Sample records for dose 28-day oral

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

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

    2014-06-01

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

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

    PubMed

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

    2015-02-17

    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

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

    PubMed

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

    2012-01-01

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

  5. 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.

    PubMed

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

    2004-08-01

    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 for 28 days. Plasma acetylcholinesterase was significantly decreased in the groups 2, 5 and 6 males. Total white blood cell count was significantly lower in females of group 6. Total red blood cell count, haematocrite and haemoglobin concentration was significantly reduced in both male and female rats of groups 5 and 6. Relative liver weight was significantly increased in groups 3-6 male and female rats. Absolute thyroid gland weight was significantly increased in groups 3, 5 and 6 male rats and of groups 3-6 female rats, and relative thyroid gland weight was significantly increased in groups 2-6 male rats and of groups 3-6 female rats. Absolute thymus weight of groups 3-6 male and female rats and relative thymus weight of groups 3-6 male rats and groups 3 and 4 female rats was significantly decreased. A mild degree of centrilobular cell hypertrophy of the liver was seen in all male rats and of three female rats of group 6. In the thyroid gland follicular cell hypertrophy was present in one female in the control group and in six females and seven males of group 6. It was concluded that inhibition of acetylcholinesterase activity in plasma and brain by chlorpyrifos was not enhanced by co-administration of the other four pesticides. Effects were seen in liver, thyroid, thymus and blood in the combination groups. However, identification of the pesticide(s) responsible for these changes would require further studies of the individually pesticides as well as various combinations of the pesticides. PMID:15207377

  6. 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

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

    2004-01-01

    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

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

    PubMed

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

    2011-02-01

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

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

    PubMed Central

    2012-01-01

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

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

    PubMed Central

    2014-01-01

    Background Nanosilver is used in a variety of medical and consumer products because of its antibacterial activity. This wide application results in an increased human exposure. Knowledge on the systemic toxicity of nanosilver is, however, relatively scarce. In a previous study, the systemic toxicity of 20 nm silver nanoparticles (Ag-NP) was studied in a 28-day repeated-dose toxicity study in rats. Ag-NP were intravenously administered with a maximum dose of 6 mg/kg body weight (bw)/day. Several immune parameters were affected: reduced thymus weight, increased spleen weight and spleen cell number, a strongly reduced NK cell activity, and reduced IFN-? production were observed. Methods Prompted by these affected immune parameters, we wished to assess exposure effects on the functional immune system. Therefore, in the present study the T-cell dependent antibody response (TDAR) to keyhole limpet hemocyanin (KLH) was measured in a similar 28-day intravenous repeated-dose toxicity study. In addition, a range of immunological parameters was measured. Data obtained using the benchmark dose (BMD) approach were analyzed by fitting dose-response models to the parameters measured. Results A reduction in KLH-specific IgG was seen, with a lowest 5% lower confidence bound of the BMD (BMDL) of 0.40 mg/kg bw/day. This suggests that Ag-NP induce suppression of the functional immune system. Other parameters sensitive to Ag-NP exposure were in line with our previous study: a reduced thymus weight with a BMDL of 0.76 mg/kg bw/day, and an increased spleen weight, spleen cell number, and spleen cell subsets, with BMDLs between 0.36 and 1.11 mg/kg bw/day. Because the effects on the spleen are not reflected by increased KLH-specific IgG, they, however, do not suggest immune stimulation. Conclusions Intravenous Ag-NP administration in a 28-day repeated-dose toxicity study induces suppression of the functional immune system. This finding underscores the importance to study the TDAR to evaluate immunotoxicity and not to rely solely on measuring immune cell subsets. PMID:24885556

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

    Microsoft Academic Search

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

    2011-01-01

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

  11. Daily Oral Ketamine for the Treatment of Depression and Anxiety in Patients Receiving Hospice Care: A 28-Day Open-Label Proof-of-Concept Trial

    PubMed Central

    Iglewicz, Alana; Nelesen, Richard A.; Lo, Jessica Y.; Carr, Connie H.; Romero, Sheilani D.; Lloyd, Linda S.

    2013-01-01

    Abstract Background Depression and anxiety are prevalent and undertreated in patients receiving hospice care. Standard antidepressants do not work rapidly or often enough to benefit most of these patients. Ketamine has many properties that make it an interesting candidate for rapidly treating depression and anxiety in patients receiving hospice care. To test this hypothesis, a 28-day, open-label, proof-of-concept trial of daily oral ketamine administration was conducted in order to evaluate the tolerability, potential efficacy, and time to potential efficacy in treating depression and anxiety in patients receiving hospice care. Methods In this open-label study, 14 subjects with symptoms of depression or depression mixed with anxiety warranting psychopharmacological intervention received daily oral doses of ketamine hydrochloride (0.5?mg/kg) over a 28-day period. The primary outcome measure was the Hospital Anxiety and Depression Scale (HADS), which was used to rate overall depression and anxiety symptoms at baseline, and on days 3, 7, 14, 21, and 28. Results Over the 28-day trial there was significant improvement in both depressive symptoms (F5,35=8.03, p=0.002, ?2=0.534) and symptoms of anxiety (F5,35=14.275, p<0.001, ?2=0.67) for the eight subjects that completed the trial. One hundred percent of subjects completing the trial responded to ketamine for both anxiety and depression. A significant response in depressive symptoms occurred by day 14 for depression (mean ?=3.5, d=1.14, 95% CI=1.09–5.9, p=0.01) and day 3 for anxiety (mean ?=2.4, d=0.67, 95% CI=1.0–3.7, p=0.004). These improvements remained significant through day 28 for both depression (mean ?=4.0, d=1.34, 95% CI=2.3–5.9, p=0.001) and anxiety (mean ?=6.09, d=1.34, 95% CI=3.6–8.6, p<0.001). Side effects were rare, the most common being diarrhea, trouble sleeping, and trouble sitting still. Conclusions Patients who received daily oral ketamine experienced a robust antidepressant and anxiolytic response with few adverse events. The response rate for depression is similar to those found with IV ketamine; however, the time to response is more protracted. The findings of the potential efficacy of oral ketamine for depression and the response of anxiety symptoms are novel. Further investigation with randomized, controlled clinical trials is necessary to firmly establish the efficacy and safety of oral ketamine for the treatment of depression and anxiety in patients receiving hospice care or other subject populations. PMID:23805864

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

    PubMed

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

    2015-02-01

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

  13. Distribution, elimination, and toxicity of silver nanoparticles and silver ions in rats after 28-day oral exposure.

    PubMed

    van der Zande, Meike; Vandebriel, Rob J; Van Doren, Elke; Kramer, Evelien; Herrera Rivera, Zahira; Serrano-Rojero, Cecilia S; Gremmer, Eric R; Mast, Jan; Peters, Ruud J B; Hollman, Peter C H; Hendriksen, Peter J M; Marvin, Hans J P; Peijnenburg, Ad A C M; Bouwmeester, Hans

    2012-08-28

    We report the results of a 28-day oral exposure study in rats, exposed to <20 nm noncoated, or <15 nm PVP-coated silver nanoparticles ([Ag] = 90 mg/kg body weight (bw)), or AgNO(3) ([Ag] = 9 mg/kg bw), or carrier solution only. Dissection was performed at day 29, and after a wash-out period of 1 or 8 weeks. Silver was present in all examined organs with the highest levels in the liver and spleen for all silver treatments. Silver concentrations in the organs were highly correlated to the amount of Ag(+) in the silver nanoparticle suspension, indicating that mainly Ag(+), and to a much lesser extent silver nanoparticles, passed the intestines in the silver nanoparticle exposed rats. In all groups silver was cleared from most organs after 8 weeks postdosing, but remarkably not from the brain and testis. Using single particle inductively coupled plasma mass spectrometry, silver nanoparticles were detected in silver nanoparticle exposed rats, but, remarkably also in AgNO(3) exposed rats, hereby demonstrating the formation of nanoparticles from Ag(+)in vivo that are probably composed of silver salts. Biochemical markers and antibody levels in blood, lymphocyte proliferation and cytokine release, and NK-cell activity did not reveal hepatotoxicity or immunotoxicity of the silver exposure. In conclusion, oral exposure to silver nanoparticles appears to be very similar to exposure to silver salts. However, the consequences of in vivo formation of silver nanoparticles, and of the long retention of silver in brain and testis should be considered in a risk assessment of silver nanoparticles. PMID:22857815

  14. Systemic and immunotoxicity of silver nanoparticles in an intravenous 28 days repeated dose toxicity study in rats.

    PubMed

    De Jong, Wim H; Van Der Ven, Leo T M; Sleijffers, Annemarie; Park, Margriet V D Z; Jansen, Eugene H J M; Van Loveren, Henk; Vandebriel, Rob J

    2013-11-01

    Because of its antibacterial activity nanosilver is one of the most commonly used nanomaterials. It is increasingly used in a variety of both medical and consumer products resulting in an increase in human exposure. However, the knowledge on the systemic toxicity of nanosilver is relatively limited. To determine the potential systemic toxicity of silver nanoparticles (Ag-NP) with different sizes (20 nm and 100 nm) a 28-days repeated dose toxicity study was performed in rats using intravenous administration. The toxic effect of the 20 nm Ag-NP was performed using the bench mark dose (BMD) approach. Treatment with a maximum dose of 6 mg/kg body weight was well tolerated by the animals. However, both for 20 nm and 100 nm Ag-NP growth retardation was observed during the treatment. A severe increase in spleen size and weight was present which was due to an increased cell number. Both T and B cell populations showed an increase in absolute cell number, whereas the relative cell numbers remained constant. At histopathological evaluation brown and black pigment indicating Ag-NP accumulation was noted in spleen, liver, and lymph nodes. Ag-NP was also detected incidentally in other organs. Clinical chemistry indicated liver damage (increased alkaline phosphatase, alanine transaminase, and aspartate transaminase) that could not be confirmed by histopathology. Hematology showed a decrease in several red blood cell parameters. The most striking toxic effect was the almost complete suppression of the natural killer (NK) cell activity in the spleen at high doses. Other immune parameters affected were: decreased interferon-? and interleukin (IL)-10 production by concanavalin-A stimulated spleen cells, increased IL-1? and decreased IL-6, IL-10 and TNF-? production by lipopolysaccharide stimulated spleen cells, increase in serum IgM and IgE, and increase in blood neutrophilic granulocytes. For the spleen weight a critical effect dose of 0.37 mg/kg body weight (b.w.) could be established. The lowest critical effect dose (CED) for a 5% change compared to control animals was observed for thymus weight (CED05 0.01 mg/kg b.w.) and for functional immune parameters, i.e. decrease in NK cell activity (CED05 0.06 mg/kg b.w.) and LPS stimulation of spleen cells (CED05 0.04 mg/kg b.w.). These results show that for nanosilver the most sensitive parameters for potential adverse responses were effects on the immune system. PMID:23886731

  15. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2010 CFR

    2010-07-01

    ...When possible, numerical results should be evaluated by an appropriate and generally acceptable statistical method. The statistical methods should be selected during the design of the study. (2) Test report. The test report must...

  16. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...When possible, numerical results should be evaluated by an appropriate and generally acceptable statistical method. The statistical methods should be selected during the design of the study. (2) Test report. The test report must...

  17. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2011 CFR

    2011-07-01

    ...When possible, numerical results should be evaluated by an appropriate and generally acceptable statistical method. The statistical methods should be selected during the design of the study. (2) Test report. The test report must...

  18. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...When possible, numerical results should be evaluated by an appropriate and generally acceptable statistical method. The statistical methods should be selected during the design of the study. (2) Test report. The test report must...

  19. 40 CFR 799.9305 - TSCA Repeated dose 28-day oral toxicity study in rodents.

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...When possible, numerical results should be evaluated by an appropriate and generally acceptable statistical method. The statistical methods should be selected during the design of the study. (2) Test report. The test report must...

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

    PubMed

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

    2009-06-01

    Glycoalkaloids alpha-solanine and alpha-chaconine are naturally present toxicants in the potato plant (Solanumtuberosum). Human intake of high doses of glycoalkaloids has led to acute intoxication, in severe cases coma and death. Previous studies have indicated that the ratio of alpha-solanine to alpha-chaconine may determine the degree and nature of the glycoalkaloid toxicity in potatoes, as the toxicity of the two alkaloids act synergistically. The aim of the present study was to investigate whether an altered ratio of alpha-solanine and alpha-chaconine would reduce the toxicity of the glycoalkaloids. The Syrian Golden hamster was given daily doses of alpha-solanine and alpha-chaconine by gavage for 28 days. Doses of up to 33.3 mg total glycoalkaloids/kg body weight were applied in ratios of 1:3.7 and 1:70 (alpha-solanine:alpha-chaconine). Administration of the highest doses of both ratios resulted in distended and fluid filled small intestines and stomach. Animals receiving the ratio with the reduced content of alpha-solanine were less affected compared to those receiving the other ratio. Gene expression profiling experiments were conducted using RNA from epithelial scrapings from the small intestines of the hamsters administered the highest doses of the glycoalkaloid treatments. In general, more differential gene expression was observed in the epithelial scrapings of the hamsters fed the ratio of 1:3.7. Mostly, pathways involved in lipid and energy metabolism were affected by the ratio of 1:3.7. PMID:19217925

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

    PubMed

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

    2008-06-01

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

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

    PubMed

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

    2010-06-01

    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

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

    PubMed Central

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

    2014-01-01

    Objectives To evaluate the impact of a 91-day extended regimen combined oral contraceptive (150 ?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

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

    PubMed

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

    2010-11-01

    The purpose of this study was to investigate the potential toxicity of gemifloxacin by 28-day repeated oral dose in Wistar albino rats. The test article, was administered daily by gavage to male and female rats at dose levels of 0, 50, 100, 200 mg/kg/day. At the end of treatment period, 12 rats/sex/group was sacrificed, while six extra rats/sex in the vehicle control and highest dose groups sacrificed after 14 days recovery period. During the treatment and recovery periods, clinical signs, mortality, body weights, food and water consumption, ophthalmoscopy, urinalysis, phototoxicity, hematology, serum biochemistry, synovial fluid biochemistry, electrocardiogram (ECG), gross findings, organ weights, microscopic examination of synovial fluid, and histopathology were examined. Hematological and serum biochemical investigations revealed a dose-dependent increase in the total white blood cell (WBC), total bilirubin (T-BIL), glucose (GLU), alanine aminotransferase (ALT) and significant decreases in total protein (TP) were observed in both sexes at the same dose, at the end of treatment period, but the levels returned toward normal during the recovery period. Histopathology of talar joint showed that erosion of the articular surface of that joint in both sexes at the end of treatment period at the dose level of 200 mg/kg/day. Degenerative changes in tendinocytes were observed in Achilles tendon of both sexes at the high dose level at the end of treatment period. In histopathological study shows partial effacement of liver architecture and focal ulceration in gastric mucosa at the high dose level at the end of treatment period. Based on these results, it was concluded that 28 days repeated oral dose of gemifloxacin caused increases in the liver weight, WBC count, T-BIL, glucose level, ALT, decreasing the TP, cause chronic hepatitis and acute gastritis, erosion of the articular surface of joint and histopathologic changes in Achilles tendon in rats at the dose level of 200 mg/kg/day. PMID:20580917

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

    PubMed Central

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

    2009-01-01

    Cocaine withdrawal symptoms are thought to play a role in relapse; studies characterizing the symptomatology have yielded mixed findings. This study sought to examine the pharmacodynamic/pharmacokinetic profile of repeated high dose exposure to oral cocaine and characterize acute and protracted withdrawal in cocaine abusers. This study employed a repeated-dosing, single-blind design in which subjects (n=9), resided for 40 days on a closed ward. They were maintained for two 4-day cocaine exposure periods (Days 1-4 & Days 9-12, cocaine 175 mg, p.o.; 5 hourly doses [875 mg/day]) separated by a 4-day matched placebo exposure period (Days 5-8). After these 12 days, an additional period of 28 days of placebo maintenance followed (Days 13-40). Test sessions were conducted during each phase; measures of mood, drug effects, sleep, pharmacokinetics, and prolactin were collected throughout the study. The dosing regimen produced cocaine plasma concentrations (Cmax of 680 ng/mL) 2- to 3-fold higher than typically seen in acute dose studies. Prototypic psychostimulant effects, including subjective ratings of euphoric effects [liking, high, good effects] and significant cardiopressor effects, were sustained during the active dosing periods, corresponding to the rise and fall of plasma cocaine. Withdrawal-like symptoms (i.e., disruptions of sleep, increased ratings of anxiety, irritability, crashing) were observed within 24-hr after cessation of dosing. Cocaine reduced prolactin acutely, but no sustained alterations were observed for this measure or for other signs or symptoms during the 28-day abstinence period. These findings indicate that exposure to controlled high doses of cocaine produces modest symptoms consistent with cocaine withdrawal within hours of cessation of dosing but provide no evidence of symptoms persisting beyond 24 hours. PMID:19653786

  6. Flexibility of Oral Cholera Vaccine Dosing—A Randomized Controlled Trial Measuring Immune Responses Following Alternative Vaccination Schedules in a Cholera Hyper-Endemic Zone

    PubMed Central

    Kanungo, Suman; Desai, Sachin N.; Nandy, Ranjan Kumar; Bhattacharya, Mihir Kumar; Kim, Deok Ryun; Sinha, Anuradha; Mahapatra, Tanmay; Yang, Jae Seung; Lopez, Anna Lena; Manna, Byomkesh; Bannerjee, Barnali; Ali, Mohammad; Dhingra, Mandeep Singh; Chandra, Ananga Mohan; Clemens, John D.; Sur, Dipika; Wierzba, Thomas F.

    2015-01-01

    Background A bivalent killed whole cell oral cholera vaccine has been found to be safe and efficacious for five years in the cholera endemic setting of Kolkata, India, when given in a two dose schedule, two weeks apart. A randomized controlled trial revealed that the immune response was not significantly increased following the second dose compared to that after the first dose. We aimed to evaluate the impact of an extended four week dosing schedule on vibriocidal response. Methodology/Principal Findings In this double blind randomized controlled non-inferiority trial, 356 Indian, non-pregnant residents aged 1 year or older were randomized to receive two doses of oral cholera vaccine at 14 and 28 day intervals. We compared vibriocidal immune responses between these schedules. Among adults, no significant differences were noted when comparing the rates of seroconversion for V. cholerae O1 Inaba following two dose regimens administered at a 14 day interval (55%) vs the 28 day interval (58%). Similarly, no differences in seroconversion were demonstrated in children comparing the 14 (80%) and 28 day intervals (77%). Following 14 and 28 day dosing intervals, vibriocidal response rates against V. cholerae O1 Ogawa were 45% and 49% in adults and 73% and 72% in children respectively. Responses were lower for V. cholerae O139, but similar between dosing schedules for adults (20%, 20%) and children (28%, 20%). Conclusions/Significance Comparable immune responses and safety profiles between the two dosing schedules support the option for increased flexibility of current OCV dosing. Further operational research using a longer dosing regimen will provide answers to improve implementation and delivery of cholera vaccination in endemic and epidemic outbreak scenarios. PMID:25764513

  7. Alternative Method of Oral Dosing for Rats

    PubMed Central

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

    2010-01-01

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

  8. High dose rate brachytherapy for oral cancer.

    PubMed

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

    2013-01-01

    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

  9. Glycidol induces axonopathy and aberrations of hippocampal neurogenesis affecting late-stage differentiation by exposure to rats in a framework of 28-day toxicity study.

    PubMed

    Akane, Hirotoshi; Shiraki, Ayako; Imatanaka, Nobuya; Akahori, Yumi; Itahashi, Megu; Abe, Hajime; Shibutani, Makoto

    2014-01-30

    Developmental exposure to glycidol induces aberrations of late-stage neurogenesis in the hippocampal dentate gyrus of rat offspring, whereas maternal animals develop axonopathy. To investigate the possibility whether similar effects on adult neurogenesis could be induced by exposure in a framework of 28-day toxicity study, glycidol was orally administered to 5-week-old male Sprague-Dawley rats by gavage at 0, 30 or 200 mg/kg for 28 days. At 200 mg/kg, animals revealed progressively worsening gait abnormalities as well as histopathological and immunohistochemical changes suggestive of axonal injury as evidenced by generation of neurofilament-L(+) spheroids in the cerebellar granule layer and dorsal funiculus of the medulla oblongata, central chromatolysis in the trigeminal nerve ganglion cells and axonal degeneration in the sciatic nerves. At the same dose, animals revealed aberrations in neurogenesis at late-stage differentiation as evidenced by decreases of both doublecortin(+) and dihydropyrimidinase-like 3(+) cells in the subgranular zone (SGZ) and increased reelin(+) or calbindin-2(+) ?-aminobutyric acid-ergic interneurons and neuron-specific nuclear protein(+) mature neurons in the dentate hilus. These effects were essentially similar to that observed in offspring after maternal exposure to glycidol. These results suggest that glycidol causes aberrations in adult neurogenesis in the SGZ at the late stage involving the process of neurite extension similar to the developmental exposure study in a standard 28-day toxicity study. PMID:24185127

  10. Perturbation of the indigenous rat oral microbiome by ciprofloxacin dosing.

    PubMed

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

    2013-10-01

    Mucosal surfaces such as the gut, vagina and oral cavity are colonized by microbiota that are an integral component of the healthy ecosystem. Recent molecular techniques make it feasible to correlate antimicrobial dosing levels with changes in microbiome composition. The objective of this study was to characterize the rat oral plaque microbiome composition at doses of ciprofloxacin that were considerably above and below nominal in vitro minimal inhibitory concentrations of a variety of gram-positive oral commensal bacteria. We exposed the oral cavities of rats to relatively low (0.1 ?g ml(-1) ) and high (20 ?g ml(-1)) doses of ciprofloxacin in the drinking water over a 3-day period. Plaque microbiota were characterized using 454 pyrosequencing. The rat indigenous community was dominated by the genera Rothia (74.4%) and Streptococcus (4.7%). Dosing at 0.1 ?g ml(-1) was associated with changes in Rothia and Streptococcus species that were not significant, whereas dosing at 20 ?g ml(-1) caused a pronounced (significant) reduction in the relative abundance of the Streptococcus genus. Taxonomic independent analysis indicated that the perturbation in the overall community structure attributed to dosing with ciprofloxacin at either the low or high dose was relatively low. The results suggest that it is feasible to use an antimicrobial dosing regimen to selectively target a specific subset of a mucosal microbiome for elimination with minimal perturbation of the entire community. PMID:23844936

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

    PubMed Central

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

    2012-01-01

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

  12. Single dose oral meloxicam for acute postoperative pain in adults

    PubMed Central

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

    2014-01-01

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

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

    Microsoft Academic Search

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

    1996-01-01

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

  14. Single-dose oral guanidinoacetic acid exhibits dose-dependent pharmacokinetics in healthy volunteers.

    PubMed

    Ostojic, Sergej M; Vojvodic-Ostojic, Aleksandra

    2015-03-01

    Guanidinoacetic acid (GAA), the natural precursor of creatine, has potential as a dietary supplement for human nutrition, yet no data are available regarding its dose-dependent pharmacokinetic (PK) behavior. We hypothesized that a single dose of orally administered GAA exhibited dose-dependent PK behavior in healthy volunteers. Forty-eight young adults were enrolled in a randomized, placebo-controlled, double-blind, parallel-group trial to receive single oral doses of GAA (1.2, 2.4, and 4.8 g) or a placebo. Pharmacokinetic metrics for plasma GAA and creatine were assessed immediately before (0 hours) and at 1, 2, 4, 6, 8, 12, and 24 hours after GAA ingestion. The lag time appeared to be similar after the bolus ingestion of GAA (0.14 ± 0.17 hours for low-dose GAA, 0.31 ± 0.18 hours for medium-dose GAA, and 0.38 ± 0.32 hours for high-dose GAA; P = .05). An increase in the area under the concentration-time curve for plasma GAA was found for the dose range tested, with 2.4- and 9.3-fold increases in the area under the concentration-time curve for every 2-fold increase in the GAA dose (P < .0001). No differences were found for elimination half-time between the low-dose and medium-dose groups (<1.75 hours), whereas the elimination half-time was significantly longer (>2.1 hours) for the high-dose GAA regimen (P = .001). The volume of distribution was affected by the dosage of GAA applied (102.6 ± 17.3 L for low-dose GAA, 97.5 ± 15.7 L for medium-dose GAA, and 61.1 ± 12.7 L for high-dose GAA; P < .0001). Ingestion of GAA elevated plasma creatine by 80%, 116%, and 293% compared with the placebo for the 1.2, 2.4, and 4.8 g doses, respectively (P < .0001). Guanidinoacetic acid single-dose PK metrics were nonlinear with respect to dose size. Across the dose range of 1.2 to 4.8 g, systemic exposure to GAA increased in a greater than dose-proportional manner. PMID:25622538

  15. Single dose oral nabumetone for acute postoperative pain in adults

    PubMed Central

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

    2014-01-01

    Background Nabumetone is a non-steroidal anti-inflammatory drug (NSAID) used mainly in treating pain associated with arthritis. The usual oral dose for osteoarthritis is 1000 mg daily, and higher doses are not advised in older patients. There are no known systematic reviews of its analgesic efficacy in acute postoperative pain. This review sought to evaluate the efficacy and safety of oral nabumetone in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish whether drugs have analgesic properties. Objectives To assess the efficacy of single dose oral nabumetone in acute postoperative pain, and any associated adverse events. Search methods We searched The Cochrane Library (Issue 2, 2009), MEDLINE (May 2009); EMBASE via Ovid (May 2009); and the Oxford Pain Relief Database. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of oral nabumetone for relief of acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. The area under the “pain relief versus time” curve was used to derive the proportion of participants with nabumetone and placebo experiencing at least 50% pain relief over 4 to 6 hours, using validated equations. The number needed to treat to benefit (NNT) was calculated using 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals was also collected. Main results No studies were identified by the searches that examined oral nabumetone in participants with established postoperative pain. Authors’ conclusions In the absence of evidence of efficacy, at present, for oral nabumetone in acute postoperative pain, its use in this indication is not justified. Because trials clearly demonstrating analgesic efficacy in the most basic of acute pain studies is lacking, use in other indications should be evaluated carefully. Given the large number of available drugs of this and similar classes, there is no urgent research agenda. PMID:19821428

  16. Evaluation of the in vivo mutagenicity of isopropyl methanesulfonate in acute and 28-day studies.

    PubMed

    Coffing, Stephanie L; Kenyon, Michelle O; Ackerman, Joel I; Shutsky, Thomas J; Dobo, Krista L

    2015-04-01

    Understanding the mutagenic dose response could prove beneficial in the management of pharmaceutically relevant impurities. For most alkyl ester impurities, such as isopropyl methanesulfonate (IPMS), little in vivo mutagenicity data exist for dose analysis. The likelihood of a sublinear dose response for IPMS was assessed by comparing the Swain Scott constant, the SN 1/SN 2 reaction mechanism and the O(6) :N(7) guanine adduct ratio to that of more well-known alkyl esters. Based on available information, IPMS was predicted to have a mutagenic profile most like ethyl nitrosourea. To test this hypothesis, mature male Wistar Han rats were administered IPMS using acute (single administration at 3.5 to 56 mg/kg) or subchronic (28 days at 0.125 to 2 mg/kg/day) exposures. The in vivo Pig-a mutation assay was used to identify mutant phenotype reticulocyte (Ret) and red blood cell (RBC) populations. The maximum mutant response occurred approximately 15 and 28 days after the last dose administration in the mutant Ret and RBC populations respectively in the acute study and on Day 29 and 56 in the mutant Ret and RBC populations, respectively, in the subchronic study. A comparison of RBC mutant frequencies from acute and subchronic protocols suggests a sublinear response; however, this was not substantiated by statistical analysis. A No Observed Effect Level (NOEL) of 0.25 mg/kg/day resulted in a Permitted Daily Exposure equivalent to the Threshold of Toxicological Concern. An estimate of the NOEL based on the previously mentioned factors, in practice, would have pre-empted further investigation of the potent mutagen IPMS. Environ. Mol. Mutagen. 56:322-332, 2015. © 2014 Wiley Periodicals, Inc. PMID:25229874

  17. Commentary Looking beyond 28-day all-cause mortality

    E-print Network

    Gordon Rubenfeld

    A growing body of evidence indicates that survivors of intensive care have an impaired quality of life. It is not entirely clear from the available literature whether this impairment is a complication of critical illness or a complication of therapy. There is little evidence to guide physicians to treatments in the intensive care unit that will minimize the effects of critical illness on these sequelae. Although the study by Rublee and colleagues in this issue of Critical Care provides little clinically useful information about the effects of antithrombin III on quality of life, it provides some insight into the challenges that investigators will encounter as we try to incorporate these outcomes into studies of critical illness. Keywords outcomes research, quality of life, sepsis In this issue of Critical Care, Dale Rublee and colleagues look beyond 28-day all-cause mortality, assessing the effects of antithrombin III on quality of life in sepsis survivors [1]. Although many of us would like to think that the battle has been won when a patient leaves the intensive care unit (ICU) after severe sepsis or acute respiratory distress syndrome

  18. Difloxacin metabolism and pharmacokinetics in humans after single oral doses.

    PubMed Central

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

    1986-01-01

    By using high-performance liquid chromatography, the metabolism and pharmacokinetics of difloxacin were characterized in humans after single oral doses of 200, 400, and 600 mg. Group mean peak levels in plasma were obtained 4 h after administration. The means of the individual peak levels for the 200-, 400-, and 600-mg groups were 2.17, 4.09, and 6.12 micrograms/ml, respectively. The mean respective terminal-phase half-lives were 20.6, 27.1, and 28.8 h; the mean half-life for all subjects was 25.7 h. Within the dose range studied, the behavior of difloxacin could be well described by a set of linear pharmacokinetic parameters with a one-compartment open model. Levels of unconjugated metabolites in plasma were negligible. The major urinary components were difloxacin and its glucuronide, each accounting for roughly 10% of the dose. Also present were the N-desmethyl and N-oxide metabolites, accounting for 2 to 4%. Trace levels of other metabolites were observed. Group mean renal clearances ranged from 4.1 to 5.6 ml/min, indicating extensive reabsorption from the glomerular filtrate. As a result, the terminal phase half-life and the dose-normalized area under the curve were substantially greater than those of other members of the class. PMID:3800345

  19. Continuous 28-day iododeoxyuridine infusion and hyperfractionated accelerated radiotherapy for malignant glioma: a phase I clinical study

    Microsoft Academic Search

    Craig A. Schulz; Minesh P. Mehta; Benham Badie; Cornelius J. McGinn; H. Ian Robins; Lori Hayes; Rick Chappell; Jen Volkman; Kim Binger; Rhoda Arzoomanian; Kris Simon; Dona Alberti; Christine Feierabend; Kendra D. Tutsch; Keith A. Kunugi; George Wilding; Timothy J. Kinsella

    2004-01-01

    PurposeTo investigate the maximal tolerated dose of a continuous 28-day iododeoxyuridine (IUdr) infusion combined with hyperfractionated accelerated radiotherapy (HART); to analyze the percentage of IUdr-thymidine replacement in peripheral granulocytes as a surrogate marker for IUdr incorporation into tumor cells; to measure the steady-state serum IUdr levels; and to assess the feasibility of continuous IUdr infusion and HART in the management

  20. Safety and immunogenicity of a single oral dose of recombinant double mutant heat-labile toxin derived from enterotoxigenic Escherichia coli.

    PubMed

    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

    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

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

    PubMed Central

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

    2014-01-01

    Background Flurbiprofen is a non-selective non-steroidal anti-inflammatory drug (NSAID), related to ibuprofen and naproxen, used to treat acute and chronic painful conditions. There is no systematic review of its use in acute postoperative pain. Objectives To assess efficacy, duration of action, and associated adverse events of single dose oral flurbiprofen in acute postoperative pain in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to January 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered flurbiprofen 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 (RR) and number needed to treat to benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Main results Eleven studies compared flurbiprofen (699 participants) with placebo (362 participants) in studies lasting 6 to 12 hours. Studies were of adequate reporting quality, and most participants had pain following dental extractions. The dose of flurbiprofen used was 25 mg to 100 mg, with most information for 50 mg and 100 mg. The NNT for at least 50% pain relief over 4 to 6 hours for flurbiprofen 50 mg compared with placebo (692 participants) was 2.7 (2.3 to 3.3) and for 100 mg (416 participants) it was 2.5 (2.0 to 3.1). With flurbiprofen 50 mg and 100 mg 65% to 70% of participants experienced at least 50% pain relief, compared with 25% to 30% with placebo. Rescue medication was used by 25% and 16% of participants with flurbiprofen 50 mg and 100 mg over 6 hours, compared with almost 70% with placebo. Adverse events were uncommon, and not significantly different from placebo. Authors’ conclusions Flurbiprofen at doses of 50 mg and 100 mg is an effective analgesic in moderate to severe acute postoperative pain. The NNT for at least 50% pain relief is similar to that of commonly used NSAIDs such as ibuprofen and naproxen at usual doses. Use of rescue medication indicates a duration of action exceeding 6 hours. PMID:19588427

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

    PubMed Central

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

    2014-01-01

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

  3. 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...

  4. Single dose oral nefopam for acute postoperative pain in adults

    PubMed Central

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

    2014-01-01

    Background Nefopam is a centrally-acting but non-opioid analgesic drug of the benzoxazocine chemical class, developed in the early 1970s. It is widely used, mainly in European countries, for the relief of moderate to severe pain as an alternative to opioid analgesic drugs, and used in rheumatic disease and other musculoskeletal disorders in the UK. This review sought to evaluate the efficacy and safety of oral nefopam in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish that drugs have analgesic properties. Objectives To assess the efficacy of single dose oral nefopam in acute postoperative pain, and any associated adverse events. Search methods We searched CENTRAL (Issue 2, 2009), MEDLINE (1966 to May 2009); EMBASE via Ovid (1980 to May 2009); the Oxford Pain Relief Database (1950 to 1994); and reference lists of studies found. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of oral nefopam for relief of acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. The area under the “pain relief versus time” curve was used to derive the proportion of participants with nefopam and placebo experiencing least 50% pain relief over 4 to 6 hours, using validated equations. The number-needed-to-treat-to-benefit (NNT) was calculated using 95% confidence intervals (CIs). The proportion of participants using rescue analgesia over a specified time period, and time to use of rescue analgesia, were sought as additional measures of efficacy. Information on adverse events and withdrawals was also collected. Main results No included studies were identified after examining in detail thirteen studies on oral nefopam in participants with established postoperative pain. Authors’ conclusions In the absence of evidence of efficacy for oral nefopam in acute postoperative pain, its use in this indication is not justified. Because trials clearly demonstrating analgesic efficacy in the most basic of acute pain studies are lacking, use in other indications should be evaluated carefully. Given the large number of available drugs of this and similar classes, there is no urgent research agenda. PMID:19588431

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

    PubMed Central

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

    2014-01-01

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

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

    Microsoft Academic Search

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

    1989-01-01

    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.

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

    SciTech Connect

    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

    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.

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

    PubMed

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

    2013-11-01

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

  9. 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...

  10. Reexamination of Pharmacokinetics of Oral Testosterone Undecanoate in Hypogonadal Men With a New Self-Emulsifying Formulation

    PubMed Central

    SWERDLOFF, RONALD S.; DIAZ-ARJONILLA, MARUJA; DUDLEY, ROBERT E.; FAULKNER, SANDRA; BROSS, RACHELLE; LEUNG, ANDREW; BARAVARIAN, SIMA; HULL, LAURA; LONGSTRETH, JAMES A.; KULBACK, STEVEN; FLIPPO, GREGORY; WANG, CHRISTINA

    2014-01-01

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

  11. Single dose oral analgesics for acute postoperative pain in adults

    PubMed Central

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

    2014-01-01

    Background Thirty-five Cochrane Reviews of randomised trials testing the analgesic efficacy of individual drug interventions in acute postoperative pain have been published. This overview brings together the results of all those reviews and assesses the reliability of available data. Objectives To summarise data from all Cochrane Reviews that have assessed the effects of pharmaceutical interventions for acute pain in adults with at least moderate pain following surgery, who have been given a single dose of oral analgesic taken alone. Methods We identified systematic reviews in The Cochrane Library through a simple search strategy. All reviews were overseen by a single Review Group, had a standard title, and had as their primary outcome numbers of participants with at least 50% pain relief over four to six hours compared with placebo. For individual reviews we extracted the number needed to treat (NNT) for this outcome for each drug/dose combination, and also the percentage of participants achieving at least 50% maximum pain relief, the mean of mean or median time to remedication, the percentage of participants remedicating by 6, 8, 12, or 24 hours, and results for participants experiencing at least one adverse event. Main results The overview included 35 separate Cochrane Reviews with 38 analyses of single dose oral analgesics tested in acute postoperative pain models, with results from about 45,000 participants studied in approximately 350 individual studies. The individual reviews included only high-quality trials of standardised design and outcome reporting. The reviews used standardised methods and reporting for both efficacy and harm. Event rates with placebo were consistent in larger data sets. No statistical comparison was undertaken. There were reviews but no trial data were available for acemetacin, meloxicam, nabumetone, nefopam, sulindac, tenoxicam, and tiaprofenic acid. Inadequate amounts of data were available for dexibuprofen, dextropropoxyphene 130 mg, diflunisal 125 mg, etoricoxib 60 mg, fenbufen, and indometacin. Where there was adequate information for drug/dose combinations (at least 200 participants, in at least two studies), we defined the addition of four comparisons of typical size (400 participants in total) with zero effect as making the result potentially subject to publication bias and therefore unreliable. Reliable results were obtained for 46 drug/dose combinations in all painful postsurgical conditions; 45 in dental pain and 14 in other painful conditions. NNTs varied from about 1.5 to 20 for at least 50% maximum pain relief over four to six hours compared with placebo. The proportion of participants achieving this level of benefit varied from about 30% to over 70%, and the time to remedication varied from two hours (placebo) to over 20 hours in the same pain condition. Participants reporting at least one adverse event were few and generally no different between active drug and placebo, with a few exceptions, principally for aspirin and opioids. Drug/dose combinations with good (low) NNTs were ibuprofen 400 mg (2.5; 95% confidence interval (CI) 2.4 to 2.6), diclofenac 50 mg (2.7; 95% CI 2.4 to 3.0), etoricoxib 120 mg (1.9; 95% CI 1.7 to 2.1), codeine 60 mg + paracetamol 1000 mg (2.2; 95% CI 1.8 to 2.9), celecoxib 400 mg (2.5; 95% CI 2.2 to 2.9), and naproxen 500/550 mg (2.7; 95% CI 2.3 to 3.3). Long duration of action (8 hours) was found for etoricoxib 120 mg, diflunisal 500 mg, oxycodone 10 mg + paracetamol 650 mg, naproxen 500/550 mg, and celecoxib 400 mg. Not all participants had good pain relief and for many drug/dose combinations 50% or more did not achieve at last 50% maximum pain relief over four to six hours. Authors’ conclusions There is a wealth of reliable evidence on the analgesic efficacy of single dose oral analgesics. There is also important information on drugs for which there are no data, inadequate data, or where results are unreliable due to susceptibility to publication bias. This should inform choices by professionals and consumers. PMID:21901726

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

    PubMed Central

    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

    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

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

    PubMed

    Willoughby, Darryn S; Leutholtz, Brian

    2013-10-01

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

  14. Pharmacokinetics of eltoprazine in healthy male subjects after single dose oral and intravenous administration.

    PubMed Central

    Raghoebar, M; Mak, M; Cournot, A; Pistorius, M C; Van Harten, J; Roseboom, H

    1990-01-01

    The kinetics, safety and tolerability of eltoprazine hydrochloride were studied in an open, cross-over, partially randomised design after single oral (8 mg) and intravenous (3 and 8 mg) doses to 12 healthy male subjects. After intravenous administration, the mean t1/2 ranged from 7 to 9 h, the MRT was 11 h, CL was 487 +/- 148 (3 mg dose) and 471 +/- 56 (8 mg dose) ml kg-1 h-1, while CLR was 226 +/- 124 (3 mg dose) and 189 +/- 38 (8 mg dose) ml kg-1 h-1. The Vss was 3.3 +/- 0.7 (3 mg dose) and 3.8 +/- 0.5 (8 mg dose) 1 kg-1. Cumulative renal excretion was 40%. The AUC and the cumulative urinary excretion were directly proportional to dose within the range of 3-8 mg. Values of tmax varied from 1 to 4 h after oral administration. The mean Cmax value was 24 ng ml-1 after an oral dose of 8 mg. The plasma elimination half-life after oral administration was 9.8 +/- 3.9 h. Absolute oral bioavailability was 110 +/- 32%. Dose-dependent somnolence was observed. PMID:2288834

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

    Microsoft Academic Search

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

    1984-01-01

    The influence on cobalt 60 dose distributions of typical metal parts used in oral and maxillofacial surgery was studied. Relative doses were determined by exposing x-ray films in a polystyrene phantom set-up containing samples of vitallium, titanium, and stainless steel. Optical densities were converted to doses with the aid of sensitometric curves. The results show that for normal incidence there

  16. Oral High-Dose Ankaferd Administration Effects on Gastrointestinal System

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    2013-01-01

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

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

    PubMed

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

    2014-10-15

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

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

    SciTech Connect

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

    1989-01-01

    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.

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

    PubMed Central

    Kothari, Mihir

    2014-01-01

    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

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

    E-print Network

    LeGrange, Suzanne Nauman

    1996-01-01

    for the degree of MASTER OF SCIENCE May 1996 Major Subject: Veterinary Medicine and Surgery PHARMACOKINETICS OF CISAPRIDE IN NORMAL, HEALTHY CATS AND RECOMMENDED ORAL DOSING REGIMEN A Thesis by SUZANNE NAUMAN LEGRANGE Submitted to Texas A&M University... and Surgery ABSTRACT Pharmacokinetics of Cisapride in Normal, Healthy Cats and Recommended Oral Dosing Regimen. (May 1996) Suzanne Nauman LeGrange, B. S. , Louisiana State University) D. V. M. , Louisiana State University Co-Chairs of Advisory Committee...

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

    PubMed Central

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

    2015-01-01

    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 naïve 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. PMID:25565782

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

    PubMed Central

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

    1995-01-01

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

  4. Single- and Repeat-dose Oral Toxicity Studies of Lithospermum erythrorhizon Extract in Dogs

    PubMed Central

    Hwang, Jae-Sik; Kim, Myoung-Jun; Choi, Young Whan; Han, Kyoung-Goo; Kang, Jong-Koo

    2015-01-01

    Lithospermum erythrorhizon has long been used in traditional Asian medicine for the treatment of diseases, including skin cancer. The oral toxicity of a hexane extract of Lithospermum erythrorhizon root (LEH) was investigated in Beagle dogs by using single escalating doses, two-week dose range-finding, and 4-week oral repeat dosing. In the single dose-escalating oral toxicity study, no animal died, showed adverse clinical signs, or changes in body weight gain at LEH doses of up to 2,000 mg/kg. In a 2 week dose range-finding study, no treatment-related adverse effects were detected by urinalysis, hematology, blood biochemistry, organ weights, or gross and histopathological examinations at doses of up to 500 mg LEH/kg/day. In the 4 week repeat-dose toxicity study, a weight loss or decreased weight gain was observed at 300 mg/kg/day. Although levels of serum triglyceride and total bilirubin were increased in a dose dependent manner, there were no related morphological changes. Based on these findings, the sub-acute no observable adverse effect level for 4-week oral administration of LEH in Beagles was 100 mg/kg/day.

