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1

Acute and repeated dose (28 days) oral safety studies of an alkoxyglycerol extract from shark liver oil in rats.  

PubMed

Shark liver oil has been used for over 50 years as both a therapeutic and preventive agent. The active ingredients in shark liver oil have been found to be a group of ether-linked glycerols known as alkoxyglycerols. Despite its popularity, there is little published toxicology data on alkoxyglycerols. The toxicity of a supercritical fluid extract of shark liver oil (AKG-1 extract) has been evaluated in acute and repeated dose (28 days) oral toxicity studies in rats at doses of 200 and 100 times the maximum recommended dose by supplement manufacturers in humans, respectively. The AKG-1 extract administered in a single oral gavage dose of 2000 mg kg(-1) of body weight resulted in no adverse events or mortality. The AKG-1 extract administered as a daily dose of 1000 mg kg(-1) of body weight for 28 days by gavage resulted in no adverse effects or mortality. For both studies, no abnormal clinical signs, behavioral changes, body weight changes, or change in food and water consumption occurred. There were no changes in hematological and serum chemistry values, organ weights, or gross or histological characteristics. It is concluded that the AKG-1 extract is well tolerated in rats at an acute dose of 2000 mg kg(-1) and at a subchronic (28 days) dose of 1000 mg kg(-1). PMID:20020698

Anadón, Arturo; Martínez, Maria A; Ares, Irma; Ramos, Eva; Seńoráns, Francisco J; Reglero, Guillermo; Torres, Carlos

2010-02-10

2

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

PubMed

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

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

2014-06-01

3

Repeated dose 28-day oral toxicity study of moniliformin in rats.  

PubMed

Moniliformin is a Fusarium mycotoxin mainly produced by several species infecting grains in different climatic conditions. According to our previous studies, it is acutely toxic to rats, with an LD50 cut-off value of 25mg/kg b.w. To further assess the possible health risks of low dose exposure to moniliformin, a subacute oral toxicity study was conducted in Sprague-Dawley rats, adapting OECD guideline 407. Five dose groups and two satellite groups, each consisting of five male rats, were daily exposed to moniliformin by gavage. Two rats in the highest dose group, showed decreased activity followed by acute heart failure and death. The rats of the lower doses (<9mg/kg b.w.) showed no signs of toxicity. The daily intake of moniliformin strongly reduced the phagocytic activity of neutrophils in all dose groups. The decrease continued in the satellite group during the follow-up period, indicating a severe impact on the immune system and a LOAEL value of 3mg/kg b.w. for moniliformin. Moniliformin was rapidly excreted into urine, ranging between 20.2 and 31.5% daily and showed no signs of accumulation. The concentration of moniliformin in faeces was less than 2%, which suggests efficient absorption from the gastrointestinal tract. PMID:25482064

Jonsson, Martina; Atosuo, Janne; Jestoi, Marika; Nathanail, Alexis V; Kokkonen, Ulla-Maija; Anttila, Marjukka; Koivisto, Pertti; Lilius, Esa-Matti; Peltonen, Kimmo

2015-02-17

4

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

PubMed

A 28-day subacute oral toxicity study was performed in Wistar rats with a purified preparation of the commercial pentabromodiphenyl ether (pentaBDE), DE-71. The applied OECD407 protocol was enhanced for endocrine and immune parameters, and to enable benchmark dose analysis. A vehicle control group and 7 dose groups were included, which received 0.27, 0.82, 2.47, 7.4, 22.2, 66.7 or 200 mg pentaBDE/kg bw/d (mkd). The liver appeared to be a key target organ, showing a marked increase of weight and centrilobular hepatocellular hypertrophy, probably due to the observed induction of P450 enzymes, notably CYP1A and CYP2B. A marked decrease of circulating total thyroxine (TT4) and an increase of plasma cholesterol were probably secondary to the liver effects. Furthermore, dose-dependently decreased weight of epididymis, seminal vesicles, and prostate, as well as sperm head deformities in males, and induction of CYP17 activity in adrenals in females were observed, all possibly related to anti-androgenic activity. Finally, we observed a substantial increase of large unstained cells in the blood and a decrease of apolar retinoids in the liver. All these effects had benchmark doses at the lower confidence bound (BMDL) in the low- or mid-dose range, but particular sensitive, potentially adverse effects were TT4 decrease (BMDLs 1.1 in males and 1.8 mkd in females), and decrease of hepatic apolar retinoids (BMDLs 0.5 mkd in males and 2.3 mkd in females). These results contribute to refinement of the hazard identification of pentaBDE and improved risk assessment of human exposure to this industrial chemical and environmental pollutant. PMID:18243468

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

2008-03-12

5

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

PubMed

4-Aminopyridine (4-AP) is an orphan drug indicated for the treatment of neuromuscular disorders. There is a great controversy around the use of this drug because of its narrow safety index and because a large number of adverse effects have been reported. Moreover, it was shown to induce cell death in different cell lines, being reported mainly apoptosis and necrosis as the principal pathways of cell death mediated by blockage of K channels or the Na, K-ATPase, but until now it was not described in vivo cell death induced by 4-aminipyridine. To provide new subchronic toxicity data and specifically, evaluate if 4-AP is able to induce in vivo cell death process and the main pathways related to it, a repeated dose (28 days) oral toxicity study, at therapeutic range of doses, was conducted in rats. The anatomical pathology, the biochemical and hematological parameters were analyzed and a real-time PCR array analysis was developed with an Ingenuity Pathway Analysis (IPA). The leucocytes number, the lactate dehydrogenase (LDH) and aspartate aminotransferase (AST) enzymatic activity were increased at all dose but the erythrocytes number, the hemoglobin concentration, the alkaline phosphatase (FAL) and alanine aminotransferase (ALT) enzymatic activity were increased only at highest dose studied. However, glucose levels decreased at all doses. The biochemical results are indicative of hepatic damage. The anatomy pathology studies showed cell death only on liver and kidney, and the real-time PCR array on liver tissue expressed a gene expression profile of necrotic and apoptotic induced cell death. The present work shows for the first time in vivo cell death on liver and kidney with features of apoptosis and necrosis induced by 4-AP and the gene expression profile shows that the cell death is mediated by necrotic and apoptotic pathways that support this finding. PMID:24378259

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

2014-03-01

6

Evaluation of multi-organ DNA damage by comet assay from 28 days repeated dose oral toxicity test in mice: A practical approach for test integration in regulatory toxicity testing  

Microsoft Academic Search

The use of comet assay is not new in the evaluation of genotoxic potential of different agents; however, its broad use in product safety for regulatory testing is a relatively new approach. The present study was aimed to integrate genotoxicity tests (micronucleus and comet assay) in 28days repeated dose oral toxicity of methotrexate (MTX) in mice. MTX was administered at

S. Kushwaha; D. N. Tripathi; A. Vikram; P. Ramarao; G. B. Jena

2010-01-01

7

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

Microsoft Academic Search

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

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

2004-01-01

8

Chronic renal failure is associated with increased tissue deposition of lanthanum after 28-day oral administration  

Microsoft Academic Search

Chronic renal failure is associated with increased tissue deposition of lanthanum after 28-day oral administration.BackgroundLanthanum (La) carbonate has recently been proposed as an alternative, calcium- and aluminum-free phosphate binder for the treatment of hyperphosphatemia of chronic renal failure (CRF). However, the extent to which CRF enhances tissue La accumulation induced by oral La overload above that observed under conditions of

BERNARD LACOUR; ANTHONY LUCAS; DANIEL AUCHČRE; NADYA RUELLAN; NATALIE MARIAUD DE SERRE PATEY; Tilman B. Drueke

2005-01-01

9

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

PubMed Central

Background Nuna Kadugu (NK), a Siddha medicine prepared from leaves and fruits of Morinda Pubescens, used for the treatment of various skin diseases. Though NK has been widely used for several decades, no scientific report was available on its safety. Present study was undertaken to demonstrate the oral toxicity of NK in Sprague Dawley rats. Methods Acute and 28-day repeated oral toxicity studies were performed following OECD test guidelines 423 and 407, respectively, with minor modifications. In acute oral toxicity study, NK was administered at 2000mg/kg b.wt., p.o and animals were observed for toxic signs at 0, 0.5, 1, 4, 24 h and for next 14 days. Gross pathology was performed at the end of the study. In repeated dose, the 28- day oral toxicity study, NK was administered at 300, 600 and 900 mg/kg b.wt./p.o/day. Two satellite groups (control and high dose) were also maintained to determine the delayed onset toxicity of NK. Animals were observed for mortality, morbidity, body weight changes, feed and water intake. Haematology, clinical biochemistry, electrolytes, gross pathology, relative organ weight and histopathological examination were performed. Results In acute toxicity study, no treatment related death or toxic signs were observed with NK administration. In the repeated dose study, no significant differences in body weight changes, food / water intake, haematology, clinical biochemistry and electrolytes content were observed between control and NK groups. No gross pathological findings and difference in relative organ weights were observed between control and NK treated rats. Histopathological examination revealed no abnormalities with NK treatment. Conclusion Acute study reveals that the LD50 of NK is greater than 2000mg/kg, b.wt. in fasted female rats and can be classified as Category 5. 28-day repeated oral toxicity demonstrates that the No Observed Adverse Effect Level of NK is greater than 900 mg/kg b.wt./day, p.o in rats. There were no delayed effects in NK satellite group. In conclusion, NK was found to be non-toxic in the tested doses and experimental conditions. PMID:23088610

2012-01-01

10

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

PubMed Central

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

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

2012-01-01

11

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

PubMed Central

Background The study investigated the distribution of silver after 28 days repeated oral administration of silver nanoparticles (AgNPs) and silver acetate (AgAc) to rats. Oral administration is a relevant route of exposure because of the use of silver nanoparticles in products related to food and food contact materials. Results AgNPs were synthesized with a size distribution of 14 ± 4 nm in diameter (90% of the nanoparticle volume) and stabilized in aqueous suspension by the polymer polyvinylpyrrolidone (PVP). The AgNPs remained stable throughout the duration of the 28-day oral toxicity study in rats. The organ distribution pattern of silver following administration of AgNPs and AgAc was similar. However the absolute silver concentrations in tissues were lower following oral exposure to AgNPs. This was in agreement with an indication of a higher fecal excretion following administration of AgNPs. Besides the intestinal system, the largest silver concentrations were detected in the liver and kidneys. Silver was also found in the lungs and brain. Autometallographic (AMG) staining revealed a similar cellular localization of silver in ileum, liver, and kidney tissue in rats exposed to AgNPs or AgAc. Using transmission electron microscopy (TEM), nanosized granules were detected in the ileum of animals exposed to AgNPs or AgAc and were mainly located in the basal lamina of the ileal epithelium and in lysosomes of macrophages within the lamina propria. Using energy dispersive x-ray spectroscopy it was shown that the granules in lysosomes consisted of silver, selenium, and sulfur for both AgNP and AgAc exposed rats. The diameter of the deposited granules was in the same size range as that of the administered AgNPs. No silver granules were detected by TEM in the liver. Conclusions The results of the present study demonstrate that the organ distribution of silver was similar when AgNPs or AgAc were administered orally to rats. The presence of silver granules containing selenium and sulfur in the intestinal wall of rats exposed to either of the silver forms suggests a common mechanism of their formation. Additional studies however, are needed to gain further insight into the underlying mechanisms of the granule formation, and to clarify whether AgNPs dissolve in the gastrointestinal system and/or become absorbed and translocate as intact nanoparticles to organs and tissues. PMID:21631937

2011-01-01

12

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

PubMed

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

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

2015-02-01

13

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

PubMed

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

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

2014-08-01

14

Evaluation of the immunomodulatory effects of the macrolide antibiotic, clarithromycin, in female B6C3F1 mice: a 28-day oral gavage study.  

PubMed

The macrolide antibiotic, clarithromycin, is used extensively to treat bacterial infections associated with pneumonia, duodenal ulcers, and the advanced stages of human immunodeficiency viral (HIV) infection. In addition to its antimicrobial properties, several studies have indicated that clarithromycin also has anti-inflammatory and immunomodulatory properties. In this study, clarithromycin's immunomodulatory properties were evaluated using female B6C3F1 mice and a panel of immune assays that were designed to evaluate potential changes in innate, and acquired cellular and humoral immune responses. Female B6C3F1 mice were treated daily by gavage with clarithromycin (0, 125, 250, and 500 mg/kg) for 28 days then evaluated for immunomodulation. Minimal immunological changes were observed after 28 days of treatment. A slight increase in the number of spleen antibody-forming cells was observed at the 250 mg/kg treatment level, but not at other doses. Serum IgM levels were unaffected by the clarithromycin treatment. A significant increase in the number of splenic macrophages was also observed in mice treated with 125 mg/kg of clarithromycin, but this increase was not observed at the other treatment levels. Innate and cell-mediated immunity, as measured by natural killer cell activity, and mixed leukocyte and cytotoxic T cell response, respectively, were unchanged following treatment with clarithromycin. These results suggest that the immune system is not a target for clarithromycin at doses of 500 mg/kg or below. PMID:11307632

Karrow, N A; McCay, J A; Brown, R D; Musgrove, D L; Germolec, D R; White, K L

2001-02-01

15

Effects of SiO?, ZrO?, and BaSO? nanomaterials with or without surface functionalization upon 28-day oral exposure to rats.  

PubMed

The effects of seven nanomaterials (four amorphous silicon dioxides with or without surface functionalization, two surface-functionalized zirconium dioxides, and barium sulfate) upon 28-day oral exposure to male or female rats were investigated. The studies were performed as limit tests in accordance with OECD Test Guideline 407 applying 1,000 mg test substance/kg body weight/day. Additionally, the acute phase proteins haptoglobin and ?2-macroglobulin as well as cardiac troponin I were determined, and metabolome analysis was performed in plasma samples. There were no test substance-related adverse effects for any of the seven nanomaterials. Moreover, metabolomics changes were below the threshold of effects. Since test substance organ burden was not analyzed, it was not possible to establish whether the lack of findings related to the absence of systemic exposure of the tested nanomaterials or if the substances are devoid of any potential for toxicity. The few published subacute oral or short-term inhalation studies investigating comparable nanomaterials (SiO?, ZrO?, and BaSO?) also do not report the occurrence of pronounced treatment-related findings. Overall, the results of the present survey provide a first indication that the tested nanomaterials neither cause local nor systemic effects upon subacute oral administration under the selected experimental conditions. Further investigations should aim at elucidating the extent of gastrointestinal absorption of surface-functionalized nanomaterials. PMID:25164825

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

2014-10-01

16

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

Code of Federal Regulations, 2013 CFR

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

2013-07-01

17

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

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

2014-07-01

18

Effects of a 28-day oral exposure to a 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one biocide formulation in Sprague-Dawley rats.  

PubMed

Biocides are added to biodiesels to prevent degradation resulting from microbial growth. A 28-day repeated oral dose study was conducted to assess a potential risk arising from ingestion of isothiazolinone biocides in biodiesels. A mixture of 5-chloro-2-methyl-4-isothiazolin-3-one and 2-methyl-4-isothiazolin-3-one (CMIT/MIT) diluted in corn oil was administered by gavage to male and female rats at 0, 0.26, 0.78, 2.33 and 7.0?mg/kg body weight per day. Rat water and food consumption was monitored. At the end of the dosing period, organs were weighed and histological examinations performed. Hematology, serum clinical chemistry and biomarkers of inflammation were assessed. Reduction of serum triglyceride levels in males and induction of hepatic phase 1 xenobiotic metabolizing enzymes in females accompanied by subtle histological changes in the liver were observed at the highest CMIT/MIT exposure. These changes were more indicative of an adaptive, reversible response than overt toxicity. Based on recommended levels for the control of microbial growth in fuels, CMIT/MIT contained in accidentally ingested biodiesels is not expected to represent a significant health risk. PMID:24111717

Pelletier, Guillaume; Valli, Victor E; Rigden, Marc; Poon, Raymond

2014-04-01

19

A 28-day oral toxicity study of fermentation-derived cellulose, produced by Acetobacter aceti subspecies xylinum, in F344 rats.  

PubMed

This study was designed to evaluate any adverse effect of fermentation-derived cellulose, produced by Acetobacter aceti subspecies xylinum, when administered to both sexes of F344 rats at dietary levels of 0, 1.25, 2.5, and 5.0% for 28 days. The treatment had no adverse effects on clinical signs, mortality, body weights and food and water consumption, or on urinalysis, ophthalmology, hematology, blood biochemistry, and histopathology findings. At necropsy, slight increased absolute and relative cecum weights, evident in females ingesting 2.5% and 5.0% dietary levels, were considered to be a physiological adaptation to the poorly absorbed fermentation-derived cellulose. The non-observed-adverse-effect level (NOAEL) from the present study was concluded to be 5.0% in the diet (5,331 mg/kg body weights/day for males, and 5,230 mg/kg body weights/day for females). PMID:20519840

Hagiwara, Akihiro; Imai, Norio; Sano, Masashi; Kawabe, Mayumi; Tamano, Seiko; Kitamura, Satoshi; Omoto, Toshio; Asai, Iwao; Yasuhara, Kazuo; Hayashi, Shim-Mo

2010-06-01

20

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

PubMed Central

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

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

2014-01-01

21

Norfloxacin disposition after sequentially increasing oral doses.  

PubMed Central

Single doses of norfloxacin (200, 400, 800, 1,200, and 1,600 mg) or placebo were administered orally at weekly intervals to 14 healthy male volunteers in a double-blind study. Norfloxacin was measured in serum and urine by high-pressure liquid chromatography with UV detection. The concentrations of this drug in serum peaked 1 to 2 h after each dose; the mean peak values for increasing doses were 0.75, 1.58, 2.41, 3.15, and 3.87 micrograms/ml. Mean area under the serum concentration-time curves for the first 12 h after each dose were 3.56, 6.26, 11.4, 16.1, and 19.7 micrograms . h/ml, respectively. The elimination half-life of norfloxacin was about 7 h and was similar for all doses. The concentrations of the drug in urine also peaked 1 to 2 h after dosage; mean peak values for increasing doses were 200, 478, 697, 992, and 1,045 micrograms/ml. Renal clearances approximated 285 ml/min. About 30% of each dose was excreted into urine as unmetabolized norfloxacin. Crystals of the drug were occasionally observed during microscopic examination of freshly voided urine collected after the 1,200- and 1,600-mg doses. Crystalluria was not encountered at lower doses. PMID:6220672

Swanson, B N; Boppana, V K; Vlasses, P H; Rotmensch, H H; Ferguson, R K

1983-01-01

22

High dose rate brachytherapy for oral cancer  

PubMed Central

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

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

2013-01-01

23

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

PubMed Central

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

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

2014-01-01

24

Pharmacokinetics of BILR 355 after Multiple Oral Doses Coadministered with a Low Dose of Ritonavir ?  

PubMed Central

The pharmacokinetics and safety of BILR 355 following oral repeated dosing coadministered with low doses of ritonavir (RTV) were investigated in 12 cohorts of healthy male volunteers with a ratio of 6 to 2 for BILR 355 versus the placebo. BILR 355 was given once a day (QD) coadministered with 100 mg RTV (BILR 355/r) at 5 to 50 mg in a polyethylene glycol solution or at 50 to 250 mg as tablets. BILR 355 tablets were also dosed at 150 mg twice a day (BID) coadministered with 100 mg RTV QD or BID. Following oral dosing, BILR 355 was rapidly absorbed, with the mean time to maximum concentration of drug in serum reached within 1.3 to 5 h and a mean half-life of 16 to 20 h. BILR 355 exhibited an approximately linear pharmacokinetics for doses of 5 to 50 mg when given as a solution; in contrast, when given as tablets, BILR 355 displayed a dose-proportional pharmacokinetics, with a dose range of 50 to 100 mg; from 100 to 150 mg, a slightly downward nonlinear pharmacokinetics occurred. The exposure to BILR 355 was maximized at 150 mg and higher due to a saturated dissolution/absorption process. After oral dosing of BILR 355/r, 150/100 mg BID, the values for the maximum concentration of drug in plasma at steady state, the area under the concentration-time curve from 0 to the dose interval at steady state, and the minimum concentration of drug in serum at steady state were 1,500 ng/ml, 12,500 h·ng/ml, and 570 ng/ml, respectively, providing sufficient suppressive concentration toward human immunodeficiency virus type 1. Based on pharmacokinetic modeling along with the in vitro virologic data, several BILR 355 doses were selected for phase II trials using Monte Carlo simulations. Throughout the study, BILR 355 was safe and well tolerated. PMID:18955519

Huang, Fenglei; Drda, Kristin; MacGregor, Thomas R.; Scherer, Joseph; Rowland, Lois; Nguyen, Thuy; Ballow, Charles; Castles, Mark; Robinson, Patrick

2009-01-01

25

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

SciTech Connect

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

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

2012-06-15

26

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

2013-11-01

27

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

PubMed Central

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

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

2013-01-01

28

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...

29

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

PubMed Central

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

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

2014-01-01

30

The effects of food and dose on the oral systemic availability of itraconazole in healthy subjects  

Microsoft Academic Search

We have studied the influence of food and dose (50, 100, 200 mg) on the oral systemic availability of the broad spectrum antifungal itraconazole and the pharmacokinetics after repeated dosing of 100 mg in six healthy volunteers.

A. Van Peer; R. Woestenborghs; J. Heykants; R. Gasparini; G. Gauwenbergh

1989-01-01

31

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

32

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...

33

Single dose oral rofecoxib for acute postoperative pain in adults  

PubMed Central

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

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

2014-01-01

34

Pharmacokinetics of flunitrazepam following single- and multiple-dose oral administration to healthy human subjects  

Microsoft Academic Search

Healthy human subjects received single and multiple oral doses of flunitrazepam. Absorption and disposition were first order and reproducible from administration to administration. The oral doses were virtually completely available to the liver, and elimination from the body occurred entirely via metabolism. Assuming the liver to be the sole eliminating organ, hepatic blood clearance and extraction ratio were approximately 0.235

H. G. Boxenbaum; H. N. Posmanter; T. Macasieb; K. A. Geitner; R. E. Weinfeld; J. D. Moore; A. Darragh; D. A. O'Kelly; L. Weissman; S. A. Kaplan

1978-01-01

35

Metabolism and distribution of bromodichloromethane in rats after single and multiple oral doses  

Microsoft Academic Search

The disposition of [C]bromodichloromethane (BDCM) was studied in male Fischer rats after single oral doses of 1, 10, 32, or 100 mg\\/kg and 10?d repeat oral dosing of 10 or 100 mg\\/kg\\/d. Methods were developed to quantitate exhaled CO and CO2. Bromodichloromethane was extensively (?80–90%) metabolized within 24 h postdosing with ?70–80% of the administered dose appearing as CO2 and

J. M. Mathews; P. S. Troxler; A. R. Jeffcoat

1990-01-01

36

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

PubMed Central

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

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

2013-01-01

37

Dose Escalation Study for Defining the Maximum Tolerated Dose of Continuous Oral Trofosfamide in Pretreated Patients with Metastatic Lung Cancer  

Microsoft Academic Search

Background: Trofosfamide is increasingly used in the treatment of patients with several types of malignancies. However, the optimal dose of trofosfamide for patients with advanced cancer has not been systematically investigated yet. The aim of this study was to define the maximum tolerated dose (MTD) of continuous oral trofosfamide. Patients and Methods: 16 patients with advanced lung cancer (14 nonsmall

S.-E. Al-Batran; A. Atmaca; F. Bert; C. Frisch; A. Neumann; J. Orth; A. Knuth

2004-01-01

38

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. PMID:22084566

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

2011-01-01

39

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

PubMed Central

The aim of this study was to investigate the acute oral toxicity of fermented Scutellariae Radix (JKTMHGu- 100) in rats and dogs. JKTM-HGu-100 was orally administered at a dose of 2,000 mg/kg in Sprague-Dawley rats. An escalating single-dose oral toxicity test in beagle dogs was performed at doses of 500, 1000, and 2000 mg/kg with 4-day intervals. Clinical signs, changes in body weight, mortality, and necropsy findings were examined for 2 weeks following oral administration. No toxicological changes related to the test substance nor mortality was observed after administration of a single oral dose of JKTM-HGu-100 in rats or dogs. Therefore, the approximate lethal dose (LD) for oral administration of JKTMHGu-100 in rats was considered to be over 2,000 mg/kg, and the maximum tolerance doses (MTDs) in rats and dogs were also estimated to be over 2,000 mg/kg. These results indicate that JKTM-HGu-100 shows no toxicity in rodents or non-rodents at doses of 2,000 mg/kg or less. PMID:24278619

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

2012-01-01

40

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

PubMed

Oral ?(9) -tetrahydrocannabinol (?(9) -THC) has been evaluated as a medication for cannabis dependence, but repeated administration of acute oral doses up to 40?mg has not been effective at reducing drug-taking behavior. Larger doses might be necessary to affect cannabis use. The purpose of the present study was therefore to determine the physiological and behavioural effects of oral ?(9) -THC at acute doses higher than those tested previously. The pharmacokinetic and pharmacodynamic profile of oral ?(9) -THC, administered in ascending order in 15?mg increments across separate sessions, up to a maximum of 90?mg, was determined in seven cannabis users. Five subjects received all doses and two experienced untoward side effects at lower doses. ?(9) -THC produced a constellation of effects consistent with previous clinical studies. Low cannabinoid concentrations were associated with significant effects on drug-sensitive measures, although progressively greater levels did not lead to proportionately larger drug effects. Considerable variability in Cmax and tmax was observed. Doses of oral ?(9) -THC larger than those tested previously can be administered to individuals with a history of cannabis use, although given the pharmacokinetic variability of oral ?(9) -THC and individual differences in sensitivity, individualized dose adjustment is needed to avoid side effects and maximize therapeutic response. PMID:23754596

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

2013-07-01

41

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

E-print Network

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

LeGrange, Suzanne Nauman

1996-01-01

42

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

PubMed Central

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

Kothari, Mihir

2014-01-01

43

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

44

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

E-print Network

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

Forrester, Sharon Dru

1989-01-01

45

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

PubMed Central

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

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

2015-01-01

46

Biotransformation and pharmacokinetics of ethylmorphine after a single oral dose.  

PubMed Central

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

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

1995-01-01

47

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

PubMed

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

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

2014-01-01

48

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

49

Pharmacokinetics, Safety, and Tolerability of Oral Posaconazole Administered in Single and Multiple Doses in Healthy Adults  

Microsoft Academic Search

The pharmacokinetics, safety, and tolerability of posaconazole, an investigational triazole antifungal, were evaluated following the administration of rising single and multiple oral doses. A total of 103 healthy adults were enrolled in two phase I trials. Each study had a double-blind, placebo-controlled, parallel-group design with a rising single-dose (RSD) or rising multiple-dose (RMD) scheme. In the RSD study, subjects received

Rachel Courtney; Sudhakar Pai; Mark Laughlin; Josephine Lim; Vijay Batra

2003-01-01

50

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

PubMed Central

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

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

2014-01-01

51

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

PubMed Central

Currently, no cholera vaccine is available for persons traveling from the United States to areas of high cholera transmission and who for reasons of occupation or host factors are at increased risk for development of the disease. A single-dose oral cholera vaccine with a rapid onset of protection would be particularly useful for such travelers and might also be an adjunct control measure for cholera outbreaks. The attenuated Vibrio cholerae O1 vaccine strain CVD 103-HgR harbors a 94% deletion of the cholera toxin A subunit gene (ctxA) and has a mercury resistance gene inserted in the gene encoding hemolysin A. We undertook a phase I randomized placebo-controlled two-site trial to assess the safety and immunogenicity of a preliminary formulation of CVD 103-HgR prepared from new master and working cell banks. Healthy young adults were randomized (5:1 vaccinees to placebo recipients) to receive a single oral dose of ?4.4 × 108 CFU of vaccine or a placebo. Blood serum vibriocidal and cholera toxin-specific IgG antibodies were measured before and 10, 14, and 28 days following vaccination or placebo. Excretion of the vaccine strain in the stool was assessed during the first week postvaccination. A total of 66 subjects were enrolled, comprising 55 vaccinees and 11 placebo recipients. The vaccine was well tolerated. The overall vibriocidal and anti-cholera toxin seroconversion rates were 89% and 57%, respectively. CVD 103-HgR is undergoing renewed manufacture for licensure in the United States under the auspices of PaxVax. Our data mimic those from previous commercial formulations that elicited vibriocidal antibody seroconversion (a correlate of protection) in ?90% of vaccinees. (This study has been registered at ClinicalTrials.gov under registration no. NCT01585181.) PMID:24173028

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

2014-01-01

52

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

PubMed

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

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

2013-08-01

53

Furazolidone disposition after intravascular and oral dosing in the channel catfish.  

PubMed

1. The pharmacokinetics, tissue distribution and excretion of the nitrofuran drug furazolidone have been examined in the channel catfish. [14C]Furazolidone was administered by intravascular or oral routes in a single dosage of 1 mg/kg body weight. 2. A two-compartment pharmacokinetic model best described parent furazolidone concentrations in the plasma after intravascular dosing. Elimination of parent compound was extremely rapid, with a terminal half-life of 0.27h and total body clearance of 1901 ml/h/kg. 3. After oral dosing, furazolidone concentrations in the plasma were highest at 1 h and were below the limit of determination (< 20 ng/ml) at 5 h. The oral bioavailability of parent furazolidone administered in solution was 58%, compared with 28% in a feed mixture. 4. Concentrations of furazolidone and its metabolites were highest in the excretory tissues and lowest in the muscle after oral dosing. Parent furazolidone comprised 10% of the total 14C in the muscle at 8 h and was not detectable (< 1 ng/g) at 24 h; total 14C concentrations declined from 274 to 59 ng furazolidone equiv./g between 8 and 168 h. Non-extractable (bound) residues comprised 18% of total 14C in muscle at 8 h and 33% at 168h. 5. Renal excretion was the primary route of elimination of 14C residues and accounted for nearly 55% of the oral dose. PMID:7701851

Plakas, S M; el Said, K R; Stehly, G R

1994-11-01

54

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

55

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

PubMed Central

Silymarin, derived from the milk thistle plant Silybum marianum, is widely used for self-treatment of liver diseases, including hepatitis C virus (HCV), and its antiviral activity has been demonstrated in vitro and in HCV patients administered an intravenous formulation of the major silymarin flavonolignans, silybin A and silybin B. The safety and dose-exposure relationships of higher than customary oral doses of silymarin and its acute effects on serum HCV RNA were evaluated in noncirrhotic HCV patients. Four cohorts of 8 patients with well-compensated, chronic noncirrhotic HCV who failed interferon-based therapy were randomized 3:1 to silymarin or placebo. Oral doses of 140, 280, 560, or 700 mg silymarin were administered every 8 hours for 7 days. Steady-state exposures for silybin A and silybin B increased 11-fold and 38-fold, respectively, with a 5-fold increase in dose, suggesting nonlinear pharmacokinetics. No drug-related adverse events were reported, and no clinically meaningful reductions from baseline serum transaminases or HCV RNA titer were observed. Oral doses of silymarin up to 2.1 g per day were safe and well tolerated. The nonlinear pharmacokinetics of silybin A and silybin B suggests low bioavailability associated with customary doses of silymarin may be overcome with doses above 700 mg. PMID:19841158

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

2011-01-01

56

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

PubMed

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

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

2014-09-01

57

Pharmacokinetics of flunitrazepam following single- and multiple-dose oral administration to healthy human subjects.  

PubMed

Healthy human subjects received single and multiple oral doses of flunitrazepam. Absorption and disposition were first order and reproducible from administration. The oral doses were virtually completely available to the liver, and elimination from the body occurred entirely via metabolism. Assuming the liver to be the sole eliminating organ, hepatic blood clearance and extraction ratio were approximately 0.235 liter/hr/kg and 0.154, respectively. Steady-state blood volume of distribution averaged 3.76 liters/kg in the single-dose studies. Terminal exponential half-lives from the single- and multiple-dose studies (different subjects) averaged 13.5 and 19.2 hr, respectively; these differences were not due to clearance changes but were entirely attributable to variations in volumes of distribution. PMID:29954

Boxenbaum, H G; Posmanter, H N; Macasieb, T; Geitner, K A; Weinfeld, R E; Moore, J D; Darragh, A; O'Kelly, D A; Weissman, L; Kaplan, S A

1978-08-01

58

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

59

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

PubMed Central

Objective To compare the efficacy and safety of high dose rate (HDR) and low dose rate (LDR) brachytherapy in treating early-stage oral cancer. Data Sources A systematic search of MEDLINE, EMBASE and Cochrane Library databases, restricted to English language up to June 1, 2012, was performed to identify potentially relevant studies. Study Selection Only randomized controlled trials (RCT) and controlled trials that compared HDR to LDR brachytherapy in treatment of early-stage oral cancer (stages I, II and III) were of interest. Data Extraction and Synthesis Two investigators independently extracted data from retrieved studies and controversies were solved by discussion. Meta-analysis was performed using RevMan 5.1. One RCT and five controlled trials (607 patients: 447 for LDR and 160 for HDR) met the inclusion criteria. The odds ratio showed no statistically significant difference between LDR group and HDR group in terms of local recurrence (OR?=?1.12, CI 95% 0.62–2.01), overall mortality (OR?=?1.01, CI 95% 0.61–1.66) and Grade 3/4 complications (OR?=?0.86, CI 95% 0.52–1.42). Conclusions This meta-analysis indicated that HDR brachytherapy was a comparable alternative to LDR brachytherapy in treatment of oral cancer. HDR brachytherapy might become a routine choice for early-stage oral cancer in the future. PMID:23762369

Zhang, Dongsheng

2013-01-01

60

The effects of food and divided dosing on the bioavailability of oral vinorelbine  

Microsoft Academic Search

The effects of food and divided dosing on the bioavailability of a liquid-filled gelatin capsule formulation of vinorelbine\\u000a (Navelbine), a semisynthetic vinca alkaloid with broad clinical activity, was evaluated in patients with advanced solid tumors.\\u000a A group of 13 patients were randomized to treatment with the oral formulation at the recommended phase II dose of 80?mg\\/m2?per?week either in the fasting

Eric K. Rowinsky; V. Sol Lucas; Ai-Ly Y. Hsieh; William A. Wargin; John A. Hohneker; Barbara Lubejko; Susan E. Sartorius; Ross C. Donehower

1996-01-01

61

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

PubMed Central

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

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

2014-01-01

62

Telavancin for hospital-acquired pneumonia: clinical response and 28-day survival.  

PubMed

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

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

2014-01-01

63

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

PubMed Central

Objective: To study the efficacy of oral carvedilol in acute treatment of atrial fibrillation (AF) with fast ventricular rate. Materials and Methods: In an open-label, single-arm trial, oral carvedilol was administered to 35 patients of AF in escalating doses from 3.125 mg o.d. to 12.5 mg b.i.d. Results: A successful result was seen in 25 patients (71.4%) with 4 converting to sinus rhythm, rate control to less than 90 bpm in 16 and a 20% rate reduction in 5 patients. Two patients developed hypotension needing withdrawal of the drug. Conclusion: Escalating doses of oral carvedilol can be effectively and safely used in the acute treatment of AF with fast ventricular rate. PMID:25422563

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

2014-01-01

64

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...

65

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

E-print Network

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

Paris-Sud XI, Université de

66

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

Microsoft Academic Search

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

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

2006-01-01

67

Low-dose oral or non-oral hormone therapy: effects on C-reactive protein and atrial natriuretic peptide in menopause.  

PubMed

Abstract Objective To assess the effects of oral low-dose and non-oral hormone therapy (HT) on ultra-sensitive C-reactive protein (CRP), atrial natriuretic peptide (ANP), and cardiovascular risk factors in postmenopause. Methods In this randomized, cross-over study, 44 recently postmenopausal women, with no clinical evidence of cardiovascular disease, received oral low-dose HT (estradiol 1 mg + drospirenone 2 mg/day) for 3 months. Forty-two patients received non-oral, conventional HT (1.5 mg/day percutaneous 17?-estradiol gel or equivalent for nasal route) for 3 months followed by 200 mg/day micronized progesterone by the vaginal route (14 days during each menstrual period). After 3 months, patients were crossed over without washout. Post-HT vs. pre-HT measures were determined: lipids, glucose, body mass index, waist circumference, fibrinogen, CRP-stratified levels, and ANP levels. The study was registered at clinical trials.gov (NCT01432028). Results The mean age was 51 ± 3 years and the mean time since the menopause was 22 ± 10 months. CRP-stratified high levels decreased in a higher number of non-oral HT patients, who moved to intermediate and low levels (p = 0.02). No effect of HT was observed on ANP levels (baseline 67.4 (18.4-104.5), low-dose oral 43.5 (14.4-95.9), non-oral 39.8 (15.5-67.5) pg/ml). Markers of endothelial function did not worsen with either low-dose oral or non-oral HT: von Willebrand factor (baseline 118 ± 37%, low-dose oral 119 ± 38%, non-oral 108 ± 3%, p < 0.01), fibrinogen (baseline 356 ± 58 mg/dl; low-dose oral 343 ± 77 mg/dl; non-oral 326 ± 71 mg/dl, p < 0.01). Conclusions Low-dose oral and non-oral HT for 6 months had neutral or beneficial effects in recently postmenopausal women with no clinical evidence of cardiovascular disease. PMID:25017924

Casanova, G; Dos Reis, A M; Spritzer, P M

2015-02-01

68

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

PubMed

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

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

2014-11-01

69

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

PubMed

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

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

2012-10-01

70

Pharmacokinetics of single-dose oral ciprofloxacin in patients undergoing chronic ambulatory peritoneal dialysis.  

