercise can be recommended as a countermeasure against cardiovascular deconditioning in weightlessness. PMID:7392556

Vil'-Vil'iams, I F; Shul'zhenko, E B

231

Effect of Dietary Supplementation of Galactomannan oligosaccharides and Chitosan on Performance and Serum Immune Parameters of 28-day Weaned Piglets Challenged with Pathogenic E.coli  

Microsoft Academic Search

Sun, Z.H., Tang, Z.R., Yin, Y.L., Huang, R.L., Li, T.J., Tang, S.X. and Tan, Z.L. 2009. Effect of dietary supplementation of galacto-mannan-oligosaccharides and chitosan on performance and serum immune parameters of 28-day weaned piglets challenged with pathogenic E. coli. J. Appl. Anim. Res., 36: 207–211.To determine the effects of galacto-mannan-oligosaccharides (GMOS) and chitosan (COS) on growth performance and serum immune

Z. H. Sun; Z. R. Tang; Y. L. Yin; R. L. Huang; T. J. Li; S. X. Tang; Z. L. Tan

2009-01-01

232

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

233

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

PubMed

Monochloramine has been used to provide a disinfecting residual in water distribution systems where it is difficult to maintain an adequate free-chlorine residual or where disinfection by-product formation is of concern. The goal of this study was to characterize the immunotoxic effects of chloramine in female B(6)C(3)F(1) mice when administered via the drinking water. Mice were exposed to chloramine-containing deionized tap water at 2, 10, 20, 100, or 200 ppm for 28 days. No statistically significant differences in drinking water consumption, body weight, body weight gain, organ weights, or hematological parameters between the exposed and control animals were noted during the experimental period. There were no changes in the percentages and numbers of total B-lymphocytes, T-lymphocytes, CD4(+) and CD8(+) T-lymphocytes, natural killer (NK) cells, and macrophages in the spleen. Exposure to chloramine did not affect the IgM antibody-forming cell response to sheep red blood cells (SRBC) or anti-SRBC IgM antibody production. Minimal effects, judged to be biologically insignificant, were observed in the mixed-leukocyte response and NK activity. In conclusion, chloramine produced no toxicological and immunotoxic effects in female B(6)C(3)F(1) mice when administered for 28 days in the drinking water at concentrations ranging from 2-200 ppm. PMID:22017662

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

2011-10-21

234

Risk factors for 28-day mortality in elderly patients with extended-spectrum ?-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae bacteremia.  

PubMed

Gram-negative bacteremia is common in elderly patients and, compared with younger patients, mortality rates in bacteremic elderly patients are high. ESBL-producing organisms were one of the most important risk factors associated with mortality. In addition, older age is one of risk factors for colonization or infection with ESBL-producing organisms. We conducted a retrospective cohort study to evaluate risk factors of all-cause 28-day mortality in elderly patients with ESBL-producing Escherichia coli (E. coli) and Klebsiella pneumoniae (K. pneumoniae) bacteremia. Patients aged 65 years or older, who had one or more blood cultures positive for E. coli and K. pneumoniae and who were hospitalized between January 2006 and December 2010 at a tertiary-care teaching hospital, were included. 191 bacteremic elderly patients were eligible for the study. The all-cause 28-day mortality rate was 24.6% (47/191). In multivariate analysis, prior antimicrobial therapy (p=0.014) and an elevated SOFA score (p<0.001) were independent risk factors for increased mortality, while urinary tract infection (UTI) was an independent determinant for non-mortality (p=0.011). In the current study, prior antimicrobial therapy within 30 days, an elevated SOFA score and nonurinary source of infection were significantly associated with adverse outcomes in elderly patients with ESBL-producing gram-negative bacteremia. PMID:23988261

Ku, Nam Su; Kim, Yong Chan; Kim, Min Hyung; Song, Je Eun; Oh, Dong Hyun; Ahn, Jin Young; Kim, Sun Bean; Kim, Hye-Won; Jeong, Su Jin; Han, Sang Hoon; Kim, Chang Oh; Song, Young Goo; Kim, June Myung; Choi, Jun Yong

2013-08-08

235

Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects.  

PubMed

AIMS: Apixaban is an oral factor Xa inhibitor approved for stroke prevention in atrial fibrillation and thromboprophylaxis in patients who have undergone elective hip or knee surgery and under development for treatment of venous thrombosis. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple-dose apixaban. METHODS: This double-blind, randomized, placebo-controlled, parallel-group, multiple-dose escalation study was conducted in six sequential dose panels - apixaban 2.5, 5, 10 and 25 mg twice daily (BID) and 10 and 25 mg once daily (QD) - with 8 healthy subjects per panel. Within each panel, subjects were randomized (3:1) to oral apixaban or placebo for 7 days. Subjects underwent safety assessments and were monitored for adverse events (AEs). Blood samples were taken to measure apixaban plasma concentration, international normalized ratio (INR), activated partial thromboplastin time (aPTT) and modified prothrombin time (mPT). RESULTS: Forty-eight subjects were randomized and treated (apixaban, n=36; placebo, n=12); one subject receiving 2.5 mg BID discontinued due to AEs (headache and nausea). No dose-limiting AEs were observed. Apixaban maximum plasma concentration was achieved ?3?h post-dose. Exposure increased approximately in proportion to dose. Apixaban steady-state concentrations were reached by Day 3, with an accumulation index of 1.3-1.9. Peak-to-trough ratios were lower for BID versus QD regimens. Clotting times showed dose-related increases tracking the plasma concentration-time profile. PMID:23451769

Frost, Charles; Nepal, Sunil; Wang, Jessie; Schuster, Alan; Byon, Wonkyung; Boyd, Rebecca A; Yu, Zhigang; Shenker, Andrew; Barrett, Yu Chen; Mosqueda-Garcia, Rogelio; Lacreta, Frank

2013-03-01

236

Target Site Concentrations of Ciprofloxacin after Single Intravenous and Oral Doses  

PubMed Central

To characterize the potential of ciprofloxacin penetration into human soft tissues following intravenous (i.v.) and oral (p.o.) administration, we measured the free ciprofloxacin concentrations in interstitial space fluid of skeletal muscle and subcutaneous adipose tissue by microdialysis. In addition, ciprofloxacin concentrations were measured in cantharis-induced skin blisters, saliva, and capillary plasma and were compared to the total concentrations in venous plasma. Furthermore, a pharmacodynamic in vitro model was used to simulate in vivo pharmacokinetics in bacterial culture. Eight healthy volunteers received ciprofloxacin in an open randomized crossover fashion either as a single i.v. infusion of 400 mg over 60 min or as a single p.o. dose of 500 mg. For both tissues the mean areas under the concentration-time curves (AUCs) for interstitial space fluid (AUCinterstitial?fluids) were significantly lower than the corresponding AUCplasmas, with AUCinterstitial fluid/AUCplasma ratios ranging from 0.38 to 0.68. For skeletal muscle, the AUCinterstitial fluid was significantly higher after administration of 400 mg i.v. than after administration of 500 mg p.o., with a ratio of the AUC after p.o. administration/AUC after i.v. administration of 0.64. The ratio of the concentration in skeletal muscle/concentration in plasma increased over the entire observation period, implying that ciprofloxacin concentrations were not at steady state. The ratio of the concentration in skin blister fluid/concentration in plasma reached values above 4, indicating a preferential penetration of ciprofloxacin into inflamed lesions. The concentrations in saliva and capillary blood were similar to the corresponding total levels in plasma. In vitro both in vivo ciprofloxacin concentration-time profiles were equally effective against select bacterial strains. In conclusion, single-dose administration of two bioequivalent dosage forms of ciprofloxacin might lead to differences in target site pharmacokinetics. These differences, however, are not related to a difference in target site pharmacodynamics.

Brunner, Martin; Sta?, Heino; Moller, Jan-Georg; Schrolnberger, Claudia; Erovic, Boban; Hollenstein, Ursula; Zeitlinger, Markus; Eichler, Hans Georg; Muller, Markus

2002-01-01

237

The pharmacokinetics of maropitant citrate dosed orally to dogs at 2 mg/kg and 8 mg/kg once daily for 14 days consecutive days.  

PubMed

The pharmacokinetics of maropitant were evaluated in beagle dogs dosed orally with Cerenia(®) tablets (Pfizer Animal Health) once daily for 14 consecutive days at either 2 mg/kg or 8 mg/kg bodyweight. Noncompartmental pharmacokinetic analysis was performed on the plasma concentration data to measure the AUC0-24 (after first and last doses), Ct (trough concentration-measured 24 h after each dose), Cmax (after first and last doses), tmax (after first and last doses), ?z (terminal disposition rate constant; after last dose), t1/2 (after last dose), and CL/F (oral clearance; after last dose). Maropitant accumulation in plasma was substantially greater after fourteen daily 8 mg/kg doses than after fourteen daily 2 mg/kg doses as reflected in the AUC0-24 accumulation ratio of 4.81 at 8 mg/kg and 2.46 at 2 mg/kg. This is most likely due to previously identified nonlinear pharmacokinetics of maropitant in which high doses (8 mg/kg) saturate the metabolic clearance mechanisms and delay drug elimination. To determine the time to reach steady-state maropitant plasma levels, a nonlinear model was fit to the least squares (LS) means maropitant Ct values for each treatment group. Based on this model, 90% of steady-state was determined to occur at approximately four doses for daily 2 mg/kg oral dosing and eight doses for daily 8 mg/kg oral dosing. PMID:23167698

Lesman, S P; Boucher, J F; Grover, G S; Cox, S R; Bidgood, T L

2012-11-20

238

A prospective randomized trial to evaluate different oral dose regimens of medroxyprogesterone acetate in women with advanced breast cancer.  

PubMed

A prospective randomized study was conducted to try to answer two questions: is a loading dose of medroxyprogesterone acetate (1000 mg p.o. q.d.s. for 48 h) superior to conventional dosing; and does an oral maintenance dose of 1000 mg daily offer any advantage over 500 mg daily in women with advanced breast cancer who have failed to respond to, or have relapsed after, tamoxifen? Of 211 patients randomized, 207 were evaluable. There was no improvement in response rates, time to response, response duration or overall survival as a result of the loading dose. When comparing high and low maintenance doses, there was a significant difference in response rates (48% versus 32%; chi 2 = 10.09, df = 2, P = 0.006) and survival (66% versus 41% alive at 12 months; chi 2 = 9.06, df = 1, P = 0.003) in favour of the higher dose regimen, although there was no significant difference in the duration of response. There was no additional toxicity attributable to the loading dose regimen, but side effects were more frequent with the high dose maintenance schedule (141 of 201 adverse effects occurring in these two groups) although the incidence of severe toxicity was similar with both high dose and low dose treatments. PMID:8845325

Clinton, O P; Priestman, T J; Latief, T N; Earl, H; Murphy, A; Blackledge, G R; Dunn, J; Baker, P

1995-01-01

239

Cycle control on low-dose oral contraceptives: a comparative trial.  

PubMed

Cycle control was studied comparing the monophasic oral contraceptive Loestrin with three low-dose phasic preparations (Triphasil, Ortho 10/11 and Ortho 7/7/7) in 391 women of whom 300 completed 6 cycles. Loestrin subjects had a rate of occurrence (31% of cycles) for intermenstrual bleeding (IMB) comparable to the rates for subjects on the phasic preparations (36%, 37% and 37%, respectively). Triphasil subjects had lower rates than the Ortho 10/11 and Ortho 7/7/7 subjects (p less than 0.01) in cycle one when all subjects were analyzed and in pre-study users when continuing menstrual flow (CMF) episodes were not included as IMB. IMB was a cause for dropping out of the study in 7% of subjects who were evenly distributed between groups. There were no differences between groups for BTB when perceived by subjects as a side effect. Spotting was perceived as a side effect more often with Ortho 10/11 and Ortho 7/7/7 use than with Triphasil (p less than 0.01). Loestrin, Ortho 10/11 and Ortho 7/7/7 subjects were more likely to report amenorrhea (p less than 0.001) and less likely to report leg cramps (p less than 0.01) compared to those on Triphasil. Triphasil subjects were less likely to report acne than subjects on Ortho 7/7/7 (p less than 0.01). PMID:2289388

Percival-Smith, R K; Yuzpe, A A; Desrosiers, J A; Rioux, J E; Guilbert, E

1990-09-01

240

A comparative study of two low-dose combined oral contraceptives: results from a multicenter trial.  

PubMed

A comparative multicenter clinical trial of two low-dose combined oral contraceptives (OCs) was conducted in Malaysia, Egypt, Thailand, and Mexico. Efficacy, safety and acceptability were investigated in women taking either a norgestrel-based (NG) OC or a norethindrone acetate-based (NA) OC. This paper includes analysis of 892 women, all of whom were at least 42 days but within 26 weeks postpartum and randomly allocated to one of the above OCs. Follow-up visits were scheduled at 1, 4, 8 and 12 months after admission. Baseline sociodemographic characteristics were similar for both groups, as well as compliance. There were nine unintended pregnancies reported; eight of these occurring in the NA group. Adverse experiences were minor with headaches and dizziness being the most common complaints; frequency of reports was similar in both groups. The group taking the NG-based OC had significantly (p < .05) fewer menstrual-related complaints. Discontinuations due to menstrual problems were significantly more common among NA users (primarily amenorrhea). Discontinuations in the NG group were primarily for other personal reasons, e.g. unable to return to the clinic. There was also a significant difference between the two groups for the 11-month gross cumulative life table discontinuation rates due to menstrual problems (p < .01); the NA group had the higher rate. PMID:8403908

Dunson, T R; McLaurin, V L; Israngkura, B; Leelapattana, B; Mukherjee, R; Perez-Palacios, G; Saleh, A A

1993-08-01

241

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

SciTech Connect

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

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

2007-02-01

242

Novel and Distinct Metabolites Identified Following a Single Oral Dose of ?- or ?-Hexabromocyclododecane in Mice  

PubMed Central

The metabolism of ?- and ?-hexabromocyclododecane (HBCD) was investigated in adult C57BL/6 female mice. ?- or ?-[14C]HBCD (3 mg/kg bw) was orally administered with subsequent urine and feces collection for 4 consecutive days; a separate group of mice were dosed and sacrificed 3 hours post-exposure to investigate tissue metabolite levels. Extractable and non-extractable HBCD metabolites were quantitated in liver, blood, fat, brain, bile, urine and feces and characterized by LC/MS (ESI-). Metabolites identified were distinct between the two stereoisomers. In mice exposed to ?-HBCD, four hydroxylated metabolites were detected in fecal extracts, and one of these metabolite isomers was consistently characterized in liver, brain, and adipose tissue extracts. In contrast, mice exposed to ?-HBCD contained multiple isomers of monohydroxy-pentabromocyclododecene, dihydroxy-pentabromocyclododecene, and dihydroxy-pentabromocyclododecadiene in the feces while only a single monohydroxy-pentabromocyclododecane metabolite was measured in liver and adipose tissue. Both stereoisomers were transformed to metabolites which formed covalent bonds to proteins and/or lipids in the gut as evidenced by high fecal non-extractables. Although the potential toxicity of these free and bound metabolites remains to be determined, the presence of distinct metabolic products from the two main HBCD stereoisomers should allow biomarkers to be selected that may aid in characterizing sources of HBCD exposure.

Szabo, David T.; Huwe, Janice; Diliberto, Janet; Birnbaum, Linda S.

2013-01-01

243

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

PubMed Central

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

Thulkar, Jyoti; Kriplani, Alka; Agarwal, Nutan

2012-01-01

244

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.

2011-01-01

245

High dose weekly oral prednisone improves strength in boys with Duchenne muscular dystrophy.  

PubMed

Daily prednisone improves strength in boys with Duchenne muscular dystrophy, but side effects are almost universal. We used a different dosing regimen of prednisone to determine if benefit to boys with Duchenne muscular dystrophy might be maintained with fewer side effects. Twice weekly oral prednisone was given each Friday and Saturday (5mg/kg/dose). This total dose is twice as high as the daily low dosage prednisone regimen (0.75 mg/kg/day). Twenty boys (8.0+/-1.2 years) were treated. Historical control groups included 18 untreated boys (6.1+/-1.6 years) and four boys (7.3+/-0.6 years) treated with daily prednisone. Strength (using a hand-held manometer and grip meter) and timed functional testing were measured. There was an improvement in upper extremity strength for 95% of boys (n=20) at 6 months using quantitative strength testing. Improvement in lower extremity strength occurred in all boys with antigravity quadriceps strength (17/17). The improvement (P=0.001 for proximal upper extremities; P=0.002 for grip; and P<0.0001 for proximal lower extremities) was significant compared to untreated boys. Sixteen boys were treated continuously for more than 12 months (22+/-1.5 months). Of these, 15 remained significantly stronger than prior to treatment and 8/16 showed additional gains in strength after six months of treatment. Six boys were on the weekly prednisolone 2 years or longer without interruption. All six had upper and lower extremity strength at follow-up that was as good or better than at baseline. Functional testing improved in boys less than 8 years without contractures. Three boys without antigravity quadriceps strength at the start of treatment lost the ability to walk unassisted within 6 months. Eight other boys lost the ability to ambulate unassisted between 12 and 24 months of treatment. In each, progressive contractures developed. Linear growth was maintained in all boys on weekly treatment. Obesity rates did not differ from untreated boys. Twice weekly prednisone improved strength over 6-12 months in the majority of boys, but did not slow contracture development. Sustained benefit beyond 12 months is possible with fewer side effects compared to daily prednisone. PMID:12467746

Connolly, Anne M; Schierbecker, Jeanine; Renna, Renee; Florence, Julaine

2002-12-01

246

Pharmacokinetics of EDP-420 after multiple oral doses in healthy adult volunteers and in a bioequivalence study.  

PubMed

EDP-420 (also known as EP-013420, or S-013420) is a first-in-class bridged bicyclolide currently in clinical development for the treatment of respiratory tract infections (RTI) and has previously shown favorable pharmacokinetic (PK) and safety profiles after the administration of single oral doses of a suspension to healthy volunteers. Here we report its PK profile after the administration of multiple oral doses of a suspension to healthy adults. Bioequivalence between suspension and capsule formulations, as well as the effect of food, is also reported. The most important PK features of EDP-420 observed in these clinical studies are its long half-life of 17 to 18 h and its high systemic exposure, which support once-daily dosing and treatment durations potentially shorter than those of most other macrolide antibiotics. EDP-420 is readily absorbed following oral administration in both suspension and capsule formulations. In the multiple-oral-dose study, steady state was achieved on day 1 by using a loading dose of 400 mg/day, followed by 2 days of 200 mg/day. A high-fat meal had no effect on the bioavailability of EDP-420 administered in a capsule formulation. EDP-420 was well tolerated, with no serious or severe adverse events reported, and no subject was discontinued from the study due to an adverse event. Based on its human PK and safety profiles, together with its in vitro/in vivo activities against common respiratory pathogens, EDP-420 warrants further development, including trials for clinical efficacy in the treatment of RTI. PMID:19451282

Jiang, Li-Juan; Or, Yat Sun

2009-05-18

247

Quality of life, taste, olfactory and oral function following high-dose chemotherapy and allogeneic hematopoietic cell transplantation.  