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

    SciTech Connect

    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

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

  6. Acute Oral or Dermal and Repeated Dose 90-Day Oral Toxicity of Tetrasodium Pyrophosphate in Spraque Dawley (SD) Rats

    PubMed Central

    Seo, Dong Seok; Kwon, Min; Sung, Ha Jung

    2011-01-01

    Objectives Tetrasodium pyrophosphate (TSP) is used in processed meat products, as an emulsifier in cheese, and as a color preservative in soybean paste. However, little is known about its toxicity. This study was conducted to investigate the potential acute and repeated dose toxicity of TSP in Spraque Dawley (SD) rats. Methods In the acute study, animals were administered with oral or dermal doses of 2,000 mg/kg TSP. In the repeated dose study, animals were administered doses of 0, 250, 500, and 1,000 mg/kg by oral gavage five times a week for 90 days. Results In acute toxicity studies, no dead animals or abnormal necropsy findings were found in the control or treated group. In the repeated dose toxicity study, there were no significant changes in body weight in the 1,000 mg/kg treatment group, or food consumption, urinalysis, and hematology in any group. With regards serum biochemistry, the levels of total protein, albumin, A/G ratio, triglyceride, calcium and inorganic phosphate were altered at doses of 500 and 1,000 mg/kg. However, no changes were observed at the dose of 250 mg/kg. With regards histopathological findings, cortical tubular basophilia of the kidney increased at the dose of 1,000 mg/kg, but not at doses of 250 and 500 mg/kg. No significant changes were observed in other organs at doses of 250, 500, and 1,000 mg/kg. Conclusions Based on the results, TSP is unclassified according to the Globally Harmonization System, with an LD50 value of over 2,000 mg/kg. The no observed effect level (NOEL) and no observed adverse effect level (NOAEL) were 250 and 500 mg/kg /day respectively and the target organ appears to be the kidney. PMID:22125775

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

    Microsoft Academic Search

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

    2003-01-01

    Valproic acid (VPA) has a narrow therapeutic range (50–100mg\\/l) and exhibits nonlinear protein binding. Additionally, VPA pharmacokinetics are dependent on age, induction status, and formulation; so titration and dosing vary between individuals. The aim of these simulations was to determine optimal intravenous (i.v.) loading dose, and i.v. and oral VPA maintenance regimens. A 5-min 15mg\\/kg loading dose resulted in total

  8. Metric units and the preferred dosing of orally administered liquid medications.

    PubMed

    2015-04-01

    Medication overdoses are a common, but preventable, problem among children. Volumetric dosing errors and the use of incorrect dosing delivery devices are 2 common sources of these preventable errors for orally administered liquid medications. To reduce errors and increase precision of drug administration, milliliter-based dosing should be used exclusively when prescribing and administering liquid medications. Teaspoon- and tablespoon-based dosing should not be used. Devices that allow for precise dose administration (preferably syringes with metric markings) should be used instead of household spoons and should be distributed with the medication. PMID:25825538

  9. Predicting daily maintenance dose of fluindione, an oral anticoagulant drug.

    PubMed

    Cazaux, V; Gauthier, B; Elias, A; Lefebvre, D; Tredez, J; Nguyen, F; Cambus, J P; Boneu, B; Boccalon, H

    1996-05-01

    Due to large inter-individual variations, the dose of vitamin K antagonist required to target the desired hypocoagulability is hardly predictible for a given patient, and the time needed to reach therapeutic equilibrium may be excessively long. This work reports on a simple method for predicting the daily maintenance dose of fluindione after the third intake. In a first step, 37 patients were delivered 20 mg of fluindione once a day, at 6 p.m. for 3 consecutive days. On the morning of the 4th day an INR was performed. During the following days the dose was adjusted to target an INR between 2 and 3. There was a good correlation (r = 0.83, p < 0.001) between the INR performed on the morning of day 4 and the daily maintenance dose determined later by successive approximations. This allowed us to write a decisional algorithm to predict the effective maintenance dose of fluindione from the INR performed on day 4. The usefulness and the safety of this approach was tested in a second prospective study on 46 patients receiving fluindione according to the same initial scheme. The predicted dose was compared to the effective dose soon after having reached the equilibrium, then 30 and 90 days after. To within 5 mg (one quarter of a tablet), the predicted dose was the effective dose in 98%, 86% and 81% of the patients at the 3 times respectively. The mean time needed to reach the therapeutic equilibrium was reduced from 13 days in the first study to 6 days in the second study. No hemorrhagic complication occurred. Thus the strategy formerly developed to predict the daily maintenance dose of warfarin from the prothrombin time ratio or the thrombotest performed 3 days after starting the treatment may also be applied to fluindione and the INR measurement. PMID:8725714

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

    PubMed Central

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

    2014-01-01

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

  11. Dose-proportional intraindividual single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor.

    PubMed

    Bethke, Thomas D; Böhmer, Gabriele M; Hermann, Robert; Hauns, Bernhard; Fux, Richard; Mörike, Klaus; David, Michael; Knoerzer, Dietrich; Wurst, Wilhelm; Gleiter, Christoph H

    2007-01-01

    The dose-proportional, intraindividual, single- and repeated-dose pharmacokinetics of roflumilast, an oral, once-daily phosphodiesterase 4 inhibitor under investigation for chronic obstructive pulmonary disease and asthma, was investigated in healthy subjects. In an open, randomized, 2-period, 2-sequence crossover study, 15 subjects received immediate-release tablets of roflumilast 250 or 500 microg as single (day 1) and as repeated, once-daily doses for 8 days (days 5-12). Dose-adjusted point estimates and 90% confidence intervals of test (500 microg)/reference (250 microg) ratios for AUC and Cmax of roflumilast and its pharmacologically active N-oxide metabolite after single and repeated dosing were all within the standard equivalence acceptance range (0.80, 1.25) indicating dose proportionality. The pharmacokinetic properties of both roflumilast dosage forms provide clinically relevant evidence of predictable, intraindividual total (AUC) and maximum (Cmax) exposure of roflumilast and roflumilast N-oxide. Repeated oral dosing with roflumilast 250 and 500 microg once daily was well tolerated. PMID:17192499

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

    PubMed

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

    2014-01-01

    Currently, no cholera vaccine is available for persons traveling from the United States to areas of high cholera transmission and who for reasons of occupation or host factors are at increased risk for development of the disease. A single-dose oral cholera vaccine with a rapid onset of protection would be particularly useful for such travelers and might also be an adjunct control measure for cholera outbreaks. The attenuated Vibrio cholerae O1 vaccine strain CVD 103-HgR harbors a 94% deletion of the cholera toxin A subunit gene (ctxA) and has a mercury resistance gene inserted in the gene encoding hemolysin A. We undertook a phase I randomized placebo-controlled two-site trial to assess the safety and immunogenicity of a preliminary formulation of CVD 103-HgR prepared from new master and working cell banks. Healthy young adults were randomized (5:1 vaccinees to placebo recipients) to receive a single oral dose of ?4.4 × 10(8) CFU of vaccine or a placebo. Blood serum vibriocidal and cholera toxin-specific IgG antibodies were measured before and 10, 14, and 28 days following vaccination or placebo. Excretion of the vaccine strain in the stool was assessed during the first week postvaccination. A total of 66 subjects were enrolled, comprising 55 vaccinees and 11 placebo recipients. The vaccine was well tolerated. The overall vibriocidal and anti-cholera toxin seroconversion rates were 89% and 57%, respectively. CVD 103-HgR is undergoing renewed manufacture for licensure in the United States under the auspices of PaxVax. Our data mimic those from previous commercial formulations that elicited vibriocidal antibody seroconversion (a correlate of protection) in ?90% of vaccinees. (This study has been registered at ClinicalTrials.gov under registration no. NCT01585181.). PMID:24173028

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

    PubMed

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

    2003-02-01

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

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

    PubMed

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

    2013-08-01

    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

  15. Daily dose calculations from measurements of intra-oral mercury vapor.

    PubMed

    Olsson, S; Bergman, M

    1992-02-01

    Measurements of intra-oral mercury vapor from amalgam fillings are discussed. It was shown that the only quantity which it is possible to measure is the mercury release rate, and that the concentrations of mercury vapor in the oral cavity published in most earlier studies are the mercury concentrations in the measuring cell of the measuring apparatus and not the concentrations in the oral cavity. The consequences for the daily dose equations of the facts that the mercury source is present inside the oral cavity and that the amount of mercury released during a certain time is limited are discussed. It was found that most daily dose equations used have a questionable mercury distribution on inspiration, expiration, and swallowing. Re-calculations of almost all the available daily dose data showed a mean daily dose value of about 1.3 micrograms Hg/day (range, 0.3-2.2 micrograms Hg/day). The mean swallowed amount of mercury from intra-oral mercury vapor was calculated as being in the order of 10 micrograms Hg/day (range, 2.4-17 micrograms Hg/day), resulting in an estimated absorption of about 1 microgram Hg/day from the gastro-intestinal tract. PMID:1556301

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

    SciTech Connect

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

    1988-10-01

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

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

    E-print Network

    Forrester, Sharon Dru

    1989-01-01

    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... ge E. Lees (Chair of Committe) Scott Anthony Brown (Member) Sandee M. artsf' 1d (Member) John R. August (Head of Departmen May 1989 ABSTRACT Disposition of Clorazepate in Dogs After Single- and Multiple-Dose Oral Administration. (May 1989...

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

    PubMed

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

    2014-09-01

    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

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

    EPA Science Inventory

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

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Plasma distribution and elimination of florfenicol in channel catfish were investigated after a single dose (10mg/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...

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

    Microsoft Academic Search

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

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

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

    Microsoft Academic Search

    ANN ALLEN; ELIZABETH BYGATE; MARIKA VOUSDEN; STUART OLIVER; MARTIN JOHNSON; CHRISTOPHER WARD; AE-JIN CHEON; YOUN SUNG CHOO; IN-CHULL KIM

    2001-01-01

    Gemifloxacin mesylate (SB-265805-S, LB-20304a) is a potent, novel fluoroquinolone agent with a broad spectrum of antibacterial activity. The pharmacokinetics and tolerability of oral gemifloxacin were character- ized in two parallel group studies in healthy male volunteers after doses of 160, 320, 480, and 640 mg once daily for 7 days. Multiple serum or plasma and urine samples were collected on

  3. 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...

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

    E-print Network

    Paris-Sud XI, Université de

    Short note Assessment of the oral administration of a high dose of retinol on vitamin E status as control. Then a single oral dose of D- a(5-Me3H) tocopherol (0.2 uCi/kg vitamin B) was administered (Machlin, 1980). The nutritional relationship between vita- mins A and E has been the subject of many

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

    SciTech Connect

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

    1980-09-01

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

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

    Microsoft Academic Search

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

    1998-01-01

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

  7. Low-dose continuous oral melphalan for the treatment of primary systemic (AL) amyloidosis.

    PubMed

    Sanchorawala, Vaishali; Wright, Daniel G; Seldin, David C; Falk, Rodney H; Berk, John L; Dember, Laura M; Finn, Kathleen T; Skinner, Martha

    2002-06-01

    Median survival of patients with AL amyloidosis with clinically significant cardiac involvement is 5 months when treated with cyclic melphalan and prednisone. We investigated a regimen of continuous oral melphalan as a single agent for patients with cardiac amyloidosis who were unable to tolerate prednisone or more aggressive chemotherapy. Thirty patients with amyloid cardiomyopathy were treated with continuous oral melphalan. Seven of 13 patients, evaluable after 3-4 months of treatment, achieved a partial haematological response and three achieved a complete haematological response; six patients have survived for > 1 year. This regimen appeared to be effective in inducing haematological responses in patients who received total doses of melphalan > 300 mg. PMID:12060126

  8. 29 CFR 553.230 - Maximum hours standards for work periods of 7 to 28 days-section 7(k).

    Code of Federal Regulations, 2012 CFR

    2012-07-01

    ...work periods of 7 to 28 days-section 7(k). 553.230 Section 553.230 Labor...work periods of 7 to 28 days—section 7(k). (a) For those employees engaged...compensation is required under section 7(k) until the number of hours worked...

  9. 29 CFR 553.230 - Maximum hours standards for work periods of 7 to 28 days-section 7(k).

    Code of Federal Regulations, 2014 CFR

    2014-07-01

    ...work periods of 7 to 28 days-section 7(k). 553.230 Section 553.230 Labor...work periods of 7 to 28 days—section 7(k). (a) For those employees engaged...compensation is required under section 7(k) until the number of hours worked...

  10. 29 CFR 553.230 - Maximum hours standards for work periods of 7 to 28 days-section 7(k).

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ...work periods of 7 to 28 days-section 7(k). 553.230 Section 553.230 Labor...work periods of 7 to 28 days—section 7(k). (a) For those employees engaged...compensation is required under section 7(k) until the number of hours worked...

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

    PubMed Central

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

    2015-01-01

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

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

    SciTech Connect

    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

    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.

  13. Single dose intravenous methyl prednisolone versus oral prednisolone in Bell's palsy: A randomized controlled trial

    PubMed Central

    Giri, Prithvi; Garg, Ravindra Kumar; Singh, Maneesh Kumar; Verma, Rajesh; Malhotra, Hardeep Singh; Sharma, Praveen Kumar

    2015-01-01

    Objectives: Corticosteroids have been used in the treatment of Bell's palsy and several other postinfectious neurological conditions. We hypothesized that administration of a single dose of intravenous (IV) methylprednisolone might be an effective alternative to oral prednisolone. Materials and Methods: In this open label, randomized trial, patients with acute Bell's palsy were randomized into two groups. One group received single dose (500 mg) of IV methylprednisolone while the other group received 10 days of oral prednisone. Outcome was assessed at 1 and 3 months with House–Brackmann scale. Results: At 3 months, 93 (79.48%) patients had completely recovered. IV methylprednisolone and oral prednisolone groups had similar recovery rates (80% vs. 78.33%, P > 0.05). Patients with Grade 2 and 3 recovered completely. In patients with Grade 6, the recovery rate was 20%. A better outcome was observed if corticosteroids were administered within 3 days of onset of palsy. Conclusion: Intravenous methylprednisolone and oral prednisolone showed equivalent benefit in patients with acute Bell's palsy. PMID:25878371

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

    PubMed Central

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

    1988-01-01

    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

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

    Microsoft Academic Search

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

    2010-01-01

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

  16. TREATMENT OF ACUTE AND TRANSIENT PSYCHOTIC DISORDERS WITH LOW AND HIGH DOSES OF ORAL HALOPERIDOL

    PubMed Central

    Khanna, Apurv; Lal, Narottam; Dalal, P.K.; Khalid, Abdul; Trivedi, J.K.

    1997-01-01

    The apparent rationale for the popular use of high doses of neuroleptics in psychotic patients is to increase the degree and speed of therapeutic response .However, several recent reports have questioned these claims. The present study was undertaken with the aim to compare the efficacy of high and low oral doses of haloperidol in the treatment of acute and transient psychotic disorders. The sample comprised of forty patients of both sexes diagnosed as acute and transient psychotic disorder who were randomly assigned to high dose (20 mg/day) and low dose (5 mg /day) haloperidol groups with equal number of subjects (n=20) in both groups. Weekly assessment was done on Brief Psychiatric Rating Scale and Haloperidol Side-effects Check List (day 7, 14, 21, 28, 35 & 42). Both groups showed significant improvement in BPRS from baseline scores on all assessments. Comparison of the improvement rate in both study groups revealed no significant difference. PMID:21584060

  17. Comparison between predicted and actual dose distribution in interstitial therapy of the oral cavity.

    PubMed

    van 't Riet, A; Veen, R E; Mak, A C; Stam, P W; van Slooten, F H; te Loo, H J

    1988-12-01

    During the period 1985-1986, 10 patients with lesions of the floor of the mouth or of the mobile part of the tongue were treated by interstitial curietherapie with iridium-192. In the patients treated with the looping technique essential differences were found between the predicted source configuration and that actually achieved, resulting in a disagreement between precalculated and actual dose distribution. To avoid this undesirable situation, a simple oral cavity applicator was constructed which guarantees parallelism and equidistance between the implanted needles. It was found that the use of this applicator resulted in an almost complete agreement between forecast and actual dose distribution. PMID:3217543

  18. Concentrations of ceftibuten in plasma and the respiratory tract following a single 400 mg oral dose

    Microsoft Academic Search

    J. M. Andrews; R. Wise; D. R. Baldwin; D. Honeybourne

    1995-01-01

    Concentrations of ceftibuten in bronchial mucosa, epithelial lining fluid (ELF) and alveolar macrophages were determined from samples taken from 15 subjects at bronchoscopy following a single 400 mg oral dose. Concentrations at all sites were determined using a microbiological assay method which was unaffected by the trans-isomer of ceftibuten. The time from dosage to bronchoscopy ranged from 1.4 to 20.3

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

    PubMed

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

    2014-07-01

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

  20. Oral activated charcoal in the treatment of intoxications. Role of single and repeated doses.

    PubMed

    Neuvonen, P J; Olkkola, K T

    1988-01-01

    Activated charcoal has an ability to adsorb a wide variety of substances. This property can be applied to prevent the gastrointestinal absorption of various drugs and toxins and to increase their elimination, even after systemic absorption. Single doses of oral activated charcoal effectively prevent the gastrointestinal absorption of most drugs and toxins present in the stomach at the time of charcoal administration. Known exceptions are alcohols, cyanide, and metals such as iron and lithium. In general, activated charcoal is more effective than gastric emptying. However, if the amount of drug or poison ingested is very large or if its affinity to charcoal is poor, the adsorption capacity of activated charcoal can be saturated. In such cases properly performed gastric emptying is likely to be more effective than charcoal alone. Repeated dosing with oral activated charcoal enhances the elimination of many toxicologically significant agents, e.g. aspirin, carbamazepine, dapsone, dextropropoxyphene, cardiac glycosides, meprobamate, phenobarbitone, phenytoin and theophylline. It also accelerates the elimination of many industrial and environmental intoxicants. In acute intoxications 50 to 100g activated charcoal should be administered to adult patients (to children, about 1 g/kg) as soon as possible. The exceptions are patients poisoned with caustic alkalis or acids which will immediately cause local tissue damages. To avoid delays in charcoal administration, activated charcoal should be a part of first-aid kits both at home and at work. The 'blind' administration of charcoal neither prevents later gastric emptying nor does it cause serious adverse effects provided that pulmonary aspiration in obtunded patients is prevented. In severe acute poisonings oral activated charcoal should be administered repeatedly, e.g. 20 to 50g at intervals of 4 to 6 hours, until recovery or until plasma drug concentrations have fallen to non-toxic levels. In addition to increasing the elimination of many drugs and toxins even after their systemic absorption, repeated doses of charcoal also reduce the risk of desorbing from the charcoal-toxin complex as the complex passes through the gastrointestinal tract. Charcoal will not increase the elimination of all substances taken. However, as the drug history in acute intoxications is often unreliable, repeated doses of oral activated charcoal in severe intoxications seem to be justified unless the toxicological laboratory has identified the causative agent as not being prone to adsorption by charcoal. The role of repeated doses of oral activated charcoal in chronic intoxication has not been clearly defined.(ABSTRACT TRUNCATED AT 400 WORDS) PMID:3285126

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

    PubMed Central

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

    1992-01-01

    1. The pharmacokinetics of gamma-hydroxybutyric acid (GHB) were studied in 10 alcohol dependent subjects after single and repeated therapeutic oral doses (25 mg kg-1 every 12 h for 7 days). 2. GHB was readily absorbed and rapidly eliminated (tmax = 20-45 min; mean t1/2z 27 +/- 5 s.d. min). Urinary recovery of unchanged GHB was negligible (less than 1% of the dose). gamma-butyrolactone was not detected in either plasma or urine, indicating that lactonization of GHB does not occur in vivo. 3. The multiple-dose regimen resulted neither in accumulation of GHB nor in time-dependent modification of its pharmacokinetics. 4. In five subjects, the data were consistent with nonlinear elimination kinetics of GHB. Administration of a 50 mg kg-1 dose to these subjects resulted in significant increases in dose-normalized AUC, t1/2z and mean residence time. 5. Doubling of the dose also resulted in a significant increase in tmax with little change in Cmax. 6. At the administered doses, GHB did not accumulate in the plasma and caused no serious side effects. PMID:1389947

  2. Single and multiple dose intravenous and oral pharmacokinetics of the hedgehog pathway inhibitor vismodegib in healthy female subjects

    PubMed Central

    Graham, Richard A; Hop, Cornelis E C A; Borin, Marie T; Lum, Bert L; Colburn, Dawn; Chang, Ilsung; Shin, Young G; Malhi, Vikram; Low, Jennifer A; Dresser, Mark J

    2012-01-01

    AIM Vismodegib has demonstrated clinical activity in patients with advanced basal cell carcinoma. The pharmacokinetics (PK) of vismodegib are non-linear. The objective of this study was to determine whether vismodegib PK change following repeated dosing by administering a tracer intravenous (i.v.) dose of 14C-vismodegib with single and multiple oral doses. METHODS Healthy post menopausal female subjects (n= 6/group) received either a single or daily 150 mg vismodegib oral dose with a 14C-labelled 10 µg i.v. bolus dose administered 2 h after the single or last oral dose (day 7). Plasma samples were assayed for vismodegib by LC-MS/MS and for 14C-vismodegib by accelerator mass spectrometry. RESULTS Following a single i.v. dose, mean clearance, volume of distribution and absolute bioavailability were 43.4 ml h?1, 16.4 l and 31.8%, respectively. Parallel concentration–time profiles following single oral and i.v. administration of vismodegib indicated elimination rate limited PK. Following i.v. administration at steady-state, mean clearance and volume of distribution were 78.5 ml h?1 and 26.8 l, respectively. Comparison of i.v. PK parameters after single and multiple oral dosing showed similar half-life, increased clearance and volume of distribution (81% and 63% higher, respectively) and decreased bioavailability (77% lower) after repeated dosing. Relative to single dose, the unbound fraction of vismodegib increased 2.4-fold with continuous daily dosing. CONCLUSION Vismodegib exhibited a long terminal half-life after oral and i.v. administration, moderate absolute bioavailability and non-linear PK after repeated dosing. Results from this study suggest that the non-linear PK of vismodegib result from two separate, non-linear processes, namely solubility limited absorption and high affinity, saturable plasma protein binding. PMID:22458643

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

    PubMed

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

    2015-02-20

    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 1 mg/kg body weight (bw), 5 mg/kg bw, and 20 mg/kg bw. Furthermore, total brain concentrations of the drug were determined in order to characterize its brain-to-plasma partition coefficient. Adult Wistar male rats, weighing 200-450 g, 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 13 h, 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 ± 3.80 ml/h/kg for intravenous administration, while the apparent plasma clearance for oral administration was 95.52 ± 39.45 ml/h/kg. The mean (S.E.M.) maximum plasma concentration reached after oral administration of 1 mg/kg bw and 5 mg/kg bw was 0.89 ± 0.09 ?g/ml and 3.188 ± 0.71 ?g/ml, respectively. The median (range) time to reach maximum plasma concentration (t(max)) 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 (AUC(0-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

  4. Pharmacokinetic and pharmacodynamic profile of donepezil HCl following multiple oral doses

    PubMed Central

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

    1998-01-01

    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

  5. Evaluation of toxicity to triclosan in rats following 28 days of exposure to aerosol inhalation.

    PubMed

    Yang, Young-Su; Kwon, Jung-Taek; Shim, Ilseob; Kim, Hyun-Mi; Kim, Pilje; Kim, Jong-Choon; Lee, Kyuhong

    2015-03-01

    The present study was conducted to investigate the potential subchronic toxicity of triclosan (TCS) in rats following 28 days of exposure by repeated inhalation. Four groups of six rats of each sex were exposed to TCS-containing aerosols by nose-only inhalation of 0, 0.04, 0.13, or 0.40 mg/L for 6 h/day, 5 days/week over a 28-day period. During the study period, clinical signs, mortality, body weight, food consumption, ophthalmoscopy, hematology, serum biochemistry, gross pathology, organ weights, and histopathology were examined. At 0.40 mg/L, rats of both sexes exhibited an increase in the incidence of postdosing salivation and a decrease in body weight. Histopathological alterations were found in the nasal septum and larynx. There were no treatment-related effects in rats of either sex at ?0.13 mg/L. Under the present experimental conditions, the target organs in rats were determined to be the nasal cavity and larynx. The no-observed-adverse-effect concentration in rats was determined to be 0.13 mg/L. PMID:25591546

  6. Novel three dimensional human endocervix cultures respond to 28-day hormone treatment.

    PubMed

    Arslan, Sevim Yildiz; Yu, Yanni; Burdette, Joanne E; Pavone, Mary Ellen; Hope, Thomas J; Woodruff, Teresa K; Kim, J Julie

    2015-04-01

    The endocervix has both anatomical and biological functions that participate in the delicate balance between tolerance necessary for conception and protection from pathogens. Our goal was to develop a robust 3-dimensional (3D) endocervix model that was a reliable representation of the in vivo tissues and to identify the physiological responses to changing levels of steroid hormones during a 28-day time period. Human endocervical cells were grown on polystyrene scaffolds, and the morphologic and hormonal responses of cultured cells were assessed in response to fluctuating levels of estradiol (E2) or progesterone (P4). Morphologically, the 3D cultures were composed of a mixed population of cells, including epithelial and stromal cells. Treatment with E2 and P4 (d 28) increased cell growth and proliferation as compared with no treatment control. Cells expressed estrogen receptor and P4 receptor and produced both neutral and acidic mucins, including Mucin 16. In addition, a 45-plex Luminex assay identified numerous factors secreted and regulated by hormones. Specifically, IL-1? and leukemia inhibitory factor significantly decreased in the presence of E2 and P4 as compared with the no hormone control at day 26. Cotreatment with RU486 (mifepristone) attenuated the inhibition of IL-1? and leukemia inhibitory factor secretion. In summary, a robust, novel 3D endocervical culture was developed, and physiologic responses to the menstrual cycle mimic of E2 and P4 levels for a period of 28 days were identified. PMID:25635622

  7. Effect of oral dosing vehicles on the acute hepatotoxicity of carbon tetrachloride in rats.

    PubMed

    Kim, H J; Odend'hal, S; Bruckner, J V

    1990-01-01

    Although carbon tetrachloride (CCl4) is of concern as a drinking water contaminant, it has been necessary in most oral toxicity studies to give CCl4 in an oil vehicle due to its limited water solubility. The primary objective of our study was to assess the influence of dosing vehicles on the acute hepatotoxicity of CCl4. Fasted 200- to 230-g rats were generally found to be more susceptible to CCl4 hepatotoxicity than fasted 300- to 330-g rats. A time-course study revealed that corn oil did not delay the onset or time of maximal liver injury by an oral 100 mg/kg dose of CCl4, but did reduce the extent of injury relative to that when the chemical was given undiluted or as an aqueous emulsion. Fasted 200- to 230-g male Sprague-Dawley rats were given 0, 10, 25, 50, 100, 250, 500, or 1000 mg CCl4/kg body wt by gavage: in corn oil; as an aqueous emulsion; as the undiluted chemical; and in the 10 and 25 mg/kg doses only, in water. Blood and liver samples were taken 24 hr after dosing for measurement of serum and microsomal enzymes. Pathological examination of liver samples was also conducted. Dose-dependent increases in serum enzyme levels and pathological changes and dose-dependent decreases in microsomal P450 and glucose-6-phosphatase activity were observed in each vehicle group. Both the 10 and 25 mg/kg oral doses of CCl4 in water caused significant elevations in serum enzymes and hepatic centrolobular vacuolation. The study revealed that acute hepatotoxicity was less pronounced at each dosage level in rats given CCl4 in corn oil than in other vehicle groups. These findings demonstrate that dosing vehicles can significantly influence the acute hepatotoxicity of CCl4 in rats and are a cause for additional consideration and review of the practice of routinely using vegetable oils as a diluent in studies of volatile organic compound (VOC) toxicity. The use of aqueous Emulphor emulsions appears more appropriate in acute toxicity studies of VOC drinking water contaminants such as CCl4, in that the emulsion did not substantially alter the toxicity of CCl4 from that of undiluted CCl4 or CCl4 ingested in water. PMID:2296770

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

    Microsoft Academic Search

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

    2006-01-01

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

  9. Long-Term High-dose Oral Morphine in Phantom Limb Pain with No Addiction Risk

    PubMed Central

    Kumar, Vinod; Garg, Rakesh; Bharati, Sachidanand Jee; Gupta, Nishkarsh; Bhatanagar, Sushma; Mishra, Seema; Balhara, Yatan Pal Singh

    2015-01-01

    Chronic phantom limb pain (PLP) is a type of neuropathic pain, which is located in the missing/amputated limb. Phantom pain is difficult to treat as the exact basis of pain mechanism is still unknown. Various methods of treatment for PLP have been described, including pharmacological (NSAIDs, opioids, antiepileptic, antidepressants) and non-pharmacological (TENS, sympathectomy, deep brain stimulation and motor cortex stimulation). Opioids are used for the treatment of neuropathic pain and dose of opioid is determined based on its effect and thus there is no defined ceiling dose for opioids. We report a case where a patient receiving high-dose oral morphine for chronic cancer pain did not demonstrate signs of addiction. PMID:25709194

  10. Pharmacokinetics of azithromycin in pediatric patients after oral administration of multiple doses of suspension.

    PubMed Central

    Nahata, M C; Koranyi, K I; Gadgil, S D; Hilligoss, D M; Fouda, H G; Gardner, M J

    1993-01-01

    Azithromycin is an azalide antibiotic. On the basis of data in adults, azithromycin appears to have a greater distribution into tissues, a longer elimination half-life, and a lower incidence of adverse effects than the macrolide antibiotic erythromycin. However, little about the pharmacokinetics of azithromycin in children is known. The objective of our study was to characterize the pharmacokinetics of azithromycin after oral administration of multiple doses of suspension to children with streptococcal pharyngitis. Fourteen children (6 to 15 years of age) received a single oral dose of 10 mg of azithromycin per kg of body weight on day 1 followed by single daily doses of 5 mg/kg on days 2 to 5. Each child fasted overnight before receiving the final dose on day 5. Blood samples were collected at 0, 0.5, 1, 2, 4, 6, 8, 12, 24, 48, and 72 h after this last dose. Concentrations of azithromycin in serum were measured by a specific high-performance liquid chromatography-mass spectrometry method. The mean +/- standard deviation for maximum concentration of drug in serum, time to maximum concentration of drug in serum, and area under the curve (0 to 24 h) were 383 +/- 142 ng/ml, 2.4 +/- 1.1 h, and 3,109 +/- 1,033 ng.h/ml, respectively. Concentrations in serum at 0 h (predose) and at 24, 48, and 72 h after the final dose were 67 +/- 31, 64 +/- 24, 41 +/- 17, and 29 +/- 14 ng/ml, respectively. Thus, once-daily administration of azithromycin resulted in sustained systemic exposure to the drug. PMID:8383944

  11. Effect of single oral dose of tramadol on gastric secretions pH

    PubMed Central

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

    2015-01-01

    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

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

    PubMed Central

    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

    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

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

    PubMed Central

    2014-01-01

    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

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

    PubMed Central

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

    1990-01-01

    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

  15. Pharmacokinetic and pharmacodynamic profile of donepezil HCl following single oral doses

    PubMed Central

    Rogers, S L; Friedhoff, L T

    1998-01-01

    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

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

    PubMed Central

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

    1986-01-01

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

  17. Dose-finding and pharmacokinetic study of orally administered indibulin (D-24851) to patients with advanced solid tumors.

    PubMed

    Oostendorp, R L; Witteveen, P O; Schwartz, B; Vainchtein, L D; Schot, M; Nol, A; Rosing, H; Beijnen, J H; Voest, E E; Schellens, J H M

    2010-04-01

    Indibulin (ZIO-301/D-24851) is an orally applied small molecule with antitumor activity based upon destabilization of microtubule polymerization. The purpose of this phase I study was to determine the maximum tolerated dose (MTD) as well as the dose limiting toxicity (DLT), the pharmacokinetics, safety and tolerability of orally administered indibulin as capsule formulation in patients with advanced solid tumors. Patients received a single dose of indibulin. Seven dose-levels were evaluated: 100 mg, 150 mg, 250 mg, 350 mg and 600 mg once daily (QD), 450 mg and 600 mg twice daily (BID). After a washout period, patients received indibulin at the pre-defined daily dose for 14 days every 3 weeks (multiple dose part). A total of 28 patients entered the study. Indibulin administered as capsules was generally well tolerated. The MTD was not reached. There was a disproportionate increase of the area under the plasma concentration-time curve (AUC) with dose, with declining AUC corrected for dose starting at the 250 mg dose-level. There was no significant difference in AUC of indibulin after multiple dosing (day 1-14) compared to single administration (day-4). Inter-patient variability in AUC (102% CV) was high. A plateau in drug exposure was observed prior to reaching the MTD. Continued dose-escalation was unlikely to yield any increase in exposure of indibulin. The formulation needs optimization to increase the systemic exposure upon oral administration. PMID:19404582

  18. Disposition of sulfadimethoxine in camels (Camelus dromedarius) following single intravenous and oral doses.

    PubMed

    Chatfield, J; Jensen, J; Boothe, D; Herzog, T; Junkins, K

    2001-12-01

    Single-dose pharmacokinetics of sulfadimethoxine were determined in six adult camels (Camelus dromedarius) following administration of a mean dosage of 17.5 +/- 2.7 mg/kg both i.v. and p.o. Serial blood samples were collected through an indwelling jugular catheter intermittently for 5 days for both routes. Sulfadimethoxine was assayed using high-performance liquid chromatography. Serum drug concentration versus time data for each animal was subjected to linear regression, with the best-fit model selected based on residual analysis. The data fit best into a two-compartment open model, with first-order input for oral administration. For orally administered drug, mean maximum serum concentration of 19.3 +/- 1.7 microg/ml was reached at 11.41 +/- 2.59 hr, with an elimination rate constant of 0.09/hr +/- 0.05/hr and an elimination half-life of 11.7 +/- 3 hr. Mean peak serum concentration following i.v. administration was 223 +/- 48 microg/ml. Mean volume of distribution at steady state was 0.393 +/- 0.049 L/kg. Elimination rate constants differed with i.v. and oral administration, suggesting a flip-flop model. Oral bioavailability was 103% +/- 38%. Comparison of maximum serum concentrations to the microbial breakpoint concentration reported for sulfadimethoxine (512 microg/ml) suggests that the dose used in this study, 17.5 +/- 2.7 mg/kg, is insufficient for achieving therapeutic serum levels. PMID:12785697

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

    PubMed

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

    2013-12-01

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

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

    PubMed Central

    Gustafsson, L L; Walker, O; Alván, G; Beermann, B; Estevez, F; Gleisner, L; Lindström, B; Sjöqvist, F

    1983-01-01

    1 Chloroquine was given in 300 mg single doses as an i.v. infusion, an oral solution and as tablets at intervals of at least 56 days to 11 healthy volunteers. Concentrations of chloroquine and its metabolite desethylchloroquine were measured in plasma, erythrocytes and urine using h.p.l.c. 2 Chloroquine was detectable in all plasma samples up to 23 days and occasionally up to 52 days after dosage. Urinary concentrations were monitored up to 119 days. The disposition pattern was multiexponential reflecting extensive tissue binding of the drug. 3 After i.v. dosing the volume of distribution ranged from 116 to 285 l/kg and the apparent terminal half-life from 146 to 333 h. Total plasma clearance +/- s.d. was 712 +/- 166 ml/min and renal clearance 412 +/- 139 ml/min. The mean estimated urinary recovery of chloroquine was 47%, 42% and 46% after i.v., oral solution and tablets indicating nearly complete bioavailability. The corresponding figures for the metabolite were 7%, 10% and 12%. 4 The disposition of chloroquine in erythrocytes was parallel to that in plasma. The concentrations in erythrocytes were consistently 2 to 5 times higher than in plasma. 5 Subjective side effects like difficulties with swallowing and accommodation, diplopia and fatigue occurred during intravenous infusion and were closely related to plasma concentrations. No effect was seen on the electrocardiogram, mean arterial blood pressure and pulse rate. No adverse reactions were observed after the oral doses. High frequency audiometry did not reveal any significant hearing impairment for the group as a whole. PMID:6849784

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

    PubMed Central

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

    2014-01-01

    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

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

    PubMed Central

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

    2012-01-01

    BACKGROUND Prior studies have separately examined the effects of dronabinol (oral THC) on cannabis withdrawal, cognitive performance, and the acute effects of smoked cannabis. A single study examining these clinically relevant domains would benefit the continued evaluation of dronabinol as a potential medication for the treatment of cannabis use disorders. METHODS Thirteen daily cannabis smokers completed a within-subject crossover study and received 0, 30, 60 and 120 mg dronabinol per day for 5 consecutive days. Vital signs and subjective ratings of cannabis withdrawal, craving and sleep were obtained daily; outcomes under active dose conditions were compared to those obtained under placebo dosing. On the 5th day of medication maintenance, participants completed a comprehensive cognitive performance battery and then smoked 5 puffs of cannabis for subjective effects evaluation. Each dronabinol maintenance period occurred in a counterbalanced order and was separated by 9 days of ad-libitum cannabis use. RESULTS Dronabinol dose-dependently attenuated cannabis withdrawal and resulted in few adverse side effects or decrements in cognitive performance. Surprisingly, dronabinol did not alter the subjective effects of smoked cannabis, but cannabis-induced increases in heart rate were attenuated by the 60 and 120 mg doses. CONCLUSIONS Dronabinol’s ability to dose-dependently suppress cannabis withdrawal may be therapeutically beneficial to individuals trying to stop cannabis use. The absence of gross cognitive impairment or side effects in this study supports safety of doses up to 120mg per day. Continued evaluation of dronabinol in targeted clinical studies of cannabis treatment, using an expanded range of doses, is warranted. PMID:22921474

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

    PubMed

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

    2010-06-01

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

  4. Single dose oral mefenamic acid for acute postoperative pain in adults

    PubMed Central

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

    2014-01-01

    Background Mefenamic acid is a non-steroidal anti-inflammatory drug (NSAID). It is most often used for treating pain of dysmenorrhoea in the short term (seven days or less), as well as mild to moderate pain including headache, dental pain, postoperative and postpartum pain. It is widely available in many countries worldwide. Objectives To assess the efficacy of single dose oral mefenamic acid in acute postoperative pain, and any associated adverse events. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to December 2010. Selection criteria Single oral dose, randomised, double-blind, placebo-controlled trials of mefenamic acid for relief of established moderate to severe postoperative pain in adults. Data collection and analysis Studies were assessed for methodological quality and the data extracted by two review authors independently. Summed total pain relief (TOTPAR) or pain intensity difference (SPID) over 4 to 6 hours was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over 4 to 6 hours. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results Four studies with 842 participants met the inclusion criteria; 126 participants were treated with mefenamic acid 500 mg, 67 with mefenamic acid 250 mg, 197 with placebo, and 452 with lignocaine, aspirin, zomepirac or nimesulide. Participants had pain following third molar extraction, episiotomy and orthopaedic surgery. The NNT for at least 50% pain relief over 6 hours with a single dose of mefenamic acid 500 mg compared to placebo was 4.0 (2.7 to 7.1), and the NNT to prevent use of rescue medication over 6 hours was 6.5 (3.6 to 29). There were insufficient data to analyse other doses or active comparators, or numbers of participants experiencing any adverse events. No serious adverse events or adverse event withdrawals were reported in these studies. Authors’ conclusions Oral mefenamic acid 500 mg was effective at treating moderate to severe acute postoperative pain, based on limited data. Efficacy of other doses, and safety and tolerability could not be assessed. PMID:21412904

  5. Immunotoxicity evaluation of jet a jet fuel in female rats after 28-day dermal exposure.

    PubMed

    Mann, Cynthia M; Peachee, Vanessa L; Trimmer, Gary W; Lee, Ji-Eun; Twerdok, Lorraine E; White, Kimber L

    2008-01-01

    The potential for jet fuel to modulate immune functions has been reported in mice following dermal, inhalation, and oral routes of exposure; however, a functional evaluation of the immune system in rats following jet fuel exposure has not been conducted. In this study potential effects of commercial jet fuel (Jet A) on the rat immune system were assessed using a battery of functional assays developed to screen potential immunotoxic compounds. Jet A was applied to the unoccluded skin of 6- to 7-wk-old female Crl:CD (SD)IGS BR rats at doses of 165, 330, or 495 mg/kg/d for 28 d. Mineral oil was used as a vehicle to mitigate irritation resulting from repeated exposure to jet fuel. Cyclophosphamide and anti-asialo GM1 were used as positive controls for immunotoxic effects. In contrast to reported immunotoxic effects of jet fuel in mice, dermal exposure of rats to Jet A did not result in alterations in spleen or thymus weights, splenic lymphocyte subpopulations, immunoglobulin (Ig) M antibody-forming cell response to the T-dependent antigen, sheep red blood cells (sRBC), spleen cell proliferative response to anti-CD3 antibody, or natural killer (NK) cell activity. In each of the immunotoxicological assays conducted, the positive control produced the expected results, demonstrating the assay was capable of detecting an effect if one had occurred. Based on the immunological parameters evaluated under the experimental conditions of the study, Jet A did not adversely affect immune responses of female rats. It remains to be determined whether the observed difference between this study and some other studies reflects a difference in the immunological response of rats and mice or is the result of other factors. PMID:18338284

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

    PubMed Central

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

    2014-01-01

    Background Tiaprofenic acid is a a non-steroidal anti-inflammatory drug (NSAID). It is widely available around the world, with indications for osteoarthritis, rheumatoid arthritis, ankylosing spondylitis, periarticular disorders, and strains and sprains. This review sought to evaluate the efficacy and safety of oral tiaprofenic acid in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish that drugs have analgesic properties. Objectives To assess the efficacy of single dose oral tiaprofenic acid in acute postoperative pain, and any associated adverse events. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to June 2009. Selection criteria Randomised, double blind, placebo-controlled trials of single dose orally administered tiaprofenic acid in adults with moderate to severe acute postoperative pain. Data collection and analysis Two review authors independently assessed trial quality and extracted data. We planned to use area under the “pain relief versus time” curve to derive the proportion of participants with tiaprofenic acid experiencing at least 50% pain relief over 4 to 6 hours, using validated equations; to use number needed to treat to benefit (NNT); the proportion of participants using rescue analgesia over a specified time period; time to use of rescue analgesia; information on adverse events and withdrawals. Main results Not one of eleven studies identified by the searches and examined in detail studied oral tiaprofenic acid against placebo in patients with established postoperative pain and therefore no results are available. Authors’ conclusions In the absence of evidence of efficacy for oral tiaprofenic acid in acute postoperative pain, its use in this indication is not justified at present. Because trials clearly demonstrating analgesic efficacy in the most basic of acute pain studies is lacking, use in other indications should be evaluated carefully. Given the large number of available drugs of this and similar classes which are effective, there is no urgent research agenda for this particular drug. PMID:19821426

  7. Disposition and mass balance of [14C]vernakalant after single intravenous and oral doses in healthy volunteers.

    PubMed

    Mao, Z L; Alak, A; Wheeler, J J; Keirns, J

    2011-04-01

    Vernakalant hydrochloride is a novel antiarrhythmic drug for the rapid conversion of atrial fibrillation to sinus rhythm and prevention of relapse. In this open-label, parallel design study, 8 healthy men received single 240-mg doses of [(14)C]vernakalant hydrochloride, given as a 10-minute intravenous (IV) infusion on day 1, and as an oral gel capsule on day 22. Plasma, urine, and fecal samples were collected for 7 days after dosing to measure vernakalant and its metabolites and to estimate mass balance of total [(14)C] recovery. The disposition and metabolic profile of vernakalant after both IV and oral administration, depended on cytochrome P450 (CYP)2D6 genotype. Vernakalant underwent rapid and extensive distribution during infusion, which resulted in similar maximum plasma concentrations in extensive metabolizers (EMs) and poor metabolizers (PMs) for IV but not oral administration. Vernakalant was metabolized rapidly and extensively to a 4-O-demethylated metabolite with glucuronidation in EMs; direct glucuronidation predominated in PMs. Slower clearance in PMs contributed to 3- and 6-fold higher drug exposure (AUC(0-?); IV and oral dosing, respectively). Urinary recovery of unchanged vernakalant was higher in PMs as well. Total [(14)C] was recovered predominantly in urine, while lower levels were recovered in feces. Mass balance was achieved, with a mean recovery of 99.7% of the IV dose and 98.7% of the oral dose, in EMs, and 89.2% and 88.2% of the IV and oral doses, respectively, in PMs. Vernakalant was well tolerated. The pharmacokinetics and metabolism of vernakalant depend on CYP2D6 genotype with more pronounced effects on exposure following oral administration; however, the differences between EMs and PMs are unlikely to be clinically significant following short-term IV infusion. PMID:21457140

  8. Successful treatment of Rosai-Dorfman disease with low-dose oral corticosteroid.

    PubMed

    Oka, Masahiro; Kamo, Tsuneyoshi; Goto, Noriko; Nagano, Tohru; Hirayama, Yuji; Nibu, Ken-Ichi; Nishigori, Chikako

    2009-04-01

    We present herein a Japanese case of Rosai-Dorfman disease (RDD) in which cutaneous manifestations completely remitted after treatment with low-dose oral corticosteroid. A 69-year-old Japanese man presented with a 1-year history of enlarged submandibular lymph nodes and subsequent nasal and pharyngeal bleeding. RDD was diagnosed based on biopsy results from a lymph node in the left parotid region. The patient had also noted several skin eruptions that repeatedly appeared and disappeared on the face and arms. Biopsies were taken from skin eruptions on the face and cuboidal fossa. Both biopsy specimens showed dense, well-demarcated infiltration of histiocytes, lymphocytes and multinucleated giant cells from just under the epidermis to the subcutaneous tissue. These histiocytes were positive for CD68 and S-100, but negative for CD1a, and some displayed emperipolesis. Given the histopathological findings and the fact that the patient was suffering from RDD, skin lesions were diagnosed as cutaneous manifestations of RDD. Cutaneous lesions gradually began to persist concomitant with enlargement of extranodal lymphadenopathy in the nasopharyngeal area. Increasing respiratory obstruction prompted a trial with oral prednisolone commencing at 0.4 mg/kg per day. Both the lymphadenopathy and skin lesions responded quickly. Within 3 months, all his skin lesions disappeared completely with almost complete resolution of lymphadenopathy. Twelve months after the beginning of oral prednisolone therapy, slight recurrence of mucosal and cutaneous lesions appeared, but disappeared quickly with an increase in prednisolone to 0.3 mg/kg per day. Low-dose prednisolone appeared very effective in the case of RDD. PMID:19348664

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

    PubMed Central

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

    2010-01-01

    Background The emergence of drug resistant typhoid fever is a major public health problem, especially in Asia. An oral single dose typhoid vaccine would have major advantages. M01ZH09 is a live oral single dose candidate typhoid vaccine containing Salmonella enterica serovar Typhi (Ty2 aroC? ssaV?) ZH9 with two independently attenuating deletions. Studies in healthy adults demonstrated immunogenicity and an acceptable safety profile. Objectives We conducted a randomised placebo controlled, single-blind trial to evaluate the safety and immunogenicity of M01ZH09 in healthy Vietnamese children aged 5 to 14 years. Methods Subjects were randomly assigned to receive either a nominal dose of 5×109 CFU of M01ZH09 or placebo and were followed up for 28 days. The primary safety outcome was the proportion of subjects with any adverse event attributed to M01ZH09. The primary immunogenicity endpoint was the proportion of subjects who showed a positive immune response to M01ZH09 in the Salmonella Typhi lipopolysaccharide (LPS) specific serum IgA and IgG ELISA. Principal Findings One hundred and fifty-one children were enrolled, 101 subjects received M01ZH09 and 50 subjects received placebo. An intention to treat analysis was conducted. There were no serious adverse events and no bacteraemias. In the M01ZH09 group, 26 (26%; 95% CI, 18–5%) of 101 subjects experienced adverse events compared to 11 (22%; 95% CI, 12–36%) of 50 subjects in the placebo group (odds ratio (OR) [95%CI] ?=?1.23 [0.550–2.747]; p?=?0.691). Faecal shedding of S. Typhi (Ty2 aroC? ssaV?) ZH9 was detected in 51 (51%; 95% CI, 41–61%) of 100 M01ZH09 subjects. No shedding was detected beyond day 3. A positive immune response, defined as 70% increase (1.7 fold change) in LPS specific serum IgG (day 14 or 28) and/or 50% increase (1.5 fold change) in LPS specific serum IgA (day 7 or 14) from baseline was detected in 98 (97%; 95% CI, 92–99%) of 101 M01ZH09 recipients and 8 (16%; 95% CI, 7–29%) of 50 placebo recipients. Twenty-eight (100%; 95% CI, 88–100%) of 28 vaccine recipients who were evaluated in the LPS specific IgA ELISPOT assay showed a positive response compared to none of the 14 placebo recipients tested. Conclusions This was the first phase II trial of a novel oral candidate typhoid vaccine in children in an endemic country. M01ZH09 had an appropriate safety profile and was immunogenic in children. Trial Registration Controlled-trials.comISRCTN91111837 PMID:20668668

  10. Pharmacokinetics of a low dose and FDA-labeled dose of diclazuril administered orally as a pelleted topdressing in adult horses.