PubMed Central

The prevention and treatment of peritonitis in patients undergoing peritoneal dialysis is often complicated by several factors, including nephrotoxicity, requirement for hospitalization, parenteral antibiotic therapy, and infection caused by resistant microorganisms. Ciprofloxacin, a new carboxyquinolone derivative, may offer the advantages of oral administration, a broad spectrum of antibacterial activity, and safety for the management of these patients. The pharmacokinetics of ciprofloxacin in serum and peritoneal fluid of eight adult patients undergoing chronic ambulatory peritoneal dialysis (CAPD) were investigated. Each patient ingested a single 750-mg dose of ciprofloxacin, and drug concentrations were measured by high-pressure liquid chromatography in serum and peritoneal fluid for 48 h after the dose. Serum concentrations reached a mean peak of 3.6 micrograms/ml 1 to 2 h after the oral dose. The mean terminal serum half-life was 16.8 h, and the mean peritoneal fluid/serum concentration ratio was 0.64. The mean peak ciprofloxacin concentration in peritoneal fluid was 1.3 micrograms/ml, and the bioactivity of the drug in peritoneal fluid was confirmed. These data indicated that therapeutic concentrations of ciprofloxacin against bacterial pathogens commonly associated with peritonitis in CAPD patients may be achievable in the peritoneal fluid after oral administration to patients undergoing CAPD. In addition, the pharmacokinetic data provide guidelines for further clinical studies of oral ciprofloxacin in CAPD patients. PMID:2944477

Shalit, I; Greenwood, R B; Marks, M I; Pederson, J A; Frederick, D L

1986-01-01

71

Pharmacokinetics of metamizol metabolites in healthy subjects after a single oral dose of metamizol sodium.  

PubMed

The linearity of the pharmacokinetics of the metamizol metabolites 4-methyl-amino-antipyrine (4-MAA), 4-amino-antipyrine (4-AA), 4-formyl-aminoantipyrine (4-FAA), and 4-acetyl-amino-antipyrine (4-AcAA) has been studied after administration to 15 healthy male volunteers of single oral doses of 750, 1500, and 3000 mg metamizol. The trial was open, randomized, and cross-over, with a one-week interval between dosing days. Metabolite concentrations in serum and urine were measured using reverse-phase HPLC. The mean Cmax of 4-MAA increased linearly with dose whereas its AUC was not proportional to dose after administration of 1500 and 3000 mg. With 4-AA, the increase in mean Cmax was linear, but the increase in AUC was not. The increases in mean Cmax and AUC for 4-FAA after doses of 1500 and 3000 mg were not proportional to the dose. The increases in mean Cmax and AUC for 4-AcAA were roughly proportional to the increase in dose. There were no significant differences in renal clearance between doses for any of the four metabolites. The observed non-linearities reflect the saturability of metabolic pathways. However, although they were statistically significant, the deviations from linearity were marginal and should not be of clinical relevance to the analgesic efficacy of metamizol in the dose range tested. PMID:2328750

Vlahov, V; Badian, M; Verho, M; Bacracheva, N

1990-01-01

72

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

NASA Technical Reports Server (NTRS)

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

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

1975-01-01

73

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

PubMed Central

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

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

2015-01-01

74

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

75

Enterobacteriaceae suppression by three different oral doses of polymyxin E in human volunteers.  

PubMed Central

Polymyxin E is frequently used as an oral drug for flora suppression of the gastrointestinal canal. The suppression effect is dose dependent because polymyxin E is moderately inactivated by faecal and food compounds. Three oral polymyxin E doses (150, 300, 600 mg daily) were given to six volunteers for 6 days. The Enterobacteriaceae suppression effect was compared by means of the suppression index i.e. ratio of total number of faecal samples free of Enterobacteriaceae to the total number of faecal samples. The impact on the indigenous (mostly anaerobic) flora was measured in four ways: (i) beta-aspartylglycine content; (ii) volatile fatty acid pattern; (iii) yeast overgrowth and (iv) Streptococcus faecalis decrease. Enterobacteriaceae suppression was most successful during 600 mg oral polymyxin E (suppression indices during 150, 300 and 600 mg were 0.32, 0.55 and 0.89 respectively). None of the four markers of indigenous flora alterations were positive. However, using this dosage half of the volunteers suffered rather severe gastrointestinal side-effects. Oral polymyxin E in a dosage of minimum 600 mg daily seems to possess the ideal properties of a flora suppression agent, if the gastrointestinal side-effects could be mitigated. PMID:3378584

van Saene, J. J.; van Saene, H. K.; Tarko-Smit, N. J.; Beukeveld, G. J.

1988-01-01

76

The treatment of advanced renal cell cancer with high-dose oral thalidomide  

Microsoft Academic Search

Thalidomide is reported to suppress levels of several cytokines, angiogenic and growth factors including TNF-?, basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). The resulting anti-angiogenic, immunomodulatory and growth suppressive effects form the rationale for investigating thalidomide in the treatment of malignancies. We have evaluated the use of high-dose oral thalidomide (600 mg daily) in

J Stebbing; C Benson; T Eisen; L Pyle; K Smalley; H Bridle; I Mak; F Sapunar; R Ahern; M E Gore

2001-01-01

77

Effect of Niprisan® on single oral dose pharmacokinetics of paracetamol in rats  

Microsoft Academic Search

Summary  The single oral dose pharmacokinetics of paracetamol was studied alone and after coadministration with NIPRISAN® In rats.\\u000a Paracetamol concentrations were measured in rat plasma using UV-spectrophotometer and the data were fitted into an open two-compartment\\u000a pharmacokinetic model using the computer program (STATIS® Version 3.0). Results indicated no significant difference in the\\u000a absorption of paracetamol between study and control groups but

B. Adzu; M. Garba; A. Haruna; M. Maman; C. Wambebe; K. Gamaniel

2001-01-01

78

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

PubMed

The objective of this study was to evaluate the pharmacokinetic properties and physiologic effects of a single oral dose of alprazolam in horses. Seven adult female horses received an oral administration of alprazolam at a dosage of 0.04 mg/kg body weight. Blood samples were collected at various time points and assayed for alprazolam and its metabolite, ?-hydroxyalprazolam, using liquid chromatography/mass spectrometry. Pharmacokinetic disposition of alprazolam was analyzed by a one-compartmental approach. Mean plasma pharmacokinetic parameters (±SD) following single-dose administration of alprazolam were as follows: Cmax 14.76 ± 3.72 ng/mL and area under the curve (AUC0-? ) 358.77 ± 76.26 ng·h/mL. Median (range) Tmax was 3 h (1-12 h). Alpha-hydroxyalprazolam concentrations were detected in each horse, although concentrations were low (Cmax 1.36 ± 0.28 ng/mL). Repeat physical examinations and assessment of the degree of sedation and ataxia were performed every 12 h to evaluate for adverse effects. Oral alprazolam tablets were absorbed in adult horses and no clinically relevant adverse events were observed. Further evaluation of repeated dosing and safety of administration of alprazolam to horses is warranted. PMID:25427652

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

2014-11-27

79

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

PubMed

Rufinamide is a third-generation antiepileptic drug, approved recently as an orphan drug for the treatment of Lennox-Gastaut syndrome. Although extensive research was conducted, its pharmacokinetics in rats was not described. This work addresses that area by describing in a rapid pharmacokinetic study the main pharmacokinetic properties of rufinamide at three different doses of 1mg/kg body weight (bw), 5mg/kgbw, and 20mg/kgbw. Furthermore, total brain concentrations of the drug were determined in order to characterize its brain-to-plasma partition coefficient. Adult Wistar male rats, weighing 200-450g, were administered rufinamide by intravenous and oral routes. Rufinamide concentrations from plasma samples and brain tissue homogenate were determined using a liquid chromatography-mass spectrometric method and pharmacokinetic parameters were calculated. The mean half-life was between 7 and 13h, depending on route of administration - intravenously administered drug was eliminated faster than orally administered drug. Mean (S.E.M.) total plasma clearance was 84.01±3.80ml/h/kg for intravenous administration, while the apparent plasma clearance for oral administration was 95.52±39.45ml/h/kg. The mean (S.E.M.) maximum plasma concentration reached after oral administration of 1mg/kgbw and 5mg/kgbw was 0.89±0.09?g/ml and 3.188±0.71?g/ml, respectively. The median (range) time to reach maximum plasma concentration (tmax) was 4 (2-8)h. Mean (S.E.M.) brain-to-plasma concentration ratio of rufinamide was 0.514±0.036, consistent with the brain-to-plasma ratio calculated from the area under curves (AUC0-t) of 0.441±0.047. No influence of dose, route of administration, or post-dosing time was observed on brain-to-plasma ratio. PMID:25530452

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

2015-02-20

80

Pharmacokinetic and pharmacodynamic profile of donepezil HCl following multiple oral doses  

PubMed Central

Aim The aim of this study was to characterize the pharmacokinetics and pharmacodynamics of donepezil HCl, a new, chemically distinct and specific acetylcholinesterase (AChE) inhibitor for the treatment of Alzheimer’s disease, following multiple-dose administration. Methods This was a double-blind, randomized, placebo-controlled, multiple-dose study in healthy male volunteers (n =27). Three dose levels were investigated in sequential order: 1, 3 and 5 mg. Each dose was administered orally, once a day, for 21 consecutive days. Donepezil concentrations in plasma were quantified by HPLC. Pharmacodynamic activity was determined by the radioenzymatic measurement of erythrocyte membrane acetylcholinesterase (rbc-AChE) inhibition. Results The pharmacokinetic disposition of donepezil was observed to be dose proportional. The mean terminal disposition half-life was 79.5±19.0 h which resulted in a slow approach to steady state (14–21 days). A four- to sixfold increase in donepezil plasma concentration was observed during this time; however, no further increase was evident after achievement of steady state. The mean donepezil plasma concentration at steady state (Css) was 14.2 ng ml?1. Neither the rate of accumulation nor the rate of clearance was dose dependent. Inhibition of rbc-AChE was directly correlated with donepezil concentration over a wide concentration range, with the higher concentrations showing the expected hyperbolic relationship. Donepezil was well tolerated by all subjects with no clinically significant changes in laboratory or physical parameters observed at any dose. Conclusions The pharmacokinetics of donepezil were found to be dose proportional following the administration of multiple doses to healthy volunteers. A predictable relationship was also observed between plasma donepezil concentrations and rbc-AChE inhibition. The half-life of donepezil makes it suitable for once-daily dosing. PMID:9839759

Rogers, S L; Cooper, N M; Sukovaty, R; Pederson, J E; Lee, J N; Friedhoff, L T

1998-01-01

81

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. PMID:15521894

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

2004-01-01

82

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

PubMed Central

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

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

2014-01-01

83

Effect of single oral dose of tramadol on gastric secretions pH  

PubMed Central

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

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

2015-01-01

84

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

PubMed

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

Haney, J

2015-02-01

85

Effect of repeated oral therapeutic doses of methylphenidate on food intake and growth rate in rats.  

PubMed

Central nervous system stimulants are known to produce anorexia. Previous data suggest that methylphenidate can have variable effects on caloric intake and growth rate. A dose-response study was performed to monitor caloric intake, liquid intake and growth rate in rats following repeated administration of human oral therapeutic doses 2 mg/kg/day, 5mg/kg/day and 8mg/kg/day of methylphenidate. We found that food intake and water intake, increased in all weeks and at all doses used in the study. Growth rate increased more at higher dose (8mg/kg/day) and at low dose (2mg/kg/day) of methylphenidate in 1st and 2nd week whereas more decreased by the above doses in 3rd week, suggesting that food stimulation leads to initial increase in growth rate but long term administration of methylphenidate attenuate growth rate that is not due to modulation of appetite but may be due to anxiety and increased activity produce by stimulants. A possible role of DA, 5HT receptors in modulation of appetite and anxiety is discussed. PMID:25553710

Alam, Nausheen; Najam, Rahila

2015-01-01

86

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. PMID:2393268

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

1990-01-01

87

Pharmacokinetic and pharmacodynamic profile of donepezil HCl following single oral doses  

PubMed Central

Aim The aim of this study was to characterize the pharmacokinetic and pharmacodynamic profile of donepezil HCl, a chemically distinct and specific acetylcholinesterase (AChE) inhibitor for the treatment of Alzheimer’s disease, following administration of single oral doses. Methods This was a double-blind, randomized, single-dose, placebo-controlled, sequential-group, ascending-dose study in healthy male volunteers (n = 48). Six dose levels were investigated, ranging from 0.3 to 6.0 mg. Donepezil concentrations in plasma were determined by HPLC with UV detection. Pharmacodynamic activity was determined by the radioenzymatic measurement of erythrocyte membrane acetylcholinesterase (rbc-AChE) inhibition. Results The pharmacokinetic disposition of donepezil was observed to be both linear and dose proportional following single-dose administration. The mean peak plasma concentration (Cmax) of donepezil was observed at 4.1±1.5 h. The mean terminal disposition half-life was 81.5±22.0 h. The post-absorption phase of the plasma concentration–time curves for the 4.0 mg and 6.0 mg doses appeared to be biphasic, but the rate of donepezil clearance was independent of dose. Plasma concentrations for the 0.3, 0.6 and 0.9 mg dose groups were generally below the level of HPLC detection (2.0 ng ml?1), preventing accurate characterization of these doses. A direct correlation was observed between plasma donepezil concentrations and extent of AChE inhibition. For the 4.0 and 6.0 mg donepezil dose groups, maximal AChE inhibition (Emax) ranged from 33% to 35% and there was significant correlation between AChE inhibition and donepezil plasma concentration (P<0.005). Conclusions The pharmacokinetics of donepezil were found to be linear and dose proportional following the administration of single doses to healthy volunteers. A direct correlation was also observed between plasma donepezil concentrations and AChE inhibition. The extended half-life of donepezil makes it suitable for once-daily dosing. PMID:9839758

Rogers, S L; Friedhoff, L T

1998-01-01

88

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

PubMed Central

Background Fluralaner is a novel systemic ectoparasiticide for dogs providing long-acting flea- and tick-control after a single oral dose. This study investigated the safety of oral administration of fluralaner at 3 times the highest expected clinical dose to Multi Drug Resistance Protein 1 (MDR1(-/-)) gene defect Collies. Methods Sixteen Collies homozygous for the MDR1 deletion mutation were included in the study. Eight Collies received fluralaner chewable tablets once at a dose of 168 mg/kg; eight sham dosed Collies served as controls. All Collies were clinically observed until 28 days following treatment. Results No adverse events were observed subsequent to fluralaner treatment of MDR1(-/-) Collies at three times the highest expected clinical dose. Conclusions Fluralaner chewable tablets are well tolerated in MDR1(-/-) Collies following oral administration. PMID:24602342

2014-01-01

89

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

SciTech Connect

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

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

2009-03-01

90

Preclinical pharmacokinetic evaluation of resveratrol trimethyl ether in sprague-dawley rats: the impacts of aqueous solubility, dose escalation, food and repeated dosing on oral bioavailability.  

PubMed

Resveratrol trimethyl ether (trans-3,5,4'-trimethoxystilbene, RTE) is a naturally occurring and pharmacologically active resveratrol derivative. To evaluate its suitability as a drug candidate, a pharmacokinetic study was carried out in Sprague-Dawley rats with the emphasis to identify the impact of aqueous solubility, dose escalation, food, and repeated dosing on its oral bioavailability. Upon single intravenous administration (5 mg/kg), RTE displayed moderate clearance (35.5 ± 5.3 mL/min/kg) and a fairly long terminal elimination half-life (511 ± 136 min); dose escalation (5-20 mg/kg) did not cause nonlinear pharmacokinetics. When given orally in suspension (60 mg/kg), RTE was poorly absorbed with negligible bioavailability (< 1.5%), fasting further decreased its bioavailability (<1%). However, when administered in a solution formulated with randomly methylated-?-cyclodextrin (15 mg/kg), RTE was rapidly absorbed with good bioavailability (46.5 ± 4.8%). Dose escalation resulted in increased bioavailability (64.6 ± 8.0%) at the dose of 60 mg/kg. Repeated RTE dosing (7 daily oral doses) did not alter the clearance, terminal elimination half-life and bioavailability. In summary, the aqueous solubility of RTE was a barrier to oral absorption; repeated RTE administrations did not alter its pharmacokinetic profiles; as RTE possessed appropriate pharmacokinetic profiles, further investigation on RTE as a drug candidate is warranted. PMID:21520090

Lin, Hai-Shu; Ho, Paul C

2011-10-01

91

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

PubMed Central

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

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

2014-01-01

92

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

2013-03-01

93

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

PubMed Central

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

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

1986-01-01

94

Pharmacokinetics of low-dose oral modified release, soluble and intravenous aspirin in man, and effects on platelet function.  

PubMed

The pharmacokinetics of low-dose aspirin and the resulting salicylic acid were studied in 6 healthy volunteers. Each received a single 50-mg dose of (1) oral modified release capsules, (2) oral solution and (3) intravenous solution. The volunteers also received 50 mg modified release capsules daily for 6 days to determine the effect on collagen, ADP and arachidonate induced platelet aggregation and thromboxane production, and to compare the pharmacokinetics after repeated dosing with the parameters obtained after the single dose. The formulation and route of administration profoundly influenced several pharmacokinetic parameters for aspirin: the maximum concentration (Cmax, ng.ml-1) was 221 and 191 after modified release for single and chronic dosing respectively, 1323 after the oral solution and 6000 after intravenous injection; the time to achieve this maximum concentration (tmax, h) was 3.42 and 3.02 after modified release for single and chronic dosing respectively, and 0.29 after the oral solution; the area under the plasma drug concentration versus time curve (AUC, microgram.h.ml-1) was 0.38 and 0.27 after modified release single and chronic dosing respectively, 0.68 after the oral solution and 1.57 after intravenous injection. The elimination of aspirin after the two solutions was at least biphasic. The terminal phase rate constant ranged from 1.52 h-1 after intravenous injection to 1.88 h-1 after the oral modified release form. The absorption of the oral forms of aspirin was complete as reflected by the total recovery of the doses as salicylic acid in urine.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:3181281

Bochner, F; Williams, D B; Morris, P M; Siebert, D M; Lloyd, J V

1988-01-01

95

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

PubMed

Sulfolane is a widely used industrial solvent that is often used for gas treatment (sour gas sweetening; hydrogen sulfide removal from shale and coal processes, etc.), and in the manufacture of polymers and electronics, and may be found in pharmaceuticals as a residual solvent used in the manufacturing processes. Sulfolane is considered a high production volume chemical with worldwide production around 18 000-36 000 tons per year. Given that sulfolane has been detected as a contaminant in groundwater, an important potential route of exposure is tap water ingestion. Because there are currently no federal drinking water standards for sulfolane in the USA, we developed a noncancer oral reference dose (RfD) based on benchmark dose modeling, as well as a tap water screening value that is protective of ingestion. Review of the available literature suggests that sulfolane is not likely to be mutagenic, clastogenic or carcinogenic, or pose reproductive or developmental health risks except perhaps at very high exposure concentrations. RfD values derived using benchmark dose modeling were 0.01-0.04?mg?kg(-1) per day, although modeling of developmental endpoints resulted in higher values, approximately 0.4?mg?kg(-1) per day. The lowest, most conservative, RfD of 0.01?mg?kg(-1) per day was based on reduced white blood cell counts in female rats. This RfD was used to develop a tap water screening level that is protective of ingestion, viz. 365 µg l(-1). It is anticipated that these values, along with the hazard identification and dose-response modeling described herein, should be informative for risk assessors and regulators interested in setting health-protective drinking water guideline values for sulfolane. PMID:22936336

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

2013-12-01

96

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

PubMed

Subinvolution of placental sites (SIPS) is the major cause of persistent sanguineous vaginal discharge after parturition in the bitch. Spontaneous remission is common but may take several months, and hence, medical therapy to end the discharge is often requested. In this retrospective study, we evaluated the effect of treatment for SIPS with low oral doses of a progestagen. Nine bitches with SIPS, but otherwise clinically healthy, were found in the computer database of the Department of Clinical Sciences of Companion Animals. Seven of these bitches were treated with low oral doses of a progestagen (megestrol acetate, 0.1 mg/kg body weight (bw) once daily for the 1st week, then 0.05 mg/kg bw once daily for the 2nd week). The other two bitches were untreated. Treatment results were evaluated by a telephone questionnaire. Progestagen treatment was successful in all of the treated dogs; sanguineous vaginal discharge stopped within the treatment period. One of the two untreated dogs remained symptomatic until the next oestrus, approximately 120 days after parturition, and the other remained symptomatic until 6 weeks before the start of the next pro-oestrus, 270 days after parturition. No side effects of the progestagen treatment were observed. Subsequent gestations, parturitions and puerperal periods of 5 mated bitches were uneventful. One bitch did not become pregnant after mating. In conclusion, the results of this study indicate that oral administration of low doses of progestagen for 2 weeks is effective in stopping persistent sanguineous vaginal discharge in bitches with SIPS, with neither side effects nor reduced subsequent fertility. PMID:23565694

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

2013-10-01

97

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

PubMed Central

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

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

2000-01-01

98

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

PubMed

Changes in the hardness, dissolution, and the disintegration time of brand name and generic preparations (6 preparations) of famotidine orally disintegrating tablets were investigated. Tablets had been stored in a thermo-hygrostat-controlled environment set to simulate the home conditions of patients up to 8 weeks after unit-dose packaging. Among the tablets in unit-dose packaging prepared immediately after blister packs (BP) were opened, one generic had decreased hardness to less than 2.0 kg after 1 week, 55.1% of its initial hardness value, and a shorter disintegration time of about 1/5 of its initial disintegration time. Generics met the standard for dissolution 8 weeks after unit-dose packaging. The decrease in hardness after unit-dose packaging is presumed to be associated with additives, and particularly the types and amounts of binding agents, but evidence of this association was lacking. The hardness noted in drug interview forms (IFs) and the state of sales of bulk tablet packages must be determined to facilitate the selection of generics that remain hard even after unit-dose packaging. PMID:23229147

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

2012-10-01

99

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

Microsoft Academic Search

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

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

100

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

PubMed

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

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

2014-04-01

101

Single dose oral ketoprofen and dexketoprofen for acute postoperative pain in adults  

PubMed Central

Background Ketoprofen is a non-selective non-steroidal anti-inflammatory drug (NSAID) used to treat acute and chronic painful conditions. Dexketoprofen is the (S)-enantiomer, which is believed to confer analgesia. Theoretically dexketoprofen is expected to provide equivalent analgesia to ketoprofen at half the dose, with a consequent reduction in gastrointestinal adverse events. Objectives To assess efficacy, duration of action, and associated adverse events of single dose oral ketoprofen and dexketoprofen in acute postoperative pain in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to August 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered ketoprofen and dexketoprofen in adults with moderate to severe acute postoperative pain. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number-needed-to-treat-to-benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results Fourteen studies compared ketoprofen (968 participants) at mainly 25 mg and 50 mg with placebo (520 participants). Seven studies compared dexketoprofen (681 participants) at mainly 10 mg to 25 mg with placebo (289 participants). Studies were of adequate reporting quality, and participants had pain following dental, orthopaedic, obstetric, gynaecological and general surgery. There was considerable clinical heterogeneity between studies in dental and other types of surgery, particularly bunionectomy, which limited analysis. Ketoprofen at doses between 12.5 mg and 100 mg produced NNTs for at least 50% pain relief over 4 to 6 hours of 2.4 to 3.3. For dental studies only there was a trend to more efficacy at higher doses, with NNT decreasing from 2.4 at 12.5 mg to 1.6 at 100 mg. Dexketoprofen at doses of 10/12.5 mg and 20/25 mg produced NNTs for at least 50% pain relief over 4 to 6 hours of 3.2 and 3.6, with no obvious dose response. Significantly fewer participants used rescue medication with ketoprofen and dexketoprofen than placebo. The median time to remedication was about 5 hours with ketoprofen and 4 hours with dexketoprofen. The expected equivalent efficacy with a half dose of dexketoprofen compared to ketoprofen was not demonstrated. Adverse events were uncommon with both drugs, and not significantly different from placebo. Authors’ conclusions Ketoprofen at doses of 25 mg to 100 mg is an effective analgesic in moderate to severe acute postoperative pain with an NNT for at least 50% pain relief of 3.3 with a 50 mg dose. This is similar to that of commonly used NSAIDs such as ibuprofen (NNT 2.5 for 400 mg dose) and diclofenac (NNT 2.7 at 50 mg dose). Duration of action is about 5 hours. Dexketoprofen is also effective with NNTs of 3.2 to 3.6 in the dose range 10 mg to 25 mg. Both drugs were well tolerated in single doses. PMID:19821407

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

2014-01-01

102

Pharmacokinetics of Solithromycin (CEM-101) after Single or Multiple Oral Doses and Effects of Food on Single-Dose Bioavailability in Healthy Adult Subjects?  

PubMed Central

The pharmacokinetics of orally administered solithromycin (CEM-101), a novel fluoroketolide, were evaluated in healthy subjects in three phase 1 studies. In two randomized, double-blinded, placebo-controlled studies, escalating single oral doses of solithromycin (50 to 1,600 mg) or seven oral daily doses (200 to 600 mg) of solithromycin were administered. A third study evaluated the effects of food on the bioavailability of single oral doses (400 mg) of solithromycin. Following single doses, the median time to peak concentration (Tmax) ranged from 1.5 h to 6 h. The mean maximum measured plasma concentration (Cmax) ranged from 0.0223 ?g/ml to 19.647 ?g/ml, and the area under the concentration-versus-time curve from time zero to time t (AUC0–t) ranged from 0.0402 ?g · h/ml to 28.599 ?g · h/ml. There was no effect of high-fat food on the oral bioavailability of solithromycin. In the multiple-dose study, after 7 days, the mean maximum measured plasma solithromycin concentration at steady-state (Cmax,ss) ranged from 0.248 to 1.50 ?g/ml, and the area under the concentration-versus-time curve over the final dosing interval (AUC?) ranged from 2.310 to 18.41 ?g · h/ml. These values indicate a greater than proportional increase in exposure at 200 and 400 mg but a proportional exposure at 600 mg. Median Tmax values remained constant between day 1 and day 7. Moderate accumulation ratios of solithromycin were observed after 7 days of dosing. All dose regimens of solithromycin were well tolerated, and no discontinuations due to an adverse event occurred. The human pharmacokinetic profile and tolerability of solithromycin, combined with its in vitro potency and efficacy in animal models against a broad spectrum of pathogens, support further development of solithromycin. PMID:21282444

Still, J. Gordon; Schranz, Jennifer; Degenhardt, Thorsten P.; Scott, Drusilla; Fernandes, Prabhavathi; Gutierrez, Maria J.; Clark, Kay

2011-01-01

103

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

PubMed

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

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

2010-06-01

104

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. PMID:23986622

Sinha, Rakesh; Rawat, Sudarshan

2013-01-01

105

Influence of phenytoin and phenobarbital on the disposition of a single oral dose of clonazepam.  

PubMed

Clonazepam (CZP) was measured in the plasma of eight subjects for 48 hr after a 0.03-mg/kg oral dose. After pretreatment for 19 days with phenytoin (DPH, 4.3 mg/kg/day), plasma CZP concentrations were determined in the same subjects after another 0.03 mg/kg oral dose of CZP. The same protocol was followed in eight additional subjects using phenobarbital (PB, 1.4 mg/kg/day) instead of DPH. DPH pretreatment lowered mean plasma CZP concentration in 8 of the 12 time points. DPH pretreatment increased CZP clearance by 46% to 58% and decreased CZP half-life (t1/2) by 31%. Both changes were statistically significant. After PB pretreatment the mean plasma CZP concentration was lowered by an average of 11%, but the decrease was statistically significant for only 1 of the 12 time points. PB decreased mean CZP t1/2 by 11% and increased CZP clearance by 19% to 24%, but only the increase in clearance was statistically significant. Both DPH and PB increased CZP clearances and decreased the areas under the plasma concentration-time curves without altering the volumes of distribution. This observation is consistent with induction of CZP metabolism. The overall effect of DPH (4.3 mg/kg/day) was greater than the effect of PB (1.4 mg/kg/day). Neither the DPH or PB had a significant effect on the extent of CZP protein binding. PMID:7408397

Khoo, K C; Mendels, J; Rothbart, M; Garland, W A; Colburn, W A; Min, B H; Lucek, R; Carbone, J J; Boxenbaum, H G; Kaplan, S A

1980-09-01

106

Pharmacokinetics and metabolism of BIBF 1120 after oral dosing to healthy male volunteers.  

PubMed

The pharmacokinetics and metabolism of BIBF 1120, an oral triple angiokinase inhibitor targeting vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), and fibroblast growth factor receptor (FGFR), were studied in healthy male volunteers (n?=?8) who had received a single oral dose of 100?mg [(14)C]-radiolabelled BIBF 1120 administered as solution. BIBF 1120 was well-tolerated and rapidly absorbed; median time to reach maximum plasma concentrations was 1.3?h and gMean terminal half-life was 13.7?h. A relatively high apparent total body clearance and volume of distribution possibly indicated a high tissue distribution. Plasma concentrations of BIBF 1120 plus carboxylate metabolite BIBF 1202 were lower than the total [(14)C]-radioactivity in plasma, indicating presence of additional metabolites. Total recovery in excreta was 94.7% 1 week post-dose; mass balance was considered complete after 96?h. BIBF 1120 and metabolites were mainly excreted via faeces. The major metabolic pathway for BIBF 1120 was methyl ester cleavage to BIBF 1202. Subsequently, the free carboxyl group of BIBF 1202 was glucuronidated to 1-O-acylglucuronide. Pathways of minor importance were oxidative N-demethylation to yield BIBF 1053, and oxidation of the piperazine moiety and conjugation. Glucuronidation of the parent drug and formylation of the secondary aliphatic amine of the piperazine ring played a minor role. PMID:21204634

Stopfer, Peter; Rathgen, Karin; Bischoff, Daniel; Lüdtke, Silke; Marzin, Kristell; Kaiser, Rolf; Wagner, Klaus; Ebner, Thomas

2011-04-01

107

Treatment of Plane Warts with a Low-Dose Oral Isotretinoin  

PubMed Central

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

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

2012-01-01

108

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

PubMed

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

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

2014-05-01

109

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

PubMed

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

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

2013-01-01

110

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

PubMed Central

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

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

2012-01-01

111

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

PubMed Central

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

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

2014-01-01

112

Orally administered cefpodoxime proxetil for treatment of uncomplicated gonococcal urethritis in males: a dose-response study.  

PubMed Central

An open-label, dose-response study of cefpodoxime proxetil (CPD), an expanded-spectrum cephalosporin, was conducted with 58 males with uncomplicated Neisseria gonorrhoeae infections with single doses of 600, 400, 200, 100, or 50 mg of CPD administered orally by tablet. CPD eradicated N. gonorrhoeae in all 50 evaluable patients (10 per group) at all doses studied. Eight of the isolates eradicated were beta-lactamase-producing organisms. Two patients reported three side effects, nausea, vomiting, and diarrhea, which were mild and resolved without intervention or sequelae. There were no clinically remarkable drug-related changes in vital signs or clinical laboratory assays. Results show that single oral doses of CPD are an effective and well-tolerated treatment for uncomplicated N. gonorrhoeae infection in males at doses as low as 50 mg. PMID:1416861

Novak, E; Paxton, L M; Tubbs, H J; Turner, L F; Keck, C W; Yatsu, J

1992-01-01

113

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

Technology Transfer Automated Retrieval System (TEKTRAN)

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

114

Pharmacokinetics of rebaudioside A and stevioside after single oral doses in healthy men.  

PubMed

This randomized, double-blind, cross-over study assessed the comparative pharmacokinetics of steviol and steviol glucuronide following single oral doses of rebaudioside A and stevioside in healthy adult male subjects. Steviol glucuronide appeared in the plasma of all subjects after administration of rebaudioside A or stevioside, with median tmax values of 12.0 and 8.00h post-dose, respectively. Steviol glucuronide was eliminated from the plasma, with similar t1/2 values of approximately 14h for both compounds. Administration of rebaudioside A resulted in a significantly (approximately 22%) lower steviol glucuronide geometric mean Cmax value (1472ng/mL) than administration of stevioside (1886ng/mL). The geometric mean AUC0-t value for steviol glucuronide after administration of rebaudioside A (30,788ngh/mL) was approximately 10% lower than after administration of stevioside (34,090ngh/mL). Steviol glucuronide was excreted primarily in the urine of the subjects during the 72h collection period, accounting for 59% and 62% of the rebaudioside A and stevioside doses, respectively. No steviol glucuronide was detected in feces. Pharmacokinetic analysis indicated that rebaudioside A and stevioside underwent similar metabolic and elimination pathways in humans with steviol glucuronide excreted primarily in the urine and steviol in the feces. No safety concerns were noted as determined by reporting of adverse events, laboratory assessments of safety or vital signs. PMID:18555578

Wheeler, A; Boileau, A C; Winkler, P C; Compton, J C; Prakash, I; Jiang, X; Mandarino, D A

2008-07-01

115

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

2001-01-01

116

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

Microsoft Academic Search

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

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

2010-01-01

117

Immunogenicity in Peruvian volunteers of a booster dose of oral cholera vaccine consisting of whole cells plus recombinant B subunit.  

PubMed Central

Forty-nine subjects received two doses of oral cholera vaccine consisting of whole cells plus recombinant B subunit; this was followed by a booster dose one year later. After the primary series, a significant (greater than twofold) increase in the levels of vibriocidal, anti-cholera toxin immunoglobulin G and anti-cholera toxin immunoglobulin A antibodies occurred in 54, 88, and 81% of the subjects, respectively. Within one year, titers decreased to levels close to baseline. A booster dose then induced rises to those which occurred after the initial vaccination. The results suggest that 1-year booster doses may be necessary to maintain immunity against cholera in Latin America. PMID:7642315

Begue, R E; Castellares, G; Cabezas, C; Sanchez, J L; Meza, R; Watts, D M; Taylor, D N

1995-01-01

118

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

119

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

PubMed Central

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

Maia, Hugo; Haddad, Clarice; Casoy, Julio

2014-01-01

120

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

2012-10-15

121

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

PubMed Central

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

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

2013-01-01

122

Stability of oral liquid penicillins in unit dose containers at various temperatures.  

PubMed

The effect of freezing on the stability of reconstituted, unit dose packaged oral amoxicillin trihydrate and ampicillin suspensions and penicillin V potassium solutions was studied. Powders for suspension or solution of the three penicillins were reconstituted according to manufacturers' directions to yield a concentration of 250 mg/5 ml. Samples of 5 ml then were stored in amber, screw-cap, glass vials at 25 C, 5 C, 0 C, -10 C or -20 C for 5, 10, 20, 30 or 60 days. The concentration of active constituents remaining after storage was determined spectrophotometrically. All three penicillins retained at least 90% of their original activity for at least 60 days when stored at -20 C. Ampicillin and pencillin V potassium retained at least 90% of their activity after 60 days of storage at -10 C but amoxicillin concentration decreased to 88% and 87% of initial concentration after 60 days storage at -10 C and 0 C, respectively. Degradation appeared to be by a zero-order process for amoxicillin and ampicillin and by a first-order process for penicillin V potassium. It appears that oral solutions of amoxicillin, ampicillin and penicillin V potassium can be effectively stored for at least 50 days in a freezer at -10 C with little loss of activity. PMID:105636

Allen, L V; Lo, P

1979-02-01

123

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

PubMed Central

Background With socio-economic changes, dentists and maxillofacial surgeons are more and more faced with medically compromised patients. Especially, the admission of antirheumatic drugs has increased remarkably. So dentists and maxillofacial surgeons should be aware of related adverse reactions that affect the craniofacial region. To identify possible cellular effects of disease modifying antirheumatic drugs (DMARDs) we investigated the influence of methotrexate (MTX) on human umbilical vein endothelial cells (HUVECs). Methods HUVECs were incubated with various concentrations of MTX, corresponding to serum concentrations found in rheumatoid arthritis (RA) patients. The effect of MTX on cell proliferation, differentiation as well as mitochondrial activity was measured by use of immunostaining, cell counting and 3-(4, 5-dimethylthiazol-2-yl)- 2, 5-diphenyltetrazolium bromide (MTT) assay. Results All samples incubated with MTX (1-1000 nM) showed significantly decreased cell viability when compared to controls. Cells were less proliferating, but did not lose their ability to synthesize endothelial proteins. A slight dose dependency of inhibiting effects was demonstrated. The observed differences between control and sample groups were rising with longer duration. Conclusion Because of the crucial role of endothelial cells and their precursor cells in wound healing, a negative influence of MTX on oral health has to be supposed, correlating to clinical observations of adverse reactions in the oral cavity, such as ulcerative or erosive lesions. PMID:24884884

2014-01-01

124

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

PubMed

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

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

2014-12-01

125

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

PubMed

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

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

2014-05-01

126

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

PubMed Central

High concentrations of hexavalent chromium [Cr(VI)] in drinking water induce villous cytotoxicity and compensatory crypt hyperplasia in the small intestines of mice (but not rats). Lifetime exposure to such cytotoxic concentrations increases intestinal neoplasms in mice, suggesting that the mode of action for Cr(VI)-induced intestinal tumors involves chronic wounding and compensatory cell proliferation of the intestine. Therefore, we developed a chronic oral reference dose (RfD) designed to be protective of intestinal damage and thus intestinal cancer. A physiologically based pharmacokinetic model for chromium in mice was used to estimate the amount of Cr(VI) entering each intestinal tissue section (duodenum, jejunum and ileum) from the lumen per day (normalized to intestinal tissue weight). These internal dose metrics, together with corresponding incidences for diffuse hyperplasia, were used to derive points of departure using benchmark dose modeling and constrained nonlinear regression. Both modeling techniques resulted in similar points of departure, which were subsequently converted to human equivalent doses using a human physiologically based pharmacokinetic model. Applying appropriate uncertainty factors, an RfD of 0.006?mg?kg–1?day–1 was derived for diffuse hyperplasia—an effect that precedes tumor formation. This RfD is protective of both noncancer and cancer effects in the small intestine and corresponds to a safe drinking water equivalent level of 210 µg l–1. This concentration is higher than the current federal maximum contaminant level for total Cr (100 µg l–1) and well above levels of Cr(VI) in US drinking water supplies (typically???5 µg l–1). © 2013 The Authors. Journal of Applied Toxicology published by John Wiley & Sons, Ltd. PMID:23943231

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

2014-01-01

127

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

PubMed Central

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

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

2015-01-01

128

Oral mucosal progenitor cells are potently immunosuppressive in a dose-independent manner.  