PubMed

Multiple oral complaints develop following high-dose chemo/radiotherapy and hematopoietic cell transplantation (HCT) which can influence quality of life. The purpose of this investigation was to assess quality of life, oral function, taste and smell in a cohort of patients following HCT. A general quality of life survey (the European Organization for Research and Treatment of Cancer (EORTC)) Quality of Life (QOL) questionnaire (QLQ-C30), with an added oral symptom and function scale and assessment of taste and smell was administered to a consecutive series of patients at day 90-100 post HCT. General QOL was impacted by fatigue, affecting physical, social emotional and cognitive function. While oral function scales appeared to be little affected at day 90-100 post HCT, abnormalities of taste were reported. Reports of changes in taste and smell appeared to parallel each other and changes remained at the time of the survey post-HCT. Change in taste appeared to be closely associated with dry mouth. Patients appeared to have difficulty in differentiating sour and bitter, which had been more affected than salt and sweet taste. Females appeared to report greater changes in taste than males. Increased smell sensitivity and taste change resulted in changes in food preparation in some cases, as did reported increase in sensitivity to sour and bitter taste. Acute complications are well known to affect QOL during the early period following HCT, but little assessment of long-term changes in oral QOL and taste has been conducted following transplant. The EORTC QLQ C-30 questionnaire with the oral addendum provides a measure of the quality of life and oral function, and may provide useful outcome measures for assessment of oral care prevention and management in HCT patients. PMID:12439702

Epstein, J B; Phillips, N; Parry, J; Epstein, M S; Nevill, T; Stevenson-Moore, P

2002-12-01

248

Bioequivalence of a novel high-dose oral formulation of alpha-dihydroergocryptine.  

PubMed

The plasma pharmacokinetics of alpha-dihydroergocryptine (DHEC, CAS 14271-05-7) were investigated in 24 patients with Parkinson disease after the administration of repeated oral doses of 40 mg DHEC twice daily by means of a novel 40 mg DHEC tablet (Almirid 40 mg test T) and an established 20 mg DHEC tablet (Almirid 20 mg - reference R). The trial was conducted according to a randomised, controlled, open, within-subject cross-over design; steady-state was established by means of a stepwise up-titration from 5 to 40 mg b.i.d. from day D01 to D19; investigational treatments (40 mg DHEC b.i.d. by means of formulation R and T) were administered on day D20 and D21 according to a randomised, period-balanced within-subject cross-over; treatment with DHEC was down-titrated in stepwise fashion from day D22 to D34. Morning doses of 2 x 20 mg DHEC (reference) yielded a fast and relatively short lasting peak with a geometric mean Cmax of 2157 pg/mL (CV: 0.978) after a median tmax of 1.00 h. Cmin throughout the first 12 h was on average 189 pg/mL (CV: 0.908). There was a quite distinct diurnal effect: evening doses of 2 x 20 mg DHEC (treatment R), yielded a relatively lower exposure with geometric mean Cmax, Cav- and Cmin-values of 800 pg/mL (CV: 0.870), 389 pg/mL (0.813) and 177 pg/mL (CV: 0.942). In contrast, there was relatively little within-subject distinction between the two formulations: for the day profile after the morning dose, the estimated ratios of the true means (Pr:R) for Cmax Cmin and Cav were 1.18 (90% CI: 0.96 to 1.43 - CVm: 0.394), 0.96 (90% CI: 0.86 to 1.09 - CVm: 0.230) and 1.06 (90% CI: 0.93 to 1.21 - CVm: 0.254); for the night profile after the evening dose, the estimated ratio of the true means (muT:muR) for Cmax, Cmin and Cav were 1.11 (90% CI: 0.91 to 1.35 - CVm: 0.395), 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.232) and 1.07 (90% CI: 0.95 to 1.20 - CVm: 0.220). In view of important medical-ethical constraints not to expose an unreasonably high number of subjects, these findings could be accepted as a sufficient demonstration of bioequivalence. PMID:16618013

de Mey, Christian; Stamenova, Paraskeva; Daskalov, Marin; Orozova, Milka; Staikov, Ivan; Vlahov, Vitan; Wangemann, Martina

2006-01-01

249

Aberrant activation of ubiquitin D at G2 phase and apoptosis by carcinogens that evoke cell proliferation after 28-day administration in rats.  

PubMed

We have previously reported that renal carcinogens examined in rats increase tubular cell proliferation and topoisomerase (Topo) II?(+) cells. The present study was aimed at identifying early prediction markers of carcinogens after 28-day treatment in rats. Following gene expression screening by microarrays in renal tubules with renal carcinogens, immunohistochemical analysis and TUNEL-assay were performed with carcinogens targeting different organs. All renal carcinogens tested (ferric nitrilotriacetic acid, ochratoxin A (OTA), monuron, tris(2-chloroethyl) phosphate, and potassium bromate) increased tubular cells immunoreactive for minichromosome maintenance 3 (Mcm3) or ubiquitin D (Ubd) or those showing apoptosis, compared with untreated controls or non-carcinogenic renal toxicants. Carcinogens targeting the liver (thioacetamide (TAA), fenbendazole, piperonyl butoxide (PBO) and methyleugenol), thyroid (sulfadimethoxine), urinary bladder (phenylethyl isothiocyanate), forestomach (butylated hydroxyanisole), glandular stomach (catechol), and colon (chenodeoxycholic acid and 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine) were examined for induction of Mcm3, Ubd, Topo II?, Ki-67 and apoptosis using non-carcinogenic toxicants as negative controls. All carcinogens increased Mcm3(+), Ubd(+), Topo II?(+), Ki-67(+) or TUNEL(+) cells, except for hepatocarcinogen PBO and both colon carcinogens, which did not increase cell proliferation. Ubd(+) cells co-expressing Topo II? was increased without changing phospho-Histone H3-co-expressing cell population as examined with OTA and TAA. Results revealed cooperative responses of Topo II?, Ubd and apoptosis by carcinogens inducing high proliferation activity, irrespective of target organs, examined here after a 28-day administration. Aberrant expression of Ubd at G(2) phase and increased apoptosis reflecting aberrant cell cycle regulation may be the common feature of these carcinogens. PMID:23208426

Taniai, Eriko; Yafune, Atsunori; Hayashi, Hitomi; Itahashi, Megu; Hara-Kudo, Yukiko; Suzuki, Kazuhiko; Mitsumori, Kunitoshi; Shibutani, Makoto

2012-01-01

250

Repeated Oral Dosing with Listeria monocytogenes in Mice as a Model of Central Nervous System Listeriosis in Man  

Microsoft Academic Search

Human1999 W.B. Saunders Company Ltdlisteriosis is a food-borne disease of immunosuppressed or previously healthy adults. The repeated oral administration of a sublethal dose (5×109colony-forming units) ofCopyright Listeria monocytogenesfor 7 or 10 consecutive days led to the development of severe central nervous system (CNS) lesions in 25% of experimental mice. Histopathological examination of the brain revealed rhombencephalitis and ventriculitis as two

J. Altimira; N. Prats; S. López; M. Domingo; V. Briones; L. Dom??nguez; A. Marco

1999-01-01

251

A new low-dose monophasic combination oral contraceptive (Alesse ™) with levonorgestrel 100 ?g and ethinyl estradiol 20 ?g  

Microsoft Academic Search

The efficacy and safety of a new, low-dose, 21-day combination oral contraceptive containing 100 ?g of levonorgestrel and 20 ?g of ethinyl estradiol were evaluated in an open-label, multicenter trial. A total of 1477 subjects were enrolled and had 7870 cycles of exposure as of the data cutoff of this interim report. Of these, 792 subjects had completed six cycles

David F. Archer; Rodolphe Maheux; Anthony DelConte; Francis B. O'Brien

1997-01-01

252

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

Microsoft Academic Search

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\\/m2 followed by autologous SCT

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

2009-01-01

253

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

254

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

Microsoft Academic Search

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

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

1997-01-01

255

Human Kinetics of Orally and Intravenously Administered Low-Dose 1,2-13C-Dichloroacetate  

Microsoft Academic Search

Dichloroacetate (DCA) is a putative environmental hazard, owing to its ubiquitous presence in the biosphere and its association with animal and human toxicity. We sought to determine the kinetics of environmentally relevant concentrations of 1,2-13C-DCA administered to healthy adults. Subjects received an oral or intravenous dose of 2.5 &mgr;g\\/kg of 1,2-13C-DCA. Plasma and urine concentrations of 1,2-13C-DCA were measured by

Minghong Jia; Bonnie Coats; Monisha Chadha; Barbara Frentzen; Javier Perez-Rodriguez; Paul A. Chadik; Richard A. Yost; George N. Henderson; Peter W. Stacpoole

2006-01-01

256

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

EPA Science Inventory

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

257

Safety and Pharmacokinetics of Oral Voriconazole in Patients at Risk of Fungal Infection: a Dose Escalation Study  

Microsoft Academic Search

The objective of this study was to investigate the safety, tolerability, and pharmacokinetics of oral voriconazole in subjects at high risk of developing fungal infections. This was a multicenter, randomized, double-blind, double-dummy, parallel-group, dose escalation study with a fluconazole active control. Twenty-four subjects with hematological malignancies, solid tumors, or autologous bone marrow transplants were randomized to receive voriconazole 200 mg

Hillard M. Lazarus; Jeffrey L. Blumer; Saul Yanovich; Haran Schlamm; Alain Romero

2002-01-01

258

Pharmacokinetics and systemic endocrine effects of the phyto-oestrogen 8-prenylnaringenin after single oral doses to postmenopausal women  

PubMed Central

Aims Pre-clinical data suggest that the racemic phyto-oestrogen 8-prenylnaringenin (8-PN) may have beneficial effects in postmenopausal women and may become an alternative to classical hormone replacement therapy (HRT) treatment regimes. The aim of this study was to investigate the pharmacokinetics, endocrine effects and tolerability of chemically synthesized 8-PN in postmenopausal women. Methods The study was performed using a randomized, double-blind, placebo-controlled, dose-escalation design with three groups of eight healthy postmenopausal women. In each group six subjects received 8-PN and two subjects placebo. 8-PN was given orally in doses of 50, 250 or 750 mg. Drug concentrations in serum, urine and faeces were measured up to 48 h and follicle-stimulating hormone/luteinizing hormone (LH) concentrations up to 24 h. Results All treatments were well tolerated and associated with a low incidence of (drug unrelated) adverse events. Serum concentrations of free 8-PN showed rapid drug absorption and secondary peaks suggestive of marked enterohepatic recirculation. Independent of the treatment group, approximately 30% of the dose was recovered in excreta as free compound or conjugates over the 48-h observation period. The first Cmax and AUC0–48 h showed dose linearity with ratios of 1 : 4.5 : 13.6 (Cmax) and 1 : 5.2 : 17.1 (AUC). The 750- mg dose decreased LH concentrations by 16.7% (95% confidence interval 0.5, 30.2). Conclusion Single oral doses of up to 750 mg 8-PN were well tolerated by postmenopausal women. The pharmacokinetic profile of 8-PN was characterized by rapid and probably complete enteral absorption, high metabolic stability, pronounced enterohepatic recirculation and tight dose linearity. The decrease in LH serum concentrations found after the highest dose demonstrates the ability of 8-PN to exert systemic endocrine effects in postmenopausal women.

Rad, M; Humpel, M; Schaefer, O; Schoemaker, R C; Schleuning, W-D; Cohen, A F; Burggraaf, J

2006-01-01

259

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

PubMed Central

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

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

2013-01-01

260

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

261

A phase I pharmacokinetic and safety evaluation of oral pazopanib dosing administered as crushed tablet or oral suspension in patients with advanced solid tumors.  

PubMed

Because cancer patients may have difficulty swallowing whole tablets, crushing tablets or ingesting an oral suspension is a practical alternative. This open-label, 2-part, randomized crossover, phase I study evaluated the pharmacokinetics and tolerability of pazopanib administered as a crushed tablet or an oral suspension relative to whole tablet in patients with advanced cancer (Part 1). Patients completing Part 1 were eligible for continuous daily pazopanib 800 mg (Part 2). Administration of a single pazopanib 400 mg crushed tablet increased the area under the curve from 0 to 72 h (AUC((0-72)); 46%) and maximum observed plasma concentration (C(max); ~2-fold), and decreased time to achieve maximum plasma concentration (T(max); ~2 h), indicating increased rate and extent of oral absorption relative to whole-tablet administration. Similarly, a single dose of pazopanib 400 mg suspension increased AUC((0-72)) (33%) and C(max) (29%), and decreased T(max) (1 h). These changes in pharmacokinetic parameters were not associated with increases in the magnitude or duration of short-term (ie, up to 72 h) blood pressure elevation compared with whole-tablet administration. PMID:21811833

Heath, Elisabeth I; Forman, Karen; Malburg, Lisa; Gainer, Shelby; Suttle, A Benjamin; Adams, Laurel; Ball, Howard; LoRusso, Patricia

2011-08-03

262

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

263

Oral single- and repeated-dose toxicity studies on Geranti Bio-Ge yeast, organic germanium fortified yeasts, in rats.  

PubMed

Single- and 13-week repeated-dose toxicities of Geranti Bio-Ge Yeast, organic germanium fortified yeasts, were investigated in rats. Both sexes of Sprague-Dawley rats were orally administered once at a dose of 2,000 mg/kg in single-dose toxicity or daily for 13 weeks at doses of 500, 1,000 or 2,000 mg/kg in repeated-dose toxicity tests. In single-dose toxicity test to determine dose levels in repeated-dose toxicity study, the body weight gain was suppressed at 2,000 mg/kg, although no death, clinical signs and pathological findings related to the treatment were observed. In repeated-dose toxicity test, there were no clinical signs in animals administered up to 2,000 mg/kg, except one rat died due to a gavage error. In addition, no significant changes in feed consumption and body weight gain were obtained during the treatment period, in spite of week-to-week fluctuation of water consumption. There were no considerable changes in ophthalmoscopy, urinalysis, hematology and serum biochemistry, except a significant decrease in albumin/globulin ratio in males treated with 1,000 mg/kg. In contrast, a significant increase in relative heart weight was observed in both male and female rats treated with a high dose (2,000 mg/kg) of Geranti Bio-Ge Yeast. In microscopic examination, mild lesions were found sporadically in both control and treatment groups in a dose-independent manner. In spite of some alterations in water consumption, serum biochemistry and organ weights, such effects were not considered to include toxicopathological significance, based on the lack of dose-dependency, consistent time-course and gender relationship. Taken together, it is suggested that no observed adverse effect level (NOAEL) of Geranti Bio-Ge Yeast is considered to be over 2,000 mg/kg in rats, and that long-term oral intake in humans might not exert adverse effects. PMID:15729009

Lee, Jong-Sung; Park, Jong-Il; Kim, Sun-Hee; Park, Sun-Hee; Kang, Seong-Kwi; Park, Cheol-Beom; Sohn, Tsang-Uk; Jang, Ja Young; Kang, Jong-Koo; Kim, Yun-Bae

2004-12-01

264

No protection by oral terbutaline against exercise-induced asthma in children: a dose-response study.  

PubMed

We wanted to assess the protective effects on exercise-induced asthma as well as the clinical efficacy and safety of increasing doses of a new sustained-release formulation of terbutaline sulphate, in 17 asthmatic children aged 6-12 yrs (mean 9 yrs). Placebo, 2, 4 and 6 mg terbutaline were given b.i.d. for 14 days, in a randomized, double-blind, cross-over design. At the end of each two week period, an exercise test was performed and plasma terbutaline was measured. Compared with placebo, no significant effect was seen on asthma symptoms monitored at home, or on exercise-induced asthma. The percentage falls in FEV1 after the exercise test were 36, 35, 27 and 28%, after placebo, 4, 8 and 12 mg terbutaline.day-1, respectively. There was no correlation between plasma terbutaline and dose of terbutaline. A small but statistically significant dose-related increase in morning and evening peak expiratory flow (PEF) recordings occurred, but the incidence of side-effects also increased with the dose given. There was a trend towards more side-effects when the high doses were used, and two patients withdrew from the study because of side-effects at this dose. It is concluded that continuous treatment, even with high doses of oral terbutaline, does not offer clinically useful protection against exercise-induced asthma. PMID:8491302

Fuglsang, G; Hertz, B; Holm, E B

1993-04-01

265

Noninvasive assessment of acute cardiopulmonary effects of an oral single dose of sildenafil in patients with idiopathic pulmonary hypertension.  

PubMed

We aimed to assess the acute cardiopulmonary effects of a 100-mg oral single dose of sildenafil in patients with idiopathic pulmonary hypertension (IPAH) using a well-validated but less-used noninvasive echocardiographic method for the measurement of both systolic and diastolic pulmonary artery pressure (PAP), by tricuspid regurgitation (TR) velocity curve analysis. We studied 12 consecutive patients with IPAH (10 patients with New York Heart Association functional class III, and 2 patients with functional class II). A 100-mg oral single dose of sildenafil was added to previous medications of all patients and its immediate effects were evaluated 1, 5, and 12 h after treatment. Using paired analysis, administration of a 100-mg oral single dose of sildenafil led to a significant reduction in mean PAP and a remarkable increase in pulmonary acceleration time (PAT) 1 h after treatment (P = 0.000; 95% confidence interval [CI] 18.99-26.00 and P = 0.005; 95% CI -12.89 to -2.95, respectively). In addition, although the right heart dimensions (right atrium and right ventricle) showed a trend toward improvement, the differences were not statistically significant (P = 0.13 and P = 0.08, respectively). Our results demonstrated that Doppler examination of TR alone can be easily used for the estimate of systolic and diastolic PAP in patients with IPAH. This study also shows that sildenafil is the only drug given orally that can evaluate the vasodilatory capacity of the pulmonary vascular bed in patients with IPAH, with promising effects on mPAP and PAT in these patients. PMID:20676840

Behzadnia, Neda; Najafizadeh, Katayoun; Sharif-Kashani, Babak; Dameshghi, Davoud Oulad; Shahabi, Payman

2010-07-31

266

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

PubMed Central

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

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

2013-01-01

267

Oral single- and repeated-dose toxicity studies on Geranti Bio-Ge Yeast, organic germanium fortified yeasts, in dogs.  