    PubMed

    Hunyadi, L; Papich, M G; Pusterla, N

    2014-10-20

    The purpose of this study was to determine the pharmacokinetics of the FDA-approved labeled dose of diclazuril and compare it to a low dose in plasma and CSF in adult horses. During each research period, six healthy adult horses received 0.5 mg/kg of 1.56% diclazuril pellets (Protazil(TM) , Merck Animal Health) compared to the approved labeled dose of 1 mg/kg orally once in two separate phases. A dose of 0.5 mg/kg was calculated to each horse's weight. Blood was then collected immediately before diclazuril administration and then at regular intervals up to a 168 h. After the last blood collection following the single dose at hour 168, a once daily oral dose was administered for the next 10 days to ensure the drug's concentration reached steady-state. To determine the CSF concentration at steady-state, CSF samples were collected after the 9th oral dose. Blood was then collected after the 10th dose and then at regular intervals up to 168 h. A washout period of 4 weeks was allowed before repeating this protocol for the FDA-labeled dose at 1 mg/kg. Plasma and CSF samples were analyzed by high-pressure liquid chromatography. A one-compartment pharmacokinetic model with first-order oral absorption was fitted to the single administration data. Steady-state pharmacokinetics was performed using noncompartmental analysis for steady-state analysis. The mean (standard deviation) concentration of diclazuril in CSF following the low dose was 26 ng/mL (5 ng/mL), while CSF in the FDA-labeled dose was 25 ng/mL (4 ng/mL), P = 0.3750. Substantial accumulation in plasma occurred at steady-state after the 10th dose for both doses. The results of this study show that diclazuril pellets given at the approved label dose and a lower dose both produce similar plasma drug concentrations at steady-state and attain plasma and CSF concentrations known to inhibit Sarcocystis neurona in cell culture. PMID:25329774

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

    PubMed Central

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

    1999-01-01

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

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

    Microsoft Academic Search

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

    1996-01-01

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

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

    PubMed

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

    2013-06-01

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

  14. Single Oral Dose Toxicity Study of Prebrewed Armeniacae Semen in Rats

    PubMed Central

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

    2013-01-01

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

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

    PubMed Central

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

    1992-01-01

    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

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

    PubMed Central

    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

    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

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

    Microsoft Academic Search

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

    2000-01-01

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

  18. ANALYTICAL RESULTS OF MOX COLEMANITE CONCRETE SAMPLE POURED JULY 25, 2012 - CURED 28 DAYS

    SciTech Connect

    Cozzi, A. D.; Best, D. R.; Reigel, M. M.

    2012-09-18

    The Mixed Oxide Fuel Fabrication Facility (MFFF) will use Colemanite bearing concrete neutron absorber panels credited with attenuating neutron flux in the criticality design analyses and shielding operators from radiation. The Savannah River National Laboratory is tasked with measuring the total density, partial hydrogen density, and partial boron density of the colemanite concrete. Samples 8.1.2, 8.2.2, 8.3.2, and 8.4.2 were received on 8/1/2012 and analyzed after curing for 28 days. The average total density measured by the ASTM method C 642 was 2.09 g/cm{sup 3}, within the lower bound of 1.88 g/cm{sup 3}. The average partial hydrogen density was 7.48E-02 g/cm{sup 3} as measured using method ASTM E 1311 and met the lower bound of 6.04E-02 g/cm{sup 3}. The average measured partial boron density was 1.71E-01 g/cm{sup 3} which met the lower bound of 1.65E-01 g/cm{sup 3} measured by the ASTM C 1301 method.

  19. Single dose oral codeine, as a single agent, for acute postoperative pain in adults

    PubMed Central

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

    2014-01-01

    Background Codeine is an opioid metabolised to active analgesic compounds, including morphine. It is widely available by prescription, and combination drugs including low doses of codeine are commonly available without prescription. Objectives To assess the efficacy, the time to onset of analgesia, the time to use of rescue medication and any associated adverse events of single dose oral codeine in acute postoperative pain. Search methods We searched CENTRAL, MEDLINE, EMBASE and PubMed to November 2009. Selection criteria Single oral dose, randomised, double-blind, placebo-controlled trials of codeine for relief of established moderate to severe postoperative pain in adults. Data collection and analysis Studies were assessed for methodological quality and data independently extracted by two review authors. Summed total pain relief (TOTPAR) or pain intensity difference (SPID) over 4 to 6 hours were used to calculate the number of participants achieving at least 50% pain relief, which were used to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over 4 to 6 hours. Numbers using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Data on adverse events and withdrawals were collected. Main results Thirty-five studies were included (1223 participants received codeine 60 mg, 27 codeine 90 mg, and 1252 placebo). Combining all types of surgery (33 studies, 2411 participants), codeine 60 mg had an NNT of at least 50% pain relief over 4 to 6 hours of 12 (8.4 to 18) compared with placebo. At least 50% pain relief was achieved by 26% on codeine 60 mg and 17% on placebo. Following dental surgery the NNT was 21 (12 to 96) (15 studies, 1146 participants), and following other types of surgery the NNT was 6.8 (4.6 to 13) (18 studies, 1265 participants). The NNT to prevent use of rescue medication within 4 to 6 hours was 11 (6.3 to 50) (11 studies, 765 participants, mostly non-dental); the mean time to its use was 2.7 hours with codeine and 2.0 hours with placebo. More participants experienced adverse events with codeine 60 mg than placebo; the difference was not significant and none were serious. Two adverse event withdrawals occurred with placebo. Authors’ conclusions Single dose codeine 60 mg provides good analgesia to few individuals, and does not compare favourably with commonly used alternatives such as paracetamol, NSAIDs and their combinations with codeine, especially after dental surgery; the large difference between dental and other surgery was unexpected. Higher doses were not evaluated. PMID:20393966

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

    SciTech Connect

    Narayan, Samir [Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA (United States)], E-mail: narayans@trinity-health.org; Lehmann, Joerg [Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA (United States); Coleman, Matthew A. [Lawrence Livermore National Laboratory, Livermore, CA (United States); Vaughan, Andrew; Yang, Claus Chunli [Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA (United States); Enepekides, Danny; Farwell, Gregory [Department of Otolaryngology, University of California Davis Medical Center, Sacramento, CA (United States); Purdy, James A.; Laredo, Grace [Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA (United States); Nolan, Kerry A.S.; Pearson, Francesca S. [Lawrence Livermore National Laboratory, Livermore, CA (United States); Vijayakumar, Srinivasan [Department of Radiation Oncology, University of California Davis Medical Center, Sacramento, CA (United States)

    2008-11-01

    Purpose: We conducted a clinical study to correlate oral cavity dose with clinical mucositis, perform in vivo dosimetry, and determine the feasibility of obtaining buccal mucosal cell samples in patients undergoing head-and-neck radiation therapy. The main objective is to establish a quantitative dose response for clinical oral mucositis. Methods and Materials: Twelve patients undergoing radiation therapy for head-and-neck cancer were prospectively studied. Four points were chosen in separate quadrants of the oral cavity. Calculated dose distributions were generated by using AcQPlan and Eclipse treatment planning systems. MOSFET dosimeters were used to measure dose at each sampled point. Each patient underwent buccal sampling for future RNA analysis before and after the first radiation treatment at the four selected points. Clinical and functional mucositis were assessed weekly according to National Cancer Institute Common Toxicity Criteria, Version 3. Results: Maximum and average doses for sampled sites ranged from 7.4-62.3 and 3.0-54.3 Gy, respectively. A cumulative point dose of 39.1 Gy resulted in mucositis for 3 weeks or longer. Mild severity (Grade {<=} 1) and short duration ({<=}1 week) of mucositis were found at cumulative point doses less than 32 Gy. Polymerase chain reaction consistently was able to detect basal levels of two known radiation responsive genes. Conclusions: In our sample, cumulative doses to the oral cavity of less than 32 Gy were associated with minimal acute mucositis. A dose greater than 39 Gy was associated with longer duration of mucositis. Our technique for sampling buccal mucosa yielded sufficient cells for RNA analysis using polymerase chain reaction.

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

    PubMed Central

    Maia, Hugo; Haddad, Clarice; Casoy, Julio

    2014-01-01

    Objective Menstrual symptoms such as dysmenorrhea usually occur during the hormone-free interval in oral contraceptive users. Progestin withdrawal activates NF-?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

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

    SciTech Connect

    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

    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.

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

    PubMed Central

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

    2013-01-01

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

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

    SciTech Connect

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

    1987-03-01

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

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

    PubMed Central

    2014-01-01

    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

  6. Single Oral Dose Toxicity Test of Blue Honeysuckle Concentrate in Mice

    PubMed Central

    Park, Sang-In; Choi, Seung-Hoon; Song, Chang-Hyun; Park, Soo-Jin; Shin, Yong-Kook; Han, Chang-Hyun; Lee, Young Joon; Ku, Sae-Kwang

    2015-01-01

    The objective of this study was to obtain single oral dose toxicity information for concentrated and lyophilized powder of blue honeysuckle (Lonicera caerulea L., Caprifoliaceae; BHcL) in female and male ICR mice to aid in the process of developing natural origin medicinal ingredients or foods following proximate analysis and phytochemical profile measurement. The proximate analysis revealed that BHcL had an energy value of 3.80 kcal/g and contained 0.93 g/g of carbohydrate, 0.41 g/g of sugar, 0.02 g/g of protein, and 0.20 mg/g of sodium. BHcL did not contain lipids, including saturated lipids, trans fats, or cholesterols. Further, BHcL contained 4.54% of betaine, 210.63 mg/g of total phenols, 159.30 mg/g of total flavonoids, and 133.57 mg/g of total anthocyanins. Following administration of a single oral BHcL treatment, there were no treatment-related mortalities, changes in body weight (bw) or organ weight, clinical signs, necropsy or histopathological findings up to 2,000 mg/kg bw, the limited dosage for rodents of both sexes. We concluded that BHcL is a practically non-toxic material in toxicity potency. PMID:25874034

  7. Alteration of the systemic and microcirculation by a single oral dose of flavan-3-ols.

    PubMed

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

    2014-01-01

    Several systematic reviews have reported that flow mediated dilatation (FMD) was significantly increased in subjects after ingestion of chocolate that contains flavan-3-ols; however, the mechanisms responsible for this effect are not clear. In this study, we evaluated the effects of a single oral dose of flavan-3-ols on the systemic circulation and microcirculation in the cremaster muscle using intravital video microscopy in vivo. The cremaster muscle in rats was spread over a plastic chamber and a gastric tube was placed into the stomach. Blood flow in the cremasteric artery was determined using a laser Doppler flowmeter, while blood pressure and heart rate were measured by the tail-cuff method. Red blood cell velocity in arterioles and blood flow in the artery were significantly increased 5 min after the administration of 10 mg/kg flavan-3-ols compared with distilled water treatment. The number of capillaries recruited in the cremaster muscle was also significantly increased 15 min after treatment. Microscopic observation confirmed that increased shear stress on endothelial cells was maintained during the measurement period. The mean arterial blood pressure and heart rate were also significantly elevated soon after administration and returned to baseline before the end of the observation period. Plasma nitrate and nitrite levels, and NO phosphorylation of aortic tissue were significantly increased at 60 min after administration of flavan-3-ols. According to these results, a single oral dose of flavan-3-ols elevates blood pressure and flow transiently, and these effects induce NO production through increased shear stress on endothelial cells. PMID:24740211

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

    PubMed Central

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

    2014-01-01

    Several systematic reviews have reported that flow mediated dilatation (FMD) was significantly increased in subjects after ingestion of chocolate that contains flavan-3-ols; however, the mechanisms responsible for this effect are not clear. In this study, we evaluated the effects of a single oral dose of flavan-3-ols on the systemic circulation and microcirculation in the cremaster muscle using intravital video microscopy in vivo. The cremaster muscle in rats was spread over a plastic chamber and a gastric tube was placed into the stomach. Blood flow in the cremasteric artery was determined using a laser Doppler flowmeter, while blood pressure and heart rate were measured by the tail-cuff method. Red blood cell velocity in arterioles and blood flow in the artery were significantly increased 5 min after the administration of 10 mg/kg flavan-3-ols compared with distilled water treatment. The number of capillaries recruited in the cremaster muscle was also significantly increased 15 min after treatment. Microscopic observation confirmed that increased shear stress on endothelial cells was maintained during the measurement period. The mean arterial blood pressure and heart rate were also significantly elevated soon after administration and returned to baseline before the end of the observation period. Plasma nitrate and nitrite levels, and NO phosphorylation of aortic tissue were significantly increased at 60 min after administration of flavan-3-ols. According to these results, a single oral dose of flavan-3-ols elevates blood pressure and flow transiently, and these effects induce NO production through increased shear stress on endothelial cells. PMID:24740211

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

    PubMed Central

    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

    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

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

    PubMed

    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

    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

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

    PubMed Central

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

    2015-01-01

    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

  12. Dose-Response Effect of a Single Administration of Oral Hexyl-Insulin Monoconjugate 2 in Healthy Nondiabetic Subjects

    Microsoft Academic Search

    ESTELA WAJCBERG; YOSHINORI MIYAZAKI; CURTIS TRIPLITT; EUGENIO CERSOSIMO; RALPH A. DEFRONZO

    2004-01-01

    OBJECTIVE — 1) To evaluate the effect of a single oral dose of hexyl-insulin monoconjugate 2 (HIM2) on the rate of whole-body glucose disposal (Rd) and endogenous glucose production (EGP) in healthy nondiabetic subjects, 2) to examine the reproducibility of HIM2 on glucose metabolism, and 3) to compare the results obtained with HIM2 with those using a bioequivalent dose of

  13. Single dose oral dexibuprofen [S(+)-ibuprofen] for acute postoperative pain in adults

    PubMed Central

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

    2014-01-01

    Background Dexibuprofen (S(+)-ibuprofen) is a non-steroidal anti-inflammatory drug (NSAID) licensed for use in rheumatic disease and other musculoskeletal disorders in the UK, and widely available in other countries worldwide. It is an active isomer of ibuprofen. This review sought to evaluate the efficacy and safety of oral dexibuprofen in acute postoperative pain, using clinical studies of patients with established pain, and with outcomes measured primarily over 6 hours using standard methods. This type of study has been used for many decades to establish that drugs have analgesic properties. Objectives To assess efficacy, duration of action, and associated adverse events of single dose oral dexibuprofen in acute postoperative pain in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, EMBASE and the Oxford Pain Relief Database for studies to May 2009. Selection criteria Randomised, double blind, placebo-controlled clinical trials of oral dexibuprofen for relief of acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Pain relief or pain intensity data were extracted and converted into the dichotomous outcome of number of participants with at least 50% pain relief over 4 to 6 hours, from which relative risk and number needed to treat to benefit (NNT) were calculated. Numbers of participants using rescue medication over specified time periods, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals were collected. Main results In the single included study, both S(+)-ibuprofen (dexibuprofen, an active isomer of ibuprofen) 200 mg and 400 mg gave high levels of response, with 31/51 (61%) and 35/50 (70%) respectively having at least 50% pain relief over 4 to 6 hours, compared with 2/25 (8%) with placebo. The median time to additional analgesic use was 5.8 hours, 6.1 hours, and 1.8 hours respectively. The numbers of participants was too small to calculate NNTs with any meaning. Authors’ conclusions The information from the single trial in acute postoperative pain suggests it to be a useful analgesic, but at doses not very different from racemic ibuprofen. PMID:19588434

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

    PubMed Central

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

    2015-01-01

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

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

    PubMed

    Garner, F; Jones, K

    2014-12-01

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

  16. Effects of Oral Epigallocatechin Gallate Supplementation on the Minimal Erythema Dose and UV-Induced Skin Damage

    Microsoft Academic Search

    H. Y. Jeon; J. K. Kim; W. G. Kim; S. J. Lee

    2009-01-01

    Background\\/Aims: Excessive exposure to UV radiation causes acute adverse effects like sunburn and photosensitivity reactions and is involved in the induction and development of skin cancer. It has been reported that antioxidants have photoprotective effects against solar UV radiation. We investigated the effect of oral epigallocatechin gallate (EGCG), a powerful antioxidant in green tea, on the minimal erythema dose (MED)

  17. CLINICAL TRIAL OF ORAL ARTESUNATE WITH OR WITHOUT HIGH-DOSE PRIMAQUINE FOR THE TREATMENT OF VIVAX MALARIA IN THAILAND

    Microsoft Academic Search

    UDOMSAK SILACHAMROON; SRIVICHA KRUDSOOD; SOMBAT TREEPRASERTSUK; POLRAT WILAIRATANA; KOBSIRI CHALEARMRULT; HLA YIN MINT; PANNAMAS MANEEKAN; NICHOLAS J. WHITE; VICTOR R. GOURDEUK; GARY M. BRITTENHAM; SORNCHAI LOOAREESUWAN

    We studied prospectively 801 Thai patients admitted to the Bangkok Hospital for Tropical Diseases with acute, symptomatic Plasmodium vivax malaria to determine the optimum duration of treatment with oral artesunate and the safety, tolerability, and effectiveness of a high dose of primaquine in prevention of relapse. Patients were randomly assigned to one of four treatment groups: 1) a five-day course

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

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The metabolism of alpha- and gamma-hexabromocyclododecane (HBCD) was investigated in adult C57BL/6 female mice. Alpha- or gamma-[14C]HBCD (3 mg/kg bw) was orally administered with subsequent urine and feces collection for 4 consecutive days; a separate group of mice were dosed and sacrificed 3 hour...

  19. Urinary Excretion and Bactericidal Activities of Gemifloxacin and Ofloxacin after a Single Oral Dose in Healthy Volunteers

    Microsoft Academic Search

    CHRISTOPH K. NABER; MICHAELA HAMMER; MARTINA KINZIG-SCHIPPERS; CHRISTIAN SAUBER; FRITZ SORGEL; ELIZABETH A. BYGATE; AMANDA J. FAIRLESS; KONSTANZE MACHKA; KURT G. NABER

    2001-01-01

    In a randomized crossover study, 16 volunteers (8 men, 8 women) received single oral doses of 320 mg of gemifloxacin and 400 mg of ofloxacin on two separate occasions in the fasting state to assess the urinary excretion and urinary bactericidal titers (UBTs) at intervals for up to 144 h. Ofloxacin showed higher concentrations in urine compared with those of

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

    Microsoft Academic Search

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

    2008-01-01

    Human exposure to bisphenol A (BPA) is due to that found in the diet, and BPA and its metabolites were detected at parts per billion (or less) concentrations in human urine, milk, saliva, serum, plasma, ovarian follicular fluid, and amniotic fluid. Adverse health effects in mice and rats may be induced after parenteral injection or after massive oral doses. Controlled

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

    PubMed

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

    2012-04-01

    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

  2. Biochemical alterations induced by acute oral doses of iron oxide nanoparticles in Wistar rats.

    PubMed

    Kumari, Monika; Rajak, Sheik; Singh, Shailendra P; Murty, Upadhyayula S N; Mahboob, Mohammed; Grover, Paramjit; Rahman, Mohammed F

    2013-07-01

    Magnetic iron oxide nanoparticles with appropriate surface chemistry have been widely used with potential new applications in biomedical industry. Therefore, the aim of this study was to assess the size-, dose-, and time-dependent effects, after acute oral exposure to iron oxide-30 NP (Fe(2)O(3)-30), on various biochemical enzyme activities of clinical significances in a female Wistar rat model. Rats were exposed to three different doses (500, 1,000, and 2,000?mg/kg) of Fe(2)O(3)-30 and Fe(2)O(3)-Bulk along with control. Fe(2)O(3)-30 had no effect on growth, behavior, and nutritional performance of animals. Fe(2)O(3)-30 caused significant inhibition of acetylcholinestrase in red blood cells as well as in brains of treated rats. Further, more than 50% inhibition of total, Na(+)-K(+), Mg(2+), and Ca(2+)-ATPases activities, as observed in brains of exposed female rats, may be the result of disturbances in cellular physiology and the iono-regulatory process. Activation of the hepatotoxicity marker enzymes, aspartate aminotransferase and alanine aminotransferase, was recorded in serum and liver, whereas inhibition was observed in kidney. Similarly, enhancement of lactate dehydrogenase activity was observed in serum and liver; however, a decrease in enzyme levels was observed in kidneys of Fe(2)O(3)-30-treated rats. On the other hand, Fe(2)O(3)-Bulk did not depict any significant changes in these biochemical parameters, and alterations were near to control. Therefore, this study suggests that exposure to nanosize particles at acute doses may cause adverse changes in animal biochemical profiles. The use of the rat model signifies the correlation with the human system. PMID:23025823

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

    PubMed Central

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

    2001-01-01

    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 patients with renal carcinoma. 25 patients (all men; median age, 51 years; range 34–76 years) with advanced measurable renal carcinoma, who had either progressed on or were not suitable for immunotherapy, received thalidomide in an escalating schedule up to a maximum dose of 600?mg daily. Treatment continued until disease progression or unacceptable toxicity were encountered. 22 patients were assessable for response. 2 patients showed partial responses (9%; 95% CI: 1–29), 7 (32%; 95% CI: 14–55) had stable disease for more than 6 months and a further 5 (23%; 95% CI: 8–45) had stable disease for between 3 and 6 months. We also measured levels of TNF-?, bFGF, VEGF, IL-6 and IL-12 before and during treatment. In patients with SD ? 3 months or an objective response, a statistically significant decrease in serum TNF-? levels was demonstrated (P = 0.05). The commonest toxicities were lethargy (? grade II, 10 patients), constipation (? grade II, 11 patients) and neuropathy (? grade II, 5 patients). Toxicities were of sufficient clinical significance for use of a lower and well tolerated dose of 400?mg in currently accruing studies. © 2001 Cancer Research Campaignhttp://www.bjcancer.com PMID:11592764

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

    PubMed

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

    2014-09-01

    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

  5. High- and Low-Dose Oral Delayed-Release Mesalamine in Children With Mild-to-Moderately Active Ulcerative Colitis

    PubMed Central

    Winter, Harland S.; Krzeski, Piotr; Heyman, Melvin B.; Ibarguen-Secchia, Eduardo; Iwanczak, Barbara; Kaczmarski, Maciej; Kierkus, Jaroslaw; Kola?ek, Sanja; Osuntokun, Bankole; Quiros, J. Antonio; Shah, Manoj; Yacyshyn, Bruce; Dunnmon, Preston M.

    2014-01-01

    ABSTRACT Objective: The aim of the study was to assess the safety and efficacy of high- and low-dose oral, delayed-release mesalamine in a randomized, double-blind, active control study of children with mild-to-moderately active ulcerative colitis. Methods: Patients ages 5 to 17 years, with a Pediatric Ulcerative Colitis Activity Index (PUCAI) score of ?10 to ?55 and a truncated Mayo Score of ?1 for both rectal bleeding and stool frequency, were enrolled. They received body weight–dependent doses of oral, delayed-release mesalamine for 6 weeks in a low- (27–71 mg · g?1 · day?1) or high-dose group (53–118 mg · g?1 · day?1). The primary endpoint was treatment success, defined as the proportion of patients who achieved remission (PUCAI score <10) or partial response (PUCAI score ?10 with a decrease from baseline by ?20 points). Secondary endpoints included truncated Mayo Score and global assessment of change of disease activity. Results: The modified intent-to-treat population included 81 of 83 patients enrolled. Treatment success by PUCAI was achieved by 23 of 41 (56%) and 22 of 40 (55%) patients in the mesalamine low- and high-dose groups, respectively (P?=?0.924). Truncated Mayo Score (low-dose 30 [73%] and high-dose 28 [70%] patients) and other efficacy results did not differ between the groups. The type and severity of adverse events were consistent with those reported in previous studies of adults with ulcerative colitis and did not differ between groups. Conclusions: Both low- and high-dose oral, delayed-release mesalamine doses were equally effective as short-term treatment of mild-to-moderately active ulcerative colitis in children, without a specific benefit or risk to using either dose. PMID:25419597

  6. Radiation dose vs. image quality for low-dose CT protocols of the head for maxillofacial surgery and oral implant planning.

    PubMed

    Loubele, M; Jacobs, R; Maes, F; Schutyser, F; Debaveye, D; Bogaerts, R; Coudyzer, W; Vandermeulen, D; van Cleynenbreugel, J; Marchal, G; Suetens, P

    2005-01-01

    The goal of this study was to determine the acquisition parameters for a low-dose multi-slice CT protocol and to compare the effective dose and the image quality of this low-dose protocol with the image quality of a clinical multi-slice CT protocol, routinely used for visualisation of the head. The low-dose protocol was derived from a clinical multi-slice CT protocol by lowering mA s and kV and increasing the pitch. The low-dose protocol yielded a dose reduction from 1.5 to 0.18 mSv for a multi-slice CT scan of the whole head, whereas noise in the low-dose CT images was increased. For bone segmentation, noise could be reduced by use of a non-linear edge preserving smoothing filter. Tests on ESP and skull phantom indicated that the accuracy of the measurements on low-dose CT is acceptable for image-based planning of maxillofacial and oral implant surgery, reducing the dose by a factor of 8. PMID:16461498

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

    NASA Astrophysics Data System (ADS)

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

    2014-05-01

    Nanotechnology, through nanomedicine, allowed drugs to be manipulated into nanoscale sizes for delivery to the different parts of the body, at the same time, retaining the valuable pharmacological properties of the drugs. However, efficient drug delivery and excellent release potential of these delivery systems may be hindered by possible untoward side effects. In this study, the sub-acute toxicity of oral zinc aluminium nanocomposite with and without levodopa was assessed using the Organization for Economic Co-operation and Development guidelines. No sign or symptom of toxicity was observed in orally treated rats with the nanocomposite at 5 and 500 mg/kg concentrations. Body weight gain, feeding, water intake, general survival and organosomatic index were not significantly different between control and treatment groups. Aspartate aminotransferase (AST) in 500 mg/kg levodopa nanocomposite (169 ± 30 U/L), 5 mg/kg levodopa nanocomposite (172 ± 49 U/L), and 500 mg/kg layered double hydroxides (LDH) nanocomposite (175 ± 25 U/L) were notably elevated compared to controls (143 ± 05 U/L); but the difference were not significant ( p > 0.05). However, the differences in aspartate aminotransferase/alanine aminotransferase (AST/ALT) ratio of 500 mg/kg levodopa nanocomposite (0.32 ± 0.12) and 500 mg/kg LDH nanocomposite (0.34 ± 0.12) were statistically significant ( p < 0.05) compared to the control (0.51 ± 0.07). Histology of the liver, spleen and brain was found to be of similar morphology in both control and experimental groups. The kidneys of 500-mg/kg-treated rats with levodopa nanocomposite and LDH nanocomposite were found to have slight inflammatory changes, notably leukocyte infiltration around the glomeruli. The ultra-structure of the neurons from the substantia nigra of nanocomposite-exposed group was similar to those receiving only normal saline. The observed result has suggested possible liver and renal toxicity in orally administered levodopa intercalated nanocomposite; it is also dose-dependent that needs further assessment.

  8. A double-blind, placebo-controlled evaluation of the effect of oral doses of rizatriptan 10 mg on oral contraceptive pharmacokinetics in healthy female volunteers.

    PubMed

    Shadle, C R; Liu, G; Goldberg, M R

    2000-03-01

    Rizatriptan (MAXALT), a potent, oral 5-HT1B/1D agonist with a rapid onset of action, is available now for the acute treatment of migraine. This study examined the pharmacokinetic and clinical interaction between rizatriptan 10 mg and the components (ethinyl estradiol [EE] 35 micrograms and norethindrone [NET] 1.0 mg) of a well-established oral contraceptive combination product, ORTHO-NOVUM 1/35. Levels of sex hormone binding globulin (SHBG), a protein increased by EE to which NET binds, were also examined. In this two-period crossover study, 20 healthy young female subjects received a coadministration of 8 days of rizatriptan treatment (6 days of single-dose 10 mg rizatriptan and 2 days of multiple-dose rizatriptan, 10 mg q 4 hours for three doses, giving a total daily dose of 30 mg on Days 7 and 8) or matching placebo along with their daily dose (one tablet) of ORTHO-NOVUM 1/35 within their oral contraceptive cycle. Plasma was sampled for EE, NET, and SHBG concentrations. Safety evaluations included routine laboratory safety studies, physical examinations, and monitoring for ECG, vital signs, and adverse events. There were no statistically significant differences in any of the pharmacokinetic parameters of EE or NET between the rizatriptan and placebo treatment periods, thus indicating that rizatriptan had no meaningful effect on the disposition of either the EE or the NET component of ORTHO-NOVUM 1/35. The SHBG concentration did not change throughout the entire study. Clinically, coadministration of rizatriptan with ORTHO-NOVUM 1/35 was well tolerated. Blood pressure, heart rate, and temperature showed no consistent trend or clinically important changes. Adverse events following coadministration of rizatriptan with ORTHO-NOVUM 1/35 were similar to those reported when placebo was given with ORTHO-NOVUM 1/35. The findings of this study indicate that there is little potential for dosages as high as 30 mg/day, the maximum recommended dosing schedule, of rizatriptan to alter the plasma concentrations of oral contraceptives. PMID:10709161

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

    PubMed

    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

    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

  10. Plasma and brain concentrations of oral therapeutic doses of methylphenidate and their impact on brain monoamine content in mice.

    PubMed

    Balcioglu, Aygul; Ren, Jia-Qian; McCarthy, Deirdre; Spencer, Thomas J; Biederman, Joseph; Bhide, Pradeep G

    2009-12-01

    Methylphenidate is a frequently prescribed stimulant for the treatment of attention deficit hyperactivity disorder (ADHD). An important assumption in the animal models that have been employed to study methylphenidate's effects on the brain and behavior is that bioavailability of methylphenidate in the animal models reflects that in human subjects. From this perspective, the dose and route of administration of methylphenidate assume critical importance because both these factors likely influence rate of uptake, plasma and brain concentrations of the drug. In the present study, plasma and brain concentrations of d- and l-methylphenidate and d- and l-ritalinic acid were measured in 2-month old mice (equivalent to young adulthood in humans) following a single oral administration of a racemic mixture. Our data show that oral administration of 0.75 mg/kg dose produced within 15 min, plasma levels of d-methylphenidate that correspond to the clinically effective plasma levels in human subjects (estimated to be 6-10 ng/ml). Brain concentrations of d- and l-methylphenidate tended to exceed their plasma concentrations, while the plasma concentrations of d- and l-ritalinic acid exceeded their brain concentrations. A single oral administration at 0.75 mg/kg dose increased dopamine content of the frontal cortex within 1 h, without producing statistically significant changes in serotonin or noradrenaline contents. Striatal monoamine levels remained unaltered. These data highlight disparities between plasma and brain concentrations of methylphenidate and its metabolites following oral administration and illustrate brain region- and monoamine-specific changes produced by the low oral dose of methylphenidate. PMID:19631228

  11. Plasma and brain concentrations of oral therapeutic doses of methylphenidate and their impact on brain monoamine content in mice

    PubMed Central

    Balcioglu, Aygul; Ren, Jia-Qian; McCarthy, Deirdre; Spencer, Thomas J.; Biederman, Joseph; Bhide, Pradeep G.

    2009-01-01

    Summary Methylphenidate is a frequently prescribed stimulant for the treatment of attention deficit hyperactivity disorder (ADHD). An important assumption in the animal models that have been employed to study methylphenidate’s effects on the brain and behavior is that bioavailability of methylphenidate in the animal models reflects that in human subjects. From this perspective, the dose and route of administration of methylphenidate assume critical importance because both these factors likely influence rate of uptake, plasma and brain concentrations of the drug. In the present study, plasma and brain concentrations of D- and L-methylphenidate and D- and L-ritalinic acid were measured in 2-month old mice (equivalent to young adulthood in humans) following a single oral administration of a racemic mixture. Our data show that oral administration of 0.75 mg/kg dose produced within 15 min, plasma levels of D-methylphenidate that correspond to the clinically effective plasma levels in human subjects (estimated to be 6-10 ng/ml). Brain concentrations of D- and L-methylphenidate tended to exceed their plasma concentrations, while the plasma concentrations of D- and L-ritalinic acid exceeded their brain concentrations. A single oral administration at 0.75 mg/kg dose increased dopamine content of the frontal cortex within 1 hr, without producing statistically significant changes in serotonin or noradrenaline contents. Striatal monoamine levels remained unaltered. These data highlight disparities between plasma and brain concentrations of methylphenidate and its metabolites following oral administration and illustrate brain region- and monoamine-specific changes produced by the low oral dose of methylphenidate. PMID:19631228

  12. Effects of multiple oral dosing on IgE synthesis in mice: oral sensitization by albumin extracts from seeds of Jack fruit (Artocarpus integrifolia) containing lectins.

    PubMed Central

    Restum-Miguel, N; Prouvost-Danon, A

    1985-01-01

    The IgE antibody response was studied in DBA/2 mice; the mice were pretreated orally with albumin extracts from seeds of Jack fruit (Jackalbumin) and subsequently immunized subcutaneously with Jackalbumin mixed with ovalbumin (OA) and a synthetic adjuvant, muramyl dipeptide (MDP). The allergenicity of Jackalbumin was evaluated by its capacity to induce a specific IgE response which was measured by passive cutaneous anaphylaxis (PCA) and by degranulation of washed peritoneal mast cells following antigen challenge (Jackalbumin or OA). Antibody against the crude extracts and anti-lectin (FIISP) IgE responses were also tested by PCA. After being fed eight doses of 1 mg Jackalbumin, DBA/2 mice became immunized: i.e. specific IgE antibody responses were observed and the peritoneal mast cells became sensitized. An increase in IgE response was verified in mice that were pre-fed and subsequently immunized. The results indicated that: the albumin extracts from Jack seeds, containing lectins, can be allergenic by the oral route; multiple oral doses with these extracts can induce an enhancement of the IgE response on subsequent subcutaneous immunization; antigenically, Jackalbumin does not seem to cross-react with OA; the lectins contained in the albumin fraction from Artocarpus seeds were also shown to be allergenic; the IgE titres showed an inverse correlation to the degree of purification of the lectin used for PCA challenge. PMID:3972438

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

    PubMed Central

    García-Avilés, Álvaro; Albert-Gascó, Héctor; Arnal-Vicente, Isabel; Elhajj, Ebtisam; Sanjuan-Arias, Julio; Sanchez-Perez, Ana María; Olucha-Bordonau, Francisco

    2015-01-01

    Methylphenidate (MPD) is a commonly administered drug to treat children suffering from attention deficit hyperactivity disorder (ADHD). Alterations in septal driven hippocampal theta rhythm may underlie attention deficits observed in these patients. Amongst others, the septo-hippocampal connections have long been acknowledged to be important in preserving hippocampal function. Thus, we wanted to ascertain if MPD administration, which improves attention in patients, could affect septal areas connecting with hippocampus. We used low and orally administered MPD doses (1.3, 2.7 and 5 mg/Kg) to rats what mimics the dosage range in humans. In our model, we observed no effect when using 1.3 mg/Kg MPD; whereas 2.7 and 5 mg/Kg induced a significant increase in c-fos expression specifically in the medial septum (MS), an area intimately connected to the hippocampus. We analyzed dopaminergic areas such as nucleus accumbens and striatum, and found that only 5 mg/Kg induced c-fos levels increase. In these areas tyrosine hydroxylase correlated well with c-fos staining, whereas in the MS the sparse tyrosine hydroxylase fibers did not overlap with c-fos positive neurons. Double immunofluorescence of c-fos with neuronal markers in the septal area revealed that co-localization with choline acethyl transferase, parvalbumin, and calbindin with c-fos did not change with MPD treatment; whereas, calretinin and c-fos double labeled neurons increased after MPD administration. Altogether, these results suggest that low and acute doses of methylphenidate primary target specific populations of caltretinin medial septal neurons. PMID:25852493

  14. [Repeated dose toxicity studies of taltirelin tetrahydrate (TA-0910) with oral administration to dogs].

    PubMed

    Inui, T; Yuasa, H; Adachi, T; Kawai, Y; Kudow, S

    1997-11-01

    Taltirelin tetrahydrate (TA-0910), novel thyrotropin-releasing hormone (TRH) analogue, was orally administered to dogs as dose levels 0.5, 5, and 50 mg/kg for 13 weeks and 0.15, 1.5 and 15 mg/kg for 52 weeks. Blood concentrations of test substance measured in 52-week study revealed that absorption of TA-0910 was with dose-dependent manner and not changed through the treatment period. These toxicokinetics suggested that there were no alterations on metabolism of TA-0910 with repeated treatment. The animals receiving 5 or 50 mg/kg showed decrease in body weight or suppression of body weight gain, and decrease in food intake (13-week study). As an abnormality in general conditions, vomiting and salivation (5 mg/kg or more, both in 13- and 52-week studies), increase in behavior as water intake (5 mg/kg or more, 13-week study), and hyperlocomotion (50 mg/kg) were observed. Elevating GPT values were noted temporally in the animals treated with 5 mg/kg or more (both in 13- and 52-week studies) without abnormal findings in histopathology. The thyroid weights were increased in treated animals receiving 5 or 50 mg/kg in 13-week study, but no histopathological changes were noted. Electron microscopy revealed dilatation of granular endoplasmic reticulums in follicular cells of thyroid from 50 mg/kg group in 13-week study. It was concluded that no-effect levels of 13- and 52-week studies were 0.5 mg/kg and 1.5 mg/kg, respectively. PMID:9430094

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

    PubMed

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

    2007-05-01

    Listeriosis, a severe disease that results from exposure to the foodborne pathogen Listeria monocytogenes, is responsible for approximately 2500 illnesses and 500 deaths in the United States each year. Pregnant women are 20 times more likely to develop listeriosis than the general population, with adverse pregnancy outcomes that include spontaneous abortions, stillbirths, and neonatal meningitis. The objective of this study was to determine an infective dose that resulted in stillbirths and infectivity of selected tissues in pregnant guinea pigs. Pregnant guinea pigs were exposed orally on gestation day 35 to 10(4) to 10(8) L. monocytogenes CFU in sterile whipping cream. L. monocytogenes was recovered at 64, 73, 90, and 100% from the livers of animals infected with 10(5), 10(6), 10(7), and 10(8) CFU, respectively. In dams exposed to > or =10(6) CFU, L. monocytogenes was cultured from 50% of the spleen samples and 33% of the gallbladder samples. Eleven of 34 dams infected with > or =10(6) CFU delivered stillborn pups. L. monocytogenes was cultured from the placenta, liver, and brain tissue of all stillbirths. Dams that delivered nonviable fetuses after treatment with > or =10(7) L. monocytogenes CFU had fecal samples positive for L. monocytogenes at every collection posttreatment. On the basis of a log-logistic model, the dose that adversely affected 50% of the pregnancies was approximately 10(7) L. monocytogenes CFU compared with that estimated from a human outbreak of 106 CFU. Listeriosis in pregnant guinea pigs can result in stillbirths, and the overall disease is similar to that described in nonhuman primates and in humans. PMID:17536670

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

    PubMed Central

    2011-01-01

    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

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

    PubMed

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

    2015-03-01

    Because of an increase in the commercial applications of manufactured nanoparticles, the issue of potential adverse health effects of nanoparticles following intended or unintended exposure is rapidly gaining attention. In this study, we evaluated the toxicity of aluminum oxide nanoparticles (AlNPs, rod-type, 1.5, 3, and 6 mg/kg) after oral administration to mice for 13 weeks. Compared with the control group, the consumption of diet and drinking water and body weight gain decreased in the group treated with AlNPs. The group treated with 6 mg/kg AlNPs also showed a marked elevation in the count of white blood cells that associated with a significant decrease and increase to the proportion of eosinophils and lymphocytes, respectively. In addition, the secretion of IL-6 and monocyte chemotactic protein-1 increased in a dose-dependent manner in the treated groups. Furthermore, AlNPs showed the highest accumulation in the liver and kidneys compared with the control group, increased the lactate dehydrogenase level in the blood, and induced the development of a pathological lesion in the liver and kidneys. Taken together, we suggest that the target organs of rod-type AlNPs may be the liver, kidneys and the immune system, and the not-observed adverse effect level may be lower than 6 mg/kg. PMID:24798085

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

    PubMed Central

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

    2013-01-01

    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

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

    Microsoft Academic Search

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

    1998-01-01

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

  20. A phase I trial of perillyl alcohol administered four times daily for 14 days out of 28 days

    Microsoft Academic Search

    Howard H. Bailey; George Wilding; Kendra D. Tutsch; Rhoda Z. Arzoomanian; Dona Alberti; Chris Feierabend; Kris Simon; Rebecca Marnocha; Sarah A. Holstein; Jan Stewart; Kriste A. Lewis; Raymond J. Hohl

    2004-01-01

    Purpose Perillyl alcohol (POH) has been shown to have both chemopreventative and chemotherapeutic activities in preclinical studies. The underlying mechanism(s) of action of POH have yet to be delineated but may involve effects on the transforming growth factor ? (TGF?) and\\/or the Ras signaling pathways. A phase I study of POH for 14 days out of every 28 days in subjects with

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

    PubMed

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

    1997-03-01

    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

  2. Phase II trial of daily oral perillyl alcohol (NSC 641066) in treatment-refractory metastatic breast cancer

    Microsoft Academic Search

    Howard H. Bailey; Steven Attia; Richard R. Love; Terri Fass; Rick Chappell; Kendra Tutsch; Linda Harris; Alcee Jumonville; Richard Hansen; Gary R. Shapiro; James A. Stewart

    2008-01-01

    Purpose  Perillyl alcohol (POH) is a naturally occurring lipid with preclinical activity against mammary carcinomas. We conducted a\\u000a phase II multi-institutional study of oral POH administered four times daily in women with advanced treatment-refractory breast\\u000a cancer.\\u000a \\u000a \\u000a \\u000a Methods  Eligible women were treated with POH four times daily at 1,200–1,500 mg m?2 dose?1 on a 28-day cycle. Patients tolerating 1,200 mg m?2 day?1 four times daily after one cycle were dose-escalated

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

    PubMed

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

    2014-06-16

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

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

    PubMed

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

    2015-02-01

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

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

    PubMed Central

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

    1978-01-01

    The British comparative thromboplastin (BCT) was used to monitor the effectiveness of oral anticoagulants in preventing deep vein thrombosis (DVT) in patients undergoing major gynaecological surgery. All patients were screened for DVT with the use of the 125I-fibrinogen scan. One hundred and forty-five patients aged 40 years or more were randomised into three groups. Group 1 received oral anticoagulant (nicoumalone) treatment, stabilised over five days before surgery and continuing into the second postoperative week. The other patients served as two contrast groups and were managed on a double-blind basis. Group 2 received a subcutaneous low-dose regimen of heparin calcium. Group 3 received subcutaneous saline. Eleven of 48 patients in the saline group, three of 49 patients in the heparin group, and three of 48 patients in the oral anticoagulant group developed DVT as judged by 125I-fibrinogen scanning. The incidences in groups 1 and 2 were significantly lower than in the saline group. The falls in haemoglobin concentration and incidence of haemorrhage were similar in all three groups. The study showed that oral anticoagulant prophylaxis stabilised preoperatively and low-dose heparin were equally effective in preventing deep vein thrombosis in a moderate-risk group. Immediate preoperative prothrombin ratios of 2·0-2·5 and postoperative ratios of 2·0-4·0 with the BCT gave adequate protection without increased haemorrhagic risk. PMID:340005

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

    EPA Science Inventory

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

  7. The pharmacokinetics of C-glycosyl flavones of Hawthorn leaf flavonoids in rat after single dose oral administration

    Microsoft Academic Search

    L. Y. Ma; R. H. Liu; X. D. Xu; M. Q. Yu; Q. Zhang; H. L. Liu

    2010-01-01

    Hawthorn leaf flavonoids (HLF) are used in the treatment of cardiovascular diseases. Various potential pharmacodynamic effects have been observed for vitexin-4?-O-glucoside (VOG) and vitexin-2?-O-rhamnoside (VOR) which are the main constituents of HLF. The aim of this study was to investigate the pharmacokinetics of VOG and VOR when a single dose of HLF was administrated orally. The levels of VOG and

  8. Sexual behavior of women taking low-dose oral contraceptive containing 15 ?g ethinylestradiol\\/60 ?g gestodene

    Microsoft Academic Search

    Salvatore Caruso; Carmela Agnello; Giorgia Intelisano; Marco Farina; Lucia Di Mari; Antonio Cianci

    2004-01-01

    The objective of this prospective study was to assess the effects of a low-dose oral contraceptive (OC) containing 15 ?g ethinylestradiol and 60 ?g gestodene on sexuality. Forty-eight healthy volunteers (age range, 18–35 years), having regular menstrual cycles with ovulation, participated in the study. Sexual behavior was assessed using the self-administered Personal Experience Questionnaire, at baseline, and at 3, 6

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

    SciTech Connect

    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

    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.

