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Sample records for single oral dose

  1. Single oral dose safety of D-allulose in dogs

    PubMed Central

    NISHII, Naohito; NOMIZO, Toru; TAKASHIMA, Satoshi; MATSUBARA, Tatsuya; TOKUDA, Masaaki; KITAGAWA, Hitoshi

    2016-01-01

    Healthy dogs were administered acute oral doses of D-allulose (also called D-psicose) to evaluate its toxicity. Six dogs received oral doses of either a placebo or D-allulose solution (1 and 4 g/kg) on three different study days. One dog experienced vomiting, and five dogs showed transient diarrhea when 4 g/kg of D-allulose was administered. All dogs were active and had a good appetite throughout the study period. Blood glucose concentration slightly decreased without a rise in plasma insulin concentration 2 hr after D-allulose administration. Plasma alkaline phosphatase activities showed a mild increase between 12 and 48 hr after D-allulose administration. These data suggested that a single oral dose of D-allulose does not show severe toxicity in dogs. PMID:26972334

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

    PubMed Central

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

    2014-01-01

    Background Diclofenac is a non-steroidal anti-inflammatory drug (NSAID), available as a potassium salt (immediate-release) or sodium salt (delayed-release). This review updates an earlier review published in The Cochrane Database of Systematic Reviews (Issue 2, 2004) on ‘Single dose oral diclofenac for postoperative pain’. Objectives To assess single dose oral diclofenac for the treatment of acute postoperative pain. Search methods Cochrane CENTRAL, MEDLINE, EMBASE, Biological Abstracts, the Oxford Pain Relief Database, and reference lists of articles were searched; last search December 2008. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of single dose, oral diclofenac (sodium or potassium) for acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed studies for inclusion and quality, and extracted data. The area under the pain relief versus time curve was used to derive the proportion of participants with at least 50% pain relief over 4 to 6 hours, using validated equations. Relative benefit (risk) and number needed to treat to benefit (NNT) were calculated. Information on adverse events, time to remedication, and participants needing additional analgesia was also collected. Main results Fifteen studies (eight additional studies) with 1512 participants more than doubled the information available at each dose. Overall 50% to 60% of participants experienced at least 50% pain relief over 4 to 6 hours at any dose with diclofenac, compared to 10 to 20% with placebo, giving NNTs of about 2.5 for doses of 25 mg to 100 mg (similar to earlier review); no dose response was demonstrated. At 50 mg and 100 mg, NNTs for diclofenac potassium (2.1 (1.8 to 2.4) and 1.9 (1.7 to 2.2)) were significantly lower (better) than for diclofenac sodium (6.7 (4.2 to 17) and 4.5 (3.2 to 7.7)). The median time to use of rescue medication was 2 hours for placebo, 4.3 hours for diclofenac 50 mg and 4.9 hours

  3. Single oral dose proportionality pharmacokinetics of almitrine bismesylate in humans.

    PubMed

    Stavchansky, S; Doluisio, J T; Macleod, C M; Szalkowski, M B; Bachand, R T; Heilman, R; Sebree, T B; Geary, R S

    1989-01-01

    A single-blind study was conducted in 10 healthy male subjects. Each subject was tested with four single oral doses of capsules containing 25, 50, 100, 200mg almitrine bismesylate and one dose of placebo. Blood samples were drawn as a function of time and the concentration of almitrine in plasma was determined by gas chromatography utilizing nitrogen-phosphorus detection. Linear regression analysis of the data suggested that a deviation from linearity existed between the area under the plasma concentration time curves and the dose (R = 0.96). Linear analysis of the individual data indicates that a slight negative deviation from linearity is apparent for the 200 mg dose. The same trend was observed for the mean maximum almitrine plasma concentration, Cmax, which ranged from 38.9 +/- 11.8 to 286.2 +/- 99.1 ng ml-1 for the 25 and 200 mg dose, respectively. The time to peak was relatively constant regardless of the administered dose and ranged from 2.4 +/- 0.5 h to 2.8 +/- 0.8 h. Good agreement was obtained between the observed bioavailability parameters and those predicted from the nonlinear fit of the data. Further kinetic analysis of the data revealed mean total body clearance over fraction of dose absorbed ranging from 268.2 +/- 132.8 to 436.4 +/- 191.4 ml min-1 for doses 50 and 200mg, respectively. PMID:2566337

  4. Pharmacokinetics of single-dose oral ponazuril in weanling goats.

    PubMed

    Love, D; Gibbons, P; Fajt, V; Jones, M

    2016-06-01

    Ponazuril (toltrazuril sulfone) is a triazine antiprotozoal agent that targets apicomplexan organisms. Ponazuril may have clinical application in the treatment of clinical coccidiosis due to Eimeria species in goats, along with other protozoal infections. To evaluate the absorption, distribution and elimination characteristics of ponazuril in goats, a sensitive, validated high-pressure liquid chromatography and mass spectroscopy method for ponazuril in caprine plasma was developed. After a single oral dose of ponazuril at 10 mg/kg, plasma samples from seven weanling goats were collected and assayed. Plasma concentrations of ponazuril in the goats peaked at 36 ± 13 h post drug administration at a concentration of 9 ± 2 μg/mL. Concentrations declined to an average of 4.2 ± 0.8 μg/mL after 168 h with an average elimination half-life of 129 ± 72 h post drug administration. This study shows that ponazuril is relatively well absorbed after a single oral dose in goats. Efficacy trials are underway to determine clinical efficacy of ponazuril in the treatment of clinical coccidiosis in goats at 10 mg/kg dosage. PMID:26542450

  5. Single-Dose Radiation-Induced Oral Mucositis Mouse Model

    PubMed Central

    Maria, Osama Muhammad; Syme, Alasdair; Eliopoulos, Nicoletta; Muanza, Thierry

    2016-01-01

    The generation of a self-resolved radiation-induced oral mucositis (RIOM) mouse model using the highest possibly tolerable single ionizing radiation (RT) dose was needed in order to study RIOM management solutions. We used 10-week-old male BALB/c mice with average weight of 23 g for model production. Mice were treated with an orthovoltage X-ray irradiator to induce the RIOM ulceration at the intermolar eminence of the animal tongue. General anesthesia was injected intraperitoneally for proper animal immobilization during the procedure. Ten days after irradiation, a single RT dose of 10, 15, 18, 20, and 25 Gy generated a RIOM ulcer at the intermolar eminence (posterior upper tongue surface) with mean ulcer floor (posterior epithelium) heights of 190, 150, 25, 10, and 10 μm, respectively, compared to 200 μm in non-irradiated animals. The mean RIOM ulcer size % of the total epithelialized upper surface of the animal tongue was RT dose dependent. At day 10, the ulcer size % was 2, 5, 27, and 31% for 15, 18, 20, and 25 Gy RT, respectively. The mean relative surface area of the total epithelialized upper surface of the tongue was RT dose dependent, since it was significantly decreased to 97, 95, 88, and 38% with 15, 18, 20, and 25 Gy doses, respectively, at day 10 after RT. Subcutaneous injection of 1 mL of 0.9% saline/6 h for 24 h yielded a 100% survival only with 18 Gy self-resolved RIOM, which had 5.6 ± 0.3 days ulcer duration. In conclusion, we have generated a 100% survival self-resolved single-dose RIOM male mouse model with long enough duration for application in RIOM management research. Oral mucositis ulceration was radiation dose dependent. Sufficient hydration of animals after radiation exposure significantly improved their survival. PMID:27446800

  6. Single dose oral piroxicam for acute postoperative pain

    PubMed Central

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

    2014-01-01

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

  7. 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

  8. Single dose oral lumiracoxib for postoperative pain in adults

    PubMed Central

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

    2014-01-01

    Background Lumiracoxib is a selective cyclooxygenase-2 (COX-2) inhibitor. COX-2 inhibitors were developed to avoid COX-1-related gastrointestinal (GI) problems while maintaining the analgesic and anti-inflammatory activity of traditional non-steriodal anti-inflammatory drugs (NSAIDs). Objectives To review the analgesic efficacy, duration of analgesia, and adverse effects of a single oral dose of lumiracoxib for moderate to severe postoperative pain in adults. Search methods We searched Cochrane CENTRAL, MEDLINE, and EMBASE to February 2010. Selection criteria Single oral dose, randomised, double-blind, placebo-controlled trials of lumiracoxib for relief of established moderate to severe postoperative pain in adults. Data collection and analysis Studies were assessed for methodological quality and the data extracted by two review authors independently. Summed total pain relief over six hours (TOTPAR 6) was used to calculate the number of participants achieving at least 50% pain relief. These derived results were used to calculate, with 95% confidence intervals, the relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over six hours. Numbers of participants using rescue medication, and time to use of rescue medication, were sought as additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results In this updated review four studies met the inclusion criteria. In total 366 participants were treated with lumiracoxib 400 mg, 51 with lumiracoxib 100 mg, and 212 with placebo. Active comparators were naproxen 500 mg, rofecoxib 50 mg, celecoxib 200 mg, celecoxib 400 mg, and ibuprofen 400 mg. With lumiracoxib 400 mg 50% of participants had at least 50% pain relief over six hours, compared with 8% given placebo; RB 6.9 (95% CI 4.1 to 12), NNT 2.4 (2.1 to 2.8). Median time to onset of analgesia was shorter for lumiracoxib 400 mg (0.6 to 1.5 hours) than

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

    PubMed Central

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

    2014-01-01

    Background This is an updated version of the original Cochrane review published in Issue 1, 2004 - this original review had been split from a previous title on ‘Single dose paracetamol (acetaminophen) with and without codeine for postoperative pain’. The last version of this review concluded that paracetamol is an effective analgesic for postoperative pain, but additional trials have since been published. This review sought to evaluate the efficacy and safety of paracetamol using current data, and to compare the findings with other analgesics evaluated in the same way. Objectives To assess the efficacy of single dose oral paracetamol for the treatment of acute postoperative pain. Search methods We searched The Cochrane Library, MEDLINE, EMBASE, the Oxford Pain Relief Database and reference lists of articles to update an existing version of the review in July 2008. Selection criteria Randomised, double-blind, placebo-controlled clinical trials of paracetamol for acute postoperative pain in adults. Data collection and analysis Two review authors independently assessed trial quality and extracted data. Area under the “pain relief versus time” curve was used to derive the proportion of participants with paracetamol or placebo experiencing at least 50% pain relief over four to six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated, with 95% confidence intervals (CI). The proportion of participants using rescue analgesia over a specified time period, and time to use, were sought as measures of duration of analgesia. Information on adverse events and withdrawals was also collected. Main results Fifty-one studies, with 5762 participants, were included: 3277 participants were treated with a single oral dose of paracetamol and 2425 with placebo. About half of participants treated with paracetamol at standard doses achieved at least 50% pain relief over four to six hours, compared with about 20% treated with placebo. NNTs for at

  10. 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

  11. 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

  12. 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

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

    PubMed Central

    Roh, Seong-Soo

    2010-01-01

    This study was conducted to obtain acute information of the oral dose toxicity of DHU001, a polyherbal formula in male and female mice. In order to calculated 50% lethal dose (LD50) and approximate lethal dose (LD) , test material was once orally administered to male and female ICR mice at dose levels of 2000, 1000, 500, 250 and 0 (vehicle control) ml/kg (body weight) . The mortality and changes on body weight, clinical signs, gross observation, organ weight and histopathology of principle organs were monitored 14 days after treatment with DHU001. We could not find any mortalities, DHU001 treatment-related clinical signs, changes on the body and organ weights, gross and histopathological findings. The results obtained in this study suggest that LD50 and approximate LD in mice after single oral dose of DHU001 were considered over 2000 mg/kg in both female and male mice. PMID:24278506

  14. 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...

  15. Bioavailability of ambroxol sustained release preparations. Part II: Single and multiple oral dose studies in man.

    PubMed

    Janssen, T J; Guelen, P J; Vree, T B; Botterblom, M H; Valducci, R

    1988-01-01

    The bioavailability of a new ambroxol sustained release preparation (75 mg) based on a dialyzing membrane for controlled release was studied in healthy volunteers after single and multiple oral dose in comparison with a standard sustained release formulation in a cross-over study under carefully controlled conditions. Plasma concentrations of ambroxol were measured by means of a HPLC method. Based on AUC data both preparations are found to be bioequivalent, but show different plasma concentration profiles. The test preparation showed a more pronounced sustained release profile than the reference preparation (single dose) resulting in significantly higher steady state plasma levels. PMID:3365282

  16. Miltefosine Lipid Nanocapsules for Single Dose Oral Treatment of Schistosomiasis Mansoni: A Preclinical Study

    PubMed Central

    Eissa, Maha M.; El-Moslemany, Riham M.; Ramadan, Alyaa A.; Amer, Eglal I.; El-Azzouni, Mervat Z.; El-Khordagui, Labiba K.

    2015-01-01

    Miltefosine (MFS) is an alkylphosphocholine used for the local treatment of cutaneous metastases of breast cancer and oral therapy of visceral leishmaniasis. Recently, the drug was reported in in vitro and preclinical studies to exert significant activity against different developmental stages of schistosomiasis mansoni, a widespread chronic neglected tropical disease (NTD). This justified MFS repurposing as a potential antischistosomal drug. However, five consecutive daily 20 mg/kg doses were needed for the treatment of schistosomiasis mansoni in mice. The present study aims at enhancing MFS efficacy to allow for a single 20mg/kg oral dose therapy using a nanotechnological approach based on lipid nanocapsules (LNCs) as oral nanovectors. MFS was incorporated in LNCs both as membrane-active structural alkylphospholipid component and active antischistosomal agent. MFS-LNC formulations showed high entrapment efficiency (EE%), good colloidal properties, sustained release pattern and physical stability. Further, LNCs generally decreased MFS-induced erythrocyte hemolytic activity used as surrogate indicator of membrane activity. While MFS-free LNCs exerted no antischistosomal effect, statistically significant enhancement was observed with all MFS-LNC formulations. A maximum effect was achieved with MFS-LNCs incorporating CTAB as positive charge imparting agent or oleic acid as membrane permeabilizer. Reduction of worm load, ameliorated liver pathology and extensive damage of the worm tegument provided evidence for formulation-related efficacy enhancement. Non-compartmental analysis of pharmacokinetic data obtained in rats indicated independence of antischistosomal activity on systemic drug exposure, suggesting possible gut uptake of the stable LNCs and targeting of the fluke tegument which was verified by SEM. The study findings put forward MFS-LNCs as unique oral nanovectors combining the bioactivity of MFS and biopharmaceutical advantages of LNCs, allowing targeting

  17. PHARMACOKINETICS OF SINGLE-DOSE ORALLY ADMINISTERED CIPROFLOXACIN IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

    PubMed

    Barbosa, Lorraine; Johnson, Shawn P; Papich, Mark G; Gulland, Frances

    2015-06-01

    Ciprofloxacin is commonly selected for clinical use due to its broad-spectrum efficacy and is a frequently administered antibiotic at The Marine Mammal Center, a marine mammal rehabilitation facility. Ciprofloxacin is used for treatment of California sea lions ( Zalophus californianus ) suffering from a variety of bacterial infections at doses extrapolated from other mammalian species. However, as oral absorption is variable both within and across species, a more accurate determination of appropriate dosage is needed to ensure effective treatment and avoid emergence of drug-resistant bacterial strains. A pharmacokinetic study was performed to assess plasma concentrations of ciprofloxacin in California sea lions after a single oral dose. Twenty healthy California sea lions received a single 10-mg/kg oral dose of ciprofloxacin administered in a herring fish. Blood was then collected at two of the following times from each individual: 0.5, 0.75, 1, 2, 4, 8, 10, 12, 18, and 24 hr postingestion. Plasma ciprofloxacin concentration was assessed via high-performance liquid chromatography. A population pharmacokinetics model demonstrated that an oral ciprofloxacin dose of 10 mg/kg achieved an area under the concentration vs. time curve of 6.01 μg hr/ml. Absorption was rapid, with ciprofloxacin detectable in plasma 0.54 hr after drug administration; absorption half-life was 0.09 hr. A maximum plasma concentration of 1.21 μg/ml was observed at 1.01 hr, with an elimination half-life of 3.09 hr. Ciprofloxacin administered orally at 10 mg/kg produced therapeutic antibacterial exposure for only some of the most susceptible bacterial organisms commonly isolated from California sea lions. PMID:26056878

  18. Guaifenesin Pharmacokinetics Following Single-Dose Oral Administration in Children Aged 2 to 17 Years.

    PubMed

    Thompson, Gary A; Solomon, Gail; Albrecht, Helmut H; Reitberg, Donald P; Guenin, Eric

    2016-07-01

    This study characterized guaifenesin pharmacokinetics in children aged 2 to 17 years (n = 40) who received a single oral dose of guaifenesin (age-based doses of 100-400 mg) 2 hours after breakfast. Plasma samples were obtained before and for 8 hours after dosing and analyzed for guaifenesin using liquid chromatography-tandem mass spectrometry. Pharmacokinetic parameters were estimated using noncompartmental methods, relationships with age were assessed using linear regression, and dose proportionality was assessed on 95% confidence intervals. Based on the upper dose recommended in the monograph (for both children and adolescents), area under the curve from time zero to infinity and maximum plasma concentration both increased with age. However, when comparing the upper dose for children aged 2 to 11 years with the lower dose for adolescents aged 12 to 17 years, similar systemic exposure was observed. As expected due to increasing body size, oral clearance (CLo ) and terminal volume of distribution (Vz /F) increased with age. Due to a larger increase in Vz /F than CLo , an increase in terminal exponential half-life was also observed. Allometric scaling indicated no maturation-related changes in CLo and Vz /F. PMID:26632082

  19. 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

  20. Pharmacokinetics and cyclooxygenase inhibition of itazigrel in normal volunteers after single oral doses.

    PubMed

    Hsyu, P H; Koets, M D; Luderer, J R

    1994-12-01

    The pharmacokinetics and cyclooxygenase inhibition of itazigrel were studied in normal male volunteers. In a low-dose study, subjects received a single oral dose of 5-100 mg of itazigrel. Serum concentration and the production rate of thromboxane B2, an indicator of cyclooxygenase activity, were monitored for 48 h. In a high-dose study, single oral doses of 100-600 mg of itazigrel were administered. Serum concentrations were monitored for 72 h. Production rates of thromboxane B2 and leukotriene B4, an indicator of lipoxygenase activity, were monitored for the first 2 h after drug administration. Pharmacokinetics of itazigrel appeared to follow biexponential elimination with an alpha half-life between 1.2 and 2 h and a beta half-life between 23 and 28 h. The relationship between dose and area under the serum concentration curve was nonlinear, probably due to saturable systemic metabolism or saturable first-pass metabolism. Cyclooxygenase inhibition by itazigrel was related to the serum concentration by the Hill's equation with a mean IC50 value of 2.1 ng/mL. Itazigrel did not appear to affect the lipoxygenase activity in the study. PMID:7891305

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

    PubMed

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

    2011-12-01

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

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

    PubMed

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

    2015-06-01

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

  3. Evidence for CVD 103-HgR as an effective single-dose oral cholera vaccine.

    PubMed

    Jackson, Sarah S; Chen, Wilbur H

    2015-01-01

    We propose the ideal oral cholera vaccine (OCV) should be an inexpensive, single, oral dose that rapidly confers immunity for a long duration, and is well tolerated by individuals vulnerable to cholera. Vaccine trials in industrialized countries of a single oral dose of 5 × 10(8) colony forming units (CFU) of the live, attenuated cholera strain CVD 103-HgR have shown 88-97% serum vibriocidal antibody seroconversion rates, a correlate of protection and documented vaccine efficacy of ≥80% using volunteer challenge studies with wild-type cholera. For individuals of developing countries, a 5 × 10(9) CFU dose of CVD 103-HgR is necessary to elicit similar antibody responses. Presently, a reformulation of CVD 103-HgR is in late-stage clinical development for prospective US FDA licensure; making a cholera vaccine for US travelers potentially accessible in 2016. The availability of CVD 103-HgR should be a welcome addition to the currently available OCVs. PMID:26228388

  4. Single Oral Dose Toxicity Test of Platycodin D, a Saponin from Platycodin Radix in Mice

    PubMed Central

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

    2011-01-01

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

  5. Safety and pharmacokinetics of dicloxacillin in healthy Chinese volunteers following single and multiple oral doses

    PubMed Central

    Wu, Guolan; Zheng, Yunliang; Zhou, Huili; Hu, Xingjiang; Liu, Jian; Zhai, You; Zhu, Meixiang; Wu, Lihua; Shentu, Jianzhong

    2015-01-01

    Background Dicloxacillin, a semisynthetic isoxazolyl penicillin antibiotic, has antimicrobial activity against a wide variety of gram-positive bacteria including Staphylococcus aureus, Streptococcus pyogenes, Streptococcus pneumonia, Streptococcus epidermidis, Streptococcus viridans, Streptococcus agalactiae, and Neisseria meningitidis. The objective of this study was to evaluate the safety and pharmacokinetic profile of dicloxacillin after single and multiple oral dose in healthy Chinese volunteers. Methods A single-center, open-label, randomized, two-phase study was conducted in 16 subjects. In the single-dose phase, subjects were randomly assigned to receive single doses of 0.25, 0.5, 1.0, and 2.0 g of dicloxacillin sodium capsule in a 4-way crossover design with a 5-day washout period between administrations. In the multiple-dose phase, subjects were assigned to receive 0.25 or 0.5 g every 6 hours for 3 days in a 2-way crossover design. Plasma and urine pharmacokinetic samples were assayed by a validated high-performance liquid chromatography-tandem mass spectrometry method. Pharmacokinetic parameters were calculated and analyzed statistically. Safety assessments were conducted throughout the study. Results Following a single oral dose of 0.25–2.0 g dicloxacillin sodium, the maximum plasma drug concentration (Cmax) and the corresponding values for the area under the concentration– time curve from 0 to 10 hours (AUC0–10 h) increased in a dose-proportional manner. The mean elimination half-life (t1/2) was in the range of 1.38–1.71 hours. Dicloxacillin was excreted in its unchanged form via the kidney, with no tendency of accumulation, and varied from 38.65% to 50.10%. No appreciable accumulation of drug occurred with multiple oral doses of dicloxacillin. No serious adverse events were reported. Adverse events were generally mild. Conclusion Dicloxacillin was safe and well tolerated in the volunteers and displayed linear increases in the Cmax and AUC0–10

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

    PubMed

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

    2015-08-01

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

  7. 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

  8. Detection of marijuana use by oral fluid and urine analysis following single-dose administration of smoked and oral marijuana.

    PubMed

    Niedbala, R S; Kardos, K W; Fritch, D F; Kardos, S; Fries, T; Waga, J; Robb, J; Cone, E J

    2001-01-01

    We compared oral fluid testing to urine testing in subjects who were administered single doses of marijuana by smoked and oral routes. Oral fluid specimens were collected with the Intercept DOA Oral Specimen Collection Device, screened for THC with the Cannabinoids Intercept MICRO-PLATE Enzyme Immunoassay (EIA) utilizing a 1.0-ng/mL cutoff concentration, and confirmed for THC by gas chromatography-tandem mass spectrometry (GC-MS-MS) with a 0.5-ng/mL cutoff concentration. Urine specimens were screened for 11-nor-carboxy-delta9-tetrahydrocannabinol (THCCOOH) by immunoassay utilizing a 50-ng/mL cutoff concentration and confirmed for THCCOOH by GC-MS with a 15-ng/mL cutoff concentration. Oral fluid specimens tested positive following smoked marijuana (N = 10) consecutively for average periods (+/-SEM; range) of 15 (+/-2; 1-24) and 13 h (+/-3; 1-24) by EIA and GC-MS-MS, respectively. The average THC detection times of the last oral fluid positive specimen following smoked marijuana by EIA and GC-MS-MS were 31 (+/-9; 1-72) and 34 h (+/-11; 1-72), respectively. In comparison to oral fluid, urine specimens generally tested negative for THCCOOH immediately after marijuana use. The average times to detection of the first urine specimen positive for THCCOOH by EIA and GC-MS were 6 (+/-2; 1-16) and 4 h (+/-1; 2-8), respectively. Urine specimens tested positive consecutively for average periods of 26 (+/-9; 2-72) and 33 h (+/-10; 4-72) for EIA and GC-MS, respectively. The average THCCOOH detection times of the last specimen by EIA and GC-MS were 42 (+/-10; 2-72) and 58 h (+/-6; 16-72), respectively. Considering the noninvasive nature of oral fluid collection and improved detection of recent marijuana use compared to urine testing, it was concluded that oral fluid testing for THC offers specific advantages over other means of marijuana testing when used in safety-sensitive testing programs. PMID:11499881

  9. Single-dose oral toxicity of fermented rice extracts (FREs): a 14-day observation.

    PubMed

    Choi, Jae-Suk; Kim, Joo-Wan; Kim, Ki-Young; Ku, Sae-Kwang; Sohn, Jae Hak

    2014-01-01

    The aim of present research was to determine the acute oral toxicity of fermented rice extracts (FREs), in female and male ICR mice. To investigate the toxicity and identify target organs, FREs were orally administered once to male and female ICR mice at doses of 0 (vehicle control), 500, 1000, or 2000 mg/kg body weight (BW). Effects on mortality, BW, and clinical signs were monitored over 14 days, including changes in the weights and histopathological characteristics of 14 organs, as described in the Korea Food and Drug Administration (KFDA) Guidelines (2009-116, 2009). No treatment-related mortality was observed during the 14-day observation period in either gender. In addition, no FRE-related change was observed in BW or organ weight (OW), clinical indicators, or histopathological findings in this study. Our results suggest that the FRE is non-toxic in mice and is therefore likely to be safe for clinical use. The approximate LD and LD50 in mice after single oral dose of FRE are greater than 2000 mg/kg in female and male ICR mice. Additionally, no specific target organ or negative clinical indicator was detected in this study. PMID:24374435

  10. Concentrations of cefpodoxime in plasma and pleural fluid after a single oral dose of cefpodoxime proxetil.

    PubMed

    Dumont, R; Guetat, F; Andrews, J M; Sultan, E; Lenfant, B

    1990-12-01

    Eighteen patients of either sex with pleural effusions underwent aspiration 3, 6 or 12 h after receiving a single oral dose of cefpodoxime proxetil equivalent to 200 mg cefpodoxime. The mean concentrations of cefpodoxime in pleural fluid were, respectively, 0.62, 1.84 and 0.78 mg/l for these three time intervals, the corresponding ratios between pleural fluid and plasma concentrations being 0.24, 0.67 and 1.07. The findings indicate that there is good penetration of cefpodoxime into pleural fluid. Concentrations between 3 and 12 h after dosing were equal to or above the MIC90 for most of the organisms commonly found in lower respiratory tract infections. PMID:2292529

  11. Successful comeback of the single-dose live oral cholera vaccine CVD 103-HgR.

    PubMed

    Herzog, Christian

    2016-01-01

    Effective and easy to administer cholera vaccines are in need more than ever, for at risk populations and travellers alike. In many parts of the world cholera is still endemic, causing outbreaks and constituting repeatedly serious public health problems. The oral live cholera vaccine CVD 103-HgR (Orochol, Mutachol), the first genetically modified organism (GMO) used as vaccine, was in its time (launched 1993, Switzerland) the ideal cholera vaccine: single-dose, protective efficacy of 80-100% against moderate to severe cholera, acting within 8 days and exhibiting excellent safety, indiscernible from placebo. However, there were strong headwinds: In the 1990s the indication for cholera vaccines was generally downplayed by experts and in 1997 the European Commission called for a moratorium of GMOs which blocked the registration in the European Union. Thus, demand for this vaccine remained low and in 2003 it was taken off the market for economic reasons. After a decade in obscurity it (Vaxchora) has resurfaced again, now produced in the U.S. and equipped with a U.S. FDA license (June 10, 2016). What had happened? This commentary gives a critical account of an almost unbelievable string of misadventures, emerging adverse circumstances and man-made failures which nearly killed this single-dose live oral cholera vaccine. The good news is that patience and persistence lead to success in the end, allowing good science to prevail for the benefit of those in need. PMID:27425792

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

    PubMed

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

    2009-09-01

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

  13. 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

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

    SciTech Connect

    Kopp, Eva Katharina; Dekant, Wolfgang

    2009-03-01

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

  15. 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

  16. 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

  17. Single oral dose toxicity test of blue honeysuckle concentrate in mice.

    PubMed

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

    2015-03-01

    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

  18. 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

  19. Pharmacokinetics of difloxacin in pigs and broilers following intravenous, intramuscular, and oral single-dose applications.