PubMed

Single- and 13-week repeated-dose toxicities of Geranti Bio-Ge Yeast, organic germanium fortified yeasts, were investigated in dogs. Both sexes of Beagle dogs were orally administered once at a dose of 2,000 mg/kg in single-dose toxicity or daily for 13 weeks at doses of 500, 1,000 or 2,000 mg/kg in repeated-dose toxicity tests. In single-dose toxicity test, no animal dead, moribund, or showing clinical signs or changes in body weight gain was found. In repeated-dose toxicity study, there were no considerable changes in ophthalmoscopy and urinalysis. Several alterations were observed in electrocardiography, hematology and blood biochemistry, including heart rate, R-R interval, QT correcting, reticulocytes, activated partial thromboplastin time and albumin/globulin ratio in only male dogs, but not in females, administered with Geranti Bio-Ge Yeast in a dose-independent manner. In gross findings, several cases of abnormal findings were observed in both control and treatment groups, showing diffuse dark brown to black discoloration of liver, in a dose-independent manner. In microscopic examination, mild lesions, including cholestasis and inflammatory cell foci in liver, kidneys and prostate, were found sporadically in both control and treatment groups. In spite of some alterations in electrocardiography, hematology, blood biochemistry, gross and microscopic findings, such effects were not considered to include toxicopathological significance, based on the marginal changes within normal ranges and lack of dose-dependency, consistent time-course and gender relationship. Taken together, it is suggested that no observed adverse effect level (NOAEL) of Geranti Bio-Ge Yeast is considered to be 2,000 mg/kg in dogs, and that long-term treatment in clinical trials might not exert adverse effects. PMID:15729010

Lee, Jong-Sung; Park, Jong-Il; Kim, Sun-Hee; Lee, Hye-Young; Hwang, Zai-Zhi; Park, Cheol-Beom; Sohn, Tsang-Uk; Shin, Sunhee; Kang, Jong-Koo; Kim, Yun-Bae

2004-12-01

268

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

PubMed Central

AIMS Brivaracetam is a novel synaptic vesicle protein 2A ligand that has shown potent activity in animal models of epilepsy. This study examined the pharmacokinetics, central nervous system pharmacodynamics and adverse event profile of multiple oral doses of brivaracetam in healthy male subjects. METHODS Three successive panels of 12 healthy male subjects received double-blind brivaracetam 200, 400 or 800 mg day?1 (all doses well above the expected therapeutic range) or placebo (9 : 3), in two divided doses, for 14 days. RESULTS Brivaracetam was rapidly absorbed (tmax?2 h) and eliminated (t1/2 7–8 h). Volume of distribution was slightly lower than total body water. A small fraction of the dose (5–8%) was excreted unchanged in urine together with significant levels of metabolites, suggesting predominantly metabolic clearance. Based on 6-?-hydroxycortisol/cortisol ratios in urine, there was no evidence of induction of CYP3A4 activity. Saliva and plasma brivaracetam levels were highly correlated. Adverse events were mostly mild to moderate, central nervous system-related and resolved within the first day of treatment. No clinically relevant changes were observed in laboratory tests, vital signs, physical examinations or ECGs. Pharmacodynamic tests showed dose-related sedation and decreased alertness that only persisted at 800 mg daily. CONCLUSIONS Brivaracetam was well tolerated by healthy male volunteers at doses of 200–800 mg daily for 2 weeks, well above the expected clinically effective dose range. Brivaracetam had a favourable pharmacokinetic profile in this population, characterized by rapid absorption, volume of distribution limited to total body water, apparent single-compartment elimination and dose proportionality. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT The pharmacokinetic profile, metabolism and proof of concept of a single oral dose of brivaracetam have been reported.Previous studies have shown that it was well absorbed, had linear kinetics and was well tolerated, and suggested effective doses of 10–80 mg in photoparoxysmal epilepsy. WHAT THIS STUDY ADDS We now report the pharmacokinetics, pharmacodynamics and tolerability in healthy volunteers after multiple doses.

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

2008-01-01

269

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

Microsoft Academic Search

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

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

2009-01-01

270

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

Microsoft Academic Search

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

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

2010-01-01

271

Pharmacokinetics of oral dexamethasone and midazolam when administered with single-dose intravenous 150 mg fosaprepitant in healthy adult subjects.  

PubMed

Aprepitant or its prodrug fosaprepitant, in combination with a corticosteroid and a 5-HT(3) receptor antagonist, are used to prevent chemotherapy-induced nausea and vomiting. This study evaluated the effect of fosaprepitant 150 mg on CYP3A4 metabolism. Fosaprepitant 150 mg has been submitted to regulatory agencies for consideration of approval as a single-day alternative to the 3-day oral aprepitant antiemetic regimen currently marketed. Part 1 of the study evaluated the drug interaction between fosaprepitant 150 mg and oral dexamethasone (8 mg daily for 3 days). Part 2 of the study evaluated the drug interaction between fosaprepitant 150 mg and oral midazolam (2 mg on days 1 and 4). Thirteen subjects were enrolled in part 1 and 10 in part 2. For dexamethasone, fosaprepitant increased the area under the plasma concentration-time curve from 0 to 24 hours by approximately 2.0-fold on days 1 and 2 and to a lesser extent (~1.2-fold) on day 3. Similarly, for midazolam, fosaprepitant increased the area under the plasma concentration-time curve from 0 hours to infinity by approximately 1.8-fold on day 1 but had no effect on midazolam pharmacokinetics on day 4. Fosaprepitant 150 mg is a weak inhibitor of CYP3A4. Oral dexamethasone doses on days 1 and 2 should be reduced by approximately 50% when coadministered with intravenous fosaprepitant 150 mg on day 1. PMID:21209230

Marbury, Thomas C; Ngo, Phung L; Shadle, Craig R; Jin, Bo; Panebianco, Deborah; Caro, Luzelena; Valentine, Jack; Murphy, Gail

2011-01-05

272

Comparative assessment of two low-dose oral contraceptives, Lo-Femenal and Lo-Estrin, in Mexican women.  

PubMed

This trial was designed to determine the differences in effectiveness, clinical acceptability, and one-year discontinuation rates of two low-dose oral contraceptives: Lo-Estrin (norethindrone acetate 1.5 mg plus ethinyl estradiol 0.030 mg) and Lo-Femenal (norgestrel 0.30 mg plus ethinyl estradiol 0.030 mg) in 148 Mexican women. In addition, the effects of both oral contraceptive preparations on blood lipids were prospectively evaluated in a subgroup of 41 women. The results indicated that there were no differences in pregnancy rates, discontinuation or clinical acceptability between the two groups. The lipid changes observed were minimal for the Lo-Femenal subgroup and somewhat greater for the Lo-Estrin group, mainly an increase in serum triglycerides. These changes were interpreted as estrogen induced effects of norethindrone-containing oral contraceptives. Overall, the data indicate that both Lo-Femenal and Lo-Estrin are effective and safe combined oral contraceptives. PMID:1290331

Garza-Flores, J; Martínez, M; Valles De Bourges, V; Vázquez-Estrada, L; McMullen, S; Dunson, R; Pérez-Palacios, G

1992-12-01

273

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.

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

2007-01-01

274

Randomized phase II study of three doses of oral TAS-108 in postmenopausal patients with metastatic breast cancer.  

PubMed

This randomized phase II study was intended to identify the optimal dose of TAS-108, a novel steroidal antiestrogen, for the treatment of breast cancer in postmenopausal Japanese women. The potential clinical effects of TAS-108 on the uterus, bone, serum lipids, and hormones were also investigated. Postmenopausal women with hormone receptor-positive metastatic breast cancer who had previously received one or two endocrine therapies were randomly assigned to one of the three possible dose levels of TAS-108 (40, 80 or 120 mg/day). Oral TAS-108 was given daily, and the efficacy and safety of the three doses were evaluated. A total of 97 patients (33, 32, and 32 in the 40-, 80-, and 120-mg groups, respectively) were treated with TAS-108. The clinical benefit rate was 30.3% for the 40-mg, 25.0% for the 80-mg, and 25.0% for the 120-mg group. The 40-mg group achieved the prespecified target threshold. TAS-108 at all dose levels was well tolerated and appeared to have no harmful effects in terms of the variables examined in this study. We conclude that the optimal dose of TAS-108 among the three doses is 40 mg, once daily, for further studies. JAPIC Clinical Trials Information number: Japic CTI - 121754. PMID:22676245

Inaji, Hideo; Iwata, Hiroji; Nakayama, Takahiro; Yamamoto, Naohito; Sato, Yasuyuki; Tokuda, Yutaka; Aogi, Kenjiro; Saji, Shigehira; Watanabe, Kenichi; Saito, Tsuyoshi; Yoshida, Masayuki; Sato, Nobuaki; Saeki, Toshiaki; Takatsuka, Yuichi; Kuranami, Masaru; Yamashita, Hiroko; Kikuchi, Atsushi; Tabei, Toshio; Ikeda, Tadashi; Noguchi, Shinzaburo

2012-07-16

275

Risk factors and dose-effect relationship for osteoradionecrosis after hyperfractionated and conventionally fractionated radiotherapy for oral cancer.  

PubMed

A high frequency of osteoradionecrosis after hyperfractionated radiotherapy (RT) of head and neck tumours led to a detailed analysis of risk factors in the dental, surgical, and radiotherapeutic areas. 168 patients with oral cancer were analysed retrospectively. 19% of them had been irradiated primarily and 81% postoperatively. 116 patients received a total dose mostly ranging from 60 Gy to 70 Gy to the ICRU 29 reference point (daily single dose 2 Gy). 52 patients were treated hyperfractionally with two daily fractions of 1.2 Gy per day, 4 h minimum apart and a total dose 82.8 Gy. Dental findings could be evaluated in 126 patients. Factors were checked for prognostic significance for osteoradionecrosis (ORN). Dose dependency was computed using a PROBIT analysis. Dental status before radiotherapy was generally poor (mean 11/32 teeth present, of these 1 was dead, 2.4 carious, 2.4 loose, 0.3 destroyed). On average, six teeth (range 0-27 teeth) had to be extracted. In one-third of the patients bone surgery was necessary. ORN occurred in 8.6% of the patients treated conventionally but in 22.9% of those treated hyperfractionally (p = 0.029). Biologically effective dose (p = 0.032) and deep paradontitis (p = 0.034) proved to be significant risk factors for ORN. PROBIT analysis showed a steadily rising dose dependency of the ORN frequency after conventional radiotherapy. Using total doses up to 70 Gy the frequency of ORN was 8.6%. Dose escalation using hyperfractionation led to an intolerable ORN frequency (22.9%) where a short interfraction interval was a significant factor. The use of this dose fractionation was therefore discontinued in 1992. PMID:8983589

Niewald, M; Barbie, O; Schnabel, K; Engel, M; Schedler, M; Nieder, C; Berberich, W

1996-09-01

276

Short Report: Comparison of Oral Infectious Dose of West Nile Virus Isolates Representing Three Distinct Genotypes in Culex quinquefasciatus  

PubMed Central

Phylogenetic analysis of West Nile virus in North America has identified replacement of the originally introduced clade, Eastern United States (NY99), by the North American clade. In addition, the transient emergence of other clades and genetic variants has also been observed. In this study, we investigated the potential role of the mosquito in the selection of these clades and genetic variants. We determined the relative susceptibility of Culex quinquefasciatus to infection with isolates from the Eastern U.S. clade, the North American clade, and the Southeast coastal Texas clade. Although significant differences were observed in 50% oral infectious dose values between the Eastern U.S. and two attenuated North American genetic variants compared with the North American and Southeast coastal Texas clade viruses, these differences did not correlate with persistence of the genotype in nature. These results indicate that selection of these viral genotypes was independent of viral oral infectivity in the mosquito.

Vanlandingham, Dana L.; McGee, Charles E.; Klingler, Kimberly A.; Galbraith, Sareen E.; Barrett, Alan D. T.; Higgs, Stephen

2009-01-01

277

[The determination of the optimal inoculation dose of an oral cholera chemical bivalent vaccine in a controlled experiment].  

PubMed

276 volunteers aged 19 years and over were placed under observation in the course of the trial of oral cholera vaccine in tablets, containing choleragen toxoid, O-antigens of serovars Inaba and Ogawa and a number of Vibrio cholerae exoenzymes, for safety, reactogenic properties and immunological effectiveness. The vaccine was found to produce no reactions in a dose of 1-4 tablets; the administration of 3 tablets (300,000 binding units of the toxoid and 10,000 units of O-antigens, serovars Inaba and Ogawa) was shown to induce the most intensive synthesis of both antitoxins and vibriocidal antibodies in the blood sera of volunteers, as well as IgA coproantibodies. The oral vaccine was found to have an advantage over parenteral vaccines due to the absence of reactogenic properties and the formation of local immunity: coproantibodies appeared in 80% and 9% of the vaccinees respectively. PMID:2099071

Sumarokov, A A; Ivanov, N R; Dzhaparidze, M N; Reznikov, Iu B; Rystsova, E A; Nikitina, G P; Matusevich, L Ia; Popov, A A; Plotnikova, M N; Shustov, V Ia

1990-12-01

278

Safety, tolerance, and pharmacokinetic studies of OPT-80 in healthy volunteers following single and multiple oral doses.  

PubMed

Current therapies for Clostridium difficile infection (CDI) are encumbered by treatment failures and recurrences. Due to its high in vitro activity against C. difficile but low activity against the typical intestinal flora, minimal absorption, and durable cure in the hamster model of C. difficile infection, OPT-80 was considered for clinical development as a therapy for CDI. This trial consisted of two phases. Four single oral doses of OPT-80 (100, 200, 300, and 450 mg) were administered in a crossover manner to 16 healthy volunteers in a double-blind, placebo-controlled phase 1A study; a 1- to 2-week washout interval separated the treatments. In the double-blind phase 1B study, 24 healthy subjects were randomized to receive OPT-80 (150, 300, or 450 mg) or placebo for 10 days. In both studies, OPT-80's safety and tolerability were evaluated and the concentrations of OPT-80 and its primary metabolite (OP-1118) in plasma and feces were determined. OPT-80 levels in the urine were also analyzed for the phase 1A study. In both the single-dose and the multiple-dose studies, OPT-80 was well tolerated by all subjects in all dose groups. Maximal plasma concentrations were near or below the limit of quantification (5 ng/ml) across the dose range; urine concentrations were below the detection limit. The fecal total recovery of OPT-80 plus its major metabolite, OP-1118, approximated 100%. The tolerability, high fecal concentration, and low systemic exposure data from these studies support the further clinical development of OPT-80 as an oral therapy for CDI. PMID:18268081

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

2008-02-11

279

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

PubMed

Methylphenidate is a piperidine derivative and is the drug most often used to treat attention deficit/hyperactivity disorder of children and young adults. Our aim is to investigate dose-dependent dopamine-2 receptor and glial fibrillary acidic protein expression and ultrastructural changes of the rat brain, to demonstrate possible toxicity of the long-term and high dose use of the methylphenidate. In this study, 27 female prepubertal Wistar albino rats, divided into three different dose groups (5, 10 and 20 mg/kg) were treated orally with methylphenidate dissolved in saline solution for 5 days per week during 3 months. At the end of the third month, tissues were removed and sections were collected for immunohistochemical and ultrastructural studies. We believe that methylphenidate causes dose-related activation of the dopaminergic system in several brain regions especially in ventral tegmental area and also causing neuronal degeneration and capillary wall structural changes such as basal membrane thickness and augmentation of the pinostatic vesicle in the endothelial cells. Also, increased dose of Ritalin is inducing astrocytes hypertrophy especially astrogliosis in pia-glial membrane and this is the result of the degenerative changes in prefrontal cortex region due to high dose methylphenidate administration. The dose-related accumulation of the astrocytes in capillary wall might well be a consequence of the need for nutrition of the neuronal tissue, due to transport mechanism deficiency related to neuronal and vascular degeneration. Thus, we believe that the therapeutic dose of methylphenidate must be kept in minimum level to prevent ultrastructural changes. PMID:19707959

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

2009-01-01

280

A randomized double-blind trial of two low dose combined oral contraceptives.  

PubMed

Fifty-five women using Loestrin-20 (20 microgram ethinyl oestradiol and 1 mg norethisterone acetate) as an oral contraceptive have been compared with a like number using Microgynon-30 (30 microgram ethinyl oestradiol and 150 microgram levonorgestrel) in a randomized, double-blind trial. Despite the small sample size, the main finding in the trial is clear-cut; Loestrin-20 provides poor cycle control and is thus less acceptable as an oral contraceptive than Microgynon-30. Although there is also a suggestion that Loestrin-20 may be less effective than Microgynon-30, the difference in the accidental pregnancy rates is not statistically significant. PMID:373792

Bounds, W; Vessey, M; Wiggins, P

1979-04-01

281

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

PubMed Central

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

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

2011-01-01

282

Intermediate-term toxicity of repeated orally administered doses of the anti-malarial beta-artemether in dogs.  

PubMed

The artemisinin derivative beta-artemether, an anti-malarial, was evaluated for its toxicity and tolerability in a 2-week, multiple-dose study in dogs. Eight beagle dogs (4 females, 4 males) were given beta-artemether by oral gavage 3 times daily at 45 mg/kg/dosing (a total daily dose-level of 135 mg/kg) for 2 weeks. This beta-artemether dose regime was well tolerated. Body weight changes were normal although feed consumption during the treatment period reduced compared to that of the pre-trial period. Clinical signs were transient spells of soft to liquid feces. On completion of the treatment period, the animals were sacrificed and submitted to a full macroscopic post-mortem examination. Designated organs were weighed and a complete light microscopic examination was performed on 43 selected tissues from 1 animal per sex, and on the liver, kidneys, thymus, mandibular lymph nodes and lungs of the three other animals per sex. Major findings were high liver weight and histopathologic findings of slight diffuse hepatocellular hypertrophy and distal tubular dilatation, together with flattened epithelium, in the kidneys. With the dose regime used in this trial beta-artemether produced no clinical or apparent histopathological signs of neurotoxicity in dogs. PMID:16368229

Peys, Eric; Vandenkerckhove, Jan; Van Hemel, Johan; Sas, Benedikt

2005-12-20

283

Repeated oral dosing with Listeria monocytogenes in mice as a model of central nervous system listeriosis in man.  

PubMed

Human listeriosis is a food-borne disease of immunosuppressed or previously healthy adults. The repeated oral administration of a sublethal dose (5x10(9)colony-forming units) of Listeria monocytogenes for 7 or 10 consecutive days led to the development of severe central nervous system (CNS) lesions in 25% of experimental mice. Histopathological examination of the brain revealed rhombencephalitis and ventriculitis as two distinct inflammatory patterns, resembling those seen in human listeriosis. This model would seem to be potentially useful for research on pathogenesis, predisposing factors and therapy in CNS listeriosis in man. 1999 W.B. Saunders and Company Ltd. PMID:10405304

Altimira, J; Prats, N; López, S; Domingo, M; Briones, V; Domínguez, L; Marco, A

1999-08-01

284

Single oral doses of amisulpride do not enhance the effects of alcohol on the performance and memory of healthy subjects  

Microsoft Academic Search

Objectives: Amisulpride is a benzamide antipsychotic that binds selectively to dopamine D2- and D3-receptors, preferentially in limbic and hippocampal structures. Since other substituted benzamides have a limited or negligible\\u000a interaction with alcohol on human performance, amisulpride was studied for this potential.\\u000a \\u000a Methods:\\u000a \\u000a \\u000a In a randomised double-blind crossover study, 18 young, non-smoking men took single oral doses of placebo and amisulpride

M. J. Mattila; A. Patat; T. Seppälä; H. Kalska; M.-L. Jalava; J. Vanakoski; C. Lavanant

1996-01-01

285

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

PubMed Central

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

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

2008-01-01

286

Drug therapy: dose-response relationship of oral mesalazine in inflammatory bowel disease.  