PubMed

Oral mucosal lamina propria progenitor cells (OMLP-PCs) are a novel, clonally derived PC population of neural crest origin with the potential to differentiate down both mesenchymal and neuronal cell lineages. In this study we aimed to determine the immunological properties of OMLP-PCs and to establish whether they would be suitable candidates for allogeneic tissue engineering and in the treatment of immune-related diseases. OMLP-PCs demonstrated no inherent immunogenicity with insignificant expression of costimulatory molecules (CD40, CD80, CD86, CD154, and CD178) or human leukocyte antigen (HLA) class II. OMLP-PCs required 7 days of stimulation with interferon-? (IFN-?) to induce cell surface expression of HLA II. Mixed lymphocyte cultures and mitogen stimulation demonstrated the potent immunosuppressive capability of OMLP-PCs in a contact-independent manner. Complete inhibition of lymphocyte proliferation was seen at doses as low as 0.001% OMLP-PCs to responder lymphocytes, while annexin V staining confirmed that this immunosuppressive effect was not due to the induction of lymphocyte apoptosis. These data demonstrate, for the first time, that OMLP-PC immunomodulation, unlike that for mesenchymal stem cells, occurs via a dose- and HLA II-independent mechanism by the release of immunosuppressive soluble factors and suggests these cells may have wide ranging potential in future immune-related therapies. PMID:21988324

Davies, Lindsay C; Lönnies, Helena; Locke, Matthew; Sundberg, Berit; Rosendahl, Kerstin; Götherström, Cecilia; Le Blanc, Katarina; Stephens, Phil

2012-06-10

129

Biological monitoring for exposure to methamidophos: A human oral dosing study.  

PubMed

An oral dose of the organophosphate insecticide methamidophos was administered to six volunteers at the acceptable daily intake (ADI, 0.004mg/kg). Urine was collected from the volunteers at timed intervals for 24h post-exposure. Methamidophos itself was quantified in urine using liquid/liquid extraction and LC-MS-MS analysis (detection limit 7nmol/L/1?g/L). Methamidophos exhibited a rapid elimination half-life of 1.1h, (range 0.4-1.5h). Mean metabolite levels found in 24h total urine collections (normalised for a 70kg volunteer) were 9.2nmol/L (range 1.0-19.1). One volunteer was anomalous; excluding this result the range was 6.7-19.1nmol/L, with a mean of 10.9nmol/L. Individual urine samples collected during the first 24h ranged from below the detection limit (ND) to 237nmol/L. The mean dose recovery excreted as methamidophos in urine was 1.1% (range 0.04-1.71%). Three environmental studies have been reported in the literature with levels ranging from ND to 66nmol/L. The number of positive results in all three studies was low (<1.5% of total samples analyzed). When compared with our results (ND - 237nmol/L), the studies suggest general population exposures are within the ADI. However, the very short half-life makes determining intermittent environmental exposures difficult. PMID:25310994

Garner, F; Jones, K

2014-12-01

130

Population pharmacokinetic model to analyze nevirapine multiple-peaks profile after a single oral dose.  

PubMed

Nevirapine (NVP) extensive data obtained after oral single dose administration of 200 mg in a crossover study involving 16 healthy subjects was used to develop a descriptive population pharmacokinetic model including drug recirculation, since secondary peaks were observed in plasma concentration-time profiles for all subjects. Through implementation of model event time feature in NONMEM 7.3.0, a simple mechanistic model physiologically consistent with the process of drug cycling was able to describe multiple peaks phenomena and quantify its pharmacokinetic parameters, achieving a better performance than its analogue conventional one. Absorption process, between subject and-between occasion variability of pharmacokinetic parameters was also assessed. Estimated mean fraction of NVP bioavailable dose undergoing recirculation process was 51.6 %, a magnitude which could hardly be explained by enterohepatic cycling. In this work we propose an alternative disposition process to explain NVP drug recirculation: gastric secretion with posterior intestinal reabsorption. Due to physicochemical and pharmacokinetic properties of the drug, this neglected phenomenon is more likely to explain the results obtained, and might be present in disposition of several basic drugs. PMID:25064169

Ibarra, Manuel; Vázquez, Marta; Fagiolino, Pietro

2014-08-01

131

Individualized aminophylline therapy in patients with obstructive airway disease: Oral dosage prediction from an intravenous test dose  

Microsoft Academic Search

Theophylline disposition after an intravenous test dose of aminophylline was determined in 83 subjects: 7 patients with and 58 without congestive heart failure (CHF), and 18 healthy controls. Based on the pharmacokinetics of theophylline in the individual, the oral dosage of aminophylline was scheduled to attain steady-state trough theophylline concentrations (Cpred) near the therapeutic margin. Significant differences in theophylline clearance

Y. Horai; T. Ishizaki; T. Sasaki; M. Watanabe; J. Kabe

1982-01-01

132

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

PubMed Central

Oral cannabinoids are taken for medicinal or recreational purposes, yet little is known about tolerance to their effects after high-dose extended exposure. The development of tolerance to effects of around-the-clock oral synthetic ?9-tetrahydrocannabinol (THC) (20 mg every 3.5–6 h) was evaluated in 13 healthy male daily cannabis smokers residing on a secure research unit: 40 mg on Day 1; 100 mg on Days 2–4; 120 mg on Days 5–6. Systolic and diastolic blood pressure (BP), heart rate, and symptoms of subjective intoxication (100 mm visual-analogue scales, VAS) were assessed the morning of Day 1 (before any oral THC), and on Days 2, 4 and 6, every 30 min for 3 h after the first morning THC dose. Morning subjective intoxication ratings increased from Days 1 to 2, and then declined on Days 4 and 6. The morning THC dose increased intoxication ratings on Day 2, but had less effect on Days 4 and 6, a pattern consistent with tolerance. THC lowered BP and increased heart rate over the six days. Plasma THC and 11-OH-THC concentrations increased significantly over the first five days of dosing. Six days of around-the-clock, oral THC produced tolerance to subjective intoxication, but not to cardiovascular effects. PMID:23074216

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

2013-01-01

133

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

PubMed

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

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

2014-03-01

134

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

135

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

PubMed

Oral cannabinoids are taken for medicinal or recreational purposes, yet little is known about tolerance to their effects after high-dose extended exposure. The development of tolerance to effects of around-the-clock oral synthetic ?9-tetrahydrocannabinol (THC) (20 mg every 3.5-6 h) was evaluated in 13 healthy male daily cannabis smokers residing on a secure research unit: 40 mg on Day 1; 100 mg on Days 2-4; 120 mg on Days 5-6. Systolic and diastolic blood pressure (BP), heart rate, and symptoms of subjective intoxication (100 mm visual-analogue scales, VAS) were assessed the morning of Day 1 (before any oral THC), and on Days 2, 4 and 6, every 30 min for 3 h after the first morning THC dose. Morning subjective intoxication ratings increased from Days 1 to 2, and then declined on Days 4 and 6. The morning THC dose increased intoxication ratings on Day 2, but had less effect on Days 4 and 6, a pattern consistent with tolerance. THC lowered BP and increased heart rate over the six days. Plasma THC and 11-OH-THC concentrations increased significantly over the first five days of dosing. Six days of around-the-clock, oral THC produced tolerance to subjective intoxication, but not to cardiovascular effects. PMID:23074216

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

2013-01-01

136

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

PubMed

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

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

2012-04-01

137

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

PubMed

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

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

2014-09-01

138

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

PubMed Central

Aim 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 replacement surgery and under development for treatment of venous thromboembolism. This study examined the safety, pharmacokinetics and pharmacodynamics of multiple dose apixaban. Method 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 and 10 and 25 mg once daily– with eight 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 twice daily 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 : trough ratios were lower for twice daily vs. once daily regimens. Clotting times showed dose-related increases tracking the plasma concentration–time profile. Conclusion Multiple oral doses of apixaban were safe and well tolerated over a 10-fold dose range, with pharmacokinetics with low variability and concentration-related increases in clotting time measures. 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

2013-01-01

139

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

PubMed

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

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

2013-06-01

140

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

PubMed

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

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

2013-06-01

141

Comparative kinetics of digoxin in serum and vitreous humor in a guinea pig model. II. Single oral dose administration.  

PubMed

In a continuation of work previously reported involving the comparative kinetics of digoxin in vitreous humor and serum after an intravenous dose, the present report describes the pharmacokinetics of digoxin in this model following the administration of a single oral dose. Serum and vitreous humor concentrations of digoxin were monitored by radioimmunoassay for 720 min after a single oral dose of 0.1 mg digoxin/kg. Serum concentrations peaked by 60 min and declined over the remaining observation period with a half-life of 360 min. Vitreous humor concentrations lagged behind the serum concentrations, peaked between 60 and 120 min, and then declined at a rate less than that of serum with convergence of concentration occurring in the 720-min samples. The vitreous humor-serum ratios ranged from a low of 0.003 (15 min) to a high of 0.98 at convergence. The impact of these findings upon forensic toxicologic practice is reviewed. PMID:1522706

Balkon, J; Donnelly, B

1992-01-01

142

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

PubMed

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

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

2014-01-01

143

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

PubMed Central

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

2014-01-01

144

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

PubMed

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

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

2014-12-01

145

A phase I and pharmacology study of an oral platinum complex, JM216: dose-dependent pharmacokinetics with single-dose administration  

Microsoft Academic Search

JM216 [bis-acetato-ammine-dichloro-cyclohexylamine-platinum (IV)] is an oral platinum complex with in vivo activity against murine and human tumor models and a lack of nephro- and neurotoxicity in rodents. During a phase I study of a single-dose schedule, JM216 was given in dry-filled hard gelatin capsules by mouth without hydration or diuresis. In all, 37 patients were given a total of 88

M. J. McKeage; Prakash Mistry; Janet Ward; Frances E. Boxall; Swee Loh; Ciaran O’Neill; Paul Ellis; Lloyd R. Kelland; Sarah E. Morgan; Barry Murrer; Pedro Santabarbara; Kenneth R. Harrap; Ian R. Judson

1995-01-01

146

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

PubMed Central

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

2011-01-01

147

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

PubMed

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

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

2012-01-01

148

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. PMID:23171393

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

2013-01-01

149

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

PubMed Central

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

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

2011-01-01

150

Relative bioavailability of different butamirate citrate preparations after single dose oral administration to 18 healthy volunteers.  

PubMed

Eighteen volunteers have been treated with different oral formulations of butamirate citrate according to 2 randomized 2-way crossover designs. In the first study (study I) the test preparation was a syrup (Demotussol Hustensirup, Demopharm), and the reference preparation was a syrup already marketed (Sinecod Sirup, Zyma SA). A test preparation (Demotussol Tabletten) was compared to a solution (Demotussol Hustentropfen) in the second study (study II). Within the 2 study periods the volunteers received single 45 mg doses of the test and the reference formulation, respectively. Blood samples have been drawn immediately prior to each administration and at 17 sampling points within 96 h after dosing. A wash-out period of 1 week was maintained between successive drug doses. The plasma concentration of one of the main metabolites, 2-phenylbutyric acid, was determined by a validated reversed-phase HPLC method with UV detection, with a lower limit of quantification of 50 ng/ml. The following mean values have been obtained in study I (syrup preparations) for the test: AUC0-infinity 46.9 micrograms x h/ml, Cmax of 1.77 micrograms/ml at 1.1 h, t1/2 28 h and after administration of the reference: AUC0-infinity 50.4 micrograms x h/ml, Cmax 1.86 micrograms/ml, tmax 1.5 h, t1/2 26 h. In study II the following mean values have been obtained for the test preparation (tablet): AUC0-infinity 54.7 micrograms x h/ml, Cmax of 1.88 micrograms/ml at 1.1 h, t1/2 27 h and for the reference (solution): AUC0-infinity 54.5 micrograms x h/ml, Cmax 1.94 micrograms/ml, tmax 1.1 h, t1/2 26 h. Both preparations have been proven to be bioequivalent to their corresponding references regarding extent and rate of absorption. PMID:9089001

Bohner, H; Janiak, P S; Nitsche, V; Eichinger, A; Schütz, H

1997-03-01

151

Dose-independent pharmacokinetics of clindamycin after intravenous and oral administration to rats: contribution of gastric first-pass effect to low bioavailability.  

PubMed

The pharmacokinetic parameters of clindamycin were evaluated after intravenous (at doses of 50, 100, and 200mg/kg) and oral (at doses of 75, 150, and 300mg/kg) administration of the drug to rats. The first-pass effect of clindamycin was also evaluated after intraportal, intragastric, and intraduodenal administration of the drug at a dose of 150mg/kg to rats. After both intravenous and oral administration of clindamycin, the pharmacokinetic parameters of the drug were dose-independent. Hence, the extent of absolute oral bioavailability (F) was also independent of oral doses. After oral administration of clindamycin (150mg/kg), 7.68% of oral dose was not absorbed up to 24h and F value was 28.2%. The gastric first-pass effect of clindamycin was 60.7% of oral dose. The first-pass effects of clindamycin in the lung, heart, intestine, and liver were almost negligible, if any, in rats. The low F of clindamycin in rats was mainly due to considerable gastric first-pass effect. Clindamycin was stable in rat gastric juice and various buffer solutions having pHs ranging from 1 to 13. The plasma-to-blood cells partition ratio of clindamycin was 7.59 in rat blood. The plasma protein binding of clindamycin in rats was 67.5%. PMID:17157458

Yang, Si H; Lee, Myung G

2007-03-01

152

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

PubMed

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

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

2014-06-16

153

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

PubMed

Chronic invasive aspergillosis of the sinus is frequently fatal in the absence of early surgical and chemotherapeutic intervention because of its invasion of vascular tissue. We attempted to control a case of inoperable invasive aspergillosis of the sinus with micafungin and itraconazole oral solution. We prescribed a daily oral dose of 400 mg of itraconazole, which is twice the usual dose, and monitored the serum concentration of the drug. Finally, we were able to control the spread of the lesion. This case indicates that combination therapy with micafungin and a daily dose of 400 mg itraconazole oral solution is an alternative treatment strategy for inoperable invasive aspergillosis of the sinus. PMID:25444671

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

2015-02-01

154

Combining diclofenac with acetaminophen or acetaminophen-codeine after oral surgery: A randomized, double-blind single-dose study  

Microsoft Academic Search

In a randomized double-blind study, 120 patients with moderate to strong pain after surgical removal of wisdom teeth were given the following in single oral doses: 100-mg enteric-coated diclofenac tablets; 1 g acetaminophen (INN, paracetamol); 1 g acetaminophen plus 60 mg codeine; 100-mg enteric-coated diclofenac tablets plus 1 g acetaminophen; or 100-mg enteric-coated diclofenac tablets plus 1 g acetaminophen plus

Else Kristine Breivik; Pĺl Barkvoll; Eva Skovlund

1999-01-01

155

Pharmacokinetics of Sulfadimethoxine and Sulfamethoxazole in Combination with Trimethoprim after Oral Single and Multiple-Dose Administration to Healthy Pigs  

Microsoft Academic Search

The pharmacokinetics were studied of sulfadimethoxine (SDM) or sulfamethoxazole (SMX) in combination with trimethoprim (TMP) administered as a single oral dose (25 mg + 5 mg per kg body weight) to two groups of 6 healthy pigs. The elimination half-lives of SMX and TMP were quite similar (2–3 h); SDM had a relatively long half-life of 13 h. Both sulfonamides

M. J. B. Mengelers; E. R. van Gogh; M. B. M. Huveneers; P. E. Hougee; H. A. Kuiper; A. Pijpers; J. H. M. Verheijden; A. S. J. P. A. M. van Miert

2001-01-01

156

Pharmacokinetics and clinical effects of alprazolam following single and multiple oral doses in patients with panic disorder.  

PubMed

The anxiolytic triazolobenzodiazepine alprazolam was administered to six male patients, aged 26 to 46 years, with panic disorder or agoraphobia (with panic attacks) to assess clinical effects and steady-state pharmacokinetics following multiple dosing at three levels: 3.0 mg/d, 6.0 mg/d, and 9.0 mg/d. Multiple-dose kinetics of alprazolam were compared with alprazolam disposition after a 1.0-mg oral dose in the same patients. Kinetic variables after the single dose were very similar to those reported previously for healthy young male volunteers. Mean values were peak plasma concentration, 19 ng/mL; time of peak, 1.33 hours after dosage; elimination half-life, 10.0 hours; total oral clearance, 1.11 mL/min/kg. During multiple dosage, mean steady-state plasma concentrations (Css) was proportional to dosing rate, and steady-state clearance was independent of dosage. Clinical improvement was rapid, with the greatest decrement in symptoms at the 3-mg/d dosage, at a mean Css of 30 ng/mL. Further improvement was not seen at 6 mg/d (Css, 62 ng/mL), or at 9 mg/d (Css, 103 ng/mL). Side effects, however, were directly related to dosage and plasma level, and increased progressively in number at the 3-, 6-, and 9-mg/d dosage levels. Thus, the disposition of alprazolam in young male patients with panic disorder is essentially identical to that in healthy male volunteers of similar age. Alprazolam clearance is independent of dose and plasma concentration up to daily doses of at least 9 mg/d, with steady-state plasma level proportional to dosing rate. PMID:2871050

Ciraulo, D A; Barnhill, J G; Boxenbaum, H G; Greenblatt, D J; Smith, R B

1986-04-01

157

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. PMID:22759198

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

2013-01-01

158

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

159

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

PubMed

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

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

2014-03-01

160

Assessment of total body water in hemodialysis patients by a single oral dose of antipyrine.  

PubMed

Accurate determination of total body water in hemodialysis patients is important for calculation of the amount of fluid excess that should be removed by ultrafiltration, and for dialysis prescribing by KT/V. Indirect methods using 0.6 x body weight or pre and post serum urea concentrations are inaccurate and determination by tritiated water space requires the use of radioactivity. The authors measured the volume of distribution for antipyrine that is distributed in body water, and compared it to tritiated water space in hemodialysis patients. Sixteen patients on hemodialysis were given 500 mg antipyrine and saliva samples were collected at fixed time points. Concentrations of antipyrine in saliva were measured by high pressure liquid chromatography. Volume of distribution for antipyrine was calculated by pharmacokinetic methods. Fluid excess was determined as the difference between tritiated water space or volume of distribution for antipyrine and ideal total body water measured anthropometrically. Total body water as the volume of distribution for antipyrine was 24.8 to 61.5 (mean 44.0 +/- 10.3) L, or 68% of body weight, and tritiated water space 27.0 to 56.6 L (43.6 +/- 7.7), 67% of body weight. Volume of distribution for antipyrine correlated well with tritiated water space (r = 0.997 and p = 0.001). Fluid excess calculated from tritiated water space was between 2.5 and 12.4 (6.0 +/- 4.0) L, and from volume of distribution for antipyrine -0.7 to 13.3 (5.7 +/- 5.1) L (r = 0.80, p = 0.001). The authors conclude that by using a single oral dose of antipyrine, one can simply and accurately measures total body water in hemodialysis patients. PMID:8828783

Odar-Cederlöf, I; Eriksson, C G; Albertioni, F; Ericsson, F; Kjellstrand, C M

1996-01-01

161

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

PubMed Central

Background We previously demonstrated the benefits of daily, oral pentosan polysulfate (PPS) treatment in a rat model of mucopolysaccharidosis (MPS) type VI. Herein we compare these effects to once weekly, subcutaneous (sc) injection. The bioavailability of injected PPS is greater than oral, suggesting better delivery to difficult tissues such as bone and cartilage. Injected PPS also effectively treats osteoarthritis in animals, and has shown success in osteoarthritis patients. Methodology/Principal Findings One-month-old MPS VI rats were given once weekly sc injections of PPS (1, 2 and 4 mg/kg, human equivalent dose (HED)), or daily oral PPS (4 mg/kg HED) for 6 months. Serum inflammatory markers and total glycosaminoglycans (GAGs) were measured, as were several histological, morphological and functional endpoints. Overall, weekly sc PPS injections led to similar or greater therapeutic effects as daily oral administration. Common findings between the two treatment approaches included reduced serum inflammatory markers, improved dentition and skull lengths, reduced tracheal deformities, and improved mobility. Enhanced effects of sc treatment included GAG reduction in urine and tissues, greater endurance on a rotarod, and better improvements in articular cartilage and bone in some dose groups. Optimal therapeutic effects were observed at 2 mg/kg, sc. No drug-related increases in liver enzymes, coagulation factor abnormalities or other adverse effects were identified following 6 months of sc PPS administration. Conclusions Once weekly sc administration of PPS in MPS VI rats led to equal or better therapeutic effects than daily oral administration, including a surprising reduction in urine and tissue GAGs. No adverse effects from sc PPS administration were observed over the 6-month study period. PMID:24964042

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

2014-01-01

162

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

PubMed Central

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

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

1994-01-01

163

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

PubMed Central

Objectives To assess the impact of reduced frequency of oral therapies from multiple-dosing schedules to a once-daily (OD) dosing schedule on adherence, compliance, persistence, and associated economic impact. Methods A meta-analysis was performed based on relevant articles identified from a comprehensive literature review using MEDLINE® and Embase®. The review included studies assessing adherence with OD, twice-daily (BID), thrice-daily (TID), and four-times daily (QID) dosing schedules and costs associated with optimal/suboptimal adherence among patients with acute and chronic diseases. Effect estimates across studies were pooled and analyzed using the DerSimonian and Laird random-effect model. Results Forty-three studies met inclusion criteria, and meta-analyzable data were available from 13 studies. The overall results indicated that OD schedules were associated with higher adherence rates (odds ratio [OR] 3.07, 95% confidence interval [CI] 1.80–5.23; P < 0.001 for OD versus > OD dosing) and compliance rates (OR 3.50, 95% CI 1.73–7.08; P < 0.001 for OD versus > OD dosing); persistence rates showed the same direction but were not statistically significant (OR 1.43, 95% CI 0.62–3.29; P = 0.405 for OD versus BID dosing). Results for each of the conditions were consistent with those observed overall with respect to showing the benefits of less frequent dosing. From a health economic perspective, higher adherence rates with OD relative to multiple dosing in a number of conditions were consistently associated with corresponding lower costs of health care resources utilization. Conclusion Current meta-analyses suggested that across acute and chronic disease states, reducing dosage frequency from multiple dosing to OD dosing may improve adherence to therapies among patients. Improving adherence may result in subsequent decreases in health care costs. PMID:23737662

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

2013-01-01

164

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. PMID:18341673

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

2008-01-01

165

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

PubMed Central

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

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

2007-01-01

166

Human dolasetron pharmacokinetics: II. Absorption and disposition following single-dose oral administration to normal male subjects.  

PubMed

Dolasetron is a 5-hydroxytryptamine antagonist active at type III receptors; it is presently undergoing clinical evaluation for the reduction/prevention of cancer chemotherapy-induced nausea and vomiting. A previous study demonstrated that following intravenous administration to healthy male subjects, dolasetron disappeared extremely rapidly from plasma, and less than 1 per cent of the dose appeared in the urine. A major plasma metabolite, reduced dolasetron, peaked rapidly in the plasma. In this study, dolasetron was administered orally to healthy male subjects at doses ranging from 50 to 400 mg (mesylate monohydrate). Plasma concentrations of dolasetron were low and sporadic, and there was little excreted in urine; this prevented dolasetron pharmacokinetic analysis. Reduced metabolite concentrations peaked rapidly, with a median value of 1.00 h. The median terminal disposition half-life was 7.80 h. Median values for fraction of dose excreted in urine and renal clearance were 22.2 per cent and 2.56 ml min-1 kg-1. Whereas areas under the plasma concentration-time curves were proportional to dose, renal clearance increased with dose (p < 0.05). However, given dose proportionality to AUC, this is probably of little therapeutic consequence. Since reduced dolasetron has significant anti-emetic activity in the ferret model, it appears that this metabolite may play a significant role in pharmacodynamic activity. PMID:8453023

Boxenbaum, H; Gillespie, T; Heck, K; Hahne, W

1993-03-01

167

Brivaracetam single and multiple rising oral dose study in healthy Japanese participants: influence of CYP2C19 genotype.  

PubMed

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

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

2014-01-01

168

Patient adherence with the contraceptive patch dosing schedule versus oral contraceptives  

Microsoft Academic Search

Objective: To evaluate patient compliance with a novel contraceptive patch (EVRA) versus two oral contraceptive (OC) regimens.Methods: In three international studies (002\\/003\\/004), subjects were randomly (003\\/004) assigned to treatment with either: EVRA (designed to deliver 150 ?g of 17-deacetylnorgestimate [17d-NGM] and 20 ?g of ethinyl estradiol [EE] daily) (n = 3,329; studies 002\\/003\\/004), oral desogestrel 150 ?g \\/EE 20 ?g

George Creasy; Nancy Hall; Gary Shangold

2000-01-01

169

Short report: comparison of oral infectious dose of West Nile virus isolates representing three distinct genotypes in Culex quinquefasciatus.  

PubMed

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. PMID:19052310

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

2008-12-01

170

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. PMID:19052310

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

2009-01-01

171

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

PubMed

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

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

2014-03-01

172

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

PubMed

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

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

2014-08-01

173

?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. PMID:19833841

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

174

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

PubMed

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

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

2014-11-01

175

Induction of lymphokine-activated killer cells with low-dose interleukin 2 and interferon-? in oral cancer patients  

Microsoft Academic Search

Lymphokine-activated killer (LAK) cells were induced with low-dose recombinant interleukin 2 (rIL-2) and recombinant interferon-? (IFN-?) in 28 oral carcinoma patients. The patients received daily intravenous injections of rIL-2 (1.2×105 U\\/m2) and rIFN-? (7.0×104 U\\/m2), and both natural killer (NK) and LAK activities were periodically examined. A significant increase in CD16+CD57+ and CD16+CD57- NK subsets was observed after the induction.

Kazunori Yoneda; Tetsuya Yamamoto; Eisaku Ueta; Tokio Osaki

1992-01-01

176

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. PMID:22129044

2011-01-01

177

Reduction of suture associated inflammation after 28 days using novel biocompatible pseudoprotein poly(ester amide) biomaterials.  

PubMed

Sutures elicit an inflammatory response, which may impede the healing process and result in wound complications. We recently reported a novel family of biocompatible, biodegradable polymers, amino acid-based poly(ester amide)s (AA-PEA), which we have shown to significantly attenuate the foreign body inflammatory response in vitro. Two types of AA-PEA (Phe-PEA and Arg-Phe-PEA) were used to coat silk or plain-gut sutures, which were implanted in the gluteus muscle of C57BL/6 mice, while the uncoated control sutures were implanted in the contralateral side. After 3, 7, 14, and 28 days the mean area of inflammation surrounding the sutures was compared. Phe-PEA coating of silk sutures significantly decreased inflammation compared with noncoated controls (67.8?±?17.4% after 3d [p?=?0.0014], 51.6?±?7.2% after 7d [p?28 days. © 2014 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 103B: 457-463, 2015. PMID:24916020

Hernandez, Karina A; Hooper, Rachel Campbell; Boyko, Tatiana; Golas, Alyssa R; van Harten, Michel; Wu, D Q; Weinstein, Andrew; Chu, C C; Spector, Jason A

2015-02-01

178

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.

179

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

USGS Publications Warehouse

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

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

1998-01-01

180

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

Microsoft Academic Search

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

Leslie Citrome

2009-01-01

181

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...

182

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

PubMed Central

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

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

2013-01-01

183

The pharmacokinetics of a single oral or rectal dose of concurrently administered isoniazid, rifampin, pyrazinamide, and ethambutol in Asian elephants (Elephas maximus).  

PubMed

Tuberculosis, caused by Mycobacterium tuberculosis, is a disease of concern in captive Asian elephants (Elephas maximus). Treatment for tuberculosis in elephants utilizes multidrug protocols combining isoniazid, rifampin, pyrazinamide, and/or ethambutol. In this study, a single, coformulated dose of isoniazid 5 mg/kg, rifampin 10 mg/kg, pyrazinamide 30 mg/kg, and ethambutol 30 mg/kg was administered orally to six Asian elephants, and rectally to five elephants using a cross-over design. Blood samples were collected serially over 24 h. Pyrazinamide and ethambutol concentrations were determined using validated gas chromatography assays. Isoniazid and rifampin concentrations were determined using validated high-performance liquid chromatography assays. Rectal isoniazid produced an earlier Tmax compared with oral administration. Oral isoniazid resulted in a comparatively lower Cmax , but higher AUC values compared with rectal isoniazid. Oral rifampin and oral ethambutol were well absorbed while rectal rifampin was not. Oral pyrazinamide produced comparatively higher Cmax and AUC values compared with rectal pyrazinamide. Results of this study indicate that currently recommended therapeutic monitoring sample collection times for rectal isoniazid and oral rifampin do not provide an accurate assessment of exposure for these drugs. This study demonstrates notable individual variability, indicating that dosing of these medications requires individual monitoring and provides additional information to guide the clinician when treating elephants. PMID:24684601

P Brock, A; Isaza, R; Egelund, E F; Hunter, R P; Peloquin, C A

2014-10-01

184

Use of Sustained Release Oral Morphine as a Bridge in Withdrawal of Morphine in Patients on High Doses of Oral Immediate Release Morphine for Cancer Pain  

Microsoft Academic Search

According to World Health Organization (WHO), cancer pain can be controlled effectively with oral morphine in up to 90% of patients. Due to advancement in anticancer therapy and early presentation of cancer patients, the likelihood of cure is on an increasing trend. Awareness and education in the use of oral morphine, and easier regulations in procurement of oral morphine for

Arif Ahmed; Himanshu Khurana; Vikas Gogia; Seema Mishra; Sushma Bhatnagar

2010-01-01

185

A randomized clinical trial comparing doses and efficacy of lormetazepam tablets or oral solution for insomnia in a general practice setting.  

PubMed

Lormetazepam is a short-acting benzodiazepine hypnotic which is beneficial in shortening the time to onset of sleep. The aim of the study was to assess a new formulation of lormetazepam (oral solution) in comparison with lormetazepam tablets in out-patients with insomnia. This trial was an open randomized parallel group study conducted by 30 general practitioners. One hundred and eight patients took 0.5 mg on the first night and were allowed to increase their dosage by 0.25 mg (for oral solution) and 0.5 mg (for tablets), respectively, each day and every 2 days. The patients assessed the efficacy, acceptability and tolerance of lormetazepam using a diary card and a set of visual analogue scales assessing their sleep. Over 14 days of treatment, the mean daily dose of lormetazepam was lower in the oral solution group than in the tablets group (0.78 mg versus 0.97 mg). The cumulated dose of lormetazepam was lower with the oral solution (18% reduction). No significant difference between the two groups was found in the assessment of sleep characteristics. The occurrence of side effects did not differ between the two groups. These results suggest that a unitary dose as achieved by an oral solution of lormetazepam allows easier determination of the minimal individual effective dose. PMID:14994324

Ancolio, C; Tardieu, S; Soubrouillard, C; Alquier, C; Pradel, V; Micallef, J; Blin, O

2004-03-01

186

Comparative pharmacokinetics and bile transformation of R-enantiomer and racemic bambuterol after single-dose intravenous, oral administration in rats and beagle dogs.  

PubMed

This study was to compare pharmacokinetics and bile transformation of R-enantiomer bambuterol with its racemate. Pharmacokinetics of R-enantiomer was investigated after single-dose intravenous and three doses of oral administration to rats and beagle dogs. To compare the pharmacokinetics with racemic bambuterol, the same oral doses of racemic bambuterol were also administrated; the blood and bile samples were collected by cannulation. A validated LC-MS/MS method was used to assess the level of bambuterol in plasma and bile. After single intravenous administration, no significant differences were observed between the two drugs in pharmacokinetic data. After oral dosing of R-bambuterol, the AUCs of R-enantiomer presented linear correlation. After same oral dosing of R-enantiomer and its racemate, all the pharmacokinetic parameters were equivalent. However, the clearance and apparent distribution had different results due to species and administration route difference. The bile transformation of these two compounds was similar and implicated that liver transformation accounted for the major metabolism of them. The bioavailability of R-enantiomer and racemate were comparative and relatively high in beagle dogs. Thus, R-enantiomer had a comparative pharmacokinetic profile and bile transformation with racemic bambuterol in rats and beagle dogs. These findings provided references for further clinical study. PMID:25281237

Guan, Su; Hu, Chun-Yun; He, Meng-Ying; Yang, Ying-Ying; Tang, Yu-Xin; Chen, Jie-di; Huang, Li-Jie; Tan, Wen

2014-10-01

187

Pituitary hormone secretion in normal male humans: acute responses to a large, oral dose of monosodium glutamate.  

PubMed

Numerous studies have shown that the administration of a glutamate receptor agonist or a high dose of glutamate stimulates pituitary hormone secretion in animals. However, only a single human study has reported that an oral load of glutamic acid induced the secretion of prolactin and probably adrenocorticotropic hormone (ACTH) (but not other pituitary hormones). Because of glutamate's use in foods as monosodium glutamate (MSG), a flavoring agent, and the limited amount of human data, we studied the effect of a large oral dose of MSG in humans on the secretion of prolactin and other pituitary hormones. Fasting male subjects bearing venous catheters received on separate days each of the following four treatments: a vehicle, MSG (12.7 g), a high protein meal (a physiologic stimulus of prolactin secretion) by mouth, or an intravenous infusion of thyrotropin-releasing hormone (TRH, a pharmacologic stimulus of prolactin secretion). Plasma hormone responses were quantitated by RIA at 20-min intervals for 4 h. The protein meal induced a modest increase and TRH infusion a substantial increase in plasma prolactin, whereas MSG ingestion did not. MSG ingestion also did not raise the plasma concentrations of any of the other pituitary hormones measured (luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, growth hormone) or of cortisol. Ingestion of MSG raised plasma glutamate concentrations 11-fold; the protein meal did not raise plasma glutamate. The results demonstrate that MSG ingestion in humans does not modify anterior pituitary hormone secretion. One implication is that diet-derived glutamate may not penetrate into hypothalamic regions controlling anterior pituitary function. PMID:10736381

Fernstrom, J D

2000-04-01

188

Population Pharmacokinetic Model of THC Integrates Oral, Intravenous, and Pulmonary Dosing and Characterizes Short- and Long-term Pharmacokinetics.  

PubMed

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

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

2015-02-01

189

Correlation analysis of hypothalamic mRNA levels of appetite regulatory neuropeptides and several metabolic parameters in 28-day-old layer chickens.  

PubMed

Various lines of evidence suggest that appetite-related neuropeptides in the hypothalamus are regulated by adiposity signals such as leptin and insulin in mammals. In the present study, we examined age-dependent changes in the weight of abdominal fat and hypothalamic mRNA levels of neuropeptide Y (NPY, an orexigenic neuropeptide) and proopiomelanocortin (POMC, a precursor of anorexigenic neuropeptides) in growing chickens at 7, 14, 21 and 28 days of age. Hypothalamic NPY mRNA levels were significantly (P?28 days of age. The percentage of abdominal fat was significantly increased after 14 days of age in chickens. We next examined the correlation of hypothalamic NPY and POMC mRNA levels and several parameters at 28 days of age. There were no significant correlations between hypothalamic mRNA levels of NPY or POMC and the percentage of abdominal fat. These findings suggest that the gene expressions of NPY and POMC do not depend on adiposity in chickens, at least in 28-day-old layer chickens. PMID:25441031

Honda, Kazuhisa; Saneyasu, Takaoki; Aoki, Koji; Shimatani, Tomohiko; Yamaguchi, Takuya; Kamisoyama, Hiroshi

2014-11-30

190

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

PubMed Central

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

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

2014-01-01

191

[A 90-day repeated dose oral toxicity study of magnesium chloride in F344 rats].  

PubMed

In order to examine the toxicity of magnesium chloride hexahydrate, four groups of 10 male and 10 female F344 rats received the compound by dietary supplementation at 2.5, 0.5, 0.1 or 0% for 90 days. No treatment-related death was observed during the study. Transient soft stool and sustained increase in water consumption were observed both in males and females of the 2.5% group and slight reduction in body weight gain was noted in the high-dose males. There were no toxic changes in food consumption, organ weights, hematology and biochemistry, and histopathological examinations in any treated-groups. Based on these results, the no-observed-adverse-effect-level was estimated to be 0.5%, and 2.5% is considered to be appropriate as highest dose for a 2-year carcinogenicity study. PMID:11534129

Takizawa, T; Yasuhara, K; Mitsumori, K; Onodera, H; Koujitani, T; Tamura, T; Takagi, H; Hirose, M

2000-01-01

192

Behavioral effects of adult rats concurrently exposed to high doses of oral manganese and restraint stress  

Microsoft Academic Search

The behavioral effects of concurrent exposure of high doses of manganese (Mn) and restraint stress were assessed in adult rats. Male Sprague-Dawley rats (250–300g) received 0, 275 and 550mg\\/kg\\/day of Mn in the drinking water for 19 weeks. Each group was divided into two subgroups. Animals in one subgroup were restrained for 2h\\/day. During the treatment period, food and water

Margarita Torrente; M. Teresa Colomina; José L. Domingo

2005-01-01

193

Pharmacokinetics of dipotassium chlorazepate in patients after repeated 50 mg oral doses  

Microsoft Academic Search

Dipotassium chlorazepate (DPC) was administered to ten patients (five males and five females), aged 18–37 years (mean 27.4), as a once daily dose of 50 mg until a steady state was reached. Plasma concentrations of the main metabolite N-desmethyldiazepam (DMD) were monitored by a high pressure liquid chromatographic (HPLC) method during the medication period and for 5 days after withdrawal

Ĺke Bertler; Sune Lindgren; Harry Malmgren

1980-01-01

194

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

PubMed

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

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

2015-02-01

195

Clinical trial of high-dose oral medroxyprogesterone acetate in the treatment of metastatic breast cancer and review of the literature.  