    PubMed

    Ding, H Z; Yang, G X; Huang, X H; Chen, Z L; Zeng, Z L

    2008-06-01

    Pharmacokinetics of difloxacin, a fluoroquinolone antibiotic, was determined in pigs and broilers after intravenous (i.v.), intramuscular (i.m.), or oral (p.o.) administration at a single dose of five (pigs) or 10 mg/kg (broilers). Plasma concentration profiles were analyzed by a compartmental pharmacokinetic method. Following i.v., i.m. and p.o. doses, the elimination half-lives (t(1/2beta)) were 17.14 +/- 4.14, 25.79 +/- 8.10, 16.67 +/- 4.04 (pigs) and 6.11 +/- 1.50, 5.64 +/- 0.74, 8.20 +/- 3.12 h (broilers), respectively. After single i.m. and p.o. administration, difloxacin was rapidly absorbed, with peak plasma concentrations (C(max)) of 1.77 +/- 0.66, 2.29 +/- 0.85 (pigs) and 2.51 +/- 0.36, 1.00 +/- 0.21 microg/mL (broilers) attained at t(max) of 1.29 +/- 0.26, 1.41 +/- 0.88 (pigs) and 0.86 +/- 0.4, 4.34 +/- 2.40 h (broilers), respectively. Bioavailabilities (F) were (95.3 +/- 28.9)% and (105.7 +/- 37.1)% (pigs) and (77.0 +/- 11.8)% and (54.2 +/- 12.6)% (broilers) after i.m. and p.o. doses, respectively. Apparent distribution volumes(V(d(area))) of 4.91 +/- 1.88 and 3.10 +/- 0.67 L/kg and total body clearances(Cl(B)) of 0.20 +/- 0.06 and 0.37 +/- 0.10 L/kg/h were determined in pigs and broilers, respectively. Areas under the curve (AUC), the half-lives of both absorption and distribution(t(1/2ka), t(1/2alpha)) were also determined. Based on the single-dose pharmacokinetic parameters determined, multiple dosage regimens were recommended as: a dosage of 5 mg/kg given intramuscularly every 24 h in pigs, or administered orally every 24 h at the dosage of 10 mg/kg in broilers, can maintain effective plasma concentrations with bacteria infections, in which MIC(90) are <0.25 microg/mL and <0.1 microg/mL respectively. PMID:18471140

  20. Comparative metabolism studies of hexabromocyclododecane (HBCD) diastereomers in male rats following a single oral dose

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Male Sprague-Dawley rats were dosed orally with 3 mg/kg of one of three hexabromocyclododecane (HBCD) diastereomers. Each diastereomer was well absorbed (73-83%), and distributed preferentially to lipophilic tissues. Feces were the major route of excretion; cumulatively 42% of dose for alpha-HBCD,...

  1. Single dose oral naproxen and naproxen sodium for acute postoperative pain (Review)

    PubMed Central

    Mason, L; Edwards, JE; Moore, RA; McQuay, HJ

    2014-01-01

    Background Postoperative pain is often poorly managed. Treatment options include a range of drug therapies such as non-steroidal anti-inflammatory drugs (NSAIDs) of which naproxen is one. Naproxen is used to treat a variety of painful conditions including acute postoperative pain, and is often combined with sodium to improve its solubility for oral administration. Naproxen sodium 550 mg (equivalent to 500 mg of naproxen) is considered to be an effective dose for treating postoperative pain but to date no systematic review of the effectiveness of naproxen/naproxen sodium at different doses has been published. Objectives To assess the efficacy, safety and duration of action of a single oral dose of naproxen or naproxen sodium for acute postoperative pain in adults. Search strategy We searched The Cochrane Library, MEDLINE, EMBASE and the Oxford Pain Relief Database for relevant studies. Additional studies were identified from the reference list of retrieved reports. The most recent search was undertaken in July 2004. Selection criteria Included studies were randomised, double blind, placebo-controlled trials of a single dose of orally administered naproxen or naproxen sodium in adults with moderate to severe acute postoperative pain. Data collection and analysis Pain relief or pain intensity data were extracted and converted into dichotomous information to give the number of patients with at least 50% pain relief over four to six hours. Relative risk estimates (RR) and the number-needed-to-treat (NNT) for at least 50% pain relief were then calculated. Information was sought on the percentage of patients experiencing any adverse event, and the number-needed-to-harm was derived. Time to remedication was also estimated. Main results Ten trials (996 patients) met the inclusion criteria: nine assessed naproxen sodium; one combined the results from two small trials of naproxen alone. Included studies scored well for methodological quality. Meta-analysis of six trials (500

  2. 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 μM). 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

  3. The pharmacokinetics of methocarbamol and guaifenesin after single intravenous and multiple-dose oral administration of methocarbamol in the horse.

    PubMed

    Rumpler, M J; Colahan, P; Sams, R A

    2014-02-01

    A simple LC/MSMS method has been developed and fully validated to determine concentrations and characterize the concentration vs. time course of methocarbamol (MCBL) and guaifenesin (GGE) in plasma after a single intravenous dose and multiple oral dose administrations of MCBL to conditioned Thoroughbred horses. The plasma concentration-time profiles for MCBL after a single intravenous dose of 15 mg/kg of MCBL were best described by a three-compartment model. Mean extrapolated peak (C0 ) plasma concentrations were 23.2 (± 5.93) μg/mL. Terminal half-life, volume of distribution at steady-state, mean residence time, and systemic clearance were characterized by a median (range) of 2.96 (2.46-4.71) h, 1.05 (0.943-1.21) L/kg, 1.98 (1.45-2.51) h, and 8.99 (6.68-10.8) mL/min/kg, respectively. Oral dose of MCBL was characterized by a median (range) terminal half-life, mean transit time, mean absorption time, and apparent oral clearance of 2.89 (2.21-4.88) h, 2.67 (1.80-2.87) h, 0.410 (0.350-0.770) h, and 16.5 (13.0-20) mL/min/kg. Bioavailability of orally administered MCBL was characterized by a median (range) of 54.4 (43.2-72.8)%. Guaifenesin plasma concentrations were below the limit of detection in all samples collected after the single intravenous dose of MCBL whereas they were detected for up to 24 h after the last dose of the multiple-dose oral regimen. This difference may be attributed to first-pass metabolism of MCBL to GGE after oral administration and may provide a means of differentiating the two routes of administration. PMID:23859819

  4. Single, Escalating Dose Pharmacokinetics, Safety and Food Effects of a New Oral Androgen Dimethandrolone Undecanoate in Man: A prototype oral male hormonal contraceptive

    PubMed Central

    Swerdloff, Ronald S.; Nya-Ngatchou, Jean Jacques; Liu, Peter Y.; Amory, John K.; Leung, Andrew; Hull, Laura; Blithe, Diana L.; Woo, Jason; Bremner, William J.; Wang, Christina

    2014-01-01

    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 to 800 mg), ten male volunteers received DMAU and two received placebo at two academic medical centers. DMAU was administered both fasting and after a high fat meal (200–800 mg doses). Serial serum samples were collected over 24h 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 800mg dose. When administered with a 50% fat meal, serum DMA was detectable in all participants given 200mg DMAU and showed a dose-incremental increase up to 800mg, with peak levels 4 to 8h after taking the dose. Serum gonadotropins and sex hormone concentrations were significantly suppressed 12h after DMAU administration with food at doses above 200mg. 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

  5. Oral contraception does not alter single dose saquinavir pharmacokinetics in women

    PubMed Central

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

    2004-01-01

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

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

    PubMed Central

    Thulkar, Jyoti; Kriplani, Alka; Agarwal, Nutan

    2012-01-01

    Objective: To compare the cure rates of oral single dose of metronidazole (2 g), tinidazole (2 g), secnidazole (2 g), and ornidazole (1.5 g) in cases of bacterial vaginosis. Materials and Methods: This was a prospective, comparative, randomized clinical trial on 344 Indian women (86 women in each group) who attended a gynecology outpatient department with complaint of abnormal vaginal discharge or who had abnormal vaginal discharge on Gynecological examination but they did not complaint of it. For diagnosis and cure rate of bacterial vaginosis, Amsel's criteria were used. Statistical analysis was done by Chi-square test of proportions. The cure rate was compared considering metronidazole cure rate as gold standard. Results: At 1 week, the cure rate of tinidazole and ornidazole was 100% and at 4 weeks, it was 97.7% for both drugs (P<0.001). Secnidazole had cure rate of 80.2% at 4 weeks (P=NS). Metronidazole showed a cure rate of 77.9% at 4 weeks, which is the lowest of all four drugs. Conclusion: Tinidazole and ornidazole have better cure rate as compared to metronidazole in cases of bacterial vaginosis. PMID:22529484

  7. Single dose oral paracetamol (acetaminophen) with codeine for postoperative pain in adults

    PubMed Central

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

    2014-01-01

    Background This is an updated version of the Cochrane review published in Issue 4, 1998. Combining drugs from different classes with different modes of action may offer opportunity to optimise efficacy and tolerability, using lower doses of each drug to achieve the same degree of pain relief. Previously we concluded that addition of codeine to paracetamol provided additional pain relief, but at expense of additional adverse events. New studies have been published since. This review sought to evaluate efficacy and safety of paracetamol plus codeine using current data, and compare findings with other analgesics evaluated similarly. Objectives Assess efficacy of single dose oral paracetamol plus codeine in acute postoperative pain, increase in efficacy due to the codeine component, and associated adverse events. Search methods We searched CENTRAL, MEDLINE, EMBASE, the Oxford Pain Relief Database in October 2008 for this update. Selection criteria Randomised, double-blind, placebo-controlled trials of paracetamol plus codeine, compared with placebo or the same dose of paracetamol alone, for relief of acute postoperative pain in adults. Data collection and analysis Two authors assessed trial quality and extracted data. The area under the “pain relief versus time” curve was used to derive proportion of participants with paracetamol plus codeine and placebo or paracetamol alone experiencing least 50% pain relief over four-to-six hours, using validated equations. Number-needed-to-treat-to-benefit (NNT) was calculated using 95% confidence intervals (CIs). 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 were collected. Main results Twenty-six studies, with 2295 participants, were included comparing paracetamol plus codeine with placebo. Significant dose response was seen for the outcome of at least 50% pain

  8. Miltefosine lipid nanocapsules: Intersection of drug repurposing and nanotechnology for single dose oral treatment of pre-patent schistosomiasis mansoni.

    PubMed

    El-Moslemany, Riham M; Eissa, Maha M; Ramadan, Alyaa A; El-Khordagui, Labiba K; El-Azzouni, Mervat Z

    2016-07-01

    A dual drug repurposing/nanotechnological approach was used to develop an alternative oral treatment for schistosomiasis mansoni using miltefosine (MFS), an anticancer alkylphosphocholine, and lipid nanocapsules (LNCs) as oral nanovectors. We demonstrated earlier that MFS possesses significant activity against different developmental stages of Schistosoma mansoni in the mouse model using 5 successive 20mg/kg/day oral doses. Moreover, an effective single dose (20mg/kg) oral treatment against the adult stage of S. mansoni in mice was developed using LNCs, particularly modified with CTAB, a positive charge imparting agent (MFS-LNC-CTAB(+)), or oleic acid as membrane permeabilizer (MFS-LNC-OA). Efficacy enhancement involved, at least in part, targeting of the worm tegument with MFS-LNCs as a new therapeutic entity. As the tegument surface charge and composition may differ in pre-patent stages of the parasite, it was of importance in the present study to assess the efficacy of a single oral dose of the two MFS-LNC formulations against invasive and immature stages for potential advantage relative to praziquantel. Results indicated potent schistosomicidal effects against both invasive and immature stages of S. mansoni in infected mice, efficacy being both formulation and developmental stage dependent. This was indicated by the significant reduction in the total worm burden of the invasive stage by 91.6% and 76.8% and the immature stage by 82.7% and 96.7% for MFS-LNC-CTAB+ and MFS-LNC-OA, respectively. Histopathological findings indicated amelioration of hepatic pathology with regression of the granulomatous inflammatory reaction and reduction in granulomas number and size, verifying marked improvement in architecture of hepatic lobules. From a clinical perspective, MFS-LNCs offer potential as an alternative single oral dose nanomedicine with a wide therapeutic profile for the mass chemotherapy of schistosomiasis mansoni. PMID:27039667

  9. Stimulation of colonic motility by oral PEG electrolyte bowel preparation assessed by MRI: comparison of split vs single dose

    PubMed Central

    Marciani, L; Garsed, K C; Hoad, C L; Fields, A; Fordham, I; Pritchard, S E; Placidi, E; Murray, K; Chaddock, G; Costigan, C; Lam, C; Jalanka-Tuovinen, J; De Vos, W M; Gowland, P A; Spiller, R C

    2014-01-01

    Background Most methods of assessing colonic motility are poorly acceptable to patients. Magnetic resonance imaging (MRI) can monitor gastrointestinal motility and fluid distributions. We predicted that a dose of oral polyethylene glycol (PEG) and electrolyte solution would increase ileo-colonic inflow and stimulate colonic motility. We aimed to investigate the colonic response to distension by oral PEG electrolyte in healthy volunteers (HVs) and to evaluate the effect of single 2 L vs split (2 × 1 L) dosing. Methods Twelve HVs received a split dose (1 L the evening before and 1 L on the study day) and another 12 HVs a single dose (2 L on the main study day) of PEG electrolyte. They underwent MRI scans, completed symptom questionnaires, and provided stool samples. Outcomes included small bowel water content, ascending colon motility index, and regional colonic volumes. Key Results Small bowel water content increased fourfold from baseline after ingesting both split (p = 0.0010) and single dose (p = 0.0005). The total colonic volume increase from baseline was smaller for the split dose at 35 ± 8% than for the single dose at 102 ± 27%, p = 0.0332. The ascending colon motility index after treatment was twofold higher for the single dose group (p = 0.0103). Conclusions & Inferences Ingestion of 1 and 2 L PEG electrolyte solution caused a rapid increase in the small bowel and colonic volumes and a robust rise in colonic motility. The increase in both volumes and motility was dose dependent. Such a challenge, being well-tolerated, could be a useful way of assessing colonic motility in future studies. PMID:25060551

  10. Pharmacokinetics of Ferrous Sulphate (Tardyferon®) after Single Oral Dose Administration in Women with Iron Deficiency Anaemia.

    PubMed

    Leary, A; Barthe, L; Clavel, T; Sanchez, C; Oulmi-Castel, M; Paillard, B; Edmond, J M; Brunner, V

    2016-01-01

    Iron-containing preparations available on the market vary in dosage, salt, and chemical state of iron contained in the preparation, as well as in the iron delivery process (immediate or prolonged-release). The present study aimed at characterizing the serum pharmacokinetics of iron in non pregnant women with iron deficiency anaemia (IDA) following a single oral administration of a prolonged-release ferrous sulphate tablet. This multicenter, single dose, open-label study was conducted in 30 women aged between 18 and 45 years with IDA. A single 160 mg oral dose of ferrous sulphate was given as 2 tablets of 80 mg of Tardyferon(®) under fasting conditions. Blood samples were collected before dosing and until 24 h post-dosing. Serum iron concentrations were determined using a routine colorimetric analytical method. Pharmacokinetic parameters were determined from the serum concentration profiles using a non compartmental approach. Serum profiles showed elevated levels of iron up to 12 h after drug intake. The median time to maximum serum concentrations (Tmax) occurred 4 h post-dosing. Between 2 and 8 h post-dosing, mean serum iron concentrations fluctuated by only 20%. Additionally, C8h and C12h represented on average 78.6% and 47.5% of the Cmax, respectively. This study demonstrates that a single oral dose of 160 mg Tardyferon(®) administered under fasting condition to 30 women with IDA leads to an optimal long-lasting release of iron in the gastrointestinal tract in the targeted population. This allows the attainment and maintenance of elevated serum iron levels for up to 12 h after administration. PMID:25989284

  11. Pharmacokinetics of ketorolac tromethamine in horses after intravenous, intramuscular, and oral single-dose administration.

    PubMed

    Bianco, A W; Constable, P D; Cooper, B R; Taylor, S D

    2016-04-01

    Nonsteroidal anti-inflammatory drugs (NSAIDs) are an integral component of equine analgesia, yet currently available NSAIDs are both limited in their analgesic efficacy and have adverse effects. The NSAID ketorolac tromethamine (KT) is widely used in humans as a potent morphine-sparing analgesic drug but has not been fully evaluated in horses. The purpose of this study was to determine the pharmacokinetic profile of KT in horses after intravenous (i.v.), intramuscular (i.m.), and oral (p.o.) administration. Nine healthy adult horses received a single 0.5-mg/kg dose of KT via each route of administration. Plasma was collected up to 48 h postadministration and analyzed for KT concentration using HPLC/MS/MS. Noncompartmental analysis of i.v. dosage indicated a mean plasma clearance of 8.4 (mL/min)/kg and an estimated mean volume of distribution at steady-state of 0.77 L/kg. Noncompartmental analysis of i.v., i.m., and p.o. dosages indicated mean residence times of 2.0, 2.6, and 7.1 h, respectively. The drug was rapidly absorbed after i.m. and p.o. administration, and mean bioavailability was 71% and 57% for i.m. and p.o. administration, respectively. Adverse effects were not observed after i.v., i.m., and p.o. administration. More studies are needed to evaluate the analgesic and anti-inflammatory properties of KT in horses. PMID:26416348

  12. Pharmacokinetics of a Single Dose of Oral and Subcutaneous Meloxicam in Caribbean Flamingos ( Phoenicopterus ruber ruber).

    PubMed

    Lindemann, Dana M; Carpenter, James W; KuKanich, Butch

    2016-03-01

    To determine the pharmacokinetics of meloxicam in Caribbean flamingos ( Phoenicopterus ruber ruber), a pilot study was performed first, followed by a complete pharmacokinetic study. Four healthy birds were divided into 2 groups and administered 1 mg/kg of either oral (n = 2) or subcutaneous (n = 2) meloxicam. Plasma meloxicam concentrations were determined with liquid chromatography-mass spectrometry. Based on the pilot study results, 12 healthy birds were assigned into 2 groups and administered either 3 mg/kg PO (n = 6) or 1.5 mg/kg SC (n = 6) of meloxicam. Blood samples were collected at baseline and at 9 time intervals per group after administration of meloxicam in all flamingos. Plasma concentrations after administration of 3 mg/kg PO meloxicam reached a mean maximum plasma concentration of 1.449 μg/mL at 2.35 hours with a terminal half-life of 1.832 hours. After administration of 1.5 mg/kg SC meloxicam, maximum plasma concentration was 4.059 μg/mL at 0.91 hour with a terminal half-life of 1.104 hours. The plasma profile from the main oral study (3 mg/kg PO) differed markedly from the pilot study (1 mg/kg PO), suggesting a delayed absorption with the higher dose and lack of dose proportionality. The different doses for subcutaneous administration resulted in a proportional change in plasma concentrations. Further studies are needed to evaluate the effects of the drug volume administered and fasting status when oral dosing is used. Future studies are also needed to investigate multiple-dose pharmacokinetics of meloxicam and to determine the therapeutic meloxicam plasma concentration in Caribbean flamingos. PMID:27088740

  13. Human metabolism and excretion kinetics of aniline after a single oral dose.

    PubMed

    Modick, Hendrik; Weiss, Tobias; Dierkes, Georg; Koslitz, Stephan; Käfferlein, Heiko Udo; Brüning, Thomas; Koch, Holger Martin

    2016-06-01

    Aniline is an important source material in the chemical industry (e.g., rubber, pesticides, and pharmaceuticals). The general population is known to be ubiquitously exposed to aniline. Thus, assessment of aniline exposure is of both occupational and environmental relevance. Knowledge on human metabolism of aniline is scarce. We orally dosed four healthy male volunteers (two fast and two slow acetylators) with 5 mg isotope-labeled aniline, consecutively collected all urine samples over a period of 2 days, and investigated the renal excretion of aniline and its metabolites by LS-MS/MS and GC-MS. After enzymatic hydrolysis of glucuronide and sulfate conjugates, N-acetyl-4-aminophenol was the predominant urinary aniline metabolite representing 55.7-68.9 % of the oral dose, followed by the mercapturic acid conjugate of N-acetyl-4-aminophenol accounting for 2.5-6.1 %. Acetanilide and free aniline were found only in minor amounts accounting for 0.14-0.36 % of the dose. Overall, these four biomarkers excreted in urine over 48 h post-dose represented 62.4-72.1 % of the oral aniline dose. Elimination half-times were 3.4-4.3 h for N-acetyl-4-aminophenol, 4.1-5.5 h for the mercapturic acid conjugate, and 1.3-1.6 and 0.6-1.2 h for acetanilide and free aniline, respectively. Urinary maximum concentrations of N-acetyl-4-aminophenol were reached after about 4 h and maximum concentrations of the mercapturic acid conjugate after about 6 h, whereas concentrations of acetanilide and free aniline peaked after about 1 h. The present study is one of the first to provide reliable urinary excretion factors for aniline and its metabolites in humans after oral dosage, including data on the predominant urinary metabolite N-acetyl-4-aminophenol, also known as an analgesic under the name paracetamol/acetaminophen. PMID:26233686

  14. 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

  15. Immunization with Single Oral Dose of Alginate-Encapsulated BCG Elicits Effective and Long-Lasting Mucosal Immune Responses.

    PubMed

    Hosseini, M; Dobakhti, F; Pakzad, S R; Ajdary, S

    2015-12-01

    Effective vaccination against pathogens, which enter the body through mucosal surfaces, requires the induction of both mucosal and systemic immune responses. Here, mucosal as well as systemic immune responses in the lung and spleen of BALB/c mice which were orally vaccinated with a single dose of alginate-encapsulated bacille Calmette-Guerin (BCG) were evaluated. Twenty weeks after immunization, the vaccinated mice were challenged intranasally with BCG. Twelve weeks after immunization and 5 weeks after challenge, the immune responses were evaluated. Moreover, immune responses were compared with those of mice that were vaccinated with free BCG by subcutaneous (sc) and oral routes. Twelve weeks after the immunization, serum IgG level was higher in the sc-immunized mice, while serum IgA level was higher in the orally immunized mice with encapsulated BCG. Significant productions of both IgG and IgA were only detected in lungs of mice orally immunized with encapsulated BCG. Proliferative and delayed-type hypersensitivity responses and IFN-γ production were significantly higher in mice immunized orally with encapsulated BCG, compared to mice immunized orally with free BCG. After challenge, the levels of IFN-γ were comparable between sc-immunized mice with free BCG and orally immunized with encapsulated BCG; however, significantly less IL-4 was detected in mice which had received encapsulated BCG via oral route. Moreover, significant control of the bacilli growth in the lung of the immunized mice after intranasal challenge with BCG was documented in mice vaccinated with encapsulated BCG. These results suggest that oral immunization with alginate-encapsulated BCG is an effective mean of inducing mucosal and systemic specific immune responses. PMID:26286252

  16. 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

  17. Calcium absorption in corticoid treated subjects effects of a single oral dose of calcitriol.

    PubMed

    Colette, C; Monnier, L; Pares Herbute, N; Blotman, F; Mirouze, J

    1987-07-01

    We compared the fractional absorption of calcium (FACa, 6 h, % TD) and the radiocalcium transit (% TD per min) in seven glucocorticoid-treated patients (10-25 mg prednisolone per day) and in seven normal subjects, in the basal state and 12 h after an oral dose of synthetic 1,25-(OH)2D (3 micrograms). In the basal state, the radiocalcium transit was significantly decreased (P less than 0.02) at 15 min in patients treated with prednisolone, but FACa at 6 h was not significantly decreased (51 +/- 5 vs. 60 +/- 5% TD). 12 h after an oral dose of 1,25-(OH)2D which resulted in supraphysiologic plasma levels, FACa increased significantly (P less than 0.02) in both groups but the peak absorption rate of Ca remained lower in the corticoid-treated patients than in controls (P less than 0.02). The results suggest that glucocorticoids decrease the 1,25-(OH)2D-dependent transport of calcium across the proximal small intestine. PMID:3623424

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

    PubMed

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

    2001-04-01

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

  19. Albendazole and its metabolites in the breast milk of lactating women following a single oral dose of albendazole

    PubMed Central

    Abdel-tawab, Ahmed M; Bradley, Mark; Ghazaly, Essam A; Horton, John; El-Setouhy, Maged

    2009-01-01

    AIMS Albendazole (ABZ) is used in several anthelminthic drug programmws. ABZ side-effects are generally mild, but ABZ-induced pancytopenia may be serious. In filariasis programmes, it may be necessary to administer ABZ to breastfeeding women. Few data are available on safety of ABZ for breastfed infants. In addition, the pharmacokinetics of ABZ and its metabolites in human milk is insufficiently investigated. The aim was to study pharmacokinetics of ABZ and its metabolites [ABZ sulphoxide (ABSX) and ABZ sulphone] in the breast milk lactating women after one single oral dose of ABZ. METHODS Thirty-three lactating women (age 18–40 years) participated in the study. They received a single oral 400-mg dose of ABZ. Five milk samples were taken at 0, 6, 12, 24 and 36 h. One serum sample was taken after 6 h. Samples were analysed using high-performance liquid chromatography and pharmacokinetic analysis was performed. RESULTS ABZ was detectable in milk samples 6 h after the oral dose. The mean concentration of serum ABZ was 63.7 ± 11.9 ng ml−1. The pharmacokinetic parameters for ABSX were calculated as follows: 351.9 ± 32.4 ng ml−1, 6.9 ± 0.5 h, 12.4 ± 2.2 h and 5190.3 ± 482.8 ng*h ml−1 for Cmax, Tmax, t½ and AUC0–36, respectively. The milk-to-serum ratios (range) for ABZ and ABSX were 0.9 (0.2–6.5) and 0.6 (0.1–1.5), respectively. CONCLUSIONS After an oral dose of 400 mg, ABZ and ABSX attain low concentrations in breast milk that are unlikely to be considered harmful for the breastfed infant. PMID:19916998

  20. Safety, tolerability, pharmacokinetics and pharmacodynamics of losmapimod following a single intravenous or oral dose in healthy volunteers

    PubMed Central

    Barbour, April M; Sarov-Blat, Lea; Cai, Gengqian; Fossler, Michael J; Sprecher, Dennis L; Graggaber, Johann; McGeoch, Adam T; Maison, Jo; Cheriyan, Joseph

    2013-01-01

    Aims The purpose of this study was to establish safety and tolerability of a single intravenous (IV) infusion of a p38 mitogen-activated protein kinase inhibitor, losmapimod, to obtain therapeutic levels rapidly for a potential acute coronary syndrome indication. Pharmacokinetics (PK) following IV dosing were characterized, and pharmacokinetic/pharmacodynamic (PK/PD) relationships between losmapimod and phosphorylated heat shock protein 27 (pHSP27) and high-sensitivity C-reactive protein were explored. Methods Healthy volunteers received 1 mg losmapimod IV over 15 min (n = 4) or 3 mg IV over 15 min followed by a washout period and then 15 mg orally (PO; n = 12). Pharmacokinetic parameters were calculated by noncompartmental methods. The PK/PD relationships were explored using modelling and simulation. Results There were no deaths, nonfatal serious adverse events or adverse events leading to withdrawal. Headache was the only adverse event reported more than once (n = 3 following oral dosing). Following 3 mg IV and 15 mg PO, Cmax was 59.4 and 45.9 μg l−1 and AUC0–∞ was 171.1 and 528.0 μg h l−1, respectively. Absolute oral bioavailability was 0.62 [90% confidence interval (CI) 0.56, 0.68]. Following 3 mg IV and 15 mg PO, maximal reductions in pHSP27 were 44% (95% CI 38%, 50%) and 55% (95% CI 50%, 59%) occurring at 30 min and 4 h, respectively. There was a 17% decrease (95% CI 9%, 24%) in high-sensitivity C-reactive protein 24 h following oral dosing. A direct-link maximal inhibitory effect model related plasma concentrations to pHSP27 concentrations. Conclusions A single IV infusion of losmapimod in healthy volunteers was safe and well tolerated, and may potentially serve as an initial loading dose in acute coronary syndrome as rapid exposure is achieved. PMID:23215699

  1. Comparative Metabolism Studies of Hexabromocyclododecane (HBCD) Diastereomers in Male Rats Following a Single Oral Dose.