PubMed Central

Mesalazine is widely used in the treatment of inflammatory bowel disease. Little is known about the dose-response relationship and about possible dose related side effects. In ulcerative colitis higher dosages of mesalazine (3 g) are more effective in maintaining a remission than lower dosages (1.5 g). In mild to moderately active ulcerative colitis, studies also indicate that higher dosages might be more effective in inducing remission. Dose-comparing studies in Crohn's disease are even more sparse, but the available results indicate higher efficacy at higher dose levels. None of the known side effects of mesalazine are clearly dose-related. A pH-dependent release system, however, can cause a sudden release of high doses of mesalazine. Consequent peak levels in serum have been implicated in mesalazine induced nephrotoxicity. In conclusion, despite the current practice of using increasing dosages of mesalazine in inflammatory bowel disease, both efficacy and safety have been established tentatively.

Mulder, C J; van den Hazel, S J

1998-01-01

287

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

288

Effect or Oral Dosing Vehicles on the Acute Hepatotoxicity of Carbon Tetrachloride in Rats.  

National Technical Information Service (NTIS)

Although carbon tetrachloride (CCl4) is of concern as a drinking water contaminant, it has been necessary in most oral toxicity studies to give CCl4 in an oil vehicle due to its limited water solubility. The primary objective of our study was to assess th...

H. J. Kim S. Odend'hal J. V. Bruckner

1990-01-01

289

Evaluation of fipronil oral dosing to cattle for control of adult and larval sand flies under controlled conditions.  

PubMed

Visceral Leishmaniasis (VL) is a vector-borne disease endemic to the Indian subcontinent. The Phlebotomus genus of sand flies is the vector for VL in the Old World, with the vector on the Indian Subcontinent being Phlebotomus argentipes. Cattle are a commodity in this region and a frequent host source of P. argentipes bloodmeals. The purpose of this study was to determine the efficacy of a single oral dose fipronil against adult and larval P. argentipes. Ten Bos indicus cattle were used during the study in a controlled environment. The study was conducted in Bihar, India, and involved adult and larval bioassays using laboratory-reared P. argentipes. The results were positive in that they led to up to 100% mortality in both adult and larval sand flies over a 21-d period after a single dose of fipronil. PMID:23926782

Poché, Richard M; Garlapati, Rajesh; Singh, Mutum I; Poché, David M

2013-07-01

290

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

Microsoft Academic Search

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

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

2002-01-01

291

PHARMACOKINETICS OF AZITHROMYCIN IN LUNG TISSUE, BRONCHIAL WASHING, AND PLASMA IN PATIENTS GIVEN MULTIPLE ORAL DOSES OF 500 AND 1000 MG DAILY  

Microsoft Academic Search

The present study compares the pharmacokinetics of azithromycin in plasma, lung tissue, and bronchial washing after oral administration of 500mg (standard dose) versus 1000mg daily for 3 days. Samples were taken during surgery for lung resection at various time points up to 204h after the last drug dose, and azithromycin levels were analyzed by HPLC method. Azithromycin was widely distributed

ANTONELLO DI PAOLO; CECILIA BARBARA; ANTONIO CHELLA; CARLO ALBERTO ANGELETTI; MARIO DEL TACCA

2002-01-01

292

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

PubMed Central

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

2011-01-01

293

Disease control using low-dose-rate brachytherapy is unaffected by comorbid severity in oral cancer patients  

PubMed Central

Objective The aim of this study was to evaluate the outcome and complications of low-dose-rate brachytherapy (LDR-BT) for oral cancer according to comorbidity. Methods The records of a total of 180 patients who received LDR-BT for T1-2N0M0 oral cancers between January 2005 and December 2007 were analysed. The comorbidities of the patients were retrospectively graded according to the Adult Comorbidity Evaluation-27, and the relationships between the comorbidity grades and survival, disease control and the incidence of complications were analysed. Results The 2 year overall survival rates of patients with no comorbidity, Grade 1, Grade 2 and Grade 3 comorbidity were 87%, 85%, 76% and 65%, respectively, and the reduction in the survival rate according to comorbid severity was significant in a univariate analysis (p = 0.032) but not in a multivariate analysis including other clinical factors. Cause-specific survival, locoregional control and local control were not related to the comorbidity grade, or any other clinical factors. Grade 2 or 3 complications developed in 27% of the patients. The incidence of complications was unrelated to the comorbidity grade. Conclusion The disease control of oral cancer and the incidence of complications after LDR-BT were not related to comorbid severity. LDR-BT is a useful and safe treatment for patients regardless of the presence of severe comorbidity.

Yoshimura, R; Shibuya, H; Hayashi, K; Toda, K; Watanabe, H; Miura, M

2011-01-01

294

Bioavailability study of triamterene and xipamide using urinary pharmacokinetic data following single oral dose of each drug or their combination.  

PubMed

An efficient chromatographic method for the simultaneous determination of triamterene (TRI) and xipamide (XIP) in urine samples, based on high performance liquid chromatography with photodiode array detector (HPLC-DAD) has been developed. The HPLC separation was performed on a RP stainless-steel C-18 analytical column (250 mm × 4.6 mm, 5 ?m) with a gradient elution system of 0.05 M phosphate buffer adjusted to pH 4.0 and methanol as the mobile phase. The method was used to determine the urinary excretion profile and to calculate different urinary pharmacokinetic parameters following oral dose of their combination compared with single oral doses of each drug and hence comparing their bioavailability. Quantitation was performed using chlorthalidone as internal standard. The calibration graphs of each drug were rectilinear in the range of 0.2-40 ?g/mL urine for TRI and 0.2-15 ?g/mL urine for XIP. An HPLC-DAD method was also successfully developed for the simultaneous determination of the investigated drugs in pharmaceutical preparations. The methods were validated in terms of linearity, accuracy, precision, selectivity, limits of detection and quantitation and other aspects of analytical validation. PMID:22197154

Maher, Hadir M; Youssef, Rasha M; El-Kimary, Eman I; Hassan, Ekram M; Barary, Magda A

2011-12-06

295

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

PubMed

The major objective of the study was to assess the pharmacokinetics of tetracycline administered orally to fasted and nonfasted American alligators (Alligator mississippiensis) at 50 mg/kg. Plasma levels of tetracycline were determined using high-performance liquid chromatography with ultraviolet detection. The concentration versus time curve was analyzed using a compartmental modeling technique. A one-compartment model with first-order absorption and elimination, as well as a lag time to absorption, best described the data. The area under the curve and mean residence time values differed significantly between the fasted and nonfasted groups. Based on the results of this study, tetracycline suspension administered once orally at 50 mg/kg to American alligators is not expected to reach plasma concentrations above the breakpoint minimum inhibitory concentration of 4 microg/ml for susceptible organisms. PMID:23272354

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

2012-12-01

296

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

Microsoft Academic Search

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

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

2001-01-01

297

Disposition and Clearance of Tungsten after Single-dose Oral and Intravenous Exposure in Rodents  

Microsoft Academic Search

Tungsten (W) has been nominated for study to the National Toxicology Program (NTP) because of reported associations between concentrations of W in drinking water and childhood leukemia. The disposition of W (administered as sodium tungstate dihydrate in water) in plasma, liver, kidneys, uterus, femur, and intestine of rodents (Sprague-Dawley rats and C57BL\\/6N mice) was characterized after exposures by oral gavage

Jacob D. McDonald; Waylon M. Weber; Rena Marr; Dean Kracko; Hnin Khain; Richard Arimoto

2007-01-01

298

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

299

Safe administration of oral BU twice daily during conditioning for stem cell transplantation in a paediatric population: a comparative study between the standard 4-dose and a 2-dose regimen  

Microsoft Academic Search

We compared outcome and toxicity in two paediatric groups undergoing SCT and treated with busulphan (BU) by the oral route of administration. One group receiving the standard dose of 1 mg\\/kg q.i.d. for a total of 16 doses was compared with age- and disease-matched patients receiving 2 mg\\/kg of BU b.i.d. for a total of eight doses. Seventy-two patients from

K Mellgren; C Nilsson; A Fasth; J Abrahamsson; J Winiarski; O Ringdén; M Hassan

2008-01-01

300

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

Microsoft Academic Search

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

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

2003-01-01

301

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...

302

Pharmacokinetics of licarbazepine in healthy volunteers: single and multiple oral doses and effect of food.  

PubMed

Two studies characterized single- and multiple-dose pharmacokinetics of licarbazepine immediate-release tablets and food effects on single-dose pharmacokinetics. In 1 study, 12 volunteers received 500 mg licarbazepine on day 1, 500 mg bid on days 3 to 6, and 500 mg on day 7. In the second study, 12 subjects received one 500-mg licarbazepine dose under fasted and fed conditions. After multiple dosing, geometric mean (%CV) Cmax ss, Cmin ss, and AUCtau were 77.6 micromol/L (18), 45.3 micromol/L (25), and 747 h.mol/L (19), respectively, with a tmax of 2 hours. Mean half-lives were 9.3 and 11.3 hours for single and multiple dosing, respectively. Food had no clinically significant effect on single-dose pharmacokinetics. Half-life ( approximately 10 hours) and low intersubject variability in main pharmacokinetic parameters were similar under fasted and fed conditions. Median tmax increased from 1.5 to 2.5 hours with food. Licarbazepine is well tolerated and has predictable pharmacokinetics. PMID:18258749

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

2008-02-07

303

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

PubMed

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

Chen, Minjun; Borlak, Jürgen; Tong, Weida

2013-05-27

304

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

SciTech Connect

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

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

1983-04-01

305

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

National Technical Information Service (NTIS)

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

J. J. Schlesselman

1991-01-01

306

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

PubMed

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

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

2013-05-29

307

Oral Glucosamine for 6 Weeks at Standard Doses Does Not Cause or Worsen Insulin Resistance or Endothelial Dysfunction in Lean or Obese Subjects  

Microsoft Academic Search

Glucosamine is a popular nutritional supplement used to treat osteoarthritis. Intravenous administration of glu- cosamine causes insulin resistance and endothelial dys- function. However, rigorous clinical studies evaluating the safety of oral glucosamine with respect to metabolic and cardiovascular pathophysiology are lacking. Therefore, we conducted a randomized, placebo-controlled, double-blind, crossover trial of oral glucosamine at standard doses (500 mg p.o. t.i.d.)

Ranganath Muniyappa; Rajaram J. Karne; Gail Hall; Sonja K. Crandon; Joel A. Bronstein; Maria R. Ver; Glen L. Hortin; Michael J. Quon

2006-01-01

308

Efficacy and safety of a low-dose monophasic combination oral contraceptive containing 100 ?g levonorgestrel and 20 ?g ethinyl estradiol (Alesse ®)  

Microsoft Academic Search

The efficacy and safety of a low-dose 21-day combination oral contraceptive containing 100 ?g levonorgestrel and 20 ?g ethinyl estradiol were evaluated in an open-label, multicenter trial. A total of 1708 subjects with regular menstrual cycles (27,011 cycles) were evaluated. The oral contraceptive was administered once a day for 21 days, followed by 7 days of placebo for a complete

David F. Archer; Rodolphe Maheux; Anthony DelConte; Francis B. O’Brien

1999-01-01

309

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

PubMed

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

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

310

Weight change and adverse event incidence with a low-dose oral contraceptive: two randomized, placebo-controlled trials.  

PubMed

Changes in body weight and the incidence of estrogen-related side effects with low-dose oral contraceptives (OCs) containing 20 microg ethinyl estradiol (EE) have not been demonstrated in placebo-controlled trials. Two placebo-controlled, randomized trials demonstrated the efficacy of a low-dose OC for the treatment of acne in healthy females (n = 704; >or=14 years old) with regular menstrual cycles and moderate facial acne. Patients were randomized to receive 20 microg EE/100 microg levonorgestrel (LNG) or placebo for six cycles. Body weight was measured at baseline and during Cycles 1, 3, and 6. The occurrence of adverse events was recorded at each visit. Mean changes in weight from baseline were similar with 20 microg EE/100 microg LNG [0.72 kg +/- 2.64 (SD; n = 349)] and placebo [0.56 kg +/- 2.64 (SD; n = 355; p > 0.05)] for the last measured weight of each patient. Rates of headache, nausea, weight gain, and breast pain, side effects commonly attributed to OCs, were also similar between groups (p > 0.05). No serious, unexpected, drug-related adverse events occurred during the study. The low-dose OC containing 20 microg EE/100 microg LNG is safe, well tolerated, and does not cause weight gain. PMID:11672550

Coney, P; Washenik, K; Langley, R G; DiGiovanna, J J; Harrison, D D

2001-06-01

311

Repeated dose oral toxicity of Trivanga Bhasma in Swiss albino mice.  

PubMed

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

312

Therapeutic dosing of an orally active, selective cathepsin S inhibitor suppresses disease in models of autoimmunity.  

PubMed

The purpose of the study was to examine the potential of inhibition of cathepsin S as a treatment for autoimmune diseases. A highly selective cathepsin S inhibitor, CSI-75, was shown to upregulate levels of the cathepsin S substrate, invariant chain Lip10, in vitro as well as in vivo in C57Bl/6 mice after oral administration. Functional activity of the compound was shown by a reduction in the OVA-specific response of OVA-sensitized splenocytes from C57Bl/6 mice as well as from OVA-TCR transgenic mice (DO11.10). Since these studies revealed a selective suppression of the Th1 and Th17 cytokines causing a shift to Th2, CSI-75 was tested in the murine HC-gp39-immunization model. Indeed, CSI-75 specifically reduced the circulating HC-gp39-specific IgG2a in these mice indicating selective inhibition of the Th1 type of response in vivo. The importance of especially the Th1 and Th17 cell subsets in the pathology of autoimmune diseases, renders CatS inhibition a highly interesting potential therapeutic treatment of autoimmune diseases. Therefore, CSI-75 was tested in a murine model of multiple sclerosis (i.e. experimental autoimmune encephalomyelitis (EAE)) in a semi-therapeutic setting (ie. oral treatment after initial sensitization to antigen). Finally, in a murine model with features resembling rheumatoid arthritis (the collagen-induced arthritis (CIA) model), CSI-75 was tested in a therapeutic manner (after disease development). CSI-75 caused a significant reduction in disease score in both disease models, indicating a promising role for CatS inhibitors in the area of therapeutic treatments for autoimmune diseases. PMID:21439785

Baugh, Mark; Black, Darcey; Westwood, Paul; Kinghorn, Emma; McGregor, Kieran; Bruin, John; Hamilton, William; Dempster, Maureen; Claxton, Christopher; Cai, Jiaqiang; Bennett, Jonathan; Long, Clive; McKinnon, Heather; Vink, Paul; den Hoed, Leontien; Gorecka, Monika; Vora, Kalpit; Grant, Ethan; Percival, M David; Boots, A Mieke H; van Lierop, Marie-José

2011-03-24

313

Single oral dose pharmacokinetics of decursin, decursinol angelate, and decursinol in rats.  

PubMed

Decursin and decursinol angelate are the major components in the alcoholic extract of the root of Angelica gigas Nakai. Our previous work convincingly demonstrated that both decursin and decursinol angelate were rapidly converted to decursinol in mice after administration by either oral gavage or i. p. injection. In the current study, we compared for the first time the plasma profiles of decursinol, when equal moles of decursin/decursinol angelate or decursinol were given to rats by oral gavage, and investigated the effect of different formulas and other chemicals in Angelica gigas extract on the bioavailability of decursinol. Our results show that gavage of decursinol led to a faster attainment of plasma decursinol peak (Tmax ~ 0.7 h) and much higher peak levels than an equal molar amount administered as decursin/decursinol angelate mixture or as Angelica gigas ethanol extract, resulting in 2-3 fold higher bioavailability as estimated by the area under the curve of the respective regimens (65 012 vs. 27 033 h · ng/mL for decursinol and decursin/decursinol angelate treatment groups, respectively). Compared to a formula based on ethanol-PEG400-Tween80, carboxyl methyl cellulose was a less optimized vehicle. In addition, we detected peak levels of decursin and decursinol angelate in the plasma of rats administered with decursin/decursinol angelate or Angelica gigas extract in the nM range (Tmax ~ 0.5 h) with a newly established sensitive UHPLC-MS/MS method. Furthermore, our data support the liver, instead of intestine, as a major organ site where decursin and decursinol angelate were hydrolyzed to decursinol with a S9 microsomal in vitro metabolism assay. Taken together, our study provided important PK, LC-MS/MS methodology, formulation and metabolism insights in a rodent model for the rational design of in vivo efficacy studies of the corresponding chemicals in the future. PMID:23364885

Li, Li; Zhang, Jinhui; Xing, Chengguo; Kim, Sung-Hoon; Lü, Junxuan

2013-01-30

314

EROD activity induction in peripheral blood lymphocytes, liver and brain tissues of rats orally exposed to polycyclic aromatic hydrocarbons.  

PubMed

Little is known in terms of multi-matrix cytochrome P450 activity induction under repeated oral exposure to planar halogenated and polycyclic aromatic hydrocarbons (PHH, PAH). In the present study, 60 rats were daily exposed, during 28 days, to oral ingestion of a mixture consisting of phenanthrene, pyrene and benzo(a)pyrene at 0, 6 or 600 ?g/day. EROD activity, reflecting almost exclusively CYP1A1 and CYP1B1 activities, was measured in brain and liver microsomes as well as in peripheral blood lymphocytes (PBLs). All induction kinetics could be appropriately fitted using logistic-like models. After 28 days of exposure to a 6 ?g/day dose, EROD activity was found to be 91, 152 and 94-fold increased in lymphocytes, liver and brain, respectively, compared to day 0. Plateau activities could be appropriately fitted versus ingested doses using Hill or Michaelis-Menten models. Correlations between matrices made it possible to conclude that EROD activity in PBL should be considered as a sensitive, convenient and non-destructive approach for (i) evaluating EROD activity in liver, which was found to represent 98% of the observed EROD activities in the three tested matrices and (ii) evaluating oral exposure of homogeneous groups of farm animals (race, diet) to CYP inducing PAH and PHH. PMID:23500776

Chahin, Abir; Peiffer, Julie; Olry, Jean-Charles; Crepeaux, Guillemette; Schroeder, Henri; Rychen, Guido; Guiavarc'h, Yann

2013-03-14

315

Derivation of a melamine oral reference dose (RfD) and drinking-water total allowable concentration.  