  10. Influence of body condition on plasma prednisolone and prednisone concentrations in clinically healthy cats after single oral dose administration.

    PubMed

    Center, Sharon A; Randolph, John F; Warner, Karen L; Simpson, Kenneth W; Rishniw, Mark

    2013-08-01

    Influence of body condition (over-conditioned vs. normal-conditioned) on plasma glucocorticoid concentrations after single dose oral prednisolone or prednisone in 11 cats (5 normal-conditioned and 6-over-conditioned) was investigated using a two-drug crossover trial (3-week washout interval). Body condition was determined using criterion-referenced bioelectrical impedance together with plasma drug concentrations (prednisolone [active drug] and prednisone [pro-drug]) measured by HPLC. Although interconversion of each drug to the other was confirmed, a single 2mg/kg body weight oral dose of prednisolone produced significantly higher plasma prednisolone concentration (?4-fold higher AUC) compared to prednisone. Significantly higher plasma drug concentrations in over-conditioned cats (?2-fold) compared to normal-conditioned cats might explain their perceived increased risk for glucocorticoid associated side effects (hepatic lipidosis, diabetes mellitus). Findings suggest low comparative bioavailability of oral prednisone compared to prednisolone in cats and consideration of lean body mass or ideal body weight for dosing practices. PMID:23473553

  11. Efficacy of a small single dose of oral dexamethasone for outpatient croup: a double blind placebo controlled clinical trial.

    PubMed Central

    Geelhoed, G. C.; Turner, J.; Macdonald, W. B.

    1996-01-01

    OBJECTIVE--To assess the efficacy of a single dose of oral dexamethasone 0.15 mg/kg in children with mild croup not admitted to hospital. DESIGN--Double blind, randomised, placebo controlled clinical trial. SETTING--The emergency department of a tertiary paediatric hospital. SUBJECTS--100 children aged 4-122 months presenting with mild croup. INTERVENTION--A single oral dose of dexamethasone 0.15 mg/kg or placebo. MAIN OUTCOME MEASURE--Return to medical care with ongoing croup. RESULTS--Baseline characteristics of the two treatment groups were similar. Eight children (all from the placebo group) returned to medical care with ongoing croup, one being admitted. There was no reported difference in duration of croup symptoms, duration of viral symptoms, or rate of return to medical care for other reasons. CONCLUSION--Oral dexamethasone in a dose of 0.15 mg/kg is effective in reducing return to medical care with ongoing croup in children with mild croup. PMID:8688774

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

    PubMed

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

    2014-03-01

    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

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

    PubMed Central

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

    2014-01-01

    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)] Cmax 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

  14. Acute and Repeated Dose Toxicity Studies of Different ?-Cyclodextrin-Based Nanosponge Formulations.

    PubMed

    Shende, Pravin; Kulkarni, Yogesh A; Gaud, R S; Deshmukh, Kiran; Cavalli, Roberta; Trotta, Francesco; Caldera, Fabrizio

    2015-05-01

    Nanosponges (NS) show promising results in different fields such as medicine, agriculture, water purification, fire engineering and so on. The present study was designed to evaluate toxicity of different NS formulations (namely, S1-S6) synthesized with different cross-linking agents such as carbonyl diimidazole, pyromellitic dianhydride and hexamethylene diisocynate; and preparation methods in experimental animals. Acute and repeated dose toxicity studies of formulations were carried out as per OECD guidelines 423 and 407, respectively. For acute toxicity study, formulations were administered to female rats at doses of 300 and 2000 mg/kg orally. The general behaviour of the rats was continuously monitored for 1 h after dosing, periodically during the first 24 h and daily thereafter for a total of 14 days. On day 14, animals were fasted overnight, weighed, and sacrificed. After sacrification, animals were subjected to necropsy. For repeated dose toxicity study, rats of either sex were orally administered with formulations at the dose of 300 mg/kg per day for a period of 28 days. The maximally tolerated dose of all formulations was found to be 2000 mg/kg. Repeated administration of formulations for 28 days did not show any significant changes in haematological and biochemical parameters in experimental animals. These results indicate that the formulations are safe, when tested in experimental animals. © 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1856-1863, 2015. PMID:25754724

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

    PubMed Central

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

    1995-01-01

    1. The pharmacokinetics of perindopril and perindoprilat and the hormonal and haemodynamic responses following a single oral dose were studied in 12 Chinese and 10 Caucasian healthy, normotensive volunteers on two occasions. Perindopril was given on the first occasion as a 4 mg dose and then after at least 10 days as a weight-adjusted dose of 4 mg/70 kg. Plasma was sampled for assay of perindopril, perindoprilat, plasma renin activity (PRA), aldosterone, angiotensin I (AI) and ACE activity. Urine was collected for perindopril and perindoprilat assay. A radioimmunoassay technique was used to measure the prodrug and its active metabolite. 2. The time to maximum concentration (tmax) for perindopril was shorter for the Chinese group after the 4 mg dose (median 0.5, range 0.5-1.5 h vs median 1.0, 0.5-1.5 h P < 0.05) and also tended to be shorter after the weight-adjusted dose (median 0.5, range 0.5-1.0 h vs median 1.0, range 0.5-3.0 h). Cmax and AUC tended to be higher after the 4 mg dose in the Chinese group who had a lower body weight than the Caucasians. 3. The tmax of perindoprilat tended to be shorter for both doses and there was a tendency towards a higher Cmax after the 4 mg dose in the Chinese group but there was no statistically significant difference between the two groups. 4. There were no differences in the levels of PRA, plasma AI, plasma aldosterone or the degree of ACE-inhibition for either dose in the two ethnic groups. 5. Blood pressure was measured at intervals up to 24 h post-dose in both the supine and standing positions. Perindopril reduced blood pressure acutely with respect to the pre-dose level with good tolerability in both groups.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7640141

  16. Oral delivery of plant-derived HIV-1 p24 antigen in low doses shows a superior priming effect in mice compared to high doses.

    PubMed

    Lindh, Ingrid; Bråve, Andreas; Hallengärd, David; Hadad, Ronza; Kalbina, Irina; Strid, Åke; Andersson, Sören

    2014-04-25

    During early infection with human immunodeficiency virus type 1 (HIV-1), there is a rapid depletion of CD4(+) T-cells in the gut-associated lymphoid tissue (GALT) in the gastrointestinal tract. Therefore, immediate protection at these surfaces is of high priority for the development of an HIV-1 vaccine. Thus, transgenic plants expressing HIV-1 antigens, which are exposed to immune competent cells in the GALT during oral administration, can be interesting as potential vaccine candidates. In the present study, we used two HIV-1 p24 antigen-expressing transgenic plant systems, Arabidopsis thaliana and Daucus carota, in oral immunization experiments. Both transgenic plant systems showed a priming effect in mice and induced humoral immune responses, which could be detected as anti-p24-specific IgG in sera after an intramuscular p24 protein boost. Dose-dependent antigen analyses using transgenic A. thaliana indicated that low p24 antigen doses were superior to high p24 antigen doses. PMID:24631072

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

    PubMed Central

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

    2014-01-01

    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

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

    PubMed Central

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

    2008-01-01

    AIMS Brivaracetam is a novel synaptic vesicle protein 2A ligand that has shown potent activity in animal models of epilepsy. This study examined the pharmacokinetics, central nervous system pharmacodynamics and adverse event profile of multiple oral doses of brivaracetam in healthy male subjects. METHODS Three successive panels of 12 healthy male subjects received double-blind brivaracetam 200, 400 or 800 mg day?1 (all doses well above the expected therapeutic range) or placebo (9 : 3), in two divided doses, for 14 days. RESULTS Brivaracetam was rapidly absorbed (tmax?2 h) and eliminated (t1/2 7–8 h). Volume of distribution was slightly lower than total body water. A small fraction of the dose (5–8%) was excreted unchanged in urine together with significant levels of metabolites, suggesting predominantly metabolic clearance. Based on 6-?-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

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

    PubMed Central

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

    2013-01-01

    ABSTRACT Clarithromycin (CLM) has been known to increase the cyclosporine (CsA) trough level in human and feline organ transplant patients. However, the interaction of CLM with CsA has not been reported in dogs. In this study, the effects of multiple dosing of CLM on the pharmacokinetics of CsA in three healthy beagles were investigated. The treatments included CsA 10 mg/kg alone and CsA 10 mg/kg + multiple-dose of CLM 10 mg/kg. Co-administration of CLM with CsA resulted in significant increases of oral bioavailability of CsA. The results of our study suggest that administration of multiple therapeutic doses of CLM may decrease the required CsA dosage in CsA-based immunosuppressive therapy in renal transplanted dogs. PMID:24189617

  20. The single dose pharmacokinetic profile of a novel oral human parathyroid hormone formulation in healthy postmenopausal women.

    PubMed

    Hämmerle, Sibylle P; Mindeholm, Linda; Launonen, Aino; Kiese, Beate; Loeffler, Rolf; Harfst, Evita; Azria, Moise; Arnold, Michel; John, Markus R

    2012-04-01

    Parathyroid hormone (PTH), currently the only marketed anabolic treatment for osteoporosis, is available as the full-length hormone, human PTH1-84, or as the human PTH1-34 fragment (teriparatide). Both must be administered as a daily subcutaneous (sc) injection. A new oral formulation of human PTH1-34 (PTH134) is being developed as a more convenient option for patients. In this single-center, partially-blinded, incomplete cross-over study, the safety, tolerability, and exposure of oral PTH134 (teriparatide combined with 2 different quantities of the absorption enhancer 5-CNAC) were assessed in 32 healthy postmenopausal women. 16 subjects were randomized to receive 4 single doses out of 6 different treatments: placebo, teriparatide 20 ?g sc, or 1, 2.5, 5 or 10 mg of oral PTH134 formulated with 200 mg 5-CNAC. Subsequently, another 16 subjects were randomized to receive 4 out of 6 different treatments: placebo, teriparatide 20 ?g sc, or 2.5 or 5 mg of oral PTH134 formulated with either 100 or 200 mg 5-CNAC. Doses were given ?6 days apart. All doses of PTH134 were rapidly absorbed, and showed robust blood concentrations in a dose-dependent manner. Interestingly, PTH1-34 disappeared from blood faster after oral than after sc administration. Specifically, 2.5 and 5 mg PTH134 (containing 200 mg 5-CNAC) demonstrated Cmax and AUC0-last values closest to those of sc teriparatide 20 ?g (Forsteo®). Mean+/-SD hPTH134 Cmax values were, respectively, 74+/-59, 138+/-101, 717+/-496, and 1624+/-1579 pg/mL for 1, 2.5, 5, and 10 mg doses of this peptide administered with 200 mg 5-CNAC; while mean+/-SD AUC (0-last) values were, respectively, 30+/-40, 62+/-69, 320+/-269, and 627+/-633 h*pg/mL. The corresponding estimates for teriparatide 20 ?g sc were 149+/-35 for Cmax and 236+/-58 for AUC (0-last) Ionized calcium remained within normal limits in all treatment groups except for 3 isolated events. Nine subjects withdrew due to treatment-related AEs. Of those, seven were taking PTH134 2.5 or 5 mg: three withdrew for symptomatic hypotension (two of whom were in the 200 mg 5-CNAC group), three because of delayed vomiting (two from the 200 mg 5-CNAC group), one was proactively withdrawn by the investigator for symptomatic hypercalcemia (receiving 2.5 mg/100 mg 5-CNAC) at slightly supra-normal total calcium but normal ionized serum calcium levels. One subject receiving teriparatide and one receiving placebo withdrew for symptomatic hypotension. No serious AEs were reported. In conclusion, the study demonstrated potential therapeutically relevant PTH1-34 systemic exposure levels after oral administration of PTH1-34 formulated with the absorption enhancer 5-CNAC. Doses of 2.5 and 5 mg of oral PTH134 achieved exposure levels closest to those of teriparatide 20 ?g sc, with a comparable incidence of AEs in healthy postmenopausal women. PMID:22289659

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

    PubMed Central

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

    2007-01-01

    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

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

    PubMed

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

    2014-01-01

    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

  3. Single Oral Dose Pharmacokinetics of Decursin and Decursinol Angelate in Healthy Adult Men and Women

    PubMed Central

    Zhang, Jinhui; Li, Li; Hale, Thomas W.; Chee, Wayne; Xing, Chengguo; Jiang, Cheng; Lü, Junxuan

    2015-01-01

    The ethanol extract of Angelica gigas Nakai (AGN) root has promising anti-cancer and other bioactivities in rodent models. It is currently believed that the pyranocoumarin isomers decursin (D) and decursinol angelate (DA) contribute to these activities. We and others have documented that D and DA were rapidly converted to decursinol (DOH) in rodents. However, our in vitro metabolism studies suggested that D and DA might be metabolized differently in humans. To test this hypothesis and address a key question for human translatability of animal model studies of D and DA or AGN extract, we conducted a single oral dose human pharmacokinetic study of D and DA delivered through an AGN-based dietary supplement Cogni.Q (purchased from Quality of Life Labs, Purchase, NY) in twenty healthy subjects, i.e., 10 men and 10 women, each consuming 119 mg D and 77 mg DA from 4 vegicaps. Analyses of plasma samples using UHPLC-MS/MS showed mean time to peak concentration (Tmax) of 2.1, 2.4 and 3.3 h and mean peak concentration (Cmax) of 5.3, 48.1 and 2,480 nmol/L for D, DA and DOH, respectively. The terminal elimination half-life (t1/2) for D and DA was similar (17.4 and 19.3 h) and each was much longer than that of DOH (7.4 h). The mean area under the curve (AUC0-48h) for D, DA and DOH was estimated as 37, 335 and 27,579 h?nmol/L, respectively. Gender-wise, men absorbed the parent compounds faster and took shorter time to reach DOH peak concentration. The human data supported an extensive conversion of D and DA to DOH, even though they metabolized DA slightly slower than rodents. Therefore, the data generated in rodent models concerning anti-cancer efficacy, safety, tissue distribution and pharmacodynamic biomarkers will likely be relevant for human translation. Trial Registration ClinicalTrials.gov NCT02114957 PMID:25695490

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

    PubMed

    Abu-Qare, A W; Brownie, C F; Abou-Donia, M B

    2000-09-01

    The pharmacokinetics and placental transfer of a single oral dose of 100 mg/kg (10 microCi/kg, 16% of acute oral LD50) of uniformly phenyl-labeled [14C]p-nitrophenol were investigated in pregnant Sprague-Dawley rats at 14-18 days of gestation. Three animals were killed on gestation day 18, at 0.5, 1, 2, 4, 12, 24, and 48 h after dosing. Radioactivity was rapidly absorbed and distributed throughout the maternal and fetal tissues. The gastrointestinal tract contents retained 20% and 2% of the dose at 0.5 h and 4 h after dosing. The peak maternal plasma concentration of radioactivity (microg p-nitrophenol equivalent/ml) was 7.17 compared with 0.37 for fetal plasma at 0.5 h. Maximum concentration of radioactivity (microg p-nitrophenol equivalent/g fresh tissue) was detected in most tissues 0.5 h after dosing and was in descending order: kidney 23.27, liver 12.37, placenta 3.56, fetus 2.17, and brain 1.99. Radioactivity was eliminated from plasma and all tissues beiexponentially. The half-lives of elimination of 14C were 34.65 h and 69.30 h for maternal and fetal plasma, respectively. p-Nitrophenol, detected by HPLC, was the major compound identified in plasma and tissues. While p-nitrophenol disappeared biphasically from maternal plasma and kidney, it was eliminated monophasically from brain, placenta, and liver. p-Nitrocatechol and p-aminophenol were detected in the liver with peak concentrations at 0.5 h of 1.13 and 1.00 microg/g fresh tissue, respectively. While the change in the concentration of p-nitrocatechol with time was monophasic, that of p-aminophenol showed a biphasic pattern with elimination half-lives of 1.93 h and 4.95 h, respectively. Radioactivity was rapidly excreted in the urine mostly as polar metabolites, while only 3% of the dose was recovered in the feces. Radioactive materials excreted in the urine comprised: glucuronides 4%, sulfates 8%, hot-acid hydrolysates 11%, nonconjugated compounds 16%, and water-soluble metabolites 61%. This study demonstrated that although orally administered p-nitrophenol is a rapidly absorbed and excreted compound, it is transported to the maternal brain and the fetus and may pose a health risk following exposure to toxic doses during pregnancy. PMID:11043494

  5. Relative toxicity of bifenthrin to Hyalella azteca in 10 day versus 28 day exposures.

    PubMed

    Anderson, Brian S; Phillips, Bryn M; Voorhees, Jennifer P; Petersen, Megan A; Jennings, Lydia L; Fojut, Tessa L; Vasquez, Martice E; Siegler, Catherine; Tjeerdema, Ronald S

    2015-04-01

    Many watersheds in the Central Valley region of California are listed as impaired due to pyrethroid-associated sediment toxicity. The Central Valley Regional Water Quality Control Board is developing numeric sediment quality criteria for pyrethroids, beginning with bifenthrin. Criteria are being developed using existing data, along with data from 10?d and 28?d toxicity tests with Hyalella azteca conducted as part of the current study. A single range-finder and 2 definitive tests were conducted for each test duration. Median lethal concentrations (LC50s), as well as LC20s and inhibition concentrations (IC20s) were calculated based on measured whole sediment bifenthrin concentrations and interstitial water concentrations. Sediment LC50s were also corrected for organic C content. Average LC50s were not significantly different in 10?d versus 28?d tests with H. azteca: 9.1 and 9.6?ng/g bifenthrin for 10?d and 28?d tests, respectively. Average LC20 values were also similar with concentrations at 7.1 and 7.0 for 10?d and 28?d tests, respectively. Bifenthrin inhibition concentrations (IC20s) based on amphipod growth were variable, particularly in the 28?d tests, where a clear dose-response relationship was observed in only 1 of the definitive experiments. Average amphipod growth IC20s were 3.9 and 9.0?ng/g for 10?d and 28?d tests, respectively. Amphipod growth calculated as biomass resulted in IC20s of 4.1 and 6.3?ng/g for the 10?d and 28?d tests, respectively. Lack of a clear growth effect in the longer term test may be related to the lack of food adjustment to account for amphipod mortality in whole sediment exposures. The average C-corrected LC50s were 1.03 and 1.09??g/g OC for the 10?d and 28?d tests, respectively. Interstitial water LC50s were determined as the measured dissolved concentration of bifenthrin relative to interstitial water dissolved organic carbon. The average LC50s for dissolved interstitial water bifenthrin were 4.23 and 4.28?ng/L for the 10?d and 28?d tests, respectively. In addition, a set of 10?d and 28?d tests were conducted at 15?°C to assess the relative toxicity of bifenthrin at a lower temperature than the standard 23?°C test temperature. These results showed that bifenthrin was more toxic at the lower temperature, with LC50s of 5.1 and 3.4?ng/g bifenthrin in 10?d and 28?d tests, respectively. Amphipod growth at 15?°C after a 28?d exposure resulted in the lowest effect concentration of all experiments conducted (IC20?=?0.61?ng/g). This article discusses how bifenthrin dose-response data from 10?d and 28?d exposures inform development of sediment quality criteria for this pesticide for California Central Valley watersheds. Integr Environ Assess Manag 2015;11:319-328. © 2015 SETAC. PMID:25564769

  6. Optimization of Hyalella azteca IQ Toxicity Test{trademark} for prediction of 28-day sediment toxicity tests

    SciTech Connect

    Novotny, A.N.; Ezzard, C.L.; Douglas, W.S.; Home, M.T. [Aqua Survey, Inc., Flemington, NJ (United States)

    1995-12-31

    The IQ Toxicity Test, which is a rapid screening toxicity test consisting of the observation of in-vivo inhibition of an enzymatic process using a fluorescent substrate, has proven successful for the determination of 24 and 48-hour EC50`s of D. magna, C. dubia, D. pulex and M. bahia. The application of this concept to utilize the freshwater amphipod Hyalella azteca may be an excellent way in which to reduce the standard 28-day chronic sediment toxicity test to possibly one hour`s time. This study incorporates an additive experimental design to explore the effects of and interactions between five specific variables: size of the amphipod, exposure time to the toxicant, concentration of substrate, exposure time to the substrate, and length of time starved prior to testing. The results of the IQ toxicity test were compared to those of a 28-day chronic sediment toxicity test. Preliminary data indicate that there is an optimal combination of these variables which results in a concise, reproducible toxicity test for use with Hyalella azteca, and would potentially be applicable to other freshwater amphipods in the future.

  7. 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

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

    2014-08-01

    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

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

    PubMed

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

    2014-11-01

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

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

    PubMed

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

    2008-12-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed Central

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

    2011-01-01

    Objective The aim of this study was to evaluate the outcome and complications of low-dose-rate brachytherapy (LDR-BT) for oral cancer according to comorbidity. Methods The records of a total of 180 patients who received LDR-BT for T1-2N0M0 oral cancers between January 2005 and December 2007 were analysed. The comorbidities of the patients were retrospectively graded according to the Adult Comorbidity Evaluation-27, and the relationships between the comorbidity grades and survival, disease control and the incidence of complications were analysed. Results The 2 year overall survival rates of patients with no comorbidity, Grade 1, Grade 2 and Grade 3 comorbidity were 87%, 85%, 76% and 65%, respectively, and the reduction in the survival rate according to comorbid severity was significant in a univariate analysis (p = 0.032) but not in a multivariate analysis including other clinical factors. Cause-specific survival, locoregional control and local control were not related to the comorbidity grade, or any other clinical factors. Grade 2 or 3 complications developed in 27% of the patients. The incidence of complications was unrelated to the comorbidity grade. Conclusion The disease control of oral cancer and the incidence of complications after LDR-BT were not related to comorbid severity. LDR-BT is a useful and safe treatment for patients regardless of the presence of severe comorbidity. PMID:21224307

  12. Cardiovascular and Mood Responses to Quantified Doses of Cigarette Smoke in Oral Contraceptive Users and Nonusers

    Microsoft Academic Search

    Carmen L. Masson; David G. Gilbert

    1999-01-01

    Previous research suggests that the female sex hormones may moderate cardiovascular and mood responses to cigarette smoking and abstinence. To test this possibility, acute effects of cigarette smoking on cardiovascular reactivity and mood were examined in 12 oral contraceptive users and 12 nonusers across two menstrual phases (early and late cycle). After overnight deprivation, each participant attended two sessions in

  13. Low dose oral cannabinoid therapy reduces progression of atherosclerosis in mice

    Microsoft Academic Search

    Sabine Steffens; Niels R. Veillard; Claire Arnaud; Graziano Pelli; Fabienne Burger; Christian Staub; Andreas Zimmer; Jean-Louis Frossard; François Mach

    2005-01-01

    Atherosclerosis is a chronic inflammatory disease, and is the primary cause of heart disease and stroke in Western countries. Derivatives of cannabinoids such as delta-9-tetrahydrocannabinol (THC) modulate immune functions and therefore have potential for the treatment of inflammatory diseases. We investigated the effects of THC in a murine model of established atherosclerosis. Oral administration of THC (1mgkg-1 per day) resulted

  14. Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents

    Microsoft Academic Search

    V. Chel; H. A. H. Wijnhoven; J. H. Smit; M. Ooms; P. Lips

    2008-01-01

    Summary  The effect of equivalent oral doses of vitamin D3 600 IU\\/day, 4200 IU\\/week and 18,000 IU\\/month on vitamin D status was compared\\u000a in a randomized clinical trial in nursing home residents. A daily dose was more effective than a weekly dose, and a monthly\\u000a dose was the least effective.\\u000a \\u000a \\u000a \\u000a Introduction  It is assumed that equivalent daily, weekly or monthly doses of vitamin D3 equally

  15. A Single-blind, Placebo-controlled, Dose-ranging Trial of Oral Hepatic-directed Vesicle Insulin Add-on to Oral Antidiabetic Treatment in Patients With Type 2 Diabetes Mellitus.

    PubMed

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

    2014-05-01

    The dose response of postprandial plasma glucose (PPG) to add-on, premeal oral hepatic-directed vesicle-insulin (HDV-I), an investigational lipid bio-nanoparticle hepatocyte-targeted insulin delivery system, was evaluated in a 3-test-meal/day model in type 2 diabetes patients. The single-blind, placebo-controlled, dose-escalating trial enrolled 6 patients with HbA1c 8.6 ± 2.0% (70.0 ± 21.9 mmol/mol) and on stable metformin therapy. Patients received oral HDV-I capsules daily 30 minutes before breakfast, lunch, and dinner as follows: placebo capsules, 0.05, 0.1, 0.2, and 0.4 U/kg on days 1, 2, 3, 4, and 5, respectively. Outcome measures were PPG and incremental PPG area under the concentration-time curve (AUC). All 4 doses of oral HDV-I statistically significantly lowered mean PPG (P ? .0110 each) and incremental PPG (P ? .0352 each) AUC compared to placebo. A linear dose response was not observed. The 0.05 U/kg dose was the minimum effective dose in the dosage range studied. Three adverse events unrelated to treatment were observed. Add-on oral HDV-I 0.05-0.4 U/kg significantly lowered PPG excursions and the dose response curve was flat. These results are consistent with the lack of a linear dose response between portal and systemic plasma insulin concentrations in previous animal and human studies. Oral HDV-I was safe and well tolerated. PMID:24876619

  16. Toxicity of ammonium perfluorooctanoate in male cynomolgus monkeys after oral dosing for 6 months.

    PubMed

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

    2002-09-01

    Ammonium perfluorooctanoate (APFO) is a processing aid in the production of fluoropolymers that has been shown to have a long half-life in human blood. To understand the potential toxicological response of primates, groups of male cynomolgus monkeys were given daily po (capsule) doses of either 0, 3, 10, or 30 (reduced to 20) mg/kg/day for 26 weeks. Two monkeys from each of the control and 10 mg/kg/day dose groups were observed for 90 days after the last dose. Clinical observations, clinical chemistry, determination of key hormones, gross and microscopic pathology, cell proliferation, peroxisomal proliferation, bile-acid determination, and serum and liver perfluorooctanoate (PFOA) concentrations were monitored. Toxicity, including weight loss and reduced food consumption, was noted early in the study at the 30 mg/kg/day dose; therefore, the dose was reduced to 20 mg/kg/day. The same signs of toxicity developed in 3 monkeys at 20 mg/kg/day, after which treatment of these monkeys was discontinued. One 30/20 mg/kg/day monkey developed the signs of toxicity noted above and a possible dosing injury, and this monkey was sacrificed in extremis on Day 29. A 3 mg/kg/day dose-group monkey was sacrificed in extremis on Day 137 for reasons not clearly related to APFO treatment. Dose-dependent increases in liver weight as a result of mitochondrial proliferation occurred in all APFO-treated groups. Histopathologic evidence of liver injury was not observed at either 3 or 10 mg/kg/day. Evidence of liver damage was seen in the monkey sacrificed in moribund condition at the highest dose. Body weights were decreased at 30/20 mg/kg. PFOA concentrations in serum and liver were highly variable, were not linearly proportional to dose, and cleared to background levels within 90 days after the last dose. A no observable effect level was not established in this study, and the low dose of 3 mg/kg/day was considered the lowest observable effect level based on increased liver weight and uncertainty as to the etiology leading to the moribund sacrifice of one low-dose monkey on Day 137. Other than those noted above, there were no APFO-related macroscopic or microscopic changes, changes in clinical chemistry, hormones, or urinalysis, or hematological effects. In particular, effects that have been associated with the development of pancreatic and testicular toxicity in rats were not observed in this study. PMID:12215680

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

    PubMed

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

    2013-10-01

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

  18. Single-dose oral amoxicillin or linezolid for prophylaxis of experimental endocarditis due to vancomycin-susceptible and vancomycin-resistant Enterococcus faecalis.

    PubMed

    Moreillon, Philippe; Wilson, Walter R; Leclercq, Roland; Entenza, José M

    2007-05-01

    Endocarditis prophylaxis following genitourinary or gastrointestinal procedures targets Enterococcus faecalis. Prophylaxis recommendations advocate oral amoxicillin (2 g in the United States and 3 g in the United Kingdom) in moderate-risk patients and intravenous amoxicillin (2 g) or vancomycin (1 g) plus gentamicin in high-risk patients. While ampicillin-resistant (or amoxicillin-resistant) E. faecalis is still rare, there is a concern that these regimens might fail against vancomycin-resistant and/or aminoglycoside-resistant isolates. The present study tested oral linezolid as an alternative. Rats with catheter-induced aortic vegetations were given prophylaxis simulating human pharmacokinetics of oral amoxicillin (2- to 3-g single dose), oral linezolid (600 mg, single or multiple oral doses every 12 h), or intravenous vancomycin (1-g single dose). Rats were then inoculated with the minimum inoculum infecting 90% of the animals (90% infective dose [ID(90)]) or with 10 times the ID(90) of the vancomycin-susceptible E. faecalis strain JH2-2 or the vancomycin-resistant (VanA phenotype) E. faecalis strain UCN41. Amoxicillin was also tested with two additional vancomycin-susceptible E. faecalis strains, 309 and 1209. Animals were sacrificed 3 days later. All the tested bacteria were susceptible to amoxicillin and gentamicin. Single-dose amoxicillin provided 100% protection against all four isolates at both the ID(90) and 10 times the ID(90). In contrast, linezolid required up to four consecutive doses to provide full protection against the vancomycin-resistant isolate. Vancomycin protected only against the vancomycin-susceptible strain. The high efficacy of single-dose oral amoxicillin suggests that this regimen could be used for prophylaxis in both moderate-risk and high-risk patients without additional aminoglycosides. Linezolid appears to be less reliable, at least against the vancomycin-resistant strain. PMID:17353251

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

    PubMed

    Schnellbacher, Rodney; Beaufrère, Hugues; Vet, Dr Med; Arnold, Robert D; Tully, Thomas N; Mayer, Joerg; Divers, Stephen J

    2014-09-01

    Long-term anticonvulsive treatments have been poorly described in birds, and few pharmacokinetic studies have been performed, with mixed results. Levetiracetam, a new anticonvulsive drug, has shown good efficacy for monotherapy or adjunctive treatment of seizures in both human and veterinary medicine. To determine pharmacokinetics of levetiracetam in Hispaniolan Amazon parrots ( Amazona ventralis ), 20 healthy birds were randomly divided into 2 groups and administered either a 50 mg/kg (n = 10) or a 100 mg/kg (n = 10) oral dose of levetiracetam with no observable adverse effects. Blood samples were collected at baseline and at 12 time intervals (6 per group) for 16 hours. The concentration-time profiles resembled characteristic absorption, with maximum plasma concentrations of 61.0 ?g/mL and 95.1 ?g/mL at 60 minutes; terminal half-lives at 2.38 and 2.37 hours; volumes of distribution of 0.807 and 0.773 L/kg, with an area under the curve at 14?100 and 28?820 mg × min/L; and clearance rates of 3.65 and 3.60 mL/min per kg, respectively. Plasma concentrations were greater than 5.5 mg/L for up to 9.4 and 12 hours, suggesting an 8- and 12-hour oral dosing at 50 and 100 mg/kg, respectively, would be sufficient to maintain targeted values. Clinically, doses and frequencies may need escalation based on differences in species and individuals, and drug levels should be monitored. PMID:25843318

  20. Randomized, Controlled Human Challenge Study of the Safety, Immunogenicity, and Protective Efficacy of a Single Dose of Peru15, a Live Attenuated Oral Cholera Vaccine

    Microsoft Academic Search

    Mitchell B. Cohen; Ralph A. Giannella; Judy Bean; David N. Taylor; Susan Parker; Amy Hoeper; Stephen Wowk; Jennifer Hawkins; Sims K. Kochi; Gilbert Schiff; Kevin P. Killeen; Walter Reed

    2002-01-01

    Peru-15 is a live attenuated oral vaccine derived from a Vibrio cholerae O1 El Tor Inaba strain by a series of deletions and modifications, including deletion of the entire CT genetic element. Peru-15 is also a stable, motility-defective strain and is unable to recombine with homologous DNA. We wished to determine whether a single oral dose of Peru-15 was safe

  1. 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...

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

    PubMed

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

    2014-10-01

    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

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

    PubMed

    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

    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. PMID:24916020

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

    SciTech Connect

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

    2013-03-31

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

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

    PubMed Central

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

    2009-01-01

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

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

    Microsoft Academic Search

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

    2010-01-01

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

  7. In vivo study with quartz-containing ceramic dusts: Inflammatory effects of two factory samples in lungs after intratracheal instillation in a 28-day study with rats

    NASA Astrophysics Data System (ADS)

    Creutzenberg, O.; Ziemann, C.; Hansen, T.; Ernst, H.; Jackson, P.; Cartlidge, D.; Brown, R.

    2009-02-01

    As various quartz polymorphs react differently in lungs, a differentiation of effects is needed while setting occupational exposure levels. The objective of this European Collective Research Project SILICERAM was to characterize differences in biological activity of four quartz species, i.) 2 quartz-containing materials collected at typical ceramic manufacturing sites (Tableware granulate, TG and Tableware cast, TC) versus ii.) a designed ceramic dust sample (Contrived Sample, CS) and iii.) ground quartz DQ12 (well-characterised standard quartz (Positive Control, PC) and TiO2 (negative control). TG and TC had been selected as the most promising two candidates based on a preceding in vitro screening of 5 factory samples. Total doses of 5 mg per rat of the TG and TC, 1.1 mg of the CS and 0.33 mg of the PC corresponding to 0.29, 0.16, 0.29 and 0.29 mg quartz per rat, respectively, were administered to rats by intratracheal instillation. After 3 days, bronchoalveolar lavagate (BAL) analysis resulted in polymorphonuclear neutrophil (PMN) levels of 15%, 25%, 0.6% and 25% in the TG, TC, CS and PC groups, respectively. At 28 days, the values were 29%, 20%, 7% and 45%. Histopathologically, the TG and TC groups showed very slight to slight effects, the PC group, however, stronger effects after the same period. In conclusion, the following ranking was found: PC > TG > TC > CS > TiO2 > Vehicle Control. Thus, a clear differentiation of effects for TG and TC, CS and PC was found. From a regulatory point of view, the substance-specific toxic potentials of TG and TC may need to be considered when devising occupational exposure limits.

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

    PubMed Central

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

    2009-01-01

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

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

    USGS Publications Warehouse

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

    1998-01-01

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

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

    PubMed Central

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

    2014-01-01

    Aim The aim of the current study is to assess the mortality prediction accuracy of circulating cell-free DNA (CFD) level at admission measured by a new simplified method. Materials and Methods CFD levels were measured by a direct fluorescence assay in severe sepsis patients on intensive care unit (ICU) admission. In-hospital and/or twenty eight day all-cause mortality was the primary outcome. Results Out of 108 patients with median APACHE II of 20, 32.4% have died in hospital/or at 28-day. CFD levels were higher in decedents: median 3469.0 vs. 1659 ng/ml, p<0.001. In multivariable model APACHE II score and CFD (quartiles) were significantly associated with the mortality: odds ratio of 1.05, p?=?0.049 and 2.57, p<0.001 per quartile respectively. C-statistics for the models was 0.79 for CFD and 0.68 for APACHE II. Integrated discrimination improvement (IDI) analyses showed that CFD and CFD+APACHE II score models had better discriminatory ability than APACHE II score alone. Conclusions CFD level assessed by a new, simple fluorometric-assay is an accurate predictor of acute mortality among ICU patients with severe sepsis. Comparison of CFD to APACHE II score and Procalcitonin (PCT), suggests that CFD has the potential to improve clinical decision making. PMID:24955978

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

    PubMed

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

    2001-08-01

    This study investigated the possible influence of oral caffeine administration on endogenous glucose production and energy substrate metabolism during prolonged endurance exercise. Twelve trained endurance athletes [seven male, five female; peak oxygen consumption (VO2peak) = 65.5 ml.kg-1.min-1] performed 60 min of cycle ergometry at 65% VO2peak twice, once after oral caffeine administration (6 mg.kg-1) (CAF) and once following consumption of a placebo (PLA). CAF and PLA were administered in a randomized double-blind manner 75 min prior to exercise. Plasma glucose kinetics were determined with a primed-continuous infusion of [6,6-2H]glucose. No differences in oxygen consumption (VO2), and carbon dioxide production (VCO2) were observed between CAF and PLA, at rest or during exercise. Blood glucose concentrations were similar between the two conditions at rest and also during exercise. Exercise did lead to an increase in serum free fatty acid (FFA) concentrations for both conditions; however, no differences were observed between CAF and PLA. Both the plasma glucose rate of appearance (Ra) and disappearance (Rd) increased at the onset of exercise (P < 0.05), but were not affected by CAF, as compared to PLA. CAF did lead to a higher plasma lactate concentration during exercise (P < 0.05). It was concluded that an acute oral dose of caffeine does not influence plasma glucose kinetics or energy substrate oxidation during prolonged exercise in trained endurance athletes. However, CAF did lead to elevated plasma lactate concentrations. The exact mechanism of the increase in plasma lactate concentrations remains to be determined. PMID:11560082

  12. Effects of daily oral subtoxic doses of a wet lead-based paint on cattle

    Microsoft Academic Search

    F. C. Wright; R. L. Younger; J. C. Riner; C. A. McBeth; M. Haufler

    1976-01-01

    Summary Cattle were dosed daily with a wet lead-based paint at a rate of about 6 mg of lead per kg per day for 60 weeks. The cattle did not exhibit overt symptoms of lead toxicosis. Blood and fecal samples collected during the study, and tissue samples obtained at slaughter of the animals were analyzed for lead by atomic absorption

  13. Therapeutic Doses of Oral Methylphenidate Significantly Increase Extracellular Dopamine in the Human Brain

    Microsoft Academic Search

    Nora D. Volkow; Gene-Jack Wang; Joanna S. Fowler; Jean Logan; Madina Gerasimov; Laurence Maynard; Yu-Shin Ding; Samuel J. Gatley; Andrew Gifford; Dinko Franceschi

    2001-01-01

    Methylphenidate (Ritalin) is the most commonly prescribed psychoactive drug in children for the treatment of attention deficit hyperactivity disorder (ADHD), yet the mechanisms re- sponsible for its therapeutic effects are poorly understood. Whereas methylphenidate blocks the dopamine transporter (main mechanism for removal of extracellular dopamine), it is unclear whether at doses used therapeutically it significantly changes extracellular dopamine (DA) concentration.

  14. Population pharmacokinetic model of THC integrates oral, intravenous, and pulmonary dosing and characterizes short- and long-term pharmacokinetics.

    PubMed

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

    2015-02-01

    ?(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

  15. Multiple-dose pharmacokinetics and safety of the new antifungal triazole BAL4815 after intravenous infusion and oral administration of its prodrug, BAL8557, in healthy volunteers.

    PubMed

    Schmitt-Hoffmann, Anne; Roos, Brigitte; Maares, Jürgen; Heep, Markus; Spickerman, Jochen; Weidekamm, Erhard; Brown, Tom; Roehrle, Michael

    2006-01-01

    BAL8557 is the water-soluble prodrug of BAL4815, a new broad-spectrum antifungal. Healthy male subjects were randomly assigned to four treatment cohorts to receive multiple oral doses or multiple 1-h constant-rate intravenous infusions of BAL8557. Loading doses of BAL8557 were equivalent to 100 mg (followed by once-daily maintenance doses of 50 mg) or 200 mg (followed by once-daily maintenance doses of 100 mg) of BAL4815. In each cohort, six subjects received active drug and two subjects received the placebo. Study duration was 21 days (oral) and 14 days (intravenous). All adverse events reported were mild or moderate, except one severe rhinitis event which was not related to trial medication. After both routes of administration, maximum drug concentration observed in plasma (C(max)) and area under the concentration-time curve (AUC) values of BAL4815 increased proportionally to the administered dose. AUC values reflected a fourfold to fivefold accumulation of active drug in plasma during once-daily dosing, which is in line with the long elimination half-life of BAL4815 determined after the last administration (mean, 84.5 to 117 h). At steady state, the volume of distribution was large and amounted to 308 to 542 liters. Systemic clearance reached only 2.4 to 4.1 liter/h. At the levels obtained in the present study, C(max) values of 2.56 and 2.55 microg/ml after oral and intravenous administrations, respectively, there was no indication of CYP3A4 induction or inhibition (as revealed by the urinary 6-beta-hydroxycortisol/cortisol test). Based on AUC values after oral and intravenous administration, an excellent oral bioavailability can be predicted for BAL4815. Once-daily oral dosing of 50- or 100-mg equivalents of BAL8557 were recently demonstrated to be efficacious in a phase 2 study conducted with patients with esophageal candidiasis. These doses (preceded by adequate loading dose[s]) will be further explored in the treatment of systemic mycoses. PMID:16377699

  16. Single oral doses of (±) 3,4-methylenedioxymethamphetamine ('Ecstasy') produce lasting serotonergic deficits in non-human primates: relationship to plasma drug and metabolite concentrations.

    PubMed

    Mueller, Melanie; Yuan, Jie; McCann, Una D; Hatzidimitriou, George; Ricaurte, George A

    2013-05-01

    Repeated doses of the popular recreational drug methylenedioxymethamphetamine (MDMA, 'Ecstasy') are known to produce neurotoxic effects on brain serotonin (5-HT) neurons but it is widely believed that typical single oral doses of MDMA are free of neurotoxic risk. Experimental and therapeutic trials with MDMA in humans are underway. The mechanisms by which MDMA produces neurotoxic effects are not understood but drug metabolites have been implicated. The aim of the present study was to assess the neurotoxic potential of a range of clinically relevant single oral doses of MDMA in a non-human primate species that metabolizes MDMA in a manner similar to humans, the squirrel monkey. A secondary objective was to explore the relationship between plasma MDMA and metabolite concentrations and lasting serotonergic deficits. Single oral doses of MDMA produced lasting dose-related serotonergic neurochemical deficits in the brains of squirrel monkeys. Notably, even the lowest dose of MDMA tested (5.7 mg/kg, estimated to be equivalent to 1.6 mg/kg in humans) produced significant effects in some brain regions. Plasma levels of MDMA engendered by neurotoxic doses of MDMA were on the order of those found in humans. Serotonergic neurochemical markers were inversely correlated with plasma concentrations of MDMA, but not with those of its major metabolites, 3,4-dihydroxymethamphetamine and 4-hydroxy-3-methoxymethamphetamine. These results suggest that single oral doses of MDMA in the range of those used by humans pose a neurotoxic risk and implicate the parent compound (MDMA), rather than one of its metabolites, in MDMA-induced 5-HT neural injury. PMID:22824226

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

    Microsoft Academic Search

    Joachim Haselbach; Ted Berner; Harris Wright; Elizabeth Dunlap

    2000-01-01

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

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

    Microsoft Academic Search

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

    2007-01-01

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

  19. Phase I Study of Oral Azacitidine in Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia, and Acute Myeloid Leukemia

    PubMed Central

    Garcia-Manero, Guillermo; Gore, Steven D.; Cogle, Christopher; Ward, Renee; Shi, Tao; MacBeth, Kyle J.; Laille, Eric; Giordano, Heidi; Sakoian, Sarah; Jabbour, Elias; Kantarjian, Hagop; Skikne, Barry

    2011-01-01

    Purpose To determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). Patients and Methods Patients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m2) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received ? 6 cycles of oral azacitidine. Results Overall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (ie, complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients. Conclusion Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML. PMID:21576646

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

    PubMed Central

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

    2014-01-01

    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

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

    PubMed

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

    2015-02-01

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

  2. Oral postdialysis cholecalciferol supplementation in patients on maintenance hemodialysis: a dose-response approach.

    PubMed

    Descombes, Eric; Fellay, Benoit; Hemett, Ould Maouloud; Magnin, Jean-Luc; Fellay, Gilbert

    2014-01-01

    The aim of the present study was to evaluate the dose of postdialysis cholecalciferol needed to maintain the 25-hydroxyvitamin D [25(OH)D] levels in the optimal range of 75-150?nmol/L. Twenty-six patients who had low baseline 25(OH)D levels (mean 27.5 ± 14.9?nmol/L) were studied. The 25(OH)D levels were measured every 2 months for one year. During the first two months, all the patients received 2000?IU of cholecalciferol after each hemodialysis (=6000?IU/wk). Thereafter, the dose was individualized and adapted every 2 months by administering 1 to 6 cholecalciferol tablets (2000?IU each) per week (total weekly dose = 2000-12000?IU/wk). During cholecalciferol supplementation, the 25(OH)D concentrations rapidly increased from baseline to 140.1 ± 28.3?nmol/L at month 6 and 95.6 ± 20.9?nmol/L at month 12. At month twelve, 86% of the patients had 25(OH)D levels within the target range with a mean dose of 5917 ± 4106?IU/wk of cholecalciferol; however, the amount needed to maintain these levels varied widely from 0 (n = 2) to 12000?IU/wk (n = 5). In conclusion, postdialysis cholecalciferol prescription is quite effective in correcting vitamin D deficiency/insufficiency, but the amount of cholecalciferol needed to maintain the 25(OH)D levels within the optimal range over the long-term varies widely among patients and must be individualized. PMID:24579049

  3. Oral Postdialysis Cholecalciferol Supplementation in Patients on Maintenance Hemodialysis: A Dose-Response Approach

    PubMed Central

    Fellay, Benoit; Hemett, Ould Maouloud; Magnin, Jean-Luc; Fellay, Gilbert

    2014-01-01

    The aim of the present study was to evaluate the dose of postdialysis cholecalciferol needed to maintain the 25-hydroxyvitamin D [25(OH)D] levels in the optimal range of 75–150?nmol/L. Twenty-six patients who had low baseline 25(OH)D levels (mean 27.5 ± 14.9?nmol/L) were studied. The 25(OH)D levels were measured every 2 months for one year. During the first two months, all the patients received 2000?IU of cholecalciferol after each hemodialysis (=6000?IU/wk). Thereafter, the dose was individualized and adapted every 2 months by administering 1 to 6 cholecalciferol tablets (2000?IU each) per week (total weekly dose = 2000–12000?IU/wk). During cholecalciferol supplementation, the 25(OH)D concentrations rapidly increased from baseline to 140.1 ± 28.3?nmol/L at month 6 and 95.6 ± 20.9?nmol/L at month 12. At month twelve, 86% of the patients had 25(OH)D levels within the target range with a mean dose of 5917 ± 4106?IU/wk of cholecalciferol; however, the amount needed to maintain these levels varied widely from 0 (n = 2) to 12000?IU/wk (n = 5). In conclusion, postdialysis cholecalciferol prescription is quite effective in correcting vitamin D deficiency/insufficiency, but the amount of cholecalciferol needed to maintain the 25(OH)D levels within the optimal range over the long-term varies widely among patients and must be individualized. PMID:24579049

  4. Low-dose oral lorazepam administration in Alzheimer subjects and age-matched controls

    Microsoft Academic Search

    Trey Sunderland; Herbert Weingartner; Robert M. Cohen; Pierre N. Tariot; Paul A. Newhouse; Karen E. Thompson; Brian A. Lawlor; Edward A. Mueller

    1989-01-01

    Ten patients with Alzheimer's disease and ten age-matched normal controls were studied in a double-blind, placebo-controlled acute trial of 1 mg PO lorazepam to test the effects of low-dose benzodiazepine on memory and behavior in a mostly older population. Cognitive effects differed somewhat between Alzheimer patients and normal controls, with Alzheimer patients revealing predominantly “attentional” impairments and age-matched controls showing

  5. Prescription Opioids. III. Disposition of Oxycodone in Oral Fluid and Blood Following Controlled Single-Dose Administration.