    PubMed

    Hakk, Heldur

    2016-01-01

    Male Sprague-Dawley rats were dosed orally with 3 mg/kg of one of three hexabromocyclododecane (HBCD) diastereomers. Each diastereomer was well absorbed (73-83%), and distributed preferentially to lipophilic tissues. Feces were the major route of excretion; cumulatively accounting for 42% of dose for α-HBCD, 59% for ß-HBCD, and 53% for γ-HBCD. Urine was also an important route of HBCD excretion, accounting for 13% of dose for α-HBCD, 30% for ß-HBCD, and 21% for γ-HBCD. Total metabolism of HBCD diastereomers followed the rank order ß > γ > α, and was >65% of that administered. The metabolites formed were distinct in male rats: α-HBCD did not debrominate or stereoisomerize, but formed two hydroxylated metabolites; ß- and γ-HBCD were both extensively metabolized via pathways of stereoisomerization, oxidation, dehydrogenation, reductive debromination, and ring opening. ß-HBCD was biotransformed to two mercapturic acid pathway metabolites. The metabolites of ß- and γ-HBCD were largely distinct, and could possibly be used as markers of exposure. These isomer-specific data suggest that α-HBCD would be the most dominant HBCD diastereomer in biological tissues because it was metabolized to the lowest degree and also accumulated from the stereoisomerization of the β- and γ- diastereomers. PMID:26629593

  2. Voriconazole Disposition After Single and Multiple, Oral Doses in Healthy, Adult Red-tailed Hawks ( Buteo jamaicensis ).

    PubMed

    Gentry, Jordan; Montgerard, Christy; Crandall, Elizabeth; Cruz-Espindola, Crisanta; Boothe, Dawn; Bellah, Jamie

    2014-09-01

    Voriconazole is effective for treatment of aspergillosis, a common disease in captive red-tailed hawks ( Buteo jamaicensis ). To determine the disposition and safety of voriconazole after single and multiple, oral doses, 12 adult red-tailed hawks were studied in 2 phases. In phase 1, each bird received a single dose of voriconazole solution (10 mg/kg) by gavage. Blood samples were collected at 0, 0.5, 1, 3, 6, 9, 12, 16, 24, and 36 hours after treatment. In phase 2, each of 8 birds received voriconazole oral solution at 10 mg/kg PO q12h for 14 days. Plasma samples were collected on days 0, 5, and 10 and after the final dose and were processed as in phase 1. Plasma samples were submitted for analysis of voriconazole levels by high-performance liquid chromatography and ultraviolet spectrophotometry and for measurement of selected plasma biochemical parameters. After single dosing, voriconazole concentrations reached a (mean ± SD) peak (Cmax) of 4.7 ± 1.3 μg/mL at 2.0 ± 1.2 hours. The disappearance half-life (t1/2) was 2.8 ± 0.7 hours, and the mean residence time (MRT) was 4.6 ± 0.9 hours. After the last dose at 14 days, the mean Cmax of voriconazole was 4.5 ± 2.7 μg/mL at 2.4 ± 1.1 hours. The t1/2 was 2.1 ± 0.8 hours, and the MRT was 3.5 ± 1.1 hours. Although concentrations of several plasma biochemical parameters were significantly different at study end compared with prestudy concentrations, only plasma creatine kinase activity was outside the reference range. No adverse reactions were observed in any of the birds. After both single and multiple dosing at 10 mg/kg, voriconazole concentrations exceeded the minimum inhibitory concentration to inhibit 90% (MIC90) of Aspergillus species (1 μg/mL) by at least fourfold and remained above the MIC90 for 8.8 ± 1.1 hours after single dosing versus 6.5 ± 1.5 hours after multiple dosing (P = .003). This difference suggests that more frequent dosing (eg, up to q8h) may be necessary to maintain target

  3. A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles.

    PubMed

    Kurosawa, Yuko; Nirengi, Shinsuke; Homma, Toshiyuki; Esaki, Kazuki; Ohta, Mitsuhiro; Clark, Joseph F; Hamaoka, Takafumi

    2015-01-01

    Our aim was to determine the quantitative effects of a single-dose of Nattokinase (NK) administration on coagulation/fibrinolysis parameters comprehensively in healthy male subjects. A double-blind, placebo-controlled cross-over NK intervention study was carried out in 12 healthy young males. Following the baseline blood draw, each subject was randomized to receive either a single-dose of 2,000 FU NK (NSK-SD, Japan Bio Science Laboratory Co., Ltd) or placebo with subsequent cross-over of the groups. Subjects donated blood samples at 2, 4, 6 and 8 hours following administration for analysis of coagulation/fibrinolysis parameters. As a result, D-dimer concentrations at 6, and 8 hours, and blood fibrin/fibrinogen degradation products at 4 hours after NK administration elevated significantly (p < 0.05, respectively). Factor VIII activity declined at 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial thromboplastin time prolonged significantly at 2 and 4 hours following NK administration (p < 0.05 and p < 0.01, respectively). All the changes, however, were within the normal range. In conclusion, thus, a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously. PMID:26109079

  4. A single-dose of oral nattokinase potentiates thrombolysis and anti-coagulation profiles

    PubMed Central

    Kurosawa, Yuko; Nirengi, Shinsuke; Homma, Toshiyuki; Esaki, Kazuki; Ohta, Mitsuhiro; Clark, Joseph F.; Hamaoka, Takafumi

    2015-01-01

    Our aim was to determine the quantitative effects of a single-dose of Nattokinase (NK) administration on coagulation/fibrinolysis parameters comprehensively in healthy male subjects. A double-blind, placebo-controlled cross-over NK intervention study was carried out in 12 healthy young males. Following the baseline blood draw, each subject was randomized to receive either a single-dose of 2,000 FU NK (NSK-SD, Japan Bio Science Laboratory Co., Ltd) or placebo with subsequent cross-over of the groups. Subjects donated blood samples at 2, 4, 6 and 8 hours following administration for analysis of coagulation/fibrinolysis parameters. As a result, D-dimer concentrations at 6, and 8 hours, and blood fibrin/fibrinogen degradation products at 4 hours after NK administration elevated significantly (p < 0.05, respectively). Factor VIII activity declined at 4 and 6 hours (p < 0.05, respectively), blood antithrombin concentration was higher at 2 and 4 hours (p < 0.05, respectively), and the activated partial thromboplastin time prolonged significantly at 2 and 4 hours following NK administration (p < 0.05 and p < 0.01, respectively). All the changes, however, were within the normal range. In conclusion, thus, a single-dose of NK administration appears enhancing fibrinolysis and anti-coagulation via several different pathways simultaneously. PMID:26109079

  5. Pharmacokinetics and tolerance of DU-6859a, a new fluoroquinolone, after single and multiple oral doses in healthy volunteers.

    PubMed Central

    Nakashima, M; Uematsu, T; Kosuge, K; Umemura, K; Hakusui, H; Tanaka, M

    1995-01-01

    The pharmacokinetics and tolerance of DU-6859a, 7-[(7S)-7-amino-5-azaspiro[2,4]heptan-5-yl]-8-chloro-6-fluor o-1-[(1R, 2S)-2-fluoro-1-cyclopropyl]-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid sesquihydrate, were investigated in healthy male Japanese volunteers after single (25, 50, 100, and 200 mg) and multiple (100 mg three times a day for 6 days plus once a day on the 7th day and 50 mg every 12 h for 13 doses) oral doses. DU-6859a was well tolerated at all doses, and all 36 subjects completed the study; mild transient soft stool in five volunteers and mild transient diarrhea in one volunteer on the multiple-dose (100 mg three times a day) study were the only side effects reported. No drug crystals were observed in the urine after the single 200-mg dose and the 100-mg three times a day regimen. DU-6859a was rapidly absorbed in the fasted state. The mean maximum concentration in serum (Cmax) ranged from 0.29 to 1.86 micrograms/ml for the 25- to 200-mg dose, and the mean time to reach Cmax ranged from 1.0 to 1.3 h. The terminal half-life ranged from 4.4 to 5.0 h. The area under the curve increased dose dependently. The serum protein binding of the drug was approximately 50%. The apparent volume of distribution clearly exceeded 1 liter/kg, suggesting good tissue penetration. Within 48 h, the cumulative urinary recovery of unchanged drug amounted to 69 to 74% of the dose administered, while fecal excretion up to 48 h after the 200-mg dose accounted for ca. 3% of the dose. Food intake did not affect the rate and extend of absorption of DU-6859a to a clinically significant extent. During multiple oral dosing, the accumulation of the drug in serum was close to the theoretically predicted values, which indicated that there was virtually no drug accumulation. PMID:7695301

  6. Comparison of single-dose oral grepafloxacin with cefixime for treatment of uncomplicated gonorrhea in men. The STD Study Group.

    PubMed Central

    Hook, E W; McCormack, W M; Martin, D; Jones, R B; Bean, K; Maroli, A N

    1997-01-01

    In a randomized open study, 351 male patients with uncomplicated gonorrhea were given single oral doses of grepafloxacin (400 mg) or cefixime (400 mg). In the 299 microbiologically evaluable patients, urethral infections were cured in 99% (147 of 149) of those receiving grepafloxacin and 97% (145 of 150) of those given cefixime. Eradication rates for both regimens were 100% in the 16% (47 of 299) of participants who were infected with penicillin-resistant Neisseria gonorrhoeae and 97% in the 21% (62 of 299) of participants infected with tetracycline-resistant strains. Grepafloxacin is a well-tolerated alternative to cefixime for treatment of uncomplicated gonorrhea in males. PMID:9257777

  7. Bioavailability of a new oral formulation of medroxyprogesterone acetate compared with the standard formulation: a single dose randomized study.

    PubMed

    Kjaer, M; Brunsgaard, N; Jakobsen, P; Edwards, D M; Strolin-Benedetti, M

    1993-08-01

    Twenty-six female patients with breast cancer participated in an open, randomized, cross-over study comparing single dose bioavailability of a recently developed oral medroxyprogesterone acetate (MPA) formulation (200 mg sachet where MPA is loaded in a polyvinylpyrrolidone cross-linked polymer, MPA/PVP) with the standard formulation (500 mg tablet). Blood tests were performed under standardized conditions for 120 h in all patients and MPA plasma concentrations determined by means of HPLC. Dose-normalized AUC(0-tz), AUC (0-infinity) and Cmax were all significantly higher for the MPA/PVP formulation than for the standard formulation. The relative bioavailability of the MPA/PVP formulation was on average three times superior to that of the standard formulation. This new MPA formulation might have important clinical implications for the treatment of hormone-sensitive cancer. PMID:8400345

  8. Single dose pharmacokinetics of atorvastatin oral formulations using a simple HPLC-UV method.

    PubMed

    Sohail, Muhammad; Ahmad, Mahmood; Minhas, Muhammad Usman

    2016-07-01

    The study was aimed to assess pharmacokinetics of atorvastatin (40 mg) in healthy fasted human subjects by a simple and inexpensive high performance liquid chromatography. Experimental design of the study was a randomized, two way, two periods, crossover study (single dose in fasted conditions). Eighteen (18) healthy male volunteers were enrolled according to FDA guidelines. The plasma samples were assayed using an isocratic High Performance Liquid Chromatography (HPLC) system of Agilent technologies USA consisted of an isocratic pump with column of Thermo Electron Corporation USA (ODS hypersil C(18) 4.6 mm x 250 mm), a UV-visible detector set at λ(max) 237 nm. Maximum plasma concentrations (C(max)) of atorvastatin (Mean ± SEM) for the reference product (A) found to be 13.739±0.210ng/ml & 13.374±0.145ng/ml for test product (B). T(max) values (Mean±SEM) of atorvastatin were 1.222 ±0.060 hours and 1.167±0.057 hours for reference and test products, respectively. The values of AUC(0-oo) (Mean ± SEM) for the reference (A) and test product (B) were 73.955 ± 1.715ng.h/ml and 77.773 ± 1.858ng. h/ml, respectively. Other pharmacokinetic parameters of both products were also determined. A statistical non-significant difference between pharmacokinetic parameters has been found and both brands of atorvastatin showed the same rate and extent of absorption in healthy fasted human volunteers after single dose. A simple and cost effective HPLC method was developed and applied. PMID:27393428

  9. Hydrastine pharmacokinetics and metabolism after a single oral dose of goldenseal (Hydrastis canadensis) to humans.

    PubMed

    Gupta, Prem K; Barone, Gary; Gurley, Bill J; Fifer, E Kim; Hendrickson, Howard P

    2015-04-01

    The disposition and metabolism of hydrastine was investigated in 11 healthy subjects following an oral dose of 2.7 g of goldenseal supplement containing 78 mg of hydrastine. Serial blood samples were collected for 48 hours, and urine was collected for 24 hours. Hydrastine serum and urine concentrations were determined by Liquid Chromatography-tandem mass spectrometry (LC-MS/MS). Pharmacokinetic parameters for hydrastine were calculated using noncompartmental methods. The maximal serum concentration (Cmax) was 225 ± 100 ng/ml, Tmax was 1.5 ± 0.3 hours, and area under the curve was 6.4 ± 4.1 ng ⋅ h/ml ⋅ kg. The elimination half-life was 4.8 ± 1.4 hours. Metabolites of hydrastine were identified in serum and urine by using liquid chromatography coupled to high-resolution mass spectrometry. Hydrastine metabolites were identified by various mass spectrometric techniques, such as accurate mass measurement, neutral loss scanning, and product ion scanning using Quadrupole-Time of Flight (Q-ToF) and triple quadrupole instruments. The identity of phase II metabolites was further confirmed by hydrolysis of glucuronide and sulfate conjugates using bovine β-glucuronidase and a Helix pomatia sulfatase/glucuronidase enzyme preparation. Hydrastine was found to undergo rapid and extensive phase I and phase II metabolism. Reduction, O-demethylation, N-demethylation, hydroxylation, aromatization, lactone hydrolysis, and dehydrogenation of the alcohol group formed by lactone hydrolysis to the ketone group were observed during phase I biotransformation of hydrastine. Phase II metabolites were primarily glucuronide and sulfate conjugates. Hydrastine undergoes extensive biotransformation, and some metabolites may have pharmacological activity. Further study is needed in this area. PMID:25609220

  10. A Study on the Single-dose Oral Toxicity of Super Key in Sprague-Dawley Rats

    PubMed Central

    Kim, Jinhee; Lee, Jongcheol; Kim, Sungchul

    2015-01-01

    Objectives: This study was performed to analyze the single-dose oral toxicity of the super key (processed sulfur). Methods: All experiments were conducted at Medvill, an institution authorized to perform non-clinical studies, under the Good Laboratory Practice (GLP) regulations. In order to investigate the oral toxicity of super key We administered it orally to Sprague-Dawley (SD) rats. The SD rats were divided into four groups of five male and five female animals per group: group 1 being the control group and groups 2, 3, and 4 being the experimental groups. Doses of super key 500 mg/kg, 1,000 mg/kg and 2,000 mg/kg were administered to the experimental groups, and a dose of normal saline solution, 10 mL/kg, was administered to the control group. We examined the survival rates, weights, clinical signs, gross findings and necropsy findings. This study was conducted under the approval of the Institutional Animal Ethics Committee. (Approval number: A01-14018). Results: No deaths or abnormalities occurred in any of the four groups. Although slight decreases in the weights of some female rats were noted, no significant changes in weights or differences in the gross findings between the control group and the experimental groups were observed. To check for abnormalities in organs, we used microscopy to examine representative histological sections of each specified organ; the results showed no significant differences in any of the organs. Conclusion: The results of this research showed that administration of 500 ─ 2,000 mg/kg of super key did not cause any changes in the weights or in the results of necropsy examinations. Neither did it result in any mortalities. The above findings suggest that treatment with super key is relatively safe. Further studies on this subject are needed to yield more concrete evidence. PMID:26392913

  11. Sensitive and specific radioimmunoassay for fialuridine: initial assessment of pharmacokinetics after single oral doses to healthy volunteers.

    PubMed Central

    Bowsher, R R; Compton, J A; Kirkwood, J A; Place, G D; Jones, C D; Mabry, T E; Hyslop, D L; Hatcher, B L; DeSante, K A

    1994-01-01

    Fialuridine (FIAU) is a halogen-substituted analog of thymidine that was undergoing clinical investigation as a drug for the treatment of chronic hepatitis B viral infection. However, clinical trials of FIAU were terminated after adverse events occurred following chronic oral administration. Prior to the termination of clinical trials, a sensitive assay was needed for the measurement of FIAU because of the anticipated low dose administered to patients. We therefore undertook the development of a radioimmunoassay (RIA). A specific antiserum was raised in rabbits following immunization with a 5'-O-hemisuccinate analog of FIAU coupled to keyhole limpet hemocyanin. Radiolabeled FIAU was synthesized by a destannylation procedure by using sodium [125I]iodide. We developed a competitive-binding procedure and used precipitation with polyethylene glycol as the method for separating the bound and free forms of FIAU. The RIA is sensitive (0.2 ng/ml), specific (negligible interference from known metabolites and endogenous nucleosides), and reproducible (interassay coefficients of variation range from 5 to 19.7% for serum controls). We used the RIA to assess the pharmacokinetics of FIAU in healthy adult volunteers following administration of a single 5-mg oral dose. The sensitivity of the RIA permitted the detection of a prolonged elimination phase for FIAU in healthy volunteers and dogs, with mean elimination half-lives of 29.3 and 35.3 h, respectively. We conclude the RIA is a valid method for the quantification of FIAU in biological fluids. PMID:7811032

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

    PubMed Central

    2009-01-01

    Background The population pharmacokinetics of artesunate (AS) and its active metabolite dihydroartemisinin (DHA) were studied in healthy subjects receiving single- or multiple-dosing of AS orally either in combination with pyronaridine (PYR) or as a monotherapy with or without food. Methods Data from 118 concentration-time profiles arising from 91 healthy Korean subjects were pooled from four Phase I clinical studies. Subjects received 2-5 mg/kg of single- and multiple-dosing of oral AS either in combination with PYR or as a monotherapy with or without food. Plasma AS and DHA were measured simultaneously using a validated liquid chromatography- mass spectrometric method with a lower limit of quantification of 1 ng/mL for both AS and DHA. Nonlinear mixed-effect modelling was used to obtain the pharmacokinetic and variability (inter-individual and residual variability) parameter estimates. Results A novel parent-metabolite pharmacokinetic model consisting of a dosing compartment, a central compartment for AS, a central compartment and a peripheral compartment for DHA was developed. AS and DHA data were modelled simultaneously assuming stoichiometric conversion to DHA. AS was rapidly absorbed with a population estimate of absorption rate constant (Ka) of 3.85 h-1. The population estimates of apparent clearance (CL/F) and volume of distribution (V2/F) for AS were 1190 L/h with 36.2% inter-individual variability (IIV) and 1210 L with 57.4% IIV, respectively. For DHA, the population estimates of apparent clearance (CLM/F) and central volume of distribution (V3/F) were 93.7 L/h with 28% IIV and 97.1 L with 30% IIV, respectively. The population estimates of apparent inter-compartmental clearance (Q/F) and peripheral volume of distribution (V4/F) for DHA were 5.74 L/h and 18.5 L, respectively. Intake of high-fat and high-caloric meal prior to the drug administration resulted in 84% reduction in Ka. Body weight impacted CLM/F, such that a unit change in weight resulted in 1

  13. A single dose of sodium nitrate does not improve oral glucose tolerance in patients with type 2 diabetes mellitus.

    PubMed

    Cermak, Naomi M; Hansen, Dominique; Kouw, Imre W K; van Dijk, Jan-Willem; Blackwell, Jamie R; Jones, Andrew M; Gibala, Martin J; van Loon, Luc J C

    2015-08-01

    Dietary nitrate (NO3(-)) supplementation has been proposed as an emerging treatment strategy for type 2 diabetes. We hypothesized that ingestion of a single bolus of dietary NO3(-) ingestion improves oral glucose tolerance in patients with type 2 diabetes. Seventeen men with type 2 diabetes (glycated hemoglobin, 7.3% ± 0.2%) participated in a randomized crossover experiment. The subjects ingested a glucose beverage 2.5 hours after consumption of either sodium NO3(-) (0.15 mmol NaNO3(-) · kg(-1)) or a placebo solution. Venous blood samples were collected before ingestion of the glucose beverage and every 30 minutes thereafter during a 2-hour period to assess postprandial plasma glucose and insulin concentrations. The results show that plasma NO3(-) and nitrite levels were increased after NaNO3(-) as opposed to placebo ingestion (treatment-effect, P = .001). Despite the elevated plasma NO3(-) and nitrite levels, ingestion of NaNO3(-) did not attenuate the postprandial rise in plasma glucose and insulin concentrations (time × treatment interaction, P = .41 for glucose, P = .93 for insulin). Despite the lack of effect on oral glucose tolerance, basal plasma glucose concentrations measured 2.5 hours after NaNO3(-) ingestion were lower when compared with the placebo treatment (7.5 ± 0.4 vs 8.3 ± 0.4 mmol/L, respectively; P = .04). We conclude that ingestion of a single dose of dietary NO3(-) does not improve subsequent oral glucose tolerance in patients with type 2 diabetes. PMID:26092495

  14. A single oral dose of flavan-3-ols enhances energy expenditure by sympathetic nerve stimulation in mice.

    PubMed

    Kamio, Naoya; Suzuki, Takuma; Watanabe, Yuto; Suhara, Yoshitomo; Osakabe, Naomi

    2016-02-01

    Numerous clinical studies have found that ingestion of chocolate reduces the risk of metabolic syndrome, however, the mechanisms were remain unclear. We have reported that a single dose of a flavan-3-ol fraction derived from cocoa (FL) enhanced energy expenditure (EE) and increased the mRNA expression levels of uncoupling proteins (UCPs) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α), and the protein level of phosphorylated AMP-activated protein kinase (AMPK)α in tissues, along with plasma adrenaline level. In the present study, we examined whether the EE enhancing activity of FL is mediated by adrenergic effect using several adrenalin receptor (AR) blockers. In the first study, mice were butoxamine, as β2AR blocker, with vehicle or 10mg/kg FL orally. We found that pretreatment with butoxamine prevented the increases of EE, the mRNA expression of UCP-3, and phosphorylated AMPKα that were induced in the gastrocnemius muscle of mice by 10mg/kg FL. Secondly, mice were given SR52930, as β3AR blocker. Pretreatment with SR52930 prevented the increases of EE, the mRNA expression of UCP-3, and phosphorylated AMPKα that were induced in the gastrocnemius muscle of mice by 10mg/kg FL. Pretreatment with a combination of both blockers also reduced the increments in mRNA expression levels of UCPs and PGC-1α, however, phosphorylated AMPKα in skeletal muscle was rather increased. These results suggest that the ability of a single oral dose of FL to enhance metabolic activity is mediated by sympathetic nerve system (SNS). PMID:26738802

  15. Effects of a single, high oral dose of 25-hydroxycholecalciferol on the mineral metabolism markers in hemodialysis patients.

    PubMed

    Merino, Jose Luis; Teruel, Jose Luis; Fernández-Lucas, Milagros; Villafruela, Juan José; Bueno, Blanca; Gomis, Antonio; Paraíso, Vicente; Quereda, Carlos

    2015-06-01

    Vitamin D deficiency is common in dialysis patients with chronic kidney disease. Low levels have been associated with increased cardiovascular risk and mortality. We evaluated the administration of a high, single oral dose of 25-OH cholecalciferol (3 mg of Hidroferol, 180 000 IU) in patients on chronic hemodialysis. The 94 chronic hemodialysis patients with vitamin D deficiency 25 (OH)D <30 ng/mL included in the study were randomized into two groups. Follow-up time was 16 weeks. Neither the usual treatment for controlling Ca/P levels nor the dialysis bath (calcium of 2.5 mEq/L) were modified. Of the 86 patients who finished the study, 42 were in the treated group and 44 in the control group. An increase in 25(OH)D levels was observed in the treated group that persisted after 16 weeks and was associated with a significant decrease in parathyroid hormone (PTH) levels during the 8 weeks post-treatment. Baseline 1,25(OH)2 D levels of the treated group increased two weeks after treatment (5.9 vs. 21.9 pg/mL, P<0.001) but gradually reduced to 8.4 at week 16. The administration of a single 3 mg dose of 25-OH cholecalciferol seems safe in patients on hemodialysis and maintains sufficient levels of 25(OH)D with a decrease in PTH for 3 months. PMID:25656524

  16. 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

  17. Effects of single oral doses of lysine clonixinate and acetylsalicylic acid on platelet functions in man.

    PubMed

    Pallapies, D; Muhs, A; Bertram, L; Rohleder, G; Nagyiványi, P; Peskar, B A

    1996-01-01

    Lysine clonixinate is an analgesic drug with a so far unknown mechanism of action. We have determined its effect on platelet cyclooxygenase in man. Biosynthesis of thromboxane (TX)B2 and prostaglandin (PG)F2 alpha in clotting whole blood ex vivo as well as collagen-induced platelet aggregation measured before and at various time points after oral administration of 125 mg lysine clonixinate were compared to results obtained with 500 mg acetylsalicylic acid (ASA). While biosynthesis of both TXB2 and PGF2 alpha measured radioimmunologically was inhibited significantly 2.5 h, but not 6 h, after administration of lysine clonixinate, inhibition by ASA was much greater and still highly significant after 48 h. Similarly, collagen-induced aggregation of platelet-rich plasma was inhibited for a longer period and to a greater extent after administration of ASA than after lysine clonixinate. Our results indicate that lysine clonixinate is a cyclooxygenase inhibitor of moderate potency. It remains to be investigated whether mechanisms other than inhibition of cyclooxygenase contribute to the analgesic activity of lysine clonixinate. PMID:8866627

  18. 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

    administration of a single oral dose of FL. PMID:25375880

  19. 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

    administration of a single oral dose of FL. PMID:25375880

  20. Antimalarial Preclinical Drug Development: A Single Oral Dose of A 5-Carbon-linked Trioxane Dimer Plus Mefloquine Cures Malaria-Infected Mice.