PubMed

Due to its high nitrogen content, melamine has been used to adulterate food to increase apparent protein content. In 2008, thousands of Chinese infants consumed reconstituted formula derived from melamine-adulterated milk. Urinary-tract stones (comprised of melamine and uric acid) accumulated in some victims and lead to acute renal failure or death. Premature infants and children (<2 yr) have an increased susceptibility to ingested melamine. Due to incomplete reporting, the human data were inadequate to identify a no-observed-adverse-effect level (NOAEL) for melamine-induced pediatric urolithiasis. Urolithiasis, urinary bladder cystitis, and ulcerations were observed in F344 rats after subchronic or chronic ingestion of melamine at > or =72 mg/kg-d. Bladder epithelial damage was followed by epithelial hyperplasia that progressed to bladder papillomas and carcinomas in male but not female F344 rats or male or female B6C3F1 mice. Short-term assays suggest, at best, weak genotoxic activity, and kinetic data show that melamine is not metabolized. Since reliable exposure information was lacking from the clinical reports, an oral reference dose (RfD) based on urolithiasis in male rats after 13 wk of continuous melamine ingestion was calculated as a 10% benchmark dose (38 mg/kg-d). Incorporation of 10-fold interspecies and intraspecies (for the increased susceptibility of infants) uncertainty factors and a threefold database uncertainty factor (for the lack of immunological, neurological and reproduction toxicity data) yields an oral RfD of 0.13 mg/kg-d. Assuming the 70-kg adult consumes 2 L of drinking water daily, a total allowable concentration of 0.9 mg/L (900 microg/L) was calculated for melamine in drinking water. PMID:20336578

Bhat, Virunya S; Ball, Gwen L; McLellan, Clifton J

2010-01-01

316

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

PubMed Central

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

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

2013-01-01

317

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

Microsoft Academic Search

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

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

2005-01-01

318

Toxicity of Ammonium Perfluorooctanoate in Male Cynomolgus Monkeys after Oral Dosing for 6 Months  

Microsoft Academic Search

Ammonium perfluorooctanoate (APFO) is a processing aid in the production of fluoropolymers that has been shown to have a long half-life in human blood. To understand the potential toxicological response of primates, groups of male cynomolgus monkeys were given daily po (capsule) doses of either 0, 3, 10, or 30 (reduced to 20) mg\\/kg\\/day for 26 weeks. Two monkeys from

John Butenhoff; Giovanni Costa; Cliff Elcombe; David Farrar; Kristin Hansen; Hiroyuki Iwai; Reinhard Jung; Gerald Kennedy; Paul Lieder; Geary Olsen; Peter Thomford

2002-01-01

319

Subchronic oral toxicity of a standardized white kidney bean (Phaseolus vulgaris) extract in rats.  

PubMed

Dietary supplements containing "starch blockers" are believed to reduce carbohydrate-derived calories by interfering with alpha-amylase, the digestive enzyme responsible for conversion of complex carbohydrates to simple, absorbable sugars. The present paper reports the findings of a 28-day oral toxicity study in rats of Phase 2, a standardized extract derived from the common white kidney bean (Phaseolus vulgaris), which has been shown to have alpha-amylase-inhibiting activity. In order to establish safety, eighty male and female Sprague-Dawley rats (10 animals/sex/group) received Phase 2 via oral gavage at doses of 0, 625, 1250, and 2500 mg/kg (7 days/wk) for a period of 31 (males) or 32 (females) days. There were no mortalities, clinical signs, body weight or nutritional effects, gross alterations, clinical or histopathological alterations that were considered attributable to test substance administration. Under conditions of this study and based on toxicological endpoints evaluated, the no-observed-adverse-effect level (NOAEL) of Phase 2 was judged to be 2500 mg/kg/day in each sex for administration by oral gavage of a standardized white kidney bean extract, Phase 2 for 28 days. PMID:17045383

Chokshi, Dilip

2006-07-08

320

Dose-Modified Oral Chemotherapy in the Treatment of AIDS-Related Non-Hodgkin's Lymphoma in East Africa  

PubMed Central

Purpose Africa is burdened by the AIDS epidemic and attendant increase in HIV/AIDS-related malignancies. Pragmatic approaches to therapeutic intervention could be of great value. Dose-modified oral chemotherapy for AIDS-related non-Hodgkin's lymphoma is one such approach. Patients and Methods The oral regimen consisted of lomustine 50 mg/m2 on day 1 (cycle 1 only), etoposide 100 mg/m2 on days 1 to 3, and cyclophosphamide/procarbazine 50 mg/m2 each on days 22 to 26 at 6-week intervals (one cycle) for two total cycles in HIV-infected patients with biopsy-proven non-Hodgkin's lymphoma. Results Forty-nine patients (21 in Uganda and 28 in Kenya) were treated. The majority of patients were female (59%) and had a poor performance status (63%); 69% of patients had advanced-stage disease; and 18 patients (37%) had access to antiretroviral therapy. In total, 79.5 cycles of therapy were administered. The regimen was well tolerated, had modest effects (decline) on CD4+ lymphocyte counts (P = .077), and had negligible effects on HIV-1 viral replication. Four febrile neutropenia episodes and three treatment-related deaths (6% mortality rate) occurred. The overall objective response rate was 78% (95% CI, 62% to 88%); median follow-up time was 8.2 months (range, 0.1 to 71 months); median event-free and overall survival times were 7.9 months (95% CI, 3.3 to 13.0 months) and 12.3 months (95% CI, 4.9 to 32.4 months), respectively; and 33% of patients survived 5 years. Conclusion Dose-modified oral chemotherapy is efficacious, has comparable outcome to that in the United States in the pre–highly active antiretroviral therapy setting, has an acceptable safety profile, and is pragmatic in sub-Saharan Africa. The international collaboration has been highly successful, and subsequent projects should focus on strategies to optimize combination antiretroviral therapy and chemotherapy and follow-up tissue correlative studies.

Mwanda, Walter O.; Orem, Jackson; Fu, Pingfu; Banura, Cecilia; Kakembo, Joweria; Onyango, Caren Auma; Ness, Anne; Reynolds, Sherrie; Johnson, John L.; Subbiah, Vivek; Bako, Jacob; Wabinga, Henry; Abdallah, Fatuma K.; Meyerson, Howard J.; Whalen, Christopher C.; Lederman, Michael M.; Black, Jodi; Ayers, Leona W.; Katongole-Mbidde, Edward; Remick, Scot C.

2009-01-01

321

A phase I dose-escalation study of oral BR-DIM (BioResponse 3,3?- Diindolylmethane) in castrate-resistant, non-metastatic prostate cancer  

PubMed Central

3, 3?-diindolylmethane (DIM) modulates estrogen metabolism and acts as an anti-androgen which down-regulates the androgen receptor and prostate specific antigen (PSA). We conducted a dose-escalation, phase I study of BioResponse (BR)-DIM with objectives to determine the maximum tolerated dose (MTD), toxicity profile, and phar-macokinetics (PK) of BR-DIM, and to assess its effects on serum PSA and quality of life (QoL). Patients and Methods: Cohorts of 3-6 patients received escalating doses of twice daily oral BR-DIM providing DIM at 75 mg, then 150 mg, 225 mg, and 300 mg. Toxicity was evaluated monthly. Serum PSA and QoL were measured at baseline, monthly during treatment, and at end of study. Results: 12 patients with castrate-resistant, non-metastatic, PSA relapse prostate cancer were treated over 4 dose cohorts; 2 patients (at 150 mg and 225 mg, respectively) underwent intra-patient dose escalation, by one dose level. After oral administration of the first dose of BR-DIM, the plasma exposure to DIM appeared dose proportional at doses ranging from 75 to 300 mg, with the mean Cmax and mean AUClast increasing from 41.6 to 236.4 ng/ml and from 192.0 to 899.0 ng/ml*h, respectively. Continued relatively stable systemic exposure to DIM was achieved following twice daily oral administration of BR-DIM. Minimal toxicity was observed. Two of the four patients treated at 300 mg had grade 3 asymptomatic hyponatremia (AH) discovered on routine blood work. The other 2 patients at this dose had no AH. Therefore, the maximum tolerated dose (MTD) was deemed to be 300 mgand the recommended phase II dose (RP2D) of BR-DIM was 225 mg twice daily. One patient without AH at 225 mg experienced a 50% PSA decline. One patient with BR-DIM dose of 225 mg had PSA stabilization. The other 10 patients had an initial deceleration of their PSA rise (decrease in slope), but eventually progressed based on continual PSA rise or evidence of metastatic disease. Ten patients completed monthly QoL reports for a mean of 6 months (range: 1-13). QoL measures emotional functioning may have held up somewhat better over time than their physical functioning. Conclusion: BR-DIM was well tolerated. Increasing systemic exposure to DIM was achieved with the increase of BR-DIM dose. Modest efficacy was demonstrated. Patients' QoL varied over time with length of treatment. Phase II studies are recommended at the dose of 225 mg orally twice daily.

Heath, Elisabeth I; Heilbrun, Lance K; Li, Jing; Vaishampayan, Ulka; Harper, Felicity; Pemberton, Pam; Sarkar, Fazlul H

2010-01-01

322

Effect of Low-Dose Oral Contraceptives on Metabolic Risk Factors in African-American Women  

PubMed Central

Context: The effect of oral contraceptive pill (OCP) use on cardiovascular risk in African-American women is unknown. Objective: Our objective was to examine in African-American women the effect of OCP use on insulin resistance, glucose intolerance, and triglycerides (TGs). Design: This was a cross-sectional study. Setting: The study was conducted at the National Institutes of Health Clinical Research Center. Participants: A total of 104 healthy nondiabetic African-American women [21 OCP users, 83 controls, age mean ± sd, 34.7 ± 7.6 yr, body mass index (BMI) 31 ± 8.4 kg/m2] was included in the study. Interventions: Subjects had oral glucose tolerance tests, insulin-modified frequently sampled iv glucose tolerance tests, and fasting lipid profiles. Insulin resistance was determined by the insulin sensitivity index (SI). Main Outcome Measures: Insulin resistance, glucose tolerance status, and TG levels were determined. Results: Fasting glucose did not differ between OCP users and controls (P = 0.27). In contrast, compared with controls, 2-h glucose (135 ± 23 vs.120 ± 25 mg/dl; P = 0.01) and fasting TGs (73 ± 31 vs.57 ± 27 mg/dl; P = 0.02) were higher in OCP users. OCP users tended to be more insulin resistant than controls (SI: 2.51 ± 2.01 vs. 3.46 ± 2.09; P = 0.09). Multiple regression analysis revealed that BMI, age, and OCP use were significant determinants of 2-h glucose (adjusted R2 = 0.37; P < 0.001) and TG levels (adjusted R2 = 0.21; P < 0.001). As BMI was a determinant of both 2-h glucose and TGs, participants were divided into nonobese and obese groups, and the analyses repeated. Among the nonobese women, the OCP users were more insulin resistant (SI: 2.91 ± 1.58 vs. 4.35 ± 1.88; P = 0.03) and had a higher prevalence of glucose intolerance than controls (odds ratio 5.7; 95% confidence interval 1.4–24; P = 0.01). Conclusion: In African-American women, OCP use is associated with an increase in markers of cardiovascular risk manifested by increased insulin resistance, glucose intolerance, and elevated TGs.

Frempong, Barbara A.; Ricks, Madia; Sen, Sabyasachi; Sumner, Anne E.

2008-01-01

323

Oral low dose and topical tamoxifen for breast cancer prevention: modern approaches for an old drug.  

PubMed

ABSTRACT: Tamoxifen is a drug that has been in worldwide use for the treatment of estrogen receptor (ER)-positive breast cancer for over 30 years; it has been used in both the metastatic and adjuvant settings. Tamoxifen's approval for breast cancer risk reduction dates back to 1998, after results from the Breast Cancer Prevention Trial, co-sponsored by the National Cancer Institute and the National Surgical Adjuvant Breast and Bowel Project, showed a 49% reduction in the incidence of invasive, ER-positive breast cancer in high-risk women. Despite these positive findings, however, the public's attitude toward breast cancer chemoprevention remains ambivalent, and the toxicities associated with tamoxifen, particularly endometrial cancer and thromboembolic events, have hampered the drug's uptake by high-risk women who should benefit from its preventive effects. Among the strategies to overcome such obstacles to preventive tamoxifen, two novel and potentially safer modes of delivery of this agent are discussed in this paper. Low-dose tamoxifen, expected to confer fewer adverse events, is being investigated in both clinical biomarker-based trials and observational studies. A series of systemic biomarkers (including lipid and insulin-like growth factor levels) and tissue biomarkers (including Ki-67) are known to be favorably affected by conventional tamoxifen dosing and have been shown to be modulated in a direction consistent with a putative anti-cancer effect. These findings suggest possible beneficial clinical preventive effects by low-dose tamoxifen regimens and they are supported by observational studies. An alternative approach is topical administration of active tamoxifen metabolites directly onto the breast, the site where the cancer is to be prevented. Avoidance of systemic administration is expected to reduce the distribution of drug to tissues susceptible to tamoxifen-induced toxicity. Clinical trials of topical tamoxifen with biological endpoints are still ongoing whereas pharmacokinetic studies have already shown that appropriate formulations of drug successfully penetrate the skin to reach breast tissue, where a preventive effect is sought. PMID:23106852

Lazzeroni, Matteo; Serrano, Davide; Dunn, Barbara K; Heckman-Stoddard, Brandy M; Lee, Oukseub; Khan, Seema; Decensi, Andrea

2012-10-29

324

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

PubMed

(1)H 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

2013-06-30

325

Simultaneous pharmacodynamic modeling of the non-steady-state effects of three oral doses of 1,3-glyceryl dinitrate upon blood pressure in healthy volunteers  

Microsoft Academic Search

The organic nitrate 1,3-glyceryl dinitrate (1,3-GDN) is one of the primary dinitrate metabolites of the antianginal agent nitroglycerin (GTN). Investigational New Drug Approval was sought to administer oral solution doses of 1,3-GDN to a small number (n=3) of healthy volunteers; each subject receiving three doses at 1.2, 2.4, and 3.6 mg. With volunteers confined to a semirecumbent posture for the

Mark Gumbleton; Leslie Z. Benet

1993-01-01

326

Pharmacokinetics of 14C-radioactivity after oral intake of a single dose of 14C-labeled fampridine (4-aminopyridine) in healthy volunteers  

Microsoft Academic Search

Background: Fampridine (4-aminopyridine) is a potassium channel blocker that has been evaluated as a treatment for patients with spinal cord injury and multiple sclerosis.Objective: The purpose of this study was to determine the pharmacokinetics of a single dose of an orally administered solution of 14C-labeled fampridine in healthy volunteers.Methods: In this open-label, single-dose study conducted in an inpatient setting, healthy

Andrew R. Blight; Herbert R. Henney III

2009-01-01

327

Cell-mediated immune responses in humans after immunization with one or two doses of oral live attenuated typhoid vaccine CVD 909  

Microsoft Academic Search

CVD 909 is a novel live attenuated S. Typhi oral vaccine candidate derived from strain CVD 908-htrA which constitutively expresses Vi. Herein we investigated whether the genetic manipulations involved in modifying CVD 908-htrA altered its ability to induce potent T-cell immune responses (CMI) after a single dose (five subjects) and, in a separate trial, whether a second dose (eight subjects)

Rezwanul Wahid; Rosangela Salerno-Gonçalves; Carol O. Tacket; Myron M. Levine; Marcelo B. Sztein

2007-01-01

328

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

329

Oral dosing with papaya latex is an effective anthelmintic treatment for sheep infected with Haemonchus contortus  

PubMed Central

Background The cysteine proteinases in papaya latex have been shown to have potent anthelmintic properties in monogastric hosts such as rodents, pigs and humans, but this has not been demonstrated in ruminants. Methods In two experiments, sheep were infected concurrently with 5,000 infective larvae of Haemonchus contortus and 10,000 infective larvae of Trichostrongylus colubriformis and were then treated with the supernatant from a suspension of papaya latex from day 28 to day 32 post-infection. Faecal egg counts were monitored from a week before treatment until the end of the experiment and worm burdens were assessed on day 35 post-infection. Results We found that the soluble fraction of papaya latex had a potent in vivo effect on the abomasal nematode H. contortus, but not on the small intestinal nematode T. colubriformis. This effect was dose-dependent and at tolerated levels of gavage with papaya latex (117 ?mol of active papaya latex supernatant for 4 days), the H. contortus worm burdens were reduced by 98%. Repeated treatment, daily for 4 days, was more effective than a single dose, but efficacy was not enhanced by concurrent treatment with the antacid cimetidine. Conclusions Our results provide support for the idea that cysteine proteinases derived from papaya latex may be developed into novel anthelmintics for the treatment of lumenal stages of gastro-intestinal nematode infections in sheep, particularly those parasitizing the abomasum.

2011-01-01

330

Preclinical Toxicology of Nsc 17251E Administered by Oral Route in Dogs. Part II.  

National Technical Information Service (NTIS)

NSC 17251E* has been studied for preclinical toxicological effects following repeated oral administration in young adult beagle dogs. All animals survived the 28-day treatment, and no serious clinical signs of toxicity were noted with dosages of 168, 336,...

P. E. Palm M. S. Nick C. J. Kensler D. A. Cooney R. D. Davis

1969-01-01

331

Phase I trial of ixabepilone administered as three oral doses each separated by 6 hours every 3 weeks in patients with advanced solid tumors  

PubMed Central

Summary Background Ixabepilone, which stabilizes microtubules, has low susceptibility to drug resistance mediated by P-glycoprotein or ?III-tubulin. Materials and Methods This study was designed to determine the maximum tolerated dose (MTD) of oral ixabepilone when administered every 6 h for three doses, every 3 weeks, to patients with refractory advanced cancers. Eighteen patients were treated with escalating doses of ixabepilone: three at cohort 1 (30 mg/dose; 90 mg on Day 1), nine at cohort 2 (40 mg/dose; 120 mg on Day 1), and six at cohort 3 (50 mg/ dose; 150 mg on Day 1). Serial plasma samples were collected during cycle 1 for pharmacokinetic (PK) measurements. Results Of the 18 treated patients, eight were male and ten were female. The median age was 59 years, and most had an excellent performance status (KPS 90–100; 61%). There were two dose limiting toxicities (DLT): Grade 4 febrile neutropenia at the 120 mg dose and Grade 4 neutropenic sepsis at the 150 mg dose. Because of the severity and duration of neutropenic sepsis at level 3, level 2 (120 mg) was defined as the MTD and this cohort was expanded to nine patients. High inter-individual variability in plasma drug concentrations was observed during the study, with particularly high levels in two patients with DLT. Conclusions On the basis of this safety profile, the MTD of oral ixabepilone was defined as 120 mg given as three 40 mg doses each separated by 6 h on Day 1 of a 3-week cycle. However, the PK variability observed makes further development of this oral formulation unlikely.

Kunz, Pamela L.; He, Aiwu R.; Colevas, A. Dimitrios; Pishvaian, Michael J.; Hwang, Jimmy J.; Clemens, Pamela L.; Messina, Marianne; Kaleta, Remigiusz; Abrahao, Fernanda; Marshall, John L.

2013-01-01

332

Effects of an oral dose of isosorbide dinitrate on platelet function and fibrinolysis in healthy volunteers.  