    PubMed

    Cone, Edward J; DePriest, Anne Z; Heltsley, Rebecca; Black, David L; Mitchell, John M; LoDico, Charles; Flegel, Ron

    2015-04-01

    Oxycodone (OC) is recommended to be included as an analyte tested in the proposed Substance Abuse and Mental Health Services Administration (SAMHSA's) Mandatory Guidelines for Federal Workplace Drug Testing Programs using Oral Fluid (OF) Specimens. This study demonstrates the time course of OC and metabolites, noroxycodone (NOC), oxymorphone (OM) and noroxymorphone (NOM), in near-simultaneous paired OF and whole blood (BL) specimens by liquid chromatography-tandem mass spectrometry (LC-MS-MS) (limit of detection = 1 ng/mL OF, 5 ng/mL BL). A single dose of OC 20 mg controlled-release was administered to 12 healthy subjects followed by specimen collections for 52 h. Analyte prevalence was as follows: OF, OC > NOC > OM; and BL, OC > NOC > NOM. OC and NOC were frequently detected within 15-30 min in OF and 30 min to 2 h in BL. NOM and OM appeared between 1.5-5 h post-dose. The mean OF-to-BL (OF:BL) ratios and correlations were 5.4 for OC (r = 0.719) and 1.0 for NOC (r = 0.651). The period of detection for OF exceeded BL by ?2-fold at similar cutoff concentrations. At a 1 ng/mL cutoff for OF, the mean detection time was 34 h for OC and NOC. These data provide new information that should facilitate interpretation of OC test results. PMID:25589778

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

    PubMed Central

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

    2003-01-01

    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

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

    PubMed

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

    2013-09-01

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

  8. Comparison of Serum Ethinyl Estradiol, Sex-Hormone-Binding Globulin, Corticoid-Binding Globulin and Cortisol Levels in Women Using Two Low-Dose Combined Oral Contraceptives

    Microsoft Academic Search

    M. Hümpel; U. Täuber; W. Kuhnz; M. Pfeffer; K. Brill; R. Heithecker; T. Louton; B. Steinberg

    1990-01-01

    The study included 69 women taking a desogestrel (n = 30)- or gestodene (n = 39)-containing low-dose combined oral contraceptive for at least 3 months. Group size was calculated to detect a difference in mean values of 80% of 1 standard deviation (? = 0.05, ? = 0.1). Seven serum samples were obtained up to 4 h, and 1 sample

  9. 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

    Lawrence C Hookey; William T Depew; Stephen J Vanner

    2004-01-01

    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

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

    Microsoft Academic Search

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

    1981-01-01

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

  11. Oral High Dose Dexamethasone for Pure Red Cell Aplasia Following ABO-Mismatched Allogeneic Peripheral Blood Stem Cell Transplantation: A Case Report.

    PubMed

    Sharma, Sanjeev Kumar; Kumar, Suman; Agrawal, Narendra; Mishra, Pravas; Seth, Tulika; Mahapatra, Manoranjan

    2015-06-01

    Management of pure red cell aplasia following major ABO-mismatched hematopoietic stem cell transplantation is a therapeutic challenge. Various therapeutic modalities have been tried with variable responses, and patient remains transfusion dependent for a long time. We report here the use of pulsed oral high dose dexamethasone for pure red cell aplasia following ABO-mismatched allogeneic transplant with complete recovery. PMID:25825583

  12. Long-term follow-up analysis of zolpidem in fingernails after a single oral dose.

    PubMed

    Hang, Chen; Ping, Xiang; Min, Shen

    2013-09-01

    The determination of xenobiotics in keratinized matrices, such as nails and hair, has received considerable attention because of the relatively long detection window for compounds. The distribution of xenobiotics in fingernails, unlike hair, was equivocal. The main aim of this study was to use follow-up surveys to measure zolpidem profiles in nails after subjects consumed a single dose of the drug. In addition, the zolpidem concentrations in nails were compared with data for different biosamples, such as hair and blood from previous work. With these preconditions, a high-performance liquid chromatography-tandem mass spectrometry method was developed and validated for the determination of zolpidem in nails. Nails underwent alkaline hydrolysis and were extracted with diethyl ether. A Capcell Pak C18 MGII column was used to separate the target compound, and an API 4000 Qtrap mass spectrometer was used as a detector. The results for nail samples from seven subjects who had taken a single 10 mg zolpidem dose were significant: two relatively high zolpidem concentrations were observed in the long-term follow-up analysis of nails. The zolpidem concentration was less than 1.74 pg/mg and less than 3.29 pg/mg in fingernails and toenails, respectively. The subsequent peak concentration of zolpidem was observed between 10 and 15 weeks after each subject took a single dose of the drug. This result suggested that the germinal matrix area was a primary in vivo pathway for zolpidem secretion into the nail. The analysis of biosamples, such as nails, may be a useful adjunct to conventional methods of drug testing and hair analysis. Further research is needed concerning the contamination risk in analysis of nail biosamples. PMID:23857143

  13. The pharmacokinetics of C-glycosyl flavones of Hawthorn leaf flavonoids in rat after single dose oral administration.

    PubMed

    Ma, L Y; Liu, R H; Xu, X D; Yu, M Q; Zhang, Q; Liu, H L

    2010-07-01

    Hawthorn leaf flavonoids (HLF) are used in the treatment of cardiovascular diseases. Various potential pharmacodynamic effects have been observed for vitexin-4''-O-glucoside (VOG) and vitexin-2''-O-rhamnoside (VOR) which are the main constituents of HLF. The aim of this study was to investigate the pharmacokinetics of VOG and VOR when a single dose of HLF was administrated orally. The levels of VOG and VOR in plasma, tissues (heart, liver, spleen, lung, kidney and brain), bile, urine and feces were measured by HPLC-UV. The results showed that VOG and VOR have the similar pharmacokinetics. Both of them were absorbed quickly into plasma with maximal plasma concentrations of VOG and VOR being reached within 0.75 h. The mean elimination half-life (t(1/2)) of VOG and VOR were 2.53 h and 2.32 h, respectively. High levels of tissue distribution of VOG and VOR were observed in liver and kidney. No VOG and VOR were detected in brain tissue. There was no long-term accumulation of VOG and VOR in rat tissues examined. The total recovery of the dose in 24 hours was 64.91% (0.70% in urine; 64.21% in feces) for VOG and 89.01% (0.72% in urine; 88.29% in feces) for VOR. The cumulative VOG and VOR excreted in bile represented 0.58% and 13.38% of the doses, respectively. VOG and VOR in HLF were not efficiently absorbed in the rodent gastrointestinal tract. PMID:20096549

  14. Evaluating the enantioselective degradation and novel metabolites following a single oral dose of metalaxyl in mice.

    PubMed

    Zhang, Ping; Zhu, Wentao; Qiu, Jing; Wang, Dezhen; Wang, Xinru; Wang, Yao; Zhou, Zhiqiang

    2014-11-01

    Metalaxyl [N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D,L-alaninemethylester] is a systemic fungicide widely used in agriculture. In this study, the enantioselective distribution, degradation and excretion of metalaxyl were investigated after oral gavage administration of rac-metalaxyl to mice. Concentration of metalaxyl and its enantiomers was determined by HPLC-MS/MS. The results showed that R-metalaxyl was much higher than S-metalaxyl in heart, liver, lung, urine and feces. As for the strong first pass effect, concentrations of metalaxyl in liver were much higher than those in other tissues. The total body clearance (CL) of metalaxyl in mice was 1.77?L?h(-1?)kg(-1) and degradation half-lives of (t1/2) of S-metalaxyl and R-metalaxyl in liver were 2.2?h and 3.0?h, respectively. Such results indicated the enantioselectivity of metalaxyl lies in distribution, degradation and excretion processes in mice. Main metabolites were also determined and biotransformation reactions were hydroxylation, demethylation and didemethylation. Furthermore, metabolite concentrations in urine and feces were much higher than those in tissues. These results may have potential implications to predict toxicity and provide additional information associated with adverse health effects for risk assessment of metalaxyl. PMID:25454518

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

    PubMed Central

    2011-01-01

    Background The cysteine proteinases in papaya latex have been shown to have potent anthelmintic properties in monogastric hosts such as rodents, pigs and humans, but this has not been demonstrated in ruminants. Methods In two experiments, sheep were infected concurrently with 5,000 infective larvae of Haemonchus contortus and 10,000 infective larvae of Trichostrongylus colubriformis and were then treated with the supernatant from a suspension of papaya latex from day 28 to day 32 post-infection. Faecal egg counts were monitored from a week before treatment until the end of the experiment and worm burdens were assessed on day 35 post-infection. Results We found that the soluble fraction of papaya latex had a potent in vivo effect on the abomasal nematode H. contortus, but not on the small intestinal nematode T. colubriformis. This effect was dose-dependent and at tolerated levels of gavage with papaya latex (117 ?mol of active papaya latex supernatant for 4 days), the H. contortus worm burdens were reduced by 98%. Repeated treatment, daily for 4 days, was more effective than a single dose, but efficacy was not enhanced by concurrent treatment with the antacid cimetidine. Conclusions Our results provide support for the idea that cysteine proteinases derived from papaya latex may be developed into novel anthelmintics for the treatment of lumenal stages of gastro-intestinal nematode infections in sheep, particularly those parasitizing the abomasum. PMID:21406090

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

    PubMed

    Guzman, David Sanchez-Migallon; Beaufrère, Hugues; KuKanich, Butch; Barker, Steven A; Brandão, João; Paul-Murphy, Joanne; Tully, Thomas N

    2014-06-01

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

  17. ?-Tocopherol abolishes postprandial increases in plasma methylglyoxal following an oral dose of glucose in healthy, college-aged men.

    PubMed

    Masterjohn, Christopher; Mah, Eunice; Guo, Yi; Koo, Sung I; Bruno, Richard S

    2012-03-01

    Postprandial hyperglycemia contributes to the risk of cardiovascular disease in part by increasing concentrations of the reactive dicarbonyl methylglyoxal (MGO), a byproduct of glucose metabolism. Oxidative stress increases MGO formation from glucose in vitro and decreases its glutathione-dependent detoxification to lactate. We hypothesized that the antioxidant ?-tocopherol, a form of vitamin E, would decrease hyperglycemia-mediated postprandial increases in plasma MGO in healthy, normoglycemic, college-aged men. Participants (n=12 men; 22.3±1.0 years; 29.3±2.4 kg/m(2)) received an oral dose of glucose (75 g) in the fasted state prior to and following 5-day ingestion of a vitamin E supplement enriched in ?-tocopherol (500 mg/day). ?-Tocopherol supplementation increased (P<.0001) plasma ?-tocopherol from 2.22±0.32 to 7.06±0.71 ?mol/l. Baseline MGO concentrations and postprandial hyperglycemic responses were unaffected by ?-tocopherol supplementation (P>.05). Postprandial MGO concentrations increased in the absence of supplemental ?-tocopherol (P<.05), but not following ?-tocopherol supplementation (P>.05). Area under the curve for plasma MGO was significantly (P<.05) smaller with the supplementation of ?-tocopherol than without (area under the curve (0-180 min), -778±1010 vs. 2277±705). Plasma concentrations of ?-carboxyethyl-hydroxychroman, reduced glutathione and markers of total antioxidant capacity increased after supplementation, and these markers and plasma ?-tocopherol were inversely correlated with plasma MGO (r=-0.48 to -0.67, P<.05). These data suggest that short-term supplementation of ?-tocopherol abolishes the oral glucose-mediated increases in postprandial MGO through its direct and indirect antioxidant properties and may reduce hyperglycemia-mediated cardiovascular disease risk. PMID:21543210

  18. Florfenicol residues in rainbow trout after oral dosing in recirculating and flow-through culture systems.

    PubMed

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

    2014-12-01

    Aquaflor is a feed premix for fish containing the broad spectrum antibacterial agent florfenicol (FFC) incorporated at a ratio of 50% (w/w). To enhance the effectiveness of FFC for salmonids infected with certain isolates of Flavobacterium psychrophilum causing cold water 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. PMID:25321636

  19. Bioavailability study of two carbamazepine containing sustained release formulations after multiple oral dose administration.

    PubMed

    Wangemann, M; Retzow, A; Evers, G; Mazur, D; Schug, B; Blume, H

    1998-12-01

    Carbamazepine (CAS 298-46-4), an iminostilbene derivative and a structural congener of the tricyclic antidepressant drugs, has been used in the treatment of epileptic seizures since 1963. The bioavailability/bioequivalence of a carbamazepine sustained release formulation (Timonil retard) was compared with a reference formulation in an open 2-period crossover study in 21 healthy male volunteers (including 1 drop-out) after multiple dose administration. During a run-in phase of 6 days the daily dose was gradually increased from 100 to 400 mg. On days 9 to 15, either the test or the reference formulation was administered twice daily, followed by a switch of preparation for a further 7 days of treatment (days 16 to 22). On the pharmacokinetic profiling days 15 and 22 blood samples were drawn over a 24-h period. In addition, blood samples were withdrawn before morning administrations for determination of carbamazepine and carbamazepine-10,11-epoxide trough values. Plasma concentrations of carbamazepine and its metabolite carbamazepine-10,11-epoxide were determined using a specific and sensitive HPLC method with UV detection. The results showed that autoinduction of carbamazepine metabolism under the chosen dosage regimen was complete within 14 days after start of treatment and that the criteria for bioequivalence were met. The 90% confidence intervals of all ratios were included by a range of 80-125% (AUC0-12: 103-120; AUC12-24: 105-119; Cmax0-12: 104-118; Cmax12-24: 104-118). During the study, 12 subjects experienced a total of 24 adverse events with mild to moderate intensity. Due to a significant increase of liver enzyme activity in serum during the course of the study, one subject was excluded from further study participation. There were no serious adverse events. It was concluded that the test formulation is bioequivalent to the reference formulation with respect to rate and extent of absorption. PMID:9893926

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

    USGS Publications Warehouse

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

    2014-01-01

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

  1. Repeat dose study of the novel proapoptotic chemotherapeutic agent alpha-tocopheryloxy acetic acid in mice.

    PubMed

    Hahn, Tobias; Akporiaye, Emmanuel T

    2012-04-01

    Alpha-tocopheryloxy acetic acid (?-TEA) is an ether derivative of vitamin E and has been shown to suppress tumor growth in various murine and human xenograft tumor models, including melanoma, breast, lung, prostate, and ovarian cancers. The purpose of this study was to assess its safety and pharmacokinetics after repeat dosing in a preclinical murine model. Male and female mice received ?-TEA doses of 100, 300, or 1500 mg/kg/day by daily oral gavage for 28 days. ?-TEA serum levels were determined weekly by high-performance liquid chromatography with mass spectrometric detection. After 28 days of dosing, complete blood counts were taken, blood chemistry was analyzed, and histology was performed. Pharmacokinetic parameters were determined after single dosing. There was no mortality, and we found no clinical signs of toxicity in any of the ?-TEA doses tested. Histopathological evaluation of major organs (heart, lung, kidney, liver, spleen, jejunum, ileum, and cecum) revealed no significant ?-TEA treatment-related lesions. Blood counts revealed low-grade anemia but no other significant differences between treatment and control groups. Blood chemistry revealed moderate liver toxicity that was dose dependent and was absent in the lowest dose group. There were no significant sex-specific differences in the toxicity profile. The half-life of orally administered ?-TEA was determined to be 52 h. This is the first report comprehensively evaluating the toxicity profile of this novel anticancer drug and will facilitate the design of clinical trials to evaluate the safety and antitumor efficacy of ?-TEA in patients with cancer. PMID:22185820

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

    PubMed Central

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

    2014-01-01

    Study Objective: To evaluate multiple doses of gabapentin 250 mg on polysomnography (PSG) and participant-reported sleep assessments in a 5-h phase advance insomnia model. Methods: Adults reporting occasional disturbed sleep received gabapentin 250 mg (n = 128) or placebo (n = 128). On Days 1 and 28, participants received medication 30 min before bedtime and were in bed from 17:00 to 01:00, ?5 h before their habitual bedtime. Sleep was assessed by PSG, a post sleep questionnaire, and the Karolinska Sleep Diary. Next-day residual effects and tolerability were evaluated. On Days 2-27, participants took medication at home 30 min before their habitual bedtime. Results: Treatment-group demographics were comparable. Gabapentin resulted in significantly less PSG wake after sleep onset (WASO) compared with placebo on Day 1 (primary endpoint, mean: 107.0 versus 149.1 min, p ? 0.001) and Day 28 (113.6 versus 152.3 min, p = 0.002), and significantly greater total sleep time (TST; Day 1: 347.6 versus 283.9 min; Day 28: 335.3 versus 289.1 min) (p ? 0.001). Participant-reported WASO and TST also showed significant treatment effects on both days. Gabapentin was associated with less %stage1 on Day 1, and greater %REM on Day 28, versus placebo. During home use, gabapentin resulted in significantly less participant-reported WASO and higher ratings of sleep quality. Gabapentin was well tolerated (most common adverse events: headache, somnolence) with no evidence of next-day impairment. Conclusion: Gabapentin 250 mg resulted in greater PSG and participant-reported sleep duration following a 5-h phase advance on Day 1 and Day 28 of use without evidence of next-day impairment, and greater sleep duration during at-home use. Citation: Furey SA, Hull SG, Leibowitz MT, Jayawardena S, Roth T. A randomized, double-blind, placebo-controlled, multicenter, 28-day, polysomnographic study of gabapentin in transient insomnia induced by sleep phase advance. J Clin Sleep Med 2014;10(10):1101-1109. PMID:25317091

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

    SciTech Connect

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

    1983-06-30

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

  4. Enhancement of energy expenditure following a single oral dose of flavan-3-ols associated with an increase in catecholamine secretion.

    PubMed

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

    2014-01-01

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

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

    PubMed Central

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

    2014-01-01

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

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

    PubMed

    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

    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

  7. Assessment of Oral Toxicity and Safety of Pentamethylchromanol (PMCol), A Potential Chemopreventative Agent, in Rats and Dogs

    PubMed Central

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

    2010-01-01

    2,2,5,7,8-pentamethyl-6-chromanol (PMCol) was administered by gavage in rats for 28 days at dose levels of 0, 100, 500, and 2000 mg/kg/day. PMCol administration induced decreases in body weight gains and food consumption, hepatotoxicity (increased TBILI, ALB, ALT, TP; increased relative liver weights; increased T4 and TSH), nephrotoxicity (increased BUN and BUN/CREAT, histopathology lesions), effect on lipid metabolism (increased CHOL), anemia, increase in WBC counts (total and differential), coagulation (FBGN?and PT?) and hyperkeratosis of the nonglandular stomach in the 2000 mg/kg/day dose group (in one or both sexes). In the 500 mg/kg/day dose group, toxicity was seen to a lesser extent. In the 100 mg/kg/day dose group, only increased CHOL (females) was observed. To assess the toxicity of PMCol in male dogs it was administered orally by capsule administration for 28 days at dose levels of 0, 50, 200 and 800 mg/kg/day (4 male dogs/dose group). PMCol treatment at 800 mg/kg/day resulted in pronounced toxicity to the male dogs. Target organs of toxicity were liver and thymus. Treatment at 200 mg/kg/day resulted in toxicity consistent with slight adverse effect on the liver only. The results of the safety pharmacology study indicate that doses of 0, 50, 200 and 800 mg/kg administered orally did not have an effect on the QT interval, blood pressures and body temperatures following dosing over a 24-hour recording period. Under the conditions of this study, the no-observed-adverse effect level (NOAEL) for daily oral administration of PMCol by gavage for 28 days to male rats was 100 mg/kg/day and 50 mg/kg in male dogs. In female rats, the NOAEL was not established due to statistically significant and biologically meaningful increases in CHOL level seen in the 100 mg/kg/day dose group. The results of these studies indicated that administration of PMCol at higher dose levels resulted in severe toxicity in dogs and moderate toxicity in rats, however, administration at lower levels is considered to be less likely to result in toxicity following 28 days of exposure. Sex-related differences were seen in rats. Male rats appeared to have greater sensitivity to nephrotoxicity, while female animals had a greater incidence of hepatoxicity and changes in hematological parameters evaluated, especially at a dose of 500 mg/kg/day, which correlated to the higher plasma drug levels in female rats. It appeared that dogs were generally more sensitive than rats to oral administration of PMCol. Further examination of the potential toxic effects of PMCol in longer term studies is required prior to understanding the full risks of PMCol administration as a chemopreventative agent. PMID:20430063

  8. A Single Dose of Oral BCG Moreau Fails to Boost Systemic IFN-? Responses to Tuberculin in Children in the Rural Tropics: Evidence for a Barrier to Mucosal Immunization.

    PubMed

    Vaca, Maritza; Moncayo, Ana-Lucia; Cosgrove, Catherine A; Chico, Martha E; Castello-Branco, Luiz R; Lewis, David J; Cooper, Philip J

    2012-01-01

    Immune responses to oral vaccines are impaired in populations living in conditions of poverty in developing countries, and there is evidence that concurrent geohelminth infections may contribute to this effect. We vaccinated 48 children living in rural communities in Ecuador with a single oral dose of 100?mg of BCG Moreau RDJ and measured the frequencies of tuberculin-stimulated peripheral blood mononuclear cells expressing IFN-? before and after vaccination. Vaccinated children had active ascariasis (n = 20) or had been infected but received short- (n = 13) or long-term (n = 15) repeated treatments with albendazole prior to vaccination to treat ascariasis. All children had a BCG scar from neonatal vaccination. There was no evidence of a boosting of postvaccination IFN-? responses in any of the 3 study groups. Our data provide support for the presence of a barrier to oral vaccination among children from the rural tropics that appeared to be independent of concurrent ascariasis. PMID:22287972

  9. Effects of food and gender on the pharmacokinetics of rhein and emodin in rats after oral dosing with Da-Cheng-Qi decoction.

    PubMed

    Gong, HanLin; Tang, WenFu; Wang, Hong; Xia, Qing; Huang, Xi

    2011-01-01

    Da-Cheng-Qi decoction (DCQD), a traditional Chinese medicine preparation used to treat digestive diseases, is composed of dahuang (Rheum officinale Baill, Polygonaceae), houpu (Magnolia officinalis Rehd., Magnoliaceae), zhishi (Citrus aurantium L, Rutaceae) and mangxiao (sodium sulphate). Rhein and emodin are the major active components of Rheum officinale Baill. To investigate the effects of food and gender on the plasma concentrations of rhein and emodin after oral administration of DCQD, a rapid high-performance liquid chromatographic method was developed and validated. A reversed phase C(18) column (150 × 4.6?mm) and a mobile phase of methanol and 0.2% acetic acid (78:22, v/v) were employed with ultraviolet detection at 254?nm. Feeding was observed to decrease the absorption of rhein and emodin in rats receiving DCQD orally. No evidence for gender-based differences in the pharmacokinetics of rhein was observed. However, the half-life and area under the concentration-time curve for emodin differed significantly between male and female rats. Because food intake and gender are anticipated to influence the pharmacokinetics of DCQD in human subjects, it is recommended that oral doses of DCQD be reduced in fasting subjects and that female patients receive lower oral doses compared with male patients. PMID:20623608

  10. Effects of a MATE Protein Inhibitor, Pyrimethamine, on the Renal Elimination of Metformin at Oral Microdose and at Therapeutic Dose in Healthy Subjects

    Microsoft Academic Search

    H Kusuhara; S Ito; Y Kumagai; M Jiang; T Shiroshita; Y Moriyama; K Inoue; H Yuasa; Y Sugiyama

    2011-01-01

    A microdose study of metformin was conducted to investigate the predictability of drug–drug interactions at the therapeutic dose (ThD). Healthy subjects received a microdose (100 µg) or ThD (250 mg) of metformin orally, with or without a potent and competitive multidrug and toxin extrusion (MATE) inhibitor, pyrimethamine (50 mg, p.o.), in a crossover fashion. Pyrimethamine significantly reduced the renal clearance

  11. Toxicity of weekly oral topotecan in relation to dosage for gynecologic malignancies: a phase I study.

    PubMed

    von Gruenigen, Vivian E; Frasure, Heidi E; Smith, Deborah A; Fusco, Nancy L; Eaton, Susan M; DeBernardo, Robert L; Heugel, Anne M; Waggoner, Steven E

    2012-08-01

    The aim of this study was to determine the dose of weekly oral topotecan that allows safe administration and to evaluate the pharmacokinetics of this dose in patients with recurrent gynecologic malignancies. The first cohort of patients received oral topotecan 6 mg/week administered orally on days 1, 8, and 15 of a 28-day regimen. A standard 3+3 dose-escalating phase design was used for dose levels II-V (8, 10, 12 and 14 mg/week). Toxicity was scored according to the Common Terminology Criteria for Adverse Events. Cumulative toxicity was summarized in the 6-12 mg/week combined cohort and 14 mg/week cohort separately. Pharmacokinetic samples were obtained for day 1, cycle 1 only in the expansion cohort (dose level V). Twenty-five patients received a total of 88 cycles of therapy. Hematologic toxicities of grade 3 (6-12 mg dose) were neutropenia (25%) and anemia (8.3%). Gastrointestinal toxicities of grade 3 were diarrhea (16.7%) and obstruction (8.3%, disease-related). Grade 3 or 4 (14 mg/week) hematologic toxicities consisted of neutropenia (38.5%), platelets (15.4%), anemia (15.4%), infection with neutropenia (7.7%), and thrombosis (7.7%). Gastrointestinal toxicities of grade 3 were diarrhea (7.7%), obstruction (7.7%), and vomiting (7.7%). One patient died secondary to neutropenic sepsis. One patient (4%; 95% confidence interval: 2.1, 22.3) showed a partial response and five patients (20%; 95% confidence interval: 7.6, 41.3) had stable disease. An oral topotecan dose of 14 mg/week for 3 consecutive weeks out of 4 is mostly associated with acceptable toxicities and may be considered for use in future single-agent phase II trials. PMID:22555194

  12. Comparison of therapeutic effect of low-dose low-molecular-weight heparin (enoxaparin) vs. oral prednisone in treatment of patients with lichen planus; A clinical trial

    PubMed Central

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

    2013-01-01

    Background: The aim of this study was to evaluate and compare the therapeutic efficacy of subcutaneous enoxaparin versus oral prednisone (as a standard treatment) in patients with disseminated lichen planus. Materials and Methods: In this parallel randomized clinical trial study, overall 48 patients completed the study. 25 patients were treated with subcutaneous enoxaparin 5 mg weekly and 23 patients with 0.5 mg/kg prednisone orally daily until complete remission or a maximum of 8 weeks. The results of itching severity, extent of active lesions and drug side effects were compared. In remission, patients were followed for 6 months for recurrent lesions. Results: In enoxaparin group, 8 patients (32%) had complete remission and 10 patients (40%) had partial improvement. In the oral prednisone group, 16 patients (69.6%) had complete remission and 6 patients (26.1%) had partial improvement (P = 0.005). Average size of active lesions in both groups decreased significantly after treatment, but analysis of covariance showed that the mean lesion size after treatment in the oral prednisone group was significantly lower than the enoxaparin group (P = 0.005). The relapse rate from improved patients in the enoxaparin group was 6 (33%) and in oral prednisone group was 9 (40.9%, P = 0.083). In the enoxaparin group no serious complications was seen. But 22% in the oral prednisone group show side effect, the most common complications were dyspepsia. Conclusion: Low dose enoxaparin on lichen Planus have therapeutic effect and is important for the least side effects but not as much as oral prednisone. But it could be accepted as an alternative treatment. PMID:24223391

  13. Sublinear response in lacZ mutant frequency of Muta(™) Mouse spermatogonial stem cells after low dose subchronic exposure to N-ethyl-N-nitrosourea.

    PubMed

    O'Brien, Jason M; Walker, Mike; Sivathayalan, Ahalya; Douglas, George R; Yauk, Carole L; Marchetti, Francesco

    2015-05-01

    The transgenic rodent mutation assay was used to compare the dose-response relationship of lacZ mutant frequency (MF) in spermatogonial stem cells exposed acutely or subchronically to N-ethyl-N-nitrosourea (ENU). Muta(™) Mouse males were exposed orally to 0, 25, 50, or 100 mg/kg ENU for acute exposures and 0, 1, 2, or 5 mg/(kg day) for 28-day subchronic exposures. LacZ MF was measured in sperm collected 70 days post-exposure to target spermatogonial stem cells. Dose-response data were fit to linear, quadratic, exponential, or power models. Acute exposure resulted in a dose-dependent increase in MF that was significant (P?doses tested and was best described by a quadratic dose-response model that was linear in the low dose range. In contrast, similar total doses fragmented over a 28-day subchronic exposure only resulted in a significant increase in lacZ MF at the highest dose tested. Therefore, the subchronic no observable genotoxic effect level (NOGEL) was 2 mg/(kg day) (or 56 mg/kg total dose). The subchronic dose-response was best described by the exponential and power models, which were sublinear in the low dose range. Benchmark dose lower confidence limits (BMDLs) for acute and subchronic exposure were 3.0 and 1.0 mg/(kg day) (or 27.4 mg/kg total dose), respectively. These findings are supportive of a saturable DNA repair mechanism as the mutagenic mode of action for ENU in spermatogonia and imply that sufficiently low exposures would not cause appreciable genotoxic effects over background. This may have important implications for the quantitative risk assessment of germ cell mutagens. Environ. Mol. Mutagen. 56:347-355, 2015. © 2015 The Authors. Environmental and Molecular Mutagenesis Published by Wiley Periodicals, Inc. PMID:25598316

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

    PubMed

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

    2014-07-01

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

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

    PubMed

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

    2013-09-01

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

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

    PubMed

    Stockis, Armel; Rolan, Paul

    2013-12-01

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

  17. Studies on combined effects of organophosphates and heavy metals in birds. I. Plasma and brain cholinesterase in Coturnix quail fed methyl mercury and orally dosed with parathion

    USGS Publications Warehouse

    Dieter, M.P.; Ludke, J.L.

    1975-01-01

    We found that mercury potentiated the toxicity and biochemical effects of parathion. Male Coturnix quail (Coturnix coturnix japonica) were fed a sublethal concentration of morsodren (4 ppm as methyl mercury) for 18 weeks. This resulted in an accumulation of 21.0 ppm of mercury in the liver and 8.4 ppm in the carcass. Birds fed clean feed and those fed morsodren-treated feed were orally dosed with 2, 4, 6, 8,and 10 mg/kg parathion, and their 48-h survival times compared. The computed LD50 was 5.86mg/kg in birds not fed morsodren and 4.24 in those fed the heavy metal. When challenged with a sublethal, oral dose of parathion (1.0 mg/kg), morsodren-fed birds exhibited significantly greater inhibition of plasma and brain cholinesterase activity than controls dosed with parathion. Brain cholinesterase activity was inhibited 41% in morsodren-fed birds and 26in clean-fed birds dosed with parathion, which suggested that the increase in parathion toxicity in the presence of morsodren was directly related to the inhibitation of brain cholinesterase.

  18. Pharmacokinetics and Pharmacodynamics of Oral Testosterone Enanthate Plus Dutasteride for 4 Weeks in Normal Men: Implications for Male Hormonal Contraception

    PubMed Central

    AMORY, JOHN K.; KALHORN, THOMAS F.; PAGE, STEPHANIE T.

    2009-01-01

    Oral administration of testosterone enanthate (TE) and dutasteride increases serum testosterone and might be useful for male hormonal contraception. To ascertain the contraceptive potential of oral TE and dutasteride by determining the degree of gonadotropin suppression mediated by 4 weeks of oral TE plus dutasteride, 20 healthy young men were randomly assigned to 4 weeks of either 400 mg oral TE twice daily or 800 mg oral TE once daily in a double-blinded, controlled fashion at a single site. All men received 0.5 mg dutasteride daily. Blood for measurement of serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone, dihydrotesterone (DHT), and estradiol was obtained prior to treatment, weekly during treatment, and 1, 2, 4, 8, 12, 13, 14, 16, 20, and 24 hours after the morning dose on the last day of treatment. FSH was significantly suppressed throughout treatment with 800 mg TE once daily and after 4 weeks of treatment with 400 mg TE twice daily. LH was significantly suppressed after 2 weeks of treatment with 800 mg TE, but not with 400 mg TE. Serum DHT was suppressed and serum estradiol increased during treatment in both groups. High-density lipoprotein cholesterol was suppresed during treatment, but liver function tests, hematocrit, creatinine, mood, and sexual function were unaffected. The administration of 800 mg oral TE daily combined with dutasteride for 28 days significantly suppresses gonadotropins without untoward side effects and might have utility as part of a male hormonal contraceptive regimen. PMID:18046048

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

    PubMed Central

    Liu, Ping; Fang, Annie F.; LaBadie, Robert R.; Crownover, Penelope H.; Arguedas, Adriano G.

    2011-01-01

    An azithromycin extended-release (ER) oral suspension was developed to improve the gastrointestinal tolerability profile without substantially compromising systemic exposure. A single dose of 30 mg/kg azithromycin immediate-release (IR) oral suspension has been used in children to treat acute otitis media (AOM). This study was conducted to compare the pharmacokinetics of a 60-mg/kg azithromycin ER single dose with a 30-mg/kg azithromycin IR single dose in children with AOM aged 6 months to 6 years (n = 19 per treatment). Serum samples were collected at 1, 2, 3, 4, 8, 24, 48, and 72 h after dosing. The area under the curve from time zero to 72 h postdosing (AUC0-72) was calculated based on a noncompartmental method. One-way analysis of variance (ANOVA) was used to compare exposure parameters (e.g., AUC0-72 and peak concentration) as well as concentrations at each time point. The adjusted geometric mean ratio of the ER/IR AUC0-72 was 157.98% (90% confidence interval [CI], 98.87%, 252.44%), which met the predefined criterion of the lower boundary of the 90% CI of ?80%. As expected, due to the slower-release profile of the ER formulation, the concentrations of the ER formulation during the first 3 h were lower than those of the IR formulation. After 3 h postdosing, the lower boundaries of the 90% CI for the ER/IR concentration ratios were greater than 100%. These results indicated that a 60-mg/kg single dose of ER azithromycin provides similar or greater systemic exposure in children than the 30-mg/kg single dose of IR azithromycin. PMID:21859932

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

    PubMed

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

    2011-05-01

    Efficient immunization against hepatitis B virus (HBV) and other pathogens with plant-based oral vaccines requires appropriate plant expressors and the optimization of vaccine compositions and administration protocols. Previous immunization studies were mainly based on a combination of the injection of a small surface antigen of HBV (S-HBsAg) and the feeding with raw tissue containing the antigen, supplemented with an adjuvant, and coming from plants conferring resistance to kanamycin. The objective of this study was to develop a prototype oral vaccine formula suitable for human immunization. Herbicide-resistant lettuce was engineered, stably expressing through progeny generation micrograms of S-HBsAg per g of fresh weight and formed into virus-like particles (VLPs). Lyophilized tissue containing a relatively low, 100-ng VLP-assembled antigen dose, administered only orally to mice with a long, 60-day interval between prime and boost immunizations and without exogenous adjuvant, elicited mucosal and systemic humoral anti-HBs responses at the nominally protective level. Lyophilized tissue was converted into tablets, which preserved S-HBsAg content for at least one year of room temperature storage. The results of the study provide indications on immunization methodology using a durable, efficacious, and convenient plant-derived prototype oral vaccine against hepatitis B. PMID:21107787

  1. A Double-Blind Randomized Controlled Study to Evaluate the Efficacy of Low-Dose Oral Interferon-Alpha in Preventing Hepatitis C Relapse

    PubMed Central

    Lee, Chuan-Mo; Chen, Chi-Yi; Chien, Rong-Nan; Tseng, Kuo-Chih; Peng, Cheng-Yuan; Tung, Shui-Yi; Fang, Yi-Jen; Huang, Yi-Hsiang; Lu, Sheng-Nan; Hung, Chao-Hung; Tsai, Tsung-Jang; Fang, Chien-Chung; Hsu, Chao-Wei

    2014-01-01

    Low-dose oral interferon could exert immune-modulating effects in human. We conducted a clinical trial to investigate the efficacy of oral interferon-alpha in preventing hepatitis C relapse. Totally 169 genotype 1b chronic hepatitis C patients having achieved end-of-therapy virological clearance were randomized to receive interferon-alpha lozenge 500?IU/day (n=59), 1,500?IU/day (n=53), or placebo (n=57) for 24 weeks. Overall, no significant differences were found for the relapse rates in the 3 groups (P>0.05). However, in patients with fibroindex 1.4–1.7, relapse occurred in 1/12 (8.3%) 500?IU-group patients versus 9/21 (42.9%) patients of the other groups (P=0.05). In 158 patients receiving at least 4 weeks of oral interferon, significantly higher platelet count was found at the end of trial in the 500?IU group (P=0.003). In thrombocytopenic patients, a significantly expedited recovery of platelet count was found in the 500?IU group (P=0.002). No drug-related severe adverse events were reported. In conclusion, at 500?IU/day, oral interferon exerted a borderline suppression effect of virological relapse in chronic hepatitis C patients with mild liver fibrosis. Additionally, it significantly expedited platelet count recovery after the end of peginterferon therapy. PMID:24237300

  2. A single-dose, randomized, open-label, two-period crossover bioequivalence study comparing a fixed-dose pediatric combination of lamivudine and stavudine tablet for oral suspension with individual liquid formulations in healthy adult male volunteers.

    PubMed

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

    2009-01-01

    Lamivudine (CAS 134678-17-4) is a synthetic nucleoside analogue with activity against HIV-1 and HBV. Stavudine (CAS 3056-17-5) is a synthetic thymidine nucleoside analogue, active against the human immunodeficiency virus (HIV). Lamivudine and stavudine in combination with other antiretroviral (ARV) agents are indicated for the treatment of HIV infection. As there are no suitable pediatric ARVs, adult fixed-dose ARVs are commonly used in children. This practice poses concerns about dose inaccuracy, which may lead to resistance or toxicity. A new fixed-dose combination (FDC) tablet for oral suspension, containing lamivudine 40 mg and stavudine 10 mg has been developed. An open-label, balanced, randomised, two-treatment, two-period, two-sequence, single-dose, crossover bioequivalence study was conducted following administration of a fixed-dose combination of lamivudine and stavudine tablet for oral suspension (test formulation) and innovator products (reference formulations) in healthy, adult, male human subjects under fasting condition. Multiple blood samples were collected up to 36 h post dose. Plasma concentrations of lamivudine and stavudine were assayed using validated high-performance liquid chromatography with mass spectrometry analytical method. Pharmacokinetic parameters were calculated using non-compartmental analysis and bioequivalence was assessed using a mixed effect ANOVA model. The ratio of the least-square means (FDC to individual products) and 90% confidence intervals (CIs) of AUC(0-t), AUC(0-infinity) and C(max) for lamivudine and stavudine were all within 80.00-125.00%, suggesting a similar rate and extent of ARVs exposure in the bloodstream. The FDC and individual products were equally safe and well tolerated. The current FDC of lamivudine and stavudine is expected to provide a similar efficacy/safety profile as co-administration of the individual products, a better adherence to treatment, and considerable cost savings in the treatment of HIV in children. PMID:19338141

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

    Microsoft Academic Search

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

    2009-01-01

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

  4. Risk of venous thromboembolism from use of oral contraceptives containing different progestogens and oestrogen doses: Danish cohort study, 2001-9

    PubMed Central

    2011-01-01

    Objective To assess the risk of venous thromboembolism from use of combined oral contraceptives according to progestogen type and oestrogen dose. Design National historical registry based cohort study. Setting Four registries in Denmark. Participants Non-pregnant Danish women aged 15-49 with no history of thrombotic disease and followed from January 2001 to December 2009. Main outcome measures Relative and absolute risks of first time venous thromboembolism. Results Within 8?010?290 women years of observation, 4307 first ever venous thromboembolic events were recorded and 4246 included, among which 2847 (67%) events were confirmed as certain. Compared with non-users of hormonal contraception, the relative risk of confirmed venous thromboembolism in users of oral contraceptives containing 30-40 µg ethinylestradiol with levonorgestrel was 2.9 (95% confidence interval 2.2 to 3.8), with desogestrel was 6.6 (5.6 to 7.8), with gestodene was 6.2 (5.6 to 7.0), and with drospirenone was 6.4 (5.4 to 7.5). With users of oral contraceptives with levonorgestrel as reference and after adjusting for length of use, the rate ratio of confirmed venous thromboembolism for users of oral contraceptives with desogestrel was 2.2 (1.7 to 3.0), with gestodene was 2.1 (1.6 to 2.8), and with drospirenone was 2.1 (1.6 to 2.8). The risk of confirmed venous thromboembolism was not increased with use of progestogen only pills or hormone releasing intrauterine devices. If oral contraceptives with desogestrel, gestodene, or drospirenone are anticipated to increase the risk of venous thromboembolism sixfold and those with levonorgestrel threefold, and the absolute risk of venous thromboembolism in current users of the former group is on average 10 per 10?000 women years, then 2000 women would need to shift from using oral contraceptives with desogestrel, gestodene, or drospirenone to those with levonorgestrel to prevent one event of venous thromboembolism in one year. Conclusion After adjustment for length of use, users of oral contraceptives with desogestrel, gestodene, or drospirenone were at least at twice the risk of venous thromboembolism compared with users of oral contraceptives with levonorgestrel. PMID:22027398

  5. Evaluation of Oral and IntravenousRoute Pharmacokinetics, Plasma Protein Binding and Uterine Tissue Dose Metrics of Bisphenol A: A Physiologically Based Pharmacokinetic Approach

    SciTech Connect

    Teeguarden, Justin G.; Waechter, John M.; Clewell, III, H. J.; Covington, Tammie R.; Barton, H. A.

    2005-06-01

    Bisphenol A (BPA) is a weakly estrogenic monomer used in the production of polycarbonate plastic and epoxy resins, both of which are used in food contact and other applications. A physiologically based pharmacokinetic (PBPK) model of BPA pharmacokinetics in rats and humans was developed to provide a physiological context in which the processes controlling BPA pharmacokinetics (e.g. plasma protein binding, enterohepatic recirculation of the glucuronide (BPAG)) could be incorporated. A uterine tissue compartment was included to allow the correlation of simulated ER binding of BPA with increases in uterine wet weight (UWW) in rats. Intravenous and oral-route blood kinetics of BPA in rats and oral-route plasma and urinary elimination kinetics in humans were well described by the model. Simulations of rat oral-route BPAG pharmacokinetics were less exact, most likely the result of oversimplification of the GI tract compartment. Comparison of metabolic clearance rates derived from fitting rat i.v. and oral-route data implied that intestinal glucuronidation of BPA is significant. In rats but not humans, terminal elimination rates were strongly influenced by enterohepatic recirculation. In the absence of BPA binding to plasma proteins, simulations showed high ER occupancy at doses without uterine effects. Restricting free BPA to the measured unbound amount demonstrated the importance of including plasma binding in BPA kinetic models: the modeled relationship between ER occupancy and UWW increases was consistent with expectations for a receptor mediated response with low ER occupancy at doses with no response and increasing occupancy with larger increases in UWW.

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

    PubMed

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

    2015-04-01

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

  7. Sex specific impact of perinatal bisphenol A (BPA) exposure over a range of orally administered doses on rat hypothalamic sexual differentiation

    PubMed Central

    McCaffrey, Katherine A.; Jones, Brian; Mabrey, Natalie; Weiss, Bernard; Swan, Shanna H.; Patisaul, Heather B.