PubMed

Recent studies have suggested that there are benefits from the use of high-dose parenteral medroxyprogesterone acetate (MPA) in the treatment of metastatic breast cancer. The present study was designed to assess the efficacy and toxicity of high-dose oral MPA in women with clinical parameters suggesting potentially hormonally sensitive metastatic breast cancer. The first 28 patients received 800 mg/day, and 11 of them had received no previous hormone (NPH) therapy. The response rate (complete plus partial) was 63% for those receiving NPH and 12% for those receiving previous hormone (PH) therapy. Toxicity was significant at these doses, especially for women treated for more than 5 weeks. Toxic effects included excessive weight gain, Cushingoid facies, worsening of diabetes mellitus, and other stigmata suggestive of hypercorticism. Nineteen other patients were treated at 400 mg/day with a 60% response rate for 10 NPH patients and 44% for patients with PH treatment. Toxicity was less severe in these patients. The median time to treatment failure was 23 weeks, and to survival, 119 weeks for all treated patients. Moderately high (400 mg/d) and higher dose (800 mg/d) oral MPA are capable of inducing reasonable response rates in patients with NPH treatment. The toxicity of these regimens was significant--profound weight gain was dose limiting in some patients. While effective, high-dose oral MPA is unlikely to supplant tamoxifen as first-line therapy in metastatic breast cancer. PMID:2966667

Davila, E; Vogel, C L; East, D; Cairns, V; Hilsenbeck, S

1988-06-01

196

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

PubMed

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

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

2014-04-01

197

Oral premedication with low dose midazolam modifies the immunological stress reaction after the setting of retrobulbar anaesthesia  

PubMed Central

Background/aims: An acute immunological stress reaction was previously reported to occur after the painful setting of retrobulbar anaesthesia before intraocular surgery. This study was conducted to find out whether an oral low dose premedication with midazolam would modify the immunological stress reaction. Methods: 32 patients undergoing intraocular surgery using retrobulbar anaesthesia were included in a randomised, double blind trial. They received premedication with either 3.75 mg midazolam or placebo 30 minutes before the retrobulbar injection. Counts of leucocyte subpopulations, cardiovascular, and psychometric parameters were measured repetitively before and after the retrobulbar injection. Results: The numbers of leucocytes increased significantly in the placebo group after the setting of retrobulbar anaesthesia (before retrobulbar injection: 6687 (SD 1025) cells ×106/l; after injection: 7067 (1022) cells ×106/l, p=0.0009) caused by rising numbers of neutrophils (before injection: 4111 (1063) cells ×106/l; after injection: 4352 (1147) cells ×106/l, p=0.0007) and natural killer cells (before injection: 290 (84) cell ×106/l; after injection 354 (133) cells ×106/l, p=0.003). There was no significant increase in total leucocytes (before injection: 5997 (1288) cells ×106/l; after injection: 6189 (1215) cells ×106/l) or in any leucocyte subpopulation in the midazolam group. A significant rise in systolic blood pressure occurred in the placebo group, but not in the midazolam group. Conclusion: A low dose premedication with midazolam attenuates the immunological and cardiovascular stress reactions occurring with retrobulbar anaesthesia. PMID:12881348

Heine, G H; Weindler, J; Gabriel, H H W; Kindermann, W; Ruprecht, K W

2003-01-01

198

Thirteen-week repeated oral dose toxicity study of ecabapide, a gastroprokinetic drug, in dogs and rats.  

PubMed

Thirteen-week oral repeated dose toxicity of ecabapide, a gastroprokinetic drug, was investigated in dogs at dosage levels of 50, 175 or 600 mg/kg, and in rats at dosage levels of 25, 100, 400 or 1600 mg/kg. In dogs, vomiting, aqueous salivation, body weight gain inhibition, and hemolytic anemia, together with an increase in Heinz body formation, were observed at 175 and/or 600 mg/kg. Histological examination revealed enhanced hemosiderin deposition in the liver and spleen, retention of erythrocytes in the splenic sinus and enhanced erythropoiesis in bone marrow at 175 and/or 600 mg/kg. In the rat study, although increases in serum total protein, albumin and calcium, as well as increased liver and kidney weights, were observed at 400 and/or 1600 mg/kg, no obvious morphological changes were seen. The hemolytic anemia and an increased Heinz body formation were not observed in rats, indicating a species difference. On the basis of these results, the non-toxic dose of ecabapide was considered to be 50 mg/kg in dogs and 100 mg/kg in rats. PMID:9760413

Jindo, T; Genda, Y; Kakihata, K; Ohno, H; Akiyama, Y

1998-07-01

199

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

E-print Network

studied the effects of single oral doses of baclofen on voluntary, isometric knee extension torques resistance to imposed passive muscle stretch,28 and spasms or hyperactive multijoint re- flexes,33 both- tijoint spasms, and reduces antagonist coactivation during unrestrained or isometric movements (as re

200

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

Microsoft Academic Search

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

Lawrence C Hookey; William T Depew; Stephen J Vanner

2004-01-01

201

A clinical multicenter study comparing efficacy and tolerability of topical combination therapy with clotrimazole (Canesten, two formats) with oral single dose fluconazole (Diflucan) in vulvovaginal mycoses.  

PubMed

Two topical formats containing clotrimazole [500 mg single dose vaginal tablet (VT) or 10% single dose vaginal cream (VC) for intravaginal use] combined with additional clotrimazole cream for topical application to the vulval area (Canesten 1 Combi, Bayer AG, Leverkusen, Germany) were compared with oral fluconazole 150 mg single dose treatment of vulvovaginal mycosis (VVM) in a single-blind clinical study. The objective of the study was to demonstrate the equivalent efficacy of the clotrimazole combination therapies (VT + 1% cream and VC + 2% cream), and fluconazole 150 mg oral capsule (Diflucan 1, Pfizer Gmbh, Karlsruhe, Germany) in terms of overall response defined as clinical cure and mycological resolution. Overall, combination therapies containing either clotrimazole 500 mg VTs or clotrimazole 10% VC were as effective as a single dose fluconazole 150 mg oral tablet in treating VVM with rates for overall response being 66%, 61% and 60%, respectively, after 14 days. There were no significant differences in the time to onset of symptom relief in the clotrimazole 500 mg tablet group and clotrimazole 10% VC compared with fluconazole 150 mg oral capsules. Only 50% of 88 patients across treatment groups with mycological recurrence also experienced return of symptoms over the entire 8 week follow-up period. All treatments administered were safe and well-tolerated and the number of patients experiencing adverse events was low. PMID:15078430

Mendling, Werner; Krauss, Christian; Fladung, Bernward

2004-04-01

202

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

Microsoft Academic Search

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

Kelly S Parsey; Annpey Pong

2000-01-01

203

Pharmacokinetics of high-dose oral CCNU in bone marrow transplant patients  

Microsoft Academic Search

Purpose: CCNU (lomustine) and other nitrosourea compounds are rapidly metabolized to alkylating moieties, which are active against\\u000a various malignancies. In humans, CCNU undergoes biotransformation to the geometric isomers of 4?-hydroxyCCNU. The pharmacokinetics\\u000a of trans- and cis-4?-hydroxyCCNU were determined in five patients with Hodgkin’s or non-Hodgkin’s lymphoma receiving sequential doses of CCNU\\u000a (15?mg\\/kg), etoposide (60?mg\\/kg) and cyclophosphamide (100?mg\\/kg) prior to autologous

Helen Kastrissios; Nelson J. Chao; Terrence F. Blaschke

1996-01-01

204

Making the leap from daily oral dosing to long-acting injectables: lessons from the antipsychotics.  

PubMed

There are now long-acting versions of six antipsychotic drugs on the U.S. market, and with them, five unique combinations of molecular form and delivery strategy long-acting-injectable-antipsychotics (LAIAs) show evidence of reduced relapses of schizophrenia, but their introduction has been slow, taking at least nine years after the approval of each oral drug. Oily solutions of lipophilic prodrugs were the first to enter the LAIA market, but they relied on esterification of a hydroxyl handle that was lost with the emergence of the atypical antipsychotics. A review of the literature and patents shows that companies tested many different approaches before reaching the currently marketed versions, including aqueous suspensions of poorly soluble salts, polymeric microspheres, and new approaches to making prodrugs. Yet, very little has been published to support faster development of safe long-acting injectables (LAIs). This review introduces some of the critical considerations in creating an LAI; then it analyzes the existing products and discusses areas where further research is needed. The available literature suggests that lipophilic prodrugs may be inherently safer than poorly soluble salts as LAIs. Other areas needing additional study include (1) the range of physical properties acceptable for LAIs and the effect of prodrug tail length in achieving them, and (2) the role of physiological responses at the injection site in the release of drug from a depot. PMID:24679167

Remenar, Julius F

2014-06-01

205

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

PubMed

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

Tashjian, Diran H; Hung, Silas S O

2006-10-01

206

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

PubMed

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

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

2012-01-01

207

Oral pelargonidin exerts dose-dependent neuroprotection in 6-hydroxydopamine rat model of hemi-parkinsonism.  

PubMed

Parkinson's disease (PD) is a neuropathological and debilitating disorder involving the degeneration of mesencephalic dopaminergic neurons. Neuroprotective effect of pelargonidin (Pel) has already been reported, therefore, this study examined whether Pel administration would attenuate behavioural and structural abnormalities and markers of oxidative stress in an experimental model of PD in rat. For this purpose, unilateral intrastriatal 6-hydroxydopamine (6-OHDA, 12.5mug/5mul of saline-ascorbate)-lesioned rats were pre-treated p.o. with Pel (10 and/or 20mg/kg). Pel administration dose-dependently attenuated the rotational behavior in lesioned rats and protected the neurons of SNC against 6-OHDA toxicity. In addition, pre-treatment with Pel (20mg/kg) significantly decreased the 6-OHDA-induced thiobarbituric acid reactive substances (TBARS) formation, indicative of a neuroprotection against lipid peroxidation. Furthermore, the increase of nitrite levels induced by 6-OHDA, indicate the nitric oxide formation and free radicals production and the decrease of antioxidant defense enzyme superoxide dismutase (SOD) was non-significantly prevented by Pel (20mg/kg). In summary, Pel administration has a dose-dependent neuroprotective effect against 6-OHDA toxicity, partly through attenuating oxidative stress. Our findings suggest that pelargonidin could provide benefits, along with other therapies, in neurodegenerative disorders including PD. PMID:20558255

Roghani, Mehrdad; Niknam, Akram; Jalali-Nadoushan, Mohammad-Reza; Kiasalari, Zahra; Khalili, Mohsen; Baluchnejadmojarad, Tourandokht

2010-07-30

208

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

PubMed

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

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

2014-06-01

209

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

2012-01-01

210

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

USGS Publications Warehouse

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

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

2014-01-01

211

Ultra-Performance Liquid Chromatography Mass Spectrometry and Sensitive Bioassay Methods for Quantification of Posaconazole Plasma Concentrations after Oral Dosing?  

PubMed Central

Posaconazole (POS) is a new antifungal agent for prevention and therapy of mycoses in immunocompromised patients. Variable POS pharmacokinetics after oral dosing may influence efficacy: a trough threshold of 0.5 ?g/ml has been recently proposed. Measurement of POS plasma concentrations by complex chromatographic techniques may thus contribute to optimize prevention and management of life-threatening infections. No microbiological analytical method is available. The objective of this study was to develop and validate a new simplified ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) method and a sensitive bioassay for quantification of POS over the clinical plasma concentration range. The UPLC-MS/MS equipment consisted of a triple quadrupole mass spectrometer, an electrospray ionization (ESI) source, and a C18 analytical column. The Candida albicans POS-hypersusceptible mutant (MIC of 0.002 ?g/ml) ?cdr1 ?cdr2 ?flu ?mdr1 ?can constructed by targeted deletion of multidrug efflux transporters and calcineurin genes was used for the bioassay. POS was extracted from plasma by protein precipitation with acetonitrile-methanol (75%/25%, vol/vol). Reproducible standard curves were obtained over the range 0.014 to 12 (UPLC-MS/MS) and 0.028 to 12 ?g/ml (bioassay). Intra- and interrun accuracy levels were 106% ± 2% and 103% ± 4% for UPLC-MS/MS and 102% ± 8% and 104% ± 1% for bioassay, respectively. The intra- and interrun coefficients of variation were 7% ± 4% and 7% ± 3% for UPLC-MS/MS and 5% ± 3% and 4% ± 2% for bioassay, respectively. An excellent correlation between POS plasma concentrations measured by UPLC-MS/MS and bioassay was found (concordance, 0.96). In 26 hemato-oncological patients receiving oral POS, 27/69 (39%) trough plasma concentrations were lower than 0.5 ?g/ml. The UPLC-MS/MS method and sensitive bioassay offer alternative tools for accurate and precise quantification of the plasma concentrations in patients receiving oral posaconazole. PMID:20921320

Rochat, Bertrand; Pascual, Andres; Pesse, Benoît; Lamoth, Frédéric; Sanglard, Dominique; Decosterd, Laurent A.; Bille, Jacques; Marchetti, Oscar

2010-01-01

212

Effect of multiple doses of oral isradipine on atrioventricular conduction in patients with first-degree atrioventricular block.  

PubMed

The purpose of this study was to investigate the effect of multiple doses of orally administered isradipine on atrioventricular nodal conduction in patients with first-degree atrioventricular block. Forty-eight patients with a P-R interval > or =0.22 seconds on a surface electrocardiogram (ECG) (first-degree atrioventricular block) with or without a bundle-branch block were randomized to one of four groups for 6 weeks of treatment with either placebo or 5.0 mg/d, 7.5 mg/d, or 10.0 mg/d isradipine. P-R interval prolongation was assessed at baseline and posttreatment using resting 12-lead ECGs and 24-hour Holter monitoring. The effect of isradipine on the following parameters were assessed: systolic and diastolic blood pressures, heart rate, respiration rate, oral temperature, and weight. Neither isradipine nor placebo treatment had a statistically significant treatment effect on the change from baseline in P-R interval, QRS duration, Q-T interval (uncorrected), or sinus heart rate at week 7 as measured by 12-lead ECG. All treatment groups, however, had small, statistically insignificant decreases from baseline in the mean P-R interval. The largest decrease (from 0.26 seconds at baseline to 0.22 seconds at week 7) was recorded for the 7.5 mg/d isradipine group, which also had the greatest posttreatment decreases in QRS duration, sinus heart rate, and systolic and diastolic blood pressures. The treatment groups did not differ significantly with respect to the change from baseline to study end in P-R interval prolongation or degree of atrioventricular block (as measured by 24-hour Holter monitoring), radial pulse rate, respiration rate, weight, or oral temperature. In this study, isradipine did not have a negative dromotropic effect on the atrioventricular node. The trend toward a posttreatment decrease in P-R interval suggests that isradipine may actually improve atrioventricular nodal conduction in patients with first-degree atrioventricular block and thus may be used safely in this population. PMID:10099039

Kerin, N Z; Hai, H H; Samuel, P

1998-03-01

213

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

Microsoft Academic Search

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

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

2010-01-01

214

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. PMID:22629364

Ferrer, Patricia; Tripathi, Abhai K.; Clark, Martha A.; Hand, Carla Cerami; Rienhoff, Hugh Young; Sullivan, David J.

2012-01-01

215

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

PubMed

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

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

2014-12-01

216

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

SciTech Connect

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

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

1983-06-30

217

Chemoembolization of oral and oropharyngeal cancer using a high-dose cisplatin crystal suspension and degradable starch microspheres.  

PubMed

The aim of the study was to achieve intensification of intraarterial chemotherapy of head and neck cancer with high-dose cisplatin by establishing a new method of chemoembolization which can be routinely used without the earlier drawbacks of the method (low drug dosage due to early occlusion of the small head and neck vessels, danger of local damage). Thirty two patients with previously untreated oral and oropharyngeal squamous cell carcinomas of all stages were treated by at least one superselective chemoembolization via femoral approach using a new preparation format of 150 mg/m(2) cisplatin which is an aqueous crystal suspension. In defined cases, combination with the delivery of degradable starch microspheres (DSM). Systemic neutralization with sodium thiosulfate. Primary end points were tolerance and response. Subsequent treatment was surgery or radiation. Chemoembolization succeeded in all 37 interventions to date. Overall response after one cycle was 64.7% using the cisplatin crystal suspension only (n=17) and 86.6% using additional DSM chemoembolization (n=15), as assessed 3 weeks after treatment. Systemic toxicity was extremely low, local side-effects (pain, swelling, small necrosis) were pronounced after additional delivery of DSM. There have been three complications (tracheotomy due to swelling, temporary facial paralysis twice due to embolization of the geniculate ganglion). Using the high-dose cisplatin crystal suspension, chemoembolization can routinely be used in the head and neck area as neoadjuvant therapy. Response was better than with former comparable regimens. The additional delivery of DSM was complicated, restricted to certain areas and unreliable in the dosage needed and might be omitted, therefore. PMID:11755826

Kovács, Adorján F; Turowski, Bernd

2002-01-01

218

Safety and pharmacokinetics of the CIME combination of drugs and their metabolites after a single oral dosing in healthy volunteers.  

PubMed

This phase I, pilot clinical study was designed to evaluate the safety and the pharmacokinetic (PK) profiles of the CIME (Metabolic Identity Card) combination of ten drugs, with a view to its use as a phenotyping cocktail. Ten healthy Caucasian subjects were orally dosed with the CIME combination (caffeine-CYP1A2, repaglinide-CYP2C8, tolbutamide-CYP2C9, omeprazole-CYP2C19, dextromethorphan-CYP2D6, midazolam-CYP3A, acetaminophen-UGT1A1, 6&9 and 2B15, digoxin-P-gp, rosuvastatin-OATP1B1&3 and memantine-active renal transport). Blood was collected over 3 days and on day 7. CIME probes and relevant metabolites were assayed by LC-MS/MS and PK parameters were calculated. Main results were: (1) good safety with reversible mild or moderate adverse effects, (2) an analytical method able to quantify simultaneously the 10 probes and the major metabolites, (3) calculation of PK parameters for all probes in general agreed with published values, and (4) identification of the low CYP2D6 metabolizer. This pilot study showed that the CIME combination was well tolerated and that its pharmacokinetics could be accurately measured in healthy volunteers. This combination can now confidently be checked for sensitivity and specificity and for lack of interaction to be validated as a phenotyping cocktail. PMID:25465228

Lenuzza, Natacha; Duval, Xavier; Nicolas, Grégory; Thévenot, Etienne; Job, Sylvie; Videau, Orianne; Narjoz, Céline; Loriot, Marie-Anne; Beaune, Philippe; Becquemont, Laurent; Mentré, France; Funck-Brentano, Christian; Alavoine, Loubna; Arnaud, Philippe; Delaforge, Marcel; Bénech, Henri

2014-12-01

219

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

PubMed

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

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

2014-10-01

220

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

221

Threshold dose for peanut: Risk characterization based upon diagnostic oral challenge of a series of 286 peanut-allergic individuals.  

PubMed

Clinical records of 286 consecutive patients reacting positively with objective symptoms to double-blind, placebo-controlled oral peanut challenges at University Hospital, Nancy, France were examined for individual No Observed Adverse Effect Levels (NOAELs) and Lowest Observed Adverse Effect Levels (LOAELs). After fitting to a log-normal probability distribution model, the ED(10) and ED(05) were 14.4 and 7.3mg (expressed as whole peanut), respectively, with 95% lower confidence intervals of 10.7 and 5.2mg, respectively. Compared to results from a previous study where the ED(10) was based upon individual peanut thresholds gleaned from 12 publications, a statistically significant difference was observed between the ED(50)'s, but not the ED(10)'s of the two probability distribution curves. The Nancy patient group contains more sensitive subjects than the group from the published literature thus contributing to the observed differences. Minimum eliciting dose-distributions for patients with histories of more severe reactions (grade 4 or 5; 40 subjects) did not differ significantly from those of patients with histories of less severe reactions (grades 1-3; 123 subjects). These data and this modeling approach could be used to establish population thresholds for peanut-allergic consumers and thereby provide a sound basis for allergen control measures in the food industry. PMID:20034533

Taylor, Steve L; Moneret-Vautrin, D A; Crevel, Rene W R; Sheffield, David; Morisset, Martine; Dumont, P; Remington, Benjamin C; Baumert, Joseph L

2010-03-01

222

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

PubMed

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

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

2008-09-10

223

Efficacy of a supersaturated calcium phosphate oral rinse for the prevention and treatment of oral mucositis in patients receiving high-dose cancer therapy: a review of current data.  

PubMed

Oral mucositis (OM) is a painful and debilitating complication of cancer therapy that can adversely affect patients' treatment regimens and quality of life. It is also considered to be a substantial burden on the financial and human resources of health services. Despite progress in the understanding of the pathophysiology of OM and the number of new treatments that have been developed, there remains an unmet need for effective preventative measures in clinical practice. Literature on oral healthcare management in oncology patients suggests that a preventative approach consisting of a supersaturated Ca2+ / PO4(3-) oral rinse (Caphosol(®)) aimed at maintaining oral hygiene, moistening and lubricating the oral cavity, effectively reduces the incidence and severity of OM. This review looked at data from all known adult and paediatric studies investigating the use of Caphosol(®) in patients receiving high-dose cancer therapy in order to evaluate its efficacy for both the prevention and treatment of OM. Thirty studies were identified. The majority of these studies (n = 24) found Caphosol(®) to be efficacious at reducing the grade and/or duration, as well as pain associated with OM. Despite important limitations, these data warrant serious consideration for the inclusion of Caphosol(®) in regimens for preventing or reducing the debilitating effects of OM. PMID:23731197

Quinn, B

2013-09-01

224

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

2011-12-01

225

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

226

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

227

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

228

Clinical controlled study on plaque and gingivitis reduction under long-term use of low-dose chlorhexidine solutions in a population exhibiting good oral hygiene  

Microsoft Academic Search

The aim of this randomized, parallel-group, placebo-controlled, blind clinical study was to examine the dental plaque and the gingivitis inhibitory effects of two low-dose 0.06% chlorhexidine (CHX) preparations in comparison to a commercially available 0.1% CHX solution, an amine fluoride\\/stannous fluoride (ASF) solution and a water control as an adjunct to the daily mechanical oral-hygiene measures. After prophylaxis, 81 medical

T. Hoffmann; G. Bruhn; S. Richter; L. Netuschil; M. Brecx

2001-01-01

229

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

2012-09-15

230

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

PubMed

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

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

2013-09-01

231

Safety and Pharmacokinetics of Abacavir (1592U89) following Oral Administration of Escalating Single Doses in Human Immunodeficiency Virus Type 1-Infected Adults  

PubMed Central

Abacavir (1592U89) is a nucleoside analog reverse transcriptase inhibitor that has been demonstrated to have selective activity against human immunodeficiency virus (HIV) in vitro and favorable safety profiles in mice and monkeys. A phase I study was conducted to evaluate the safety and pharmacokinetics of abacavir following oral administration of single escalating doses (100, 300, 600, 900, and 1,200 mg) to HIV-infected adults. In this double-blind, placebo-controlled study, subjects with baseline CD4+ cell counts ranging from <50 to 713 cells per mm3 (median, 315 cells per mm3) were randomly assigned to receive abacavir (n = 12) or placebo (n = 6). The bioavailability of the caplet formulation relative to that of the oral solution was also assessed with the 300-mg dose. Abacavir was well tolerated by all subjects; mild to moderate asthenia, abdominal pain, headache, diarrhea, and dyspepsia were the most frequently reported adverse events, and these were not dose related. No significant clinical or laboratory abnormalities were observed throughout the study. All doses resulted in mean abacavir concentrations in plasma that exceeded the mean 50% inhibitory concentration (IC50) for clinical HIV isolates in vitro (0.07 ?g/ml) for almost 3 h. Abacavir was rapidly absorbed following oral administration, with the time to the peak concentration in plasma occurring at 1.0 to 1.7 h postdosing. Mean maximum concentrations in plasma (Cmax) and the area under the plasma concentration-time curve from time zero to infinity (AUC0–?) increased slightly more than proportionally from 100 to 600 mg (from 0.6 to 4.7 ?g/ml for Cmax; from 1.0 to 15.7 ?g · h/ml for AUC0–?) but increased proportionally from 600 to 1,200 mg (from 4.7 to 9.6 ?g/ml for Cmax; from 15.7 to 32.8 ?g · h/ml for AUC0–?). The elimination of abacavir from plasma was rapid, with an apparent elimination half-life of 0.9 to 1.7 h. Abacavir was well absorbed, with a relative bioavailability of the caplet formulation of 96% versus that of an oral solution (drug substance in water). In conclusion, this study showed that abacavir is safe and is well tolerated by HIV-infected subjects and demonstrated predictable pharmacokinetic characteristics when it was administered as single oral doses ranging from 100 to 1,200 mg. PMID:10049274

Kumar, Princy N.; Sweet, Donna E.; McDowell, James A.; Symonds, William; Lou, Yu; Hetherington, Seth; LaFon, Stephen

1999-01-01

232

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

233

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

PubMed

M01ZH09, S. Typhi (Ty2 Delta aroC Delta ssaV) ZH9, is a single oral dose typhoid vaccine with independently attenuating deletions. A phase II randomized, double-blind, placebo-controlled, dose-escalating trial evaluated the safety and immunogenicity of M01ZH09 to 1.7 x 10(10) colony-forming units (CFU). 187 Healthy adults received vaccine or placebo in four cohorts. Serologic responses and IgA ELISPOT were measured. At all doses, the vaccine was well tolerated and without bacteremias. One subject had a transient low-grade fever. 62.2-86.1% of subjects seroconverted S. Typhi-specific LPS IgG and 83.3-97.4% IgA; 92.1% had a positive S. Typhi LPS ELISPOT. M01ZH09 is safe and immunogenic up to 1.7 x 10(10)CFU. Efficacy testing of this single-dose oral typhoid vaccine is needed. PMID:20188175

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

2010-04-30

234

Dose selection trial of metronomic oral vinorelbine monotherapy in patients with metastatic cancer: a hellenic cooperative oncology group clinical translational study  

PubMed Central

Background Metronomic chemotherapy is considered an anti-angiogenic therapy that involves chronic administration of low-dose chemotherapy at regular short intervals. We investigated the optimal metronomic dose of oral vinorelbine when given as monotherapy in patients with metastatic cancer. Methods Patients with recurrent metastatic breast (BC), prostate (PC) or non-small cell lung cancer (NSCLC) and adequate organ functions were randomly assigned to 30, 40 or 50 mg vinorelbine, taken orally three times a week. Treatment continued until disease progression, unacceptable toxicity, withdrawal of consent or maximum 24 months. Primary endpoint was time-to-treatment failure (TTF) and secondary were progression-free survival (PFS), toxicity, changes in blood concentrations of angiogenesis-associated biomarkers and pharmacokinetics. Results Seventy-three patients were enrolled. Four-month TTF rate did not differ between the three arms: 25.9% (11.1%-46.2% 95% Confidence Interval), 33.3% (15.6%-55.3%) and 18.2% (5.2%-40.3%) for the 30 mg, 40 mg and 50 mg arms (p-value?=?0.56). Objective response was seen in 2 patients with NSCLC (treated at 30 and 50 mg respectively), one with BC (at 40 m g) and one with PC (at 50 mg) and lasted from 4 to 100 weeks, with maximum response duration achieved at 50 mg. Adverse events were mild and negligible and did not differ between the three arms. Blood levels of vinorelbine reached steady state from the second week of treatment and mean values for the 30, 40 and 50 mg were respectively 1.8 ng/ml (SD 1.10), 2.2 ng/ml (SD 1.87) and 2.6 ng/ml (SD 0.69). Low pre-treatment blood concentrations of FGF2 and IL8 predicted favorable response to therapy (p values 0.02 and 0.006, respectively), while high levels of TEK gene transcript predicted treatment resistance. Conclusions Considering the antitumor activity and response duration, the negligible toxicity of the highest dose investigated and the lack of drug accumulation over time, we suggest that 50 mg given three times a week is the optimal dose for metronomic oral vinorelbine. Further investigation of metronomic oral vinorelbine (MOVIN) at this dose is warranted in combination with conventional chemotherapy regimens and targeted therapies. Trial registration Clinicaltrials.gov NCT00278070 PMID:23718900

2013-01-01

235

Treatment of oral leukoplakia with a low-dose of beta-carotene and vitamin C supplements: A randomized controlled trial.  

PubMed

Management of oral leukoplakia-a potentially malignant disorder-is currently not evidence-based. Of the few randomized trials that have been reported, most have negative data. Therefore, a multi-centre, randomized, double-blind controlled trial (RCT) was undertaken to evaluate the use of low-dose beta-carotene combined with vitamin C supplements for the treatment and to prevent malignant transformation of oral leukoplakia. 46 Japanese participants with oral leukoplakia were allocated randomly either to an experimental arm (10 mg day(-1) of beta-carotene and 500 mg day(-1) of vitamin C) or placebo arm (50 mg day(-1) of vitamin C). Current or ex-smokers within 3 months of cessation were excluded. The supplements were continued over a period of 1 year. The primary endpoint was clinical remission at 1-year and the likelihood of malignant transformation during a 5-year follow-up period as a secondary endpoint. The overall clinical response rate in the experimental arm was 17.4% (4/23) and 4.3% (1/23) in the placebo arm (p = 0.346). During the median 60-month follow-up period, two subjects in the experimental arm and three in the control arm developed oral cancer. Under the intention-to-treat principle, relative risk by supplementing with beta-carotene and vitamin C was 0.77 (95%CI: 0.28-1.89) (p = 0.580) by the Cox proportional hazards model. No unfavorable side-effects were noted. Beta-carotene (10 mg day(-1) ) and vitamin C were neither effective for clinical remission, nor for protection against the development of cancer. Data from this RCT does not support the hypothesis that chemoprevention with this treatment is effective for oral leukoplakia. PMID:25156040

Nagao, Toru; Warnakulasuriya, Saman; Nakamura, Tomoyasu; Kato, Shinichiro; Yamamoto, Keiichi; Fukano, Hideo; Suzuki, Koji; Shimozato, Kazuo; Hashimoto, Shuji

2015-04-01

236

Short-term effects of treatment with 300 mg oral-dose diethylcarbamazine on nocturnally periodic Wuchereria bancrofti microfilaremia and antigenemia.  

PubMed

Seven microfilaremic Myanmar patients were treated with a single 300 mg dose of diethylcarbamazine (DEC) orally, as part of a case-finding survey in Ranong Province, Southern Thailand. This was conducted in order to evaluate the short-term effects of single-dose DEC on Wuchereria bancrofti microfilaremia and antigenemia during a 12-week course of treatment. Analysis of microfilarial periodicity on initial treatment revealed the microfilarial peak density (k) was at 52 minutes after midnight (0052). The periodicity index was then 103.26%. Single-dose DEC treatment did not affect the k values. A linear model of W. bancrofti microfilarial density reduction predicts a sharp decrease in the mean microfilarial density 2 weeks after DEC intake (Z = -2.197, p = 0.028). Over a longer period, a non-linear model predicts an increase in the mean microfilarial density to pre-treatment levels, having little or no macrofilaricidal effects. We reconfirmed the existence of nocturnally periodic W. bancrofti infection in Myanmar migrants in Ranong Province, and the short-term microfilaricidal activity of 300 mg single-dose DEC treatment used for biannual mass treatment and the DEC provocative test. Without an adequate DEC treatment dose, recrudescence can occur. A rational approach to the management of introduced nocturnally periodic W. bancrofti in Myanmar migrants, who came for short periods of stay in transmission-prone areas, is needed. PMID:16295533

Siriaut, Chumsin; Bhumiratana, Adisak; Koyadun, Surachart; Anurat, Kowit; Satitvipawee, Pratana

2005-07-01

237

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

238

Dose reduction of cone beam CT scanning for the entire oral and maxillofacial regions with thyroid collars  

PubMed Central

Objective The aim of this study was to evaluate the influence of thyroid collars on radiation dose during cone beam CT (CBCT) scanning. Methods Average tissue-absorbed dose for a NewTom 9000 CBCT scanner (Quantitative Radiology, Verona, Italy) was measured using thermoluminescent dosemeter chips in a phantom. The scans were carried out with and without thyroid collars. Effective organ dose and total effective dose were derived using International Commission on Radiological Protection 2007 recommendations. Results The effective organ doses for the thyroid gland and oesophagus were 31.0 µSv and 2.4 µSv, respectively, during CBCT scanning without a collar around the neck. When the thyroid collars were used loosely around the neck, no effective organ dose reduction was observed. When one thyroid collar was used tightly on the front of the neck, the effective organ dose for the thyroid gland and oesophagus were reduced to 15.9 µSv (48.7% reduction) and 1.4 µSv (41.7% reduction), respectively. Similar organ dose reduction (46.5% and 41.7%) was achieved when CBCT scanning was performed with two collars tightly on the front and back of the neck. However, the differences to the total effective dose were not significant among the scans with and without collars around the neck (p = 0.775). Conclusions Thyroid collars can effectively reduce the radiation dose to the thyroid and oesophagus if used appropriately. PMID:22707330

Qu, XM; Li, G; Sanderink, GCH; Zhang, ZY; Ma, XC

2012-01-01

239

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

240

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

Microsoft Academic Search

.  This study investigated the possible influence of oral caffeine administration on endogenous glucose production and energy\\u000a substrate metabolism during prolonged endurance exercise. Twelve trained endurance athletes [seven male, five female; peak\\u000a oxygen consumption (\\u000a ) = 65.5 ml·kg–1·min–1] performed 60 min of cycle ergometry at 65% \\u000a twice, once after oral caffeine administration (6 mg·kg–1) (CAF) and once following consumption of a placebo (PLA).

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

2001-01-01

241

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

Microsoft Academic Search

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

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

1999-01-01

242

ABSORPTION, DISTRIBUTION, EXCRETION, AND METABOLISM OF A SINGLE ORAL DOSE OF O-ETHYL O-4-NITROPHENYL PHENYLPHOSPHONOTHIOATE IN HENS  

EPA Science Inventory

The disposition and metabolism of a single oral 10 mg/kg (LD50) of uniformly phenyl-labeled (14C)EPN (O-ethyl O-4 nitrophenyl (14C) phenylphosphonothioate) were studied in adult hens. The birds were protected from acute toxicity with atropine sulfate. Three treated hens were kill...

243

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

PubMed Central

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

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

2014-01-01

244

Microdosing clinical study: pharmacokinetic, pharmacogenomic (SLCO2B1), and interaction (grapefruit juice) profiles of celiprolol following the oral microdose and therapeutic dose.  