PubMed Central

1. A randomised double-blind placebo-controlled study was performed to investigate the effects of isosorbide dinitrate (ISDN; 20 mg orally) on various aspects of platelet function and fibrinolysis in vivo in 12 healthy volunteers. 2. Measurements were performed at rest (before and after tablet ingestion) and during platelet activation by adrenaline (0.4 nmol kg-1 min-1; 30 min infusion). 3. At rest, ISDN did not alter plasma concentrations of beta-thromboglobulin (beta TG). EC50 values for ADP induced aggregation in vitro (Born aggregometry) or ex vivo filtragometry readings. Adrenaline markedly increased platelet aggregability in vivo as measured by filtragometry and elevated levels of beta TG in plasma. ISDN treatment did not affect these responses in the group as a whole. 4. Individuals responding to ISDN with more pronounced vasodilatation at rest showed a lesser increase in aggregability during the ensuing adrenaline infusion (r = -0.66, P = 0.02) despite higher adrenaline levels during ISDN. In individuals showing a significant decrease in systolic blood pressure (n = 8) ISDN tended to attenuate the adrenaline induced increase in platelet aggregability (filtragometry; P = 0.08), despite higher plasma adrenaline and noradrenaline levels after ISDN ingestion. 5. Plasma concentrations of ISDN and its active metabolites isosorbide-5-mononitrate and isosorbide-2-mononitrate were not correlated to haemodynamic or platelet variables. 6. Fibrinolytic activity (t-PA antigen and activity, PAI-1 antigen and activity) increased similarly during the adrenaline infusion following ISDN and placebo. 7. It is concluded that ISDN may affect platelet aggregation responses to adrenaline in vivo, but only in individuals showing significant haemodynamic responses to ISDN.(ABSTRACT TRUNCATED AT 250 WORDS)

Wallen, N H; Larsson, P T; Broijersen, A; Andersson, A; Hjemdahl, P

1993-01-01

333

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

334

Monotherapy with Intravenous Followed by Oral High-Dose Ciprofloxacin versus Combination Therapy with Ceftazidime plus Amikacin as Initial Empiric Therapy for Granulocytopenic Patients with Fever  

Microsoft Academic Search

The aim of the present study was to obtain clinical experience with the use of high-dose ciprofloxacin as monotherapy for the treatment of febrile neutropenia episodes (granulocyte count, <500\\/mm3) compared to a standard regimen and to clarify whether ciprofloxacin administration may be switched to the oral route. In a prospective randomized study ciprofloxacin was given at 400 mg three times

HELEN GIAMARELLOU; HARRY P. BASSARIS; GEORGE PETRIKKOS; WILHELM BUSCH; MICHEL VOULGARELIS; ANASTASIA ANTONIADOU; ELISABETH GROUZI; NIKOLAOS ZOUMBOS

2000-01-01

335

International clinical experience with a new low-dose, Monophasic oral contraceptive containing levonorgestrel 100 ?g and ethinyl estradiol 20 ?g  

Microsoft Academic Search

Manufacturers have steadily been decreasing the amounts of estrogen and progestin in oral contraceptives (OCs) in an effort to enhance safety and tolerability while preserving contraceptive efficacy. A new formulation containing 20 ?g ethinyl estradiol (EE) and 100 ?g levonorgestrel (LNG)—representing the lowest available contraceptive dose of each hormone—has undergone extensive clinical testing in the United States and Germany. A

Peter J. Boerrigter; Herman Ellman; Michael Dolker

1999-01-01

336

Pharmacokinetics of azithromycin in serum, bronchial washings, alveolar macrophages and lung tissue following a single oral dose of extended or immediate release formulations of azithromycin  

Microsoft Academic Search

Objectives: Antibacterial efficacy of azithromycin could be improved by achieving higher concentrations at the sites of infection. Azithromycin extended release (azithromycin-ER) formulation was developed to enable a higher dosage of 2 g to be administered as a single oral dose without decreasing the safety profile. The aim of this study was to compare the pharmacokinetics of azithromycin in serum, epithelial

M. Lucchi; B. Damle; A. Fang; P. J. de Caprariis; A. Mussi; S. P. Sanchez; G. Pasqualetti; M. Del Tacca

2008-01-01

337

Absence of Age and Gender Effects on the Pharmacokinetics of a Single 500Milligram Oral Dose of Levofloxacin in Healthy Subjects  

Microsoft Academic Search

The influence of age and gender on the pharmacokinetics of levofloxacin in healthy subjects receiving a single oral 500-mg dose of levofloxacin was investigated in this parallel design study. Six young males (aged 18 to 40 years), six elderly males (aged >65 years), six young females (aged 18 to 40 years), and six elderly females (aged >65 years) were enrolled

S. C. CHIEN; A. T. CHOW; J. NATARAJAN; R. R. WILLIAMS; F. A. WONG; M. C. ROGGE; R. K. NAYAK

1997-01-01

338

[Clinical usefulness of high-dose oral nitroglycerin in patients with stable angina pectoris].  

PubMed

The aim of this study was to evaluate clinical efficacy and adverse effects of nitroglycerin 15 mg in slow-release form (N-15) after single ingestion. In randomized, double-blind and placebo (P) controlled with cross-over design study 15 male patients with stable angina received N-15 or P. Antianginal efficacy of the drug was evaluated by analysing the parameters of tolerance of effort and coronary reserve taken from serial exercise stress tests on treadmill performed preceding single oral ingestion, 2 hours and 6 hours after. Simple hemodynamic parameters were also evaluated in the rest and during exercise. N-15 significantly improved in comparison to P: total walking time both after 2 hours by 34.3% (p < 0.01) and 6 hours by 23.1% (p < 0.01); walking time to angina after 2 hours by 34.8% (p < 0.01) and 6 hours by 21.7% (p < 0.05), and walking time to ischemia after 2 hours by 66.1% (p < 0.01) and 6 hours by 39.0% (p < 0.05). N-15 significantly increased the rest heart rate in standing position 2 hours after ingestion by 12.3% (p < 0.01) and decreased rest systolic blood pressure in both positions 2 hours after ingestion: in supine by 12.9% (p < 0.01) and standing by 16.3% (p < 0.01) and after 6 hours: in supine by 9.1% (p < 0.05) and standing by 10.0% (p < 0.05). No postural hypotension in any patient occurred. Diastolic blood pressure was significantly decreased only in standing position 2 hours after N-15 ingestion by 12.3% (p < 0.01) and after 6 hours by 9.1% (p < 0.05). During maximal exercise significant reduction of systolic blood pressure occurred 2 hours after ingestion and significant reduction of diastolic blood pressure occurred both 2 hours and 6 hours after ingestion. Adverse effects after single ingestion of N-15 were the few: the headaches were presented only in 4 patients (27%), and in 53% patients any adverse effect occurred. Nitroglycerin 15 mg in slow-release form is an active coronary drug, effective not less than 6 hours after ingestion, and its adverse effects are the few. PMID:14969156

Ko?micki, Marek A; Skorykow-Sapi?ska, Alina; Sadowski, Zygmunt

2003-01-01

339

Acute effects of a single oral dose of carvedilol on cardiac sympathovagal balance in man.  

PubMed

Modulation of autonomic activity is considered to be a prognostic marker in patients with cardiovascular disease. The aim of the present study was to evaluate the modulation of sympathovagal balance after single-dose administration of carvedilol using various autonomic tests as challenges of sympathovagal balance. We conducted a randomized double-blind, placebo-controlled study in 18 male volunteers and applied a crossover design. While heart rate variability (HRV) remained unchanged in 24-hour measurements, modulatory effects on sympathovagal balance were demonstrated in controlled autonomic maneuvers at expected maximal drug levels of carvedilol: time-dependent HRV parameters indicative of vagal tone were increased during controlled breathing (15 cycles/min) in the supine body position by carvedilol. The percentage of successive normal RR intervals > 50 ms (pNN50) was increased to 39.8+/-5.1 vs. 32.7+/-4.7% in the placebo group (p < 0.05), root mean square successive differences (rMSSD) to 81.5+/-10.8 vs. 69.3+/-9.1 ms (p < 0.05 vs. placebo). In contrast, carvedilol versus placebo significantly reduced time- and frequency-domain parameters after an active standing-up procedure. This included rMSSD (26.5+/-2.8 ms vs. 34.9+/-3.8 ms), pNN50 (6.9+/-2.2% vs. 12.4+/-2.5%). total power (4329+/-592 ms2 vs. 6428+/-1158 ms2), low frequency (1472+/-179 ms2 vs. 2093+/-284 ms2) and high frequency power (251+/-42 ms2 vs. 353+/-92 ms2) of heart rate variability. Apparently, the effects of even small doses of carvedilol, too low to induce effects detectable in the 24-hour analysis of HRV testing, can be detected on controlled maneuvers of autonomic because of their ability to modulate autonomic balance. Under conditions of vagal stimulation, a potentially beneficial augmentation of HRV parameters indicative for this component is induced by carvedilol, while under conditions of sympathetic activation, carvedilol effects seem opposite. Interpretation of the latter results, in particular, requires further investigation. PMID:11471776

Haseroth, K; Löffler, P; Janson, C P; Kropff, S; Schmidt, B M; Feuring, M; Christ, M; Wehling, M

2001-07-01

340

Oral High-Dose Atorvastatin Treatment in Relapsing-Remitting Multiple Sclerosis  

PubMed Central

Background Recent data from animal models of multiple sclerosis (MS) and from a pilot study indicated a possible beneficial impact of statins on MS. Methodology/Principal Findings Safety, tolerability and effects on disease activity of atorvastatin given alone or in combination with interferon-beta (IFN-?) were assessed in a phase II open-label baseline-to-treatment trial in relapsing-remitting MS (RRMS). Patients with at least one gadolinium-enhancing lesion (CEL) at screening by magnetic resonance imaging (MRI) were eligible for the study. After a baseline period of 3 monthly MRI scans (months ?2 to 0), patients followed a 9-month treatment period on 80 mg atorvastatin daily. The number of CEL in treatment months 6 to 9 compared to baseline served as the primary endpoint. Other MRI-based parameters as well as changes in clinical scores and immune responses served as secondary endpoints. Of 80 RRMS patients screened, 41 were included, among them 16 with IFN-? comedication. The high dose of 80 mg atorvastatin was well tolerated in the majority of patients, regardless of IFN-? comedication. Atorvastatin treatment led to a substantial reduction in the number and volume of CEL in two-sided multivariate analysis (p?=?0.003 and p?=?0.008). A trend towards a significant decrease in number and volume of CEL was also detected in patients with IFN-? comedication (p?=?0.060 and p?=?0.062), in contrast to patients without IFN-? comedication (p?=?0.170 and p?=?0.140). Immunological investigations showed no suppression in T cell response but a significant increase in IL-10 production. Conclusions/Significance Our data suggest that high-dose atorvastatin treatment in RRMS is safe and well tolerated. Moreover, MRI analysis indicates a possible beneficial effect of atorvastatin, alone or in combination with IFN-?, on the development of new CEL. Thus, our findings provide a rationale for phase II/III trials, including combination of atorvastatin with already approved immunomodulatory therapy regimens. Trial Registration ClinicalTrials.gov NCT00616187

Bellmann-Strobl, Judith; Dorr, Jan; Waiczies, Helmar; Haertle, Mareile; Wernecke, Klaus D.; Volk, Hans-Dieter; Aktas, Orhan; Zipp, Frauke

2008-01-01

341

The phenomenon and cause of the dose-dependent oral absorption of chlorothiazide in rats: Extrapolation to human data based on the body surface area concept  

Microsoft Academic Search

The reported incomplete and dose-dependent absorption of chlorothiazide in humans was demonstrated in six rats after five oral solutions at doses of 0.93, 2.55, 9.23, 25.6, and 70.2 mg\\/kg. Mean 48-hr urinary recoveries of intact drug were 57.3, 50.4, 36.7, 22.8, and 15.3%, respectively. A similar degree of dose dependency in absorption was found in rat, dog, and human when

Fung-Hwa Hsu; Thomayant Prueksaritanont; Myung G. Lee; Win L. Chiou

1987-01-01

342

Tamsulosin Oral Controlled Absorption System (OCAS) in Patients with Lower Urinary Tract Symptoms Suggestive of Benign Prostatic Hyperplasia (LUTS\\/BPH): Efficacy and Tolerability in a Phase 2b Dose-Response Study  

Microsoft Academic Search

Objectives:This phase 2b randomised, placebo-controlled trial (RCT) was a dose-response study to assess the efficacy and safety of three different doses of a new formulation of tamsulosin (the oral controlled absorption system: OCAS) and to determine which dose(s) should be further evaluated in a phase 3a RCT.

Christopher R. Chapple; Jerzy Lorenz; Raymond Mortensen; Harald Pauthner; Mario O. Reis; Claude C. Schulman; Ingrid van der Putten-Slob

2005-01-01

343

Low-dose metronomic oral dosing of a prodrug of gemcitabine (LY2334737) causes antitumor effects in the absence of inhibition of systemic vasculogenesis.  

PubMed

Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at relatively low, minimally toxic doses, with no prolonged break periods; it is now showing encouraging results in various phase II clinical trials and is currently undergoing phase III trial evaluation. It is thought to cause antitumor effects primarily by antiangiogenic mechanisms, both locally by targeting endothelial cells of the tumor neovasculature and systemically by effects on bone marrow-derived cells, including circulating endothelial progenitor cells (CEP). Previous studies have shown reduction of CEPs by metronomic administration of a number of different chemotherapeutic drugs, including vinblastine, cyclophosphamide, paclitaxel, topotecan, and tegafur plus uracil (UFT). However in addition to, or even instead of, antiangiogenic effects, metronomic chemotherapy may cause suppression of tumor growth by other mechanisms such as stimulating cytotoxic T-cell responses or by direct antitumor effects. Here we report results evaluating the properties of metronomic administration of an oral prodrug of gemcitabine LY2334737 in nontumor-bearing mice and in preclinical models of human ovarian (SKOV3-13) and breast cancer (LM2-4) xenografts. Through daily gavage (at 6 mg/kg/d), the schedules tested were devoid of toxicity and caused antitumor effects; however, a suppressive effect on CEPs was not detected. Unexpectedly, metronomic LY2334737 administration caused increased blood flow in luciferase-tagged LM2-4 tumor xenografts, and this effect, readily measured using contrast micro-ultrasound, coincided with a relative increase in tumor bioluminescence. These results highlight the possibility of significant antitumor effects mediated by metronomic administration of some chemotherapy drugs without a concomitant inhibition of systemic angiogenesis. PMID:22188817

Francia, Giulio; Shaked, Yuval; Hashimoto, Kae; Sun, John; Yin, Melissa; Cesta, Carolyn; Xu, Ping; Man, Shan; Hackl, Christina; Stewart, Julie; Uhlik, Mark; Dantzig, Anne H; Foster, F Stuart; Kerbel, Robert S

2011-12-21

344

Low-dose metronomic oral dosing of a prodrug of Gemcitabine (LY2334737) causes anti-tumor effects in the absence of inhibition of systemic vasculogenesis  

PubMed Central

Metronomic chemotherapy refers to the close, regular administration of conventional chemotherapy drugs at relatively low minimally toxic doses with no prolonged break periods; it is now showing encouraging results in various phase II clinical trials, and is currently undergoing phase III trial evaluation. It is thought to cause anti-tumor effects primarily by antiangiogenic mechanisms, both locally by targeting endothelial cells of the tumor neovasculature and systemically by effects on bone marrow derived cells, including circulating endothelial progenitor cells (CEPs). Previous studies have shown reduction of CEPs by metronomic administration of a number of different chemotherapeutic drugs, including vinblastine, cyclophosphamide, paclitaxel, topotecan, and tegafur plus uracil (UFT). However in addition to, or even instead of, anti angiogenic effects, metronomic chemotherapy may cause suppression of tumor growth by other mechanisms such as stimulating cytotoxic T cell responses, or by direct anti-tumor effects. Here we report results evaluating the properties of metronomic administration of an oral prodrug of gemcitabine LY2334737 (LY) in non tumor-bearing mice, and in preclinical models of human ovarian (SKOV3-13) and breast cancer (LM2-4) xenografts. Through daily gavage (at 6mg/kg/day) the schedules tested were devoid of toxicity and caused anti-tumor effects; however, a suppressive effect on CEPs was not detected. Unexpectedly metronomic LY administration caused increased blood flow in luciferase-tagged LM2-4 tumor xenografts; and this effect coincided with a relative increase in tumor bioluminescence. These results highlight the possibility of significant anti-tumor effects mediated by metronomic administration of some chemotherapy drugs without a concomitant inhibition of systemic angiogenesis.

Francia, Giulio; Shaked, Yuval; Hashimoto, Kae; Sun, John; Yin, Melissa; Cesta, Carolyn; Xu, Ping; Man, Shan; Hackl, Christina; Stewart, Julie; Uhlik, Mark; Dantzig, Anne H.; Foster, Stuart; Kerbel, Robert S.

2012-01-01

345

Antimalarial Iron Chelator, FBS0701, Shows Asexual and Gametocyte Plasmodium falciparum Activity and Single Oral Dose Cure in a Murine Malaria Model  

PubMed Central

Iron chelators for the treatment of malaria have proven therapeutic activity in vitro and in vivo in both humans and mice, but their clinical use is limited by the unsuitable absorption and pharmacokinetic properties of the few available iron chelators. FBS0701, (S)3”-(HO)-desazadesferrithiocin-polyether [DADFT-PE], is an oral iron chelator currently in Phase 2 human studies for the treatment of transfusional iron overload. The drug has very favorable absorption and pharmacokinetic properties allowing for once-daily use to deplete circulating free iron with human plasma concentrations in the high µM range. Here we show that FBS0701 has inhibition concentration 50% (IC50) of 6 µM for Plasmodium falciparum in contrast to the IC50 for deferiprone and deferoxamine at 15 and 30 µM respectively. In combination, FBS0701 interfered with artemisinin parasite inhibition and was additive with chloroquine or quinine parasite inhibition. FBS0701 killed early stage P. falciparum gametocytes. In the P. berghei Thompson suppression test, a single dose of 100 mg/kg reduced day three parasitemia and prolonged survival, but did not cure mice. Treatment with a single oral dose of 100 mg/kg one day after infection with 10 million lethal P. yoelii 17XL cured all the mice. Pretreatment of mice with a single oral dose of FBS0701 seven days or one day before resulted in the cure of some mice. Plasma exposures and other pharmacokinetics parameters in mice of the 100 mg/kg dose are similar to a 3 mg/kg dose in humans. In conclusion, FBS0701 demonstrates a single oral dose cure of the lethal P. yoelii model. Significantly, this effect persists after the chelator has cleared from plasma. FBS0701 was demonstrated to remove labile iron from erythrocytes as well as enter erythrocytes to chelate iron. FBS0701 may find clinically utility as monotherapy, a malarial prophylactic or, more likely, in combination with other antimalarials.

Ferrer, Patricia; Tripathi, Abhai K.; Clark, Martha A.; Hand, Carla Cerami; Rienhoff, Hugh Young; Sullivan, David J.

2012-01-01

346

Failed heart rate control with oral metoprolol prior to coronary CT angiography: effect of additional intravenous metoprolol on heart rate, image quality and radiation dose.  