    PubMed

    Moon, Deuk Kyu; Singhal, Vandana; Kumar, Nirbhay; Shapiro, Theresa A; Posner, Gary H

    2009-01-01

    Three new 5-carbon-linked trioxane dimer carboxylate esters have been prepared from the natural trioxane, artemisinin in only 3-steps and 40-50% overall yields. Each one of these new chemical entities is at least as efficacious as the clinically used trioxane antimalarial drug artemether when combined with mefloquine hydrochloride in a low single oral dose cure. PMID:20686674

  1. 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

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

    PubMed

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

    2004-01-01

    A bioequivalence study of the ambroxol hydrochloride tablets was conducted. Twenty-four healthy male Korean volunteers received each medicine at the ambroxol hydrochloride dose of 30 mg in a 2 x 2 cross-over study. There was a 1-week washout period between the doses. Plasma concentrations of ambroxol were monitored by a high-performance liquid chromatography (HPLC) for over a period of 24h after the administration. AUC(t) (the area under the plasma concentration-time curve from time 0 to last sampling time, 24h) was calculated by the linear-log trapezoidal rule method. C(max) (maximum plasma drug concentration) and T(max) (time to reach C(max)) were compiled from the plasma concentration-time data. Analysis of variance was carried out using logarithmically transformed AUC(t) and C(max), and untransformed T(max). The geometric mean of AUC(t) was 495.8 ng ml(-1)h(-1) (test medication) and 468.3 ng ml(-1)h(-1) (reference medication). C(max) of 61.5 and 57.3 ng ml(-1) were achieved for the test and the reference medication, respectively. The point estimates and 90% confidence intervals for AUC(t) (parametric) and C(max) (parametric) were, in point estimate (90% confidence interval), 1.058 (0.989-1.134) and 1.073 (1.007-1.142), respectively, satisfying the bioequivalence criteria of the European Committee for Proprietary Medicinal Products and the US Food and Drug Administration Guidelines. The corresponding value of T(max) was 0.229 (0.015-0.444). These results indicate that the two medications of ambroxol hydrochloride are bioequivalent and, thus, may be prescribed interchangeably. PMID:14597158

  3. Novel and Distinct Metabolites Identified Following a Single Oral Dose of Alpha- or Gamma-Hexabromocyclododecane in Mice

    EPA Science Inventory

    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 a...

  4. Novel and Distinct Metabolites Identified Following a Single Oral Dose of α- or γ-Hexabromocyclododecane in Mice

    PubMed Central

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

    2013-01-01

    The metabolism of α- and γ-hexabromocyclododecane (HBCD) was investigated in adult C57BL/6 female mice. α- or γ-[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 α-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 γ-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

  5. Nutrition Composition and Single, 14-Day and 13-Week Repeated Oral Dose Toxicity Studies of the Leaves and Stems of Rubus coreanus Miquel.

    PubMed

    Om, Ae-Son; Song, Yu-Na; Noh, GeonMin; Kim, HaengRan; Choe, JeongSook

    2016-01-01

    The leaves and stems of the plant Rubus coreanus Miquel (RCMLS) are rich in vitamins, minerals and phytochemicals which have antioxidant, anti-hemolytic, anti-inflammatory, anti-fatigue and anti-cancer effects. However, RCMLS is not included in the Korean Food Standards Codex due to the lack of safety assurance concerning RCMLS. We evaluated single and repeated oral dose toxicity of RCMLS in Sprague-Dawley rats. RCMLS did not induce any significant toxicological changes in both male and female rats at a single doses of 2500 mg/kg/day. Repeated oral dose toxicity studies showed no adverse effects in clinical signs, body weight, food consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, organ weight, and histopathology at doses of 625, 1250, and 2500 mg/kg/day. The LD50 and LOAEL of RCMLS might be over 2500 mg/kg body weight/day and no target organs were identified. Therefore, this study revealed that single and repeated oral doses of RCMLS are safe. PMID:26760987

  6. 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

  7. 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...

  8. Single dose of diclofenac or meloxicam for control of pain, facial swelling, and trismus in oral surgery

    PubMed Central

    Orozco-Solís, Mariana; García-Ávalos, Yazmín; Pichardo-Ramírez, Celeste; Tobías-Azúa, Francisco; Zapata-Morales, Juan-Ramón; Aragon-Martínez, Othoniel-Hugo

    2016-01-01

    Background Postoperative pain associated with removal of mandibular third molars has been documented from moderate to severe during the first 24 hours after surgery, with pain peaking between 6 and 8 hours when a conventional local anesthetic is used. Dental pain is largely inflammatory, and evidence-based medicine has shown that nonsteroidal anti-inflammatory drugs are the best analgesics for dental pain. The aim of this study was to compare the analgesic, anti-inflammatory and anti-trismus effect of a single dose of diclofenac and meloxicam after mandibular third molar extraction. Material and Methods A total of 36 patients were randomized into two treatment groups, each with 18 patients, using a series of random numbers: Group A, was administered 100 mg of diclofenac; and Group B, 15 mg of meloxicam. Drugs were administered orally 1 hour prior to surgery. We evaluated pain intensity, analgesic consumption, swelling, as well as trismus. Results The results of this study showed that patients receiving 15 mg of meloxicam had less postoperative pain (P=0.04) and better aperture than those receiving 100 mg of diclofenac (P=0.03). The meloxicam group presented less swelling than diclofenac group; however, significant statistical differences were not observed. Conclusions Data of this double-blind, randomized, parallel-group clinical trial demonstrated that patients receiving 15 mg of preoperative meloxicam had a better postoperative analgesia and anti-trismus effect compared with who were given 100 mg of diclofenac after third molar extractions. Key words:Diclofenac, meloxicam, dental pain, trismus, third molar surgery. PMID:26615509

  9. Single oral dose toxicity test of polycalcium, a mixed composition of polycan and calcium lactate-gluconate 1:9 (G/G) in SD rat.

    PubMed

    Kim, Joo-Wan; Choi, Jae-Suk; Ha, Yu-Mi; Choi, In Soon; Kim, Ki-Young; Cho, Hyung-rae; Rha, Chae-hun; Ku, Sae-Kwang

    2013-11-01

    The object of this study was to obtain acute oral toxicity information of Polycalcium, a mixed composition of Polycan and Calcium lactate-gluconate 1:9 (g/g), in Sprague-Dawely (SD) rats. In order to investigate the toxicity and identify target organs, Polycalcium were once orally administered to female and male SD rats at dose levels of 2000, 1000, 500 and 0 (control) mg/kg body weights. The mortality, changes on body weight and clinical signs were monitored during 14 days after treatment with gross observation, changes on the organ weights and histopathology of principle organs and treatment sites based on the recommendation of KFDA Guidelines [2009-116, 2009]. As the results of single oral treatment of Polycalcium, no treatment related mortalities were observed within 14 days after end of treatment up to 2000 mg/kg, the limited dosage of rodents in the both genders. In addition, no Polycalcium treatment related changes on the body and organ weights, clinical signs, necropsy and histopathological findings were detected. The results obtained in this study suggest that the Polycalcium is non-toxic in rats. The LD50 and approximate LD in rats after single oral dose of Polycalcium were considered over 2000 mg/kg in both female and male, respectively. PMID:24191319

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

    PubMed Central

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

    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 of horizontal gene transfer of resistance genes or pathogenic islands to resident gut flora. Intragastric immunization of mice with EHEC ghosts without the addition of any adjuvant induced cellular and humoral immunity. Immunized mice challenged at day 55 showed 86% protection against lethal challenge with a heterologous EHEC strain after single-dose oral immunization and 93.3% protection after one booster at day 28, whereas the controls showed 26.7% and 30% survival, respectively. These results indicate that it is possible to develop an efficacious single-dose oral EHEC bacterial-ghost vaccine. PMID:16040994

  11. 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 Central

    Rosenberg, Len N.; Schwartz, Sherwyn L.; Lau, John R.; Gana, Theophilus J.

    2014-01-01

    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

  12. Evaluation of Sphingolipids in Wistar Rats Treated to Prolonged and Single Oral Doses of Fumonisin B1

    PubMed Central

    Direito, Glória M.; Almeida, Adriana P.; Aquino, Simone; dos Reis, Tatiana Alves; Pozzi, Claudia Rodrigues; Corrêa, Benedito

    2009-01-01

    The objective of the present study was to evaluate sphingolipid levels (sphingosine-So and sphinganine-Sa) and to compare the Sa/So ratio in liver, serum and urine of Wistar rats after prolonged administration (21 days) of fumonisin B1 (FB1). In parallel, the kinetics of sphingolipid elimination in urine was studied in animals receiving a single dose of FB1. Prolonged exposure to FB1 caused an increase in Sa levels in urine, serum and liver. The most marked effect on sphingolipid biosynthesis was observed in animals treated with the highest dose of FB1. Animals receiving a single dose of FB1 presented variations in Sa and So levels and in the Sa/So ratio. PMID:19333435

  13. Double-blind parallel comparison of single oral doses of ketoprofen, codeine, and placebo in patients with moderate to severe dental pain.

    PubMed

    Mehlisch, D; Frakes, L; Cavaliere, M B; Gelman, M

    1984-01-01

    Ketoprofen, 25, 50, and 100 mg, was compared with 90 mg codeine and placebo for relief of pain due to removal of impacted third molar teeth. Treatment was self-administered as a single oral dose under double-blind conditions in five parallel groups established by a random code in healthy young adults. Based on 129 patient evaluations of pain experience and pain relief, ketoprofen was shown to have a more rapid onset and longer duration of action than codeine. In the derived variables of SPID (Sum of Pain Intensity Differences) and TOPAR (Total Pain Relief), all three doses of ketoprofen, with no dose-related differences among them, were found to provide statistically superior analgesia to codeine and placebo. All five treatments were associated with some adverse reactions. PMID:6392354

  14. 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

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

    PubMed

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

    2011-05-01

    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

  16. A clinical trial of single dose rectal and oral administration of diazepam for the prevention of serial seizures in adult epileptic patients.

    PubMed Central

    Milligan, N M; Dhillon, S; Griffiths, A; Oxley, J; Richens, A

    1984-01-01

    The clinical anticonvulsant efficacy of single dose rectal and oral administration of diazepam 20 mg was examined in two double-blind placebo-controlled trials in adult epileptic patients. All subjects suffered from drug resistant epilepsy and frequently experienced serial seizures. Diazepam was administered rectally as a new experimental suppository formulation immediately after a seizure and was highly effective in preventing recurrent fits within a 24 h observation period (p less than 0.001). Pharmacokinetic studies revealed a wide range of serum diazepam concentrations 60 min after administration of the suppository (mean serum diazepam level 190 +/- 73 (SD ng/ml). In a similar study oral administration of diazepam 20 mg significantly reduced the incidence of serial seizures compared with a placebo (p less than 0.01) and the mean 60 min serum diazepam level was 273 +/- 190 (SD) ng/ml. PMID:6368753

  17. Significance of higher drug concentration in erythrocytes of mice infected with Schistosoma japonicum and treated orally with mefloquine at single doses.

    PubMed

    Tao, Yi; Xue, Jian; Jiang, Bin; Zhang, Hao-Bing; Xiao, Shu-Hua

    2015-12-01

    The purpose of the present study is to understand the pharmacokinetic feature of mefloquine measured by erythrocytes and plasma in Schistosoma japonicum (S. j.)-infected mice and non-infected mice after oral administration of the drug at single doses. A high-performance liquid chromatography (HPLC) method was used to measure the plasma and erythrocyte concentrations of mefloquine at varying intervals posttreatment. Our results demonstrated that in non-infected mice treated orally with mefloquine at an ineffective dose of 50 mg/kg or effective dose of 200 mg/kg for 2-72 h, the erythrocyte-to-plasma ratios of mefloquine were 5.8-11.2 or 2-14.2. On the other hand, in S. j.-infected mice treated with the same single doses of the drug, the erythrocyte and plasma drug concentration ratios were 3.1-4.6 or 2.9-8.5, manifesting that either in infected mice or in non-infected mice that received oral mefloquine resulted in higher concentration of mefloquine in erythrocytes than that in plasma. Unexpectedly, under oral administration of mefloquine at a higher single dose of 200 mg/kg, the pharmacokinetic parameter C max values for plasma from S. j.-infected and non-infected mice were 1.6 ± 0.3 and 2.0 ± 0.4 μg/mL, respectively, which were below the determined in vitro LC50 (50 % lethal concentration) value of 4.93 μg/mL. Therefore, the plasma concentration of mefloquine may display a little effect against schistosomes during the treatment. Although the values of T 1/2 and AUC0-∞ for erythrocytes were significantly longer and higher in infected mice than those of corresponding non-infect mice that received the same single mefloqine dose of 50 mg/kg, the C max value was only 2.6 ± 0.4 μg/mL lower than the determined in vitro LC50, which may explain why this low single dose is ineffective against schistosomes in vivo. After administration of higher mefloquine dose of 200 mg/kg, the C max value for erythrocytes in infected mice was 30 % (7.4 ± 0

  18. 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

    2016-04-01

    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

  19. Randomised clinical trial on the effect of a single oral administration of l-tryptophan, at three dose rates, on reaction speed, plasma concentration and haemolysis in horses.

    PubMed

    Noble, Glenys K; Li, Xiuhua; Zhang, Dagong; Sillence, Martin N

    2016-07-01

    Tryptophan (TRP) is marketed as a calmative for horses despite reservations about its efficacy. The aim of this study was to measure the effect of oral TRP administration on the reaction speed of horses. Sixty mature horses were used in a two stage randomised, blind, cross-over study, receiving a placebo and an oral dose of TRP (30, 60 or 120 mg/kg body weight), before undergoing a reaction speed test. Blood samples were taken up to 96 h after TRP administration, to identify signs of acute haemolytic anaemia. Plasma TRP concentrations were increased (P <0.001) by the administration of TRP paste. However, TRP had no effect on the reaction speed of horses when startled. There was no evidence of alterations in clinical pathology parameters in 432 blood samples. While the safety of these doses of TRP can be confirmed, there was no evidence to suggest that a single dose of TRP is an effective calmative for horses. PMID:27240921

  20. Concurrent administration of donepezil HCl and sertraline HCl in healthy volunteers: assessment of pharmacokinetic changes and safety following single and multiple oral doses

    PubMed Central

    Nagy, Christa F; Kumar, Dinesh; Perdomo, Carlos A; Wason, Suman; Cullen, Edward I; Pratt, Raymond D

    2004-01-01

    Aim This study evaluated the safety and pharmacokinetics (PK) of donepezil HCl and sertraline HCl when administered separately and in combination. Methods This was a randomized, open-label, three-period crossover study. In consecutive dosing periods separated by washout periods of ≥3 weeks, healthy volunteers received either oral donepezil HCI 5 mg once daily for 15 days, oral sertraline HCl 50 mg once daily for 5 days followed by 10 days of once-daily sertraline HCl 100 mg, or the simultaneous administration of oral donepezil HCl and sertraline HCl. Plasma donepezil and sertraline concentrations were determined by high performance liquid chromatography/mass spectrometry. Safety was evaluated by physical and laboratory evaluations and the monitoring of adverse events (AEs). Results A total of 19 volunteers (16 male and three female) were enrolled. Three male subjects withdrew from the study prematurely due to AEs (one case of nausea/stomach cramps and one case of eosinophilia during combination treatment, and one upper respiratory tract infection during treatment with sertraline HCl alone). In subjects who completed all three treatment periods (n = 16), the concurrent administration of donepezil HCl and sertraline HCl did not alter the steady-state (day 15) PK parameters of donepezil HCl. A small (<12%) but statistically significant (P = 0.02) increase in donepezil Cmax was seen after single doses of sertraline HCl and donepezil HCl on day 1 but this was not thought to be clinically meaningful. No significant differences in the tmax or AUC0–24 h of donepezil were observed between the donepezil HCl only or donepezil HCl plus sertraline HCl groups on day 1. No significant changes in sertraline PK parameters were observed either on day 1 (single dose) or on day 15 (steady state) when sertraline HCl was co-administered with donepezil HCl. Generally, the concurrent administration of donepezil HCl and sertraline HCl was well tolerated, with no serious AEs reported

  1. Vitamin K1 concentration in breast-fed neonates after oral or intramuscular administration of a single dose of a new mixed-micellar preparation of phylloquinone.

    PubMed

    Schubiger, G; Tönz, O; Grüter, J; Shearer, M J

    1993-05-01

    The plasma disposition of a new mixed-micellar preparation (KONAKION MM, Roche) of phylloquinone (vitamin K1) has been studied in 25 healthy, fully breast-fed, newborn babies, randomized to receive a single dose of either 1.5 mg i.m. (11 babies) or 3 mg p.o. (14 babies). Venous blood samples were collected at 25 h, 4 days, and 24 days. After p.o. administration, the median plasma phylloquinone concentration increased to 89 ng/ml after 24 h, then decreased to 51 ng/ml after 4 days; the respective concentrations after i.m. injection were 146 ng/ml and 34 ng/ml. The higher plasma phylloquinone level in the i.m. group after 24 h was not statistically significant compared with that of the p.o. group, but the reversed higher concentration in the p.o. group after 4 days was significant (p < 0.01). After 24 days the median plasma phylloquinone had decreased to 0.44 ng/ml (range 0.19-1.44) and 1.05 ng/ml (range 0.37-1.87) in the p.o. and i.m. groups, respectively. There was a significant difference between these plasma concentrations (p < 0.01). They were within or above the reference adult fasting range (0.17-0.68 ng/ml). The narrow range of plasma concentrations at 24 h and 4 days suggests a greater consistency of absorption from this micellar preparation than from other emulsion-based preparations. Further studies are required to assess the long-term protection of a single oral dose against late hemorrhagic disease of the newborn. Until such time, breast-fed babies given this preparation orally should receive (an) additional dose(s). PMID:8315554

  2. Safety and pharmacokinetics of single and multiple intravenous bolus doses of diclofenac sodium compared with oral diclofenac potassium 50 mg: A randomized, parallel-group, single-center study in healthy subjects.

    PubMed

    Munjal, Sagar; Gautam, Anirudh; Okumu, Franklin; McDowell, James; Allenby, Kent

    2016-01-01

    In a randomized, parallel-group, single-center study in 42 healthy adults, the safety and pharmacokinetic parameters of an intravenous formulation of 18.75 and 37.5 mg diclofenac sodium (DFP-08) following single- and multiple-dose bolus administration were compared with diclofenac potassium 50 mg oral tablets. Mean AUC0-inf values for a 50-mg oral tablet and an 18.75-mg intravenous formulation were similar (1308.9 [393.0]) vs 1232.4 [147.6]). As measured by the AUC, DFP-08 18.75 mg and 37.5 mg demonstrated dose proportionality for extent of exposure. One subject in each of the placebo and DFP-08 18.75-mg groups and 2 subjects in the DFP-08 37.5-mg group reported adverse events that were considered by the investigator to be related to the study drug. All were mild in intensity and did not require treatment. Two subjects in the placebo group and 1 subject in the DFP-08 18.75-mg group reported grade 1 thrombophlebitis; no subjects reported higher than grade 1 thrombophlebitis after receiving a single intravenous dose. The 18.75- and 37.5-mg doses of intravenous diclofenac (single and multiple) were well tolerated for 7 days. Additional efficacy and safety studies are required to fully characterize the product. PMID:26096889

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

    PubMed Central

    2012-01-01

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

  4. Safety and Pharmacokinetics of Amprenavir (141W94), a Human Immunodeficiency Virus (HIV) Type 1 Protease Inhibitor, following Oral Administration of Single Doses to HIV-Infected Adults

    PubMed Central

    Sadler, Brian M.; Hanson, Cynthia D.; Chittick, Gregory E.; Symonds, William T.; Roskell, Neil S.

    1999-01-01

    We conducted a double-blind, placebo-controlled, parallel, dose-escalation trial to evaluate the pharmacokinetics and safety of single, oral doses of amprenavir (141W94; formerly VX-478), a potent inhibitor of human immunodeficiency virus (HIV) type 1 protease, administered as hard gelatin capsules in 12 HIV-infected subjects. The doses of amprenavir evaluated were 150, 300, 600, 900, and 1,200 mg. Amprenavir was rapidly absorbed, with the time to maximum concentration occurring within 1 to 2 h after dosing. On the basis of power model analysis, the increase in the maximum concentration of amprenavir in plasma (Cmax) was less than dose proportional, and the increase in the area under the concentration-time curve from time zero to infinity (AUC0–∞) was greater than dose proportional; mean slopes (with 90% confidence intervals) were 1.25 (1.16 to 1.35) and 0.78 (0.78 to 0.86) for AUC0–∞ and Cmax, respectively. Amprenavir was eliminated slowly, with a terminal-phase half-life of 8 h. A second study was conducted to determine the bioavailability of the hard gelatin capsule relative to that of a subsequently developed soft gelatin capsule. The capsules were bioequivalent in terms of AUC0–∞ but not in terms of Cmax; geometric-least-squares means ratios (with 90% confidence intervals) were 1.03 (0.92 to 1.14) and 1.25 (1.03 to 1.53) for AUC0–∞ and Cmax, respectively. Administration of soft gelatin capsules of amprenavir with a high-fat breakfast resulted in a 14% decrease in the mean AUC0–∞ (from 9.58 to 8.26 μg · h/ml), which is not likely to be clinically significant. The most common adverse events related to amprenavir were headache, nausea, and hypesthesia. Amprenavir appears to be safe and well tolerated over the dose range of 150 to 1200 mg. On the basis of the present single-dose studies, amprenavir is an HIV protease inhibitor with favorable absorption and clearance pharmacokinetics that are only minimally affected by administration with food

  5. Protection of sheep against caseous lymphadenitis by use of a single oral dose of live recombinant Corynebacterium pseudotuberculosis.

    PubMed Central

    Hodgson, A L; Tachedjian, M; Corner, L A; Radford, A J

    1994-01-01

    An inactive form of the Corynebacterium pseudotuberculosis phospholipase D (PLD) gene was constructed and expressed in a PLD-negative strain (designated Toxminus) of C. pseudotuberculosis. Antibody responses specific to Toxminus and both Toxminus and PLD proteins were detected in sheep following oral administration of Toxminus or Toxminus expressing the PLD toxoid, respectively. However, only those sheep vaccinated with Toxminus expressing PLD toxoid were protected against wild-type challenge. These results confirm the importance of PLD as a protective antigen and demonstrate both the potential for developing an oral caseous lymphadenitis vaccine and C. pseudotuberculosis Toxminus as a live vaccine vector. Images PMID:7960105

  6. 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

  7. Combination analgesic efficacy: individual patient data meta-analysis of single-dose oral tramadol plus acetaminophen in acute postoperative pain.

    PubMed

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

    2002-02-01

    The primary aims of this study were to assess the analgesic efficacy and adverse effects of single-dose oral tramadol plus acetaminophen in acute postoperative pain and to use meta-analysis to demonstrate the efficacy of the combination drug compared with its components. Individual patient data from seven randomized, double blind, placebo controlled trials of tramadol plus acetaminophen were supplied for analysis by the R.W. Johnson Pharmaceutical Research Institute, Raritan, New Jersey, USA. All trials used identical methods and assessed single-dose oral tramadol (75 mg or 112.5 mg) plus acetaminophen (650 mg or 975 mg) in adult patients with moderate or severe postoperative pain. Summed pain intensity and pain relief data over six and eight hours and global evaluations of treatment effect after eight hours were extracted. Number-needed-to-treat (NNT) for one patient to obtain at least 50% pain relief was calculated. NNTs derived from pain relief data were compared with those derived from pain intensity data and global evaluations. Information on adverse effects was collected. Combination analgesics (tramadol plus acetaminophen) had significantly lower (better) NNTs than the components alone, and comparable efficacy to ibuprofen 400 mg. This could be shown for dental but not postsurgical pain, because more patients were available for the former. Adverse effects were similar for the combination drugs and the opioid component alone. Common adverse effects were dizziness, drowsiness, nausea, vomiting, and headache. In sum, this meta-analysis demonstrated analgesic superiority of the combination drug over its components, without additional toxicity. PMID:11844632

  8. PHARMACOKINETICS OF TRAMADOL HYDROCHLORIDE AND ITS METABOLITE O-DESMETHYLTRAMADOL FOLLOWING A SINGLE, ORALLY ADMINISTERED DOSE IN CALIFORNIA SEA LIONS (ZALOPHUS CALIFORNIANUS).

    PubMed

    Boonstra, Jennifer L; Barbosa, Lorraine; Van Bonn, William G; Johnson, Shawn P; Gulland, Frances M D; Cox, Sherry K; Martin-Jimenez, Tomas

    2015-09-01

    Tramadol is a synthetic, centrally acting, opiate-like analgesic that is structurally related to codeine and morphine. The objective of this study was to determine the pharmacokinetics of tramadol hydrochloride and its major active metabolite O-desmethyltramadol (M1) in the California sea lion (Zalophus californianus). A single dose of tramadol was administered orally in fish at 2 mg/kg to a total of 15 wild California sea lions admitted for rehabilitation. Twenty-four total blood samples were collected post drug administration at 10, 20, 30, and 45 min and at 1, 3, 5, 6, 8, 12, and 24 hr. Blood plasma was separated and stored at -80°C until analysis with high-performance liquid chromatography was performed to determine levels of tramadol and M1, the major active metabolite. The results indicate that the plasma levels of parent tramadol are low or negligible during the first 30-45 min and then reach the predicted mean maximum plasma concentration of 358 ng/ml at 1.52 hr. The M1 metabolite was not detectable in 21 of 24 plasma samples, below the level of quantification of 5 ng/ml in one sample, and detectable at 11 and 17 ng/ml in two of the samples. This study suggests that a 2 mg/kg dose would need to be administered every 6-8 hr to maintain concentrations of tramadol above the minimum human analgesic level for mild to moderate pain. Based on dosing simulations, a dose of 4 mg/kg q8 hr or q12 hr, on average, may represent an adequate compromise, but further studies are needed using a larger sample size. Pharmacodynamic studies are warranted to determine if tramadol provides analgesic effects in this species. The potential for tramadol toxicosis at any dose also has not been determined in this species. PMID:26352950

  9. Kinetics and disposition of orally dosed sodium chlorate in sheep

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Experiments were conducted in sheep to determine excretory characteristics of sodium chlorate after a single oral dose. In Exp. 1 lambs (n = 16; age = 8.1 ± 1.7 d; BW = 8.2 ± 1.1 kg; mean ± SD) were dosed orally with 0, 30, 60, or 90 mg/kg BW of sodium chlorate. Twenty-four h after exposure chlorate...

  10. Kinetics of the phthalate metabolites mono-2-ethylhexyl phthalate (MEHP) and mono-n-butyl phthalate (MnBP) in male subjects after a single oral dose.