PubMed

The authors evaluated the contribution of the SLCO2B1 polymorphism to the pharmacokinetics of celiprolol at a microdose (MD) and therapeutic dose (TD) and compared pharmacokinetic proportionality between the 2 dose forms in 30 SLCO2B1 genotype-matched healthy volunteers. Three drugs (celiprolol, fexofenadine, and atenolol) were orally administered as a cassette dosing following the MD (totally 97.5 µg) and then a TD (100 mg) of celiprolol, with and without grapefruit juice. The mean AUC(0-24) of celiprolol was lower in SLCO2B1*3/*3 individuals (775 ng·h/mL) than in *1/*3 (1097 ng·h/mL) and *1/*1 (1547 ng·h/mL) individuals following the TD, and this was confirmed in population pharmacokinetic analysis with statistical significances; however, SLCO2B1 genotype-dependent differences disappeared following the MD. Dose-normalized AUC of celiprolol at the MD was much lower than that at the TD, explained by the saturation of the efflux transporter. Thus, the effect of SLCO2B1 polymorphism on the AUC of celiprolol clearly observed only at the TD may be due to the saturation of the efflux transport systems. PMID:21593283

Ieiri, Ichiro; Doi, Yohei; Maeda, Kazuya; Sasaki, Tomohiro; Kimura, Miyuki; Hirota, Takeshi; Chiyoda, Takeshi; Miyagawa, Mayuko; Irie, Shin; Iwasaki, Kazuhide; Sugiyama, Yuichi

2012-07-01

245

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

PubMed

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

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

2014-01-01

246

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

PubMed Central

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

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

2013-01-01

247

Distribution of R- and S-methadone into human milk during multiple, medium to high oral dosing  

PubMed Central

Aims To measure the interdose milk to plasma ratio (M/P) of R- and S-methadone during multiple dosing in lactating mothers taking medium to high doses of methadone (> 40 mg daily), and to assess likely infant exposure. Methods Eight mother/child pairs were studied, initially during their postpartum hospital stay (immature milk), and where possible again after 15 days (mature milk). The women were on a methadone maintenance programme with daily doses of ?40 mg day?1. Venous blood was collected at 0, 1, 2, 4, 6, 8, 12, and 24 h and milk was collected from both breasts at 0–4, 4–8, 8–12, 12–16, 16–20, and 20–24 h after dose. R- and S-methadone were quantified by h.p.l.c. The areas under the plasma and milk concentration-time curves (AUC) were estimated and M/PAUC was calculated. The relative infant dose of both enantiomers was estimated as the product of drug concentration in milk and an average daily milk intake of 0.15 l kg?1. Results For immature milk (n = 8) the M/PAUC for R-methadone was 0.68 (95% CI 0.48, 0.89) and for S-methadone 0.38 (0.26, 0.50). For mature milk (n = 2) the M/PAUCs for R-methadone were 0.39 and 0.54 and for S-methadone 0.24 and 0.30, respectively. The estimated doses of R- and S-methadone that would be received by the infant via immature milk were 3.5% (2.05, 5.03%) and 2.1% (1.3, 2.8%), respectively, of the maternal dose (assuming 50% of each enantiomer in the dose). The relative infant dose for R- plus S-methadone together was 2.8% (1.7, 3.9%). Conclusions Breastfeeding during medium to high dose methadone appears to be ‘safe’ according to conventional criteria because the dosage is < 10%. However because the absolute dose received by the infant is dependent on the maternal dose rate, the risk-benefit ratio should be considered for each individual case. The doses of methadone received via milk are unlikely to be sufficient to prevent the neonatal abstinence syndrome. PMID:11736879

Begg, Evan J; Malpas, Timothy J; Hackett, L Peter; Ilett, Kenneth F

2001-01-01

248

Human Pharmacokinetics of High Dose Oral Curcumin and Its Effect on Heme Oxygenase-1 Expression in Healthy Male Subjects  

PubMed Central

Purpose. Heme oxygenase-1 (HO-1) has been proposed to exert pharmacological benefits by its antioxidative and anti-inflammatory effects. HO-1 expression may be affected by the GT length polymorphism in the promoter region of the HO-1 gene. We investigated the inducibility of HO-1 by orally administered curcumin in healthy male subjects and its correlation with the GT length polymorphism. Methods. In an open label uncontrolled phase-1 pilot study, ten male subjects received 12?g of oral curcumin. To investigate the effects of the GT length polymorphism on the inducibility of HO-1, five subjects with homozygous short and five with homozygous long GT genotypes were studied. Plasma concentrations of curcumin, bilirubin, HO-1 mRNA, and protein expression in peripheral blood mononuclear cells (PBMCs) were analyzed over 48 hours. Results. At a detection limit of 1?µg/mL curcumin could not be detected in plasma of any subject. Compared to baseline, HO-1 mRNA and protein levels were not induced in PBMCs at any time point up to 48 hours. There was no correlation between any of the parameters and GT length polymorphism. Conclusions. Oral curcumin administration has low bioavailability and does not induce HO-1 on mRNA or protein level in PBMCs. PMID:24592391

Klickovic, Uros; Doberer, Daniel; Gouya, Ghazaleh; Aschauer, Stefan; Weisshaar, Stefan; Bilban, Martin; Wolzt, Michael

2014-01-01

249

Twenty-eight-day oral toxicity, genotoxicity, and gender-related tissue distribution of silver nanoparticles in Sprague-Dawley rats.  

PubMed

The antibacterial effect of silver nanoparticles has resulted in their extensive application in health, electronic, and home products. However, while the population exposed to silver nanoparticles continues to increase with ever new applications, silver nanoparticles remain a controversial research area as regards their toxicity to biological systems. In particular, the oral toxicity of silver nanoparticles is of particular concern to ensure public and consumer health. Accordingly, this study tested the oral toxicity of silver nanoparticles (60 nm) over a period of 28 days in Sprague-Dawley rats following Organization for Economic Cooperation and Development (OECD) test guideline 407 with Good Laboratory Practice (GLP) application. Eight-week-old rats, weighing about 283 g for the males and 192 g for the females, were divided into four 4 groups (10 rats in each group): vehicle control, low-dose group (30 mg/kg), middle-dose group (300 mg/kg), and high-dose group (1000 mg/kg). After 28 days of exposure, the blood biochemistry and hematology were investigated, along with a histopathological examination and silver distribution study. The male and female rats did not show any significant changes in body weight relative to the doses of silver nanoparticles during the 28-day experiment. However, some significant dose-dependent changes were found in the alkaline phsophatase and cholesterol values in either the male or female rats, seeming to indicate that exposure to over more than 300 mg of silver nanoparticles may result in slight liver damage. There were no statistically significant differences in the micronucleated polychromatic erythrocytes (MN PCEs) or ratio of polychromatic erythrocytes among the total erythrocytes after silver nanoparticle exposure when compared with the control. Therefore, the present results suggest that silver nanoparticles do not induce genetic toxicity in male and female rat bone marrow in vivo. Nonetheless, the tissue distribution of silver nanopaticles did show a dose-dependent accumulation of silver content in all the tissues examined. In particular, a gender-related difference in the accumulation of silver was noted in the kidneys, with a twofold increase in the female kidneys when compared with the male kidneys. PMID:18444010

Kim, Yong Soon; Kim, Jin Sik; Cho, Hyun Sun; Rha, Dae Sik; Kim, Jae Min; Park, Jung Duck; Choi, Byung Sun; Lim, Ruth; Chang, Hee Kyung; Chung, Yong Hyun; Kwon, Il Hoon; Jeong, Jayoung; Han, Beom Seok; Yu, Il Je

2008-04-01

250

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

PubMed Central

Objective Muscle loss and metabolic changes occur with disuse [i.e. bed rest (BR)]. We hypothesized that BR would lead to a metabolically unhealthy profile defined by: increased circulating tumor necrosis factor (TNF)-?, decreased circulating insulin-like-growth-factor (IGF)-1, decreased HDL-cholesterol, and decreased muscle density (MD; measured by mid-thigh computerized tomography). Methods We investigated the metabolic profile after 28 days of BR with 8±6% energy deficit in male individuals (30-55 years) randomized to resistance exercise with amino acid supplementation (RT, n=24) or amino acid supplementation alone (EAA, n=7). Upper and lower body exercises were performed in the horizontal position. Blood samples were taken at baseline, after 28 days of BR and 14 days of recovery. Results We found a shift toward a metabolically unfavourable profile after BR [compared to baseline (BLN)] in both groups as shown by decreased HDL-cholesterol levels (EAA: BLN: 39±4 vs. BR: 32±2 mg/dL, RT: BLN: 39±1 vs. BR: 32±1 mg/dL; p<0.001) and Low MD (EAA: BLN: 27±4 vs. BR: 22±3 cm2, RT: BLN: 28±2 vs. BR: 23±2 cm2; p<0.001). A healthier metabolic profile was maintained with exercise, including NormalMD (EAA: BLN: 124±6 vs. BR: 110±5 cm2, RT: BLN: 132±3 vs. BR: 131±4 cm2; p<0.001, time-by-group); although, exercise did not completely alleviate the unfavourable metabolic changes seen with BR. Interestingly, both groups had increased plasma IGF-1 levels (EAA: BLN:168±22 vs. BR 213±20 ng/mL, RT: BLN:180±10 vs. BR: 219±13 ng/mL; p<0.001) and neither group showed TNF? changes (p>0.05). Conclusions We conclude that RT can be incorporated to potentially offset the metabolic complications of BR. PMID:25317071

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

2014-01-01

251

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

PubMed

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

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

2014-11-01

252

Lack of a pre-emptive effect of low-dose ketamine on postoperative pain following oral surgery  

Microsoft Academic Search

\\u000a Abstract\\u000a Purpose  The aim of this study was to assess the effect of pre- vs postincisional low-doseiv ketamine on postoperative pain in outpatients scheduled for oral surgery under general anesthesia.\\u000a \\u000a \\u000a \\u000a Methods  Eighty-four patients were randomly assigned to receive intravenously saline before and after surgery in Group 1, ketamine\\u000a 300 µg·kg-1\\u000a iv before and saline after surgery in Group 2, saline before and

Thierry Lebrun; Alain C. Van Elstraete; Ignace Sandefo; Bruno Polin; Luc Pierre-Louis

2006-01-01

253

Pharmacokinetics of High-Dose Weekly Oral Vitamin D3 Supplementation during the Third Trimester of Pregnancy in Dhaka, Bangladesh  

PubMed Central

A pharmacokinetic study was conducted to assess the biochemical dose-response and tolerability of high-dose prenatal vitamin D3 supplementation in Dhaka, Bangladesh (23°N). Pregnant women at 27–30 weeks gestation (n = 28) were randomized to 70,000 IU once + 35,000 IU/week vitamin D3 (group PH: pregnant, higher dose) or 14,000 IU/week vitamin D3 (PL: pregnant, lower dose) until delivery. A group of non-pregnant women (n = 16) was similarly administered 70,000 IU once + 35,000 IU/week for 10 weeks (NH: non-pregnant, higher-dose). Rise (?) in serum 25-hydroxyvitamin D concentration ([25(OH)D]) above baseline was the primary pharmacokinetic outcome. Baseline mean [25(OH)D] were similar in PH and PL (35 nmol/L vs. 31 nmol/L, p = 0.34). A dose-response effect was observed: ?[25(OH)D] at modeled steady-state was 19 nmol/L (95% CI, 1 to 37) higher in PH vs. PL (p = 0.044). ?[25(OH)D] at modeled steady-state was lower in PH versus NH but the difference was not significant (?15 nmol/L, 95% CI ?34 to 5; p = 0.13). In PH, 100% attained [25(OH)D] ? 50 nmol/L and 90% attained [25(OH)D] ? 80 nmol/L; in PL, 89% attained [25(OH)D] ? 50 nmol/L but 56% attained [25(OH)D] ? 80 nmol/L. Cord [25(OH)D] (n = 23) was slightly higher in PH versus PL (117 nmol/L vs. 98 nmol/L; p = 0.07). Vitamin D3 was well tolerated; there were no supplement-related serious adverse clinical events or hypercalcemia. In summary, a regimen of an initial dose of 70,000 IU and 35,000 IU/week vitamin D3 in the third trimester of pregnancy was non-hypercalcemic and attained [25(OH)D] ? 80 nmol/L in virtually all mothers and newborns. Further research is required to establish the safety of high-dose vitamin D3 in pregnancy and to determine if supplement-induced [25(OH)D] elevations lead to maternal-infant health benefits. PMID:23482056

Roth, Daniel E.; Al Mahmud, Abdullah; Raqib, Rubhana; Akhtar, Evana; Black, Robert E.; Baqui, Abdullah H.

2013-01-01

254

Pharmacokinetics of high-dose weekly oral vitamin D3 supplementation during the third trimester of pregnancy in Dhaka, Bangladesh.  

PubMed

A pharmacokinetic study was conducted to assess the biochemical dose-response and tolerability of high-dose prenatal vitamin D3 supplementation in Dhaka, Bangladesh (23°N). Pregnant women at 27-30 weeks gestation (n = 28) were randomized to 70,000 IU once + 35,000 IU/week vitamin D3 (group PH: pregnant, higher dose) or 14,000 IU/week vitamin D3 (PL: pregnant, lower dose) until delivery. A group of non-pregnant women (n = 16) was similarly administered 70,000 IU once + 35,000 IU/week for 10 weeks (NH: non-pregnant, higher-dose). Rise (?) in serum 25-hydroxyvitamin D concentration ([25(OH)D]) above baseline was the primary pharmacokinetic outcome. Baseline mean [25(OH)D] were similar in PH and PL (35 nmol/L vs. 31 nmol/L, p = 0.34). A dose-response effect was observed: ?[25(OH)D] at modeled steady-state was 19 nmol/L (95% CI, 1 to 37) higher in PH vs. PL (p = 0.044). ?[25(OH)D] at modeled steady-state was lower in PH versus NH but the difference was not significant (-15 nmol/L, 95% CI -34 to 5; p = 0.13). In PH, 100% attained [25(OH)D] ? 50 nmol/L and 90% attained [25(OH)D] ? 80 nmol/L; in PL, 89% attained [25(OH)D] ? 50 nmol/L but 56% attained [25(OH)D] ? 80 nmol/L. Cord [25(OH)D] (n = 23) was slightly higher in PH versus PL (117 nmol/L vs. 98 nmol/L; p = 0.07). Vitamin D3 was well tolerated; there were no supplement-related serious adverse clinical events or hypercalcemia. In summary, a regimen of an initial dose of 70,000 IU and 35,000 IU/week vitamin D3 in the third trimester of pregnancy was non-hypercalcemic and attained [25(OH)D] ? 80 nmol/L in virtually all mothers and newborns. Further research is required to establish the safety of high-dose vitamin D3 in pregnancy and to determine if supplement-induced [25(OH)D] elevations lead to maternal-infant health benefits. PMID:23482056

Roth, Daniel E; Al Mahmud, Abdullah; Raqib, Rubhana; Akhtar, Evana; Black, Robert E; Baqui, Abdullah H

2013-03-01

255

Thermoplastic polyurethanes for the manufacturing of highly dosed oral sustained release matrices via hot melt extrusion and injection molding.  

PubMed

This study evaluated thermoplastic polyurethanes (TPUR) as matrix excipients for the production of oral solid dosage forms via hot melt extrusion (HME) in combination with injection molding (IM). We demonstrated that TPURs enable the production of solid dispersions - crystalline API in a crystalline carrier - at an extrusion temperature below the drug melting temperature (Tm) with a drug content up to 65% (wt.%). The release of metoprolol tartrate was controlled over 24h, whereas a complete release of diprophylline was only possible in combination with a drug release modifier: polyethylene glycol 4000 (PEG 4000) or Tween 80. No burst release nor a change in tablet size and geometry was detected for any of the formulations after dissolution testing. The total matrix porosity increased gradually upon drug release. Oral administration of TPUR did not affect the GI ecosystem (pH, bacterial count, short chain fatty acids), monitored via the Simulator of the Human Intestinal Microbial Ecosystem (SHIME). The high drug load (65wt.%) in combination with (in vitro and in vivo) controlled release capacity of the formulations, is noteworthy in the field of formulations produced via HME/IM. PMID:25448075

Claeys, Bart; Vervaeck, Anouk; Hillewaere, Xander K D; Possemiers, Sam; Hansen, Laurent; De Beer, Thomas; Remon, Jean Paul; Vervaet, Chris

2014-11-15

256

Prolonged oral versus high-dose intravenous etoposide in combination with carboplatin for stage IV non-small-cell lung cancer (NSCLC): a randomized trial.  

PubMed

In order to investigate whether dose-intensive intravenous (i.v.) etoposide offers an advantage over prolonged oral administration of etoposide when combined with carboplatin (CBDCA), between January, 1991 and December, 1994, 171 patients with metastatic (stage IV) non-small cell lung cancer were randomized to receive CBDCA, 400 mg/m2, day 1 with either oral etoposide, 50 mg/m2, days 1-21 (group I) or i.v. etoposide, 200 mg/m2, days 1-3 (group II), every 4 weeks for up to six cycles or until tumour progression. Of the patients 168 were fully assessable for response, survival and toxicity. There were three (4%) CR and 16 (19%) PR in group 1, and the overall response rate was 23%. There were four (5%) CR and 12 (14%) PR in group II, and the overall response rate was 19% (P = 0.82). The median survival time (MST) in group I was 8 months, and 1- and 2-year survival rates were 35 and 9.5%, respectively, while the corresponding figures for group II were 7 months, and 31 and 7.1%, respectively (P = 0.40). Both haematological and non-haematological toxicity was significantly more frequent in group II with six (7%) patients in that group dying of treatment-related infection. Intensive i.v. etoposide combined with CBDCA was similar in efficacy to but more toxic than prolonged oral etoposide plus carboplatin and we do not recommend it for further investigation. PMID:10512132

Jeremic, B; Shibamoto, Y; Milicic, B; Milisavljevic, S; Nikolic, N; Dagovic, A; Aleksandrovic, J; Radosavljevic-Asic, G

1999-09-01

257

Plasma Pharmacokinetics of High-Dose Oral Melphalan in Patients Treated with Trialkylator Chemotherapy and Autologous Bone Marrow Reinfusion1  

Microsoft Academic Search

The pharmacokinetics of melphalan following high-dose p.o. admin istration were determined in 17 patients with various malignancies for the purpose of assessing interpatient and intrapatient pharmacokinetic variability. All patients underwent bone marrow harvest on day -8 (relative to bone marrow reinfusion). On days â€\\

Kyung E. Choi; Mark J. Ratain; Stephanie F. Williams; Janet A. Golick; Janet C. Beschorner; Jacob D. Bitran

1989-01-01

258

Chemoembolization of oral and oropharyngeal cancer using a high-dose cisplatin crystal suspension and degradable starch microspheres  

Microsoft Academic Search

The aim of the study was to achieve intensification of intraarterial chemotherapy of head and neck cancer with high-dose cisplatin by establishing a new method of chemoembolization which can be routinely used without the earlier drawbacks of the method (low drug dosage due to early occlusion of the small head and neck vessels, danger of local damage). Thirty two patients

Adorján F Kovács; Bernd Turowski

2002-01-01

259

Improvement of the Cramer classification for oral exposure using the database TTC RepDose - A strategy description  

EPA Science Inventory

The present report describes a strategy to refine the current Cramer classification of the TTC concept using a broad database (DB) termed TTC RepDose. Cramer classes 1-3 overlap to some extent, indicating a need for a better separation of structural classes likely to be toxic, mo...

260

Phase Ib, Dose Escalation Study of Oral LDE225 in Combination With BKM120 in Patients With Advanced Solid Tumors  

ClinicalTrials.gov

Dose Escalation; Safety; Preliminary Efficacy; Advanced Solid Tumors; Metastatic Breast Cancer; Advanced Pancreatic Adenocarcinoma; Metastatic Colorectal Cancer; Recurrent Glioblastoma Multiforme; Gastric Cancer; Gastroesophageal Junction Cancer; Triple Negative Metastatic Breast Cancer; Hormone Receptor Positive (ER+/PR+, and Her2-) Metastatic Breast Cancer

2014-09-24

261

Efficacy of dosing and re-dosing of two oral fixed combinations of indomethacin, prochlorperazine and caffeine compared with oral sumatriptan in the acute treatment of multiple migraine attacks: a double-blind, double-dummy, randomised, parallel group, multicentre study  

PubMed Central

Aims and methods: In this double-blind, double-dummy, randomised, parallel group, multicentre study, the efficacy of dosing and re-dosing of a fixed combination of indomethacin, prochlorperazine and caffeine (Indoprocaf) was compared with encapsulated sumatriptan in the acute treatment of two migraine attacks. Additionally, in the group taking Indoprocaf, two different oral formulations were tested: effervescent tablets and encapsulated coated tablets. Results: Of 297 patients randomised (150 assigned to Indoprocaf and 147 to sumatriptan), 281 were included in the intention-to-treat efficacy analysis. The initial dosing of Indoprocaf and sumatriptan was similarly effective with pain-free rates higher than 30% (95% CI of odds-ratio: 0.57–1.28) and headache relief rates of about 60% (95% CI of odds-ratio: 0.82–1.84) with both the drugs. The efficacy of re-dosing of Indoprocaf as rescue medication was more effective than that of sumatriptan with pain-free values of 47% vs. 27% in the total attacks with a statistically significant difference in the first migraine attack in favour of Indoprocaf. The efficacy of re-dosing to treat a recurrence/relapse was very high without differences between the drugs (pain-free: 60% with Indoprocaf and 50% with sumatriptan in the total attacks). Indoprocaf and sumatriptan were well-tolerated. Conclusion: The study demonstrated that the efficacy of the initial dosing of Indoprocaf was not higher than that of sumatriptan, but that the strategy to use the lowest effective dose as soon as the headache occurred, followed by a second dose if the headache has not relieved or to treat a relapse, was very effective, especially with Indoprocaf. PMID:17627707

Sandrini, G; Cerbo, R; Del Bene, E; Ferrari, A; Genco, S; Grazioli, I; Martelletti, P; Nappi, G; Pinessi, L; Sarchielli, P; Tamburro, P; Uslenghi, C; Zanchin, G

2007-01-01

262

Pharmacokinetics of a single oral dose of vitamin D3 (70,000 IU) in pregnant and non-pregnant women  

PubMed Central

Background Improvements in antenatal vitamin D status may have maternal-infant health benefits. To inform the design of prenatal vitamin D3 trials, we conducted a pharmacokinetic study of single-dose vitamin D3 supplementation in women of reproductive age. Methods A single oral vitamin D3 dose (70,000 IU) was administered to 34 non-pregnant and 27 pregnant women (27 to 30 weeks gestation) enrolled in Dhaka, Bangladesh (23°N). The primary pharmacokinetic outcome measure was the change in serum 25-hydroxyvitamin D concentration over time, estimated using model-independent pharmacokinetic parameters. Results Baseline mean serum 25-hydroxyvitamin D concentration was 54 nmol/L (95% CI 47, 62) in non-pregnant participants and 39 nmol/L (95% CI 34, 45) in pregnant women. Mean peak rise in serum 25-hydroxyvitamin D concentration above baseline was similar in non-pregnant and pregnant women (28 nmol/L and 32 nmol/L, respectively). However, the rate of rise was slightly slower in pregnant women (i.e., lower 25-hydroxyvitamin D on day 2 and higher 25-hydroxyvitamin D on day 21 versus non-pregnant participants). Overall, average 25-hydroxyvitamin D concentration was 19 nmol/L above baseline during the first month. Supplementation did not induce hypercalcemia, and there were no supplement-related adverse events. Conclusions The response to a single 70,000 IU dose of vitamin D3 was similar in pregnant and non-pregnant women in Dhaka and consistent with previous studies in non-pregnant adults. These preliminary data support the further investigation of antenatal vitamin D3 regimens involving doses of ?70,000 IU in regions where maternal-infant vitamin D deficiency is common. Trial registration ClinicalTrials.gov (NCT00938600) PMID:23268736

2012-01-01

263

Metabolism of the plasticizer and phthalate substitute diisononyl-cyclohexane-1,2-dicarboxylate (DINCH(®)) in humans after single oral doses.  

PubMed

Hexamoll(®) DINCH(®) (diisononyl-cyclohexane-1,2-dicarboxylate) is a new high-molecular-weight plasticizer and a phthalate substitute. In this study, the metabolism of DINCH(®) was investigated by oral dosage of three male volunteers with approximately 50 mg Hexamoll(®) DINCH(®) (resulting in individual doses between 0.552 and 0.606 mg/kg body weight). Their urine samples were consecutively collected over 48 h. In analogy to di-iso-nonylphthalate (DINP) metabolism, we quantified the simple monoester mono-isononyl-cyclohexane-1,2-dicarboxylate (MINCH) and its secondary oxidized metabolites with HPLC-MS/MS via isotope dilution analysis. Additionally, we quantified the unspecific full breakdown product, cyclohexane-1,2-dicarboxylic acid (CHDA), via standard addition. All postulated metabolites were present in all samples analyzed. The unspecific CHDA was identified as the major urinary metabolite representing 23.7 % of the dose as the mean of the three volunteers (range 20.0-26.5 %). 14.8 % (11.3-16.7 %) of the dose was excreted as monoesters with oxidative modifications, in particular OH-MINCH 10.7 % (7.7-12.9 %), oxo-MINCH 2.0 % (1.5-2.6 %) and carboxy-MINCH 2.0 % (1.8-2.3 %). Less than 1 % was excreted as the simple monoester MINCH. In sum, 39.2 % (35.9-42.4 %) of the DINCH(®) dose was excreted as these metabolites in urine within 48 h. Over 90 % of the metabolites investigated were excreted within 24 h after application. The secondary oxidized metabolites, with elimination half-times between 10 and 18 h, proved to be apt and specific biomarkers to determine DINCH(®) exposure. With this study, we provide reliable urinary excretion factors to calculate DINCH(®) intakes based on these metabolites in environmental and occupational studies. PMID:23203454

Koch, Holger M; Schütze, André; Pälmke, Claudia; Angerer, Jürgen; Brüning, Thomas

2013-05-01

264

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

SciTech Connect

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

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

1989-06-01

265

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

PubMed Central

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

TANAKA, NOZOMU; SAKAMOTO, KAZUKI; OKABE, HIROYUKI; FUJIOKA, AKIO; YAMAMURA, KEISUKE; NAKAGAWA, FUMIO; NAGASE, HIDEKI; YOKOGAWA, TATSUSHI; OGUCHI, KEI; ISHIDA, KEIJI; OSADA, AKIKO; KAZUNO, HIROMI; YAMADA, YUKARI; MATSUO, KENICHI

2014-01-01

266

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

PubMed

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

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

2014-12-01

267

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

PubMed Central

Purpose To investigate the possible associations between serum levels of soluble receptor for advanced glycation end products (sRAGE) and specific clinical markers and prognosis in critically ill patients diagnosed with stress hyperglycemia. Patients and methods A total of 70 critically ill patients and 25 normal controls were recruited for this study. Serum levels of sRAGE and advanced glycation end products (AGEs) were determined using enzyme-linked immunosorbent assay. Additional data on other clinical markers were obtained from patient records in the intensive care unit. Comparisons of sRAGE and AGEs levels between groups were assessed by t-test. The relationships between sRAGE and other clinical markers were assessed by Pearson’s correlation analyses and multiple linear regression analyses. Risk factors for prognosis, such as 28-day mortality were analyzed using logistic regression analysis. Results Serum sRAGE and AGEs levels were significantly higher in critically ill patients, compared to normal controls (P<0.05). The increase in serum sRAGE levels was significantly correlated with AGEs levels, interleukin-6 levels, and the sequential organ failure assessment score (P<0.01). Using multiple linear regression analysis, the association between AGEs and sRAGE remained significant after adjustment of other clinical factors. However, there were no significant correlations between sRAGE levels and patient outcome in these critically ill patients. Conclusion Serum sRAGE levels were significantly elevated in critically ill patients and positively correlated with higher AGEs levels, but sRAGE levels were not associated with increased mortality, suggesting sRAGE levels are not a predictor of prognosis in critically ill patients. PMID:25429209

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

2014-01-01

268

Intra-arterial induction high-dose chemotherapy with cisplatin for oral and oropharyngeal cancer: long-term results  

Microsoft Academic Search

Intra-arterial (IA) chemotherapy for curative treatment of head and neck cancer experienced a revival in the last decade. Mainly, it was used in concurrent combination with radiation in organ-preserving settings. The modern method of transfemoral approach for catheterisation, superselective perfusion of the tumour-feeding vessel, and high-dose (150 mg m?2) administration of cisplatin with parallel systemic neutralisation with sodium thiosulphate (9

A F Kovács

2004-01-01

269

Safety assessment of dietary bamboo charcoal powder: A 90-day subchronic oral toxicity and mutagenicity studies.  

PubMed

Vegetable carbon has been used as food additive in EU (E153) and China for many years; however, no experimental data have been available on its dietary safety. This study was designed to evaluate the subchronic toxicity and genotoxicity of bamboo charcoal powder (BCP). In the study of subchronic oral toxicity, BCP was administered orally at doses of 2.81, 5.62, and 11.24?g/kg BW for 90 days to SD rats. Additional satellite groups from the control group and high dose group were observed for a 28-day recovery period. At the end of the treatment and recovery periods, animals were sacrificed, and their organs were weighed and blood samples were collected. The toxicological endpoints observed included clinical signs, food consumption, body and organ weights, hematological and biochemical parameters, macroscopic and microscopic examinations. The results showed no significant differences between the BCP treated groups and control group. The genotoxicity of BCP was assessed with the Salmonella typhimurium mutagenicity assay (Ames test) and a combination of comet assay and mammalian erythrocyte micronucleus protocol. The results did not reveal any genotoxicity of BCP. Based on our study, the no-observed-adverse-effect level (NOAEL) for BCP is 11.24?g/kg BW/day. PMID:25445512

Zhenchao, Jia; Yuting, Zhong; Jiuming, Yan; Yedan, Lu; Yang, Song; Jinyao, Chen; Lishi, Zhang

2015-01-01

270

Modifications in rat testicular morphology and increases in IFN-gamma serum levels by the oral administration of subtoxic doses of mercuric chloride.  

PubMed

Mercury induces structural and functional damage in several organs, however the effects of subtoxic doses of the metal on the male reproductive system are not well defined. In order to analyze testicular and epididymal morphological alterations and changes in IL-4 or IFN-gamma serum levels, adult male Sprague-Dawley rats received 0.01, 0.05 or 0.1 microg/ml of mercuric chloride (HgCl(2)) in deionized water for 1 to 7 months by oral route. Controls received deionized water alone. Twenty rats, separated in four groups of five animals each, were used per time of exposure. Progressive degenerative lesions consisting of lack of germ cell cohesion and desquamation, arrest at spermatocyte stage and hypospermatogenesis were observed in seminiferous epithelium by light and electron microscopy. Leydig cells showed cytoplasmic vacuolation and nuclear signs of cell death. Loss of peritubular cell aggregation was evidenced in the epididymis. Mercury accumulation was detected in both organs by mass spectroscopy. Rats showed enhanced IFN-gamma serum levels as compared to controls but only reached significance after 7 months of mercury administration. Subtoxic doses of inorganic mercury could lead to reproductive and immunological alterations. The results demonstrate that sublethal concentrations of mercuric chloride are enough to induce morphological and ultrastructural modifications in male reproductive organs. These contribute to functional alterations of spermatogenesis with arrest at spermatocyte stage, hypospermatogenesis and possibly impaired steroidogenesis which together could affect male fertility. PMID:19462287

Penna, Salvador; Pocino, Marisol; Marval, Maria Josefina; Lloreta, José; Gallardo, Luis; Vila, Joan

2009-01-01

271

Efficacy and acceptability of the new oral phosphate binder Lenziaren(®) in healthy cats fed a renal diet.  

PubMed

The efficacy and acceptability of the new oral phosphate binder Lenziaren(®) (SBR759) were evaluated in healthy cats fed with a commercial diet containing low amounts of phosphate ('renal diet'). Lenziaren(®) at 0.125, 0.25, 0.5 and 1 g/day was compared to a reference product Lantharenol(®) (3.0 g/day) and a placebo in a masked, randomized, parallel-group design study in 36 cats (n = 6 per group). All products were mixed with the ration which was fed once daily for 28 days. Lenziaren(®) produced significant dose-related reductions in serum and urine phosphate concentrations, faecal apparent phosphorus digestibility and fractional urinary phosphate excretion. Cats administered Lenziaren(®) consumed significantly less food than the placebo group, but this had no negative impact on body weight or acceptability assessments. When compared to the positive control, Lantharenol(®) , Lenziaren(®) was significantly more acceptable (0.125, 0.5 and 1.0 g/day doses), was associated with higher food consumption (0.125, 0.5 and 1.0 g/day doses) and had greater efficacy in reducing serum phosphate (0.5 and 1.0 g/day) and urine phosphate concentrations (1.0 g/day). In conclusion, Lenziaren(®) was an effective oral phosphate binder in healthy cats fed with a renal diet. Lenziaren(®) was well accepted and tolerated. Dosages of 0.25-1.0 g/cat per day are recommended for clinical testing. PMID:25363785

King, J N; Delport, P C; Luus, H G; Erasmus, H L; Barnes, P M; Speranza, C

2014-11-01

272

cent PPC. From the age of 28 days, these diets were progressively replaced by 2nd age diets containing 19 per cent crude protein: barley, soya-bean, herring meal in group i and barley,  

E-print Network

cent PPC. From the age of 28 days, these diets were progressively replaced by 2nd age diets was offered. The protein digestibility of the 1st age diet (group 5) was reduced by 3.2 per cent, but this was compensated for by a 4.5 per cent improvement of this parameter in the 2nd age diet, notably in comparison

Paris-Sud XI, Université de

273

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

PubMed

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

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

2014-11-01

274

A Phase I Study of High-Dose Calcitriol in Combination with Temozolomide for Patients with Metastatic Melanoma  

PubMed Central

Background: Temozolomide is efficacious as an oral alternative for patients with metastatic melanoma (MM). Calcitriol has anti-proliferative properties and vitamin D receptor (VDR) polymorphisms are associated with alterations in melanoma susceptibility and progression. Methods: Tem 150 mg/m2 was administered on days 2–8 and 16–22 every 28 days. Calcitriol was given on days 1 and 15 every 28 days. VDR gene analysis was completed using PCR-RFLP based assays. Tolerability was the primary objective with secondary objectives of time to progression (TTP) and overall survival (OS). Results: Twenty pts with MM were registered. Cytopenias and thrombosis were the most common grade 3 or 4 toxicities. Median TTP was 1.8 mo. Pts with high-risk VDR genotype tt+/?ff (n = 6) had an OS of 3.8 mo from time of enrollment, compared to 7.4 mo for those with non-tt/ff genotypes (n = 11), although not statistically significant (HR = 1.20, 95% CI 0.41–3.53, p = 0.74). Conclusions: The extended dosing of Tem with calcitriol is a well-tolerated regimen. The trend toward improved OS in non-tt/ff VDR genotypes is consistent with prior studies associating the tt/ff genotype with biologic aggressiveness. PMID:25563456

Pettijohn, Erin; Martone, Brenda; Rademaker, Alfred; Kuzel, Timothy

2014-01-01

275

Phase II Study Evaluating 2 Dosing Schedules of Oral Foretinib (GSK1363089), cMET/VEGFR2 Inhibitor, in Patients with Metastatic Gastric Cancer  

PubMed Central

Purpose The receptors for hepatocyte and vascular endothelial cell growth factors (MET and VEGFR2, respectively) are critical oncogenic mediators in gastric adenocarcinoma. The purpose is to examine the safety and efficacy of foretinib, an oral multikinase inhibitor targeting MET, RON, AXL, TIE-2, and VEGFR2 receptors, for the treatment of metastatic gastric adenocarcinoma. Patients and Methods Foretinib safety and tolerability, and objective response rate (ORR) were evaluated in patients using intermittent (240 mg/day, for 5 days every 2 weeks) or daily (80 mg/day) dosing schedules. Thirty evaluable patients were required to achieve alpha?=?0.10 and beta?=?0.2 to test the alternative hypothesis that single-agent foretinib would result in an ORR of ?25%. Up to 10 additional patients could be enrolled to ensure at least eight with MET amplification. Correlative studies included tumor MET amplification, MET signaling, pharmacokinetics and plasma biomarkers of foretinib activity. Results From March 2007 until October 2009, 74 patients were enrolled; 74% male; median age, 61 years (range, 25–88); 93% had received prior therapy. Best response was stable disease (SD) in 10 (23%) patients receiving intermittent dosing and five (20%) receiving daily dosing; SD duration was 1.9–7.2 months (median 3.2 months). Of 67 patients with tumor samples, 3 had MET amplification, one of whom had SD. Treatment-related adverse events occurred in 91% of patients. Rates of hypertension (35% vs. 15%) and elevated aspartate aminotransferase (23% vs. 8%) were higher with intermittent dosing. In both patients with high baseline tumor phospho-MET (pMET), the pMET:total MET protein ratio decreased with foretinib treatment. Conclusion These results indicate that few gastric carcinomas are driven solely by MET and VEGFR2, and underscore the diverse molecular oncogenesis of this disease. Despite evidence of MET inhibition by foretinib, single-agent foretinib lacked efficacy in unselected patients with metastatic gastric cancer. Trial Registration ClinicalTrials.gov NCT00725712 PMID:23516391

Shah, Manish A.; Wainberg, Zev A.; Catenacci, Daniel V. T.; Hochster, Howard S.; Ford, James; Kunz, Pamela; Lee, Fa-Chyi; Kallender, Howard; Cecchi, Fabiola; Rabe, Daniel C.; Keer, Harold; Martin, Anne-Marie; Liu, Yuan; Gagnon, Robert; Bonate, Peter; Liu, Li; Gilmer, Tona; Bottaro, Donald P.

2013-01-01

276

Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis  

PubMed Central

Background We earlier showed that 4-phenylbutyrate (PB) can induce cathelicidin LL-37 expression synergistically with 1,25-dihydroxyvitamin D3 in a lung epithelial cell line. We aimed to evaluate a therapeutic dose of PB alone or in combination with vitamin D3 for induction of LL-37 expression in immune cells and enhancement of antimycobacterial activity in monocyte-derived macrophages (MDM). Methods Healthy volunteers were enrolled in an 8-days open trial with three doses of PB [250 mg (Group-I), 500 mg (Group-II) or 1000 mg (Group-III)] twice daily (b.d.) together with vitamin D3 {5000 IU once daily (o.d.)}, PB (500 mg b.d.) (Group-IV) or vitamin D3 (5000 IU o.d.) (Group-V), given orally for 4 days. Blood was collected on day-0, day-4 and day-8; plasma was separated, peripheral blood mononuclear cells (PBMC), non-adherent lymphocytes (NAL) and MDM were cultured. LL-37 transcript in cells and peptide concentrations in supernatant were determined by qPCR and ELISA, respectively. In plasma, 25-hydorxyvitamin D3 levels were determined by ELISA. MDM-mediated killing of Mycobacterium tuberculosis (Mtb) (H37Rv) was performed by conventional culture method. Results MDM from Group-II had increased concentration of LL-37 peptide and transcript at day-4, while Group-I showed increased transcript at day-4 and day-8 compared to day-0 (p?dose for the induction of LL-37 in macrophages and lymphocytes and intracellular killing of Mtb by macrophages. Hence, this dose has potential application in the treatment of TB and is now being used in a clinical trial of adults with active pulmonary TB (NCT01580007). PMID:23590701

2013-01-01

277

Beta-carotene isomers in human serum, breast milk and buccal mucosa cells after continuous oral doses of all-trans and 9-cis beta-carotene.  