    2013-01-01

    Bisphenol A (BPA) is a high volume production chemical used in polycarbonate plastics, epoxy resins, thermal paper receipts, and other household products. The neural effects of early life BPA exposure, particularly to low doses administered orally, remain unclear. Thus, to better characterize the dose range over which BPA alters sex specific neuroanatomy, we examined the impact of perinatal BPA exposure on two sexually dimorphic regions in the anterior hypothalamus, the sexually dimorphic nucleus of the preoptic area (SDN-POA) and the anterioventral periventricular (AVPV) nucleus. Both are sexually differentiated by estradiol and play a role in sex specific reproductive physiology and behavior. Long Evans rats were prenatally exposed to 10, 100, 1000, 10,000 mg/kg bw/day BPA through daily, noninvasive oral administration of dosed-cookies to the dams. Offspring were reared to adulthood. Their brains were collected and immunolabeled for tyrosine hydroxylase (TH) in the AVPV and calbindin (CALB) in the SDN-POA. We observed decreased TH-ir cell numbers in the female AVPV across all exposure groups, an effect indicative of masculinization. In males, AVPV TH-ir cell numbers were significantly reduced in only the BPA 10 and BPA 10,000 groups. SDN-POA endpoints were unaltered in females but in males SDN-POA volume was significantly lower in all BPA exposure groups. CALB-ir was significantly lower in all but the BPA 1000 group. These effects are consistent with demasculinization. Collectively these data demonstrate that early life oral exposure to BPA at levels well below the current No Observed Adverse Effect Level (NOAEL) of 50 mg/kg/day can alter sex specific hypothalamic morphology in the rat. PMID:23500335

  8. Type V Collagen-Induced Oral Tolerance Plus Low-Dose Cyclosporine Prevents Rejection of MHC Class I and II Incompatible Lung Allografts1

    PubMed Central

    Yamada, Yoshito; Sekine, Yasuo; Yoshida, Shigetoshi; Yasufuku, Kazuhiro; Petrache, Irina; Benson, Heather L.; Brand, David D.; Yoshino, Ichiro; Wilkes, David S.

    2010-01-01

    Autoimmunity to type V collagen (col(V)) is a major risk factor for lung allograft rejection. Although col(V)-induced oral tolerance abrogates rejection of minor histoincompatible lung transplants, its ability to prevent rejection of fully MHC incompatible lung allografts is unknown. Rat lung allografts fully incompatible at MHC class I and II loci (Brown Norway (RT1n)) were transplanted into untreated Wistar Kyoto rat recipients (WKY, RT1l), or WKY rats were fed col(V) pretransplantation. To determine whether col(V) enhanced cyclosporine (CsA)-mediated immune suppression, WKY rats were treated with low-dose CsA (5 mg/kg), post-transplant, or oral col(V) plus CsA. The data showed that in contrast to col(V) or CsA, col(V) plus low-dose CsA significantly prevented rejection pathology, down-regulated alloantigen-induced production of IFN-? and IL-17A, and suppressed chemotaxis for lung macrophages in allograft bronchoalveolar lavage fluid that was associated with lower local levels of MCP-1 (CCL2). Col(V) plus CsA was associated with alloantigen-induced expression of IL-10 in mediastinal lymph node or splenic T cells, intragraft expression of IL-10 and Foxp3 in perivascular and peribronchiolar mononuclear cells, and constitutive production of IL-10 from allograft alveolar macrophages. These data demonstrate that col(V) enhances low-dose CsA-mediated immune suppression, and suggest a role for oral col(V) in immune modulation in lung transplantation. PMID:19542435

  9. Food allergy population thresholds: an evaluation of the number of oral food challenges and dosing schemes on the accuracy of threshold dose distribution modeling.

    PubMed

    Klein Entink, Rinke H; Remington, Benjamin C; Blom, W Marty; Rubingh, Carina M; Kruizinga, Astrid G; Baumert, Joseph L; Taylor, Steve L; Houben, Geert F

    2014-08-01

    For most allergenic foods, limited availability of threshold dose information within the population restricts the advice on action levels of unintended allergenic foods which should trigger advisory labeling on packaged foods. The objective of this paper is to provide guidance for selecting an optimal sample size for threshold dosing studies for major allergenic foods and to identify factors influencing the accuracy of estimation. A simulation study was performed to evaluate the effects of sample size and dosing schemes on the accuracy of the threshold distribution curve. The relationships between sample size, dosing scheme and the employed statistical distribution on the one hand and accuracy of estimation on the other hand were obtained. It showed that the largest relative gains in accuracy are obtained when sample size increases from N=20 to N=60. Moreover, it showed that the EuroPrevall dosing scheme is a useful start, but that it may need revision for a specific allergen as more data become available, because a proper allocation of the dosing steps is important. The results may guide risk assessors in minimum sample sizes for new studies and in the allocation of proper dosing schemes for allergens in provocation studies. PMID:24815821

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

    PubMed

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

    2011-01-01

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

  11. A single, low, oral dose of a 5-carbon-linked trioxane dimer orthoester plus mefloquine cures malaria-infected mice

    PubMed Central

    Moon, Deuk Kyu; Tripathi, Abhai; Sullivan, David; Siegler, Maxime A.; Parkin, Sean; Posner, Gary H.

    2010-01-01

    Four 5-carbon-linked trioxane dimer orthoesters (6a–6d) have been prepared in 4 or 5 chemical steps from the natural trioxane artemisinin (1). When administered orally to malaria-infected mice using a single dose of only 6 mg/kg body weight along with 18 mg/kg of mefloquine hydrochloride, trioxane dimer orthoester sulfone 6d completely and safely cured the mice; after 30 days, the cured mice showed no detectable parasitemia, gained at least as much weight as the control mice (no infection), and behaved normally. PMID:20952197

  12. Hematological and Immunological Changes Due to Short-term Oral Administration of Acephate

    PubMed Central

    Sankhala, Laxmi N.; Tripathi, Syamantak M.; Bhavsar, S. K.; Thaker, Aswin M.; Sharma, Pramod

    2012-01-01

    To evaluate immunotoxicological effects of environmental chemical, subacute toxicity of repeated (28 day) oral administration of acephate (Ace) in BALB/c mice was assessed. Thirty two (sixteen male and sixteen female) mice were divided into four different groups with each group containing eight (four male and four female) mice. Mice of Group C1 were administered normal saline only and served as control. Group T1 was given 1/40th of apparent LD50 (ALD50) (8.78 mg/kg), and group T2 was put on 1/30th of ALD50 [11.7 mg/kg], while group T3 received 1/20th of ALD50 [17.55 mg/kg] of Ace suspended in normal saline. The blood samples were collected from mice after 28 days of oral administration and analyzed for hematological, biochemical, and immunological parameters. The study showed that hematological parameters (monocytes and granulocytes) remained unaffected except total leukocyte count and lymphocyte which were decreased highly significantly [P?0.01] in mice of group T3 on the 28th day of experiment. Serum total protein (TP) and serum globulin decreased significantly in mice of treatment groups dose dependently; however, no significant change was seen in serum albumin. Progressive increase in live body weight of mice decreased significantly in extremely toxic group only while spleen:body weight ratio decreased significantly in dose-dependent manner. Furthermore, Ace produced suppressed humoral immune response and the delayed-type hypersensitivity response to Sheep red blood cells (SRBCs) was altered nonsignificantly. The results of this study describe the suppression of immune responses following exposure to Ace at low concentrations in experimental mice. PMID:22778515

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

    Microsoft Academic Search

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

    2001-01-01

    .  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).

  14. 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...

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

    Microsoft Academic Search

    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

    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

  16. Estimation by a 24-hour study of the daily dose of intra-oral mercury vapor inhaled after release from dental amalgam

    SciTech Connect

    Berglund, A. (Univ. of Umea (Sweden))

    1990-10-01

    The difficulties associated with estimations of daily doses of inhaled mercury vapor released from dental amalgam are considerable. Existing data are often unreliable, especially if they are based on a single or a small series of samples of intra-oral concentrations of mercury vapor before, during, and after chewing stimulation. In the present paper, the aim was to obtain a more representative estimation of the daily dose of mercury vapor inhaled from amalgam fillings by measurement of amounts of mercury vapor released in the oral cavity during 24 h, under conditions that were as normal as possible. A series of measurements was carried out on each of 15 subjects, with at least nine occlusal surfaces restored with dental amalgam, and on five subjects without any amalgam restorations. The subjects had to follow a standardized schedule for 24 h, whereby they ate, drank, and brushed their teeth at pre-determined time periods. The amount of mercury vapor released per time unit was measured at intervals of 30-45 min by means of a measuring system based on atomic absorption spectrophotometry. None of the subjects was professionally exposed to mercury, and all of their amalgam fillings were more than one year old. Study casts were made for each subject, and the area of the amalgam surfaces was measured. Samples of urine and saliva were analyzed so that values for the mercury concentrations and the rate of release of mercury into saliva could be obtained. The average frequency of fish meals per month was noted.

  17. Effect of mild and moderate liver disease on the pharmacokinetics of isavuconazole after intravenous and oral administration of a single dose of the prodrug BAL8557.

    PubMed

    Schmitt-Hoffmann, A; Roos, B; Spickermann, J; Heep, M; Peterfaí, E; Edwards, D J; Stoeckel, K

    2009-11-01

    Isavuconazole is a promising new antifungal drug with favorable pharmacokinetic properties and excellent activity against a number of fungi. It is administered as a water-soluble prodrug (BAL8557) that is cleaved by plasma esterases to isavuconazole, which is eliminated primarily by hepatic metabolism. The objective of this investigation was to assess the effect of alcohol-related liver disease on the pharmacokinetics of isavuconazole. Subjects were 16 healthy individuals, 16 with mild liver impairment, and 16 with moderate liver impairment who were randomized to receive a single oral or intravenous dose of BAL8557 equivalent to 100 mg isavuconazole. Blood samples were collected for 21 days following drug administration, and plasma concentrations of isavuconazole, BAL8557, and the cleavage product BAL8728 were measured using high-pressure liquid chromatography coupled with tandem mass spectrometry. Following intravenous administration, the half-life of isavuconazole increased from 123 h for healthy volunteers to 224 h and 302 h for subjects with mild and moderate liver impairment, respectively. The systemic clearance of isavuconazole following intravenous administration decreased from 2.73 liters/h for healthy subjects to 1.43 liters/h for subjects with moderate liver impairment (47.6% decrease [P < 0.05]). A similar decrease (23.5%) was observed after oral administration. These results suggest that a dose adjustment may be needed when isavuconazole is used to treat fungal infections in patients with liver disease. PMID:19667286

  18. 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

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

    2009-01-01

    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

  19. 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

    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

    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

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

    PubMed

    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

    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

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

    PubMed

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

    2014-04-01

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

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

    NASA Astrophysics Data System (ADS)

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

    1997-06-01

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

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

    PubMed

    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

    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

  4. 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

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

    2013-01-01

    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

  5. Effects of the food contaminant semicarbazide following oral administration in juvenile Sprague-Dawley rats.

    PubMed

    Maranghi, F; Tassinari, R; Lagatta, V; Moracci, G; Macrì, C; Eusepi, A; Di Virgilio, A; Scattoni, M L; Calamandrei, G

    2009-02-01

    Semicarbazide (SEM) is an azodicarbonamide by-product present in glass jar packaged foods including babyfoods, in bleaching steps and flour treatment. Experimental data showed SEM acting as osteolathyrogen agent, but few toxicological data are available in susceptible life-stages. This study aimed to evaluate effects of SEM oral administration for 28 days at 0, 40, 75, 140 mg/kg bw day during the juvenile period in Sprague-Dawley rats. Histopatological examinations of: epiphyseal cartilage - potential target of SEM lathyrogen action - testes, ovary, uterus, thyroid, thymus, spleen, adrenals, representative of the main developing organs relevant to juvenile toxicity, and neurobehavioural tests in males, were performed. Mortality at high and mid dose levels and significantly decreased body weight gain were observed in males even at the lowest dose. Lack of mineralization in cartilage at all dose levels was present. Marked alterations of spontaneous motor and exploratory behaviours were evident even at 40 mg/kg. Histological alterations were observed in all tissues; thyroid and ovary effects were present also at 40 mg/kg. The present study indicate that the NOAEL in juvenile rats is lower than 40 mg/kg for SEM oral administration. SEM administration during juvenile period exerted pleiotropic effects and further studies are suggested to elucidate mechanisms. PMID:19110027

  6. Renal Hemodynamic and Morphological Changes after 7 and 28 Days of Leptin Treatment: The Participation of Angiotensin II via the AT1 Receptor.

    PubMed

    Thieme, Karina; Oliveira-Souza, Maria

    2015-01-01

    The role of hyperleptinemia in cardiovascular diseases is well known; however, in the renal tissue, the exact site of leptin's action has not been established. This study was conducted to assess the effect of leptin treatment for 7 and 28 days on renal function and morphology and the participation of angiotensin II (Ang II), through its AT1 receptor. Rats were divided into four groups: sham, losartan (10 mg/kg/day, s.c.), leptin (0.5 mg/kg/day for the 7 days group and 0.25 mg/kg/day for the 28 days group) and leptin plus losartan. Plasma leptin, Ang II and endothelin 1 (ET-1) levels were measured using an enzymatic immuno assay. The systolic blood pressure (SBP) was evaluated using the tail-cuff method. The renal plasma flow (RPF) and the glomerular filtration rate (GFR) were determined by p-aminohippuric acid and inulin clearance, respectively. Urinary Na+ and K+ levels were also analyzed. Renal morphological analyses, desmin and ED-1 immunostaining were performed. Proteinuria was analyzed by silver staining. mRNA expression of renin-angiotensin system (RAS) components, TNF-? and collagen type III was analyzed by quantitative PCR. Our results showed that leptin treatment increased Ang II plasma levels and progressively increased the SBP, achieving a pre-hypertension state. Rats treated with leptin 7 days showed a normal RPF and GFR, but increased filtration fraction (FF) and natriuresis. However, rats treated with leptin for 28 showed a decrease in the RPF, an increase in the FF and no changes in the GFR or tubular function. Leptin treatment-induced renal injury was demonstrated by: glomerular hypertrophy, increased desmin staining, macrophage infiltration in the renal tissue, TNF-? and collagen type III mRNA expression and proteinuria. In conclusion, our study demonstrated the progressive renal morphological changes in experimental hyperleptinemia and the interaction between leptin and the RAS on these effects. PMID:25793389

  7. Renal Hemodynamic and Morphological Changes after 7 and 28 Days of Leptin Treatment: The Participation of Angiotensin II via the AT1 Receptor

    PubMed Central

    Thieme, Karina; Oliveira-Souza, Maria

    2015-01-01

    The role of hyperleptinemia in cardiovascular diseases is well known; however, in the renal tissue, the exact site of leptin’s action has not been established. This study was conducted to assess the effect of leptin treatment for 7 and 28 days on renal function and morphology and the participation of angiotensin II (Ang II), through its AT1 receptor. Rats were divided into four groups: sham, losartan (10 mg/kg/day, s.c.), leptin (0.5 mg/kg/day for the 7 days group and 0.25 mg/kg/day for the 28 days group) and leptin plus losartan. Plasma leptin, Ang II and endothelin 1 (ET-1) levels were measured using an enzymatic immuno assay. The systolic blood pressure (SBP) was evaluated using the tail-cuff method. The renal plasma flow (RPF) and the glomerular filtration rate (GFR) were determined by p-aminohippuric acid and inulin clearance, respectively. Urinary Na+ and K+ levels were also analyzed. Renal morphological analyses, desmin and ED-1 immunostaining were performed. Proteinuria was analyzed by silver staining. mRNA expression of renin-angiotensin system (RAS) components, TNF-? and collagen type III was analyzed by quantitative PCR. Our results showed that leptin treatment increased Ang II plasma levels and progressively increased the SBP, achieving a pre-hypertension state. Rats treated with leptin 7 days showed a normal RPF and GFR, but increased filtration fraction (FF) and natriuresis. However, rats treated with leptin for 28 showed a decrease in the RPF, an increase in the FF and no changes in the GFR or tubular function. Leptin treatment-induced renal injury was demonstrated by: glomerular hypertrophy, increased desmin staining, macrophage infiltration in the renal tissue, TNF-? and collagen type III mRNA expression and proteinuria. In conclusion, our study demonstrated the progressive renal morphological changes in experimental hyperleptinemia and the interaction between leptin and the RAS on these effects. PMID:25793389

  8. Silica-Lipid Hybrid (SLH) Versus Non-lipid Formulations for Optimising the Dose-Dependent Oral Absorption of Celecoxib

    Microsoft Academic Search

    Angel Tan; Andrew K. Davey; Clive A. Prestidge

    Purpose  To investigate the dose linearity of celecoxib (CEL) pharmacokinetics from various non-lipid and lipid-based formulations;\\u000a to probe the mechanisms of CEL absorption from a nano-structured silica-lipid hybrid (SLH) microparticle dosage form.\\u000a \\u000a \\u000a \\u000a \\u000a Methods  Single-dose pharmacokinetic parameters of CEL were determined in fasted rats at dose levels of 5, 20 and 50 mg\\/kg in aqueous\\u000a suspensions of pure CEL, Celebrex® and CEL-SLH microparticles formulated

  9. Dose-related Endocrine Effects and Pharmacokinetics of Oral and Intramuscular 4Hydroxyandrostenedione in Postmenopausal Breast Cancer Patients1

    Microsoft Academic Search

    M. Dowsett; D. C. Cunningham; R. C. Stein; S. Evans; L. Dehennin; A. Hedley; R. C. Coombes

    Hydroxyandrostenedione (CGP32349; 4-OHA) is a clinically effec tive treatment for advanced postmenopausal breast cancer by both the parenteral and p.o. routes, as a result of its inhibition of ¡immutasi- and consequent suppression of plasma estrogen levels. Thirty patients were randomized to treatment with 250 mg 4-OHA orally once, twice, and 4 times daily for 2 weeks and 29 of these

  10. The influence of cimetidine on the pharmacokinetics of the enantiomers of verapamil in the dog during multiple oral dosing.

    PubMed

    Johnson, L M; Lankford, S M; Bai, S A

    1995-04-01

    The disposition of intravenously (0.5 mg/kg) and orally (5 mg/kg) administered verapamil was studied in six dogs after 3 days' pre-treatment with verapamil alone (5 mg/kg, every 8 h) and during concomitant oral administration of cimetidine (16 mg/kg, every 8 h). Racemic verapamil and norverapamil, an active metabolite of verapamil, were measured by fluorescence high performance liquid chromatography using an achiral phenyl column. The isolated racemic verapamil was rechromatographed on an Ultron-OVM chiral column, which separated the two verapamil enantiomers. Cimetidine co-administration significantly reduced the systemic clearance of racemic verapamil as well as that of its enantiomers by 25-29%. The clearance of racemic verapamil administered orally as well as that of its enantiomers was also reduced by 28% during cimetidine coadministration. The decrease in verapamil metabolism by cimetidine appeared to be non-stereoselective. On the other hand, cimetidine co-administration had no significant effect on the apparent volume of distribution of racemic verapamil and its enantiomers or the plasma protein binding or the blood to plasma concentration ratio of racemic verapamil. In addition, the ratio of the area under the plasma concentration-time curve for norverapamil to that of verapamil was unaffected by cimetidine co-administration.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7629925

  11. Low-dose oral bexarotene in combination with low-dose interferon alfa in the treatment of cutaneous T-cell lymphoma: clinical synergism and possible immunologic mechanisms

    Microsoft Academic Search

    Karen S McGinnis; Jacqueline M Junkins-Hopkins; Glen Crawford; Michael Shapiro; Alain H Rook; Carmela C Vittorio

    2004-01-01

    BackgroundFor nearly 2 decades clinicians have been treating cutaneous T-cell lymphoma (CTCL) with regimens that combine interferon alfa with retinoid compounds. In December 1999 a new retinoid, bexarotene, was approved by the US Food and Drug Administration for the treatment of CTCL. At the manufacturer's recommended dose of bexarotene (300 mg\\/m2 of body surface area), it has proven to be

  12. Subchronic oral toxicity study of Decitabine (DAC) in Combination with Tetrahydrouridine (THU) in CD-1 Mice

    PubMed Central

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

    2014-01-01

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

  13. In vitro antiviral activity and single-dose pharmacokinetics in humans of a novel, orally bioavailable inhibitor of human rhinovirus 3C protease.

    PubMed

    Patick, Amy K; Brothers, Mary A; Maldonado, Fausto; Binford, Susan; Maldonado, Oscar; Fuhrman, Shella; Petersen, Annkatrin; Smith, George J; Zalman, Leora S; Burns-Naas, Leigh Ann; Tran, Jonathan Q

    2005-06-01

    (E)-(S)-4-((S)-2-{3-[(5-methyl-isoxazole-3-carbonyl)-amino]-2-oxo-2H-pyridin-1-yl}-pent-4-ynoylamino)-5-((S)-2-oxo-pyrrolidin-3-yl)-pent-2-enoic acid ethyl ester (Compound 1) is a novel, irreversible inhibitor of human rhinovirus (HRV) 3C protease {inactivation rate constant (Kobs/[I]) of 223,000 M-1s-1}. In cell-based assays, Compound 1 was active against all HRV serotypes (35 of 35), HRV clinical isolates (5 of 5), and related picornaviruses (8 of 8) tested with mean 50% effective concentration (EC50) values of 50 nM (range, 14 to 122 nM), 77 nM (range, 72 to 89 nM), and 75 nM (range, 7 to 249 nM), respectively. Compound 1 inhibited HRV 3C-mediated polyprotein processing in infected cells in a concentration-dependent manner, providing direct confirmation that the cell-based antiviral activity is due to inhibition of 3C protease. In vitro and in vivo nonclinical safety studies showed Compound 1 to be without adverse effects at maximum achievable doses. Single oral doses of Compound 1 up to 2,000 mg in healthy volunteers were found to be safe and well tolerated in a phase I-ascending, single-dose study. Compound 1 estimated free observed maximum concentration in plasma (Cmax) for 500-, 1,000-, and 2,000-mg doses were higher than the protein binding-corrected EC50 required to inhibit 80% of the HRV serotypes tested. Treatment of HRV 52-infected cells with one to five 2-h pulses of 150 nM Compound 1 (corresponding to the Cmax at the 500-mg dose) was sufficient to effect a significant reduction in viral replication. These experiments highlight Compound 1 as a potent, orally bioavailable, irreversible inhibitor of HRV 3C protease and provide data that suggest that Cmax rather than the Cmin might be the key variable predicting clinical efficacy. PMID:15917520

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

    PubMed

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

    2014-11-01

    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

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

    PubMed

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

    2015-02-01

    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

  16. Safety, dose, immunogenicity, and transmissibility of an oral live attenuated Shigella flexneri 2a vaccine candidate (SC602) among healthy adults and school children in Matlab, Bangladesh.

    PubMed

    Rahman, Kazi Mizanur; Arifeen, Shams El; Zaman, K; Rahman, Mahbubur; Raqib, Rubhana; Yunus, Mohammad; Begum, Nazma; Islam, Md Shaheenul; Sohel, Badrul Munir; Rahman, Muntasirur; Venkatesan, Malabi; Hale, Thomas L; Isenbarger, Daniel W; Sansonetti, Philippe J; Black, Robert E; Baqui, Abdullah H

    2011-02-01

    In double-blind trials in Bangladesh, 88 adults, and 79 children (8-10 years) were randomized to receive either a single oral dose of 1 × 10(4), 1 × 10(5) or 1 × 10(6)CFU of SC602 (a live, attenuated Shigella flexneri 2a strain vaccine) or placebo. In the adult outpatient 1 × 10(6) CFU group, severe joint pain and body aches were reported by one and two vaccinees respectively. In the adult inpatient trial, SC602 was isolated from 3 volunteers, pre-vaccination antibody titers were high, and fourfold increases in serum IgG anti-LPS responses were observed in 2 of 5 subjects of the 1 × 10(6)CFU group. None of the volunteers developed diarrhea. Overall, SC602 was found to be associated with minimal vaccine shedding, minimal reactogenicity, no transmission risk, and low immune stimulation. PMID:21040694

  17. Oral pamidronate prevents high-dose glucocorticoid-induced lumbar spine bone loss in premenopausal connective tissue disease (mainly lupus) patients.

    PubMed

    Nzeusseu Toukap, A; Depresseux, G; Devogelaer, J-P; Houssiau, F A

    2005-01-01

    Glucocorticoid (GC)-induced osteoporosis contributes to chronic damage in patients suffering from connective tissue diseases (CTD) such as systemic lupus erythematosus (SLE). In this study, performed in an highly selected cohort of premenopausal female CTD (mostly lupus) patients, given high-dose GC therapy for severe disease, we show that lumbar spine bone loss can be averted by treatment with oral disodium pamidronate combined with calcium salts and vitamin D3 supplements and not by calcium salts and vitamin D3 supplements alone. We stress the need for optimal GC-induced bone loss prevention therapy in premenopausal patients, a too often neglected issue in patients whose survival has dramatically improved over the last decades. PMID:16130506

  18. Application of a radioreceptor assay in a pharmacokinetic study of oxitropium bromide in healthy volunteers after single i.v., oral and inhalation doses.

    PubMed

    Ensing, K; de Zeeuw, R A; in 't Hout, W G; Cornelissen, P J

    1989-01-01

    Oxitropium bromide (OXBR) is a new anticholinergic drug, which is expected to be useful in the treatment of nocturnal asthma. The only pharmacokinetic data were obtained with the 14C-labelled compound. A sensitive radioreceptor assay for the determination of unlabelled OXBR in plasma was developed, based on competition between OXBR and 3H-N-methylscopolamine for binding to muscarinic receptors. OXBR was isolated from plasma by ion-pair extraction and re-extraction. Active metabolites present in significant amounts might interfere in the assay, but this was not the case for OXBR metabolites. Detection limits were 300 pg.ml-1 and 3 ng.ml-1 for plasma and urine, respectively. For the latter no extraction step was required. The single dose pharmacokinetics of OXBR was studied following inhalation (3 mg), oral (2 mg) and i.v. (1 mg) administration to 12 men, following an open, cross-over design. After i.v. administration the kinetic parameters were: Vc 38.41; t1/2 alpha 5.3 min; t1/2 beta 142 min; AUC 8.9 h.ng.ml-1; renal excretion 50.2%, k10 3.5 l.h-1 and total clearance 1874 ml/min. The apparent bioavailabilities were 0.48% and 12.4% by the oral and inhalation routes, respectively, based on the cumulative renal excretion. There were moderate adverse reactions due to the anticholinergic properties of the drug. PMID:2598990

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

    ClinicalTrials.gov

    2014-09-24

    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

  20. Plasma and brain concentrations of oral therapeutic doses of methylphenidate and their impact on brain monoamine content in mice

    Microsoft Academic Search

    Aygul Balcioglu; Jia-Qian Ren; Deirdre McCarthy; Thomas J. Spencer; Joseph Biederman; Pradeep G. Bhide

    2009-01-01

    Methylphenidate is a frequently prescribed stimulant for the treatment of attention deficit hyperactivity disorder (ADHD). An important assumption in the animal models that have been employed to study methylphenidate's effects on the brain and behavior is that bioavailability of methylphenidate in the animal models reflects that in human subjects. From this perspective, the dose and route of administration of methylphenidate

  1. 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...

  2. Dose-related effects following oral exposure of 2,4-dinitrotoluene on the Western fence lizard, Sceloporus occidentalis.

    PubMed

    Suski, Jamie G; Salice, Christopher; Houpt, John T; Bazar, Matthew A; Talent, Larry G

    2008-02-01

    2,4-dintitrotoluene (2,4-DNT) is an explosive frequently found in the soil of military installations. Because reptiles can be common on these sites, ecological risk assessments for compounds such as 2,4-DNT could be improved with toxicity data specific to reptiles. Western fence lizards, Sceloporus occidentalis, were used to develop a laboratory toxicity model for reptiles. A hierarchical approach was used; acute to subchronic studies were conducted to provide toxicity data relevant to short- and long-term exposures. First, a modified median lethal dose (LD50) study was conducted on male and female lizards using a stage-wise probit model. The LD50 was 577 mg/kg for female and 380 mg/kg for male lizards. Subsequently, a subacute experiment was conducted to further assess 2,4-DNT toxicity to male lizards and to define exposure levels for a longer term, subchronic study. The subchronic study was conducted for 60 consecutive days; male lizards were exposed to 0, 9, 15, 25, 42, 70 mg/kg/d. Dose-dependent mortality was observed in the three highest dose groups (25, 42, and 70 mg/kg/d); all other animals survived the study duration. Benchmark dose model calculations based on mortality indicated a 5% effect level of 15.8 mg/kg/d. At study termination, a gross necropsy was performed, organ weights were taken, and blood was collected for clinical and hematological analysis. Body weight, kidney weight, food consumption, postdose observations, and blood chemistries all were found to be significantly different from controls at doses above 9 mg/kg/d. Also, preliminary results suggest behavioral observations, and reduced food consumption may be a sensitive indicator of toxicity. The present study indicates Sceloporus occidentalis is suitable for evaluating toxicity of compounds to reptilian species. PMID:18348623

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

    PubMed

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

    2013-05-01

    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

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

    PubMed Central

    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

    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

  5. Effects of artemether, artesunate and dihydroartemisinin administered orally at multiple doses or combination in treatment of mice infected with Schistosoma japonicum.

    PubMed

    Li, Hong-Jun; Wang, Wei; Li, You-Zi; Qu, Guo-Li; Xing, Yun-Tian; Tao, Yong-Hui; Wei, Jian-Ying; Dai, Jian-Rong; Liang, You-Sheng

    2011-08-01

    Artemether and artesunate, derivatives of the antimalarial artemisinin, as well as their main metabolite, dihydroartemisinin, all exhibit antischistosomal activities. The purpose of the current study was to compare the effects of artemether, artesunate and dihydroartemisinin administered orally at multiple doses or combination in treatment of mice infected with Schistosoma japonicum. We carried out experiments with mice, infected with 40 cercariae of S. japonicum, and treated with artemether, artesunate and dihydroartemisinin (all at a single dose of 300 mg/kg, and the dose of the mixed three drugs is also 300 mg/kg) at multiple doses or combination therapy on days 6-8 or 34-36 post-infection. Administration with artemether, artesunate or dihydroartemisinin for 3 successive days reduced total worm burdens by 79.5-86% (30.86 ± 4.98 of mean total worm burden in control), female worm burdens by 79.4-86.7% (11.29 ± 2.63 of mean female worm burden in control) (all P values <0.01 vs. control), depending on different treatment protocols given on days 6-8 post-infection. However, no differences were seen between each treatment group (all P > 0.05). While the same treatment was given on days 34-36 post-infection, total worm burden reductions of 73.8-75.8% were achieved (29.44 ± 3.36 of mean total worm burden in control), which were significant when compared with the untreated control group (all P values <0.01). In all different treatment groups, female worm reductions (ranging from 88.7% to 93.1%, while the mean female worm burden in control is 10.33 ± 1.80) were consistently higher than the total worm reductions, resulting always in significantly lower female worm burdens when compared to the corresponding control (all P values < 0.01). However, there were no significant differences found between each treatment group (all P values >0.05). It is concluded that artemether, artesunate and dihydroartemisinin can be used to control schistosomiasis japonica, as a strategy to prevent S. japonicum infection. Administration with artemether, artesunate and dihydroartemisinin at multiple doses or in combined treatment damages both juvenile and adult S. japonicum, without statistically significant differences among the three drugs at the same dose. PMID:21626153

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

    PubMed

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

    2015-01-01

    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

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

    PubMed Central

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

    2014-01-01

    The long-lasting anticoagulant effect of vitamin K antagonists can be problematic in cases of adverse drug reactions or when patients are switched to another anticoagulant therapy. The objective of this study was to examine in silico the anticoagulant effect of rivaroxaban, an oral, direct Factor Xa inhibitor, combined with the residual effect of discontinued warfarin. Our simulations were based on the recommended anticoagulant dosing regimen for stroke prevention in patients with atrial fibrillation. The effects of the combination of discontinued warfarin plus rivaroxaban were simulated using an extended version of a previously validated blood coagulation computer model. A strong synergistic effect of the two distinct mechanisms of action was observed in the first 2–3 days after warfarin discontinuation; thereafter, the effect was close to additive. Nomograms for the introduction of rivaroxaban therapy after warfarin discontinuation were derived for Caucasian and Japanese patients using safety and efficacy criteria described previously, together with the coagulation model. The findings of our study provide a mechanistic pharmacologic rationale for dosing schedules during the therapy switch from warfarin to rivaroxaban and support the switching strategies as outlined in the Summary of Product Characteristics and Prescribing Information for rivaroxaban. PMID:25426077

  8. Chemoimmunotherapy with oral low-dose fludarabine, cyclophosphamide and rituximab (old-FCR) as treatment for elderly patients with chronic lymphocytic leukaemia.

    PubMed

    Gozzetti, Alessandro; Candi, Veronica; Fabbri, Alberto; Schiattone, Luana; Cencini, Emanuele; Lauria, Francesco; Frasconi, Adele; Crupi, Rosaria; Raspadori, Donatella; Papini, Giulia; Defina, Marzia; Bartalucci, Giulia; Bocchia, Monica

    2014-08-01

    Median age at diagnosis for chronic lymphocytic leukaemia (CLL) patients is now 72 years, thus a consistent number of patients may not tolerate standard doses i.v. of fludarabine, cyclophosphamide and rituximab (FCR), the best available therapy, due to unacceptable myelotoxicity and risk of severe infections. We studied safety and efficacy of the addition of rituximab to the oral low-dose FC regimen (old-FCR) in a selected population of 30 elderly (median age 75, 15 untreated, 15 treated with 1 prior therapy) CLL patients. Complete remission (CR) rate was 80% in the untreated patients (overall response rate, ORR 93%), and 30% in pretreated patients (ORR 74%). Progression free survivals (PFS) were 45 months and 30 months in the untreated and treated patients, respectively. In patients achieving CR, old-FCR led to PFS of 67 months. Moreover, haematological toxicity was mild (grade 3-4: 15%) and patients were treated mostly in outpatient clinic. Old-FCR could be a good therapy option for elderly CLL patients outside clinical trials, larger studies are needed to confirm our findings. PMID:24934847

  9. Reductions in milk ?(9)-desaturation ratios to oral dosing of cobalt-acetate are accompanied by the downregulation of SCD1 in lactating ewes.

    PubMed

    Toral, P G; Hervás, G; Frutos, P

    2015-03-01

    Oral administration of cobalt has been proven to alter milk fatty acid (FA) composition consistent with an inhibition of mammary stearoyl-coenzyme A desaturase (SCD) activity in ruminants, but the mechanisms explaining its mode of action remain uncertain. In this study, Co (as Co-acetate) was dosed to lactating ewes with the aims of examining mammary gene expression during Co-induced changes in milk FA composition, and estimating the endogenous synthesis of SCD products in milk of sheep fed an 18:3n-3-enriched diet. Twelve Assaf ewes fed a diet supplemented with 2% linseed oil were allocated to 2 experimental groups and received an oral drench supplying either 0 (control) or 9mg of Co/kg of body weight per day. Treatments were administered in 3 equal doses at 8-h intervals for 6 d. No effects of Co administration on animal performance were observed. The changes in milk FA (namely, reductions in most cis-9-containing FA) were consistent with an inhibition of SCD in the absence of detectable effects on the relative importance of mammary de novo synthesis and FA uptake. The high proportion of endogenous cis-9 trans-11 18:2 observed in this study (89%) would agree with a greater supply of trans-11 18:1 of ruminal origin in ewes fed linseed oil, compared with previous estimates in sheep fed a diet without lipid supplementation. Differences between studies could also be related to diet-induced changes in SCD activity. Altogether, both mechanisms would support that basal diet composition is a major determinant of the relative contribution of ?(9)-desaturation to milk FA profile. Similarly, the consumption of a diet rich in 18:3n-3might also explain the low proportion of milk cis-9 18:1 estimated to derive from ?(9)-desaturation (29%). The administration of Co to ewes fed linseed oil allowed to discriminate minor 18:3 isomers in milk, such as cis-9 trans-12 cis-15 18:3, as SCD products. Finally, Co dosing lowered the mRNA abundance of SCD1 in the mammary secretory tissue (33%), whereas no changes were detected in the SCD5 isoform or in the studied transcription factors (SREBF1, PPARG, SP1, and EGR2). These results suggest that the mode of action of Co in dairy ewes would be at least partly mediated by the downregulation of SCD1. PMID:25547303

  10. Chronic toxicity and oncogenic dose-response effects of lifetime oral acrylonitrile exposure to Fischer 344 rats.

    PubMed

    Johannsen, Frederick R; Levinskas, George J

    2002-06-24

    Acrylonitrile (AN) was administered in the drinking water for approximately 2 years to groups of 100 male and 100 female Fischer 344 rats at nominal concentrations of 1, 3, 10, 30, and 100 ppm. Two groups, each of 100 males and 100 females, were used as untreated controls. Average daily intake was 0.1, 0.3, 0.8, 2.5 or 8.4 mg AN per kg body weight per day, respectively, for treated male rats and 0.1, 0.4, 1.3, 3.7, or 10.9 mg AN per kg per body weight per day, respectively, for dosed females. Clinical biochemistry, interim necropsies, organ weights and microscopic evaluation of tissues and organs were performed on groups of ten rats per sex per group at months 6, 12, and 18 and at study termination. Females were sacrificed in the 24th month and males were terminated after 26 months of dosing. A consistent decrease in survival, lower body weight and reduced water intake, as well as small reductions in hematological parameters, were observed in both sexes of the 100 ppm group. Elevated numbers of early deaths were observed in groups of males receiving 10 ppm AN and females receiving 30 ppm AN. Organ:body weight ratios at various study intervals were consistently elevated in the high dose group and likely were related to lower body weights. At these same intervals, mean absolute weights were either comparable to controls or only slightly elevated and few changes in weight ratios were seen when organ weights were compared with brain weights. No biochemical changes suggested a treatment-related effect. An increase in urine specific gravity in 100 ppm male rats was reflective of a decrease in liquid intake at this level. The only significant non-neoplastic finding observed histologically was a dose-related increase in hyperplasia/hyperkeratosis in squamous cells of the forestomach in male and female rats given 3 ppm and higher AN. This observation correlated with the induction of treatment-related squamous cell tumors (papillomas and carcinomas) of the forestomach seen primarily in rats at 3 ppm AN and higher. Mammary gland carcinomas were observed only in female groups. Both sexes given 10 ppm AN or more in their drinking water for their lifetime had astrocytomas of the brain/spinal cord and adenomas/carcinomas of the Zymbal's gland. PMID:12044705

  11. Comparison of Intake and Systemic Relative Effect Potencies of Dioxin-like Compounds in Female Mice after a Single Oral Dose

    PubMed Central

    Andersson, Patrik L.; Gaisch, Konrad P.J.; van den Berg, Martin; van Duursen, Majorie B.M.

    2013-01-01

    Background: Risk assessment for mixtures of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and polychlorinated biphenyls (PCBs) is performed using the toxic equivalency factor (TEF) approach. These TEF values are derived mainly from relative effect potencies (REPs) linking an administered dose to an in vivo toxic or biological effect, resulting in “intake” TEFs. At present, there is insufficient data available to conclude that intake TEFs are also applicable for systemic concentrations (e.g., blood and tissues). Objective: We compared intake and systemic REPs of 1,2,3,7,8-pentachlorodibenzodioxin (PeCDD), 2,3,4,7,8-pentachlorodibenzofuran (4-PeCDF), 3,3´,4,4´,5-pentachlorobiphenyl (PCB-126), 2,3´,4,4´,5-pentachlorobiphenyl (PCB-118), and 2,3,3´,4,4´,5-hexachlorobiphenyl (PCB-156) in female C57BL/6 mice 3 days after a single oral dose. Methods: We calculated intake REPs and systemic REPs based on administered dose and liver, adipose, or plasma concentrations relative to TCDD. Hepatic cytochrome P450 1A1–associated ethoxyresorufin-O-deethylase (EROD) activity and gene expression of Cyp1a1, 1a2 and 1b1 in the liver and peripheral blood lymphocytes (PBLs) were used as biological end points. Results: We observed up to one order of magnitude difference between intake REPs and systemic REPs. Two different patterns were discerned. Compared with intake REPs, systemic REPs based on plasma or adipose levels were higher for PeCDD, 4-PeCDF, and PCB-126 but lower for the mono-ortho PCBs 118 and 156. Conclusions: Based on these mouse data, the comparison between intake REPs and systemic REPs reveals significant congener-specific differences that warrants the development of systemic TEFs to calculate toxic equivalents (TEQs) in blood and body tissues. PMID:23674508

  12. Lack of male-female differences in disposition and esterase hydrolysis of ramipril to ramiprilat in healthy volunteers after a single oral dose.

    PubMed

    Vree, Tom B; Dammers, Erik; Ulc, Ivan; Horkovics-Kovats, Stefan; Ryska, Miroslav; Merkx; Ijsbrand

    2003-12-11

    The objective of this study was to identify differences in disposition and esterase hydrolysis of ramipril between male and female volunteers. Plasma concentration and area under the concentration-time curve until the last measured concentration (AUCt) data of ramipril and its active metabolite ramiprilat (-diacid) were obtained from a randomised, cross-over bioequivalence study in 36 subjects (18 females and 18 males). Participants received a single 5-mg oral dose of two different formulations of ramipril (Formulation I and II). Plasma ramipril and ramiprilat concentrations were determined according to validated methods involving liquid chromatography-mass spectrometry. A total number of 2 x 34 available plasma concentration-time curves of both the parent drug and the metabolite could be analysed, and variations (50-100% coefficient of variation [CV]) in plasma concentrations of both parent drug and metabolite were found. With both the formulations, the mean plasma concentrations-time curves of males and females were identical. The groups of female and male volunteers showed similar yields (AUCt = microg x h/L) of the metabolite ramiprilat (p = 0.37); however, females showed a higher AUCt/kg than males (p = 0.046). This difference was solely attributed to the difference in body weight between males and females (p = 0.00049). In both male and female groups, a subject-dependent yield of active metabolite ramiprilat was demonstrated, which was independent of the formulation. There is a large variation in the ramiprilat t1/2beta (50-60% CV). There is a group of subjects who showed a t1/2beta of approximately 80 h (15% CV), and two apparent groups with a longer t1/2beta for each formulation (124 h, 22.5% CV; 166 h, 21.6% CV, respectively, p = 0.0013). This variation in the terminal half-life of ramiprilat is not sex related. In all three groups of half-lives, the corresponding Cmax values (mean +/- SD) of ramiprilat in males and females were identical. Thus, with identical Cmax and half-lives, the difference found in the AUCt/kg of ramiprilat must be due to the difference in dose, as the consequence of the difference in body weight, following a standard dose of 5 mg in both males and females. This study showed clearly that despite subject-dependent hydrolysis of ramipril to the active metabolite ramiprilat, the variability in the rate of hydrolysis between males and females is similar. With a fixed dose (5 mg), females received a higher dose/kg than males and consequently showed a higher AUCt/kg of the active metabolite ramiprilat. PMID:14755115

  13. Odanacatib, a selective cathepsin K inhibitor to treat osteoporosis: safety, tolerability, pharmacokinetics and pharmacodynamics – results from single oral dose studies in healthy volunteers

    PubMed Central

    Stoch, S Aubrey; Zajic, Stefan; Stone, Julie A; Miller, Deborah L; Bortel, Lucas; Lasseter, Kenneth C; Pramanik, Barnali; Cilissen, Caroline; Liu, Qi; Liu, Lida; Scott, Boyd B; Panebianco, Deborah; Ding, Yu; Gottesdiener, Keith; Wagner, John A

    2013-01-01

    Aims To evaluate the safety, tolerability, pharmacokinetics and pharmacodynamics of odanacatib (ODN), a cathepsin K inhibitor, in humans. Methods Two double-blind, randomized, placebo-controlled, single oral dose studies were performed with ODN (2–600 mg) in 44 healthy volunteers (36 men and eight postmenopausal women). Results Adverse experiences (AEs) with single doses of ODN were transient and mild to moderate, with the exception of one severe AE of gastroenteritis. Headache was the most frequent AE. After absorption of ODN (initial peak concentrations 4–6 h postdose), plasma concentrations exhibited a monophasic decline, with an apparent terminal half-life of ?40–80 h. The area under the curve0-24 hours (AUC0–24 h), concentration at 24 hours (C24 h) and maximum concentration (Cmax,overal) increased in a less than dose-proportional manner from 2 to 600 mg. Administration of ODN with a high-fat meal led to ?100% increases in AUC0–24 h, Cmax,day1, Cmax,overall and C24 h relative to the fasted state, while administration with a low-fat meal led to a ?30% increase in those parameters. Reduction of biomarkers of bone resorption, the C- and N-telopeptides of cross-links of type I collagen, (CTx and NTx, respectively), was noted at 24 h for doses ?5 mg and at 168 h postdose for ?10 mg. In postmenopausal women administered 50 mg ODN, reductions in serum CTx of ?66% and urine NTx/creatinine (uNTx/Cr) of ?51% relative to placebo were observed at 24 h. At 168 h, reductions in serum CTx (?70%) and uNTx/Cr (?78%) were observed relative to baseline. Pharmacokinetic/pharmacodynamic modeling characterized the ODN concentration/uNTx/Cr relation, with a modeled EC50 value of 43.8 nM and ?80% maximal reduction. Conclusions Odanacatib was well tolerated and has a pharmacokinetic and pharmacodynamic profile suitable for once weekly dosing. PMID:23013236

  14. Surface area assessment of the murine intestinal tract as a prerequisite for oral dose translation from mouse to man.