    PubMed

    Mittermeier, Astrid; Völkel, Wolfgang; Fromme, Hermann

    2016-06-11

    Humans have been exposed to dialkyl ortho-phthalates for decades. Due to degradation the phthalate monoesters, responsible for the toxic effects, are additionally found in environmental media as well as food samples. Nevertheless, the toxicokinetic properties of the monoesters are not known. Therefore, metabolism of the phthalate monoesters mono-2-ethylhexyl phthalate (MEHP) and mono-n-butyl phthalate (MnBP) was studied in four male volunteers (23-58 years of age) after ingestion of a single dose of 50μg/kg bw D4-MEHP or 10μg/kg bw D4-MnBP. The main metabolites in urine were determined up to 46h after administration. In the MEHP-study, more than 90% of each metabolite appeared in the urine within the first 22h, and the average excreted amount of D4-MEHP and its four secondary metabolites was 62% of the administered dose. The highest value of 15% was observed for mono-2-ethyl-5-carboxy-pentyl phthalate (D4-5cx-MEPP). The mean elimination half-life of D4-MEHP was estimated to be 3.5±1.4h. In the MnBP-study, the total recovered values of D4-MnBP and its secondary metabolites ranged from 52% to 130%. The monoester itself, with a half-life of 1.9±0.5h, accounted for the majority of the ingested dose (92%), while the secondary metabolites D4-mono-3-hydroxy-n-butyl phthalate (D4-3OH-MnBP) and D4-3-carboxy-mono-propyl phthalate (D4-3cx-MPP) represented only 7.1% and 1.0% of the ingested dose, respectively. Overall, this study determined that the kinetics of the phthalate monoesters MEHP and MnBP after oral dosage are comparable to the properties of their diesters. PMID:27091076

  11. 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

  12. 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

  13. Assessment of the effects of renal impairment and smoking on the pharmacokinetics of a single oral dose of the soluble guanylate cyclase stimulator riociguat (BAY 63-2521)

    PubMed Central

    Becker, Corina; Unger, Sigrun; Schmidt, Anja; Wensing, Georg; Mück, Wolfgang

    2016-01-01

    Abstract Renal impairment is a common comborbidity in patients with pulmonary hypertension. The breakdown of riociguat, an oral soluble guanylate cyclase stimulator used to treat pulmonary hypertension, may be affected by smoking because polycyclic aromatic hydrocarbons in tobacco smoke induce expression of one of the metabolizing enzymes, CYP1A1. Two nonrandomized, nonblinded studies were therefore performed to investigate the pharmacokinetics and safety of a single oral dose of riociguat 1.0 mg in individuals with mild, moderate, or severe renal impairment compared with age-, weight-, and sex-matched healthy controls, including either smokers and nonsmokers (study I) or nonsmokers alone (study II). Pharmacokinetic analyses focused on the integrated per-protocol data set of both studies (N = 63). In patients with renal impairment, the renal clearance of riociguat was reduced and its terminal half-life prolonged compared with those in healthy controls. There was a monotonic relationship between creatinine clearance on treatment day and riociguat renal clearance (R2 = 0.62). However, increased riociguat exposure with decreasing renal function was not strictly proportional. Riociguat exposure appeared to be greater in nonsmokers than in the combined population of smokers and nonsmokers, irrespective of renal function. Adverse events were mild to moderate and in line with the mode of action of riociguat. No serious adverse events occurred. In conclusion, renal impairment was associated with reduced riociguat clearance compared with that in controls; however, riociguat exposure in patients with renal impairment was highly variable, and ranges overlapped with those observed in healthy controls. PMID:27162624

  14. Randomized, Controlled Human Challenge Study of the Safety, Immunogenicity, and Protective Efficacy of a Single Dose of Peru-15, a Live Attenuated Oral Cholera Vaccine

    PubMed Central

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

    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 and immunogenic and whether it would provide significant protection against moderate and severe diarrhea in a randomized, double-blind, placebo-controlled human volunteer cholera challenge model. A total of 59 volunteers were randomly allocated to groups to receive either 2 × 108 CFU of reconstituted, lyophilized Peru-15 vaccine diluted in CeraVacx buffer or placebo (CeraVacx buffer alone). Approximately 3 months after vaccination, 36 of these volunteers were challenged with approximately 105 CFU of virulent V. cholerae O1 El Tor Inaba strain N16961, prepared from a standardized frozen inoculum. Among vaccinees, 98% showed at least a fourfold increase in vibriocidal antibody titers. After challenge, 5 (42%) of the 12 placebo recipients and none (0%) of the 24 vaccinees had moderate or severe diarrhea (≥3,000 g of diarrheal stool) (P = 0.002; protective efficacy, 100%; lower one-sided 95% confidence limit, 75%). A total of 7 (58%) of the 12 placebo recipients and 1 (4%) of the 24 vaccinees had any diarrhea (P < 0.001; protective efficacy, 93%; lower one-sided 95% confidence limit, 62%). The total number of diarrheal stools, weight of diarrheal stools, incidence of fever, and peak stool V. cholerae excretion among vaccinees were all significantly lower than in placebo recipients. Peru-15 is a well-tolerated and immunogenic oral cholera vaccine that affords protective efficacy against life-threatening cholera diarrhea in a human volunteer challenge model. This vaccine may therefore be a safe and effective tool to prevent cholera in travelers and is a strong candidate for further evaluation to prevent cholera

  15. Assessment of the effects of hepatic impairment and smoking on the pharmacokinetics of a single oral dose of the soluble guanylate cyclase stimulator riociguat (BAY 63-2521)

    PubMed Central

    Becker, Corina; Unger, Sigrun; Schmidt, Anja; Wensing, Georg; Mück, Wolfgang

    2016-01-01

    Abstract Riociguat, a soluble guanylate cyclase stimulator developed for the treatment of pulmonary hypertension, is metabolized in part by the liver. Expression of one of the metabolizing enzymes, CYP1A1, is induced by aromatic hydrocarbons in tobacco smoke. Two nonrandomized, nonblinded studies were conducted to investigate the pharmacokinetics of riociguat in individuals with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment associated with liver cirrhosis compared with that in age-, weight-, and sex-matched healthy controls: study 1 included smokers and nonsmokers, and study 2 included nonsmokers only. Data from these studies were integrated for analysis. All participants (N = 64) received a single oral dose of riociguat 1.0 mg. Riociguat exposure was significantly higher in individuals with Child-Pugh B hepatic impairment than in healthy controls (ratio: 153% [90% confidence interval: 103%–228%]) but was similar in those with Child-Pugh A hepatic impairment and controls. The half-life of the riociguat metabolite M1 was prolonged in patients with Child-Pugh B or A hepatic impairment compared with that in controls by approximately 43% and 24%, respectively. Impaired hepatic function was associated with higher riociguat exposure in nonsmokers compared with the population of smokers and nonsmokers combined. Riociguat’s safety profile was similar in individuals with impaired or normal liver function. In conclusion, moderate hepatic impairment was associated with increased riociguat exposure compared with that in controls, probably as a result of reduced clearance of the metabolite M1. This suggests that dose titration of riociguat should be administered with particular care in patients with moderate hepatic impairment. PMID:27162628

  16. A Single-Dose, Single-Period Pharmacokinetic Assessment of an Extended-Release Orally Disintegrating Tablet of Methylphenidate in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder

    PubMed Central

    Childress, Ann; Newcorn, Jeffrey; Stark, Jeffrey G.; McMahen, Russ; Tengler, Mark

    2016-01-01

    Abstract Objective: To determine the pharmacokinetic (PK) profile of a proprietary formulation of methylphenidate (MPH) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) in a phase 1 study. Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) combine two technologies in a single-tablet formulation—an extended-release profile that was designed for once-daily dosing in an ODT that does not require water or chewing for ingestion. Methods: This was a single-dose, open-label, single-period, single-treatment study, in which 32 children with ADHD who were receiving MPH in doses of 40 or 60 mg before beginning the study each received a 60-mg dose (2 × 30 mg) of MPH XR-ODT. The following plasma PK parameters of MPH were determined for participants grouped by age (6–7, 8–9, 10–12, and 13–17 years old): maximum concentration (Cmax), time to maximum concentration (Tmax), elimination half-life (T½), area under the curve from 0 hours to infinity (AUCinf), oral clearance (CL/F), and volume of distribution in the terminal phase (Vz/F). Safety and tolerability were also assessed. Results: A total of 32 participants received the study drug. For all participants, plasma concentration–time profiles of MPH exhibited a broad peak after administration of MPH XR-ODT through ∼8 hours, indicating extended release from the formulation, followed by an apparent first-order elimination phase. As age increased, MPH exposure decreased and mean estimates of CL/F increased; however, weight-normalized CL/F values were comparable across age groups. Similarly, mean estimates of Vz/F increased with age, but weight-normalization decreased differences across age groups, with the exception of the youngest age group, which had higher values. All adverse events (AEs) were mild. Conclusion: This XR-ODT formulation of MPH demonstrated weight-normalized clearance rates that were consistent across all age groups, a PK profile

  17. N,N-dimethyl-2-phenylpropan-1-amine quantification in urine: application to excretion study following single oral dietary supplement dose.

    PubMed

    Wójtowicz, Marzena; Jarek, Anna; Chajewska, Katarzyna; Kwiatkowska, Dorota

    2016-07-01

    N,N-dimethyl-2-phenylpropan-1-amine (NN-DMPPA) is a new designer stimulant prohibited in sport in-competition according to the List of Prohibited Substances and Methods published by the World Anti-Doping Agency (WADA). The first published data on the excretion study of NN-DMPPA to support the knowledge of NN-DMPPA in routine anti-doping control have been presented. The reliable gas chromatography-mass spectrometry quantitative method (GC-MS) has been validated and applied to the excretion study of NN-DMPPA. The validation parameters of the GC-MS method for determination of NN-DMPPA in human urine were the linear calibration range of 100 to 7500 ng/mL, the LOD of 13.9 ng/mL and the LOQ of 42.2 ng/mL. According to the obtained repeatability, intermediate precision, and trueness, the applied GC-MS method was precise and accurate. Urine samples from three volunteers in the excretion study were collected for 5 days after single oral administration of the supplement NOXPUMP containing NN-DMPPA. The obtained results showed the maximum concentration of NN-DMPPA (189-303 ng/mL) in urine samples at a time of 2-3 h post-administration. The NN-DMPPA concentration in urine samples was higher than 50 ng/mL until 22-23 h after the dietary supplement ingestion. This means that according to the WADA rules the use of a supplement containing NN-DMPPA may be related to a positive case when athletes took this supplement in-competition. Moreover, excretion results demonstrate also that NN-DMPPA may be detected in urine samples by the applied GC-MS method till 46 h after supplement administration. Additionally, the excretion study of β-methylphenethylamine as the second prohibited substance present in the supplement NOXPUMP has been investigated. Graphical Abstract Excretion study of new designer stimulant, N,N-dimethyl-2-phenylpropan-1-amine, and β-methylphenethylamine following single oral NOXPUMP supplement dose. PMID:27178556

  18. A Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of JDTic.

    PubMed

    Buda, Jeffrey J; Carroll, F I; Kosten, Thomas R; Swearingen, Dennis; Walters, Bradford B

    2015-08-01

    Animal studies suggest that kappa opioid receptor antagonists (KORAn) potentially could treat a wide variety of addictive and depressive disorders. We assessed the KORAn JDTic for safety, tolerability, and pharmacokinetics in a double-blind, placebo-controlled, randomized trial evaluating single oral doses in healthy adult males. Predose and postdose safety assessments included orthostatic vital signs; 6-lead continuous telemetry monitoring (approximately 16 h predose to 24 h postdose); 12-lead electrocardiograms (ECGs); clinical chemistry, hematology, coagulation, and urinalysis; psychomotor functioning (using the Wayne Saccadic Fixator (WSF)); and adverse events. As a potential indicator of JDTic effects on affect, the POMS Standard instrument was administered predose and daily postdose Days 1-6. At 1 mg, 2 of the 6 JDTic (and 0/6 placebo) subjects experienced a single, asymptomatic event of multiple beats of nonsustained ventricular tachycardia (NSVT). Their events were temporally similar with respect to time postdose (and the postdose timing of an NSVT event in a monkey). These events triggered a study stopping rule. No differences were observed between the placebo and JDTic subjects with respect to clinical chemistry, hematology, coagulation, urinalysis, orthostatic vital signs, WSF, or 12-lead ECG parameters. Plasma JDTic levels were below the lower limit of quantitation (0.1 nM) in all subjects. There were no significant differences in POMS scores between the placebo and JDTic groups. Although the evidence is circumstantial, it suggests that NSVT is a potential JDTic toxicity in humans. Given the therapeutic potential of KORAn, further investigation is needed to determine whether a significant JDTic human cardiac effect indeed exists, and if so, whether it is specific to JDTic or represents a KORAn class effect. PMID:25628006

  19. A Double-Blind, Placebo-Controlled Trial to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single, Escalating Oral Doses of JDTic

    PubMed Central

    Buda, Jeffrey J; Carroll, F I; Kosten, Thomas R; Swearingen, Dennis; Walters, Bradford B

    2015-01-01

    Animal studies suggest that kappa opioid receptor antagonists (KORAn) potentially could treat a wide variety of addictive and depressive disorders. We assessed the KORAn JDTic for safety, tolerability, and pharmacokinetics in a double-blind, placebo-controlled, randomized trial evaluating single oral doses in healthy adult males. Predose and postdose safety assessments included orthostatic vital signs; 6-lead continuous telemetry monitoring (approximately 16 h predose to 24 h postdose); 12-lead electrocardiograms (ECGs); clinical chemistry, hematology, coagulation, and urinalysis; psychomotor functioning (using the Wayne Saccadic Fixator (WSF)); and adverse events. As a potential indicator of JDTic effects on affect, the POMS Standard instrument was administered predose and daily postdose Days 1–6. At 1 mg, 2 of the 6 JDTic (and 0/6 placebo) subjects experienced a single, asymptomatic event of multiple beats of nonsustained ventricular tachycardia (NSVT). Their events were temporally similar with respect to time postdose (and the postdose timing of an NSVT event in a monkey). These events triggered a study stopping rule. No differences were observed between the placebo and JDTic subjects with respect to clinical chemistry, hematology, coagulation, urinalysis, orthostatic vital signs, WSF, or 12-lead ECG parameters. Plasma JDTic levels were below the lower limit of quantitation (0.1 nM) in all subjects. There were no significant differences in POMS scores between the placebo and JDTic groups. Although the evidence is circumstantial, it suggests that NSVT is a potential JDTic toxicity in humans. Given the therapeutic potential of KORAn, further investigation is needed to determine whether a significant JDTic human cardiac effect indeed exists, and if so, whether it is specific to JDTic or represents a KORAn class effect. PMID:25628006

  20. Pooled post hoc analysis of population pharmacokinetics of oxycodone and acetaminophen following a single oral dose of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets

    PubMed Central

    Franke, Ryan M; Morton, Terri; Devarakonda, Krishna

    2015-01-01

    This analysis evaluated the single-dose population pharmacokinetics (PK) of biphasic immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP) 7.5/325 mg tablets administered under fasted conditions and the effects of a meal on their single-dose population PK. Data were pooled from four randomized, single-dose crossover trials enrolling healthy adult (18–55 years old) participants (three trials) and nondependent recreational users of prescription opioids (one trial) with a body weight of ≥59 kg. Participants received IR/ER OC/APAP 7.5/325 mg tablets in single doses of 7.5/325 mg (one tablet), 15/650 mg (two tablets), or 30/1,300 mg (four tablets) under fasted or fed conditions. Six variables were examined: sex, race, age, weight, height, and body mass index. Single-dose population PK was analyzed using first-order conditional estimation methods. A total of 151 participants were included in the analysis under fasted conditions, and 31 participants were included in the fed analysis. Under fasted conditions, a 10% change in body weight was accompanied by ~7.5% change in total body clearance (CL/F) and volume of distribution (V/F) of OC and APAP. Black participants had 17.3% lower CL/F and a 16.9% lower V/F of OC compared with white participants. Under fed conditions, the absorption rate constant of OC and APAP decreased significantly, although there was no effect on CL/F and V/F. Considering that the recommended dose for IR/ER OC/APAP 7.5/325 mg tablets is two tablets every 12 hours, adjustments of <50% are not clinically relevant. Dose adjustment may be necessary for large deviations from average body weight, but the small PK effects associated with race and consumption of a meal are not clinically relevant. PMID:26316698

  1. Pooled post hoc analysis of population pharmacokinetics of oxycodone and acetaminophen following a single oral dose of biphasic immediate-release/extended-release oxycodone/acetaminophen tablets.

    PubMed

    Franke, Ryan M; Morton, Terri; Devarakonda, Krishna

    2015-01-01

    This analysis evaluated the single-dose population pharmacokinetics (PK) of biphasic immediate-release (IR)/extended-release (ER) oxycodone (OC)/acetaminophen (APAP) 7.5/325 mg tablets administered under fasted conditions and the effects of a meal on their single-dose population PK. Data were pooled from four randomized, single-dose crossover trials enrolling healthy adult (18-55 years old) participants (three trials) and nondependent recreational users of prescription opioids (one trial) with a body weight of ≥59 kg. Participants received IR/ER OC/APAP 7.5/325 mg tablets in single doses of 7.5/325 mg (one tablet), 15/650 mg (two tablets), or 30/1,300 mg (four tablets) under fasted or fed conditions. Six variables were examined: sex, race, age, weight, height, and body mass index. Single-dose population PK was analyzed using first-order conditional estimation methods. A total of 151 participants were included in the analysis under fasted conditions, and 31 participants were included in the fed analysis. Under fasted conditions, a 10% change in body weight was accompanied by ~7.5% change in total body clearance (CL/F) and volume of distribution (V/F) of OC and APAP. Black participants had 17.3% lower CL/F and a 16.9% lower V/F of OC compared with white participants. Under fed conditions, the absorption rate constant of OC and APAP decreased significantly, although there was no effect on CL/F and V/F. Considering that the recommended dose for IR/ER OC/APAP 7.5/325 mg tablets is two tablets every 12 hours, adjustments of <50% are not clinically relevant. Dose adjustment may be necessary for large deviations from average body weight, but the small PK effects associated with race and consumption of a meal are not clinically relevant. PMID:26316698

  2. 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...

  3. Exposure-safety-efficacy analysis of single-agent ixazomib, an oral proteasome inhibitor, in relapsed/refractory multiple myeloma: dose selection for a phase 3 maintenance study.

    PubMed

    Gupta, Neeraj; Labotka, Richard; Liu, Guohui; Hui, Ai-Min; Venkatakrishnan, Karthik

    2016-06-01

    Background Ixazomib is the first oral, small molecule proteasome inhibitor to reach phase 3 trials. The current analysis characterized the exposure-safety and exposure-efficacy relationships of ixazomib in patients with relapsed/refractory multiple myeloma (MM) with a purpose of recommending an approach to ixazomib dosing for maintenance therapy. Methods Logistic regression was used to investigate relationships between ixazomib plasma exposure (area under the curve/day; derived from individual apparent clearance values from a published population pharmacokinetic analysis) and safety/efficacy outcomes (hematologic [grade ≥ 3 vs ≤ 2] or non-hematologic [grade ≥ 2 vs ≤ 1] adverse events [AEs], and clinical benefit [≥stable disease vs progressive disease]) using phase 1 data in relapsed/refractory MM (NCT00963820; N = 44). Results Significant relationships to ixazomib exposure were observed for five AEs (neutropenia, thrombocytopenia, rash, fatigue, and diarrhea) and clinical benefit (p < 0.05). Dose-response relationships indicated a favorable benefit/risk ratio at 3 mg and 4 mg weekly, which are below the maximum tolerated dose of 5.5 mg. At 3 mg, the model predicted that: 37 % of patients will achieve clinical benefit; incidence of grade ≥ 3 neutropenia and thrombocytopenia will be 10 % and 23 %, respectively; and incidence of grade ≥ 2 rash, fatigue, and diarrhea will be 8 %, 19 %, and 19 %, respectively. Conclusions Based on the findings, patients in the phase 3 maintenance trial will initiate ixazomib at a once-weekly dose of 3 mg, increasing to 4 mg if acceptable tolerability after 4 cycles, to provide maximum clinical benefit balanced with adequate tolerability. PMID:27039387

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

    PubMed Central

    2014-01-01

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

  5. A first-in-human randomized, double-blind, placebo-controlled, single- and multiple-ascending oral dose study of novel Imidazolopiperazine KAF156 to assess its safety, tolerability, and pharmacokinetics in healthy adult volunteers.

    PubMed

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

    2014-11-01

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

  6. Pharmacokinetics and Safety of FV-100, a Novel Oral Anti-Herpes Zoster Nucleoside Analogue, Administered in Single and Multiple Doses to Healthy Young Adult and Elderly Adult Volunteers▿

    PubMed Central

    Pentikis, Helen S.; Matson, Mark; Atiee, George; Boehlecke, Brian; Hutchins, Jeff T.; Patti, Joseph M.; Henson, Geoffrey W.; Morris, Amy

    2011-01-01

    FV-100 is the prodrug of the highly potent anti-varicella zoster virus bicyclic nucleoside analogue CF-1743. To characterize the pharmacokinetics and safety of oral FV-100, 3 randomized, double-blind, placebo-controlled clinical trials were conducted: (i) a single-ascending-dose study in 32 healthy subjects aged 18 to 55 years (100-, 200-, 400-, and 800-mg doses) with an evaluation of the food effect in the 400-mg group; (ii) a multiple-ascending-dose study in 48 subjects aged 18 to 55 years (100 mg once daily [QD], 200 mg QD, 400 mg QD, 400 mg twice a day, and 800 mg QD for 7 days); and (iii) a 2-part study in subjects aged 65 years and older with a single 400-mg dose in 15 subjects and a 400-mg QD dosing regimen for 7 days in 12 subjects. FV-100 was rapidly and extensively converted to CF-1743, the concentration of which remained above that required to reduce viral activity by 50% for the 24-hour dosing period. Renal excretion of CF-1743 was very low. A high-fat meal reduced exposure to CF-1743; a low-fat meal did not. Pharmacokinetic parameters for the elderly subjects were comparable to those for the younger subjects. FV-100 was well tolerated by all subjects. The pharmacokinetic and safety profiles of FV-100 support its continued investigation for the treatment of herpes zoster and prevention of postherpetic neuralgia with once-daily dosing and without dose modifications for elderly or renally impaired patients. PMID:21444712

  7. Pharmacokinetics and tolerability of single oral doses of 882C87, a potent, new anti-varicella-zoster virus agent, in healthy volunteers.

    PubMed Central

    Peck, R W; Weatherley, B C; Wootton, R; Crome, P; Holdich, T A; Posner, J

    1995-01-01

    882C87 is a nucleoside analog with potent, specific activity against varicella-zoster virus. It is approximately seven times as potent as acyclovir with an in vitro 50% inhibitory concentration of 1 to 2 microM. The tolerability and pharmacokinetics of single doses of 882C87 have been investigated in a series of studies with healthy young and elderly adult volunteers. The young received 50 to 1,600 mg, and the elderly received 50 and 100 mg. Concentrations of 882C87 and its main metabolite, the pyrimidine base 5-(1-propynyl)uracil (5PU), in plasma and urine were assayed by an automated sequential trace enrichment of dialysate-high-performance liquid chromatography procedure, and noncompartmental pharmacokinetic parameters were derived from the data. Concentrations of 882C87 in plasma increased proportionally for doses of up to 400 mg, but after higher doses the increase was less than dose proportional. In young adults, after 200, 400, and 1,600 mg, the maximum concentrations of the drug in plasma were 9.0, 16.3, and 34.7 microM, respectively, and the areas under the concentration-time curve (AUC) from 0 h to infinity were 166.6, 333.7, and 822.9 microM.h, respectively. Elimination half-life was 11.3 to 13.0 h after 50 to 400 mg, increasing to 15.3 h after 1,600 mg, associated with a small decrease in renal clearance. In healthy elderly volunteers concentrations of 882C87 in plasma after 50 and 100 mg were similar to those in young adults after twice the dose; apparent clearance and renal clearance were significantly reduced, and half-life was significantly longer at 15 h. Administration of 882C87 with food produced a small, nonsignificant reduction in mean AUC from 0 h to infinity, but in subjects with a low fasting AUC there was an increase after food and in subjects with a high fasting AUC there was a decrease. Concentrations of 5PU in plasma were one-third to one-half those of 882C87 and, in most subjects, were not dose proportional. There was a lag of at least

  8. Distribution of radio-labeled N-Acetyl-L-Cysteine in Sprague-Dawley rats and its effect on glutathione metabolism following single and repeat dosing by oral gavage.

    PubMed

    Arfsten, Darryl P; Johnson, Eric W; Wilfong, Erin R; Jung, Anne E; Bobb, Andrew J

    2007-01-01

    The distribution of radio-labeled N-Acetyl-L-Cysteine (NAC) and its impact on glutathione (GSH) metabolism was studied in Sprague-Dawley rats following single and multiple dosing with NAC by oral gavage. Radioactivity associated with administration of (14)C-NAC distributed to most tissues examined within 1 hour of administration with peak radioactivity levels occurring within 1 hour to 4 hours and for a majority of the tissues examined, radioactivity remained elevated for up to 12 hours or more. Administration of a second dose of 1,200 mg/kg NAC + (14)C-NAC 4 hours after the first increased liver, kidney, skin, thymus, spleen, eye, and serum radioactivity significantly beyond levels achieved following 1 dose. Administration of a third dose of 1,200 mg/kg NAC + (14)C-NAC 4 hours after the second dose did not significantly increase tissue radioactivity further except in the skin. GSH concentrations were increased 20% in the skin and 50% in the liver after one dose of 1,200 mg/kg NAC whereas lung and kidney GSH were unaffected. Administration of a second and third dose of 1,200 mg/kg NAC at 4 hours and 8 hours after the first did not increase tissue GSH concentrations above background with the exception that skin GSH levels were elevated to levels similar to those obtained after a single dose of NAC. Glutathione-S-transferase (GST) activity was increased 150% in the kidney and 10% in the liver, decreased 60% in the skin, and had no effect on lung GST activity following a single dose of 1,200 mg/kg NAC. Administration of a second dose of 1,200 mg/kg NAC 4 hours after the first decreased skin GST activity a further 20% whereas kidney GST activity remained elevated at levels similar to those obtained after 1 dose of NAC. Administration of a third dose of NAC 4 hours after the second dose increased liver GST activity significantly as compared to background but did not affect skin, kidney, or lung GST activity. Transient decreases in glutathione reductase (GR) activity

  9. Blood phenylalanine concentrations in patients with PAH-deficient hyperphenylalaninaemia off diet without and with three different single oral doses of tetrahydrobiopterin: assessing responsiveness in a model of statistical process control.

    PubMed

    Lindner, M; Gramer, G; Garbade, S F; Burgard, P

    2009-08-01

    Tetrahydrobiopterin (BH(4)) cofactor loading is a standard procedure to differentiate defects of BH(4) metabolism from phenylalanine hydroxylase (PAH) deficiency. BH(4) responsiveness also exists in PAH-deficient patients with high residual PAH activity. Unexpectedly, single cases with presumed nil residual PAH activity have been reported to be BH(4) responsive, too. BH(4) responsiveness has been defined either by a >or=30% reduction of blood Phe concentration after a single BH(4) dose or by a decline greater than the individual circadian Phe level variation. Since both methods have methodological disadvantages, we present a model of statistical process control (SPC) to assess BH(4) responsiveness. Phe levels in 17 adult PKU patients of three phenotypic groups off diet were compared without and with three different single oral dosages of BH(4) applied in a double-blind randomized cross-over design. Results are compared for >or=30% reduction and SPC. The effect of BH(4) by >or=30% reduction was significant for groups (p < 0.01) but not for dose (p = 0.064), with no interaction of group with dose (p = 0.24). SPC revealed significant effects for group (p < 0.01) and the interaction for group with dose (p < 0.05) but not for dose alone (p = 0.87). After one or more loadings, seven patients would be judged to be BH(4) responsive either by the 30% criterion or by the SPC model, but only three by both. Results for patients with identical PAH genotype were not very consistent within (for different BH(4) doses) and between the two models. We conclude that a comparison of protein loadings without and with BH(4) combined with a standardized procedure for data analysis and decision would increase the reliability of diagnostic results. PMID:19513811

  10. Tumor induction in the glandular stomach of rats after oral administration of a single or a few doses of N-methyl-N'-nitro-N-nitrosoguanidine during the newborn period.