PubMed

The concentrations of all-trans beta-carotene (tBC) and 9-cis beta-carotene (9cBC) isomers in serum, breast milk and buccal mucosa cells were determined after continuous oral doses as a simple, non-invasive method to determine whether differences in tissue uptake are important determinants of serum responses. Twelve healthy lactating women were recruited for a nonresidential study. On d 1, blood samples were obtained from fasting subjects for baseline concentrations of beta-carotene isomers. Over a 1-wk period, subjects were given either seven doses of a placebo (n = 4) or seven doses of naturally occurring BC (n = 8) derived from Dunaliella bardawil (64 mg tBC, 69 mg 9cBC). Subjects were instructed to consume a single beta-carotene dose along with a meal containing adequate fat each day for 1 wk. On d 2, 3, 5 and 8, blood samples and breast milk were collected from fasting subjects. On d 1 and 8, buccal mucosa cells were collected. Samples were analyzed for carotenoids by HPLC. In the experimental group, the mean serum concentration of tBC significantly increased to seven times the baseline level by the end of the supplementation period (P < 0.0001). The serum concentration of 9cBC significantly increased to three times the baseline level by the end of the supplementation period (P < 0.0001). The changes in milk and buccal mucosa cells levels of tBC and 9cBC followed a pattern similar to that for serum, showing significant increases at the end of the supplementation period. In the control group, the serum, milk and buccal mucosa cell concentrations of BC isomers did not change. This study confirms the previously reported differences in the serum response curves of tBC and 9cBC and provides evidence that there is no difference in tissue uptake of tBC and 9cBC. PMID:9311956

Johnson, E J; Qin, J; Krinsky, N I; Russell, R M

1997-10-01

278

Challenges and opportunities in implementing the FDA default parametric tolerance interval two one-sided test for delivered dose uniformity of orally inhaled products.  

PubMed

The goal of this article is to discuss considerations regarding implementation of the parametric tolerance interval two one-sided test (PTI-TOST) for delivered dose uniformity (DDU) of orally inhaled products (OIPs). That test was proposed by FDA in 2005 as an alternative to the counting test described in the 1998 draft FDA guidance for metered dose inhalers and dry powder inhalers. The 2005 PTI-TOST, however, still has not found much use in practice despite the general desirability of parametric approaches in modern pharmaceutical quality control. A key reason for its slow uptake is that it rejects, with high probability, batches whose quality is considered acceptable by all other published regulatory and pharmacopeial standards as well as by the DDU specifications for many approved OIPs. Manufacturers therefore continue using nonparametric counting tests for control of DDU. A simulated case study presented here compares the consequences of the PTI-TOST compared to the counting test. The article discusses three possibilities that would help increase the uptake of the PTI-TOST approach, namely: product-specific quality standards, a different default standard suitable for the majority of OIPs, and integration of the PTI-TOST with a continuous verification control strategy rather than using it as an isolated-batch (transactional) end-product testing. In any of these efforts, if a parametric test is used, it is critical not to set the target quality close to, or at the boundary of the process/product capabilities, because PTI tests are designed to reject with high probability the identified target quality. PMID:21901649

Larner, Greg; Cooper, Andrew; Lyapustina, Svetlana; Leiner, Stefan; Christopher, David; Strickland, Helen; Golden, Michael; Delzeit, Hans-Joachim; Friedman, Emil M

2011-12-01

279

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

PubMed Central

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

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

2013-01-01

280

Factors affecting the infectivity of tissues from pigs with classical swine fever: Thermal inactivation rates and oral infectious dose.  

PubMed

Outbreaks of classical swine fever are often associated with ingestion of pig meat or products derived from infected pigs. Assessment of the disease risks associated with material of porcine origin requires knowledge on the likely amount of virus in the original material, how long the virus may remain viable within the resulting product and how much of that product would need to be ingested to result in infection. Using material from pigs infected with CSFV, we determined the viable virus concentrations in tissues that comprise the majority of pork products. Decimal reduction values (D values), the time required to reduce the viable virus load by 90% (or 1log10), were determined at temperatures of relevance for chilling, cooking, composting and ambient storage. The rate of CSFV inactivation varied in different tissues. At lower temperatures, virus remained viable for substantially longer in muscle and serum compared to lymphoid and fat tissues. To enable estimation of the temperature dependence of inactivation, the temperature change required to change the D values by 90% (Z values) were determined as 13°C, 14°C, 12°C and 10°C for lymph node, fat, muscle and serum, respectively. The amount of virus required to infect 50% of pigs by ingestion was determined by feeding groups of animals with moderately and highly virulent CSFV. Interestingly, the virulent virus did not initiate infection at a lower dose than the moderately virulent strain. Although higher than for intranasal inoculation, the amount of virus required for infection via ingestion is present in only a few grams of tissue from infected animals. PMID:25592758

Cowan, Lucie; Haines, Felicity J; Everett, Helen E; Crudgington, Bentley; Johns, Helen L; Clifford, Derek; Drew, Trevor W; Crooke, Helen R

2015-03-23

281

Transfer of melamine from feed to milk and from milk to cheese and whey in lactating dairy cows fed single oral doses.  

PubMed

A study was conducted to evaluate the excretion pattern, after a single oral dose, of melamine from feed into milk, and the subsequent transfer to cheese and whey. The transfer of cyanuric acid was also investigated. Twenty-four lactating Holstein cows were randomly allocated to 4 treatments and received single doses of melamine as follows: 0.05, 0.50, 5.00, and 50.00 g/cow for groups D1, D2, D3, and D4, respectively. Individual milk samples were collected for melamine and cyanuric acid analyses on d 1, 2, 3, 4, 5, and 7. Milk collected individually from the second milking after melamine ingestion was used to make cheese on a laboratory scale. Melamine and cyanuric acid were extracted using a solid-phase extraction cartridge, and analyses were carried out by liquid chromatography-mass spectrometry/mass spectrometry. Maximal melamine concentrations occurred between 6 and 18 h after treatment and increased with log dose (linear and quadratic), ranging from 0.019 to 35.105 mg/kg. More than 60% of the melamine that was transferred to the milk was observed within 30 h after melamine ingestion. Melamine was not detected (limit of detection was 0.002 mg/kg) in milk 5 d after treatment in group D1, and 7 d after treatment in groups D2, D3, and D4. Blood urea nitrogen was not influenced by melamine ingestion. During cheese making, melamine was transferred mainly to the whey fraction. Cyanuric acid was not detected in any of the samples (milk, cheese, or whey). The excretion pattern of melamine in milk and whey may represent a health concern when cows ingest more than 0.50 g of melamine/d. However, only at intake levels of 5 and 50 g/d did cheese exceed the limits as set forth by the European Union. The results confirmed that melamine contamination of milk and milk products may be related not only to direct contamination, but also to adulteration of animal feeds. PMID:20965350

Battaglia, M; Cruywagen, C W; Bertuzzi, T; Gallo, A; Moschini, M; Piva, G; Masoero, F

2010-11-01

282

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

PubMed Central

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

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

2014-01-01

283

Chemotherapy of Second Stage Human African Trypanosomiasis: Comparison between the Parenteral Diamidine DB829 and Its Oral Prodrug DB868 in Vervet Monkeys.  

PubMed

Human African trypanosomiasis (HAT, sleeping sickness) ranks among the most neglected tropical diseases based on limited availability of drugs that are safe and efficacious, particularly against the second stage (central nervous system [CNS]) of infection. In response to this largely unmet need for new treatments, the Consortium for Parasitic Drug Development developed novel parenteral diamidines and corresponding oral prodrugs that have shown cure of a murine model of second stage HAT. As a rationale for selection of one of these compounds for further development, the pharmacokinetics and efficacy of intramuscular (IM) active diamidine 2,5-bis(5-amidino-2-pyridyl)furan (DB829; CPD-0802) and oral prodrug2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868) were compared in the vervet monkey model of second stage HAT. Treatment was initiated 28 days post-infection of monkeys with T. b. rhodesiense KETRI 2537. Results showed that IM DB829 at 5 mg/kg/day for 5 consecutive days, 5 mg/kg/day every other day for 5 doses, or 2.5 mg/kg/day for 5 consecutive days cured all monkeys (5/5). Oral DB868 was less successful, with no cures (0/2) at 3 mg/kg/day for 10 days and cure rates of 1/4 at 10 mg/kg/day for 10 days and 20 mg/kg/day for 10 days; in total, only 2/10 monkeys were cured with DB868 dose regimens. The geometric mean plasma Cmax of IM DB829 at 5 mg/kg following the last of 5 doses was 25-fold greater than that after 10 daily oral doses of DB868 at 20 mg/kg. These data suggest that the active diamidine DB829, administered IM, should be considered for further development as a potential new treatment for second stage HAT. PMID:25654243

Thuita, John K; Wolf, Kristina K; Murilla, Grace A; Bridges, Arlene S; Boykin, David W; Mutuku, James N; Liu, Qiang; Jones, Susan K; Gem, Charles O; Ching, Shelley; Tidwell, Richard R; Wang, Michael Z; Paine, Mary F; Brun, Reto

2015-02-01

284

Chemotherapy of Second Stage Human African Trypanosomiasis: Comparison between the Parenteral Diamidine DB829 and Its Oral Prodrug DB868 in Vervet Monkeys  

PubMed Central

Human African trypanosomiasis (HAT, sleeping sickness) ranks among the most neglected tropical diseases based on limited availability of drugs that are safe and efficacious, particularly against the second stage (central nervous system [CNS]) of infection. In response to this largely unmet need for new treatments, the Consortium for Parasitic Drug Development developed novel parenteral diamidines and corresponding oral prodrugs that have shown cure of a murine model of second stage HAT. As a rationale for selection of one of these compounds for further development, the pharmacokinetics and efficacy of intramuscular (IM) active diamidine 2,5-bis(5-amidino-2-pyridyl)furan (DB829; CPD-0802) and oral prodrug2,5-bis[5-(N-methoxyamidino)-2-pyridyl]furan (DB868) were compared in the vervet monkey model of second stage HAT. Treatment was initiated 28 days post-infection of monkeys with T. b. rhodesiense KETRI 2537. Results showed that IM DB829 at 5 mg/kg/day for 5 consecutive days, 5 mg/kg/day every other day for 5 doses, or 2.5 mg/kg/day for 5 consecutive days cured all monkeys (5/5). Oral DB868 was less successful, with no cures (0/2) at 3 mg/kg/day for 10 days and cure rates of 1/4 at 10 mg/kg/day for 10 days and 20 mg/kg/day for 10 days; in total, only 2/10 monkeys were cured with DB868 dose regimens. The geometric mean plasma Cmax of IM DB829 at 5 mg/kg following the last of 5 doses was 25-fold greater than that after 10 daily oral doses of DB868 at 20 mg/kg. These data suggest that the active diamidine DB829, administered IM, should be considered for further development as a potential new treatment for second stage HAT. PMID:25654243

Thuita, John K.; Wolf, Kristina K.; Murilla, Grace A.; Bridges, Arlene S.; Boykin, David W.; Mutuku, James N.; Liu, Qiang; Jones, Susan K.; Gem, Charles O.; Ching, Shelley; Tidwell, Richard R.; Wang, Michael Z.; Paine, Mary F.; Brun, Reto

2015-01-01

285

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

SciTech Connect

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

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

2011-04-01

286

Radiation Induced Oral Mucositis  

PubMed Central

Patients receiving radiotherapy or chemotherapy will receive some degree of oral mucositis The incidence of oral mucositis was especially high in patients: (i) With primary tumors in the oral cavity, oropharynx, or nasopharynx; (ii) who also received concomitant chemotherapy; (iii) who received a total dose over 5,000 cGy; and (iv) who were treated with altered fractionation radiation schedules. Radiation-induced oral mucositis affects the quality of life of the patients and the family concerned. The present day management of oral mucositis is mostly palliative and or supportive care. The newer guidelines are suggesting Palifermin, which is the first active mucositis drug as well as Amifostine, for radiation protection and cryotherapy. The current management should focus more on palliative measures, such as pain management, nutritional support, and maintenance, of good oral hygiene PMID:20668585

PS, Satheesh Kumar; Balan, Anita; Sankar, Arun; Bose, Tinky

2009-01-01

287

Distribution of the anthelmintic drug albendazole and its major metabolites in ovine milk and milk products after a single oral dose.  

PubMed

The distribution of albendazole (ABZ) and its main metabolites albendazole sulphoxide (ABZSO), albendazole sulphone (ABZSO2) and albendazole 2-aminosulphone (NH2ABZSO2) were investigated in bulk milk and milk products after administration of a single oral dose of the drug (12.5 mg/kg) to 80 Laticauda sheep. An analytical method was developed for this investigation from an existing procedure used for the determination of these compounds in plasma and digesta samples. No traces of the parent compound or NH2ABZSO2 were found in milk or milk products, with the exception of the milk collected 36 h after treatment in which 89 micrograms NH2ABZSO2/kg was detected. Results indicated that ABZ was rapidly oxidized to ABZSO and then to ABZSO2. These metabolites were found at high levels (1-4 mg/kg) in milk collected within 24 h after treatment. Products derived from such milk also contained high concentrations of the two oxidized metabolites, including up to 5 mg ABZSO/kg in Pecorino cheese. Only small quantities of these two metabolites were found in milk collected during the second day after treatment (range 50-500 micrograms/kg). They were no longer detectable in milk collected during the third day after dosing, nor were they found in products made from such milk. These findings confirm that the two polar metabolites ABZSO and ABZSO2 were efficiently excreted from the body. Considering that the established maximum residue limit for ovine milk is 100 micrograms/kg for ABZ plus its metabolites, our results confirmed the appropriateness of the currently prescribed withdrawal time (3 d) after the use of ABZ in lactating sheep. However, considerable levels of ABZSO were detected in milk collected within 24 h after treatment as well as in products and by-products derived from such milk. Owing to the known toxicity of the ABZSO, we stress the need for careful control to ensure adherence to the prescribed withdrawal time. PMID:8933305

De Liguoro, M; Longo, F; Brambilla, G; Cinquina, A; Bocca, A; Lucisano, A

1996-11-01

288

Tissue distribution of tungsten in mice following oral exposure to sodium tungstate.  

PubMed

Heavy metal tungsten alloys have replaced lead and depleted uranium in many munitions applications, due to public perception of these elements as environmentally unsafe. Tungsten materials left in the environment may become bioaccessible as tungstate, which might lead to population exposure through water and soil contamination. Although tungsten had been considered a relatively inert and toxicologically safe material, recent research findings have raised concerns about possible deleterious health effects after acute and chronic exposure to this metal. This investigation describes tissue distribution of tungsten in mice following oral exposure to sodium tungstate. Twenty-four 6-9 weeks-old C57BL/6 laboratory mice were exposed to different oral doses of sodium tungstate (0, 62.5, 125, and 200 mg/kg/d) for 28 days, and after one day, six organs were harvested for trace element analysis with inductively coupled plasma mass spectrometry (ICP-MS). Kidney, liver, colon, bone, brain, and spleen were analyzed by sector-field high-resolution ICP-MS. The results showed increasing tungsten levels in all organs with increased dose of exposure, with the highest concentration found in the bones and the lowest concentration found in brain tissue. Gender differences were noticed only in the spleen (higher concentration of tungsten in female animals), and increasing tungsten levels in this organ were correlated with increased iron levels, something that was not observed for any other organ or either of the two other metals analyzed (nickel and cobalt). These findings confirmed most of what has been published on tungsten tissue distribution; they also showed that the brain is relatively protected from oral exposure. Further studies are necessary to clarify the findings in splenic tissue, focusing on possible immunological effects of tungsten exposure. PMID:21375269

Guandalini, Gustavo S; Zhang, Lingsu; Fornero, Elisa; Centeno, Jose A; Mokashi, Vishwesh P; Ortiz, Pedro A; Stockelman, Michael D; Osterburg, Andrew R; Chapman, Gail G

2011-04-18

289

Oral health Oral health  

E-print Network

Prams asks about the care of teeth during pregnancy: whether the mother had a dental problem, went to a dentist or dental clinic or discussed oral hygiene with a dentist or other healthcare worker. Public health importance A pregnant woman’s oral health affects the woman, her fetus and infant. In pregnant women, periodontal disease, which affects the gums and adjacent bone, is associated with pre-term and/or low birth-weight delivery. 1, 2, 3 After delivery, infants or young children may develop cavities from maternal oral bacteria. 4 All health care providers can promote oral health through oral examinations; advising patients about oral hygiene, diet and smoking cessation; and by making referrals to oral health practitioners. 5 Access to oral health services during pregnancy may be constrained by the American Dental Association recommendations to avoid elective dental care during the first trimester and last half of the third trimester. 6 In four PRAMS states, among mothers who reported having a dental problem, about one-half did not go for care. 7 NM PRAMS findings In 2002, 25 % of mothers recalled discussion of oral hygiene during prenatal care (Table 56 / Figure 28), 13% had a dental problem and 33 % had dental care (Table 57 / Figure 29). Among women with a dental problem, 56% had dental care (Table 58 / Figure 30). In 2001-2002, women who were more likely to have dental care included those with insurance, without public assistance or with more than high school education. Use of oral health

unknown authors

290

MNT and MutaMouse studies to define the in vivo dose response relations of the genotoxicity of EMS and ENU.  

PubMed

Although there are a multitude of in vitro and in vivo studies on the genotoxic activity of EMS, no lifetime carcinogenicity studies, repeat dose mutation data or exposure analysis are available to serve as a solid basis for risk assessment for human exposure cases. The present studies were undertaken to investigate whether a threshold for mutagenic and clastogenic activity in vivo could be established, using the bone marrow micronucleus (MNT) and MutaMouse test systems, in the hope to provide reassurance to the patients that their accidental exposure to EMS at doses up to 0.055 mg/kg did not carry a toxicological risk. Dose levels ranging from 1.25 to 260 mg/kg/day were applied orally for up to 28 days. As a reference we included ENU at doses of 1.1-22 mg/kg/day. Our studies showed that daily doses of up to 25mg/kg/day (bone marrow, GI tract) and 50 mg/kg/day (liver) did not induce mutations in the lacZ gene in the three organs tested. Doses up to 80mg/kg/day (7-day dosing regime) did not induce micronuclei in mouse bone marrow. The genotoxic activity of EMS became apparent only at higher dose levels. Dose fractionation of EMS (28 times 12.5mg/kg versus a single high dose 350 mg/kg) provided further evidence for the thresholded dose response of EMS and showed that no cumulation of gene mutations below a threshold was occurring. In contrast, for ENU no threshold was apparent and dose fractionation indicated full additivity of individual dose effects. PMID:19446969

Gocke, Elmar; Ballantyne, Mark; Whitwell, James; Müller, Lutz

2009-11-12

291

Effects of orally administered Bdellovibrio bacteriovorus on the well-being and Salmonella colonization of young chicks.  

PubMed

Bdellovibrio bacteriovorus is a bacterium which preys upon and kills Gram-negative bacteria, including the zoonotic pathogens Escherichia coli and Salmonella. Bdellovibrio has potential as a biocontrol agent, but no reports of it being tested in living animals have been published, and no data on whether Bdellovibrio might spread between animals are available. In this study, we tried to fill this knowledge gap, using B. bacteriovorus HD100 doses in poultry with a normal gut microbiota or predosed with a colonizing Salmonella strain. In both cases, Bdellovibrio was dosed orally along with antacids. After dosing non-Salmonella-infected birds with Bdellovibrio, we measured the health and well-being of the birds and any changes in their gut pathology and culturable microbiota, finding that although a Bdellovibrio dose at 2 days of age altered the overall diversity of the natural gut microbiota in 28-day-old birds, there were no adverse effects on their growth and well-being. Drinking water and fecal matter from the pens in which the birds were housed as groups showed no contamination by Bdellovibrio after dosing. Predatory Bdellovibrio orally administered to birds that had been predosed with a gut-colonizing Salmonella enterica serovar Enteritidis phage type 4 strain (an important zoonotic pathogen) significantly reduced Salmonella numbers in bird gut cecal contents and reduced abnormal cecal morphology, indicating reduced cecal inflammation, compared to the ceca of the untreated controls or a nonpredatory ?pilA strain, suggesting that these effects were due to predatory action. This work is a first step to applying Bdellovibrio therapeutically for other animal, and possibly human, infections. PMID:21705523

Atterbury, Robert J; Hobley, Laura; Till, Robert; Lambert, Carey; Capeness, Michael J; Lerner, Thomas R; Fenton, Andrew K; Barrow, Paul; Sockett, R Elizabeth

2011-08-15

292

Effects of Orally Administered Bdellovibrio bacteriovorus on the Well-Being and Salmonella Colonization of Young Chicks ? †  

PubMed Central

Bdellovibrio bacteriovorus is a bacterium which preys upon and kills Gram-negative bacteria, including the zoonotic pathogens Escherichia coli and Salmonella. Bdellovibrio has potential as a biocontrol agent, but no reports of it being tested in living animals have been published, and no data on whether Bdellovibrio might spread between animals are available. In this study, we tried to fill this knowledge gap, using B. bacteriovorus HD100 doses in poultry with a normal gut microbiota or predosed with a colonizing Salmonella strain. In both cases, Bdellovibrio was dosed orally along with antacids. After dosing non-Salmonella-infected birds with Bdellovibrio, we measured the health and well-being of the birds and any changes in their gut pathology and culturable microbiota, finding that although a Bdellovibrio dose at 2 days of age altered the overall diversity of the natural gut microbiota in 28-day-old birds, there were no adverse effects on their growth and well-being. Drinking water and fecal matter from the pens in which the birds were housed as groups showed no contamination by Bdellovibrio after dosing. Predatory Bdellovibrio orally administered to birds that had been predosed with a gut-colonizing Salmonella enterica serovar Enteritidis phage type 4 strain (an important zoonotic pathogen) significantly reduced Salmonella numbers in bird gut cecal contents and reduced abnormal cecal morphology, indicating reduced cecal inflammation, compared to the ceca of the untreated controls or a nonpredatory ?pilA strain, suggesting that these effects were due to predatory action. This work is a first step to applying Bdellovibrio therapeutically for other animal, and possibly human, infections. PMID:21705523

Atterbury, Robert J.; Hobley, Laura; Till, Robert; Lambert, Carey; Capeness, Michael J.; Lerner, Thomas R.; Fenton, Andrew K.; Barrow, Paul; Sockett, R. Elizabeth

2011-01-01

293

Dose-related neurocognitive effects of marijuana use  

Microsoft Academic Search

Abstract—Background: Although about 7 million people in the US population use marijuana at least weekly, there is a paucity,of scientific data,on persistent,neurocognitive,effects of marijuana,use. Objective: To determine,if neurocognitive deficits persist,in 28-day abstinent,heavy,marijuana,users,and,if these,deficits are,dose-related,to the,number,of marijuana,joints smoked,per,week.,Methods: A battery,of neurocognitive,tests was,given,to 28-day abstinent,heavy marijuana abusers. Results: As joints smoked per week increased, performance decreased on tests measuring memory, executive functioning,

K. I. Bolla; K. Brown; D. Eldreth; K. Tate; J. L. Cadet

2006-01-01

294

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

PubMed

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

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

2014-01-01

295

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

PubMed

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

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

2012-11-01

296

Oral budesonide as maintenance treatment for Crohn's disease: A placebo- controlled, dose-ranging study. Canadian Inflammatory Bowel Disease Study Group  

Microsoft Academic Search

BACKGROUND & AIMS: Budesonide is a corticosteroid with high topical anti-inflammatory activity and low systemic activity due to rapid hepatic metabolism. The efficacy and safety of an oral controlled- release preparation of budesonide for maintenance of remission was evaluated in patients with ileal or ileocecal Crohn's disease. METHODS: In a double-blind, multicenter trial, 105 patients were randomly assigned to receive

GR Greenberg; BG Feagan; F Martin; LR Sutherland; AB Thomson; CN Williams; LG Nilsson; T Persson

1996-01-01

297

Phase I study of XL281 (BMS-908662), a potent oral RAF kinase inhibitor, in patients with advanced solid tumors.  

PubMed

Background XL281 is a potent and selective inhibitor of wild-type and mutant RAF kinases with anti-tumor activity in multiple xenograft models. Mutations in KRAS or BRAF can activate the RAF/MEK/ERK pathway in human tumors and may confer sensitivity to RAF kinase inhibitors. Methods We performed a phase I study of XL281 in patients with advanced solid tumors. Patients were enrolled in successive cohorts of XL281 orally once daily in 28-day cycles. Twice daily dosing, different formulations, and the effect of food and famotidine were also studied. At the MTD expanded cohorts with defined mutations were treated. Results In total, 160 patients were treated. The MTD on the QD schedule was 150 mg. The most common toxicities were diarrhea, nausea, and fatigue. Plasma Cmax and AUC increased with dose. Famotidine resulted in lower AUC while food had no effect. Two patients had partial responses by RECIST: One with papillary thyroid cancer with NRAS mutation and one with uveal melanoma. Another nine patients had tumor decrease of >10 % but did not meet RECIST criteria for PR. Matched tumors pairs from 33 patients showed evidence of RAF inhibition with significant decreases in pERK, pMEK and pAKT. Conclusions XL281 was generally well tolerated and the MTD was established at 150 mg/day. Partial responses and clinical benefit were observed in several patients. Tumor biopsies demonstrated effective target inhibition. PMID:25476894

Dickson, Mark A; Gordon, Michael S; Edelman, Gerald; Bendell, Johanna C; Kudchadkar, Ragini R; LoRusso, Patricia M; Johnston, Stuart H; Clary, Douglas O; Schwartz, Gary K

2014-12-01

298

Pharmacokinetics of IV and oral acetyl-L-carnitine in a multiple dose regimen in patients with senile dementia of Alzheimer type  

Microsoft Academic Search

Acetyl-L-carnitine (ALC), a physiological component of the L-carnitine family, has been proposed for treating Alzheimer's disease in pharmacological doses. As this condition requires prolonged therapy, its kinetics has been examined after a multiple dose regimen, involving different routes of administration, in 11 patients suffering from Senile Dementia of Alzheimer Type.

L. Parnetti; A. Gaiti; P. Mecocci; D. Cadini; U. Senin

1992-01-01

299

"Sequential" boron neutron capture therapy (BNCT): a novel approach to BNCT for the treatment of oral cancer in the hamster cheek pouch model.  

PubMed

In the present study the therapeutic effect and potential toxicity of the novel "Sequential" boron neutron capture therapy (Seq-BNCT) for the treatment of oral cancer was evaluated in the hamster cheek pouch model at the RA-3 Nuclear Reactor. Two groups of animals were treated with "Sequential" BNCT, i.e., BNCT mediated by boronophenylalanine (BPA) followed by BNCT mediated by sodium decahydrodecaborate (GB-10) either 24 h (Seq-24h-BNCT) or 48 h (Seq-48h-BNCT) later. In an additional group of animals, BPA and GB-10 were administered concomitantly [(BPA + GB-10)-BNCT]. The single-application BNCT was to the same total physical tumor dose as the "Sequential" BNCT treatments. At 28 days post-treatment, Seq-24h-BNCT and Seq-48h-BNCT induced, respectively, overall tumor responses of 95 ± 2% and 91 ± 3%, with no statistically significant differences between protocols. Overall response for the single treatment with (BPA + GB-10)-BNCT was 75 ± 5%, significantly lower than for Seq-BNCT. Both Seq-BNCT protocols and (BPA + GB-10)-BNCT induced reversible mucositis in the dose-limiting precancerous tissue around treated tumors, reaching Grade 3/4 mucositis in 47 ± 12% and 60 ± 22% of the animals, respectively. No normal tissue toxicity was associated with tumor response for any of the protocols. "Sequential" BNCT enhanced tumor response without an increase in mucositis in dose-limiting precancerous tissue. PMID:21294607

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

2011-04-01

300

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

Microsoft Academic Search

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

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

2011-01-01

301

A First-in-Human Randomized, Double-Blind, Placebo-Controlled, Single- and Multiple-Ascending Oral Dose Study of Novel Antimalarial Spiroindolone KAE609 (Cipargamin) To Assess Its Safety, Tolerability, and Pharmacokinetics in Healthy Adult Volunteers  

PubMed Central

This first-in-human randomized, double-blind, placebo-controlled, ascending-single and -multiple oral dose study was designed to evaluate the safety, tolerability, and pharmacokinetics in healthy volunteers of KAE609 (cipargamin; formerly NITD609), a spiroindolone now in trials for malaria treatment. It was studied in single-dose cohorts (1 to 300 mg, including one 30-mg food effect cohort) with 4 to 10 subjects in each cohort and in multiple-dose cohorts (10 to 150 mg once daily for 3 days) with 8 subjects in each cohort. The follow-up period was 6 to 8 days post-last dose. Safety and pharmacokinetics were assessed at scheduled time points during the study. Systemic exposure in terms of the area under the concentration-time curve from 0 h extrapolated to infinity (AUC0–?) increased in a dose-proportional manner over the dose range of 1 to 300 mg. The AUC from time zero to the time of the last quantifiable concentration (AUClast) and the maximum concentration of drug in plasma (Cmax) also increased in an approximately dose-proportional manner. When administered daily for 3 days, the accumulation ratio on day 3 (the AUC from time zero to 24 h postdosing [AUC0–24] on day 3/AUC0–24 on day 1) was in the range of 1.5 to 2 in the studied dose range (10 to 150 mg) and was consistent with an elimination half-life of around 24 h. Urine analysis for unchanged KAE609 revealed negligible amounts (?0.01%) were excreted renally. The high fat food intake did not affect the extent of KAE609 absorption (AUC); however, the Cmax was reduced by around 27%. KAE609 was tolerated in this study, with transient gastrointestinal and genitourinary adverse events of mild to moderate intensity (semen discoloration, diarrhea, nausea and abdominal discomfort, dizziness and headache, catheter site hematoma). Gastrointestinal and genitourinary adverse events increased with rising doses. PMID:25114127

Li, Ruobing; Jain, Jay Prakash; Lefčvre, Gilbert; Magnusson, Baldur; Diagana, Thierry T.; Pertel, Peter

2014-01-01

302

Oral Insulin  

Microsoft Academic Search

Oral insulin is an exciting area of research and development in the field of diabetology. This brief review covers the various approaches used in the development of oral insulin, and highlights some of the recent data related to novel oral insulin preparation.

Sanjay Kalra; Bharti Kalra; Navneet Agrawal

2010-01-01

303

Oral Insulin  

PubMed Central

Oral insulin is an exciting area of research and development in the field of diabetology. This brief review covers the various approaches used in the development of oral insulin, and highlights some of the recent data related to novel oral insulin preparation. PMID:21059246

2010-01-01

304

Oral Medication  

MedlinePLUS

... over-the-counter items. Explore: Oral Medication How Much Do Oral Medications Cost? Save money by finding the right type and ... Options? Is There a Danger of Interactions? How Much Do Oral Medications Cost? We Can Help (Long) - we-can-help-long. ...

305

A phase l study of three different dosing schedules of the oral aurora kinase inhibitor MSC1992371A in patients with solid tumors.  

PubMed

Aurora kinase inhibitors (AKIs) are a class of antimitotic, small-molecule anticancer agents. MSC1992371A is an AKI being evaluated for the treatment of patients with solid tumors. This phase I, open-label, dose-escalation study determined the maximum tolerated dose (MTD) of MSC1992371A in different dosing schedules in patients with locally advanced or metastatic solid tumors. MSC1992371A was administered on days 1 and 8 (schedule 1) or on days 1, 2, and 3 (schedule 2) of a 21-day cycle. The study was expanded with a third schedule (study drug on days 1-3 and 8-10). Adverse events were monitored throughout the study. Antitumor efficacy, drug pharmacokinetics, and pharmacodynamics were evaluated. Ninety-two patients were enrolled. MSC1992371A was dosed over eight levels in schedules 1 and 2, and the MTD was determined as 74 mg/m(2) per cycle for both schedules and as 60 mg/m(2) in schedule 3, albeit only in three patients due to discontinuation of the study. Overall, the most common grade 3 or 4 treatment-emergent adverse events were neutropenia, febrile neutropenia, thrombocytopenia, anemia, and fatigue. The most frequent dose-limiting toxicity over all schedules was neutropenia. MSC1992371A plasma concentrations tended to increase with increasing dose levels. Although no complete or partial responses were seen, stable disease ?3 months was observed in 11 patients. Analysis for markers of target modulation and pharmacodynamics effects was unsuccessful. MSC1992371A was generally well tolerated in patients, with mainly transient hematologic toxicities apparent at an MTD of 60-74 mg/m(2)/21-day cycle, independent of dosing frequency. PMID:23832397

Mita, M; Gordon, M; Rejeb, N; Gianella-Borradori, A; Jego, V; Mita, A; Sarantopoulos, J; Sankhala, K; Mendelson, D

2014-09-01

306

Dose and time dependence of the cellular phenotype in rat hepatic preneoplasia and neoplasia induced in stop experiments by oral exposure to N-nitrosomorpholine.  

PubMed

The dose and time dependence of the cellular phenotype in preneoplastic and neoplastic liver lesions was evaluated quantitatively in groups of male Sprague-Dawley rats exposed for 7 weeks to 0, 12 and 24 mg/kg body wt of N-nitrosomorpholine (NNM) and studied at different time points up to 80 weeks after withdrawal of NNM (stop model). NNM-treated rats showed a dose- and time-dependent increase in the total number and volume of preneoplastic foci of altered hepatocytes (FAH) and in the incidence of hepatocellular adenomas (HCA) and carcinomas (HCC) at both dose levels, compared with the untreated controls. After stopping treatment with 12 mg/kg body wt, the well-known sequence of cellular changes leading from glycogenotic clear and clear/acidophilic cell foci to mixed and diffusely basophilic cell populations poor in glycogen was found. In contrast, at the higher NNM dose level (24 mg/kg) predominantly mixed and diffusely basophilic cell foci appeared immediately after cessation of treatment, but their number rapidly declined up to 13 weeks after withdrawal. At the same time, there was a reciprocal increase in the number of the less altered clear/acidophilic cell foci, indicating an early reversion-linked phenotypic instability of FAH. However, in spite of this reversion higher numbers of mixed and diffusely basophilic cell foci were retained after treatment with 24 compared to 12 mg/kg of NNM at all time points studied, and there was even a slow additional increase in the number of these types of FAH 20 weeks after withdrawal of NNM. At both dose levels, the volume fraction of the persistent mixed cell foci correlated positively with the incidence of HCA and HCC, suggesting that this phenotype of FAH represents a direct precursor of the neoplastic lesions. Tigroid cell foci, which appeared most frequently after treatment with the lower dose of NNM, were not integrated into the predominant sequence of cellular changes leading to HCC, but they may represent an intermediate stage in a side lineage of this sequence, endowed with the potential to progress at least to HCA. Our results show that reversion-linked phenotypic instability of FAH occurs mainly after high dose treatment, possibly resulting from rapid adaptive cellular responses to the primary carcinogenic lesion(s) which may be fixed by genetic or epigenetic mechanisms. In contrast, progression-linked phenotypic instability of FAH is a slow process developing in a dose- and time-dependent manner at all dose levels leading to hepatic neoplasia. PMID:8020160

Weber, E; Bannasch, P

1994-06-01

307

Oral immunization with recombinant Salmonella typhimurium expressing surface protein antigen A of Streptococcus sobrinus: dose response and induction of protective humoral responses in rats.  

PubMed Central

An attenuated, recombinant Salmonella typhimurium mutant, chi 4072(pYA2905), expressing the surface protein antigen A (SpaA) of Streptococcus sobrinus was investigated for its effectiveness in inducing protective immune responses against S. sobrinus-induced dental caries in an experimental caries model. Fischer rats were orally immunized with either 10(8) or 10(9) CFU of S. typhimurium chi 4072(pYA2905). Persistence of salmonellae in Peyer's patches and spleens and the induction of immune responses were determined. Maximum numbers of salmonellae were recovered from Peyer's patches of rats within the first week of immunization, with higher numbers recovered from rats given 10(9) CFU than from those given 10(8) CFU. Serum anti-Salmonella and anti-SpaA responses increased more rapidly in rats given 10(9) CFU than in rats given 10(8) CFU. The salivary antibody response to SpaA increased with time, but the response varied in the two groups. In a separate study, rats were orally immunized with the recombinant Salmonella mutant and then challenged with cariogenic S. sobrinus 6715. The levels of serum and salivary antibody and caries activity were assessed at the termination of the experiment. Higher levels of salivary immunoglobulin A antibody to SpaA and Salmonella carrier were detected in rats given 10(9) CFU than in those given 10(8) CFU, and these responses were higher than those in nonimmunized controls. Mandibular molars from immunized rats had lower numbers of recoverable streptococci and less extensive carious lesions than those from nonimmunized, control rats. These data indicate that oral immunization with an attenuated recombinant S. typhimurium expressing SpaA of S. sobrinus induces the production of antigen-specific mucosal antibody and confers protection against dental caries. PMID:7729915

Redman, T K; Harmon, C C; Lallone, R L; Michalek, S M

1995-01-01

308

Pharmacokinetics of oral vitamin C  

Microsoft Academic Search

Purpose . To test whether plasma vitamin C levels, following oral doses in supplemented volunteers, are tightly controlled and subject to a maximum in the region of 220 mML 21 , as suggested by previous researchers for depleted subjects. To determine plasma levels following single, variable-sized doses of standard and liposomal formulations of vitamin C and compare the effects of

Stephen Hickey; HILARY J. ROBERTS; NICHOLAS J. MILLER

2008-01-01

309

Phase 1b dose-finding study of motesanib with docetaxel or paclitaxel in patients with metastatic breast cancer.  