PubMed

The purpose of this study was to evaluate the effect of intravenous (i.v.) metoprolol after a suboptimal heart rate (HR) response to oral metoprolol (75-150 mg) on HR control, image quality (IQ) and radiation dose during coronary CTA using 320-MDCT. Fifty-three consecutive patients who failed to achieve a target HR of < 60 bpm after an oral dose of metoprolol and required supplementary i.v. metoprolol (5-20 mg) prior to coronary CTA were evaluated. Patients with HR < 60 bpm during image acquisition were defined as responders (R) and those with HR ? 60 bpm as non-responders (NR). Two observers assessed IQ using a 3-point scale (1-2, diagnostic and 3, non-diagnostic). Effective dose (ED) was estimated using dose-length product and a 0.014 mSV/mGy.cm conversion factor. Baseline characteristics and HR on arrival were similar in the two groups. 58% of patients didn't achieve the target HR after receiving i.v. metoprolol (NR). R had a significantly higher HR reduction after oral (mean HR 63.9 ± 4.5 bpm vs. 69.6 ± 5.6 bpm) (p < 0.005) and i.v. (mean HR 55.4 ± 3.9 bpm vs. 67.4 ± 5.3 bpm) (p < 0.005) doses of metoprolol. Studies from NR showed a significantly higher ED in comparison to R (8.0 ± 2.9 vs. 6.1 ± 2.2 mSv) (p = 0.016) and a significantly higher proportion of non-diagnostic coronary segments (9.2 vs. 2.5%) (p < 0.001). 58% of patients who do not achieve a HR of <60 bpm prior to coronary CTA with oral fail to respond to additional i.v. metoprolol and have studies with higher radiation dose and worse image quality. PMID:22527260

Jiménez-Juan, Laura; Nguyen, Elsie T; Wintersperger, Bernd J; Moshonov, Hadas; Crean, Andrew M; Deva, Djeven P; Paul, Narinder S; Torres, Felipe S

2012-04-24

347

Effect of in vivo administration of anti-CTLA-4 monoclonal antibody and IL-12 on the induction of low-dose oral tolerance  

PubMed Central

Oral tolerance has been characterized as an immunological hyporesponsiveness to fed antigen. Previous studies have suggested that high-dose oral tolerance involves the preferential interaction of B7 with CTLA-4 on the T cell. To determine whether similar mechanisms are involved in the induction of low-dose oral tolerance, mice were treated with anti-CTLA-4 monoclonal antibody (MoAb), with or without IL-12, at the time of feeding. Results showed that anti-CTLA-4 MoAb alone failed to restore cellular proliferation, antibody titres and IFN-? levels; however, IL-4 cytokine levels in OVA-fed mice were partially restored. In contrast, administration of IL-12 along with anti-CTLA-4 MoAb to mice during feeding completely prevented the suppression of Th1 immune responses, as shown by increased serum IgG2a titres, IFN-? production and cell proliferation. These results suggest that blocking B7-CTLA-4 interactions in the presence of IL-12 prevents the induction of low-dose oral tolerance at the Th1 cell level.

Barone, K S; Herms, B; Karlosky, L; Murray, S; Qualls, J

2002-01-01

348

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

PubMed Central

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

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

2012-01-01

349

Efficacy of a single oral dose of 200 mg pramiconazole in vulvovaginal yeast infections: an exploratory phase IIa trial.  

PubMed

Pramiconazole (R126638) is a novel azole with potent antifungal activity against yeasts, dermatophytes and many other fungal species. The aim of this study was to evaluate the efficacy and tolerance of a single oral dose of 200 mg pramiconazole in acute and recurrent vulvovaginal yeast infections. Thirty-two patients (15 acute and 17 recurrent cases) were KOH microscopy- and culture-positive at inclusion. Clinical cure was 53% at one week and 66% at one month. Mycological eradication was obtained in 88% at one week, whereas at one month 75% of the patients were still culture-negative. Effects in both acute and recurrent cases appeared to be similar for mycological cure. The composite sign and symptom score (sum of scores for oedema, erythema, excoriation pruritus, burning and irritation) had a median value of 7.5 (range 2-17) at inclusion. At one week this value was reduced to 1.0 (range 0-8) and at one month a further reduction to 0 (range 0-11) was seen. p-values compared with baseline at both follow-up visits were <0.001. The drug was well tolerated and the reported adverse events were rare and minimal. In conclusion, the results of this trial indicate that pramiconazole possesses properties that warrant further clinical studies in a larger number of patients with acute and recurrent vulvo notvaginal yeast infection to confirm its efficacy and tolerability. PMID:18779883

Donders, Gilbert; Ausma, Jannie; Wouters, Luc; Cauwenbergh, Geert; Borgers, Marcel; Janssens, Dirk

2008-01-01

350

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

351

A phase I pharmacokinetic and safety evaluation of oral pazopanib dosing administered as crushed tablet or oral suspension in patients with advanced solid tumors  

Microsoft Academic Search

Summary  Because cancer patients may have difficulty swallowing whole tablets, crushing tablets or ingesting an oral suspension is\\u000a a practical alternative. This open-label, 2-part, randomized crossover, phase I study evaluated the pharmacokinetics and tolerability\\u000a of pazopanib administered as a crushed tablet or an oral suspension relative to whole tablet in patients with advanced cancer\\u000a (Part 1). Patients completing Part 1 were

Elisabeth I. Heath; Karen Forman; Lisa Malburg; Shelby Gainer; A. Benjamin Suttle; Laurel Adams; Howard Ball; Patricia LoRusso

352

Oral glucosamine for 6 weeks at standard doses does not cause or worsen insulin resistance or endothelial dysfunction in lean or obese subjects.  

PubMed

Glucosamine is a popular nutritional supplement used to treat osteoarthritis. Intravenous administration of glucosamine causes insulin resistance and endothelial dysfunction. However, rigorous clinical studies evaluating the safety of oral glucosamine with respect to metabolic and cardiovascular pathophysiology are lacking. Therefore, we conducted a randomized, placebo-controlled, double-blind, crossover trial of oral glucosamine at standard doses (500 mg p.o. t.i.d.) in lean (n = 20) and obese (n = 20) subjects. Glucosamine or placebo treatment for 6 weeks was followed by a 1-week washout and crossover to the other arm. At baseline, and after each treatment period, insulin sensitivity was assessed by hyperinsulinemic-isoglycemic glucose clamp (SI(Clamp)) and endothelial function evaluated by brachial artery blood flow (BAF; Doppler ultrasound) and forearm skeletal muscle microvascular recruitment (ultrasound with microbubble contrast) before and during steady-state hyperinsulinemia. Plasma glucosamine pharmacokinetics after oral dosing were determined in each subject using a high-performance liquid chromatography method. As expected, at baseline, obese subjects had insulin resistance and endothelial dysfunction when compared with lean subjects (SI(Clamp) [median {25th-75th percentile}] = 4.3 [2.9-5.3] vs. 7.3 [5.7-11.3], P < 0.0001; insulin-stimulated changes in BAF [% over basal] = 12 [-6 to 84] vs. 39 [2-108], P < 0.04). When compared with placebo, glucosamine did not cause insulin resistance or endothelial dysfunction in lean subjects or significantly worsen these findings in obese subjects. The half-life of plasma glucosamine after oral dosing was approximately 150 min, with no significant changes in steady-state glucosamine levels detectable after 6 weeks of therapy. We conclude that oral glucosamine at standard doses for 6 weeks does not cause or significantly worsen insulin resistance or endothelial dysfunction in lean or obese subjects. PMID:17065354

Muniyappa, Ranganath; Karne, Rajaram J; Hall, Gail; Crandon, Sonja K; Bronstein, Joel A; Ver, Maria R; Hortin, Glen L; Quon, Michael J

2006-11-01

353

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.

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

2012-01-01

354

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

PubMed

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

2012-06-04

355

Oral Administration of OKT3 Monoclonal Antibody to Human Subjects Induces a Dose-Dependent Immunologic Effect in T Cells and Dendritic Cells  

PubMed Central

Introduction Parenteral OKT3 is used to treat transplant rejection and a humanized anti-CD3 Mab has shown positive clinical effects in new onset diabetes. Oral administration of anti-CD3 has not been tested in humans, but suppresses autoimmunity in animal models. Beta-glucosylceramide enhances NKT cell and regulatory T cell activity and enhances the effects of oral anti-CD3 in animals. Materials and methods Fifteen healthy volunteers (three per group) received orally administered OKT3 over a dose range of 0.2 to 5.0 mg daily with or without beta-glucosylceramide 7.5 mg for 5 days. Safety and immune parameters were measured on days 5, 10, and 30. Results and discussion Oral OKT3 enhanced T cell proliferation, suppressed Th1 and Th17 responses by 43% and 41%, respectively, increased TGF-?/IL-10 expression and decreased IL-23/IL-6 expression by dendritic cells, and affected the IgG repertoire as measured by antigen arrays. Co-administration of oral beta-glucosylceramide induced similar effects. No side effects were observed and no subjects developed human anti-mouse antibodies. Conclusion These findings demonstrate that oral anti-CD3 monoclonal antibody is safe and biologically active in humans and presents a new avenue for the treatment of autoimmune diseases.

Ilan, Yaron; Zigmond, Ehud; Lalazar, Gadi; Dembinsky, Adi; Ya'acov, Ami Ben; Hemed, Nila; Kasis, Ibrahim; Axelrod, Elizabeth; Zolotarov, Lidya; Klein, Athalia; El Haj, Madi; Gandhi, Roopali; Baecher-Allan, Claire; Wu, Henry; Murugaiyan, Gopal; Kivisakk, Pia; Farez, Mauricio F.; Quintana, Francisco J.; Khoury, Samia J.; Weiner, Howard L.

2009-01-01

356

Multiple dose pharmacokinetics and concentration effect relationship of the orally active renin inhibitor remikiren (Ro 42-5892) in hypertensive patients.  

PubMed Central

1 Three double-blind, randomized, placebo controlled, multiple oral dose studies in patients with mild to moderate hypertension were performed to study tolerability, pharmacodynamics and pharmacokinetics of remikiren. Doses of 100-800 mg remikiren or placebo were given over 8 days to altogether 144 patient volunteers. In some cases (n = 46) single i.v. doses of 100 mg were administered 4 h after the last oral dose. Plasma remikiren concentrations, plasma renin activity and immunoreactive renin concentrations were measured. Pharmacokinetic parameters were estimated using model independent techniques and the concentration-effect relationship was evaluated using population pharmacometric methods. 2 In most patients no distinct absorption and disposition phase could be identified, since plasma concentrations fluctuated widely over a period of approximately 10 h. Peak plasma concentrations (Cmax) were achieved within 0.25-2 h postdose. Mean Cmax values (on the first and last day of oral treatment) were in the magnitude of 4-6 ng ml(-1) (200 mg), 23-27 ng ml(-1) (300 mg), 65-83 ng ml(-1) (600 mg) and 47-48 ng ml(-1) (800 mg). Cmax and AUC0-t values were clearly different for different doses within single studies. Intersubject variability in pharmacokinetic parameters was much higher than intrasubject variability. No drug accumulation in plasma was apparent. 3 Inhibition of the angiotensin I production rate correlated well with plasma drug concentrations according to the Emax-model. An IC50 value of 0.5 ng ml(-1) (0.8 nM) was estimated. No correlation between blood pressure changes on the last day of oral treatment and either plasma remikiren concentrations or plasma renin inhibition was found.

Weber, C; Birnbock, H; Leube, J; Kobrin, I; Kleinbloesem, C H; Van Brummelen, P

1993-01-01

357

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

358

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

359

A single 210-mumol oral dose of retinol does not enhance the immune response in children with measles.  

PubMed

This trial assessed the effect of vitamin A on reversing measles-induced unresponsiveness to recall antigens and on enhancing measles antibody production. These assessments were part of a randomized, double-masked clinical trial of the efficacy of 210 mumol of retinol as retinyl palmitate for reducing measles-associated morbidity. Two hundred children between 5 mo and 17 y of age with acute measles were enrolled at the Urban Health Centers in Ndola, Zambia; 110 subjects received a placebo and 90 received vitamin A. At enrollment and 2 wk later, blood samples were collected to determine measles hemagglutinin antibody titer and, at 1 and 2 wk post-enrollment, cutaneous delayed-type hypersensitivity tests (DTH) for seven antigens were applied. Both groups of subjects showed marked DTH unresponsiveness, but vitamin A-treated subjects had a significant prolongation of unresponsiveness to tuberculin [odds ratio (OR) 3.22 and 95% confidence interval (CI) 1.27-8.2], Candida (OR 5.43, CI 1.13-25.9) and Proteus (OR 5.17, CI 1.14-28.4), after adjustment for previous vaccination and age. DTH unresponsiveness was antigen specific, reflecting prior vaccination history, and was not associated with acute respiratory infection status. In addition, children in both treatment groups showed a significant increase in measles antibody titer from baseline to wk 2, but this increment was not significantly different between the groups (P = 0.25). These results indicate that a single oral dose of 210 mumol of retinol as retinyl palmitate in oil does not enhance the immune system during measles. PMID:8089728

Rosales, F J; Kjolhede, C

1994-09-01

360

Repeated oral administration of high doses of the pomegranate ellagitannin punicalagin to rats for 37 days is not toxic.  

PubMed

The water-soluble ellagitanin punicalagin has been reported to be toxic to cattle. Taking into account that this antioxidant polyphenol is very abundant in pomegranate juice (> or =2 g/L), the present study evaluated the possible toxic effect of punicalagin in Sprague-Dawley rats upon repeated oral administration of a 6% punicalagin-containing diet for 37 days. Punicalagin and related metabolites were identified by HPLC-DAD-MS-MS in plasma, liver, and kidney. Five punicalagin-related metabolites were detected in liver and kidney, that is, two ellagic acid derivatives, gallagic acid, 3,8-dihydroxy-6H-dibenzo[b,d]pyran-6-one glucuronide, and 3,8,10-trihydroxy-6H-dibenzo[b,d]pyran-6-one. Feedstuff intake, food utility index, and growth rate were lower in treated rats during the first 15 days without significant adverse effects, which could be due to the lower nutritional value of the punicalagin-enriched diet together with a decrease in its palatability (lower food intake). No significant differences were found in treated rats in any blood parameter analyzed (including the antioxidant enzymes gluthatione peroxidase and superoxide dismutase) with the exception of urea and triglycerides, which remained at low values throughout the experiment. Although the reason for the decrease is unclear, it could be due to the lower nutritional value of the punicalagin-enriched diet with respect to the standard rat food. Histopathological analysis of liver and kidney corroborated the absence of toxicity. In principle, the results reported here, together with the large safety margin considered, indicate the lack of toxic effect of punicalagin in rats during the 37 day period investigated. However, taking into account the high punicalagin content of pomegranate-derived foodstuffs, safety evaluation should be also carried out in humans with a lower dose and during a longer period of intake. PMID:12744688

Cerdá, Begońa; Cerón, José J; Tomás-Barberán, Francisco A; Espín, Juan Carlos

2003-05-21

361

Genetic Programming and Other Machine Learning Approaches to Predict Median Oral Lethal Dose (LD50) and Plasma Protein Binding Levels (%PPB) of Drugs  

Microsoft Academic Search

Computational methods allowing reliable pharmacokinetics predictions for newly synthesized compounds are critically relevant\\u000a for drug discovery and development. Here we present an empirical study focusing on various versions of Genetic Programming\\u000a and other well known Machine Learning techniques to predict Median Oral Lethal Dose (LD50) and Plasma Protein Binding (%PPB) levels. Since these two parameters respectively characterize the harmful effects

Francesco Archetti; Stefano Lanzeni; Enza Messina; Leonardo Vanneschi

2007-01-01

362

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

Microsoft Academic Search

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

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

2000-01-01

363

Efficacy and safety of out-of-hospital self-administered single-dose oral drug treatment in the management of infrequent, well-tolerated paroxysmal supraventricular tachycardia  

Microsoft Academic Search

OBJECTIVESWe tested the efficacy of two drug treatments, flecainide (F) and the combination of diltiazem and propranolol (D\\/P), administered as a single oral dose for termination of the arrhythmic episodes.BACKGROUNDBoth prophylactic drug therapy and catheter ablation are questionable as first-line treatments in patients with infrequent and well-tolerated episodes of paroxysmal supraventricular tachycardia (SVT).METHODSAmong 42 eligible patients (13% of all screened

Paolo Alboni; Corrado Tomasi; Carlo Menozzi; Nicola Bottoni; Nelly Paparella; Giuseppe Fucŕ; Michele Brignole; Riccardo Cappato

2001-01-01

364

A single dose of intramuscularly administered dexamethasone acetate is as effective as oral prednisone to treat asthma exacerbations in young children  

Microsoft Academic Search

Objective: To evaluate whether a single dose of intramuscularly administered dexamethasone acetate (IM Dex) was as safe and effective as a 5-day course of oral prednisone (PO Pred) in the treatment of young children with mild-moderate exacerbations of asthma. Study design: A prospective, randomized, investigator-blinded study was done in a tertiary care medical center in children (6 months to 7

Delores M Gries; Donald R Moffitt; Elizabeth Pulos; Edward R Carter

2000-01-01

365

A prospective randomized study comparing the clinical effects of a norethisterone and a levonorgestrel containing low dose oestrogen oral contraceptive pills.  

PubMed

The two types of low dose oral contraceptives one containing levonorgestrel the other containing norethisterone have been compared in a randomized prospective study. We have found that cycle control was much poorer with the norethisterone pill and would therefore recommend that if the norethisterone-containing pill needs to be prescribed then either the 1 mg or the 'synphasic' preparation should be considered. PMID:8498949

Anstee, P; Kovacs, G T

1993-02-01

366

Effects of a MATE Protein Inhibitor, Pyrimethamine, on the Renal Elimination of Metformin at Oral Microdose and at Therapeutic Dose in Healthy Subjects  

Microsoft Academic Search

A microdose study of metformin was conducted to investigate the predictability of drug–drug interactions at the therapeutic dose (ThD). Healthy subjects received a microdose (100 µg) or ThD (250 mg) of metformin orally, with or without a potent and competitive multidrug and toxin extrusion (MATE) inhibitor, pyrimethamine (50 mg, p.o.), in a crossover fashion. Pyrimethamine significantly reduced the renal clearance

H Kusuhara; S Ito; Y Kumagai; M Jiang; T Shiroshita; Y Moriyama; K Inoue; H Yuasa; Y Sugiyama

2011-01-01

367

Comparison of the effect of two dose schedules of oral omeprazole with oral ranitidine on gastric aspirate pH and volume in patients undergoing elective surgery  

Microsoft Academic Search

Summary We have compared gastric aspirate pH and volume at induction of anaesthesia in 222 patients who had received either omeprazole or ranitidine before elective operations. Omeprazole was given orally either as 40 mg on the evening before and 40 mg on the morning of surgery or as 80 mg on the morning of surgery. Ranitidine 150 mg was given

I. D. LEVACK; R. A. BOWIE; D. P. BRAID; A. J. ASBURY; R. L. MARSHALL; K. B. SLAWSON; H. BIRRELL; K. R. W. GILLON

368

Pharmacokinetics of olanzapine after single-dose oral administration of standard tablet versus normal and sublingual administration of an orally disintegrating tablet in normal volunteers.  

PubMed

Olanzapine (OLZ) is a second-generation antipsychotic agent available in 2 solid oral dosage forms, a standard oral tablet (SOT) and an orally disintegrating tablet (ODT). This study assessed the absorption of each by different routes of administration. Secondarily, the influence of P-glycoprotein (P-gp) genotype was assessed. It was hypothesized that more rapid absorption of the OLZ ODT would occur when administered sublingually versus standard oral administration. A randomized, 3-way crossover study assessed the 5-mg OLZ formulations in healthy volunteers (n = 10). Blood was collected (0-8 hours) to assess OLZ pharmacokinetics using liquid chromatography/mass spectrometry. Both routes of ODT administration resulted in more measurable early concentrations relative to SOT. However, there were no statistically significant differences observed between any of the OLZ exposures for observed pharmacokinetic parameters (C(max), T(max), AUC(0-8h)). The homozygous TT genotype for P-gp resulted in an increased AUC of OLZ for SOT administration but not for either condition where sublingual absorption could occur. PMID:16432268

Markowitz, John S; DeVane, C Lindsay; Malcolm, Robert J; Gefroh, Holly A; Wang, Jun-Sheng; Zhu, Hao-Jie; Donovan, Jennifer L

2006-02-01

369

Oral administration of a nephrotoxic dose of potassium bromate, a food additive, alters renal redox and metabolic status and inhibits brush border membrane enzymes in rats.  