    PubMed

    Sumi, Y; Miyakawa, M

    1978-12-01

    When N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) was orally intubated to conventional newborn rats by the catheter technique, the rats were found with tumors almost exclusively developed in the glandular stomach, mostly until 280 days after the first intubation. Tumor incidence was about 50% in both sexs of rats that survived the intubation of a single dose of MNNG in rats of less than 24 hr after birth and almost 100% in both sexes of rats that survived the intubation of three consecutive daily doses of MNNG on 5th day after birth. Out of 52 rats treated with MNNG, 40.4% developed carcinomas (20 adenocarcinomas and 1 squamous cell carcinoma), three of them having metastatic lesions. The predilective localization of tumors in the glandular, especially fundic, portion of the stomach, might be attributed to the use of newborns and to the catheter technique devised here. PMID:750273

  11. Efficacy and safety of premedication with single dose of oral pregabalin in children with dental anxiety: A randomized double-blind placebo-controlled crossover clinical trial

    PubMed Central

    Eskandarian, Tahereh; Eftekharian, Hamidreza; Soleymanzade, Rojin

    2015-01-01

    Background: Dental anxiety is a relatively frequent problem that can lead to more serious problems such as a child entering a vicious cycle as he/she becomes reluctant to accept the required dental treatments. The aim of this randomized double-blind clinical trial study was to evaluate the anxiolytic and sedative effect of pregabalin in children. Materials and Methods: Twenty-five children were randomized to a double-blind placebo-controlled crossover clinical trial. Two visits were scheduled for each patient. At the first visit, 75 mg pregabalin or placebo was given randomly, and the alternative was administered at the next visit. Anxiolytic and sedative effects were measured using the visual analogue scale. The child's behavior was rated with the Frankl behavioral rating scale and the sedation level during the dental procedure was scored using the Ramsay sedation scale. The unpaired, two-tailed Student's t-test was used to compare the mean changes of visual analog scale (VAS) for anxiety in the pregabalin group with that of the placebo group. A repeated measures MANOVA model was used to detect differences in sedation level in the pregabalin and placebo groups regarding the interaction of 3-time measurements; sub-group analysis was performed using Student's t-test. The Mann–Whitney U-test was used to analyze the nonparametric data of the Frankl and Ramsay scales. A P < 0.05 was considered significant. Results: The reduction of the VAS-anxiety score from 2 h post-dose was statistically significant in the pregabalin group. From 2 h to 4 h post-dose, the VAS-sedation score increased significantly in the pregabalin group. The child's behavior rating was not significantly different between the groups. The number of “successful” treatment visits was higher in the pregabalin group compared to the placebo group. Conclusion: Significant anxiolytic and sedative effects can be anticipated 2 h after oral administration of pregabalin without serious side effects. PMID

  12. Comparison of the effect of a single oral L-thyroxine dose (150 micrograms) in tablet and in solution on serum thyroxine and TSH concentrations.

    PubMed

    Carpi, A; De Gaudio, C; Cirigliano, G; Toni, M G

    1993-04-01

    150 micrograms of L-thyroxine were administered to each of 14 euthyroid goitrous patients orally between 7:30 and 8:30 a.m. after fasting overnight. The L-T4 dose given was one and half tablets of the drug "Eutirox" (L-T4 tablet of 100 micrograms distributed by Bracco, Milan, Italy) or one and half ml of the solution "Tiroxen" (solution containing 100 micrograms/ml of L-T4 distributed by Laboratori Baldacci, Pisa, Italy). Two studies (one with tablet and one with solution) were performed on each patient. The tablet or the liquid form of L-T4 were administered in random order. In each study a blood sample for serum hormone determination was drawn immediately before L-T4 administration, then 30 minutes later and every hour up to the fifth hour after. The second study was performed in similar fashion later. The mean serum TT4 concentration value at any time was very similar in the two studies, thus showing the same time course after the administration of solution and the tablet formulation. The mean basal TT4 value (9.07 +/- 0.56 and 8.90 +/- 0.73 micrograms/dl respectively) increased significantly at the first and second hours. The highest value was reached at the second and at the third hour after the solution (11.15 +/- 0.58 micrograms/dl) and the tablet (11.81 +/- 0.78 micrograms/dl) respectively. Subsequently, the mean TT4 values remained significantly higher than basally over the entire 5 hours. The FT4 mean serum concentration at all times were very similar in the two studies and showed the same time course.(ABSTRACT TRUNCATED AT 250 WORDS) PMID:7508742

  13. Efficacy and safety of short duration azithromycin eye drops versus azithromycin single oral dose for the treatment of trachoma in children: a randomised, controlled, double‐masked clinical trial

    PubMed Central

    Cochereau, Isabelle; Goldschmidt, Pablo; Goepogui, André; Afghani, Tayyab; Delval, Laurent; Pouliquen, Pascale; Bourcier, Tristan; Robert, Pierre‐Yves

    2007-01-01

    Aims Efficacy and safety of a short‐duration treatment of azithromycin 1.5% eye drops versus oral azithromycin to treat active trachoma. Methods Randomised, controlled, double‐masked, double‐dummy, non‐inferiority explanatory study including 670 children from Guinea Conakry and Pakistan if: 1–10 years old; active trachoma (TF+TI0 or TF+TI+ on simplified World Health Organisation (WHO) scale). Three groups received either: azithromycin 1.5% eye drops twice daily for 2 days, for 3 days or azithromycin single 20 mg/kg oral dose. Patients' contacts were treated whenever possible. Clinical evaluation was performed using a binocular loupe. Primary efficacy variable was the cure (no active trachoma (TF0)) at day 60. Non‐inferiority margin for difference between cure rates was 10%. Results Cure rate in per protocol set was as follows: 93.0%, 96.3% and 96.6% in 2‐day group 3‐day group, and oral treatment group, respectively. Azithromycin 1.5% groups were non‐inferior to oral azithromycin. The intend to treat (ITT) analysis supported the results. Clinical re‐emergence rate was low: 4.2%. Ocular tolerance was similar for all groups. No treatment related adverse events were reported. Logistic regression analyses found prognostic factors such as: country (p<0.001) and trachoma severity (p = 0.003). Conclusions In active trachoma, azithromycin eye drops twice daily for 2 or 3 days are as efficient as the WHO's reference treatment and represent an innovative alternative to oral azithromycin. PMID:17005549

  14. Single dose dipyrone for acute postoperative pain

    PubMed Central

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

    2014-01-01

    Background Dipyrone (metamizole) is a non-steroidal anti-inflammatory drug used in some countries to treat pain (postoperative, colic, cancer, and migraine); it is banned in others because of an association with life-threatening blood agranulocytosis. This review updates a 2001 Cochrane review, and no relevant new studies were identified, but additional outcomes were sought. Objectives To assess the efficacy and adverse events of single dose dipyrone in acute postoperative pain. Search methods The earlier review searched CENTRAL, MEDLINE, EMBASE, LILACS and the Oxford Pain Relief Database to December 1999. For the update we searched CENTRAL, MEDLINE,EMBASE and LILACS to February 2010. Selection criteria Single dose, randomised, double-blind, placebo or active controlled trials of dipyrone for relief of established moderate to severe postoperative pain in adults. We included oral, rectal, intramuscular or intravenous administration of study drugs. Data collection and analysis Studies were assessed for methodological quality and data extracted by two review authors independently. Summed total pain relief over six hours (TOTPAR) was used to calculate the number of participants achieving at least 50% pain relief. Derived results were used to calculate, with 95% confidence intervals, relative benefit compared to placebo, and the number needed to treat (NNT) for one participant to experience at least 50% pain relief over six hours. Use and time to use of rescue medication were additional measures of efficacy. Information on adverse events and withdrawals was collected. Main results Fifteen studies tested mainly 500 mg oral dipyrone (173 participants), 2.5 g intravenous dipyrone (101), 2.5 g intramuscular dipyrone (99); fewer than 60 participants received any other dose. All studies used active controls (ibuprofen, paracetamol, aspirin, flurbiprofen, ketoprofen, dexketoprofen, ketorolac, pethidine, tramadol, suprofen); eight used placebo controls. Over 70% of participants

  15. Determination of designer doping agent--2-ethylamino-1-phenylbutane--in dietary supplements and excretion study following single oral supplement dose.

    PubMed

    Wójtowicz, Marzena; Jarek, Anna; Chajewska, Katarzyna; Turek-Lepa, Ewa; Kwiatkowska, Dorota

    2015-11-10

    The quantitative analysis of a new designer doping agent, 2-ethylamino-1-phenylbutane (EAPB) and its metabolite, 2-amino-1-phenylbutane (APB) in urine samples, and the determination of EAPB in dietary supplement samples, have been presented. The main purpose of the present study was to develop simple and reliable gas chromatography-mass spectrometry method (GC-MS) for excretion study following a single oral administration of dietary supplements containing EAPB. Three analytical methods for the determination of EAPB in urine and supplement samples, and APB in urine samples using the GC-MS system, have been validated. The method of the determination of EAPB in supplement samples was applied to analyze seventeen dietary supplements, CRAZE and DETONATE. Two other methods were used to determine the urinary excretion profile of EAPB and APB in the case of three healthy volunteers and, on further investigation, it was applied to the anti-doping control in sport. Quantification was obtained on the basis of the ions at m/z 86, 58 and 169, monitored for EAPB, APB and diphenylamine (used as an internal standard), respectively. The limits of detection and quantification were 2.4 and 7.3μg/g for EAPB in the case of supplement analysis, 2.9 and 8.8ng/mL for EAPB in the case of urine analysis, and 3.2 and 9.7ng/mL for APB. The other validation parameters as linearity, precision and trueness have been also investigated with the acceptable results. The extraction yield of all presented methods was above 69%. EAPB was detected in fourteen analyzed supplements (not included EAPB in their labels) and its content varied between 1.8 and 16.1mg/g. Following oral administration of three supplements with EAPB to one male and two female volunteers, the parent compound of EAPB and its metabolite were monitored and the excretion parameters as the maximum concentration of the analyte in urine (2.2-4.2μg/mL for EAPB; 1.1-5.1μg/mL for APB) and the time for the maximum height of the excretion

  16. 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

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

    PubMed

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

    2013-01-01

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

  18. Pharmacokinetics of high-dose oral thiamine hydrochloride in healthy subjects

    PubMed Central

    2012-01-01

    Background High dose oral thiamine may have a role in treating diabetes, heart failure, and hypermetabolic states. The purpose of this study was to determine the pharmacokinetic profile of oral thiamine hydrochloride at 100 mg, 500 mg and 1500 mg doses in healthy subjects. Methods This was a randomized, double-blind, single-dose, 4-way crossover study. Pharmacokinetic measures were calculated. Results The AUC0-10 hr and Cmax values increased nonlinearly between100 mg and 1500 mg. The slope of the AUC0-10 hr vs dose, as well as the Cmax vs dose, plots are steepest at the lowest thiamine doses. Conclusion Our study demonstrates that high blood levels of thiamine can be achieved rapidly with oral thiamine hydrochloride. Thiamine is absorbed by both an active and nonsaturable passive process. Trial Registration ClinicalTrials.gov: NCT00981877 PMID:22305197

  19. 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...

  20. Pharmacokinetic profile of rizatriptan 10-mg tablet and 10-mg orally disintegrating tablet administered with or without water in healthy subjects: an open-label, randomized, single-dose, 3-period crossover study.

    PubMed

    Swan, Suzanne K; Alcorn, Harry; Rodgers, Anthony; Hustad, Carolyn M; Ramsey, Karen E; Woll, Susan; Skobieranda, Franck

    2006-02-01

    This open-label, 3-period crossover study compared the plasma concentration profiles of rizatriptan tablet, orally disintegrating tablet with water (ODTc), and ODT without water (ODTs) in 24 healthy volunteers aged 18 to 45 years. At each period, subjects received a single dose of either 10-mg rizatriptan tablet, 10-mg rizatriptan ODTs, or 10-mg rizatriptan ODTc. The authors hypothesized that ODTc has a greater geometric mean AUC(0-2h) than ODTs and that ODTc has a greater geometric mean AUC(0-1h) than tablet. A secondary end point was to compare the time of occurrence of the maximum rizatriptan plasma concentration (t(max)) of each dosing method. ODTc had a statistically significantly greater geometric mean AUC(0-2h) compared with ODTs (33.84 h x ng/mL vs 18.83 h x ng/mL; P < .001). ODTc had a slightly, but not statistically significantly, greater geometric mean AUC(0-1h) compared with rizatriptan tablet (17.07 h x ng/mL vs 13.32 h x ng/mL). The median t(max) was 0.67 hours for ODTc and tablet and 1.33 hours for ODTs. ODTc showed a slightly, but not significantly, faster rate of absorption compared with tablet. ODTs with water had a faster rate of absorption than ODTc. Future studies are needed to determine whether this pharmacokinetic difference produces differential efficacy in a clinical setting. PMID:16432269

  1. Effect of renal impairment on the pharmacokinetics of levomilnacipran following a single oral dose of levomilnacipran extended-release capsule in humans

    PubMed Central

    Chen, Laishun; Greenberg, William M; Brand-Schieber, Elimor; Wangsa, Julie; Periclou, Antonia; Ghahramani, Parviz

    2015-01-01

    Purpose Levomilnacipran extended-release (ER) is indicated for treatment of major depressive disorder in adults. We evaluated the pharmacokinetic and safety profile of levomilnacipran ER in individuals with impaired renal function. Methods A total of 32 individuals participated in four groups (eight in each group) with normal, mild, moderately, or severely impaired renal function. Each participant received one dose of levomilnacipran ER 40 mg. Blood and urine were assayed using liquid chromatography/tandem mass spectrometry. Results between normal and renally impaired groups were compared using analysis of variance. Safety measures included adverse events, laboratory evaluations, vital signs, suicidality, and electrocardiograms. Results Following administration of levomilnacipran, mean (standard deviation) maximum plasma concentration in participants with normal renal function, and mild, moderate, or severe renal impairment was 83.9 (21.0), 81.8 (23.4), 98.7 (18.1), and 122.1 (35.1) (ng/mL), respectively; area under the curve from time zero to infinity was 2,101.0 (516.9), 2,587.8 (649.9), 4,016.4 (995.4), and 5,900.8 (1,799.3) (h·ng/mL), respectively; terminal elimination half-life was 13.5 (2.8), 17.3 (3.5), 19.1 (4.6), and 27.7 (7.4) (hours), respectively; and renal clearance was 175.9 mL/min, 114.7 mL/min, 69.9 mL/min, and 28.6 mL/min, respectively. Levomilnacipran ER was generally well tolerated with no safety issues of concern identified. Conclusion Renal impairment was associated with increased plasma levels of levomilnacipran and prolonged half-life. No dose adjustment is required for individuals with mild renal impairment; the recommended maximum daily maintenance dose of levomilnacipran ER should not exceed 80 mg for individuals with moderate renal impairment and 40 mg for individuals with severe renal impairment. PMID:26150701

  2. An open-label, single-dose, crossover study of the pharmacokinetics and metabolism of two oral formulations of 1-octanol in patients with essential tremor.

    PubMed

    Nahab, Fatta B; Wittevrongel, Loretta; Ippolito, Dominic; Toro, Camilo; Grimes, George J; Starling, Judith; Potti, Gopal; Haubenberger, Dietrich; Bowen, Daniel; Buchwald, Peter; Dong, Chuanhui; Kalowitz, Daniel; Hallett, Mark

    2011-10-01

    Existing therapeutic options for management of essential tremor are frequently limited by poor efficacy and adverse effects. Likely the most potent tremor suppressant used is ethanol, although its use is prohibitive due to a brief therapeutic window, and the obvious implications of excessive alcohol use. Longer-chain alcohols have been shown to suppress tremor in harmaline animal models, and appear to be safe and well tolerated in 2 prior studies in humans. Here we report on the findings of a phase I/II study of 1-octanol designed to explore pharmacokinetics, efficacy, and safety. The most significant finding was the identification of octanoic acid as the product of rapid 1-octanol metabolism. Furthermore, the temporal profile of efficacy closely matches the plasma concentration of octanoic acid. Therefore, these findings identify a novel class of compound (e.g., carboxylic acids) with tremor suppressive properties in ET. Administration of 1-octanol also appears to be safe based on various measures collected. Essential tremor (ET) is the most common tremor disorder, with tremors occurring during static posturing or movement. These tremors are known to briefly improve in many cases after alcohol (ethanol) consumption. Two previous studies of a longer chain alcohol, 1-octanol, have demonstrated longer duration tremor-suppressive effects without the occurrence of intoxication. The aim of this study was to characterize the pharmacokinetics of 1-octanol and its primary metabolite octanoic acid using two formulations, along with additional safety and efficacy measures. Participants with proven ethanol-responsive ET were recruited into 1 of 2 parts: (part A) a dose escalation study (1-64 mg/kg; n = 4), and (part B) a fixed dose (64 mg/kg; n = 10) balanced, open-label crossover design. Two participants in part B then completed an exploratory part C evaluating 128 mg/kg.Plasma samples were collected at 10 intervals during a 6-hour period postingestion. Efficacy was

  3. Developmental toxicity of clarified slurry oil, syntower bottoms, and distillate aromatic extract administered as a single oral dose to pregnant rats

    SciTech Connect

    Feuston, M.H.; Mackerer, C.R.

    1996-09-01

    Clarified slurry oil (CSO), syntower bottoms (STB), and distillate aromatic extract (DAE) are refinery streams produced by processing crude oil. Available data indicate that some refinery streams are developmentally toxic by the dermal route of exposure. However, there is no conclusive evidence for their being teratogenic. The present studies were designed to further explore the suspected teratogenic potency of refinery streams while at the same time limiting embryolethality. In general, evidence of maternal toxicity (i.e., decreased body weight gain, decreased thymus weight) was observed at doses greater than or equal to 500 mg/kg. For each refinery stream tested, the incidence of resorption was greatest on GD 11. A common pattern of fetal malformations was observed for all of the refinery streams tested and included cleft palate, diaphragmatic hernia, and paw and tail defects. The incidence and type of malformation observed were influenced by the gestation day of exposure. The incidence and type of malformation observed were influenced by the gestation day of exposure. The incidences of external and skeletal malformations were greatest on GD 11 and 12 for fetuses exposed to CSO; on GD 13 and 14, the incidence of malformation was comparable for CSO- and STB-exposed fetuses. The incidence of visceral anomalies was greatest on GD 11-13 for fetuses exposed to CSO and STB; on Gestation D 14, the incidence was comparable for each of the refinery streams tested. In general, the ability to produce adverse effects on development was greatest for CSO and least for DAE. Effects produced by STB were comparable to or less severe than those observed for CSO. 24 refs., 11 tabs.

  4. Comparative oral dose toxicokinetics of sodium selenite and selenomethionine

    Technology Transfer Automated Retrieval System (TEKTRAN)

    The toxicokinetics of selenium (Se) absorption, distribution, and elimination were determined in serum and whole blood of lambs that were orally dosed with various doses of Se as sodium selenite (inorganic Se) or selenomethionine (organic Se). Thirty-two lambs were randomly assigned to eight treatm...

  5. Single-dose kinetics of mefloquine in Brazilian male subjects

    PubMed Central

    de Souza, J. M.; Heizmann, P.; Schwartz, D. E.

    1987-01-01

    Ten male subjects from a region of the state of Pará, Brazil, where malaria is endemic received a single oral dose of 1000 mg mefloquine. The plasma levels of the drug and of its metabolite, 2,8-bis(trifluoromethyl)-4-quinolinecarboxylic acid, were determined densitometrically on thin-layer chromatography plates. The pharmacokinetic parameters obtained fell well within the range of values reported previously for Africans and Caucasians. PMID:3499250

  6. [Sudden death following a single oral administration of haloperidol].

    PubMed

    Remijnse, P L; Eeckhout, A M; van Guldener, C

    2002-04-20

    A 39-year-old man was admitted with myasthenia, alcoholic hepatitis and electrolyte abnormalities due to an inadequate nutritional state. On admission the ECG showed a prolonged QTc interval (0.46 s). The patient was treated with intravenous fluid and supplementary vitamins and minerals. On the third day of admission the patient developed a delirium, partly due to alcohol withdrawal, and was therefore treated with oxazepam 50 mg 3 times daily and a single dose of haloperidol 5 mg. One hour after ingesting haloperidol, the patient suddenly succumbed and resuscitation was not successful. The autopsy revealed a cardiomyopathy but no explanation for the sudden death. Due to the temporal relationship between the ingestion of haloperidol and this sudden death, we assume that haloperidol induced a fatal arrhythmia in the presence of a preexisting prolonged repolarisation time. To the best of our knowledge, sudden death after a single oral therapeutic dose of haloperidol has not previously been described. PMID:11998355

  7. Torsade de pointes and low-dose oral haloperidol.

    PubMed

    Jackson, T; Ditmanson, L; Phibbs, B

    1997-09-22

    Haloperidol, used to treat patients with psychoses, is considered minimally cardiotoxic. Several cases of torsade de pointes have been reported in association with the use of oral haloperidol. In each of those cases, a prolonged QTc preceded the torsade de pointes episode and thus may be considered a predictor for ventricular arrhythmias in elderly women treated with haloperidol. However, the following case may demonstrate the inability to predict an episode of torsade de pointes with low-dose oral haloperidol use. PMID:9308514

  8. Chemical warfare agents: estimating oral reference doses.

    PubMed

    Opresko, D M; Young, R A; Faust, R A; Talmage, S S; Watson, A P; Ross, R H; Davidson, K A; King, J

    1998-01-01

    Health risk assessments for sites contaminated with chemical warfare agents require a comparison of the potential levels of exposure with a characterization of the toxic potency of each chemical. For noncancer health effects, toxic potency is expressed in terms of Reference Doses (RfD). A RfD is a daily exposure level or dose (usually expressed in units of milligrams of chemical per kilogram body weight per day) for the human population, including sensitive subpopulations, that is likely to be without an appreciable risk of deleterious effects. A daily exposure at or below the RfD is not likely to be associated with health risks, but as the amount of chemical that an individual is exposed to increases above the RfD, the probability that an adverse effect will occur also increases. A RfD is derived by first examining the available human or animal toxicity data to identify a dose or exposure that corresponds to a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-effect level (LOAEL). The NOAEL is the exposure level at which there are no statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Effects may be produced at this level, but they are not considered to be adverse if they do not result in functional impairment or pathological lesions that affect the performance of the whole organism or which reduce an organism's ability to cope with additional challenge. The LOAEL is the lowest exposure level at which there are statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. If only a LOAEL is identified by the toxicity data, a NOAEL is estimated by dividing the LOAEL by a factor no greater than 10. This extrapolation factor of 10 or less is termed the LOAEL-to-NOAEL Uncertainty Factor (UFL). The NOAEL is also adjusted by the application of other

  9. Single and multiple dose pharmacokinetics of etizolam in healthy subjects.

    PubMed

    Fracasso, C; Confalonieri, S; Garattini, S; Caccia, S

    1991-01-01

    The pharmacokinetics of etizolam, a new thienodiazepine derivative, has been examined after single and multiple (0.5 mg tablet) (0.5 mg b.d for 1 week) oral therapeutic doses in healthy volunteers. The single-dose kinetic profile of etizolam suggested that absorption after oral dosage was reasonably rapid, the maximum plasma concentration (Cmax) being attained within 0.5-2 h in all subjects. The mean elimination half-life (t1/2) averaged 3.4 h. Consistent with this, steady-state concentration were rapidly achieved and accumulation was extremely limited. Predicted average plasma concentrations (Cp) did not differ significantly from those actually measured at steady-state, suggesting that the kinetics of etizolam was linear, at least at therapeutic doses. The mean wash-out t1/2 was comparable to the elimination t1/2 of the single dose, which means that the drug probably has no effect on hepatic microsomal enzymes and other kinetic variables after repeated dosing. At steady state plasma concentrations of the main metabolite, alpha-hydroxyetizolam, were higher and disappeared more slowly (mean t1/2 8.2 h) than those of the parent compound. Taken with the fact that in animals the metabolite shows almost the same potency of pharmacological action as etizolam, this suggests that it may contribute significantly to the clinical effects of the parent compound. Based on the kinetic characteristics of the parent drug and its metabolite, etizolam can be regarded as a short-acting benzodiazepine, with elimination kinetics between those of short-intermediate derivatives and ultra-rapidly eliminated benzodiazepines. PMID:2065698

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

    PubMed Central

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

    2014-01-01

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

  11. Treating acne with oral contraceptives: use of lower doses.

    PubMed

    Huber, Johannes; Walch, Katharina

    2006-01-01

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

  12. The pharmacokinetics of cefadroxil over a range of oral doses and animal ages in the foal.

    PubMed

    Duffee, N E; Stang, B E; Schaeffer, D J

    1997-12-01

    To evaluate the effect of foal age on the pharmacokinetics of cefadroxil, five foals were administered cefadroxil in a single intravenous dose (5 mg/kg) and a single oral dose (10 or 20 mg/kg) at ages of 0.5, 1, 2, 3 and 5 months. Pharmacokinetic parameters of terminal elimination rate constant (beta(po)), oral mean residence time (MRTpo), mean absorption time (MAT), rate constant for oral absorption (Ka), bioavailability F, peak serum concentrations (Cmax) and time of peak concentration (tmax), were evaluated in a repeated measures analysis over dose. Across animal ages, parameters for the intravenous dose did not change significantly over animal age (P > or = 0.05). Mean values +/- SEM were: beta(IV) = 0.633 +/- 0.038 h-1; Cl = 0.316 +/- 0.010 L/kg/h; Vc = 0.196 +/- 0.008 L/kg; Varea = 0.526 +/- 0.024 L/kg; VSS = 0.374 +/- 0.014 L/kg; MRTiv = 1.22 +/- 0.07 h; Kel = 1.67 +/- 0.08 h-1. Following oral administration, drug absorption became faster with age (P < 0.05), as reflected by MRTpo, MAT, Ka and tmax. However, oral bioavailability (+/- SE) declined significantly (P < 0.05) from 99.6 +/- 3.69% at 0.5 months to 14.5 +/- 1.40% at 5 months of age. To evaluate a dose effect on the pharmacokinetic parameters, a series of oral doses (5, 10, 20 and 40 mg/kg) were administered to these foals at 1 month of age. beta(po) (0.548 +/- 0.023 h-1) and F (68.26 +/- 2.43%) were not affected significantly by the size of the dose. Cmax was approximately doubled with each two-fold increase in dose: 3.15 +/- 0.15, 5.84 +/- 0.48, 12.17 +/- 0.93 and 19.71 +/- 2.19 micrograms/mL. Dose-dependent kinetics were observed in MRTpo, MAT, Ka and tmax. PMID:9430765

  13. Single-Dose Doxycycline for Cholera

    PubMed Central

    Sack, David A.; Islam, Sirajul; Rabbani, Hassan; Islam, Asma

    1978-01-01

    To determine the efficacy of single-dose doxycycline in the treatment of cholera, we carried out a randomized prospective trial in 65 patients. Treatment consisted of either a single dose of 200 mg of doxycycline (or 4 mg/kg in patients less than 15 years old) or multiple doses of doxycycline, 500 mg over 4 days (or 10 mg/kg in patients less than 15 years old). There were no differences between the groups in the volumes of intravenous fluid required, volumes of diarrheal stool, or durations of diarrhea. The mean duration of positive stool cultures for Vibrio cholerae was similar for the two groups, although in both groups several patients continued to excrete Vibrios in the stool for more than 3 days. Blood levels of antibiotic demonstrated that the doxycycline was absorbed in spite of the rapid transit time associated with severe diarrhea. These results suggest that although tetracycline remains the drug of choice for cholera, doxycycline is a reasonable alternative, and that a single dose of 200 mg (4 mg/kg in children) is effective clinically. PMID:708024

  14. Derivation of a chronic oral reference dose for cobalt.

    PubMed

    Finley, Brent L; Monnot, Andrew D; Paustenbach, Dennis J; Gaffney, Shannon H

    2012-12-01

    Cobalt (Co) is an essential element in humans as a component of vitamin B12. However, at high levels Co exposure has been shown to have detrimental effects. This study was designed to identify a chronic oral reference dose (RfD) for Co. Currently available data indicate that non-cancer health effects associated with Co exposure may include hematological, neurological, immunological, reproductive, cardiovascular, and endocrine responses. This analysis employs the standard US EPA risk assessment methodology for establishing a chronic RfD. In this analysis, the Jaimet and Thode (1955) 10-week, multiple dose human study of thyroid effects (decreased iodine uptake) in children was determined to be the most robust and sensitive study for identifying a potential point of departure dose (POD). A dose of 0.9 mgCo/kg-day was chosen as the POD. Consistent with the US EPA's previous derivation of the perchlorate RfD, which is also based on decreased iodine uptake in humans, we considered several uncertainly factors (UFs), and determined that a factor of 10 for human variability was appropriate, as well as a factor of three for database adequacy. Applying an aggregate uncertainty factor of 30 to the POD yields a chronic oral RfD of 0.03 mg/kg-day. We believe this value would be protective of non-cancer health effects in the general population for a lifetime of daily exposure to Co. PMID:22982439

  15. Efficacy and Safety of Single and Double Doses of Ivermectin versus 7-Day High Dose Albendazole for Chronic Strongyloidiasis

    PubMed Central

    Suputtamongkol, Yupin; Premasathian, Nalinee; Bhumimuang, Kid; Waywa, Duangdao; Nilganuwong, Surasak; Karuphong, Ekkapun; Anekthananon, Thanomsak; Wanachiwanawin, Darawan; Silpasakorn, Saowaluk

    2011-01-01

    Background Strongyloidiasis, caused by an intestinal helminth Strongyloides stercoralis, is common throughout the tropics. It remains an important health problem due to autoinfection, which may result in hyperinfection and disseminated infection in immunosuppressed patients, especially patients receiving chemotherapy or corticosteroid treatment. Ivermectin and albendazole are effective against strongyloidiasis. However, the efficacy and the most effective dosing regimen are to be determined. Methods A prospective, randomized, open study was conducted in which a 7-day course of oral albendazole 800 mg daily was compared with a single dose (200 microgram/kilogram body weight), or double doses, given 2 weeks apart, of ivermectin in Thai patients with chronic strongyloidiasis. Patients were followed-up with 2 weeks after initiation of treatment, then 1 month, 3 months, 6 months, 9 months, and 1 year after treatment. Combination of direct microscopic examination of fecal smear, formol-ether concentration method, and modified Koga agar plate culture were used to detect strongyloides larvae in two consecutive fecal samples in each follow-up visit. The primary endpoint was clearance of strongyloides larvae from feces after treatment and at one year follow-up. Results Ninety patients were included in the analysis (30, 31 and 29 patients in albendazole, single dose, and double doses ivermectin group, respectively). All except one patient in this study had at least one concomitant disease. Diabetes mellitus, systemic lupus erythrematosus, nephrotic syndrome, hematologic malignancy, solid tumor and human immunodeficiency virus infection were common concomitant diseases in these patients. The median (range) duration of follow-up were 19 (2–76) weeks in albendazole group, 39 (2–74) weeks in single dose ivermectin group, and 26 (2–74) weeks in double doses ivermectin group. Parasitological cure rate were 63.3%, 96.8% and 93.1% in albendazole, single dose oral ivermectin

  16. KAE609 (Cipargamin), a New Spiroindolone Agent for the Treatment of Malaria: Evaluation of the Absorption, Distribution, Metabolism, and Excretion of a Single Oral 300-mg Dose of [14C]KAE609 in Healthy Male Subjects.