PubMed

The purpose of this study was to investigate the safety, tolerability, and pharmacokinetics of motesanib when combined with docetaxel or paclitaxel in patients with metastatic breast cancer. In this open-label, dose-finding, phase 1b study, patients received motesanib 50 or 125-mg orally once daily (QD), beginning day 3 of cycle 1 of chemotherapy, continuously in combination with either paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 28-day cycle (Arm A) or docetaxel 100 mg/m(2) on day 1 every 21-day cycle (Arm B). Dose escalation to motesanib 125 mg QD occurred if the incidence of dose-limiting toxicities (DLTs, primary endpoint) was ? 33 %. If the maximum tolerated dose (MTD) of motesanib was established in Arm B, additional patients could receive motesanib at the MTD plus docetaxel 75 mg/m(2). Forty-six patients were enrolled and 45 received ? 1 dose of motesanib. The incidence of DLTs was <33 % in all cohorts; thus, motesanib 125 mg QD was established as the MTD. Seven patients (16 %) had grade 3 motesanib-related adverse events including cholecystitis (2 patients) and hypertension (2 patients). Pharmacokinetic parameters of motesanib were similar to those reported in previous studies. The objective response rate was 56 % among patients with measurable disease at baseline who received motesanib in combination with taxane-based chemotherapy. The addition of motesanib to either paclitaxel or docetaxel was generally tolerable up to the 125-mg QD dose of motesanib. The objective response rate of 56 % suggests a potential benefit of motesanib in combination with taxane-based chemotherapy. PMID:22872523

De Boer, Richard H; Kotasek, Dusan; White, Shane; Koczwara, Bogda; Mainwaring, Paul; Chan, Arlene; Melara, Rebeca; Ye, Yining; Adewoye, Adeboye H; Sikorski, Robert; Kaufman, Peter A

2012-08-01

310

Subchronic Oral Exposure to Benzo(a)pyrene Leads to Distinct Transcriptomic Changes in the Lungs That Are Related to Carcinogenesis  

PubMed Central

We have previously shown that acute oral exposure to the environmental carcinogen benzo(a)pyrene (BaP) elicits comparable levels of DNA adducts, but distinct transcriptomic changes, in mouse lungs and livers, the two main BaP bioactivating organs. Oral BaP exposure is predominantly associated with lung cancer and not hepatic cancer in some animal models, suggesting that gene expression differences may provide insight into the drivers of tissue-specific carcinogenesis. In the present study, we examine pulmonary DNA adduct formation, lacZ mutant frequency, and mRNA profiles in adult male MutaMouse following subchronic (28 day) oral exposure to BaP (0, 25, 50, and 75mg/kg/day) and sacrificed 3 days postexposure. The results are compared with those obtained from livers of the same mice (previously published). Although there was a 1.8- to 3.3-fold increase in the levels of DNA adducts in lung compared with liver, the lacZ transgene mutant frequency was similar in both tissues. At the transcriptomic level, a transition from activation of the DNA damage response p53 pathway at the low dose to the induction of genes involved in angiogenesis, evasion of apoptosis and growth signals at the high doses was evident only in the lungs. These results suggest that tissue DNA adducts and mutant frequency are sensitive markers of target tissue exposure and mode of action, whereas early changes in gene expression may provide a better indication of the likelihood of carcinogenic transformation in selected tissues. Moreover, the study provides new information on the underlying mecha- nisms that contribute to tissue-specific responses to BaP. PMID:22610609

Halappanavar, Sabina

2012-01-01

311

A Randomized, Placebo-Controlled Trial of the Bivalent Killed, Whole-Cell, Oral Cholera Vaccine in Adults and Children in a Cholera Endemic Area in Kolkata, India  

PubMed Central

Objectives An effective vaccine against cholera has been used for public health purposes in Vietnam since the 1990s. This vaccine was reformulated to meet WHO requirements. We assessed the safety and immunogenicity of the reformulated bivalent (Vibrio cholerae 01 and 0139) killed whole cell oral vaccine in a cholera endemic area in Kolkata, India. Design Double-blind, randomized, placebo controlled trial Setting The trial was conducted in the clinical trial ward of the Infectious Diseases Hospital in Kolkata, India Participants The participants were 101 healthy adults (males and non-pregnant females) aged 18–40 years and 100 healthy children (males and non-pregnant females) aged 1–17 years. Interventions Participants were randomized to receive either the bivalent killed whole cell oral cholera vaccine or placebo (killed oral Escherichia coli K12) Outcome Measures For safety: proportion of subjects with adverse events during the duration of study participation. For immunogenicity: Proportion of subjects who had a ?4-fold rise in serum vibriocidal antibody titers 14 days after the second dose of vaccine or placebo. Results Adverse reactions were observed with similar frequency among vaccine and placebo recipients in both age groups. Among adults 4% of vaccine and 8% of placebo recipients and among children 4% of vaccine and 2% of placebo recipients had at least one adverse event within 28 days of the first dose of the vaccine. Following immunization, 53% of adult and 80% of children vaccinees showed a ?4 fold rise in serum V. cholerae O1 vibriocidal antibody titers. A less pronounced response to V. cholerae O139 vibriocidal antibody titers post-immunization was noted among vaccinees. Conclusions We found the vaccine to be safe and immunogenic in a cholera-endemic area in India. Trial Registration ClinicalTrials.gov NCT00119197 PMID:18523643

Mahalanabis, Dilip; Lopez, Anna Lena; Sur, Dipika; Deen, Jacqueline; Manna, Byomkesh; Kanungo, Suman; von Seidlein, Lorenz; Carbis, Rodney; Han, Seung Hyun; Shin, Seong Hye; Attridge, Stephen; Rao, Raman; Holmgren, Jan; Clemens, John; Bhattacharya, Sujit K.

2008-01-01

312

Single- and multiple-dose pharmacokinetics of a novel tetramethylpyrazine reservoir-type transdermal patch versus tetramethylpyrazine phosphate oral tablets in healthy normal volunteers, and in vitro/in vivo correlation.  

PubMed

A novel reservoir-type transdermal system of 2,3,5,6-tetramethylpyrazine (TMP) was developed containing eucalyptus oil as a penetration enhancer. The single and multiple-dose pharmacokinetic profiles of TMP administrated by TMP transdermal patch were characterized in healthy volunteers using an in vivo, randomized, open-label, two-way crossover design. 2,3,5,6-Tetramethylpyrazine phosphate (TMPP) oral tablets were chosen as reference. Following single/multiple oral administration of 200/100 mg TMPP tablets, a TMP C(max) of 1284/613.5 ng/mL was observed within 0.75 h. Single/multiple applications of the TMP patch yielded mean C(max) of 309/325 ng/mL at a median T(max) of 5/4 h, with steady state achieved at second application. The mean C(min) of the patch was 131±30.38 ng/mL, contrasting to nearly zero for the tablet. Multiple applications of patch produced an accumulative effect over single application. At steady state 250 mg/20 cm(2) TMP patch given daily provided comparable exposure to 100 mg TMPP tablets three times daily (3753.91 versus 3563.67 ng·h/mL). TMP tablets and patch yielded similar steady-state plasma concentrations: C(av) (148.48±51.27, 156.41±40.31 ng/mL). The results demonstrated that TMP patch can achieve a therapeutic effect that is comparable to oral administration, exhibited prolonged and sustained plasma levels, fewer drug fluctuations, lower adverse effects, more convenience, and improved patient compliance. In-vitro permeation through human skin demonstrated zero-order kinetics with the flux of 364 µg/cm(2)/h. The predicted C(av) (163.9 ng/mL) was in agreement with the observed C(av) (156.4 ng/mL). PMID:23514701

Shen, Teng; Xu, Huinan; Weng, Weiyu; Zhang, Jianfang

2013-01-01

313

Fluoroquinolone levels in healthy dog urine following a 20-mg/kg oral dose of enrofloxacin exceed mutant prevention concentration targets against Escherichia coli isolated from canine urinary tract infections.  

PubMed

A 3-day course of oral enrofloxacin is effective for treating uncomplicated urinary tract infection (UTI) in dogs when administered 20 mg/kg Q24H. However, emergence of fluoroquinolone-resistant mutants of uropathogens is a concern. Urine concentrations of enrofloxacin and ciprofloxacin were measured in six healthy dogs following dose of enrofloxacin 20 mg/kg. Mutant prevention concentrations of Escherichia coli isolated from canine UTI were also determined against ciprofloxacin. Urine AUC(24)/MPC ratios considering ciprofloxacin concentrations ranged 3819-7767, indicating that selection of resistant E. coli mutants in dogs with uncomplicated UTIs is unlikely in the bladder given that an AUC(24)/MPC = 39 is considered to be protective against mutant selection for ciprofloxacin. However, additional studies are required to evaluate the effects of this enrofloxacin treatment protocol on bacteria that colonize anatomic sites where fluoroquinolones achieve lower concentrations compared to the urinary bladder. PMID:23859001

Daniels, J B; Tracy, G; Irom, S J; Lakritz, J

2014-04-01

314

Di-n-butyl Phthalate (DNBP) and Diisobutyl Phthalate (DiBP) Metabolism in a Human Volunteer after Single Oral Doses [Journal Article  

EPA Science Inventory

An individual (male, 36 years, 87 kg) ingested two separate doses of di-n-butyl phthalate (DnBP) and diisobutyl phthalate (DiBP) at a rate of ~60 µg/kg. Key monoester and oxidized metabolites were identified and quantified in urine continuously collected until 48 hours post dos...

315

A DESCRIPTIVE FEASIBILITY STUDY TO EVALUATE SCHEDULED ORAL ANALGESIC DOSING AT HOME FOR THE MANAGEMENT OF POSTOPERATIVE PAIN IN PRESCHOOL CHILDREN FOLLOWING TONSILLECTOMY  

PubMed Central

Objectives The purpose of this study, in a sample of preschool children (ages 3 to 5 years; N=47), was to evaluate the feasibility of scheduled analgesic dosing following outpatient tonsillectomy in order to optimize pain management. Methods Parents were instructed to give their child acetaminophen with hydrocodone (167mg/5ml) every 4 hours around-the-clock for the first 3 days following surgery. Parents recorded ratings of their child’s pain with/without swallowing using the Faces, Legs, Activity, Cry, and Consolability (FLACC) behavioral pain scale, pain relief ratings, and severity of analgesic side effects in a home diary. Audiotaped interviews were conducted with parents to document descriptions of their experiences in managing their child’s pain at home. Results Mean FLACC scores with/without swallowing were less than 2 at each measurement time and pain relief scores increased over time. Total analgesic dose decreased and the number of missed doses increased over the first 3 days after surgery. Moderate-to-severe daytime sedation, nausea, vomiting, and constipation were reported by parents. Discussion Study results suggest that acetaminophen with hydrocodone is effective in relieving preschool children’s pain following tonsillectomy, and that parental adherence to a scheduled analgesic regimen decreases over time. Time-contingent dosing was associated with moderate to severe side effects, and should be addressed in discharge teaching with parents. Findings provide insight into parents’ perspective of pain management at home following tonsillectomy and methods for relieving their child’s pain. PMID:22313591

Sutters, Kimberly A.; Holdridge-Zeuner, Danielle; Waite, Steven; Paul, Steven M.; Savedra, Marilyn C.; Lanier, Brent; Mahoney, Karla; Miaskowski, Christine

2012-01-01

316

Quantification of absorption, retention and elimination of two different oral doses of vitamin A in Zambian boys using accelerator mass spectrometry  

SciTech Connect

A recent survey indicated that high-dose vitamin A supplements (HD-VAS) had no apparent effect on vitamin A (VA) status of Zambian children <5 y of age. To explore possible reasons for the lack of response to HD-VAS among Zambian children, we quantified the absorption, retention, and urinary elimination of either a single HDVAS (60 mg) or a smaller dose of stable isotope (SI)-labeled VA (5 mg), which was used to estimate VA pool size, in 3-4 y old Zambian boys (n = 4 for each VA dose). A 25 nCi tracer dose of [{sup 14}C{sub 2}]-labeled VA was co-administered with the HD-VAS or SI-labeled VA, and 24-hr stool and urine samples were collected for 3 and 7 consecutive days, respectively, and 24-hr urine samples at 4 later time points. Accelerator Mass Spectrometry (AMS) was used to measure the cumulative excretion of {sup 14}C in stool and urine 3d after dosing to estimate, respectively, absorption and retention of the VAS and SI-labeled VA. The urinary elimination rate (UER) was estimated by plotting {sup 14}C in urine vs. time, and fitting an exponential equation to the data. Estimates of mean absorption, retention and the UER were 83.8 {+-} 7.1%, 76.3 {+-} 6.7%, and 1.9 {+-} 0.6%/d, respectively, for the HD-VAS and 76.5 {+-} 9.5%, 71.1 {+-} 9.4%, and 1.8 {+-} 1.2%/d, respectively for the smaller dose of SI-labeled VA. Estimates of absorption, retention and the UER did not differ by size of the VA dose administered (P=0.26, 0.40, 0.88, respectively). Estimated absorption and retention were negatively associated with reported fever (P=0.011) and malaria (P =0.010). HD-VAS and SI-labeled VA were adequately absorbed, retained and utilized in apparently healthy Zambian preschool-age boys, although absorption and retention may be affected by recent infections.

Aklamati, E K; Mulenga, M; Dueker, S R; Buchholz, B A; Peerson, J M; Kafwembe, E; Brown, K H; Haskell, M J

2009-10-12

317

Antigen-Specific Memory B-Cell Responses in Bangladeshi Adults after One- or Two-Dose Oral Killed Cholera Vaccination and Comparison with Responses in Patients with Naturally Acquired Cholera ?  

PubMed Central

The mediators of protective immunity against cholera are currently unknown, but memory B-cell responses may play a central role in facilitating long-term and anamnestic responses against Vibrio cholerae, the cause of cholera. We compared memory B-cell responses in adults with natural cholera in Bangladesh (n = 70) to responses in Bangladeshi adults after one-dose (n = 30) or two-dose (n = 30) administration of an oral killed cholera vaccine, WC-rBS (Dukoral; Crucell), assessing the responses at the acute stage of disease or prevaccination and then on days 3, 30, 90, 180, 270, and 360. Individuals with natural cholera developed prominent vibriocidal and plasma anti-cholera toxin B subunit (CtxB) and lipopolysaccharide (LPS) IgG and IgA responses, but these responses returned to baseline by 1 year of follow-up. Vaccinees developed plasma anti-CtxB and anti-LPS IgG and IgA responses that were generally comparable to those in individuals recovering from natural disease, but vibriocidal responses were lower in vaccinees than in infected patients. Individuals recovering from natural disease developed memory B-cell IgG and IgA anti-CtxB and anti-LPS responses by day 30, and these responses were detectable through at least days 180 to 360. In contrast, we detected no IgA or IgG memory B-cell responses to LPS in vaccinees; anti-CtxB IgA responses were only detectable on day 30, and anti-CtxB IgG responses were detectable until days 90 to 180, compared to days 270 to 360 in patients. These findings may explain in part the relatively short-term protection afforded by oral cholera vaccination compared to natural disease. PMID:21346055

Alam, Mohammad Murshid; Riyadh, M. Asrafuzzaman; Fatema, Kaniz; Rahman, Mohammad Arif; Akhtar, Nayeema; Ahmed, Tanvir; Chowdhury, Mohiul Islam; Chowdhury, Fahima; Calderwood, Stephen B.; Harris, Jason B.; Ryan, Edward T.; Qadri, Firdausi

2011-01-01

318

Bioequivalence of Two Formulations of a Single Oral Dose of 500-mg Azithromycin Granules: A Randomized, Open-Label, Two-Period Crossover Study in Healthy Han Chinese Volunteers  

PubMed Central

Background: In recent years, the use of generic drugs has been increasing due to their effectiveness and to the increasing variety of drugs that are now available in generic formulations. Although several generic oral formulations of azithromycin are available in China, information concerning the bioavailability of these formulations in the Chinese population is unavailable. Objective: The purpose of this study was to compare the bioequivalence and tolerability of a single oral dose of 2 commercial brands of 500-mg azithromycin granules in healthy Han Chinese volunteers. Methods: In a randomized, open-label, 2-period crossover study, the bioequivalence and tolerability of 2 commercial formulations of azithromycin granules (test: Dayin Ocean Biochemical Company Ltd., Shandong, China; reference: Taiyang Drug Company Ltd., Beijing, China) were compared in healthy adult Han Chinese volunteers. Both the test and the reference formulations were administered to each subject. The 2 treatment phases were separated by a 3-week washout period. Liquid chromatography-tandem mass spectrometry was used to determine plasma drug concentrations. The formulations were considered bioequivalent if the natural log-transformed ratios of Cmax and AUC were within the predetermined equivalence range of 70% to 143% and 80% to 125%, respectively, and if P ? 0.05 for the 90% CIs. Results: Twenty-four male Han Chinese volunteers (mean [SD] age, 21.0 [2.0] years [range, 18-25 years]; mean [SD] weight, 67.6 [5.6] kg [range, 56-81 kg]; mean [SD] height, 176.0 [5.0] cm [range, 165-188 cm]) were enrolled. Twenty-two subjects completed the study, with 2 withdrawing for personal reasons. No period or sequence effect was observed. The 90% CIs for the corresponding ratios of Cmax, AUC from hour 0 to time t, and AUC from hour 0 to any time point were 85.9 to 103.9, 83.6 to 106.0, and 84.7 to 105.9 (in the 2 one-sided t tests; all, P < 0.05), respectively. Similar results were found in data without a logarithmic transformation. There were no significant differences in the plasma concentration-time curves of the test and reference formulations. No adverse events were reported by the subjects or revealed by clinical or laboratory tests. Conclusions: Single oral doses of 2 commercial brands of azithromycin granules (500 mg) were equivalent with regard to the rate and extent of absorption among these healthy Han Chinese volunteers. Both formulations were well tolerated. PMID:24692768

Ren, Jing; Jiang, Xue-Hua; Li, Kejia; Zhang, Chuanchuan; Li, Chenrui; Wang, Ling

2007-01-01

319

Phase II of oral gimatecan in patients with recurrent epithelial ovarian, fallopian tube or peritoneal cancer, previously treated with platinum and taxanes  

PubMed Central

Background: A prospective phase II study was conducted to evaluate the efficacy and toxicity of oral gimatecan in patients with recurrent epithelial ovarian, fallopian tube or peritoneal cancer. Patients and methods: Patients had a maximum of three prior chemotherapy lines with no more than two prior platinum-containing regimens and a progression-free interval after the last dose of platinum <12 months. A total dose of 4 mg/m2/cycle (0.8 mg/m2/day from day 1 to day 5) was administered, repeated every 28 days. Results: From June 2005 to December 2005, 69 assessable patients were enrolled. The best overall response to study treatment by combined CA-125 and RECIST criteria was partial response in 17 patients (24.6%) and disease stabilization in 22 patients (31.9%). The median time to progression and overall survival were 3.8 and 16.2 months, respectively. A total of 312 cycles were administered. Neutropenia grade 4 and thrombocytopenia grade 4 occurred in 17.4% and 7.2% of patients, respectively. Diarrhea grade 4 was never observed. Asthenia and fatigue were reported by 36.2% and 18.8% of patients, but were all grade 2 or less. Conclusion: Gimatecan is a new active agent in previously treated ovarian cancer with myelosuppression as main toxicity. PMID:19906760

Pecorelli, S.; Ray-Coquard, I.; Tredan, O.; Colombo, N.; Parma, G.; Tisi, G.; Katsarňs, D.; Lhommé, C.; Lissoni, A. A.; Vermorken, J. B.; du Bois, A.; Poveda, A.; Frigerio, L.; Barbieri, P.; Carminati, P.; Brienza, S.; Guastalla, J. P.

2010-01-01

320

Placebo-controlled randomized clinical trial on the immunomodulating activities of low- and high-dose bromelain after oral administration - new evidence on the antiinflammatory mode of action of bromelain.  

PubMed

Bromelain has been used for treatment of inflammatory diseases for decades. However, the exact mechanism of action remains poorly understood. While in vitro investigations have shown conflicting effects on the release of various cytokines, no in vivo data were available. In this study, the effects on inflammation-related cytokines of two doses of bromelain were tested in a single dose placebo-controlled 3?×?crossover randomized clinical trial. Cytokine circadian profiles were used to investigate the effects of bromelain on the human immune system by using stimulated whole-blood leukocytes. The effects seen in these cultures demonstrated a significant shift in the circadian profiles of the Th1 cell mediator interferon gamma (IFN?; p?oral use. It is postulated that the immunomodulating effect of bromelain observed in this trial is part of its known antiinflammatory activities. Further investigations will be necessary to verify the relevance of these findings to a diseased immune system. PMID:22517542

Müller, Silke; März, Reinhard; Schmolz, Manfred; Drewelow, Bernd; Eschmann, Klaus; Meiser, Peter

2013-02-01

321

Pharmacokinetics of oral dichloroacetate in dogs.  

PubMed

We characterized the pharmacokinetics and dynamics of dichloroacetate (DCA), an investigational drug for mitochondrial diseases, pulmonary arterial hypertension, and cancer. Adult Beagle dogs were orally administered 6.25 mg/kg q12h DCA for 4 weeks. Plasma kinetics was determined after 1, 14, and 28 days. The activity and expression of glutathione transferase zeta 1 (GSTZ1), which biotransforms DCA to glyoxylate, were determined from liver biopsies at baseline and after 27 days. Dogs demonstrate much slower clearance and greater inhibition of DCA metabolism and GSTZ1 activity and expression than rodents and most humans. Indeed, the plasma kinetics of DCA in dogs is similar to humans with GSTZ1 polymorphisms that confer exceptionally slow plasma clearance. Dogs may be a useful model to further investigate the toxicokinetics and therapeutic potential of DCA. PMID:24038869

Maisenbacher, Herbert W; Shroads, Albert L; Zhong, Guo; Daigle, Adam D; Abdelmalak, Monica M; Samper, Ivan Sosa; Mincey, Brandy D; James, Margaret O; Stacpoole, Peter W

2013-12-01

322

A Dose- rather than Delivery Profile–Dependent Mechanism Regulates the “Muscle-Full” Effect in Response to Oral Essential Amino Acid Intake in Young Men12  

PubMed Central

Background: The anabolic response of skeletal muscle to essential amino acids (EAAs) is dose dependent, maximal at modest doses, and short lived, even with continued EAA availability, a phenomenon termed “muscle-full.” However, the effect of EAA ingestion profile on muscle metabolism remains undefined. Objective: We determined the effect of Bolus vs. Spread EAA feeding in young men and hypothesized that muscle-full is regulated by a dose-, not delivery profile–, dependent mechanism. Methods: We provided 16 young healthy men with 15 g mixed-EAA, either as a single dose (“Bolus”; n = 8) or in 4 fractions at 45-min intervals (“Spread”; n = 8). Plasma insulin and EAA concentrations were assayed by ELISA and ion-exchange chromatography, respectively. Limb blood flow by was determined by Doppler ultrasound, muscle microvascular flow by Sonovue (Bracco) contrast-enhanced ultrasound, and phosphorylation of mammalian target of rapamycin complex 1 substrates by immunoblotting. Intermittent muscle biopsies were taken to quantify myofibrillar-bound 13C6-phenylalanine to determine muscle protein synthesis (MPS). Results: Bolus feeding achieved rapid insulinemia (13.6 ?IU · mL?1, 25 min after commencement of feeding), aminoacidemia (?2500 ?M at 45 min), and capillary recruitment (+45% at 45 min), whereas Spread feeding achieved attenuated insulin responses, gradual low-amplitude aminoacidemia (peak: ?1500 ?M at 135 min), and no detectable capillary recruitment (all P < 0.01 vs. Bolus). Despite these differences, identical anabolic responses were observed; fasting fractional synthetic rates of 0.054% · h?1 (Bolus) and 0.066% · h?1 (Spread) increased to 0.095% and 0.104% · h?1 (no difference in increment or final values between regimens). With both Spread and Bolus feeding strategies, a latency of at least 90 min was observed before an upswing in MPS was evident. Similarly with both feeding strategies, MPS returned to fasting rates by 180 min despite elevated circulating EAAs. Conclusion: These data do not support EAA delivery profile as an important determinant of anabolism in young men at rest, nor rapid aminoacidemia/leucinemia as being a key factor in maximizing MPS. This trial was registered at clinicaltrials.gov as NCT01735539. PMID:25644339

Mitchell, William Kyle; Phillips, Beth E; Williams, John P; Rankin, Debbie; Lund, Jonathan N; Smith, Kenneth; Atherton, Philip J

2015-01-01

323

Absorption, distribution, and excretion of [14C]-3-chloro-4-methylaniline hydrochloride in two species of birds following a single oral dose.  

PubMed

Ring-labeled [14C]-3-chloro-4-methylaniline hydrochloride (250 microg per bird) was delivered to 21 red-winged blackbirds (Agelaius phoeniceus) and 21 dark-eyed juncos (Junco hyemalis) via oral gavage, and the distribution and excretion of radioactivity were determined at 15 and 30 min and 1, 4, 8, 12, and 24 h (n = 3 per time point). Direct measurement of radioactivity as well as measurement following combustion was accomplished using a liquid scintillation counter. Elimination from most tissues followed a two-compartment model, with very rapid elimination occurring between time 0 and 4 h and a much slower elimination phase occurring after that. The average half-life of elimination for the initial phase in most tissues examined was 0.16 h for juncos and 0.62 h for blackbirds. The average for the slower second phase of elimination was 3.4 h for juncos and 5.4 h for blackbirds. The radioactivity in blackbird kidney tissues did not change significantly for the duration of the test, pointing toward the kidney as a possible site of action for this important agricultural chemical. PMID:15612798

Goldade, David A; Tessari, John D; Johnston, John J

2004-12-29

324

Investigation of the effects of subchronic low dose oral exposure to bisphenol A (BPA) and ethinyl estradiol (EE) on estrogen receptor expression in the juvenile and adult female rat hypothalamus.  

PubMed

Concerns have been raised regarding the long-term impacts of early life exposure to the ubiquitous environmental contaminant bisphenol A (BPA) on brain organization. Because BPA has been reported to affect estrogen signaling, and steroid hormones play a critical role in brain sexual differentiation, there is also concern that BPA exposure could alter neural sex differences. Here, we examine the impact of subchronic exposure from gestation to adulthood to oral doses of BPA below the current no-observed-adverse-effect level (NOAEL) of 5 mg/kg body weight (bw)/day on estrogen receptor (ESR) expression in sexually dimorphic brain regions of prepubertal and adult female rats. The dams were gavaged daily with vehicle (0.3% carboxymethylcellulose), 2.5, 25, 260, or 2700 ?g BPA/kg bw/day, or 0.5 or 5.0 ?g ethinyl estradiol (EE)/kg bw/day from gestational day 6 until labor began. Offspring were then gavaged directly from the day after birth until the day before scheduled sacrifice on postnatal days 21 or 90. Using in situ hybridization, one or more BPA doses produced significant decreases in Esr1 expression in the juvenile female rat anteroventral periventricular nucleus (AVPV) of the hypothalamus and significant decreases in Esr2 expression in the adult female rat AVPV and medial preoptic area (MPOA), relative to vehicle controls. BPA did not simply reproduce EE effects, indicating that BPA is not acting solely as an estrogen mimic. The possible consequences of long-term changes in hypothalamic ESR expression resulting from subchronic low dose BPA exposure on neuroendocrine effects are discussed and being addressed in ongoing, related work. PMID:24752507

Rebuli, Meghan E; Cao, Jinyan; Sluzas, Emily; Delclos, K Barry; Camacho, Luísa; Lewis, Sherry M; Vanlandingham, Michelle M; Patisaul, Heather B

2014-07-01

325

A comparative study on the anti-inflammatory effects of single oral doses of naproxen and its hydrogen sulfide (H2S)-releasing derivative ATB-346 in rats with carrageenan-induced synovitis  

PubMed Central

Background Non-steroidal antiinflammatory drugs (NSAIDs) are the most commonly prescribed agents for arthritic patients, although gastric effects limit their long-term use. Considering the reported gastric safety of hydrogen sulfide (H2S)-releasing NSAIDs, in addition to the anti-inflammatory effects of H2S administration to rats with synovitis, we decided to evaluate the effects of the H2S-releasing naproxen derivative ATB-346 in this animal model. Methods Male Wistar rats were anesthetized with inhalatory halothane and pre-treated with equimolar oral doses of either naproxen (0.3, 1, 3 or 10 mg/kg) or ATB-346 (0.48, 1.6, 4.8, or 16 mg/kg) 30 min before the i.art. injection of 7.5 mg of carrageenan (CGN) into the right knee joint cavity. Joint swelling and pain score were assessed after 1, 3 and 5 h, and tactile allodynia after 2 and 4 h. After the last measurement, the joint cavity lavages were performed for counting of the recruited leukocytes. The drugs (at the highest doses) were also tested for their gastric effects by evaluating macroscopical damage score and neutrophil recruitment (measured as myeloperoxidase – MPO activity) in the stomachs 5 h after administration of the drugs. In addition, the serum naproxen pharmacokinetic profiles of both compounds, administered at the highest equimolar doses, were obtained during the first 6 h after dosing. Results At the two highest tested doses, both naproxen and ATB-346 reduced edema and pain score (measured 3 and 5 h after CGN; P?

2013-01-01

326

Evaluation of a single oral dose of diethylcarbamazine 300 mg as provocative test and simultaneous treatment in Myanmar migrant workers with Wuchereria bancrofti infection in Thailand.  

PubMed

We assessed the efficiency of oral diethylcarbamazine (DEC) 300 mg as a provocative test on blood examination 30 minutes after administration, while gauging the overall infection rate in Myanmar migrant workers with Wuchereria bancrofti infection who enrolled for work permits in Thailand in 2002, using circulating filarial antigens (CFA) assays, the NOW ICT Filariasis card test and the Og4C3 ELISA as reference. Overall infection rates of 0.3% (95% CI=0-0.7%), 4.2% (95% CI=1.8-6.5%) and 5.9% (95% CI=3.2-8.7%) by three diagnostic tests, respectively, were observed. Among three different location groups of Myanmar population sample tested, there were no statistically significant differences in the overall infection detection rates. When either the ICT card test or the Og4C3 ELISA was used as a reference, the specificity and positive predictive value of the DEC-provocative day test was the same, 100%. The sensitivities were 25.0% (95% CI = 0.5-49.5%) and 17.6% (95% CI = 0-35.8%) on the ICT and ELISA tests, respectively. The negative predictive values were 96.8% (95% CI = 94.8-98.9%) and 95.1% (95% CI = 92.6-97.6%), respectively. In three microfilaremic persons followed-up monitored at 8-weeks DEC post-provocation, there were 6 x 10(-1) and 7 x 10(-1) decreases in microfilaremia and antigenemia. These findings suggested that, unlike the CFA assays, the DEC-provocative day test is unsuitable for the diagnosis of active W. bancrofti infection in the population tested, and for gauging current infection prevalence. The treatment would likely be beneficial to reduce microfilaremia and antigenemia. PMID:15689072

Bhumiratana, Adisak; Siriaut, Chumsin; Koyadun, Surachart; Satitvipawee, Pratana

2004-09-01

327

Low-dose oral imatinib in the treatment of systemic sclerosis interstitial lung disease unresponsive to cyclophosphamide: a phase II pilot study  

PubMed Central

Introduction Pulmonary involvement represents a major cause of death of systemic sclerosis (SSc) patients. Recent data suggest that tyrosine kinase inhibitors, such as imatinib, may be a therapeutic option for SSc patients. However, preliminary published clinical trials were inconclusive about imatinib efficacy and showed side effects. The purpose of this study was to verify efficacy and tolerability of low-dose imatinib on interstitial lung disease in a cohort of SSc patients unresponsive to cyclophosphamide therapy. Methods Thirty consecutive SSc patients with active pulmonary involvement, unresponsive to cyclophosphamide, were treated with imatinib 200 mg/day for 6 months followed by a 6-month follow-up. A “good response” was defined as an increase of forced vital capacity (FVC) by more of 15% and/or increase of diffusing capacity of carbon monoxide (DLCO) >15% and PaO2?>?90% of initial value and high-resolution computed tomography (HRCT)-scan pattern unchanged or improved. Results Twenty-six patients completed the study. Three patients died and one patient was lost to follow-up. Four patients (15.32%) had a good response, 7 worsened and 15 had a stabilized lung disease. Overall, 19 (73.07%) patients had an improved or stabilized lung disease. After a 6-month follow-up, 12 (54.5%) of the 22 patients showed an improved or stabilized lung disease. Conclusions Lung function was stabilized in a large proportion of patients unresponsive to cyclophosphamide therapy and a beneficial outcome emerged from the analysis of HRCT lung scans. There was no significant improvement of skin involvement, and the low dose was well tolerated. These data provide useful suggestions to design future randomized clinical trials for SSc therapeutics. Trial registration ClinicalTrials.gov NCT00573326. Registered 13 December 2007. PMID:25007944

2014-01-01

328

Brain Serotonin Transporter Occupancy by Oral Sibutramine Dosed to Steady State: A PET Study Using 11C-DASB in Healthy Humans  

PubMed Central

Sibutramine is a centrally acting monoamine reuptake inhibitor prescribed as an appetite suppressant in the management of obesity. Its effects are mostly attributable to serotonin and norepinephrine transporter (SERT and NET, respectively) inhibition by its potent metabolites mono-desmethylsibutramine (M1) and di-desmethylsibutramine (M2). However, there is a paucity of in vivo data in humans about mechanisms underlying both clinical efficacy and the dose-independent non-response observed in a minority of patients. Twelve healthy male patients (mean age 41 years) completed a double-blind, placebo-controlled, within-subject crossover investigation of brain SERT occupancy by sibutramine 15?mg daily at steady state. Correlations were measured between occupancy and (i) plasma concentrations of sibutramine, M1 and M2; (ii) appetite suppression. 11C-DASB PET scans were performed on the HRRT camera. Binding potentials (BPND) were calculated by the Logan reference tissue (cerebellum) method. SERT occupancy was modest (mean 30±10%), was similar across brain regions, but varied widely across subjects (15–46%). Occupancy was correlated positively (p=0.09) with M2 concentration, but not with sibutramine or M1. No significant appetite suppression was seen at <25% occupancy and greatest suppression was associated with highest occupancy (25–46%). However, several subjects with occupancy (36–39%) in the higher range had no appetite suppression. SERT occupancy by clinical doses of sibutramine is of modest magnitude and may be mediated predominantly by M2 in humans. 5-HT reuptake inhibition may be necessary but is not sufficient for sibutramine's efficacy in humans, supporting preclinical data suggesting that the hypophagic effect requires the co-inhibition of both SERT and NET. PMID:19890256

Talbot, Peter S; Bradley, Stefan; Clarke, Cyril P; Babalola, Kola O; Philipp, Andrew W; Brown, Gavin; McMahon, Adam W; Matthews, Julian C

2010-01-01

329

Modified oral metronidazole desensitization protocol  

PubMed Central

The Center for Disease Control guidelines recommend desensitization to metronidazole in patients with trichomoniasis and hypersensitivity to metronidazole. There is only one published oral metronidazole desensitization protocol. The purpose of this study was to design a new, more gradual oral desensitization protocol to decrease systemic reactions that may occur when using the previously published protocol. We present two patients with presumed IgE-mediated allergy to metronidazole who underwent oral desensitization using our modified protocol. Case 1 was a 65-year-old woman with trichomoniasis who presented for metronidazole desensitization with a history of intraoperative anaphylaxis and positive skin tests to metronidazole. The patient tolerated six doses of the modified desensitization but developed systemic symptoms of nasal congestion and diffuse pruritus after the 25- and 100-mg doses. Both reactions were treated with intravenous (i.v.) antihistamines. Because of gastrointestinal irritation, the desensitization was completed at a dose of 250 mg orally every 6 hours. Case 2 was a 42-year-old woman with trichomoniasis and a history of hives immediately after administration of i.v. metronidazole who presented for desensitization. The patient had negative skin-prick and intradermal testing to metronidazole. She developed lip tingling and pruritus on her arms 15 minutes after the 10-mg dose. Fexofenadine at 180 mg was given orally and symptoms resolved. She tolerated the rest of the protocol without reaction and received a total dose of 2 g of metronidazole. Our oral metronidazole desensitization for presumed IgE-mediated reactions offers a second option for physicians wishing to use a more gradual escalation in dose. PMID:24612959

Pien, Lily C.; Gutta, Ravi C.; Abouhassan, Susan R.

2014-01-01

330

Vitamin D supplementation in older people (VDOP): Study protocol for a randomised controlled intervention trial with monthly oral dosing with 12,000 IU, 24,000 IU or 48,000 IU of vitamin D3  

PubMed Central

The randomised, double blind intervention trial ‘Optimising Vitamin D Status in Older People’ (VDOP) will test the effect of three oral dosages of vitamin D given for one year on bone mineral density (BMD) and biochemical markers of vitamin D metabolism, bone turnover and safety in older people. VDOP is funded by Arthritis Research UK, supported through Newcastle University and MRC Human Nutrition Research and sponsored by the Newcastle upon Tyne Hospitals NHS Foundation Trust.a Background Vitamin D insufficiency is common in older people and may lead to secondary hyperparathyroidism, bone loss, impairment of muscle function and increased risk of falls and fractures. Vitamin D supplementation trials have yielded conflicting results with regard to decreasing rates of bone loss, falls and fractures and the optimal plasma concentration of 25 hydroxy vitamin D (25OHD) for skeletal health remains unclear. Method/design Older (?70 years) community dwelling men and women are recruited through General Practices in Northern England and 375 participants are randomised to take 12,000 international units (IU), 24,000 IU or 48,000 IU of vitamin D3 orally each month for one year starting in the winter or early spring. Hip BMD and anthropometry are measured at baseline and 12 months. Fasting blood samples are collected at baseline and three-month intervals for the measurement of plasma 25OHD, parathyroid hormone (PTH), biochemical markers of bone turnover and biochemistry to assess the dose–response and safety of supplementation. Questionnaire data include falls, fractures, quality of life, adverse events and outcomes, compliance, dietary calcium intake and sunshine exposure. Discussion This is the first integrated vitamin D supplementation trial in older men and women using a range of doses given at monthly intervals to assess BMD, plasma 25OHD, PTH and biochemical markers of bone turnover and safety, quality of life and physical performance. We aim to investigate the vitamin D supplementation and plasma 25OHD concentration required to maintain bone health and to develop a set of biochemical markers that reflects the effect of vitamin D on bone. This will aid future studies investigating the effect of vitamin D supplementation on fracture risk. #ISRCTN 35648481 (assigned 16 August 2012), EudraCT 2011-004890-10.