PubMed

The time dependent effect of orally administered KBrO(3) on redox status and enzymes of brush border membrane (BBM) and carbohydrate metabolism has been studied in rat kidney. Animals were given a single oral dose of KBrO(3) (100mg/kg body weight) and sacrificed at different times after this treatment; control animals were not given KBrO(3). The administration of KBrO(3) resulted in nephrotoxicity, a decline in the specific activities of several BBM marker enzymes and also induced oxidative stress in kidney. The specific activities of enzymes of carbohydrate metabolism were also altered and suggest a shift in energy metabolism from the aerobic to anaerobic mode. The renal effects of single oral dose of KBrO(3) appeared to be reversible; maximum changes in all the parameters were 48 h after administration of KBrO(3) after which recovery took place, in many cases almost to control values, after 168 h. These results suggest that the administration of a single nephrotoxic dose of KBrO(3) inhibits brush border membrane enzymes, induces oxidative stress and alters energy metabolism of the renal system in a reversible manner. PMID:23107716

Ahmad, Mir Kaisar; Naqshbandi, Ashreeb; Fareed, Mohd; Mahmood, Riaz

2012-03-07

370

The venous thrombotic risk of oral contraceptives, effects of oestrogen dose and progestogen type: results of the MEGA case-control study  

PubMed Central

Objective To assess the thrombotic risk associated with oral contraceptive use with a focus on dose of oestrogen and type of progestogen of oral contraceptives available in the Netherlands. Design Population based case-control study. Setting Six participating anticoagulation clinics in the Netherlands (Amersfoort, Amsterdam, The Hague, Leiden, Rotterdam, and Utrecht). Participants Premenopausal women <50 years old who were not pregnant, not within four weeks postpartum, and not using a hormone excreting intrauterine device or depot contraceptive. Analysis included 1524 patients and 1760 controls. Main outcome measures First objectively diagnosed episodes of deep venous thrombosis of the leg or pulmonary embolism. Odds ratios calculated by cross-tabulation with a 95% confidence interval according to Woolf’s method; adjusted odds ratios estimated by unconditional logistic regression, standard errors derived from the model. Results Currently available oral contraceptives increased the risk of venous thrombosis fivefold compared with non-use (odds ratio 5.0, 95% CI 4.2 to 5.8). The risk clearly differed by type of progestogen and dose of oestrogen. The use of oral contraceptives containing levonorgestrel was associated with an almost fourfold increased risk of venous thrombosis (odds ratio 3.6, 2.9 to 4.6) relative to non-users, whereas the risk of venous thrombosis compared with non-use was increased 5.6-fold for gestodene (5.6, 3.7 to 8.4), 7.3-fold for desogestrel (7.3, 5.3 to 10.0), 6.8-fold for cyproterone acetate (6.8, 4.7 to 10.0), and 6.3-fold for drospirenone (6.3, 2.9 to 13.7). The risk of venous thrombosis was positively associated with oestrogen dose. We confirmed a high risk of venous thrombosis during the first months of oral contraceptive use irrespective of the type of oral contraceptives. Conclusions Currently available oral contraceptives still have a major impact on thrombosis occurrence and many women do not use the safest brands with regard to risk of venous thrombosis.

2009-01-01

371

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

PubMed

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

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

2010-04-27

372

Lowering oral contraceptive norethindrone dose increases estrogen and progesterone receptor levels with no reduction in proliferation of breast epithelium: a randomized trial  

PubMed Central

Background This study was conducted to compare breast epithelial-cell proliferation and estrogen and progesterone receptor levels in women taking one of two oral contraceptives (OCs) containing the same dose of estrogen but different doses of the progestin norethindrone (NET). Study Design Thirty-three women were randomly assigned 1:1 to one of two OCs with 35-mcg ethinylestradiol (EE2) but different doses of NET - 1 mg or 0.4 mg. At the end of the active pill phase of the third OC cycle, a breast biopsy was performed and the percentages of epithelial cells of the terminal duct lobular units were measured for Ki67 (MIB1), progesterone receptors A and B (PRA and PRB), and estrogen receptor ? (ER?). Results The biopsies from 27 women had sufficient epithelium for analysis. The percentage of cells positive for PRA, PRB, and ER? were approximately double with the lower progestin dose (PRA: p = 0.041; PRB: p = 0.030; ER?: p = 0.056). The Ki67 percentage was not reduced with the lower progestin dose (0.4-mg NET - 12.5% vs 1.0-mg NET - 7.8%). Conclusions The increase in PRA, PRB, and ER? positive cells with the 60% lower progestin dose OC appears likely to account for its failure to decrease breast-cell proliferation. This breast-cell proliferation result is contrary to that predicted from the results of lowering the medroxyprogesterone acetate dose in menopausal hormone therapy.

Hovanessian-Larsen, Linda; Taylor, DeShawn; Hawes, Debra; Spicer, Darcy V.; Press, Michael F.; Wu, Anna H.; Pike, Malcolm C.; Pearce, C. Leigh

2012-01-01

373

Potent Preclinical Impact of Metronomic Low-Dose Oral Topotecan Combined with the Antiangiogenic Drug Pazopanib for the Treatment of Ovarian Cancer  

PubMed Central

Low dose metronomic (LDM) chemotherapy has shown promising activity in many preclinical and some phase II clinical trials involving various tumor types. To evaluate the potential therapeutic impact of LDM chemotherapy for ovarian cancer, we developed a preclinical model of advanced disease and tested various LDM chemotherapy regimens alone or in concurrent combination with an antiangiogenic drug, pazopanib. Clones of the SKOV-3 human ovarian carcinoma cell line expressing secretable ?-subunit of human choriogonadotropic (?-hCG) protein and firefly luciferase were generated, and evaluated for growth after orthotopic (intraperitoneal) injection into SCID mice; a highly aggressive clone, SKOV-3-13, was selected for further study. Mice were treated beginning 10–14 days after injection of cells when evidence of carcinomatosis-like disease in the peritoneum was established as assessed by imaging analysis. Chemotherapy drugs tested for initial experiments included oral cyclophosphamide, injected irinotecan or paclitaxel alone or in doublet combinations with cyclophosphamide; the results indicated that LDM cyclophosphamide had no anti-tumor activity whereas LDM irinotecan had potent activity. We therefore tested an oral topoisomerase-1 inhibitor, oral topotecan at optimal biologic dose of 1mg/kg/daily. LDM oral topotecan showed excellent anti-tumor activity, the extent of which was significantly enhanced by concurrent pazopanib, which itself had only modest activity, with 100% survival values of the drug combination after six months of continuous therapy. In conclusion, oral topotecan may be an ideal agent to consider for clinical trial assessment of metronomic chemotherapy for ovarian cancer, especially when combined with an antiangiogenic VEGF-pathway targeting drug, such as pazopanib.

Hashimoto, Kae; Man, Shan; Xu, Ping; Cruz-Munoz, William; Tang, Terence; Kumar, Rakesh; Kerbel, Robert S.

2009-01-01

374

Hydrocortisone Oral  

MedlinePLUS

... will decrease your dose gradually to allow your body to adjust before stopping the drug completely. Watch for these side effects if you are gradually decreasing your dose and after you stop taking the tablets or oral liquid, even if you switch to an inhalation. If ...

375

Triamcinolone Oral  

MedlinePLUS

... will decrease your dose gradually to allow your body to adjust before stopping the drug completely. Watch for these side effects if you are gradually decreasing your dose and after you stop taking the tablets or oral liquid, even if you switch to an inhalation. If ...

376

Dexamethasone Oral  

MedlinePLUS

... will decrease your dose gradually to allow your body to adjust before stopping the drug completely. Watch for these side effects if you are gradually decreasing your dose and after you stop taking the tablets or oral liquid, even if you switch to an inhalation corticosteroid ...

377

Acute and Repeated Dose Toxicity Studies on Nsc 94100 Following Daily Oral Administration to Dogs and Monkeys and Acute Toxicity Following Oral Administration to Mice and Monkeys.  

National Technical Information Service (NTIS)

Compound NSC 94100, D-Mannitol, 1,6-dibromo- 1,6-dideoxy- was studied following daily oral administration in beagle dogs in dosages of 200 mg/kg x 6, 100 mg/kg x 5, 50 mg/kg x 10, 35 mg/kg x 12, 25 mg/kg x 14, and 13 mg/kg x 90, the dosages being administ...

N. Rakieten P. S. Schein R. D. Davis

1967-01-01

378

Acute and Repeated Dose Toxicity Studies on Nsc 94100 Following Daily Oral Administration to Dogs and Monkeys and Acute Toxicity Following Oral Administration to Mice and Rats.  

National Technical Information Service (NTIS)

Compound NSC 94100, D-Mannitol, 1,6-dibromo-1,6-dideoxy- was studied following daily oral administration in beagle dogs in dosages of 200 mg/kg x 6, 100 mg/kg x 5, 50 mg/kg x 10, 35 mg/kg x 12, 25 mg/kg x 14, and 13 mg/kg x 90, the dosages being administe...

N. Rakieten

1967-01-01

379

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

USGS Publications Warehouse

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

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

1975-01-01

380

Pharmacokinetics of single-dose intravenous, oral, and intraperitoneal pefloxacin in patients on chronic ambulatory peritoneal dialysis.  

PubMed Central

Comparison of plasma and dialysate concentrations of pefloxacin after intravenous, oral, or intraperitoneal administration shows excellent bidirectional diffusion of the quinolone through the peritoneal membrane, demonstrating that therapeutical concentrations can be achieved in the dialysate after intravenous or oral administration. In this study, the half-life of the drug was 18.8 +/- 1.4 h, i.e., apparently longer than that reported for normal controls or uremic patients on hemodialysis.

Schmit, J L; Hary, L; Bou, P; Renaud, H; Westeel, P F; Andrejak, M; Fournier, A

1991-01-01

381

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.

Liu, Ping; Fang, Annie F.; LaBadie, Robert R.; Crownover, Penelope H.; Arguedas, Adriano G.

2011-01-01

382

Shielding effect of a customized intraoral mold including lead material in high-dose-rate 192-Ir brachytherapy for oral cavity cancer.  

PubMed

A high-dose-rate (HDR) 192-Ir brachytherapy using a customized intraoral mold is effective for superficial oral cavity cancer, and the surrounding normal tissue is kept away from the radioactive source with gauze pads and/or mouth piece for reducing the dose on the normal tissues. In the Tokushima university hospital, the mold has a lead shield which utilizes the space prepared with sufficient border-molding by a specific dental technique using modeling compound. In HDR 192-Ir brachytherapy using a lead shielded customized intraoral mold, there are no reports measuring the absorbed dose. The purpose of the present study is to measure the absorbed dose and discuss the optimum thickness of lead in HDR 192-Ir brachytherapy using a customized intraoral mold with lead shield using a 1 cm thickness mimic mold. The thickness of lead in the mold could be changed by varying the arrangement of 0.1 cm thickness sheet of the acrylic resin plate and lead. The measured doses at the lateral surface of the mold with thermo-luminescence dosimeter were reduced to 1.12, 0.79, 0.57, 0.41, 0.31, 0.24 and 0.19 Gy and the ratios to the prescription dose were reduced to 56, 40, 29, 21, 16, 12 and 10 percent as lead thickness increased from 0 to 0.6 cm in 0.1 cm increments, respectively. A 0.3 cm thickness lead was considered to be required for a 1 cm thickness mold, and it was necessary to thicken the lead as much as possible with the constraint of limited space in the oral cavity, especially at the fornix vestibule. PMID:22223463

Kudoh, Takaharu; Ikushima, Hitoshi; Honda, Eiichi

2012-01-06

383

The acute effects of a low and high dose of oral L-arginine supplementation in young active males at rest.  

PubMed

L-arginine (2-amino-5-guanidinovaleric acid) is a conditionally essential amino acid. Intravenous (IV) administration of l-arginine invokes a large metabolic (nitrate/nitrite (NO(x))) and hormonal (growth hormone (GH), insulin-like growth factor 1 (IGF-1), and insulin) response; however, research examining oral l-arginine supplementation is conflicting, potentially owing to dose. The purpose of this study was examine a low and high dose of oral l-arginine on blood l-arginine, NO(x), GH, IGF-1, and insulin response. Fourteen physically active males (age: 25 ± 5 years; weight: 78.0 ± 8.5 kg; height: 179.4 ± 4.7 cm) volunteered to be in a randomized, double-blind, repeated-measures study. Following an overnight fast, an IV catheter was placed in a forearm vein and a resting blood sample was drawn at ?0800 hours. Each subject was then provided 1 of 3 treatment conditions (placebo, low (0.075 g·kg(-1) of body mass), or high (0.15 g·kg(-1) of body mass of l-arginine)). Blood samples were drawn at 30, 60, 90, 120, and 180 min after consumption. l-arginine plasma concentrations significantly increased (p < 0.001) to a similar level at any time point in both the low- and high-dose conditions; there was no change over time in the placebo condition. There was no significant difference between conditions for NO(x), GH, IGF-1, or insulin. Based on these findings, a low dose of l-arginine was just as effective at increasing plasma l-arginine concentrations as a high dose; however, neither dose was able to promote a significant increase in NO(x), GH, IGF-1, or insulin at rest. PMID:21574873

Forbes, Scott C; Bell, Gordon J

2011-05-16

384

Comparison of oral artemether and mefloquine in acute uncomplicated falciparum malaria.  

PubMed

Plasmodium falciparum malaria in Thailand is highly resistant to available antimalarials, and alternative drugs are needed urgently. Artemether is effective against falciparum malaria but associated with a high recrudescence rate. The proper dosage regimen remains to be defined. We have done a clinical trial comparing mefloquine 1250 mg in divided doses with oral artemether at 700 mg total dose given over 5 days in acute uncomplicated falciparum malaria. 46 patients, admitted to the Bangkok Hospital for Tropical Diseases, were randomised to receive either mefloquine (12) or artemether (34). Hospital follow-up was 28 days for the artemether group and 42 days for the mefloquine group. Oral artemether gave a significantly faster parasite clearance time than mefloquine (30 vs 64 h), and a significantly better cure rate (97 vs 64%) with fewer episodes of dizziness and vomiting. Oral artemether at 700 mg given over 5 days is effective and well tolerated. The cure rate with this regimen is higher than that reported by previous studies with 600 mg intramuscular artemether given over 5 days. Oral artemether can be considered as an alternative drug for multiple-drug-resistant falciparum malaria. PMID:1359318

Karbwang, J; Bangchang, K N; Thanavibul, A; Bunnag, D; Chongsuphajaisiddhi, T; Harinasuta, T

1992-11-21

385

A randomized, double-blind, placebo-controlled comparison of the impact of low-dose and triphasic oral contraceptives on follicular development.  

PubMed

Health practitioners randomly enrolled 48 18-35 year old healthy women into either the group receiving a low dose oral contraceptive (Loestrin, 30 mcg of ethinyl estradiol and 1.5 mg of norethindrone acetate) or the group receiving a triphasic oral contraceptive (Estrostep, 20, 30, and 35 mcg of ethinyl estradiol and 1.5 mg of norethindrone acetate) and followed them for a 4-week control period. They were able to follow only 42-45 women during active treatment. This double blind, placebo controlled study took place at the Baylor College of Medicine in Houston, Texas. Its purpose was to determine whether Estrostep was causally related to development of ovarian cysts. 63% of the women in the placebo group had a follicle 18 mm sometime during treatment compared with 43% of those treated with Estrostep and 25% of those treated with Loestrin. No group was more prone to developing follicular cysts than the other 2 groups. Mean size of these follicles were 21, 21.5, and 23.8 mm for the control, Loestrin, and Estrostep groups, respectively, and were not significantly different. The mean largest follicle sizes were also not significantly different. None of the women experienced a follicle 18 mm for 2 weeks. The results indicated that follicular development persists during oral contraceptive treatment. They also do not support the hypothesis that triphasic oral contraceptives cause continual ovarian cysts. PMID:1530022

Young, R L; Snabes, M C; Frank, M L; Reilly, M

1992-09-01

386

Organophosphorus pesticide degradation product in vitro metabolic stability and time-course uptake and elimination in rats following oral and intravenous dosing.  

PubMed

Levels of urinary dialkylphosphates (DAPs) are currently used as a biomarker of human exposure to organophosphorus insecticides (OPs). It is known that OPs degrade on food commodities to DAPs at levels that approach or exceed those of the parent OP. However, little has been reported on the extent of DAP absorption, distribution, metabolism and excretion. The metabolic stability of O,O-dimethylphosphate (DMP) was assessed using pooled human and rat hepatic microsomes. Time-course samples were collected over 2 h and analyzed by LC-MS/MS. It was found that DMP was not metabolized by rat or pooled human hepatic microsomes. Male Sprague-Dawley rats were administered DMP at 20 mg kg(-1) via oral gavage and i.v. injection. Time-course plasma and urine samples were collected and analyzed by LC-MS/MS. DMP oral bioavailability was found to be 107 ± 39% and the amount of orally administered dose recovered in the urine was 30 ± 9.9% by 48 h. The in vitro metabolic stability, high bioavailability and extent of DMP urinary excretion following oral exposure in a rat model suggests that measurement of DMP as a biomarker of OP exposure may lead to overestimation of human exposure. PMID:21446834

Forsberg, N D; Rodriguez-Proteau, R; Ma, L; Morré, J; Christensen, J M; Maier, C S; Jenkins, J J; Anderson, K A

2011-03-29

387

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

PubMed

Efficient immunization against hepatitis B virus (HBV) and other pathogens with plant-based oral vaccines requires appropriate plant expressors and the optimization of vaccine compositions and administration protocols. Previous immunization studies were mainly based on a combination of the injection of a small surface antigen of HBV (S-HBsAg) and the feeding with raw tissue containing the antigen, supplemented with an adjuvant, and coming from plants conferring resistance to kanamycin. The objective of this study was to develop a prototype oral vaccine formula suitable for human immunization. Herbicide-resistant lettuce was engineered, stably expressing through progeny generation micrograms of S-HBsAg per g of fresh weight and formed into virus-like particles (VLPs). Lyophilized tissue containing a relatively low, 100-ng VLP-assembled antigen dose, administered only orally to mice with a long, 60-day interval between prime and boost immunizations and without exogenous adjuvant, elicited mucosal and systemic humoral anti-HBs responses at the nominally protective level. Lyophilized tissue was converted into tablets, which preserved S-HBsAg content for at least one year of room temperature storage. The results of the study provide indications on immunization methodology using a durable, efficacious, and convenient plant-derived prototype oral vaccine against hepatitis B. PMID:21107787

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

2010-11-23

388

Oral mucositis in children with acute lymphoblastic leukemia after high-dose methotrexate treatment without delayed elimination of methotrexate: relation to pharmacokinetic parameters of methotrexate.  

PubMed

Oral mucositis is a common problem after high-dose methotrexate (HD-MTX) treatment. Our purpose was to identify factors associated with the development of mucositis in children w