    PubMed

    Casteleyn, C; Rekecki, A; Van der Aa, A; Simoens, P; Van den Broeck, W

    2010-07-01

    In many pharmacological and toxicological studies knowledge about the intestinal absorption, which is dependent upon the surface area of absorptive epithelia, is indispensible. Although mice are often used in such preclinical studies, very few quantitative data about their intestinal surface area are available. Especially for locally acting candidate drugs in development, this information is crucial for dose translation towards humans. Therefore, the surface area of the intestinal tract of CD-1 IGS mice was assessed in the present study. The intestinal tracts of 12 mice were collected after euthanasia. From six animals, histological sections from the duodenum, jejunum, ileum, caecum and colon-rectum were made according to common stereological principles. Using these sections, the volumes and surface areas of each intestinal segment were estimated applying stereological counting procedures. In the other six animals, the density and surface area of the microvilli present in each intestinal segment were determined by means of scanning and transmission electron microscopy to assess the increase of the intestinal surface area attributable to the presence of microvilli. The mean total volume and surface area of the intestinal tract were 1.34 cm(3) and 1.41 m(2), respectively. The relative intestinal surface area (intestinal surface area divided by the body surface area) was 119. The relative intestinal surface area of mice is very similar to that of humans. The results of this study are important for the appropriate dose translation of candidate therapeutic compounds in drug development from mouse to humans. PMID:20007641

  15. [Pharmacokinetics of tenofovir in Beagle dogs after oral dosing of tenofovir dipivoxil fumarate using HPLC-MS/MS analysis].

    PubMed

    Wang, Bao-Lian; Hu, Jin-Ping; Sheng, Li; Chen, Hui; Li, Yan

    2013-03-01

    A simple, rapid and sensitive method was developed for the quantification of tenofovir in plasma of Beagle dogs using HPLC-MS/MS analysis. The analytes tenofovir and internal standard (IS) adefovir were separated on a Zorbax SB-C18 column (3.5 microm, 100 mm x 2.1 mm, Agilent, USA) with mobile phase of methanol/water containing 0.3% formic acid using a gradient elution mode at a flow rate of 0.2 mL x min(-1). The plasma sample preparation was a simple deproteinization by the addition of 20% trichloroacetic acid followed by centrifugation. The detection was performed in positive selected reaction monitoring (SRM) mode with an electrospray ionization (ESI) source. The reactions monitored were m/z 288.1-176.2 for tenofovir and m/z 274.1-162.2 for adefovir (IS). Linear detection responses were obtained for tenofovir ranging from 10 to 5 000 ng x mL(-1). The intra- and inter-day precisions (RSD%) was no more than 6.3% with high recovery and good stability for the quantification, indicating the present method was specific, fast, accurate and reliable. The method was successfully applied to the pharmacokinetic study of two tenofovir agents. Tenofovir dipivoxil fumarate (BP0018, test agent) and tenofovir disoproxil fumarate (reference agent) were orally administrated to 8 Beagle dogs according to the 2 x 2 crossover design. Comparing with the reference agent, the longer MRT and t1/2 were obtained in the group of BP0018, while no significant difference was observed in AUC(0-t), AUC(0-infinity), C(max) and t(max) between them, suggesting that tenofovir dipivoxil fumarate was bioequivalent to the tenofovir disoproxil fumarate in Beagle dogs. PMID:23724653

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

    PubMed Central

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

    2014-01-01

    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

  17. 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

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

    2014-11-01

    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

  18. A Phase I, dose-finding and pharmacokinetic study of olaparib (AZD2281) in Japanese patients with advanced solid tumors.

    PubMed

    Yamamoto, Noboru; Nokihara, Hiroshi; Yamada, Yasuhide; Goto, Yasushi; Tanioka, Maki; Shibata, Takashi; Yamada, Kazuhiko; Asahina, Hajime; Kawata, Toshio; Shi, Xiaojin; Tamura, Tomohide

    2012-03-01

    Olaparib (AZD2281) is an orally active Poly(ADP-ribose) polymerase (PARP) inhibitor with favorable antitumor activity in advanced ovarian and breast cancers with BRCA1/2 mutations in Western (USA and European) studies. This Phase I dose-finding study evaluated the tolerability, pharmacokinetics, PARP inhibitory activity, and antitumor activity of olaparib in Japanese patients with solid tumors. Olaparib was administered as a single-dose on day 1, followed by twice-daily dosing for 28 days from 48 h after a single dose. Doses were escalated from 100 mg b.i.d. in successive cohorts, up to a maximum of 400 mg b.i.d. The present study enrolled 12 patients (n = 3, 3, and 6 in 100, 200 and 400-mg b.i.d. levels, respectively). The most common adverse events were nausea, increased blood creatinine, decreased hematocrit, leukopenia and lymphopenia; dose-limiting toxicities were not observed up to and including the 400-mg b.i.d. dose level. Following twice-daily dosing, olaparib showed no marked increase in exposure at steady state over that expected from the single-dose pharmacokinetics. PARP-1 inhibition was observed from the 100-mg b.i.d. dose level in peripheral blood mononuclear cells from 6 h post-dose on day 1 during the multiple-dosing period. A patient with metastatic breast cancer (100 mg b.i.d.) had a partial response for 13 months and four patients (two each in the 200 and 400-mg b.i.d. levels) had stable disease >8 weeks. Olaparib was well tolerated up to the 400-mg b.i.d. dose in Japanese patients with solid tumors. Preliminary evidence of antitumor activity was observed. PMID:22145984

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

    PubMed Central

    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

    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

  20. Oral calcitonin

    PubMed Central

    Hamdy, Ronald C; Daley, Dane N

    2012-01-01

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

  1. Absorption, metabolism, and excretion of oral 14C radiolabeled ibrutinib: an open-label, phase I, single-dose study in healthy men.

    PubMed

    Scheers, Ellen; Leclercq, Laurent; de Jong, Jan; Bode, Nini; Bockx, Marc; Laenen, Aline; Cuyckens, Filip; Skee, Donna; Murphy, Joe; Sukbuntherng, Juthamas; Mannens, Geert

    2015-02-01

    The absorption, metabolism, and excretion of ibrutinib were investigated in healthy men after administration of a single oral dose of 140 mg of (14)C-labeled ibrutinib. The mean (S.D.) cumulative excretion of radioactivity of the dose was 7.8% (1.4%) in urine and 80.6% (3.1%) in feces with <1% excreted as parent ibrutinib. Only oxidative metabolites and very limited parent compound were detected in feces, and this indicated that ibrutinib was completely absorbed from the gastrointestinal tract. Metabolism occurred via three major pathways (hydroxylation of the phenyl (M35), opening of the piperidine (M25 and M34), and epoxidation of the ethylene on the acryloyl moiety with further hydrolysis to dihydrodiol (PCI-45227, and M37). Additional metabolites were formed by combinations of the primary metabolic pathways or by further metabolism. In blood and plasma, a rapid initial decline in radioactivity was observed along with long terminal elimination half-life for total radioactivity. The maximum concentration (Cmax) and area under the concentration-time curve (AUC) for total radioactivity were higher in plasma compared with blood. The main circulating entities in blood and plasma were M21 (sulfate conjugate of a monooxidized metabolite on phenoxyphenyl), M25, M34, M37 (PCI-45227), and ibrutinib. At Cmax of radioactivity, 12% of total radioactivity was accounted for by covalent binding in human plasma. More than 50% of total plasma radioactivity was attributed to covalently bound material from 8 hours onward; as a result, covalent binding accounted for 38% and 51% of total radioactivity AUC0-24 h and AUC0-72 h, respectively. No effect of CYP2D6 genotype was observed on ibrutinib metabolism. Ibrutinib was well-tolerated by healthy participants. PMID:25488930

  2. DX-9065a, an orally active factor Xa inhibitor, does not facilitate haemorrhage induced by tail transection or gastric ulcer at the effective doses in rat thrombosis model.

    PubMed

    Tanabe, K; Morishima, Y; Shibutani, T; Terada, Y; Hara, T; Shinohara, Y; Aoyagi, K; Kunitada, S; Kondo, T

    1999-05-01

    DX-9065a is an antithrombin III (AT III)-independent and selective inhibitor of activated blood coagulation factor X (FXa). We evaluated the effects of DX-9065a and warfarin on bleeding time and blood loss in rat tail transection model and on blood loss in hydrochloride (HCl)-induced rat gastrointestinal haemorrhage model. The blood loss was determined by measuring the haemoglobin content in saline immersed with transected tail or hematin chloride content in the gaster after HCl administration. DX-9065a or warfarin was administered orally at 1 h or 15-21 h before the haemorrhagic stimuli, respectively. The dose required for 50% inhibition of thrombus formation (ID50) was 21 mg/kg for DX-9065a and 0.75 mg/kg for warfarin in a copper wire-inserted arteriovenous (AV) shunt model. In contrast to DX-9065a (10 or 30 mg/kg), warfarin (0.75 mg/kg) significantly prolonged the bleeding time. In rat tail transection model, the blood loss for the control group was 102+/-41 microl at 20 min after the transection. While warfarin (0.75 mg/kg) facilitated the blood loss about 5 times as much as the control, DX-9065a (10 or 30 mg/kg) did not. In rat gastrointestinal model, the blood loss for the control group was 15.9+/-5.6 microl at 15 min after HCl administration. In contrast to DX-9065a (10 or 30 mg/kg), warfarin (0.75 mg/kg) increased the blood loss about twice as much as the control. Thus, compared with warfarin, DX-9065a only increased bleeding time or blood loss to a minor extent in the doses tested. These observations suggest that direct inhibition of FXa could be preferable to warfarin in the suppression of thrombosis without haemorrhagic complications. PMID:10365760

  3. Efficacy of oral moxidectin against benzimidazole-resistant isolates of gastrointestinal nematodes in sheep

    Microsoft Academic Search

    D Kerboeuf; J Hubert; B Cardinaud; F Blond

    1995-01-01

    The efficacy of orally administered moxidectin was determined against four benzimidazole-resistant nematode isolates. At the start of the trial, 30 lambs were each infected experimentally with 20,000 third stage larvae (5000 Haemonchus contortus, 7000 Teladorsagia circumcincta, 3000 Trichostrongylus colubriformis and 5000 Cooperia curticei); 28 days later they were allocated randomly to three groups of 10: one untreated group, one group

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

    PubMed

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

    2015-03-23

    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

  5. Single and multiple dose pharmacokinetics of maritime pine bark extract (Pycnogenol) after oral administration to healthy volunteers

    PubMed Central

    Grimm, Tanja; Skrabala, Roswitha; Chovanová, Zuzana; Muchová, Jana; Sumegová, Katarína; Liptáková, Anna; ?ura?ková, Zde?ka; Högger, Petra

    2006-01-01

    Background Since plant extracts are increasingly used as phytotherapeutics or dietary supplements information on bioavailability, bioefficacy and safety are warranted. We elucidated the plasma kinetics of genuine extract components and metabolites after single and multiple ingestion of the standardized maritime pine bark extract Pycnogenol (USP quality) by human volunteers. Methods Eleven volunteers received a single dose of 300 mg pine bark extract, five volunteers ingested 200 mg daily for five days to reach steady state concentrations. Plasma samples were obtained before and at defined time points after intake of the extract. Samples were analyzed by HPLC with ion-pair reagents and simultaneous UV and electrochemical detection. Results We quantified total plasma concentrations of catechin, caffeic acid, ferulic acid, taxifolin and the metabolite M1 (?-(3,4-dihydroxy-phenyl)-?-valerolactone). Additionally, we describe plasma time courses and steady state appearance of ten so far unknown compounds, U1 to U10. After single ingestion, compounds derived from the extract were rapidly absorbed and the majority of them were detectable over whole experimental period of 14 h. The analysis of steady state plasma samples revealed significant phase II metabolism. Conclusion We present the first systematic pharmacokinetic analysis of compounds derived from maritime pine bark extract. Beyond the known constituents and metabolites we uncovered the plasma time courses of ten unknown compounds. In concert with our previous detection of anti-inflammatory bioefficacy of these plasma samples ex vivo we suggest that constituents and metabolites of Pycnogenol bear potential for disclosure of novel active principles. PMID:16887024

  6. An LC/MS/MS method for improved quantitation of the bound residues in the tissues of animals orally dosed with [(14)C]Benomyl.

    PubMed

    Moghaddam, M F; Trubey, R K; Anderson, J J

    2000-11-01

    Livers of goats orally dosed with [phenyl(U)-(14)C]benomyl contained radioactive residues which were not extractable using conventional, solvent-based extraction methods. We report a new residue method capable of enhanced extraction of benomyl-derived residues with selective and sensitive quantitation capability for methyl 4-hydroxybenzimidazol-2-ylcarbamate (4-HBC), methyl 5-hydroxybenzimidazol-2-ylcarbamate (5-HBC), and methyl benzimidazol-2-ylcarbamate (MBC). This method involves rigorous Raney-nickel reduction of hypothesized thioether bonds between benomyl residues and polar cellular components. Following acidic dehydration (desulfurization), the polar benomyl-derived residues are extracted into ethyl acetate and analyzed by LC/MS/MS. We have shown this method to be superior to alternative extraction approaches. When applied to goat liver tissue containing [phenyl(U)-(14)C]benomyl-bound residues, the extraction efficiency of total radioactive residues was approximately 30%, and the major benomyl-derived residue was 5-HBC (91-95% of extractable residue) with minor levels of carbendazim (MBC) (5-9%). HPLC/LSC data were consistent with the LC/MS/MS data. The overall method satisfies U.S. regulatory requirements in extraction efficiency, selectivity in detection, and limits of quantitation for benomyl-bound residues. PMID:11087458

  7. Discovery of a Selective S1P1 Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate

    PubMed Central

    2011-01-01

    Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors (S1P1 and S1P3?5). It has been postulated that fingolimod's efficacy is due to S1P1 agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P3 agonism. We have discovered a series of selective S1P1 agonists, which includes 3-[6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P3-sparing, orally active S1P1 agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P3 is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels. PMID:24900328

  8. A Phase I Study of Zoledronic Acid and Low Dose Cyclophosphamide in Recurrent/Refractory Neuroblastoma: A New Approaches to Neuroblastoma Therapy (NANT) Study

    PubMed Central

    Russell, Heidi V.; Groshen, Susan G.; Ara, Tasnim; DeClerck, Yves A.; Hawkins, Randy; Jackson, Hollie A.; Daldrup-Link, Heike E.; Marachelian, Araz; Skerjanec, Andrej; Park, Julie R.; Katzenstein, Howard; Matthay, Katherine K.; Blaney, Susan M.; Villablanca, Judith G.

    2010-01-01

    Background Zoledronic acid, a bisphosphonate, delays progression of bone metastases in adult malignancies. Bone is a common metastatic site of advanced neuroblastoma. We previously reported efficacy of zoledronic acid in a murine model of neuroblastoma bone invasion prompting this Phase I trial of zoledronic acid with cyclophosphamide in children with neuroblastoma and bone metastases. The primary objective was to determine recommended dosing of zoledronic acid for future trials. Procedure Escalating doses of intravenous zoledronic acid were given every 28 days with oral metronomic cyclophosphamide (25 mg/m2/day). Toxicity, response, zoledronic acid pharmacokinetics, bone turnover markers, serum IL-6, and sIL-6R were evaluated. Results Twenty-one patients, median age 7.5 (range 0.8 - 25.6) years were treated with 2 mg/m2 (n=4), 3 mg/m2 (n=3), or 4 mg/m2 (n=14) zoledronic acid. Fourteen patients were evaluable for dose escalation. A median of one (range 1-18) courses was given. Two dose limiting toxicities (Grade 3 hypophosphatemia) occurred at 4 mg/m2 zoledronic acid. Other Grade 3-4 toxicities included hypocalcemia (n=2), elevated transaminases (n=1), neutropenia (n=2), anemia (n=1), lymphopenia (n=1), and hypokalemia (n=1). Osteosclerosis contributed to fractures in one patient after 18 courses. Responses in evaluable patients included 1 partial response, 9 stable disease (median 4.5 courses, range 3-18), and 10 progressions. Zoledronic acid pharmacokinetics were similar to adults. Markers of osteoclast activity and serum IL-6 levels decreased with therapy. Conclusions Zoledronic acid with metronomic cyclophosphamide is well tolerated with clinical and biologic responses in recurrent/refractory neuroblastoma. The recommended dose of zoledronic acid is 4 mg/m2 every 28 days. PMID:21671363

  9. [Examination of anti-emetic effect, safety and usefulness of single oral dose of ondansetron tablet in nausea and emesis induced by anti-cancer drugs--dose-finding study of ondansetron tablet in patients receiving non-platinum anti-cancer drugs].

    PubMed

    Nukariya, N; Niitani, H; Taguchi, T; Furue, H; Ota, K; Tsukagoshi, S; Ariyoshi, Y; Ikeda, M; Akasaka, Y; Ohta, J

    1992-08-01

    Inhibitory effects on acute nausea and emesis, safety and usefulness of a single oral dose of Ondansetron tablet were evaluated in 3 different dose levels for comparison by telephone registration system, in patients receiving non-platinum anti-cancer drugs. A single dose of ondansetron at 4 mg, 8 mg or 12 mg was given orally at 2 hrs before the initial administration of anti-cancer drugs. The patients were observed for 24 hours after administration of anti-cancer drugs, for occurrence of nausea and emesis. Efficacy rates of inhibitory effects on nausea and emesis were 83.3% (10/12 cases) in 4 mg dose group, 78.6% (11/14 cases) in 8 mg dose group and 84.6% (11/13 cases) in 12 mg dose group, without statistically significant difference. Side effects were observed in 3 cases (headache, cold feeling and trembling in limbs, sleepiness) in 12 mg dose group, but these symptoms were not severe and disappeared after several hours or several days. No abnormality in clinical laboratory findings attributable to Ondansetron was observed. From the above, it was considered that Ondansetron was a clinically useful anti-emetic for nausea and emesis induced by non-platinum anti-cancer drugs and that 4 mg once daily was the optimal dose. PMID:1386976

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

    PubMed Central

    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

    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

  11. “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

    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

    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.

  12. Effects of low-dose gestagen (Lynestrenol 0.5 mg) and combination-type oral contraception (Lynestrenol 1 mg and Ethinyloestradiol 0.05 mg) on blood glucose and serum insulin levels after a glucose load

    Microsoft Academic Search

    D. Leis; P. Bottermann; R. Ermler; W. Schlauch

    1980-01-01

    Summary Forty 3-h oral glucose tolerance tests (OGTTs) were performed in 10 apparently healthy female volunteers aged 21–34 years, each serving four times as her own control. Each subject was taking either a low-dose gestagen contraceptive (lynestrenol 0.5 mg) or a combination-type pill (lynestrenol 1 mg + ethinyloestradiol 0.05 mg) alternatingly in four consecutive treatment cycles. Blood glucose and serum

  13. Individualising netilmicin dosing in neonates

    Microsoft Academic Search

    Catherine M. T. Sherwin; Roland S. Broadbent; Natalie J. Medlicott; David M. Reith

    2008-01-01

    Purpose  The aim of this study was develop an optimal dosing regimen for netilmicin in neonates.\\u000a \\u000a \\u000a \\u000a Methods  This was a population pharmacokinetic study in 97 neonates aged from 2 to 28 days after the due date who were being treated\\u000a with netilmicin for suspected sepsis. The model was used to simulate dosing regimens.\\u000a \\u000a \\u000a \\u000a Results  The principle factors influencing netilmicin clearance (CL) were postmenstrual age

  14. Comparison of total and salivary cortisol in a low-dose ACTH (Synacthen) test: influence of three-month oral contraceptives administration to healthy women.

    PubMed

    Sim?nková, K; Stárka, L; Hill, M; Kríz, L; Hampl, R; Vondra, K

    2008-01-01

    The objective of this study was to evaluate the influence of low-dose combined oral contraception (COC) on basal and stimulated (1 microg ACTH test) levels of serum and salivary cortisol (F), cortisone and on basal serum cortisol binding globulin (CBG), adrenocorticotropic hormone (ACTH), dehydroepiadrosterone (DHEA) and calculated free cortisol in healthy young women. Three-month administration of COC resulted in 1) significant increase of basal (454.0+/-125.0 to 860.9+/-179.7 nmol/l) and ACTH-stimulated serum cortisol in 30th min (652.3+/-60.5 to 1374.1+/-240.6 nmol/l); 2) no significant change of basal (15.4+/-7.3 to 18.9+/-8.5 nmol/l) and ACTH-stimulated salivary cortisol at the 30th min (32.4+/-8.8 to 32.9+/-9.0 nmol/l); 3) no significant change of basal serum cortisone (38,8+/-7.68 to 45.2+/-24.2 nmol/l) and ACTH-stimulated cortisone at the 30th (34.8+/-10.9 to 47.0+/-35.7 nmol/l); 4) significant increase of basal ACTH (17.2+/-9.0 to 38.2+/-29.4 ng/l), CBG (991.0+/-161.0 to 2332.0+/-428.0 nmol/l), and 5) no significant change of basal DHEA (24.6+/-15.7 to 22.6+/-11.7 micromol/l) and calculated basal value for free cortisol (22.8+/-14.9 to 19.2+/-6.9 nmol/l). In conclusions, higher basal and ACTH-stimulated serum cortisol were found after three-month administration of COC, while basal and stimulated salivary cortisol were not significantly affected. Therefore, salivary cortisol can be used for assessment of adrenal function in women regularly using COC. PMID:18271677

  15. Determination of gemifloxacin in different tissues of rat after oral dosing of gemifloxacin mesylate by LC-MS/MS and its application in drug tissue distribution study.

    PubMed

    Roy, Bikash; Das, Ayan; Bhaumik, Uttam; Sarkar, Amlan Kanti; Bose, Anirbandeep; Mukharjee, Jayanti; Chakrabarty, Uday Sankar; Das, Anjan Kumar; Pal, Tapan Kumar

    2010-06-01

    A simple, sensitive and specific liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed and validated to evaluate the accumulation of gemifloxacin in different tissues of Wister albino rat. The analytical method consists of the homogenization of tissues followed by simple liquid-liquid extraction and determination of gemifloxacin by an LC-MS/MS. The analyte was separated on a Peerless basic C(18) column (33 mm x 4.6 mm, 3 microm) with an isocratic mobile phase of methanol-water containing formic acid (1.0%, v/v) (9:1, v/v) at a flow rate of 0.6 ml/min. The MS/MS detection was carried out by monitoring the fragmentation of m/z 390.100-->372.100 for gemifloxacin and m/z 332.100-->314.200 for ciprofloxacin (internal standard; IS) on a triple quadrupole mass spectrometer. The validated method was accurate, precise and rugged with good linearity in all tissue homogenates. The accuracy and precision value obtained from six different sets of quality control samples of all tissues and serum analyzed in separate occasions within 91.833-102.283% and 0.897-5.291%, respectively. The method has been successfully applied to tissue distribution studies of gemifloxacin. The present study demonstrates that the highest tissue concentration of gemifloxacin was obtained in lung (11.891 ng/g), followed by liver (10.110 ng/g), kidney (10.095 ng/g), heart (4.251 ng/g), testis (3.750 ng/g), stomach (3.182 ng/g), adipose tissue (1.116 ng/g) and brain (0.982 ng/ml) in 3h after multiple oral dosing of 200mg gemifloxacin mesylate for 7 days. This method may also be used for gemifloxacin tissue distribution modeling study in rat tissues and antibiotic residue analyses in other animal tissues. PMID:20092976

  16. Bioequivalence of acenocoumarol in chilean volunteers: an open, randomized, double-blind, single-dose, 2-period, and 2-sequence crossover study for 2 oral formulations.

    PubMed

    Sasso, J; Carmona, P; Quiñones, L; Ortiz, M; Tamayo, E; Varela, N; Cáceres, D; Saavedra, I

    2012-08-01

    The aim of this study was to compare the bioavailability of an oral formulation of the coumarin derivative-vitamine K antagonist acenocoumarol (Acebron™ 4 mg, Test) with the reference formulation (Neo-Sintrom™ 4 mg). We performed a single-dose, double-blind, fasting, 2-period, 2-sequence, crossover study design. Plasma concentrations of acenocoumarol were determined using a validated UPLC-MS/MS method. 24 healthy Chilean volunteers (11 male, 13 female) were enrolled and all of them completed the study. Adverse events were monitored throughout the study. The values of the pharmacokinetic parameters were (mean ± SD): AUC0-24 =1 364.38±499.26 ngxh/mL for the test and 1 328.39±429.20 ngxh/mL for the reference; AUC0-? =1 786.00±732.85 ngxh/mL for the test and 1 706.71±599.66 ngxh/mL for the reference; Cmax =180.69±35.11 ng/mL with a Tmax of 1.83±0.95 h for the test and 186.97±38.21 ng/mL with a Tmax of 2.19±0.83 h for the reference. Regarding half life measurements, the mean ± SD of t1/2 were 11.84±4.54 h for the test and 11.08±3.28 h for the reference. The 90% confidence intervals for the test/reference ratio using logarithmic transformed data were 97.89-100.87%, 98.62-101.99% and 98.64-102.38% for Cmax, AUC0-t(24) and AUC0-?. There were no significant differences in pharmacokinetic parameters between groups.The results obtained in this study lead us to conclude, based on FDA criteria, that the test acenocoumarol formulation (Acebron™, 4 mg tablets) is bioequivalent to the reference product (Neo-Sintrom™, 4 mg tablets). PMID:22773430

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

    PubMed

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

    2014-01-01

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

  18. Radiation induced oral mucositis.

    PubMed

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

    2009-07-01

    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

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

    PubMed

    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

    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

  20. 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

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

    2014-01-01

    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

  1. Effects of a short course of oral phosphate treatment on serum parathyroid hormone (1–84) and biochemical markers of bone turnover: A dose-response study

    Microsoft Academic Search

    Kiln Brixen; Henning K. Nielsen; Peder Charles; Leif Mosekilde

    1992-01-01

    To investigate the possible use of oral phosphate as an activator of bone remodeling in coherence treatment of osteoporosis, 82 postmenopausal females, aged 50–75 years, were randomized to treatment with oral phosphate (750, 1500, or 2550 mg\\/day) or placebo for 7 days and followed for 4 months thereafter. All patients had sustained at least one previous fracture of the distal

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

    Microsoft Academic Search

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

    2005-01-01

    Enterohemorrhagic Escherichia coli (EHEC) is a bacterial pathogen that is associated with several life- threatening diseases for humans. The combination of protein E-mediated cell lysis to produce EHEC ghosts and staphylococcal nuclease A to degrade DNA was used for the development of an oral EHEC vaccine. The lack of genetic material in the oral EHEC bacterial-ghost vaccine abolished any hazard

  3. Dose-related neurocognitive effects of marijuana use

    Microsoft Academic Search

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

    2006-01-01

    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,

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

    PubMed Central

    2012-01-01

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

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

    PubMed Central

    2014-01-01

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

  6. Phase I trial of split-dose induction docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy followed by curative surgery combined with postoperative radiotherapy in patients with locally advanced oral and oropharyngeal squamous cell cancer (TISOC-1)

    PubMed Central

    2012-01-01

    Background Induction chemotherapy (ICT) with docetaxel, cisplatin and fluorouracil (TPF) followed by radiotherapy is an effective treatment option for unresectable locally advanced head and neck cancer. This phase I study was designed to investigate the safety and tolerability of a split-dose TPF ICT regimen prior to surgery for locally advanced resectable oral and oropharyngeal cancer. Methods Patients received TPF split on two dosages on day 1 and 8 per cycle for one or three 3-week cycles prior to surgery and postoperative radiotherapy or radiochemotherapy. Docetaxel was escalated in two dose levels, 40 mg/m2 (DL 0) and 30 mg/m2 (DL ?1), plus 40 mg/m2 cisplatin and 2000 mg/m2 fluorouracil per week using a 3 +3 dose escalation algorithm. Results Eighteen patients were enrolled and were eligible for toxicity and response. A maximum tolerated dose of 30 mg/m2 docetaxel per week was reached. The most common grade 3+ adverse event was neutropenia during ICT in 10 patients. Surgery reached R0 resection in all cases. Nine patients (50%) showed complete pathologic regression. Conclusions A split-dose regime of TPF prior to surgery is feasible, tolerated and merits additional investigation in a phase II study with a dose of 30 mg/m docetaxel per week. Trial registration number NCT01108042 (ClinicalTrials.gov Identifier) PMID:23083061

  7. Wuchereria bancrofti antigenemia clearance among Myanmar migrants after biannual mass treatments with diethylcarbamazine, 300 mg oral-dose FILADEC tablet, in Southern Thailand.

    PubMed

    Koyadun, Surachart; Bhumiratana, Adisak; Prikchu, Pathomporn

    2003-12-01

    Using qualitative ICT Filariasis and quantitative Og4C3 ELISA, we assessed a long-term macrofilaricidal effect of two-year biannual mass treatments with a 300 mg oral-dose FILADEC tablet, a reformulation of 6 mg/kg diethylcarbamazine (DEC), on clearance of the Wuchereria bancrofti adult worm circulating filarial antigens (CFA) in Myanmar migrants, at risk of emergence of imported bancroftian filariasis in Southern Thailand. Of the 34 antigenemic Myanmar index cases of varying initial CFA levels, who were initially screened out with the ICT Filariasis, 13 index cases were follow-up treated and monitored at the DEC post treatments, 6, 12, and 18 months. At the 18-month post treatment, residual antigenemias (%) in 4 of 5 index cases (group 1) with high antigen titers (99.7-181.6 x 10(3) AU/ml) were 54.44%, 33.58%, 27.43%, and 9.97%. Significant decreases of the CFA levels in only 3 out of 5 index cases were affected by the response to DEC treatments (p < 0.007). The treatment effects on clearance of the CFA in 8 index cases (group II) with low antigen titers (15.4-37.2 x 10(3) AU/ml) were shown for at least 6 months post DEC treatment and hence had 100% efficacy in the first 6 months of the first year of year round treatment. Group I, was more likely to show an increase of the DEC efficacy after the first 6 months of the second year round treatment, but there was no statistically significant difference (p = 0.063). We reemphasized that, for use in the national program to eliminate lymphatic filariasis (PELF) in Thailand, such a DEC regimen had a macrofilaricidal effect on antigenemia clearance, and confirmed its value in evaluating response to the treatment and monitoring the long-term efficacy of the DEC regimen in W. bancrofti adult worm burden reductions in Myanmar migrants on a wide scale. PMID:15115084

  8. Polychlorinated biphenyls as oxidative stress inducers in liver of subacutely exposed rats: implication for dose-dependence toxicity and benchmark dose concept.

    PubMed

    Buha, Aleksandra; Antonijevi?, Biljana; Milovanovi?, Vesna; Jankovi?, Saša; Bulat, Zorica; Matovi?, Vesna

    2015-01-01

    Hepatotoxicity is one of the well-documented adverse health effects of polychlorinated biphenyls (PCBs)-persistent organic pollutants widely present in the environment. Although previous studies suggest possible role of oxidative stress, the precise mechanisms of PCB-induced ROS production in liver still remain to be fully assessed. The aim of this study was to evaluate the effects of different doses of PCBs on the parameters of oxidative stress and to investigate whether these effects are dose dependent. Furthermore, a comparison between calculated benchmark doses (BMD) and estimated NOAEL values for investigated parameters, was made. Six groups of male albino Wistar rats (7 animals per group) were receiving Aroclor 1254 dissolved in corn oil in the doses of 0.5, 1, 2, 4, 8, 16 mg PCBs/kg b.w./day by oral gavage during 28 days while control animals were receiving corn oil only. The following parameters of oxidative stress were analyzed in liver homogenates: superoxide dismutase activity, glutathione, malondialdehyde (MDA) and total protein thiol levels. Hepatic enzymes AST, ALT, ALP and protein albumin were also determined in serum as clinical parameters of liver function. Collected data on the investigated parameters were analyzed by the BMD method. The results of this study demonstrate that subacute exposure to PCBs causes induction of oxidative stress in liver with dose-dependent changes of the investigated parameters, although more pronounced adverse effects were observed on enzymatic than on non-enzymatic components of antioxidant protection. The obtained values for BMD and NOAEL support the use of BMD concept in the prediction of health risks associated with PCBs exposure. Furthermore, our results implicate possible use of MDA in PCBs risk assessment, since MDA was the most sensitive investigated parameter with calculated low critical effect dose of 0.07 mg/kg b.w. PMID:25460651

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

    PubMed

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

    2014-01-01

    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

  10. Phase I dose-escalation study of S-222611, an oral reversible dual tyrosine kinase inhibitor of EGFR and HER2, in patients with solid tumours

    E-print Network

    Spicer, James; Baird, Richard; Suder, Aneta; Cresti, Nicola; Corbacho, Javier Garcia; Hogarth, Linda; Frenkel, Eugene; Matsumoto, Sayaka; Kawabata, Izumi; Donaldson, Kirsteen; Posner, John; Sarker, Debashis; Jodrell, Duncan; Plummer, Ruth

    2014-11-27

    once daily dosing. Responses were seen over a wide range of doses, including one complete clinical response in a patient with HER2-positive breast carcinoma previously treated with lapatinib and trastuzumab. Six partial responses were seen in EGFR- and...

  11. Oral myiasis.

    PubMed

    Saravanan, Thalaimalai; Mohan, Mathan A; Thinakaran, Meera; Ahammed, Saneem

    2015-01-01

    Myiasis is a pathologic condition in humans occurring because of parasitic infestation. Parasites causing myiasis belong to the order Diptera. Oral myiasis is seen secondary to oral wounds, suppurative lesions, and extraction wounds, especially in individuals with neurological deficit. In such cases, neglected oral hygiene and halitosis attracts the flies to lay eggs in oral wounds resulting in oral myiasis. We present a case of oral myiasis in 40-year-old male patient with mental disability and history of epilepsy. PMID:25709196

  12. Oral Myiasis

    PubMed Central

    Saravanan, Thalaimalai; Mohan, Mathan A; Thinakaran, Meera; Ahammed, Saneem

    2015-01-01

    Myiasis is a pathologic condition in humans occurring because of parasitic infestation. Parasites causing myiasis belong to the order Diptera. Oral myiasis is seen secondary to oral wounds, suppurative lesions, and extraction wounds, especially in individuals with neurological deficit. In such cases, neglected oral hygiene and halitosis attracts the flies to lay eggs in oral wounds resulting in oral myiasis. We present a case of oral myiasis in 40-year-old male patient with mental disability and history of epilepsy. PMID:25709196

  13. Influence of transdermal rotigotine on ovulation suppression by a combined oral contraceptive

    PubMed Central

    Braun, Marina; Elshoff, Jan-Peer; Andreas, Jens-Otto; Müller, Louise Ischen; Horstmann, Rolf

    2009-01-01

    AIMS To assess the influence of the transdermally applied dopamine agonist rotigotine on ovulation suppression by a combined oral contraceptive (0.03 mg ethinyloestradiol and 0.15 mg levonorgestrel) in a randomized, double-blind crossover study in 40 healthy females. METHODS Treatment A consisted of the combined oral contraceptive for 28 days plus rotigotine for the first 13 days (2 mg (24 h)?1 on days 1–3, 3 mg (24 h)?1 maintenance dose thereafter). During treatment B, subjects received matching placebo patches instead of rotigotine. Pharmacodynamic parameters (progesterone, oestradiol, luteinizing hormone, and follicle stimulating hormone serum concentrations), pharmacokinetic parameters for ethinyloestradiol/levonorgestrel and rotigotine, and safety and tolerability of the treatment were assessed. RESULTS Progesterone serum concentrations remained below 2 ng ml?1 in all subjects during the luteal phase. Median serum concentrations of all other pharmacodynamic parameters were similar during both treatments. Pharmacokinetic parameters Cmax,ss and AUC(0,24 h)ss at steady state were similar with or without co-administration of rotigotine for both ethinyloestradiol and levonorgestrel with geometric mean ratios close to 1 and 90% confidence intervals within the acceptance range of bioequivalence (0.8, 1.25): Cmax,ss 1.05 (0.93, 1.19), AUC(0,24 h)ss 1.05 (0.9, 1.22) for ethinyloestradiol; Cmax,ss 1.01 (0.96, 1.06), AUC(0,24 h)ss 0.98 (0.95, 1.01) for levonorgestrel. Mean plasma concentrations of unconjugated rotigotine remained stable throughout the patch-on period (day 13). CONCLUSIONS Concomitant administration of 3 mg (24 h)?1 transdermal rotigotine had no impact on the pharmacodynamics and pharmacokinetics of a combined oral contraceptive containing 0.03 mg ethinyloestradiol and 0.15 mg levonorgestrel, suggesting that the dopamine agonist does not influence contraception efficacy. PMID:19740396

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

    SciTech Connect

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

    2011-05-01

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

  15. Acute, sub-chronic oral toxicity studies and evaluation of antiulcer activity of Sooktyn in experimental animals

    PubMed Central

    Chandra, Phool; Sachan, Neetu; Kishore, Kamal; Ghosh, Ashoke Kumar

    2012-01-01

    Sooktyn (SKN), mineralo-herbal drug which is being used largely by the patients for its extremely good therapeutic value to treat the gastric ulcers. The present study was undertaken to evaluate the toxicity studies and antiulcer activity of SKN. Acute and sub-chronic toxicities were studied in male and female Wistar rats. A single acute SKN of 2 000 mg/kg was administered by oral gavage for acute toxicity. Sub-chronic doses were 400 and 800 mg/kg/day. The major toxicological end points examined included animal body weight and food intake, selected tissue weights, and detailed gross necropsy. In addition, we examined blood elements: hematocrit, hemoglobin concentration, erythrocyte count, total leukocyte count and MCH, MCHC and platelets as well as biochemical parameters: urea, sugar, alanine transaminase, aspartate transaminase, alkaline phosphatase, total proteins, and creatinine. Also, anti-ulcer activity was carried out by employing indomethacin, ethanol, pylorus ligation, and hypothermic-stress-induced ulcer models. LD50 may be greater than 2 000 mg/kg (orally) for SKN and there were no signs of toxicity on 28 days sub-chronic oral administration of 400 and 800 mg/kg of SKN in rats on the basis of blood elements and biochemical parameters. The ulcer indices decrease in all ulcer models with 66.62%, 61.24%, 80.18%, and 74.76% in indomethacin, ethanol, pylorus ligation, and hypothermic-stress-induced ulcer models, respectively. The results suggest that SKN has no signs of toxicity at 2 000 mg/kg body weight of rats orally; sub-chronically. The drug is safe and has antiulcer activity. PMID:22837960

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

    PubMed

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

    2011-10-01

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

  17. The lowest-dose, extended-cycle combined oral contraceptive pill with continuous ethinyl estradiol in the United States: a review of the literature on ethinyl estradiol 20 ?g/levonorgestrel 100 ?g + ethinyl estradiol 10 ?g.

    PubMed

    Krishnan, Sheila; Kiley, Jessica

    2010-01-01

    Extended-cycle oral contraceptives (OCs) are increasing in popularity in the United States. A new extended-cycle OC that contains the lowest doses of ethinyl estradiol (EE) and levonorgestrel (LNG) + continuous EE throughout the cycle is now available. It provides 84 days of a low-dose, combined active pill containing levonorgestrel 100 ?g and ethinyl estradiol 20 ?g. Instead of 7 days of placebo following the active pills, the regimen delivers 7 days of ethinyl estradiol 10 ?g. Existing studies reveal a similar efficacy and adverse effect profile compared with other extended-regimen OCs. Specifically, the unscheduled bleeding profile is similar to other extended-cycle OCs and improves with the increase in the duration of use. Although lower daily doses of hormonal exposure have potential benefit, to our knowledge, there are no published studies indicating that this specific regimen offers a lower incidence of hormone-related side effects or adverse events. In summary, this new extended-cycle OC provides patients a low-dose, extended-regimen OC option without sacrificing efficacy or tolerability. PMID:21151728

  18. Development of an extemporaneous oral liquid formulation of oxandrolone and its stability evaluation.

    PubMed

    Garg, Alka; Garg, Sanjay; She, Richard Wong

    2011-11-01

    Many references exist in the literature identifying the usefulness of oxandrolone in treating muscle wasting due to various conditions including severe burns. However, there is an absence of dosage form alternatives as it is only available as tablets. The dose for children is weight based (0.1 mg/kg) which is difficult to achieve with the currently available tablets of 2.5 mg and 10 mg. The literature provides ample evidence of clinical importance but little guidance on extemporaneous oral liquid formulation of oxandrolone. In order to develop and validate an extemporaneous liquid formulation, suspensions of oxandrolone were developed using locally available (New Zealand) vehicles. Combinations of these vehicles with ethanol, as advised in some articles were also tried. Assay method was developed for oxandrolone using High Performance Liquid Chromatography (HPLC) and Mass Spectroscopy (LC-MS). The formulations were evaluated for stability as per the International Conference on Harmonization (ICH) stability guidelines. They were observed for physical and chemical stability at different time points over a period of 28 days. A stable and validated liquid formulation of oxandrolone has been developed which can be made under the hospital and community pharmacy conditions. The formula utilises commercially available oxandrolone tablets, crushed and dispersed in Simple Syrup BP or Orablend(®) vehicle. The formulation has confirmed stability for 21 days and can be easily made with locally available vehicles. PMID:21764219

  19. Methotrexate and oral ulceration

    Microsoft Academic Search

    G M J Deeming; J Collingwood; M N Pemberton

    2005-01-01

    Methotrexate is well established in the drug treatment of various neoplastic diseases. More recently it has become increasingly used as a once-weekly, low-dose treatment of disorders such as psoriasis and rheumatoid arthritis. Clinical trials have shown its effectiveness in these conditions and it is likely that dentists will encounter patients taking this drug in general dental practice. Oral ulceration can

  20. Deficient induction of the immune response to oral immunization with cholera toxin in malnourished rats during suckling.

    PubMed Central

    Fló, J; Roux, M E; Massouh, E

    1994-01-01

    Malnourished rats during suckling were orally immunized with cholera toxin (CT) after different periods of refeeding. Intestinal fluids, sera, and supernatant fluids from cultured mesenteric lymph node (MLN) cells were obtained after rats were given three doses of CT and analyzed by enzyme-linked immunosorbent assay (ELISA) to evaluate the specific antibody response. Serum-specific immunoglobulin G (IgG), IgA, and IgM were severely diminished in malnourished rats immunized with three doses of CT after 1 week of refeeding when compared with those of controls. Also, a decreased IgA ELISA titer of the intestinal fluids and abrogation of the capacity to neutralize the CT in the intestinal ligated loop test were found. When a booster was given at 113 days of age, the immune response continued to be affected in the serum and the intestinal fluid. The results from the analysis of the supernatant fluids from cultured MLN cells were coincident with those mentioned above. When one dose of CT was administered into Peyer's patches (PP) after 1 week of refeeding, an impaired immune response was found in the intestinal fluid of malnourished rats during suckling compared with that of controls. This result together with the analysis of supernatant from MLN and PP cell cultures suggests that antigen triggering in the PP was affected. When the refeeding period was extended to 30 days and then the first dose of CT was administered, the antibody immune responses in intestinal fluid serum and supernatant fluid approached control values. These observations reinforce the fact that the gut-associated lymphoid tissue immaturity of the rats when they received the first CT dose (at 28 days old) was the main reason for the decreased immune response observed in the experimental group. PMID:7927775

  1. Halitosis, Oral Health and Quality of Life during Treatment with Invisalign ® and the Effect of a Low-dose Chlorhexidine Solution

    Microsoft Academic Search

    Isabelle Schaefer; Bert Braumann

    2010-01-01

    \\u000a Abstract\\u000a \\u000a \\u000a Aim:\\u000a   This study examined how halitosis, oral dryness and\\u000a general oral health were impacted during treatment with\\u000a the Invisalign® system. Furthermore, the effect of a lowdose\\u000a chlorhexidine solution (CHX) was evaluated.\\u000a \\u000a \\u000a \\u000a \\u000a \\u000a Patients and Methods:\\u000a   Thirtyone patients with good periodontal\\u000a health participated in this crossover study and were\\u000a divided into two groups (group 1: CHX\\/no CHX, group 2:\\u000a no CHX\\/CHX).