    PubMed

    Huskey, Su-Er W; Zhu, Chun-Qi; Fredenhagen, Andreas; Kühnöl, Jürgen; Luneau, Alexandre; Jian, Zhigang; Yang, Ziping; Miao, Zhuang; Yang, Fan; Jain, Jay P; Sunkara, Gangadhar; Mangold, James B; Stein, Daniel S

    2016-05-01

    KAE609 [(1'R,3'S)-5,7'-dichloro-6'-fluoro-3'-methyl-2',3',4',9'-tetrahydrospiro[indoline-3,1'-pyridol[3,4-b]indol]-2-one] is a potent, fast-acting, schizonticidal agent in clinical development for the treatment of malaria. This study investigated the absorption, distribution, metabolism, and excretion of KAE609 after oral administration of [(14)C]KAE609 in healthy subjects. After oral administration to human subjects, KAE609 was the major radioactive component (approximately 76% of the total radioactivity in plasma); M23 was the major circulating oxidative metabolite (approximately 12% of the total radioactivity in plasma). Several minor oxidative metabolites (M14, M16, M18, and M23.5B) were also identified, each accounting for approximately 3%-8% of the total radioactivity in plasma. KAE609 was well absorbed and extensively metabolized, such that KAE609 accounted for approximately 32% of the dose in feces. The elimination of KAE609 and metabolites was primarily mediated via biliary pathways. M23 was the major metabolite in feces. Subjects reported semen discoloration after dosing in prior studies; therefore, semen samples were collected once from each subject to further evaluate this clinical observation. Radioactivity excreted in semen was negligible, but the major component in semen was M23, supporting the rationale that this yellow-colored metabolite was the main source of semen discoloration. In this study, a new metabolite, M16, was identified in all biologic matrices albeit at low levels. All 19 recombinant human cytochrome P450 enzymes were capable of catalyzing the hydroxylation of M23 to form M16 even though the extent of turnover was very low. Thus, electrochemistry was used to generate a sufficient quantity of M16 for structural elucidation. Metabolic pathways of KAE609 in humans are summarized herein and M23 is the major metabolite in plasma and excreta. PMID:26921387

  17. 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 < 0.001). Tactile allodynia was similarly inhibited by ~45% 4 h after CGN by both naproxen (at 1, 3 and 10 mg/kg) and ATB-346 (at 1.6 and 4.8 mg/kg; P < 0.001), as well as leukocyte infiltration. Naproxen (but not ATB-346) induced significant gastric damage and, despite the increased gastric MPO activity by ~130% in the naproxen-, but not in the ATB-346-treated rats, this effect was of no statistical significance. Conclusion The presence of a H2S-releasing moiety in

  18. New approach for food allergy management using low-dose oral food challenges and low-dose oral immunotherapies.

    PubMed

    Yanagida, Noriyuki; Okada, Yu; Sato, Sakura; Ebisawa, Motohiro

    2016-04-01

    A number of studies have suggested that a large subset of children (approximately 70%) who react to unheated milk or egg can tolerate extensively heated forms of these foods. A diet that includes baked milk or egg is well tolerated and appears to accelerate the development of regular milk or egg tolerance when compared with strict avoidance. However, the indications for an oral food challenge (OFC) using baked products are limited for patients with high specific IgE values or large skin prick test diameters. Oral immunotherapies (OITs) are becoming increasingly popular for the management of food allergies. However, the reported efficacy of OIT is not satisfactory, given the high frequency of symptoms and requirement for long-term therapy. With food allergies, removing the need to eliminate a food that could be consumed in low doses could significantly improve quality of life. This review discusses the importance of an OFC and OIT that use low doses of causative foods as the target volumes. Utilizing an OFC or OIT with a low dose as the target volume could be a novel approach for accelerating the tolerance to causative foods. PMID:26774524

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

    PubMed

    Lin, Hai-Shu; Ho, Paul C

    2011-10-01

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

  20. The disposition of bupropion and its metabolites in healthy male volunteers after single and multiple doses.

    PubMed

    Posner, J; Bye, A; Dean, K; Peck, A W; Whiteman, P D

    1985-01-01

    The pharmacokinetics of bupropion and 3 of its basic metabolites were determined in 8 young, healthy, male volunteers after single and multiple oral doses of bupropion. Plasma profiles were obtained: 1) after a single 100 mg oral dose of bupropion hydrochloride, 2) following administration of 100 mg 8-hourly for 14 days and 3) again after a single 100 mg dose 14 days later. Plasma concentrations of the parent drug and metabolites were determined by high-performance liquid chromatography. Saliva secretion and pupil diameters were measured, subjective assessments of sleep made using visual analogue scales and side effects, blood counts and biochemistry were monitored. After the first dose mean elimination half lives (t1/2) of bupropion, and metabolites I and II were 8, 19 and 19 h respectively. On repeated administration there was little accumulation of the parent drug and no evidence for induction of its own metabolism. Accumulation of I was consistent with its rate of elimination after single doses while that of II was greater than predicted with prolongation of t1/2 to 35 h. Metabolite III was barely detectable after single doses but its accumulation on multiple dosing was consistent with its long half life (35 h) determined on occasion 2. Saliva secretion was significantly reduced during the multiple dosing period but there were no complaints of dry mouth. Subjective assessments of sleep were not significantly altered though one subject reported vivid dreams. There were no other adverse reactions. PMID:3932079

  1. [Individualization of low-dose oral contraceptives. Pharmacological principles and practical indications for oral contraceptives].

    PubMed

    Cianci, A; De Leo, V

    2007-08-01

    The contraceptive pill has been a revolution of the last 40 years. In Italy, however, it is much less widely used than in other countries. Explanations for this phenomenon range from religious implications and customs to misinformation and word-of-mouth communication of negative experiences. The oral contraceptive pill is often used to correct menstrual disorders, leading to poor results and side-effects. Recent advances in oral contraception have led to a substantial reduction in doses and side-effects. Low-dose pills contain minimal doses of progesterones and estrogens and ensure good control of the menstrual cycle. Although reduction of ethinyl estradiol (EE) concentrations has reduced the incidence of negative systemic side effects such as water retention, edema and swollen breasts, the low estrogen dose may be associated with spotting and hypomenorrhea or amenorrhea in the long term, as well as dyspareunia due to reduced vaginal trophism, which may induce women to suspend use of the drug. It is also true that only one type of estrogen is used in the pill, albeit at different doses, whereas the progesterone may differ and in many cases is the cause of common side-effects. The choice of progesterone therefore involves not only its effect on the endometrium in synergy with estrogen, but also possible residual androgenic activity which may have negative metabolic repercussions. Indeed, addition of a progesterone, especially androgen-derived, attenuates the positive metabolic effects of estrogen. Two new monophasic oral contraceptives were recently released. They contain 30 microg (Yasmin) or 20 muicrog (Yasminelle) EE and a new progesterone, drospirenone, derived from spirolactone, which has antiandrogenic and antimineralcorticoid activity similar to endogenous progesterone. Like progesterone, the drospirenone molecule is an aldosterone antagonist and has a natriuretic effect that opposes the sodium retention effect of EE. It may, therefore, help to prevent the

  2. Fibrinolytic response in women on low-dose oral contraceptive.

    PubMed

    Ishak, R; Ahmad, R; Gudum, H R; Hassan, K; Ang, E S

    1992-06-01

    Long term use of low doses of combination oral contraceptives appears to increase plasminogen level, thereby increasing fibrinolytic activity and reducing the risk of thromboembolism. Blood levels of plasminogen, tissue plasminogen activator (tPA), and plasminogen activator inhibitor (PAI), were measured before and after stress (5 minutes of stair climbing) in a group of 30 women, 23-40 years old, who had taken 30 mcg of ethinyl estradiol with 150 mcg of desogestrel or levonorgestrel for at least 1 year. Similar measurements were taken from a control group of 30 women matched for age, height, and weight. Plasminogen and tPA levels in both groups increased significantly after exercise. The level of PAI did not change significantly with stress in either group. The level of plasminogen was significantly higher in the group taking contraceptives, whether before or after exercise, when compared to the control group. Levels of tPA and PAI, although slightly increased in the oral contraceptive group, were not significantly different between the two groups. The increase in plasminogen may be due to the estrogen component of the contraceptives. Stress seems to increase fibrinolytic response. PMID:12345026

  3. Acute and repeated dose (28 days) oral safety studies of ALIBIRD in rats.

    PubMed

    Anadón, Arturo; Martínez, María A; Ares, Irma; Castellano, Victor; Martínez-Larrañaga, Maria R; Corzo, Nieves; Olano, Agustin; Montilla, Antonia; Recio, Isidra; Martínez-Maqueda, Daniel; Miralles, Beatriz; Fornari, Tiziana; García-Risco, Mónica R; Gonzalez, Monserrat; Reglero, Guillermo

    2013-07-01

    ALIBIRD, a test substance composed of oligosaccharides derived from lactulose, a hydrolysate of a whey protein concentrate, and a supercritical extract of rosemary (1:0.5:0.05), was prepared in the laboratory and evaluated for its safety as a multifunctional food additive. In oral toxicity studies (acute and 28 days repeated dose) using Wistar rats, ALIBIRD was administered in a single oral gavage dose of 2,000 mg/kg of body weight and resulted in no adverse events or mortality; a daily dose of 2,000 mg/kg of body weight for 28 days by gavage also resulted in no adverse effects or mortality. No abnormal clinical signs, behavioral changes, body weight changes, or changes in food and water consumption occurred in either study. There were no changes in hematological and serum chemistry values, organ weights, or gross or histological characteristics. Based on test results, it is concluded that ALIBIRD is well tolerated in rats at an acute and subchronic (28 days) dose of 2,000 mg/kg of body weight. PMID:23834798

  4. 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

    2015-06-01

    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

  5. Single dose NTBC-treatment of hereditary tyrosinemia type I.

    PubMed

    Schlune, A; Thimm, E; Herebian, D; Spiekerkoetter, U

    2012-09-01

    NTBC (2-(2-nitro-4-trifluoromethylbenzoyl)-1,3cyclohexanedione) is the mainstay of treatment in tyrosinemia type 1 (HT 1). The current recommendation is to divide the total daily dose of NTBC into two doses. We monitored the plasma NTBC concentrations in a series of seven patients who were changed from multiple divided doses to a single daily dose of NTBC. Two additional patients were started on a single daily dose of NTBC after the diagnosis of HT 1 was established. In three patients, NTBC kinetics were performed over 6 and 24 hours, respectively. The use of multiple divided doses or a single daily dose did not significantly affect plasma NTBC concentrations or the mean daily dose needed to attain therapeutic plasma NTBC concentrations. Moreover, kinetic studies demonstrated that plasma NTBC concentrations were completely stable over a period of 24 hours with a single dose regimen, as expected given the known NTBC plasma half life of 54 hours. Although these preliminary results need to be confirmed in more patients, our findings show that administration of NTBC in a single daily dose may be as effective as a multiple-dose regimen in reaching therapeutic plasma NTBC concentrations and suppressing succinylacetone formation in patients with HT 1. In fact, single dose treatment may increase patients' compliance with the drug treatment and improve metabolic control. PMID:22307209

  6. Comparative evaluation of 2 g single dose versus conventional dose azithromycin in uncomplicated skin and skin structure infections

    PubMed Central

    Dey, Sudipta Kumar; Das, Amal Kanti; Sen, Sumit; Hazra, Avijit

    2015-01-01

    Objectives: Uncomplicated skin and skin structure infections (uSSSIs) are a common clinical problem. Majority are caused by staphylococci and streptococci. Different oral antibiotics are used for uSSSI, with comparable efficacy but varying treatment duration, cost, and adverse event profile. Azithromycin is used in uSSSI in adults conventionally in a dose of 500 mg once for 5 days. The extensive tissue distribution of the drug and its long elimination half-life prompted us to explore whether a single 2 g dose of the drug would produce a response in uSSSI comparable to conventional dosing. Materials and Methods: We conducted a parallel group, open-label, randomized, controlled trial (CTRI/2015/07/005969) with subjects of either sex, ≥12 years of age, presenting with uSSSI to the dermatology outpatient department. One group (n = 146) received 2 g single supervised dose while the other (n = 146) received conventional dose of 500 mg once daily for 5 days. Subjects were followed up on day 4 and day 8. Complete clinical cure implied complete healing of lesions, without residual signs or symptoms, within 7 days. Results: High cure rate was observed in both arms (97.97% and 98.63%, respectively) along with noticeable improvement in symptom profile from baseline but without statistically significant difference between groups. However, excellent adherence (defined as no tablets missed) was better in single dosing arm (98.65% vs. 86.30%). Tolerability was also comparable between groups with the majority of adverse events encountered being gastrointestinal in nature and mild. Conclusions: Single 2 g azithromycin dose achieved the same result as conventional azithromycin dosing in uSSSI with comparable tolerability but with the advantage of assured adherence. This dose can, therefore, be recommended as an alternative and administration supervised if feasible. PMID:26288467

  7. Comparing single and cumulative dosing procedures in human triazolam discriminators.

    PubMed Central

    Smith, B J; Bickel, W K

    1999-01-01

    This study evaluated a cumulative dosing procedure for drug discrimination with human participants. Four participants learned to discriminate triazolam (0.35 mg/70 kg) from placebo. A crossover design was used to compare the results under a single dosing procedure with results obtained under a cumulative dosing procedure. Under the single dosing procedure, a dose of triazolam (0, 0.05, 0.15, or 0.35 mg/70 kg) or secobarbital (0, 25, 75, or 175 mg/70 kg) was administered 45 min before assessment. Determining each dose-effect curve thus required four sessions. Under the cumulative dosing procedure, four doses of triazolam (0, 0.05, 0.10, and 0.20 mg/70 kg) or secobarbital (0, 25, 50, and 100 mg/70 kg) were administered approximately 55 min apart, producing a complete dose-effect curve in one four-trial session. Regardless of procedure, triazolam and secobarbital produced discriminative stimulus and self-reported effects similar to previous single dosing studies in humans. Shifts to the right in cumulative dose-effect curves compared to single dose-effect curves occurred on several self-report measures. When qualitative stimulus functions rather than quantitative functions are of interest, application of cumulative dosing may increase efficiency in human drug discrimination. PMID:10344022

  8. Efficacy of Single-Dose and Triple-Dose Albendazole and Mebendazole against Soil-Transmitted Helminths and Taenia spp.: A Randomized Controlled Trial

    PubMed Central

    Steinmann, Peter; Utzinger, Jürg; Du, Zun-Wei; Jiang, Jin-Yong; Chen, Jia-Xu; Hattendorf, Jan; Zhou, Hui; Zhou, Xiao-Nong

    2011-01-01

    Background The control of soil-transmitted helminth (STH) infections currently relies on the large-scale administration of single-dose oral albendazole or mebendazole. However, these treatment regimens have limited efficacy against hookworm and Trichuris trichiura in terms of cure rates (CR), whereas fecal egg reduction rates (ERR) are generally high for all common STH species. We compared the efficacy of single-dose versus triple-dose treatment against hookworm and other STHs in a community-based randomized controlled trial in the People's Republic of China. Methodology/Principal findings The hookworm CR and fecal ERR were assessed in 314 individuals aged ≥5 years who submitted two stool samples before and 3–4 weeks after administration of single-dose oral albendazole (400 mg) or mebendazole (500 mg) or triple-dose albendazole (3×400 mg over 3 consecutive days) or mebendazole (3×500 mg over 3 consecutive days). Efficacy against T. trichiura, Ascaris lumbricoides, and Taenia spp. was also assessed. Albendazole cured significantly more hookworm infections than mebendazole in both treatment regimens (single dose: respective CRs 69% (95% confidence interval [CI]: 55–81%) and 29% (95% CI: 20–45%); triple dose: respective CRs 92% (95% CI: 81–98%) and 54% (95% CI: 46–71%)). ERRs followed the same pattern (single dose: 97% versus 84%; triple dose: 99.7% versus 96%). Triple-dose regimens outperformed single doses against T. trichiura; three doses of mebendazole – the most efficacious treatment tested – cured 71% (95% CI: 57–82%). Both single and triple doses of either drug were highly efficacious against A. lumbricoides (CR: 93–97%; ERR: all >99.9%). Triple dose regimens cured all Taenia spp. infections, whereas single dose applications cured only half of them. Conclusions/Significance Single-dose oral albendazole is more efficacious against hookworm than mebendazole. To achieve high CRs against both hookworm and T. trichiura, triple-dose regimens are

  9. [Pharmacokinetics after oral and intravenous administration of d,l-monolysine acetylsalicylate and an oral dose of acetylsalicylic acid in healthy volunteers].

    PubMed

    Raschka, C; Koch, H J

    2001-01-01

    We studied the ASA pharmacokinetics of single doses of 500 mg and 1000 mg of D,L-lysine-monoacetylsalicylate (Lys-ASA) administered both orally (Delgesic) and 500 mg parenterally (Aspisol) as well as 500 mg acetylsalicylate (ASA, Aspirin) in 13 healthy volunteers. Blood samples were taken before and at defined times up to 48 h after application of Lys-ASA and ASA. Analysis for ASA and its metabolite salicylic acid were performed by HPLC. All concentration versus time data were presented descriptively. As far as ASA was concerned, differences were assessed by means of ANOVA according to Friedman including post hoc Wilcoxon tests for each time point. Pharmacokinetic parameters were calculated based on a one-compartment model. The concentration vs. time curves after oral intake of 500 mg of ASA and Lys-ASA differed significantly (p < 0.001). Peak serum ASA concentrations (Cmax) were 6.8 mg/l for oral Lys-ASA and 2.7 mg/l for ASA per os. The corresponding tmax-values were 14.2 and 38.0 min. Absolute bioavailabilities for 500 mg doses were 75.4 and 63.4 pour cent, respectively. After intake of 100 mg and 1000 mg oral doses of Lys-ASA Cmax was 2.7 mg/l and 15.9 mg/l, tmax being 14.2 min for the 1000 mg dose. The shortest half-life was found after i.v. injection with 7.5 min. Metabolism was fast with maximum rise of salicylic acid concentration after injection of Lys-ASS. We conclude that concerning time dimension oral administration of Lys-ASA is almost equivalent to i.v. Lys-ASA and may be an alternative for i.v. administration in cases of acute heart attacks. PMID:11878089

  10. Efficacy of low-dose oral metronomic dosing of the prodrug of gemcitabine, LY2334737, in human tumor xenografts.

    PubMed

    Pratt, Susan E; Durland-Busbice, Sara; Shepard, Robert L; Donoho, Gregory P; Starling, James J; Wickremsinhe, Enaksha R; Perkins, Everett J; Dantzig, Anne H

    2013-04-01

    LY2334737, an oral prodrug of gemcitabine, is cleaved in vivo, releasing gemcitabine and valproic acid. Oral dosing of mice results in absorption of intact prodrug with slow systemic hydrolysis yielding higher plasma levels of LY2334737 than gemcitabine and prolonged gemcitabine exposure. Antitumor activity was evaluated in human colon and lung tumor xenograft models. The dose response for efficacy was examined using 3 metronomic schedules, once-a-day dosing for 14 doses, every other day for 7 doses, and once a day for 7 doses, 7 days rest, followed by an additional 7 days of once-a-day dosing. These schedules gave significant antitumor activity and were well tolerated. Oral gavage of 6 mg/kg LY2334737 daily for 21 days gave equivalent activity to i.v. 240 mg/kg gemcitabine. HCl administered once a week for 3 weeks to mice bearing a patient mesothelioma tumor PXF 1118 or a non-small cell lung cancer tumor LXFE 937. The LXFE 397 tumor possessed elevated expression of the equilibrative nucleoside transporter-1 (ENT1) important for gemcitabine uptake but not prodrug uptake and responded significantly better to treatment with LY2334737 than gemcitabine (P ≤ 0.001). In 3 colon xenografts, antitumor activity of LY2334737 plus a maximally tolerated dose of capecitabine, an oral prodrug of 5-fluorouracil, was significantly greater than either monotherapy. During treatment, the expression of carboxylesterase 2 (CES2) and concentrative nucleoside transporter-3 was induced in HCT-116 tumors; both are needed for the activity of the prodrugs. Thus, metronomic oral low-dose LY2334737 is efficacious, well tolerated, and easily combined with capecitabine for improved efficacy. Elevated CES2 or ENT1 expression may enhance LY2334737 tumor response. PMID:23371859

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

    SciTech Connect

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

    1985-08-01

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

  12. Pharmacokinetic and pharmacodynamic profile of supratherapeutic oral doses of Δ9-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 Δ9-tetrahydrocannabinol (Δ9-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 Δ9-THC at acute doses higher than those tested previously. The pharmacokinetic and pharmacodynamic profile of oral Δ9-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. Δ9-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 Δ9-THC larger than those tested previously can be administered to individuals with a history of cannabis use, although given the pharmacokinetic variability of oral Δ9-THC and individual differences in sensitivity, individualized dose adjustment is needed to avoid side effects and maximize therapeutic response. PMID:23754596

  13. 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. )

    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.

  14. Pharmacokinetics of pholcodine in healthy volunteers: single and chronic dosing studies.

    PubMed Central

    Chen, Z R; Bochner, F; Somogyi, A

    1988-01-01

    1. The pharmacokinetics of pholcodine after two single doses and after chronic administration were studied in healthy human volunteers. 2. Six subjects received single oral doses of 20 and 60 mg of pholcodine according to a balanced cross-over design with an interval of 3 weeks between the two treatments. Blood and saliva samples and all urine were collected over 168 h after each dosage administration. Subsequently, the same subjects received 20 mg pholcodine 8 hourly orally for 10 days. Blood and saliva samples and all urine were collected during an 8 h dosing interval after the last dose on day 11. 3. Plasma, saliva and urine concentrations of pholcodine were determined by a high performance liquid chromatographic assay. 4. After the single doses, pholcodine was absorbed rapidly (tmax = 1.6 +/- 1.2 h) and eliminated slowly with a mean half-life of 50.1 +/- 4.1 h. The renal clearance of pholcodine was 137 +/- 34 ml min-1 and was inversely correlated with urine pH (r = 0.60) but not with urine flow rate. 26.2 +/- 3.3% of the dose was excreted as unchanged pholcodine after both doses. The concentration of pholcodine in saliva was 3.6 times higher than in plasma. 5. After chronic administration, the pharmacokinetics of pholcodine were not statistically different from the single dose parameters. 6. Pholcodine did not appear to undergo conjugation. The plasma protein binding was 23.5%. Morphine, in unconjugated or conjugated form, was not detected in the urine of any subject after pholcodine administration. PMID:3190994

  15. Single-dose versus multi-dose vaccine vials for immunization programmes in developing countries.

    PubMed Central

    Drain, Paul K.; Nelson, Carib M.; Lloyd, John S.

    2003-01-01

    Excessive vaccine wastage and safety concerns have prompted the international health community to develop and supply vaccines in formats other than the standard multi-dose vial. This article presents a programmatic and economic comparison of the major differences between the multi-dose vials and single-dose formats used for immunization services in developing countries. Multi-dose vials, in general, sell at a lower per-dose price and occupy less cold-chain capacity than single-dose formats. However, higher wastage rates may offset these benefits, especially for more expensive vaccines. Single-dose formats offer several important programmatic benefits, such as increased vaccination opportunities and improved vaccine safety. One single-dose format, the prefilled auto-disable (AD) device, provides additional injection safety and convenience features because it physically combines the vaccine and AD syringe. Selecting the appropriate vaccine presentation will depend on many factors. However, multi-dose vials are likely to be most appropriate for cheaper vaccines and in settings where cold-chain storage capacity is restricted. Single-dose formats will be most appropriate for more expensive vaccines and where there are problems with unsafe injection practices. Prefilled AD injection devices will be particularly useful in expanding outreach services while eliminating the possibility of needle reuse. PMID:14758432

  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

  17. A clinical trial of oral cholecystography using combinations of contrast agents and two consecutive doses.

    PubMed

    Thoeni, R F; Moss, A A

    1982-07-01

    Fifteen healthy volunteers underwent a randomized trial of oral cholecystography (OCG) using 5 different combinations of contrast agents given as 2 consecutive doses: Telepaque (iopanoic acid) given with food (TF) or without food (T), Bilopaque (sodium tyropanoate) given without food, and a combination of both agents (TF-B). The density of gallbladder opacification was judged visually on a scale of 1+ to 4+ and quantitatively by a densitometric method. Comparison of gallbladder opacification on the first and second days of the study revealed 52 of 75 (70%) combinations (TF-T, TF-TF,T-T, TF-B, B-B) resulted in improved opacification, 17% in equal opacification, and 13% in worse opacification on day 2. The TF-B combination showed the highest number (9) of excellent (grade 4+) results and the lowest number (2) of poor (grade 1+ and 2+) results, gave the best opacification in 8 volunteers, and had the highest average density difference (0.32) between first- and second-day opacifications. The TF-TF combination was the next most effective, and the T-T combination was the least effective. The results indicate that OCG in 2 consecutive doses is superior to single-dose OCG, and that a combination of TF-B or TF-TF will provide the greatest gallbladder opacification. The TF-B combination is recommended because of better patient tolerance. PMID:7045975

  18. Search for one-dose tetanus vaccine approaches first deadline. CVI goal: lifelong protection with a single-dose vaccine.