2013-01-01

331

Absorption, distribution, metabolism and excretion of selenium following oral administration of elemental selenium nanoparticles or selenite in rats.  

PubMed

A suspension of nanoparticles of BSA-stabilized red amorphous elemental selenium (Se) or an aqueous solution of sodium selenite was repeatedly administered by oral gavage for 28 days at 0.05 mg kg(-1) bw per day (low dose) or at 0.5 mg kg(-1) bw per day (high dose) as Se to female rats. Prior to administration, the size distribution of the Se nanoparticles was characterized by dynamic light scattering and transmission electron microscopy, which showed that the particles' mean diameter was 19 nm and ranged in size from 10 to 80 nm. Following administration of the high dose of Se nanoparticles or selenite the concentration of Se was determined by ICP-MS in the liver, kidney, urine, feces, stomach, lungs, and plasma at the ?g g(-1) level and in brain and muscle tissue at the sub-?g g(-1) level. In order to test if any elemental Se was present in the liver, kidney or feces, an in situ derivatization selective to elemental Se was performed by treatment with sulfite, which resulted in formation of the selenosulfate anion. This Se species was selectively and quantitatively determined by anion exchange HPLC and ICP-MS detection. The results showed that elemental Se was present in the livers, kidneys and feces of animals exposed to low and high doses of elemental Se nanoparticles or to selenite, and was also detected in the same samples from control animals. The fraction of Se present as elemental Se in livers and kidneys from the high dose animals was significantly larger than the similar fraction in samples from the low dose animals or from the controls. This suggested that the natural metabolic pathways of Se were exhausted when given the high dose of elemental Se or selenite resulting in a non-metabolized pool of elemental Se. Both dosage forms of Se were bioavailable as demonstrated by the blood biomarker selenoprotein P, which was equally up-regulated in the high-dose animals for both dosage forms of Se. Finally, the excretion of Se in urine and its occurrence as Se-methylseleno-N-acetyl-galactosamine and the trimethylselenonium-ion demonstrated that both dosage forms were metabolized and excreted. The results of the study showed that both forms of Se were equally absorbed, distributed, metabolized and excreted, but the detailed mechanism of the fate of the administered elemental Se or selenite in the gastro-intestinal tract of rats remains unclear. PMID:24413471

Loeschner, Katrin; Hadrup, Niels; Hansen, Marianne; Pereira, Sonia A; Gammelgaard, Bente; Mřller, Laura Hyrup; Mortensen, Alicja; Lam, Henrik Rye; Larsen, Erik H

2014-02-01

332

The Effects of Low and High Dose Oral Calcium and Phosphor Supplementation on Nephrocalcinosis Diagnosed by Sonography in Premature and Low Birth Weight Neonates  

PubMed Central

Nephrocalcinosis is defined as calcium deposition in the renal interstitium. One of the major causes of neonatal nephrocalcinosis is the use of calcium and phosphor supplements for premature neonates. This study aims at assessing the effects of calcium and phosphor supplementation in neonatal nephrocalcinosis by renal ultrasonography. In this randomized controlled trial, 37 premature neonates with birth weights <1500 g or a gestational age of <34 weeks were considered. Two different doses of calcium 75 vs. 230 mg/kg/day and phosphor 50 vs. 110 mg/kg/day were prescribed and laboratory and sonographic data were then documented and evaluated. The incidence of nephrocalcinosis was 47.8% in group 1 and 28.6% in group 2. There was a significant association between NC and positive family history of renal stones, shorter duration of TPN and NICU stay. The amount of calcium dosage, gestational age, birth weight, sex, use of surfactants, and mechanical ventilation did not have any significant association with NC. In this study, the neonates with NC were mostly the white flake type (8 cases) and the majority of the lesions were 1-2 mm. All the lesions were located in the pyramid and papilla areas, acoustic shadows were not prevalent and stones were not observed in any of the patients. Trial Registration Number: IRCT2013060810441N3 PMID:25429179

Kamali, Karmella; Pishva, Narjes; Deireh, Esmat

2014-01-01

333

Cryotherapy in the prevention of oral mucositis in patients receiving low-dose methotrexate following myeloablative allogeneic stem cell transplantation: a prospective randomized study of the Gruppo Italiano Trapianto di Midollo Osseo nurses group  

Microsoft Academic Search

Severe oral mucositis is a major cause of morbidity following allogeneic hematopoietic stem cell transplantation (AHSCT). Cryotherapy, that is, the application of ice chips on the mucosa of the oral cavity during the administration of antineoplastic agents, may reduce the incidence and severity of chemotherapy-related oral mucositis. In this multicenter randomized study, we addressed whether cryotherapy during MTX administration is

E Gori; M Arpinati; F Bonifazi; A Errico; A Mega; F Alberani; V Sabbi; G Costazza; S Leanza; C Borrelli; M Berni; C Feraut; E Polato; M C Altieri; E Pirola; M C Loddo; M Banfi; L Barzetti; S Calza; C Brignoli; G Bandini; A De Vivo; A Bosi; M Baccarani

2007-01-01

334

Oral vaccines  

PubMed Central

Oral vaccines are safe and easy to administer and convenient for all ages. They have been successfully developed to protect from many infectious diseases acquired through oral transmission. We recently found in animal models that formulation of oral vaccines in a nanoparticle-releasing microparticle delivery system is a viable approach for selectively inducing large intestinal protective immunity against infections at rectal and genital mucosae. These large-intestine targeted oral vaccines are a potential substitute for the intracolorectal immunization, which has been found to be effective against rectogenital infections but is not feasible for mass vaccination. Moreover, the newly developed delivery system can be modified to selectively target either the small or large intestine for immunization and accordingly revealed a regionalized immune system in the gut. Future applications and research endeavors suggested by the findings are discussed. PMID:23493163

Zhu, Qing; Berzofsky, Jay A.

2013-01-01

335

Oral pathology.  

PubMed

Oral disease is exceedingly common in small animal patients. In addition, there is a very wide variety of pathologies that are encountered within the oral cavity. These conditions often cause significant pain and/or localized and systemic infection; however, the majority of these conditions have little to no obvious clinical signs. Therefore, diagnosis is not typically made until late in the disease course. Knowledge of these diseases will better equip the practitioner to effectively treat them. This article covers the more common forms of oral pathology in the dog and cat, excluding periodontal disease, which is covered in its own chapter. The various pathologies are presented in graphic form, and the etiology, clinical signs, recommended diagnostic tests, and treatment options are discussed. Pathologies that are covered include: persistent deciduous teeth, fractured teeth, intrinsically stained teeth, feline tooth resorption, caries, oral neoplasia, eosinophilic granuloma complex, lymphoplasmacytic gingivostomatitis, enamel hypoplasia, and "missing" teeth. PMID:18482706

Niemiec, Brook A

2008-05-01

336

Effect of high-dose ciclosporin on the immune response to primary and booster vaccination in immunocompetent cats.  

PubMed

Ciclosporin (Atopica oral solution for cats 100 mg/ml; Novartis Animal Health) was recently approved for use in cats with feline hypersensitivity dermatitis. The immunosuppressant effect of ciclosporin on the ability of cats to mount an immune response following vaccination was determined. Thirty-two healthy, immunocompetent adult cats (16 cats/group) were treated with either ciclosporin for 56 days at a dose of 24 mg/kg once daily or sham dosed. Prior to treatment, cats had an adequate antibody response to primary vaccination against feline calicivirus (FCV), feline herpesvirus-1 (FHV-1), feline panleukopenia virus (FPV), feline leukemia virus (FeLV) and rabies. Booster vaccination or novel vaccination with feline immunodeficiency virus (FIV) was administered 28 days after initiation of treatment with ciclosporin. There were no differences between the ciclosporin-treated and control cats for FCV and FPV antibody titers following booster vaccination. There were delays/reductions in antibody response to FHV-1, FeLV and rabies in treated cats; however, adequate protection was achieved in response to all booster vaccinations. Following primary vaccination with FIV, control cats showed a response, but treated cats showed no antibody production. Adverse events commonly associated with ciclosporin treatment, including diarrhea/loose stool, vomiting, salivation and regurgitation, were reported. In adult cats treated with 24 mg/kg/day of ciclosporin (more than three times the therapeutic dose), vaccine titer levels were adequate for protection following booster vaccination. In contrast, treated cats failed to mount a humoral response to a novel (FIV) vaccination, suggesting that memory B-cell immune responses remain intact during repeated high-dose ciclosporin administration in cats, but that primary immune responses are impaired. PMID:24820998

Roberts, Elizabeth S; VanLare, Karen A; Roycroft, Linda M; King, Stephen

2015-02-01

337

A Phase II Study of Fixed-Dose Rate Gemcitabine Plus Low-Dose Cisplatin Followed by Consolidative Chemoradiation for Locally Advanced Pancreatic Cancer  

SciTech Connect

Purpose: The optimal strategy for treating locally advanced pancreatic cancer remains controversial, including the respective roles and timing of chemotherapy and radiation. We conducted a Phase II nonrandomized trial to evaluate sequential chemotherapy followed by chemoradiation in this patient population. Methods and Materials: Chemotherapy naive patients with locally advanced pancreatic adenocarcinoma were treated with fixed-dose rate gemcitabine (1,000 mg/m{sup 2} at 10 mg/m{sup 2}/min) plus cisplatin 20 mg/m{sup 2} on Days 1 and 15 of a 28-day cycle. Those without evidence of extrapancreatic metastases after six cycles of chemotherapy received radiation (5,040 cGy over 28 fractions) with concurrent capecitabine (800 mg/m{sup 2} orally twice daily on the day of radiation) as a radiosensitizer. Results: A total of 25 patients were enrolled with a median follow-up time of 656 days. Twelve patients (48%) successfully received all six cycles of chemotherapy plus chemoradiation. Eight patients (32%) progressed during chemotherapy, including 7 with extrapancreatic metastases. Grade 3/4 hematologic toxicities were uncommon. Two patients sustained myocardial infarctions during chemotherapy, and 4 were hospitalized for infectious complications, although none in the setting of neutropenia. Median time to progression was 10.5 months and median survival was 13.5 months, with an estimated 1-year survival rate of 62%. Patients receiving all components of therapy had a median survival of 17.0 months. Conclusions: A strategy of initial fixed-dose rate gemcitabine-based chemotherapy, followed by chemoradiation, shows promising efficacy for treatment of locally advanced disease. A substantial proportion of patients will be identified early on as having extrapancreatic disease and spared the potential toxicities associated with radiation.

Ko, Andrew H. [Division of Hematology/Oncology, University of California at San Francisco, San Francisco, CA (United States)]. E-mail: andrewko@medicine.ucsf.edu; Quivey, Jeanne M. [Department of Radiation Oncology, University of California at San Francisco, San Francisco, CA (United States); Venook, Alan P. [Division of Hematology/Oncology, University of California at San Francisco, San Francisco, CA (United States); Bergsland, Emily K. [Division of Hematology/Oncology, University of California at San Francisco, San Francisco, CA (United States); Dito, Elizabeth R.N. [Division of Hematology/Oncology, University of California at San Francisco, San Francisco, CA (United States); Schillinger, Brian R.N. [Division of Hematology/Oncology, University of California at San Francisco, San Francisco, CA (United States); Tempero, Margaret A. [Division of Hematology/Oncology, University of California at San Francisco, San Francisco, CA (United States)

2007-07-01

338

Low-dose corticosteroid use and mortality in severe community-acquired pneumonia patients.  

PubMed

The relationship between low-dose corticosteroid use and mortality in patients with severe community-acquired pneumonia (CAP) remains unclear. 6925 patients with severe CAP who received mechanical ventilation with or without shock (defined as use of catecholamines) at 983 hospitals were identified using a Japanese nationwide administrative database. The main outcome measure was 28-day mortality. 2524 patients with severe CAP who received catecholamines were divided into corticosteroid (n=631) and control (n=1893) groups. The 28-day mortality was significantly different between corticosteroid and control groups (unmatched: 24.6% versus 36.3%, p<0.001; propensity score-matched: 25.3% versus 32.6%, p=0.01; inverse probability-weighted: 27.5% versus 34.2%, p<0.001). 4401 patients with severe CAP who did not receive catecholamines were also divided into corticosteroid (n=1112) and control (n=3289) groups. The 28-day mortality was not significantly different between corticosteroid and control groups in propensity score-matched analyses (unmatched: 16.0% versus 19.4%, p=0.01; propensity score-matched: 17.7% versus 15.6%, p=0.22; inverse probability-weighted: 18.8% versus 18.2%, p=0.44). Low-dose corticosteroid use may be associated with reduced 28-day mortality in patients with septic shock complicating CAP. PMID:25323232

Tagami, Takashi; Matsui, Hiroki; Horiguchi, Hiromasa; Fushimi, Kiyohide; Yasunaga, Hideo

2015-02-01

339

The Importance of Body Weight for the Dose Response Relationship of Oral Vitamin D Supplementation and Serum 25-Hydroxyvitamin D in Healthy Volunteers  

PubMed Central

Unlike vitamin D recommendations by the Institute of Medicine, the Clinical Practice Guidelines by the Endocrine Society acknowledge body weight differentials and recommend obese subjects be given two to three times more vitamin D to satisfy their body's vitamin D requirement. However, the Endocrine Society also acknowledges that there are no good studies that clearly justify this. In this study we examined the combined effect of vitamin D supplementation and body weight on serum 25-hydroxyvitamin (25(OH)D) and serum calcium in healthy volunteers. We analyzed 22,214 recordings of vitamin D supplement use and serum 25(OH)D from 17,614 healthy adult volunteers participating in a preventive health program. This program encourages the use of vitamin D supplementation and monitors its use and serum 25(OH)D and serum calcium levels. Participants reported vitamin D supplementation ranging from 0 to 55,000 IU per day and had serum 25(OH)D levels ranging from 10.1 to 394 nmol/L. The dose response relationship between vitamin D supplementation and serum 25(OH)D followed an exponential curve. On average, serum 25(OH)D increased by 12.0 nmol/L per 1,000 IU in the supplementation interval of 0 to 1,000 IU per day and by 1.1 nmol/L per 1,000 IU in the supplementation interval of 15,000 to 20,000 IU per day. BMI, relative to absolute body weight, was found to be the better determinant of 25(OH)D. Relative to normal weight subjects, obese and overweight participants had serum 25(OH)D that were on average 19.8 nmol/L and 8.0 nmol/L lower, respectively (P<0.001). We did not observe any increase in the risk for hypercalcemia with increasing vitamin D supplementation. We recommend vitamin D supplementation be 2 to 3 times higher for obese subjects and 1.5 times higher for overweight subjects relative to normal weight subjects. This observational study provides body weight specific recommendations to achieve 25(OH)D targets. PMID:25372709

Ekwaru, John Paul; Zwicker, Jennifer D.; Holick, Michael F.; Giovannucci, Edward; Veugelers, Paul J.

2014-01-01

340

21 CFR 520.2220c - Sulfadimethoxine oral suspension.  

Code of Federal Regulations, 2011 CFR

...FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2220c Sulfadimethoxine oral suspension. (a) Chemical...bacterial infections in dogs and cats and enteritis associated with...day of treatment administer an oral dose of 25 milligrams...

2011-04-01

341

21 CFR 520.2220c - Sulfadimethoxine oral suspension.  

Code of Federal Regulations, 2012 CFR

...FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2220c Sulfadimethoxine oral suspension. (a) Chemical...bacterial infections in dogs and cats and enteritis associated with...day of treatment administer an oral dose of 25 milligrams...

2012-04-01

342

21 CFR 520.2220c - Sulfadimethoxine oral suspension.  

Code of Federal Regulations, 2013 CFR

...FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2220c Sulfadimethoxine oral suspension. (a) Chemical...bacterial infections in dogs and cats and enteritis associated with...day of treatment administer an oral dose of 25 milligrams...

2013-04-01

343

21 CFR 520.2220c - Sulfadimethoxine oral suspension.  

...FEEDS, AND RELATED PRODUCTS ORAL DOSAGE FORM NEW ANIMAL DRUGS § 520.2220c Sulfadimethoxine oral suspension. (a) Chemical...bacterial infections in dogs and cats and enteritis associated with...day of treatment administer an oral dose of 25 milligrams...

2014-04-01

344

Cryotherapy in the prevention of oral mucositis in patients receiving low-dose methotrexate following myeloablative allogeneic stem cell transplantation: a prospective randomized study of the Gruppo Italiano Trapianto di Midollo Osseo nurses group.  

PubMed

Severe oral mucositis is a major cause of morbidity following allogeneic hematopoietic stem cell transplantation (AHSCT). Cryotherapy, that is, the application of ice chips on the mucosa of the oral cavity during the administration of antineoplastic agents, may reduce the incidence and severity of chemotherapy-related oral mucositis. In this multicenter randomized study, we addressed whether cryotherapy during MTX administration is effective in the prevention of severe oral mucositis in patients undergoing myeloablative AHSCT. One hundred and thirty patients undergoing myeloablative AHSCT and MTX-containing GVHD prophylaxis were enrolled and randomized to receive or not receive cryotherapy during MTX administration. The incidence of severe (grade 3-4) oral mucositis, the primary end point of the study, was comparable in patients receiving or not cryotherapy. Moreover, no difference was observed in the incidence of oral mucositis grade 2-4 and the duration of oral mucositis grade 3-4 or 2-4, or in the kinetics of mucositis over time. In univariate and multivariate analysis, severe oral mucositis correlated with TBI in the conditioning regimen and lack of folinic acid rescue following MTX administration. Thus, cryotherapy during MTX administration does not reduce severe oral mucositis in patients undergoing myeloablative allogeneic HSCT. Future studies will assess cryotherapy before allogeneic HSCT. PMID:17277790

Gori, E; Arpinati, M; Bonifazi, F; Errico, A; Mega, A; Alberani, F; Sabbi, V; Costazza, G; Leanza, S; Borrelli, C; Berni, M; Feraut, C; Polato, E; Altieri, M C; Pirola, E; Loddo, M C; Banfi, M; Barzetti, L; Calza, S; Brignoli, C; Bandini, G; De Vivo, A; Bosi, A; Baccarani, M

2007-03-01

345

A study to determine the safety profile and maximum tolerated dose of micafungin (FK463) in patients undergoing haematopoietic stem cell transplantation  

Microsoft Academic Search

This open-label, dose-escalation study assessed the maximum tolerated dose (MTD) of the new antifungal micafungin in patients undergoing haematopoietic stem cell transplantation (HSCT). Participants received 3, 4, 6 or 8 mg\\/kg\\/day micafungin intravenously from 7 days to a maximum of 28 days or until neutropaenia resolved. The MTD was defined as the highest dose not causing the same Grade 3

B Sirohi; R L Powles; R Chopra; N Russell; J L Byrne; H G Prentice; M Potter; S Koblinger

2006-01-01

346

Oral Appliances  

MedlinePLUS

... weeks or months to complete. This includes examination, evaluation to determine the most appropriate oral appliance, fitting, maximizing adaptation of the appliance, and the function. Ongoing care, including short- and long-term follow-up is an essential step in the ...

347

Ampicillin Oral  

MedlinePLUS

... Tenormin), oral contraceptives, probenecid (Benemid), rifampin, sulfasalazine, and vitamins.tell your doctor if you have or have ever had kidney or liver disease, allergies, asthma, blood disease, colitis, stomach problems, or hay fever.tell your doctor if you are pregnant, plan ...

348

Oral Cancer  

MedlinePLUS

... the effects of oral cancer on speech and swallowing? The effects of cancer on speech and swallowing depend on the location and size of the ... or push food back toward the throat during swallowing. A growth on the roof of the mouth ( ...

349

Enantioselective HPLC-DAD method for the determination of etodolac enantiomers in tablets, human plasma and application to comparative pharmacokinetic study of both enantiomers after a single oral dose to twelve healthy volunteers.  

PubMed

An enantioselective high performance liquid chromatographic method with diode array detection (HPLC-DAD) was developed and validated for the determination of etodolac enantiomers in tablets and human plasma. Enantiomeric separation was achieved on a Kromasil Cellucoat chiral column (250 mm × 4.6mm i.d., 5 µm particle size) using a mobile phase consisting of hexane: isopropanol: triflouroacetic acid (90:10:0.1 v/v/v) at a flow rate of 1.0 mL min(-1). The chromatographic system enables the separation of the two enantiomers and the internal standard within a cycle time of 8 min. The resolution between the two enantiomers was 4.25 and the resolution between each enantiomer and the internal standard was more than 2.0. Detection was carried out at 274 nm, and the purity assessment was performed using a photodiode array detector. Solid phase extraction technique using C-18 cartridge was applied to extract the analytes from the plasma samples, and the percentage recovery was more than 95% for the lower quantification limit. The method has been validated with respect to selectivity, linearity, accuracy and precision, robustness, limit of detection and limit of quantification. The validation acceptance criteria were met in all cases. The linearity range for the determination of each enantiomer in human plasma was 0.4-30.0 µg mL(-1) and the limits of quantification of R-etodolac and S-etodolac were 0.20 and 0.19 µg mL(-1), respectively. The validated method was successfully applied to the determination of etodolac enantiomers in tablets and to a comparative pharmacokinetic study of the two enantiomers after the administration of 300 mg single oral dose etodolac racemate tablets to twelve healthy volunteers. PMID:25159440

Hewala, Ismail I; Moneeb, Marwa S; Elmongy, Hatem A; Wahbi, Abdel-Aziz M

2014-12-01

350

Development, validation and transfer of a near infrared method to determine in-line the end point of a fluidised drying process for commercial production batches of an approved oral solid dose pharmaceutical product.  

PubMed

Pharmaceutical companies are progressively adopting and introducing the principles of Quality by Design with the main purpose of assurance and built-in quality throughout the whole manufacturing process. Within this framework, a Partial Least Square (PLS) model, based on Near Infrared (NIR) spectra and humidity determinations, was built in order to determine in-line the drying end point of a fluidized bed process. The in-process method was successfully validated following the principles described within The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use - ICH Q2 (r1) - Validation of Analytical Procedures: Text and Methodology. However, in some aspects, the cited guidelines were not appropriate to in-process methods developed and validated exclusively with in-line samples and implemented in dynamic systems, such as drying processes. In this work, a customized interpretation of guidelines has been adopted which provided the framework of evidence to support a validated application. The application has been submitted to the United States Food and Drug Administration (FDA) and The European Medicines Agency (EMA) during applications for grant of licences. Representatives from these Regulatory Authorities have specifically reviewed this novel application during on-site inspections, and have subsequently approved both the product and this application. Currently, the NIR method is implemented as a primary in-line method to control the drying end point in real-time (to below a control limit of not greater than 1.2% w/w) for commercial production batches of an approved, solid, oral-dose medicine. The implementation of this in-process method allows real-time control with benefits including a reduction in operation time and labour; sample handling and waste generation; and a reduced risk to product quality in further unit operations due to improved consistency of intermediate output at this stage. To date, this has achieved approximately 10% savings in energy efficiency and operational time for this part of the manufacturing process. PMID:20801599

Peinado, Antonio; Hammond, Jonathan; Scott, Andrew

2011-01-01

351

Oral Tolerance: Therapeutic Implications for Autoimmune Diseases  

PubMed Central

Oral tolerance is classically defined as the suppression of immune responses to antigens (Ag) that have been administered previously by the oral route. Multiple mechanisms of tolerance are induced by oral Ag. Low doses favor active suppression, whereas higher doses favor clonal anergy/deletion. Oral Ag induces Th2 (IL-4/IL-10) and Th3 (TGF-?) regulatory T cells (Tregs) plus CD4+CD25+ regulatory cells and LAP+T cells. Induction of oral tolerance is enhanced by IL-4, IL-10, anti-IL-12, TGF-?, cholera toxin B subunit (CTB), Flt-3 ligand, anti-CD40 ligand and continuous feeding of Ag. In addition to oral tolerance, nasal tolerance has also been shown to be effective in suppressing inflammatory conditions with the advantage of a lower dose requirement. Oral and nasal tolerance suppress several animal models of autoimmune diseases including experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia, arthritis and diabetes in the nonobese diabetic (NOD) mouse, plus non-autoimmune diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been tested in human autoimmune diseases including MS, arthritis, uveitis and diabetes and in allergy, contact sensitivity to DNCB, nickel allergy. Positive results have been observed in phase II trials and new trials for arthritis, MS and diabetes are underway. Mucosal tolerance is an attractive approach for treatment of autoimmune and inflammatory diseases because of lack of toxicity, ease of administration over time and Ag-specific mechanism of action. The successful application of oral tolerance for the treatment of human diseases will depend on dose, developing immune markers to assess immunologic effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy and early therapy. PMID:17162357

Faria, Ana M. C.; Weiner, Howard L.

2006-01-01

352

Chemical Warfare Agents: Estimating Oral Reference Doses  

Microsoft Academic Search

\\u000a The FY 1993 Defense Authorization Act [Public Law (PL) 102–484, Sect. 176] directed the U.S. Department of the Army (DA) 1 to examine the scale of effort and consider plans needed to safely dispose of nonstockpile chemical materiel (NSCM), previously\\u000a identified as an area of national concern in House Appropriations Report 101–822 from the FY 1991 Defense Appropriations Act.\\u000a Non-stockpile

Dennis M. Opresko; Robert A. Young; Rosmarie A. Faust; Sylvia S. Talmage; Annetta P. Watson; Robert H. Ross; Kowetha A. Davidson; Joe King

353

First-in-Human Dose Study of the Novel Transforming Growth Factor-? Receptor I Kinase Inhibitor LY2157299 Monohydrate in Patients with Advanced Cancer and Glioma.  

PubMed

Purpose: Transforming growth factor-beta (TGF-?) signaling plays a key role in tumor progression, including malignant glioma. Small molecule inhibitors such as LY2157299 monohydrate (LY2157299) block TGF-? signaling and reduce tumor progression in preclinical models. To use LY2157299 in the treatment of malignancies, we investigated its properties in a First-in-Human Dose (FHD) study in cancer patients. Experimental Design: Sixty five patients (58 with glioma) with measurable and progressive malignancies were enrolled. Oral LY2157299 was given as a split dose morning and evening on an intermittent schedule of 14 days on and 14 days off (=28-day cycle). LY2157299 monotherapy was studied in dose escalation (Part A) first and then evaluated in combination with standard doses of lomustine (Part B). Safety was assessed using Common Terminology Criteria for Adverse Events version 3.0, echocardiography/Doppler imaging, serum troponin I and brain natriuretic peptide (BNP) levels. Anti-tumor activity was assessed by RECIST and Macdonald criteria. Results: In Part A, 16.6% (5/30) and in Part B, 7.7% (2/26) of evaluable patients with glioma had either a complete (CR) or a partial response (PR). In both parts 15 patients with glioma had stable disease (SD), 5 of whom had SD ?6 cycles of treatment. Therefore, clinical benefit (=CR+PR+SD ?6 cycles) was observed in 12/56 patients with glioma (21.4%). LY2157299 was safe with no cardiac adverse events. Conclusions: Based on the safety, PK and antitumor activity in glioma patients, the intermittent administration of LY2157299 at 300 mg/day is safe for future clinical investigation. PMID:25424852

Rodon, Jordi; Carducci, Michael A; Sepulveda-Sanchez, Juan M; Azaro, Analia; Calvo, Emiliano; Seoane, Joan; Brana, Irene; Sicart, Elisabet; Gueorguieva, Ivelina; Cleverly, Ann L; Sokalingum Pillay, N; Desaiah, Durisala; Estrem, Shawn T; Paz-Ares, Luis; Holdoff, Matthias; Blakeley, Jaishri; Lahn, Michael M; Baselga, Jose

2014-11-25

354

Oral candidiasis  

PubMed Central

Oral candidiasis is a common opportunistic infection of the oral cavity caused by an overgrowth of Candida species, the commonest being Candida albicans. The incidence varies depending on age and certain predisposing factors. There are three broad groupings consisting of acute candidiasis, chronic candidiasis, and angular cheilitis. Risk factors include impaired salivary gland function, drugs, dentures, high carbohydrate diet, and extremes of life, smoking, diabetes mellitus, Cushing's syndrome, malignancies, and immunosuppressive conditions. Management involves taking a history, an examination, and appropriate antifungal treatment with a few requiring samples to be taken for laboratory analysis. In certain high risk groups antifungal prophylaxis reduces the incidence and severity of infections. The prognosis is good in the great majority of cases. PMID:12185216

Akpan, A; Morgan, R

2002-01-01

355

The development and use of a vaccinia-rabies recombinant oral vaccine for the control of wildlife rabies; a link between Jenner and Pasteur.  

PubMed Central

To improve both safety and stability of the oral vaccines used in the field to vaccinate foxes against rabies, a recombinant vaccinia virus, which expresses the immunizing G protein of rabies virus has been developed by inserting the cDNA which codes for the immunogenic glycoprotein of rabies virus into the thymidine kinase (TK) gene of the Copenhagen strain of vaccinia virus. The efficacy of this vaccine was tested by the oral route, primarily in foxes. The immunity conferred, a minimum of 12 months in cubs and 18 months in adult animals, corresponds to the duration of the protection required for vaccination of foxes in the field. Innocuity was tested in foxes, domestic animals, and in numerous European wild animal species that could compete with the red fox for the vaccine bait. No clinical signs or lesions were observed in any of the vaccinated animals during a minimum of 28 days post vaccination. Moreover, no transmission of immunizing doses of the recombinant occurred between foxes or other species tested. To study the stability of the vaccine strain, baits containing the vaccine were placed in the field. Despite considerable variations of environmental temperatures, the vaccine remained stable for at least one month. Because bait is taken within one month, it can be assumed that most animals taking the baits are effectively vaccinated. To test the field efficacy of the recombinant vaccine, large-scale campaigns of fox vaccination were set up in a 2200 km2 region of southern Belgium, were rabies was prevalent. A dramatic decrease in the incidence of rabies was noted after the campaigns. The recombinant is presently used to control wildlife rabies in the field both in several European countries and in the United States. PMID:8666066

Pastoret, P. P.; Brochier, B.

1996-01-01

356

Oral Mucositis  

Microsoft Academic Search

Mucositis is a common, painful, treatment-disrupting toxicity of both radiotherapy and chemotherapy. Patients with cancers\\u000a of the head and neck receiving radiation therapy with and without induction or concomitant chemotherapy, and individuals being\\u000a treated with high-dose chemotherapy regimens are at particularly high risk. Importantly, even patients receiving conventional\\u000a dosing schemes for other forms of cancer have a meaningful chance of

Nathaniel Treister

357

Serial Observations after High Dose Talc Slurry in the Rabbit Model for Pleurodesis  

Microsoft Academic Search

.   The mechanisms leading to a pleurodesis after the intrapleural injection of a sclerosing agent are not completely understood.\\u000a The purpose of the present study was to make serial observations over 28 days on the pleural fluid findings and the gross\\u000a and microscopic changes in the pleura after talc slurry administered intrapleurally at a high dose. Sixty-six rabbits received\\u000a 400

C. Xie; L. R. Teixeira; N.-S. Wang; J. P. McGovern; R. W. Light

1998-01-01

358

Canine generalized demodicosis treated with varying doses of a 2.5% moxidectin+10% imidacloprid spot-on and oral ivermectin: parasiticidal effects and long-term treatment outcomes.  

PubMed

Advocate(®) (2.5% moxidectin+10% imidacloprid) (Bayer HealthCare, Leverkusen, Germany) is a multiparasiticidal spot-on authorized for treating canine demodicosis in many countries. This blinded, randomized three-phase clinical trial compared its efficacy employing different dosing regimens with that of ivermectin. In the blinded first phase, 58 dogs suffering from generalized demodicosis were randomly assigned to one of four groups and treated with monthly, biweekly or weekly applications of Advocate(®), or with oral ivermectin (IVR) at 500 ?g/kg daily. Dogs were evaluated clinically and multiple skin scrapings undertaken every 4 weeks until parasitological cure was achieved (defined as two consecutive series of deep skin scrapings at monthly intervals negative for all life forms). Forty dogs completed the 16-week initial blinded phase, with 5 cases achieving parasitological cure. Five dogs were deemed treatment failures and subsequently treated with ivermectin. The treatment protocol was then changed for the remaining 35 dogs and this cross-over phase (Phase 2) was maintained for a further 8 weeks with an additional 9 dogs achieving parasitological cure. Thereafter, all remaining animals were treated with IVR until cured (Phase 3). Overall, 26 dogs achieved parasitological cure during the clinical investigation. Of these, 23 remained disease-free for at least 12 months while two were lost to follow up and one died of unrelated causes. A total of 32 (55.2%) dogs were withdrawn at various stages of the investigation including the 5 dogs that were judged treatment failures. Other reasons for withdrawal included: non-compliance, lost to follow-up, ivermectin toxicity or reasons unrelated to the investigation. No adverse effects were attributable to the use of Advocate(®). Parasiticidal efficacy was assessed by changes in mite counts (live adult, juvenile and egg) and skin lesion extent & severity scores. Statistical significance was assessed using ANCOVA with initial mite counts or skin scores used as the covariate to account for variations in disease severity. Planned pairwise comparisons were used to identify differences between treatment groups. The efficacy of Advocate(®) increased with its rate of application across all measures of efficacy. Although ivermectin was shown to be more effective than Advocate(®) applied once weekly, both treatment protocols produced clinically satisfactory results. It was concluded that weekly application of Advocate(®) can be recommended as effective for the treatment of canine generalized demodicosis without the potential for toxicity associated with ivermectin. PMID:25262617

Paterson, Tara E; Halliwell, Richard E; Fields, Paul J; Louw, Marta Lanza; Ball, Geoff; Louw, Jakobus; Pinckney, Rhonda

2014-10-15

359

Oral Haemangioma  

PubMed Central

Vascular anomalies comprise a widely heterogeneous group of tumours and malformations. Haemangioma is the most common benign tumour of vascular origin of the head and neck region. The possible sites of occurrence in oral cavity are lips, tongue, buccal mucosa, and palate. Despite its benign origin and behaviour, it is always of clinical importance to the dental profession and requires appropriate management. This case study reports a rare case of capillary haemangioma on the palatal gingiva in a 14-year-old female. PMID:22431929

Gill, Jaspreet Singh; Gill, Sharanjeet; Bhardwaj, Amit; Grover, Harpreet Singh

2012-01-01

360

Oral Thrush (For Parents)  

MedlinePLUS

... Crisp Choosing Safe Toys Checkups: What to Expect Ebola: What to Know Oral Thrush KidsHealth > Parents > Infections > Skin Infections & Rashes > Oral Thrush Print A A A Text Size What's in this article? About Oral Thrush Symptoms Prevention Treatment About Oral Thrush Oral thrush is a very ...

361

Managing ixabepilone adverse events with dose reduction.  

PubMed

Ixabepilone is a synthetic analogue of epothilone B approved for the treatment of patients with metastatic or locally advanced breast cancer in combination with capecitabine for cancer resistant to an anthracycline and a taxane, and as monotherapy for cancer resistant or refractory to anthracyclines, taxanes, and capecitabine. The principal dose-limiting adverse events (AEs) of ixabepilone's standard dose (40 mg/m(2) administered by 3-hour infusion once every 3 weeks) are peripheral neuropathy, neutropenia, and fatigue. An effective strategy to manage ixabepilone-related AEs is dose reduction by 20% (from 40 to 32 to 25 mg/m(2)); this does not appear to affect treatment efficacy and enables continuation of treatment after recovery (grade 1 or resolved). When appropriate, treatment can be restarted with a 20% dose reduction (to 32 mg/m(2)). For heavily pretreated patients, especially those with a low performance status, 32 mg/m(2) is an appropriate initial dose; the dose of capecitabine should also be lowered by 20%. Weekly ixabepilone (15-20 mg/m(2) on days 1, 8, and 15 every 28 days) may have an improved tolerability profile, but prospective studies with a large number of patients are required to determine whether it has therapeutic benefit comparable with the current approved regimen. More information is required on dosage and scheduling of ixabepilone in combination with other agents, including novel targeted therapies. PMID:23098573

Valero, Vicente

2013-02-01

362

Confectionery-based Dose Forms.  

PubMed

Conventional dosage forms such as tablets, capsules and syrupsare prescribed in the normal course of practice. However, concerns about patient preferences and market demands have given rise to the exploration of novel unconventional dosage forms. Among these, confectionery-based dose forms have strong potential to overcome compliance problems. This report will review the availability of these unconventional dose forms used in treating the oral cavity and for systemic drug delivery, with a focus on medicated chewing gum, medicated lollipops, and oral bioadhesive devices. The aim is to stimulate increased interest in the opportunities for innovative new products that are available to formulators in this field, particularly for atypical patient populations. PMID:25146440

Tangso, Kristian J; Ho, Quy Phuong; Boyd, Ben J

2014-08-21

363

Full-course oral levofloxacin for treatment of hospitalized patients with community-acquired pneumonia.  

PubMed

Most guidelines for the management of hospitalized patients with community-acquired pneumonia (CAP) recommend commencing therapy with intravenous antibiotics, primarily because of concern about absorption of oral antibiotics in acutely ill patients. However, patients who respond are rapidly switched to oral therapy, which has been shown to reduce costs and to shorten the length of stay. The aim of the present study was to determine whether a full course of oral antibiotics is as efficacious and as safe as intravenous-to-oral sequential antibiotic therapy for the treatment of hospitalized, non-ICU patients with CA