  2. Single-Dose Oral Amoxicillin or Linezolid for Prophylaxis of Experimental Endocarditis Due to Vancomycin-Susceptible and Vancomycin-Resistant Enterococcus faecalis

    Microsoft Academic Search

    Philippe Moreillon; Walter R. Wilson; Roland Leclercq; J. M. Entenza

    2007-01-01

    Endocarditis prophylaxis following genitourinary or gastrointestinal procedures targets Enterococcus faecalis. Prophylaxis recommendations advocate oral amoxicillin (2 g in the United States an d3gi n the United Kingdom) in moderate-risk patients and intravenous amoxicillin (2 g) or vancomycin (1 g) plus gentamicin in high-risk patients. While ampicillin-resistant (or amoxicillin-resistant) E. faecalis is still rare, there is a concern that these regimens

  3. 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

    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

    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

  4. Low-dose “metronomic chemotherapy” with oral cyclophosphamide and methotrexate in metastatic breast cancer: a case report of extraordinarily prolonged clinical benefit

    PubMed Central

    Masci, G; Losurdo, A; Gandini, C; Garassino, I; di Tommaso, L; Torrisi, R; Zuradelli, M; Santoro, A

    2012-01-01

    We report the case of a 34-year-old woman affected by breast cancer that had metastasized to the bone. She had been treated with oral cyclophosphamide and methotrexate (metronomic chemotherapy) and achieved 3.5 years of clinical remission. To our knowledge, this is the first description of such a prolonged response to therapy. This case report adds weight to known data on metronomic treatment and supports further investigation of this therapy. PMID:23130087

  5. 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

    PubMed Central

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

    2009-01-01

    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 (PL) or NO-Shotgun® (NO) 30 min prior to exercise. Data were analyzed with separate 2 × 2 ANOVA and t-tests (p < 0.05). Results Total body mass was increased in both groups (p = 0.001), but without any significant increases in total body water (p = 0.77). No significant changes occurred with fat mass (p = 0.62); however fat-free mass did increase with training (p = 0.001), and NO was significantly greater than PL (p = 0.001). Bench press strength for NO was significantly greater than PL (p = 0.003). Myofibrillar protein increased with training (p = 0.001), with NO being significantly greater than PL (p = 0.019). Serum IGF-1 (p = 0.046) and HGF (p = 0.06) were significantly increased with training and for NO HGF was greater than PL (p = 0.002). Muscle phosphorylated c-met was increased with training for both groups (p = 0.019). Total DNA was increased in both groups (p = 0.006), while NO was significantly greater than PL (p = 0.038). For DNA/protein, PL was decreased and NO was not changed (p = 0.014). All of the myogenic regulatory factors were increased with training; however, NO was shown to be significantly greater than PL for Myo-D (p = 0.008) and MRF-4 (p = 0.022). No significant differences were located for any of the whole blood and serum clinical chemistry markers (p > 0.05). Conclusion When combined with heavy resistance training for 28 days, NO-Shotgun® is not associated with any negative side effects, nor does it abnormally impact any of the clinical chemistry markers. Rather, NO-Shotgun® effectively increases muscle strength and mass, myofibrillar protein content, and increases the content of markers indicative of satellite cell activation. PMID:19656392

  6. Effects of the food contaminant semicarbazide following oral administration in juvenile Sprague–Dawley rats

    Microsoft Academic Search

    F. Maranghi; R. Tassinari; V. Lagatta; G. Moracci; C. Macrì; A. Eusepi; A. Di Virgilio; M. L. Scattoni; G. Calamandrei

    2009-01-01

    Semicarbazide (SEM) is an azodicarbonamide by-product present in glass jar packaged foods including babyfoods, in bleaching steps and flour treatment. Experimental data showed SEM acting as osteolathyrogen agent, but few toxicological data are available in susceptible life-stages. This study aimed to evaluate effects of SEM oral administration for 28 days at 0, 40, 75, 140mg\\/kg bw day during the juvenile

  7. Oral Medication

    MedlinePLUS

    ... doctor before starting anything new — even over-the-counter items. Explore: Oral Medication How Much Do Oral Medications Cost? Save money by finding the right type and dosage of medicine for your needs. In this section Treatment and ...

  8. Pig-a gene mutation and micronucleated reticulocyte induction in rats exposed to tumorigenic doses of the leukemogenic agents chlorambucil, thiotepa, melphalan, and 1,3-propane sultone.

    PubMed

    Dertinger, Stephen D; Phonethepswath, Souk; Avlasevich, Svetlana L; Torous, Dorothea K; Mereness, Jared; Cottom, John; Bemis, Jeffrey C; Macgregor, James T

    2014-05-01

    To evaluate whether blood-based genotoxicity endpoints can provide temporal and dose-response data within the low-dose carcinogenic range that could contribute to carcinogenic mode of action (MoA) assessments, we evaluated the sensitivity of flow cytometry-based micronucleus and Pig-a gene mutation assays at and below tumorigenic dose rate 50 (TD50) levels. The incidence of micronucleated reticulocytes (MN-RET) was used to evaluate chromosomal damage, and the frequency of CD59-negative reticulocytes (RET(CD59-) ) and erythrocytes (RBC(CD59-) ) served as phenotypic reporters of mutation at the X-linked Pig-a gene. Several leukemogenic agents with a presumed genotoxic MoA were studied. Specifically, male Sprague Dawley rats were treated via oral gavage for 28 days with chlorambucil, thiotepa, melphalan, and 1,3-propane sultone at doses corresponding to 0.33x, 1x, and 3x TD50, as well as at the maximum tolerated dose. Frequencies of MN-RET were determined at Days 4 and 29, and RET(CD59-) and RBC(CD59-) data were collected pretreatment as well as Days 15/16, 29, and 56/57. Dose-related increases were observed for each endpoint, and time to maximal effect was consistently: MN-RET < RET(CD59-) ?< RBC(CD59-) . For each of the chemicals studied, the genotoxic events occurred long before tumors or preneoplastic lesions would be expected. Furthermore, in the case of Pig-a gene mutation, the responses were observed at or below the TD50 dose for three out of the four chemicals studied. These data illustrate the potential for quantitative blood-based analyses to provide dose-response and temporality information that relates genetic damage to cancer induction. PMID:24449360

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

    PubMed

    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

    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

  10. Oral Cancer

    MedlinePLUS

    Oral Cancer Are You at Risk? What Are the Signs & Symptoms? Should You Have an Oral Cancer Exam? U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES ... Health Early Detection It is important to find oral cancer as early as possible when it can be ...

  11. Hepatic cytochrome P4501A induction in dab (Limanda limanda) after oral dosing with the polychlorinated biphenyl mixture Clophen A40

    SciTech Connect

    Sleiderink, H.M.; Everaarts, J.M.; Boon, J.P. [Netherlands Inst. for Sea Research, Texel (Netherlands); Goksoeyr, A. [Univ. of Bergen (Norway). Lab. of Marine Molecular Biology

    1995-04-01

    The flatfish dab (Limanda limanda) serves as an indicator species in pollution monitoring programs in the North Sea. The present study investigated the induction response of the monooxygenase system and haematological changes in female dab after multiple administrations of a technical mixture of polychlorinated biphenyls (PCBs). Mature female dab were dosed with 1 mg of the PCB mixture Clophen A40 (Clo A40) in sunflower oil every 6 weeks, with a maximum of three doses per fish. In all PCB-administered groups, levels of cytochrome P4501A (CYPIA) protein, measured with a semi-quantitative ELISA method, and 7-ethoxyresorufin O-deethylase (EROD) activity showed a three- to ninefold induction 14 d after dosing compared with control groups, smaller but also significant increases were observed in total cytochrome P450 ({Sigma} P450) levels. Although the PCB concentrations and the corresponding toxic equivalent (TEQ) value in muscle tissue still increased after administration of the second and third dose of Clo A40, maximum responses of the EROD activity were already reached after the first dose at a TEQ value for chlorinated biphenyls (CB-TEQ) of 2 ng/g lipid. The PCB patterns of liver and muscle tissue of female dab from the central North Sea were found to be virtually identical. Hence, the use of PCB concentrations in muscle as a qualitative model for changes in the liver appears legitimate. Haemoglobin concentrations were elevated after the third dose of Clo A40, whereas haematocrit values and the mean corpuscular haemoglobin concentration (MCHC) between treated and control groups did not differ.

  12. Case Study: What Happened to 28 Days?

    NSDL National Science Digital Library

    Tamar Goulet (University of Mississippi Biology)

    2011-08-29

    This is a case study for undergraduate students in anatomy and/or physiology. In particular this case study explores female reproductive physiology. Users of the National Center for Case Study Teaching in Science will be required to register (free) to gain access to the answer key (and must be of teaching status to receive the key). Included in the resource are the case overview, objectives, case study, teaching notes and answer key.

  13. Malaria-Infected Mice Live Until At Least Day 30 After A New Artemisinin-Derived Thioacetal Thiocarbonate Combined with Mefloquine Are Administered Together In A Single, Low, Oral Dose

    PubMed Central

    Jacobine, Alexander M.; Mazzone, Jennifer R.; Slack, Rachel D.; Tripathi, Abhai K.; Sullivan, David J.; Posner, Gary H.

    2012-01-01

    In only three steps and in 21–67% overall yields from the natural trioxane artemisinin, a series of 21 new trioxane C-10 thioacetals was prepared. Upon receiving a single oral dose of only 6 mg/kg of the monomeric trioxane 12c combined with 18 mg/kg of mefloquine hydrochloride, Plasmodium berghei-infected mice survived on average 29.8 days after infection. Two of the four mice in this group had no parasites detectable in their blood on day 30 after infection and they behaved normally and appeared healthy. One of the mice had 11% blood parasitemia on day 30, and one mouse in this group died on day 29. Of high medicinal importance, the efficacy of this ACT chemotherapy is much better than (almost double) the efficacy under the same conditions using as a positive control the popular trioxane drug artemether plus mefloquine hydrochloride (average survival time of only 16.5 days). PMID:22891714

  14. 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

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

    2012-01-01

    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

  15. A contrast in safety, pharmacokinetics and pharmacodynamics across age groups after a single 50 mg oral dose of the ?-secretase inhibitor avagacestat

    PubMed Central

    Tong, Gary; Wang, Jun-Sheng; Sverdlov, Oleksandr; Huang, Shu-Pang; Slemmon, Randy; Croop, Robert; Castaneda, Lorna; Gu, Huidong; Wong, Oi; Li, Hewei; Berman, Robert M; Smith, Christina; Albright, Charles F; Dockens, Randy

    2013-01-01

    AIM To evaluate the single dose pharmacokinetics, pharmacodynamics, and preliminary tolerability of the ?-secretase inhibitor BMS-708163 (avagacestat) in young and elderly men and women. METHODS All subjects received double-blinded administration of a single 50 mg dose of avagacestat in capsule form or matching placebo. Main evaluations included pharmacokinetics, safety, plasma amyloid-? (A?)1–40 concentratios and exploration of Notch biomarkers. RESULTS Avagacestat 50 mg capsule was well tolerated and rapidly absorbed among young and elderly subjects, with a median tmax between 1 and 2 h post dose and an average half-life between 41 and 71 h. In general, subjects aged 75 years or more had higher AUC(0,?) values than those aged less than 75 years. An exploratory analysis of A?1–40 serum concentrations showed a pattern of decreasing concentrations over the first 4–6 h followed by a rise above baseline that was maintained until the end of the assessment period. Adverse events were generally mild, occurring more frequently in elderly subjects, with no observed difference between subjects receiving avagacestat and placebo. No dose limiting gastrointestinal effects of avagacestat were observed and exploratory biomarkers of Notch inhibition did not change significantly. CONCLUSIONS The favourable safety profile and pharmacokinetic effects of avagacestat in this study support its continued development, especially in the target population of elderly subjects with mild cognitive impairment or Alzheimer's disease. PMID:22616739

  16. 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...

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

    SciTech Connect

    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

    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.

  18. Effect of single and repeated doses of oral omeprazole on gastric acid and pepsin secretion and fasting serum gastrin and serum pepsinogen I levels

    Microsoft Academic Search

    H. P. M. Festen; H. A. R. E. Tuynman; J. Défize; G. Pals; R. R. Frants; J. P. Straub; S. G. M. Meuwissen

    1986-01-01

    The effect of omeprazole on gastric acid and pepsin secretion and fasting serum gastrin and serum pepsinogen I levels was studied in 12 healthy volunteers. Omeprazole, 40 mg enteric-coated granules, or placebo was given once daily for nine days in a double-blind crossover study design. Twenty-four hours after a single dose of omeprazole, mean basal and mean pentagastrin-stimulated acid output

  19. Suppressed Levels of Serum Cortisol Following High-Dose Oral Dexamethasone Administration Differ between Healthy Postmenopausal Females and Patients with Established Primary Vertebral Osteoporosis

    Microsoft Academic Search

    P. Kann; M. Laudes; B. Piepkorn; A. Heintz; J. Beyer

    2001-01-01

    :   Hypercortisolism and glucocorticoid treatment, even in a low dose or administered topically, may influence bone metabolism.\\u000a It was the aim of this study to investigate whether there might be differences in the regulation of endogenous cortisol secretion\\u000a between patients with established primary vertebral osteoporosis and healthy controls. Suppressed morning serum cortisol concentrations\\u000a in a 3 mg dexamethasone overnight suppression

  20. Low incidence of hepatotoxicity associated with long-term, low-dose oral methotrexate in treatment of refractory psoriasis, psoriatic arthritis, and rheumatoid arthritis

    Microsoft Academic Search

    Steven B. Lanse; Georgel L. Arnold; James D. C. Gowans; Marshall M. Kaplan

    1985-01-01

    Thirty patients with psoriasis or other nonmalignant diseases had liver biopsies done before treatment with low-dose methotrexate, 15 mg\\/week, and then at one-to two-year intervals as long as they continued the methotrexate. All patients were symptomaticaly improved on this regimen. The 15 patients who had normal liver biopsies at the start of the study had normal biopsies after methotrexate. Fifteen

  1. Prevention of surgical site infection in lower limb skin lesion excisions with single dose oral antibiotic prophylaxis: a prospective randomised placebo-controlled double-blind trial

    PubMed Central

    Smith, Samuel C; Heal, Clare F; Buttner, Petra G

    2014-01-01

    Objectives To determine the effectiveness of a single perioperative prophylactic 2?g dose of cephalexin in preventing surgical site infection (SSI) following excision of skin lesions from the lower limb. Design Prospective double-blinded placebo-controlled trial testing for difference in infection rates. Setting Primary care in regional North Queensland, Australia. Participants 52 patients undergoing lower limb skin lesion excision. Interventions 2?g dose of cephalexin 30–60?min before excision. Main outcome measures Incidence of SSI. Results Incidence of SSI was 12.5% (95% CI 2.7% to 32.4%) in the cephalexin group compared with 35.7% (95% CI 18.6% to 55.9%) in the placebo group (p=0.064). This represented an absolute reduction of 23.21% (95% CI ?0.39% to 46.82%), relative reduction of 65.00% (95% CI ?12.70% to 89.13%) and number-needed-to-treat of 4.3. Conclusions Administration of a single 2?g dose of cephalexin 30–60?min before skin lesion excision from the lower limb may produce a reduction in the incidence of infection; however, this study was underpowered to statistically determine this. Trial registration number ACTRN12611000595910. PMID:25079934

  2. Dose Response and Pharmacokinetics of Tofacitinib (CP-690,550), an Oral Janus Kinase Inhibitor, in the Treatment of Chronic Plaque Psoriasis

    PubMed Central

    Tan, H; Gupta, P; Harness, J; Wolk, R; Chapel, S; Menter, A; Strober, B; Langley, RG; Krishnaswami, S; Papp, KA

    2013-01-01

    Longitudinal nonlinear mixed effects modeling was used to characterize the dose–response profile of tofacitinib using data from a placebo-controlled dose-ranging study, where tofacitinib 2, 5, and 15?mg twice daily (b.i.d.) were evaluated for plaque psoriasis treatment. Bayesian estimation was applied with prior information derived from the literature: nonclinical and clinical data in psoriasis, as well as other indications. The probability to achieve a certain target effect associated with a given dose was calculated from the posterior samples. On the basis of these probabilities along with safety considerations, tofacitinib 5 and 10?mg b.i.d. were selected for further testing in confirmatory phase III clinical trials. Pharmacokinetics in patients with psoriasis was characterized using a population-based modeling approach, and body weight was identified as an important covariate. A subgroup analysis suggested reduced efficacy of tofacitinib with increasing body weight; however, it is unclear whether this trend could be explained by systemic exposure alone.

  3. Population pharmacokinetics of azithromycin and chloroquine in healthy adults and paediatric malaria subjects following oral administration of fixed-dose azithromycin and chloroquine combination tablets

    PubMed Central

    2014-01-01

    Background Population pharmacokinetics (PK) of azithromycin (AZ) and chloroquine (CQ) following administration of fixed-dose combination tablet formulations of AZ and CQ (AZCQ) was evaluated using data from two studies: 1) in children with symptomatic uncomplicated falciparum malaria in sub-Saharan Africa; and 2) in healthy adults in the United States. Methods Study 1 included paediatric subjects randomized to either AZCQ or artemether-lumefantrine treatment in Cohort 1 (age 5–12 years) and Cohort 2 (age 6–59 months). Dosing of AZCQ was approximately 30 mg/kg AZ and 10 mg/kg CQ once daily for 3 days (for ?20 kg weight: AZ/CQ 300/100 mg per tablet; 5 to <20 kg weight: AZ/CQ 150/50 mg per tablet). Study 2 included adults randomized to receive either two AZCQ tablets (AZ/CQ 250/155 mg per tablet) or individual commercial tablets of AZ 500 mg and CQ 300 mg. Serum AZ and plasma CQ concentrations from both studies were pooled. Population PK models were constructed using standard approaches to evaluate the concentration-time data for AZ and CQ and to identify any covariates predictive of PK behaviour. Results A three-compartment PK model with linear clearance and absorption adequately described AZ data, while a two-compartment model with linear clearance and absorption and an absorption lag adequately described CQ data. No overall bias or substantial model misspecification was evident using diagnostic plots and visual predictive checks. Body weight as an allometric function was the only covariate in the final AZ and CQ PK models. There were significantly lower AZ (0.488 vs 0.745 [mg•h/L]/[mg/kg], p?dose (mg/kg) in children compared with the adults. Conclusions The PK of AZ and CQ following administration of AZCQ was well described using a three- and two-compartment model, respectively. AZ and CQ exhibited linear absorption and clearance; the model for CQ included an absorption lag. Weight was predictive of exposure for both AZ and CQ. Assuming equivalent dosing (mg/kg), AZ and CQ exposure in children would be expected to be lower than that in adults, suggesting that children may require a higher dose (mg/kg) than adults to achieve the same AZ and CQ exposure. PMID:24472224

  4. 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

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

    2015-01-01

    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

  5. 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

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

    2014-07-01

    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

  6. Cimetidine inhibits theophylline clearance in patients with chronic obstructive pulmonary disease: a study using stable isotope methodology during multiple oral dose administration.

    PubMed Central

    Vestal, R E; Thummel, K E; Musser, B; Mercer, G D

    1983-01-01

    1 The effect of concurrent cimetidine administration on the disposition of theophylline was investigated in eight male patients (56-78 years) with chronic obstructive pulmonary disease (COPD). 2 The patients, who were taking oral theophylline preparations chronically (384-1020 mg/day), received a [15N], [13C]-labelled analogue of theophylline (10 mg i.v.) before and during cimetidine treatment (1200 mg/day p.o.). 3 During cimetidine treatment trough levels of theophylline increased 34% (6.4 +/- 0.8 to 8.6 +/- 1.0 micrograms/ml, P less than 0.05), half-life increased 48% (6.5 +/- 0.6 to 9.6 +/- 0.8 h, P less than 0.001), and total plasma clearance decreased 33% (3.88 +/- 0.46 to 2.59 +/- 0.33 l/h, P less than 0.001), without a significant change in volume of distribution or protein binding. 4 The effect of cimetidine on plasma levels of theophylline was maximal within 72 h. Levels returned to control values within 48 h after its discontinuation. 5 Although there was no correlation with mean plasma concentrations of cimetidine, the change in clearance of theophylline correlated with initial clearance values (r = 0.72). 6 Cimetidine reduced the plasma clearance of theophylline in patients with COPD to an extent similar to that reported in healthy volunteers. PMID:6849776

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

    PubMed

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

    2004-12-29

    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

  8. Drug- not carrier-dependent haematological and biochemical changes in a repeated dose study of cyclosporine encapsulated polyester nano- and micro-particles: Size does not matter.

    PubMed

    Venkatpurwar, V P; Rhodes, S; Oien, K A; Elliott, M A; Tekwe, C D; Jørgensen, H G; Kumar, M N V Ravi

    2015-04-01

    Biodegradable nanoparticles are being considered more often as drug carriers to address pharmacokinetic/pharmacodynamic issues, yet nano-product safety has not been systematically proven. In this study, haematological, biochemical and histological parameters were examined on 28 day daily dosing of rats with nano- or micro-particle encapsulated cyclosporine (CsA) to confirm if any changes observed were drug or carrier dependent. CsA encapsulated poly(lactide-co-glycolide) [PLGA] nano- (nCsA) and micro-particles (mCsA) were prepared by emulsion techniques. CsA (15, 30, 45mg/kg) were administered by oral gavage to Sprague Dawley (SD) rats over 28 days. Haematological and biochemical metrics were followed with tissue histology performed on sacrifice. Whether presented as nCsA or mCsA, 45mg/kg dose caused significant loss of body weight and lowered food consumption compared to untreated control. Across the doses, both nCsA and mCsA produce significant decreases in lymphocyte numbers compared to controls, commensurate with the proprietary product, Neoral(®) 15. Dosing with nCsA showed higher serum drug levels than mCsA presumably owing to the smaller particle size facilitating absorption. The treatment had no noticeable effects on inflammatory/oxidative stress markers or antioxidant enzyme levels, except an increase in ceruloplasmin (CP) levels for high dose nCsA/mCsA group. Further, only subtle, sub-lethal changes were observed in histology of nCsA/mCsA treated rat organs. Blank (drug-free) particles did not induce changes in the parameters studied. Therefore, it is extremely important that the encapsulated drug in the nano-products is considered when safety of the overall product is assessed rather than relying on just the particle size. This study has addressed some concerns surrounding particulate drug delivery, demonstrating safe delivery of CsA whilst achieving augmented serum concentrations. PMID:25637670

  9. 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

    2013-01-01

    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?

  10. Oral implants.

    PubMed

    van Steenberghe, D

    1991-04-01

    Today, more and more evidence suggests that even small changes in hardware for oral implants may jeopardize its biocompatibility. Even the manner in which the hardware is sterilized can influence cellular adhesion. This review discusses the surface characteristics, configuration, and success rates of various oral implants, as well as the complications that can result following implantation. PMID:1777657

  11. 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

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

    2004-09-01

    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

  12. Absorption, distribution, metabolism and excretion of selenium following oral administration of elemental selenium nanoparticles or selenite in rats.

    PubMed

    Loeschner, Katrin; Hadrup, Niels; Hansen, Marianne; Pereira, Sonia A; Gammelgaard, Bente; Møller, Laura Hyrup; Mortensen, Alicja; Lam, Henrik Rye; Larsen, Erik H

    2014-02-01

    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

  13. 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

    2013-01-01

    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. PMID:24041337

  14. Effect of high-dose ciclosporin on the immune response to primary and booster vaccination in immunocompetent cats.

    PubMed

    Roberts, Elizabeth S; VanLare, Karen A; Roycroft, Linda M; King, Stephen

    2015-02-01

    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

  15. Comparative bioavailability and pharmacokinetics of two oral formulations of flurbiprofen: a single-dose, randomized, open-label, two-period, crossover study in Pakistani subjects.

    PubMed

    Qayyum, Aisha; Najmi, Muzammil Hasan; Abbas, Mateen

    2013-11-01

    Comparative bioavailability studies are conducted to establish the bioequivalence of generic formulation with that of branded reference formulation, providing confidence to clinicians to use these products interchangeably. This study was carried out to compare a locally manufactured formulation of flurbiprofen with that of a branded product. Twenty two healthy male adults received a single dose of flurbiprofen (100mg) either generic or branded product according to randomization scheme on each of 2 periods. Blood samples were collected and plasma flurbiprofen concentration was determined by a validated HPLC method. Pharmacokinetic parameters like AUC(0-t), AUC(0-oo), Cmax, Tmax, t½, Vd and clearance were determined. The 90% CI for the ratio of geometric means of test to reference product's pharmacokinetic variables was calculated. Pharmacokinetic parameters for two formulations were comparable. Ratio of means of AUC(0-24), AUC(0-oo) and Cmax for test to reference products and 90% CI for these ratios were within the acceptable range. The p-values calculated by TOST were much less than the specified value (p-0.05). ANOVA gave p-values which were more than the specified value (p-0.05) for sequence, subject, period and formulation. Test formulation of flurbiprofen (tablet Flurso) was found to meet the criteria for bioequivalence to branded product (tablet Ansaid) based on pharmacokinetic parameters. PMID:24191330

  16. A Phase II Study of Fixed-Dose Rate Gemcitabine Plus Low-Dose Cisplatin Followed by Consolidative Chemoradiation for Locally Advanced Pancreatic Cancer

    SciTech Connect

    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

    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.

  17. A randomized, double-blind, placebo-controlled study to evaluate the effect of repeated oral doses of pazopanib on cardiac conduction in patients with solid tumors

    PubMed Central

    Heath, Elisabeth I.; Infante, Jeffrey; Lewis, Lionel D.; Luu, Thehang; Stephenson, Joe; Tan, Antoinette R.; Kasubhai, Saifuddin; LoRusso, Patricia; Ma, Bo; Suttle, A. Benjamin; Kleha, Joseph F.; Ball, Howard A.; Dar, Mohammed M.

    2013-01-01

    Purpose As tyrosine kinase inhibitors have been associated with cardiotoxicity, we evaluated the effect of pazopanib, an inhibitor of vascular endothelial growth factor receptor, platelet-derived growth factor receptor, and c-Kit, on electrocardiographic parameters in patients with cancer. Methods This double-blind, placebo-controlled, parallel-group study randomized patients (N = 96) to moxifloxacin (positive control) or placebo on Day 1 followed by pazopanib or placebo 800 mg/day (fasted) on Days 2–8 and 1,600 mg (with food) on Day 9. Treatment effects were evaluated by baseline-adjusted, time-matched, serial Holter electrocardiograms. Results Sixty-five patients were evaluable for preplanned analyses. On Day 1, the maximum mean difference in baseline-adjusted, time-matched Fridericia-corrected QT (QTcF) interval in moxifloxacin-treated patients versus placebo was 10.6 ms (90 % confidence interval [CI]: 4.2, 17.0). The administration scheme increased plasma pazopanib concentrations approximately 1.3- to 1.4-fold versus the recommended 800 mg once-daily dose. Pazopanib caused clinically significant increases from baseline in blood pressure, an anticipated class effect, and an unexpected reduction in heart rate from baseline that correlated with pazopanib exposure. On Day 9, the maximum mean difference in baseline-adjusted, time-matched QTcF interval in pazopanib-treated patients versus placebo was 4.4 ms (90 % CI: ?2.4, 11.2). Mixed-effects modeling indicated no significant concentration-dependent effect of pazopanib or its metabolites on QTcF interval. Conclusions Pazopanib as administered in this study achieved supratherapeutic concentrations, produced a concentration-dependent decrease in heart rate, and caused a small, concentration-independent prolongation of the QTcF interval. PMID:23344712

  18. Relative bioequivalence evaluation of two oral atomoxetine hydrochloride capsules: a single dose, randomized, open-label, 2-period crossover study in healthy Chinese volunteers under fasting conditions.

    PubMed

    Shang, D-W; Guo, W; Zhou, F-C; Wang, X-P; Li, A-N; Zhang, L; Li, W-B; Lu, W; Wang, C-Y

    2013-11-01

    To evaluate the bioequivalence of a new formulation of atomoxetine hydrochloride (CAS 82248-59-7) capsules (test) and an available branded capsules (reference) after administration of a single 40?mg dose, randomized, open-label, 2-period crossover study was conducted in 22 healthy male Chinese subjects with a 1-week wash-out period. This study was designed for/the Honglin Pharmaceutical Co. Ltd and contracted to be done by the Beijing Anding Hospital in order to satisfy Chinese regulatory requirements to allow marketing of this generic product and performed according to the criteria of SFDA. Blood samples were collected before and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 9, 12, 16 and 24?h after drug administration. Plasma concentrations were determined by high-performance liquid chromatography (HPLC) with UV detection. A non-compartmental method was used to calculate the pharmacokinetic parameters and evaluate bioequivalence of the 2 formulations. The 90% confidence interval (CI) of the ratios (test/reference) of atomoxetine for AUC0-24, AUC0-? and Cmax were 100.9% (93.6-108.8%), 103.1% (95.1-111.7%) and 105.2% (92.8-119.4%), respectively, which fell within the interval of 80-125% and 75-133%. No clinically significant changes or abnormalities were noted in laboratory data and vital signs. From these results it can be concluded that the test formulation of atomoxetine capsules met the regulatory criterion for bioequivalence to the reference formulation. PMID:23812961

  19. A Phase II Randomised Controlled Trial Adding Oral Flucytosine to High Dose Fluconazole, with Short-course Amphotericin B, for Cryptococcal Meningitis

    PubMed Central

    Jackson, A; Nussbaum, J; Phulusa, J; Namarika, D; Chikasema, M; Kenyemba, C; Jarvis, JN; Jaffar, S; Hosseinipour, MC; van der Horst, C; Harrison, TS

    2013-01-01

    Background Cryptococcal meningitis (CM) in Africa is associated with up to 70% mortality at 3 months and 500,000 deaths annually. We examined strategies to improve on fluconazole monotherapy: addition of flucytosine (5-FC); and/or addition of short-course amphotericin B (AmB). Methods In step 1, previously reported, patients were randomized to receive FLU 1200 mg/d with or without 5-FC 100 mg/kg/day for 14 days. In step 2, 43 patients were similarly randomised, with addition of AmB 1 mg/kg/d for 7 days to both arms. After 2 weeks, patients received FLU monotherapy and were followed to 10 weeks. The primary endpoint was rate of clearance of infection (early fungicidal activity, EFA). Secondary endpoints related to safety and mortality. Results 40 patients (25% with Glasgow Coma Scale < 15) were analyzed. EFA for the triple combination arm was greater than for AmB+FLU: ?0.50 ± 0.15 log CFU/day vs. ?0.38 ± 0.19 log CFU/day (p = 0.03); and greater than step 1 with FLU+5-FC (?0.28 ± 0.17) or FLU alone (?0.11 ± 0.09). Combined analysis across steps revealed that addition of 5-FC and AmB had significant, independent additive effects on EFA, with trends toward fewer early deaths with addition of 5-FC (4/41 vs. 11/39, p = 0.05) and fewer deaths overall with addition of AmB (13/39 vs. 20/40, p = 0.1). Conclusions Addition of 5-FC and short course AmB to high-dose FLU significantly enhance EFA and may be associated with favourable trends in survival. Both these strategies should be tested in a larger phase III study. PMID:22526517

  20. Oral Appliances

    MedlinePLUS

    ... two categories. The diverse variety is simply a variation of a few major themes. Oral appliances can be classified by mode of action or design variation. Tongue Retaining Appliances Tongue retaining appliances hold the ...

  1. 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

    Ekwaru, John Paul; Zwicker, Jennifer D.; Holick, Michael F.; Giovannucci, Edward; Veugelers, Paul J.

    2014-01-01

    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

  2. Pharmacy Benefit Spending on Oral Chemotherapy Drugs

    Microsoft Academic Search

    FREDERIC R. CURTISS

    2006-01-01

    BACKGROUND: Pharmacy benefits have historically excluded injectable drugs, resulting in coverage of injectable drugs under the medical benefit. High-cost biologics and other new drug therapies are often injectables and therefore have not presented cost threats to pharmacy benefits. The U.S. Food and Drug Administration approval of capecitabine, an oral form of fluorouracil, in 1998, and imatinib mesylate in oral dose

  3. History of oral contraception.

    PubMed

    Dhont, Marc

    2010-12-01

    On the 50th birthday of the pill, it is appropriate to recall the milestones which have led to its development and evolution during the last five decades. The main contraceptive effect of the pill being inhibition of ovulation, it may be called a small miracle that this drug was developed long before the complex regulation of ovulation and the menstrual cycle was elucidated. Another stumbling block on its way was the hostile climate with regard to contraception that prevailed at the time. Animal experiments on the effect of sex steroids on ovulation, and the synthesis of sex steroids and orally active analogues were the necessary preliminaries. We owe the development of oral contraceptives to a handful of persons: two determined feminists, Margaret Sanger and Katherine McCormick; a biologist, Gregory Pincus; and a gynaecologist, John Rock. Soon after the introduction of the first pills, some nasty and life-threatening side effects emerged, which were due to the high doses of sex steroids. This led to the development of new preparations with reduced oestrogen content, progestins with more specific action, and alternative administration routes. Almost every decade we have witnessed a breakthrough in oral contraception. Social and moral objections to birth control have gradually disappeared and, notwithstanding some pill scares, oral contraceptives are now one of the most used methods of contraception. Finally, all's well that ends well: recent reports have substantiated the multiple noncontraceptive health benefits paving the way for a bright future for this 50-year-old product. PMID:21091163

  4. Chemoprevention of oral cancer: Green tea experience

    PubMed Central

    Ramshankar, Vijayalakshmi; Krishnamurthy, Arvind

    2014-01-01

    Oral cancer has a well characterized progression from premalignant oral epithelial changes to invasive cancer, making oral squamous cell carcinoma an optimal disease for chemoprevention interventions prior to malignant transformation. The primary goal of chemoprevention here is to reverse, suppress, or inhibit the progression of premalignant lesions to cancer. Due to the extended duration of oral pathogenesis, its chemoprevention using natural products has been found promising due to their decreased dose and limited toxicity profiles. This review discusses with an emphasis on the clinical trials using green tea extract (GTE) in chemoprevention of oral premalignant lesions along with use of GTE as a chemopreventive agent in various other cancers as well. It is worthwhile to include green tea extract in an oral screening program for evaluating the premalignant lesions comparing the results between the treated and untreated group. Given the wide acceptance of green tea, its benefits may help in effective chemoprevention oral cancer. PMID:24678188

  5. Effects of SiC nanoparticles orally administered in a rat model: Biodistribution, toxicity and elemental composition changes in feces and organs

    SciTech Connect

    Lozano, Omar, E-mail: omar.lozanogarcia@fundp.ac.be [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium) [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Research Centre for the Physics of Matter and Radiation (PMR-LARN), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Laloy, Julie; Alpan, Lütfiye [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium) [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Department of Pharmacy, NAMEDIC, Namur Thrombosis and Hemostasis Center (NTHC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Mejia, Jorge [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium) [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Research Centre for the Physics of Matter and Radiation (PMR-LARN), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Rolin, Stéphanie [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium) [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Department of Pharmacy, NAMEDIC, Namur Thrombosis and Hemostasis Center (NTHC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Toussaint, Olivier [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium) [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Laboratory of Biochemistry and Cellular Biology (URBC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); Dogné, Jean-Michel [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium) [Namur Nanosafety Center (NNC), NAmur Research Institute for LIfe Sciences (NARILIS), University of Namur - FUNDP, Rue de Bruxelles 61, B-5000 Namur (Belgium); Department of Pharmacy, NAMEDIC, Namur Thrombosis and Hemostasis Center (NTHC), University of Namur (FUNDP), Rue de Bruxelles 61, B-5000 Namur (Belgium); and others

    2012-10-15

    Background: Silicon carbide (SiC) presents noteworthy properties as a material such as high hardness, thermal stability, and photoluminescent properties as a nanocrystal. However, there are very few studies in regard to the toxicological potential of SiC NPs. Objectives: To study the toxicity and biodistribution of silicon carbide (SiC) nanoparticles in an in vivo rat model after acute (24 h) and subacute (28 days) oral administrations. The acute doses were 0.5, 5, 50, 300 and 600 mg·kg{sup ?1}, while the subacute doses were 0.5 and 50 mg·kg{sup ?1}. Results: SiC biodistribution and elemental composition of feces and organs (liver, kidneys, and spleen) have been studied by Particle-Induced X-ray Emission (PIXE). SiC and other elements in feces excretion increased by the end of the subacute assessment. SiC did not accumulate in organs but some elemental composition modifications were observed after the acute assessment. Histopathological sections from organs (stomach, intestines, liver, and kidneys) indicate the absence of damage at all applied doses, in both assessments. A decrease in the concentration of urea in blood was found in the 50 mg·kg{sup ?1} group from the subacute assessment. No alterations in the urine parameters (sodium, potassium, osmolarity) were found. Conclusion: This is the first study that assesses the toxicity, biodistribution, and composition changes in feces and organs of SiC nanoparticles in an in vivo rat model. SiC was excreted mostly in feces and low traces were retrieved in urine, indicating that SiC can cross the intestinal barrier. No sign of toxicity was however found after oral administration. -- Highlights: ? SiC nanoparticles were orally administered to rats in acute and subacute doses. ? SiC was found in low traces in urine. It is mostly excreted in feces within 5 days. ? SiC excretion rate, feces and organ elemental composition change with time. ? No morphological alteration were found on GI tract, liver, kidneys, or spleen. ? Urea increased in blood in the subacute assessment. No change in urine properties.

  6. Inductive Events in Oral Tolerance in the TCR Transgenic Adoptive Transfer Model

    Microsoft Academic Search

    Youhai Chen; Jun-ichi Inobe; Howard L. Weiner

    1997-01-01

    Oral administration of antigen induces a systemic hyporesponsiveness termed oral tolerance. High doses of oral antigen lead to deletion or anergy of T-cells whereas low doses induce regulatory T-cells that secrete Th2 cytokines (IL-4\\/IL-10) and TGF-?. The initiating events associated with oral tolerance have not been well characterized. We investigated the induction phase of oral tolerance by adoptively transferring ovalbulumin

  7. Original article The pharmacokinetics of moxidectin after oral

    E-print Network

    Paris-Sud XI, Université de

    of moxidectin were determined in ten sheep following a single subcutaneous or oral drench at a dose of 0.2 mg of the subcutaneous route in comparison with oral administration. © Inra/Elsevier, Paris moxidectin / sheepOriginal article The pharmacokinetics of moxidectin after oral and subcutaneous administration

  8. Intra-oral PTH Administration Promotes Tooth Extraction Socket Healing

    PubMed Central

    Kuroshima, S.; Kovacic, B.L.; Kozloff, K.M.; McCauley, L.K.; Yamashita, J.

    2013-01-01

    Intermittent parathyroid hormone (PTH) administration increases systemic and craniofacial bone mass. However, the effect of PTH therapy on healing of tooth extraction sites is unknown. The aims of this study were to determine the effect of PTH therapy on tooth extraction socket healing and to examine whether PTH intra-oral injection promotes healing. The mandibular first molars were extracted in rats, and subcutaneous PTH was administered intermittently for 7, 14, and 28 days. In a second study, maxillary second molars were extracted, and PTH was administered by either subcutaneous or intra-oral injection to determine the efficacy of intra-oral PTH administration. Healing was assessed by micro-computed tomography and histomorphometric analyses. PTH therapy accelerated the entire healing process and promoted both hard- and soft-tissue healing by increasing bone fill and connective tissue maturation. PTH therapy by intra-oral injection was as effective as subcutaneous injection in promoting tooth extraction socket healing. The findings suggest that PTH therapy promotes tooth extraction socket healing and that intra-oral injections can be used to administer PTH. PMID:23611925

  9. The effect of multiple doses of ketoconazole or rifampin on the single- and multiple-dose pharmacokinetics of vorapaxar.

    PubMed

    Kosoglou, Teddy; Statkevich, Paul; Kumar, Bharath; Xuan, Fengjuan; Schiller, James E; Johnson-Levonas, Amy O; Young, Sophia; Cutler, David L

    2013-05-01

    This randomized, open-label, parallel-group study evaluated the effects of multiple-dose ketoconazole or rifampin on the single- and multiple-dose pharmacokinetics of vorapaxar. Healthy subjects randomly received one of the following three treatments (N = 12/group): (1) ketoconazole 400 mg once daily (QD) for 28 days (Days 1-28) and single-dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.5 mg QD for 21 days (Days 8-28); (2) rifampin 600 mg QD for 28 days (Days 1-28) and single-dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.5 mg QD for 21 days (Days 8-28); and (3) placebo QD for 28 days (Days 1-28) and single-dose vorapaxar 20 mg on Day 7 followed by vorapaxar 2.5 mg QD for 21 days (Days 8-28). Ketoconazole increased the steady-state vorapaxar AUC(0-24 h) and C(max) by approximately twofold (GMR [90% CI]: 196% [173,222]; 193% [166,223], respectively), while rifampin decreased vorapaxar AUC(0-24 h) and C(max) by approximately 50% (GMR [90% CI]: 45.5% [40,52]; 61.4% [52,72], respectively) versus vorapaxar alone. Potent CYP3A4 inhibitors or inducers may cause moderate increases or decreases in vorapaxar exposure, respectively, which may have safety and/or efficacy implications; therefore, their concomitant use with vorapaxar is not recommended. PMID:23426761

  10. The Oral, Live Attenuated Enterotoxigenic Escherichia coli Vaccine ACE527 Reduces the Incidence and Severity of Diarrhea in a Human Challenge Model of Diarrheal Disease

    PubMed Central

    Chakraborty, Subhra; DeNearing, Barbara; Sack, David A.; Feller, Andrea; Buchwaldt, Charlotte; Bourgeois, A. Louis; Walker, Richard; Harro, Clayton D.

    2012-01-01

    An oral, live attenuated, three-strain recombinant bacterial vaccine, ACE527, was demonstrated to generate strong immune responses to colonization factor and toxin antigens of enterotoxigenic Escherichia coli (ETEC) in human volunteers. The vaccine was safe and well tolerated at doses of up to 1011 CFU, administered in each of two doses given 21 days apart. These observations have now been extended in a phase 2b study with a total of 70 subjects. Fifty-six of these subjects were challenged 28 days after the second dose of vaccine with the highly virulent ETEC strain H10407 to obtain preliminary indicators of efficacy against disease and to support further development of the vaccine for both travelers and infants in countries where ETEC is endemic. The vaccine had a significant impact on intestinal colonization by the challenge strain, as measured by quantitative fecal culture 2 days after challenge, demonstrating the induction of a functional immune response to the CFA/I antigen. The incidence and severity of diarrhea were also reduced in vaccinees as measured by a number of secondary and ad hoc endpoints, although the 27% reduction seen in the primary endpoint, moderate to severe diarrhea, was not statistically significant. Together, these observations support the hypothesis that the ACE527 vaccine has a dual mode of action, targeting both colonization factors and the heat-labile enterotoxin (LT), and suggest that it should be further developed for more advanced trials to evaluate its impact on the burden of ETEC disease in field settings. PMID:23035175

  11. 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 Central

    Rodon, Jordi; Carducci, Michael A.; Sepulveda-Sánchez, Juan M; Azaro, Analia; Calvo, Emiliano; Seoane, Joan; Braña, Irene; Sicart, Elisabet; Gueorguieva, Ivelina; Cleverly, Ann L.; Pillay, N. Sokalingum; Desaiah, Durisala; Estrem, Shawn T.; Paz-Ares, Luis; Holdhoff, Matthias; Blakeley, Jaishri; Lahn, Michael M.; Baselga, Jose

    2015-01-01

    Purpose 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 patients with cancer. 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. Antitumor 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 of 56 patients with glioma (21.4%). LY2157299 was safe, with no cardiac adverse events. Conclusions On the basis of the safety, pharmacokinetics, and antitumor activity in patients with glioma, the intermittent administration of LY2157299 at 300 mg/day is safe for future clinical investigation. PMID:25424852

  12. Oral Cancer

    MedlinePLUS

    ... treatment by an SLP are important to restore speech intelligibility and swallowing skills. Treatment often includes helping people get used to the differences in the size, shape, and feel of their mouth. The SLP will ... how to produce speech sounds more clearly. Oral exercises help the client ...

  13. Oral tolerance

    Microsoft Academic Search

    P Garside; A. McI Mowat

    2001-01-01

    The ability of the mucosal immune system to distinguish between harmful and harmless antigens is essential for mounting protective immune responses and preventing the induction of mucosal pathology yet the basis for this remains unclear. As fed antigen can also exert systemic effects understanding oral tolerance and priming will also have important consequences for therapy and vaccination. Here we will

  14. Oral Care

    Microsoft Academic Search

    Irène Hitz Lindenmüller; J. Thomas Lambrecht

    2011-01-01

    Adequate dental and oral hygiene may become a challenge for all users and especially for elderly people and young children because of their limited motor skills. The same holds true for patients undergoing\\/recovering from chemo-\\/radiotherapy with accompanying sensitive mucosal conditions. Poor dental hygiene can result in tooth decay, gingivitis, periodontitis, tooth loss, bad breath (halitosis), fungal infection and gum diseases.

  15. Human aqueous humor levels of oral ciprofloxacin, levofloxacin, and moxifloxacin

    Microsoft Academic Search

    Maria Carmen Garc??a-Sáenz; Alfonso Arias-Puente; Mar??a José Fresnadillo-Martinez

    2001-01-01

    Purpose: To evaluate the penetration of ciprofloxacin, levofloxacin, and moxifloxacin into the aqueous humor after oral administration.Setting: Alcorcon Hospital, Madrid, Spain.Methods: Forty-two patients having cataract surgery were randomly divided into 3 groups the day before surgery. The first group received 2 oral 500 mg doses of ciprofloxacin at 12-hour intervals. The second group received a single oral 500 mg dose

  16. Oral care.

    PubMed

    Hitz Lindenmüller, Irène; Lambrecht, J Thomas

    2011-01-01

    Adequate dental and oral hygiene may become a challenge for all users and especially for elderly people and young children because of their limited motor skills. The same holds true for patients undergoing/recovering from chemo-/radiotherapy with accompanying sensitive mucosal conditions. Poor dental hygiene can result in tooth decay, gingivitis, periodontitis, tooth loss, bad breath (halitosis), fungal infection and gum diseases. The use of a toothbrush is the most important measure for oral hygiene. Toothbrushes with soft bristles operated carefully by hand or via an electric device help to remove plaque and to avoid mucosal trauma. A handlebar with a grip cover can be helpful for manually disabled patients or for those with reduced motor skills. In case of oral hygiene at the bedside or of patients during/after chemo-/radiotherapy a gauze pad can be helpful for gently cleaning the teeth, gums and tongue. The use of fluoride toothpaste is imperative for the daily oral hygiene. Detergents such as sodium lauryl sulphate improve the cleaning action but may also dehydrate and irritate the mucous membrane. The use of products containing detergents and flavouring agents (peppermint, menthol, cinnamon) should therefore be avoided by bedridden patients or those with dry mouth and sensitive mucosa. Aids for suitable interdental cleaning, such as dental floss, interdental brushes or dental sticks, are often complicated to operate. Their correct use should be instructed by healthcare professionals. To support dental care, additional fluoridation with a fluoride gel or rinse can be useful. Products further containing antiseptics such as chlorhexidine or triclosan reduce the quantity of bacteria in the mouth. For patients undergoing or having undergone radio-/chemotherapy, a mouthwash that concomitantly moisturizes the oral mucosa is advisable. PMID:21325845

  17. Oral Tolerance: Therapeutic Implications for Autoimmune Diseases

    PubMed Central

    Faria, Ana M. C.; Weiner, Howard L.

    2006-01-01

    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 cl