    PubMed

    1995-10-01

    Progress is reported among a Children's Vaccine Initiative (CVI) product development working group on the development of a single-dose tetanus toxoid vaccine that would change the current three-dose schedule of the diphtheria-tetanus-pertussis (DTP) combination vaccine. Development involved the participation of the vaccine development component of the World Health Organization's Global Program for Vaccines and Immunization. The single-dose approach is one in which the tetanus toxoid antigen is embedded in tiny synthetic microcapsules or microspheres, which are a mix of polymers (mostly lactic and glycolic acids). The size of the capsules and their composition determine the rate and schedule of release of the toxoid. Administration is usually by injection, but oral administration is being examined. The aim is for coverage within weeks of administration and provision of boosters one or two months later and again after eight to twelve months. Testing showed that responses were initially strong, but were inadequate one month or more later. Experimentation is ongoing using chemical modifications of the toxoid, changes in stabilizing agents, and higher concentrations of toxoids. An Australian company is ready for animal testing of its single-dose version. A Phase I safety trial is planned for an oral recombinant vaccine comprising a Salmonella vector transfected with the gene for the tetanus toxoid C fragment. Animal tests, so far inconclusive, have been conducted with a vaccine in which the alum adjuvant is replaced with a more powerful adjuvant. The working group has a number of vaccine research development projects that are at the initial stages. PMID:12290721

  19. Artemether-lumefantrine nanostructured lipid carriers for oral malaria therapy: Enhanced efficacy at reduced dose and dosing frequency.

    PubMed

    Prabhu, Priyanka; Suryavanshi, Shital; Pathak, Sulabha; Sharma, Shobhona; Patravale, Vandana

    2016-09-10

    Artemether-lumefantrine (ARM-LFN) is a World Health Organization (WHO) approved fixed-dose combination having low solubility and poor oral bioavailability. Nanostructured lipid carriers (NLC) were developed to enhance the oral efficacy of this combination using the microemulsion template technique. They were characterized for drug content, entrapment efficiency, size distribution, in vitro release, antimalarial efficacy, and toxicity. The NLC showed sustained drug release. The recommended adult therapeutic dose is 80mg ARM and 480mg LFN (4 tablets) twice a day, which amounts to 160mg ARM and 960mg LFN daily. ARM-LFN NLC given once a day at 1/5 of therapeutic dose (16mg ARM and 96mg LFN) showed complete parasite clearance and 100% survival in Plasmodium berghei-infected mice. 33% of the mice treated with marketed tablets twice a day at the therapeutic dose showed late-stage recrudescence. Thus, NLC showed enhanced efficacy at 1/10 of the daily dose of ARM-LFN. The 10-fold reduced daily dose was formulated in two soft gelatin capsules thus reducing the number of units to be taken at a time by the patient. The capsules showed good stability at room temperature for a year. The NLC were found to be safe in rats. The biocompatible NLC developed using an industrially feasible technique offer a promising solution for oral malaria therapy. PMID:27421912

  20. Dose-linear pharmacokinetics of oleanolic acid after intravenous and oral administration in rats.

    PubMed

    Jeong, Dong Won; Kim, Young Hoon; Kim, Hui Hyun; Ji, Hye Young; Yoo, Sun Dong; Choi, Won Rack; Lee, Soo Min; Han, Chang-Kyun; Lee, Hye Suk

    2007-03-01

    The pharmacokinetics of oleanolic acid was evaluated in vitro and in vivo. From Caco-2 cell permeation studies, oleanolic acid was a low permeability compound with no directional effects, suggesting a low in vivo absorption mediated by a passive diffusion. Oleanolic acid was metabolically unstable following incubation with rat liver microsomes in the presence of NADPH. After intravenous injection at doses of 0.5, 1 and 2 mg/kg doses, oleanolic acid showed dose-linear pharmacokinetics as evidenced by unaltered CL (28.6-33.0 ml/min/kg), Vss (437-583 ml/kg), dose-normalized AUC (16.0-17.9 microg min/ml based on 1 mg/kg) and t1/2 (41.9-52.7 min). Following oral administration of oleanolic acid at doses of 10, 25 and 50 mg/kg, Tmax, t1/2, dose-normalized Cmax (66-74 ng/ml based on 25 mg/kg) and dose-normalized AUC (5.4-5.9 microg min/ml based on 25 mg/kg) were comparable between 25 and 50 mg/kg dose, but the plasma concentrations at 10 mg/kg dose were not measurable as they were below the limit of quantitation (2 ng/ml). The absolute oral bioavailability was 0.7% for oral doses of 25 and 50 mg/kg. The extent of urinary excretion was minimal for both i.v. and oral doses. The very low oral bioavailability of oleanolic acid could be due to a poor absorption and extensive metabolic clearance. PMID:17163409

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

    SciTech Connect

    Wu, Vincent W.C.; Yang Zhining; Zhang Wuzhe; Wu Lili; Lin Zhixiong

    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.

  2. Bioequivalence of oral and intravenous ofloxacin after multiple-dose administration to healthy male volunteers.

    PubMed Central

    Flor, S C; Rogge, M C; Chow, A T

    1993-01-01

    The bioequivalence of oral and intravenous ofloxacin was investigated after the administration of multiple doses of 400 mg every 12 h to 20 healthy male volunteers in a randomized, crossover, open-label study. Ofloxacin concentrations in plasma were evaluated after 4 days of oral or intravenous (1-h infusion) dosing with a 3-day wash-out period between regimens. As expected, delivery to the systemic circulation took slightly longer after the oral dosing (time to maximum concentration of drug in serum of 1.7 h) relative to the 1-h intravenous infusion, but the systemic availabilities of ofloxacin by the two routes of administration were equivalent (area under the concentration-time curve from 0 to 12 h ratio of 95%). Since previous studies have not demonstrated any change in the bioavailability of ofloxacin in infectious disease patients, this study supports the interchangeability of these dosing regimens. PMID:8363378

  3. Effect of multiple doses of omeprazole on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban.

    PubMed

    Moore, Kenneth Todd; Plotnikov, Alexei Nikolaevich; Thyssen, An; Vaccaro, Nicole; Ariyawansa, Jay; Burton, Paul Bryan

    2011-12-01

    Many patients with acute coronary syndrome receive chronic dual antiplatelet therapy (acetylsalicylic acid and clopidogrel) for secondary event prophylaxis, and new oral anticoagulants are being investigated as adjunctive therapy in this indication. Gastrointestinal side effects such as bleeding are commonly associated with antiplatelet use; accordingly, many patients receive proton pump inhibitors (PPIs) to mitigate this. PPIs can reduce the antiplatelet activity of clopidogrel through cytochrome P450 2C19 inhibition, and pantoprazole reduces the bioavailability of dabigatran, a direct thrombin inhibitor that acts via cytochrome P450 2C19-independent mechanisms. These observations support the investigation of potential pharmacokinetic and pharmacodynamic interactions between PPIs and anticoagulants. We evaluated the influence of administering once-daily omeprazole 40 mg for 5 days on the pharmacokinetics and pharmacodynamics of a single 20-mg dose of the oral direct factor Xa inhibitor, rivaroxaban, in a randomized, open-label, 2-way, crossover, drug-drug interaction study in healthy subjects. No clinically meaningful interactions were observed; geometric mean ratios were 101%, 101%, and 93.5% for rivaroxaban area under the plasma concentration-time curve from time 0 to the time of the last quantifiable concentration (AUClast), or until infinity (AUC∞), and maximum plasma concentration (Cmax), respectively. Prothrombin time increased similarly in both treatment groups, with maximal values observed approximately 4 hours post rivaroxaban administration. A single 20-mg rivaroxaban dose appears well tolerated when administered alone or after 5 days of once-daily omeprazole 40 mg administration. PMID:21822144

  4. The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study

    PubMed Central

    Azman, Andrew S.; Luquero, Francisco J.; Ciglenecki, Iza; Grais, Rebecca F.; Sack, David A.; Lessler, Justin

    2015-01-01

    Background In 2013, a stockpile of oral cholera vaccine (OCV) was created for use in outbreak response, but vaccine availability remains severely limited. Innovative strategies are needed to maximize the health impact and minimize the logistical barriers to using available vaccine. Here we ask under what conditions the use of one dose rather than the internationally licensed two-dose protocol may do both. Methods and Findings Using mathematical models we determined the minimum relative single-dose efficacy (MRSE) at which single-dose reactive campaigns are expected to be as or more effective than two-dose campaigns with the same amount of vaccine. Average one- and two-dose OCV effectiveness was estimated from published literature and compared to the MRSE. Results were applied to recent outbreaks in Haiti, Zimbabwe, and Guinea using stochastic simulations to illustrate the potential impact of one- and two-dose campaigns. At the start of an epidemic, a single dose must be 35%–56% as efficacious as two doses to avert the same number of cases with a fixed amount of vaccine (i.e., MRSE between 35% and 56%). This threshold decreases as vaccination is delayed. Short-term OCV effectiveness is estimated to be 77% (95% CI 57%–88%) for two doses and 44% (95% CI −27% to 76%) for one dose. This results in a one-dose relative efficacy estimate of 57% (interquartile range 13%–88%), which is above conservative MRSE estimates. Using our best estimates of one- and two-dose efficacy, we projected that a single-dose reactive campaign could have prevented 70,584 (95% prediction interval [PI] 55,943–86,205) cases in Zimbabwe, 78,317 (95% PI 57,435–100,150) in Port-au-Prince, Haiti, and 2,826 (95% PI 2,490–3,170) cases in Conakry, Guinea: 1.1 to 1.2 times as many as a two-dose campaign. While extensive sensitivity analyses were performed, our projections of cases averted in past epidemics are based on severely limited single-dose efficacy data and may not fully capture

  5. Pharmacokinetics and cardiovascular effects following a single oral administration of a nonaqueous pimobendan solution in healthy dogs.

    PubMed

    Yata, M; McLachlan, A J; Foster, D J R; Page, S W; Beijerink, N J

    2016-02-01

    Pimobendan is an inodilator used in the treatment of canine congestive heart failure (CHF). The aim of this study was to investigate the pharmacokinetics and cardiovascular effects of a nonaqueous oral solution of pimobendan using a single-dose, operator-blinded, parallel-dose study design. Eight healthy dogs were divided into two treatment groups consisting of water (negative control) and pimobendan solution. Plasma samples and noninvasive measures of cardiovascular function were obtained over a 24-h period following dosing. Pimobendan and its active metabolite were quantified using an ultra-high-performance liquid chromatography-mass spectrometer (UHPLC-MS) assay. The oral pimobendan solution was rapidly absorbed [time taken to reach maximum concentration (Tmax ) 1.1 h] and readily converted to the active metabolite (metabolite Tmax 1.3 h). The elimination half-life was short for both pimobendan and its active metabolite (0.9 and 1.6 h, respectively). Maximal cardiovascular effects occurred at 2-4 h after a single oral dose, with measurable effects occurring primarily in echocardiographic indices of systolic function. Significant effects persisted for <8 h. The pimobendan nonaqueous oral solution was well tolerated by study dogs. PMID:25997373

  6. REPRODUCTIVE TOXICITY OF A SINGLE DOSE OF 1,3-DINITROBENZENE IN TWO AGES OF YOUNG ADULT MALE RATS

    EPA Science Inventory

    These studies evaluated the reproductive response and the possible influence of testicular maturation on the reproductive parameters, in male rats treated with 1,3-Dinitrobenzene (M-DNB). oung adult male rats (75 or 105 days of age) were given a single oral dose of 0, 8, 16, 24, ...

  7. Reproductive toxicity of a single dose of 1,3-dinitrobenzene in two ages of young adult male rats

    EPA Science Inventory

    These studies evaluated the reproductive response and the possible influence of testicular maturation on the reproductive parameters, in male rats treated with 1,3-dinitrobenzene (m-DNB). Young adult male rats (75 or 105 days of age) were given a single oral dose of 0, 8, 16, 24,...

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

    PubMed

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

    2014-06-01

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

  9. Plasma pharmacokinetics of high-dose oral busulfan in children and adults undergoing bone marrow transplantation.

    PubMed

    Bostrom, Bruce; Enockson, Karen; Johnson, Amy; Bruns, Alyssa; Blazar, Bruce

    2003-01-01

    We have analyzed the plasma pharmacokinetics of busulfan in 272 patients receiving high-dose oral busulfan and intravenous cyclophosphamide in conjunction with allogeneic or autologous bone marrow transplantation. The patients ranged in age from 2 months to 59 yr (mean 10, median 12 yr) and had the following diagnoses: thalassemia or sickle cell anemia (n = 74); leukemia or myelodysplasia (n = 112); inborn errors of metabolism (n = 41) or immunodeficiency (n = 45). Plasma specimens were collected following the first dose for each patient which ranged from 1 to 4 mg/kg (mean +/- SD, 1.21 +/- 0.41, median 1.15). Busulfan was quantitated using ultraviolet absorbance detection after derivatization and HPLC separation. Pharmacokinetic parameters were derived by modeling the raw data to fit first-order single compartment kinetics. The kinetic parameters showed wide interpatient variability independent of age and diagnosis. There was a statistically significant correlation of age with the following parameters: area under the curve (AUC); maximal concentration; minimum concentration; clearance; volume of distribution and absorption half-time. The coefficients of determination (i.e. correlation coefficient squared) were low ranging from 0.04 to 0.12 implying only a small part (i.e. 4-12%) of the variance was explained by age. Although busulfan pharmacokinetics are age-related most of the variability is not explained by age or diagnosis. PMID:12603688

  10. Pharmacokinetics of single-dose primaquine in patients with chronic kidney dysfunction

    PubMed Central

    Kulkarni, Shaunak P.; Shah, Sanjana R.; Kadam, Prashant P.; Sridharan, Kannan; Hase, Nivrutti K.; Shetty, Partha P.; Thatte, Urmila M.; Gogtay, Nithya J.

    2013-01-01

    Aim: The pharmacokinetics of primaquine has not been studied in special populations. Being a basic compound, preferential binding to alpha-1 acid glycoprotein and substrate for P-glycoprotein, may predispose the drug for an altered pharmacokinetics in states of renal dysfunction. This study attempts to evaluate the pharmacokinetics of a single oral dose (15 mg) of primaquine in severely impaired renal function and end stage renal dysfunction patients compared to healthy participants. Materials and Methods: Twelve patients each with chronic kidney disease classified as either Stage IV or V (not on dialysis) were recruited. Data from 12 healthy participants was used as concurrent controls. Serial blood collections were performed following a single dose 15 mg Primaquine orally. Primaquine concentrations were measured in the plasma using a validated HPLC method. Results: The Cmax [median (range) in ng/ml] was 29.3 (14.6-104.3), 40.3 (14.8 - 78.6), and 49.8 (15 – 169.6) and the tmax [median (range) in hours] was 3.0 (1.0- 6.0), 2.0 (1.5 – 8) and 2.0 (1.0 – 4.0) for healthy and stage IV, V (not on dialysis) CKD participants, respectively. No statistically significant difference was observed in any of the pharmacokinetic parameters between healthy, stage IV and V CKD participants. Conclusion: Pharmacokinetics of single oral dose primaquine (15 mg) does not appear to be altered in patients with severely impaired renal function and end stage renal dysfunction. A change in dose or frequency of the drug administration perhaps may not be required in this population. PMID:24014905

  11. 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

  12. Pharmacokinetics of eight anticoagulant rodenticides in mice after single oral administration.

    PubMed

    Vandenbroucke, V; Bousquet-Melou, A; De Backer, P; Croubels, S

    2008-10-01

    The first aim of the study was to investigate the pharmacokinetics of eight anticoagulant rodenticides (brodifacoum, bromadiolone, chlorophacinone, coumatetralyl, difenacoum, difethialone, flocoumafen and warfarin) in plasma and liver of the mouse after single oral administration. Eight groups of mice dosed orally with a different anticoagulant rodenticide in a dose equal to one-half the lethal dose 50 (LD(50)), were killed at various times up to 21 days after administration. The eight anticoagulant rodenticides were assayed in plasma and liver by an LC-ESI-MS/MS method. Depending on the compound, the limit of quantification was set at 1 or 5 ng/mL in plasma. In liver, the limit of quantification was set at 250 ng/g for coumatetralyl and warfarin and at 100 ng/g for the other compounds. The elimination half-lives in plasma for first-generation rodenticides were shorter than those for second-generation rodenticides. Coumatetralyl, a first-generation product, had a plasma elimination half-life of 0.52 days. Brodifacoum, a second-generation product, showed a plasma elimination half-life of 91.7 days. The elimination half-lives in liver varied from 15.8 days for coumatetralyl to 307.4 days for brodifacoum. The second aim of the study was to illustrate the applicability of the developed method in a clinical case of a dog suspected of rodenticide poisoning. PMID:19000263

  13. Complete Protection against Pneumonic and Bubonic Plague after a Single Oral Vaccination

    PubMed Central

    Derbise, Anne; Hanada, Yuri; Khalifé, Manal; Carniel, Elisabeth; Demeure, Christian E.

    2015-01-01

    Background No efficient vaccine against plague is currently available. We previously showed that a genetically attenuated Yersinia pseudotuberculosis producing the Yersinia pestis F1 antigen was an efficient live oral vaccine against pneumonic plague. This candidate vaccine however failed to confer full protection against bubonic plague and did not produce F1 stably. Methodology/Principal Findings The caf operon encoding F1 was inserted into the chromosome of a genetically attenuated Y. pseudotuberculosis, yielding the VTnF1 strain, which stably produced the F1 capsule. Given orally to mice, VTnF1 persisted two weeks in the mouse gut and induced a high humoral response targeting both F1 and other Y. pestis antigens. The strong cellular response elicited was directed mostly against targets other than F1, but also against F1. It involved cells with a Th1—Th17 effector profile, producing IFNγ, IL-17, and IL-10. A single oral dose (108 CFU) of VTnF1 conferred 100% protection against pneumonic plague using a high-dose challenge (3,300 LD50) caused by the fully virulent Y. pestis CO92. Moreover, vaccination protected 100% of mice from bubonic plague caused by a challenge with 100 LD50 Y. pestis and 93% against a high-dose infection (10,000 LD50). Protection involved fast-acting mechanisms controlling Y. pestis spread out of the injection site, and the protection provided was long-lasting, with 93% and 50% of mice surviving bubonic and pneumonic plague respectively, six months after vaccination. Vaccinated mice also survived bubonic and pneumonic plague caused by a high-dose of non-encapsulated (F1-) Y. pestis. Significance VTnF1 is an easy-to-produce, genetically stable plague vaccine candidate, providing a highly efficient and long-lasting protection against both bubonic and pneumonic plague caused by wild type or un-encapsulated (F1-negative) Y. pestis. To our knowledge, VTnF1 is the only plague vaccine ever reported that could provide high and durable protection

  14. Prolonged central mu-opioid receptor occupancy after single and repeated nalmefene dosing.

    PubMed

    Ingman, Kimmo; Hagelberg, Nora; Aalto, Sargo; Någren, Kjell; Juhakoski, Auni; Karhuvaara, Sakari; Kallio, Antero; Oikonen, Vesa; Hietala, Jarmo; Scheinin, Harry

    2005-12-01

    The opioid antagonist nalmefene offers an alternative to traditional pharmacological treatments for alcoholism. The present study was designed to investigate the relationship between nalmefene plasma concentration and central mu-opioid receptor occupancy after a clinically effective dose (20 mg, orally). Pharmacokinetics and mu-opioid receptor occupancy of nalmefene after single and repeated dosing over 7 days was studied in 12 healthy subjects. Serial blood samples were obtained after both dosings, and pharmacokinetic parameters for nalmefene and main metabolites were determined. Central mu-opioid receptor occupancy of nalmefene was measured with positron emission tomography (PET) and [(11)C]carfentanil at four time points (3, 26, 50, 74 h) after both dosings. Nalmefene was rapidly absorbed in all subjects. The mean t(1/2) of nalmefene was 13.4 h after single and repeated dosing. The accumulation of nalmefene and its main metabolites in plasma during the repeated dosing period was as expected for a drug with linear pharmacokinetics, and steady-state was reached for all analytes. Both nalmefene dosings resulted in a very high occupancy at mu-opioid receptors (87-100%), and the decline in the occupancy was similar after both dosings but clearly slower than the decline in the plasma concentration of nalmefene or metabolites. High nalmefene occupancy (83-100%) persisted at 26 h after the dosings. The prolonged mu-opioid receptor occupancy by nalmefene indicates slow dissociation of the drug from mu-opioid receptors. These results support the rational of administering nalmefene when needed before alcohol drinking, and they additionally suggest that a high mu-opioid receptor occupancy can be maintained when nalmefene is taken once daily. PMID:15956985

  15. 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...

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

    Code of Federal Regulations, 2013 CFR

    2013-07-01

    ... 40 Protection of Environment 33 2013-07-01 2013-07-01 false TSCA Repeated dose 28-day oral toxicity study in rodents. 799.9305 Section 799.9305 Protection of Environment ENVIRONMENTAL PROTECTION AGENCY (CONTINUED) TOXIC SUBSTANCES CONTROL ACT (CONTINUED) IDENTIFICATION OF SPECIFIC CHEMICAL SUBSTANCE AND MIXTURE TESTING REQUIREMENTS Health...

  17. Replacing the Measles Ten-Dose Vaccine Presentation with the Single-Dose Presentation in Thailand

    PubMed Central

    Lee, Bruce Y.; Assi, Tina-Marie; Rookkapan, Korngamon; Connor, Diana L.; Rajgopal, Jayant; Sornsrivichai, Vorasith; Brown, Shawn T.; Welling, Joel S.; Norman, Bryan A.; Chen, Sheng-I; Bailey, Rachel R.; Wiringa, Ann E.; Wateska, Angela R.; Jana, Anirban; Van Panhuis, Willem G.; Burke, Donald S.

    2011-01-01

    Introduced to minimize open vial wastage, single-dose vaccine vials require more storage space and therefore may affect vaccine supply chains (i.e., the series of steps and processes entailed to deliver vaccines from manufacturers to patients). We developed a computational model of Thailand’s Trang province vaccine supply chain to analyze the effects of switching from a ten-dose measles vaccine presentation to each of the following: a single-dose Measles-Mumps-Rubella vaccine (which Thailand is currently considering) and a single-dose measles vaccine. While the Trang province vaccine supply chain would generally have enough storage and transport capacity to accommodate the switches, the added volume could push some locations’ storage and transport space utilization close to their limits. Single-dose vaccines would allow for more precise ordering and decrease open vial waste, but decrease reserves for unanticipated demand. Moreover, the added disposal and administration costs could far outweigh the costs saved from preventing open vial wastage. PMID:21439313

  18. A pilot open label, single dose trial of fenobam in adults with fragile X syndrome

    PubMed Central

    Berry-Kravis, E; Hessl, D; Coffey, S; Hervey, C; Schneider, A; Yuhas, J; Hutchison, J; Snape, M; Tranfaglia, M; Nguyen, D V; Hagerman, R

    2009-01-01

    Objective: A pilot open label, single dose trial of fenobam, an mGluR5 antagonist, was conducted to provide an initial evaluation of safety and pharmacokinetics in adult males and females with fragile X syndrome (FXS). Methods: Twelve subjects, recruited from two fragile X clinics, received a single oral dose of 50–150 mg of fenobam. Blood for pharmacokinetic testing, vital signs and side effect screening was obtained at baseline and numerous time points for 6 h after dosing. Outcome measures included prepulse inhibition (PPI) and a continuous performance test (CPT) obtained before and after dosing to explore the effects of fenobam on core phenotypic measures of sensory gating, attention and inhibition. Results: There were no significant adverse reactions to fenobam administration. Pharmacokinetic analysis showed that fenobam concentrations were dose dependent but variable, with mean (SEM) peak values of 39.7 (18.4) ng/ml at 180 min after the 150 mg dose. PPI met a response criterion of an improvement of at least 20% over baseline in 6 of 12 individuals (4/6 males and 2/6 females). The CPT did not display improvement with treatment due to ceiling effects. Conclusions: Clinically significant adverse effects were not identified in this study of single dose fenobam across the range of dosages utilised. The positive effects seen in animal models of FXS treated with fenobam or other mGluR5 antagonists, the apparent lack of clinically significant adverse effects, and the potential beneficial clinical effects seen in this pilot trial support further study of the compound in adults with FXS. PMID:19126569

  19. Antiretroviral Therapies in Women after Single-Dose Nevirapine Exposure

    PubMed Central

    Lockman, S.; Hughes, M.D.; McIntyre, J.; Zheng, Y.; Chipato, T.; Conradie, F.; Sawe, F.; Asmelash, A.; Hosseinipour, M.C.; Mohapi, L.; Stringer, E.; Mngqibisa, R.; Siika, A.; Atwine, D.; Hakim, J.; Shaffer, D.; Kanyama, C.; Wools-Kaloustian, K.; Salata, R.A.; Hogg, E.; Alston-Smith, B.; Walawander, A.; Purcelle-Smith, E.; Eshleman, S.; Rooney, J.; Rahim, S.; Mellors, J.W.; Schooley, R.T.; Currier, J.S.

    2010-01-01

    BACKGROUND Peripartum administration of single-dose nevirapine reduces mother-to-child transmission of human immunodeficiency virus type 1 (HIV-1) but selects for nevirapine-resistant virus. METHODS In seven African countries, women infected with HIV-1 whose CD4+ T-cell counts were below 200 per cubic millimeter and who either had or had not taken single-dose nevirapine at least 6 months before enrollment were randomly assigned to receive antiretroviral therapy with tenofovir–emtricitabine plus nevirapine or tenofovir-emtricitabine plus lopinavir boosted by a low dose of ritonavir. The primary end point was the time to confirmed virologic failure or death. RESULTS A total of 241 women who had been exposed to single-dose nevirapine began the study treatments (121 received nevirapine and 120 received ritonavir-boosted lopinavir). Significantly more women in the nevirapine group reached the primary end point than in the ritonavir-boosted lopinavir group (26% vs. 8%) (adjusted P = 0.001). Virologic failure occurred in 37 (28 in the nevirapine group and 9 in the ritonavir-boosted lopinavir group), and 5 died without prior virologic failure (4 in the nevirapine group and 1 in the ritonavir-boosted lopinavir group). The group differences appeared to decrease as the interval between single-dose nevirapine exposure and the start of antiretroviral therapy increased. Retrospective bulk sequencing of baseline plasma samples showed nevirapine resistance in 33 of 239 women tested (14%). Among 500 women without prior exposure to single-dose nevirapine, 34 of 249 in the nevirapine group (14%) and 36 of 251 in the ritonavir-boosted lopinavir group (14%) had virologic failure or died. CONCLUSIONS In women with prior exposure to peripartum single-dose nevirapine (but not in those without prior exposure), ritonavir-boosted lopinavir plus tenofovir–emtricitabine was superior to nevirapine plus tenofovir–emtricitabine for initial antiretroviral therapy. (Funded by the National

  20. Orally administered betaine has an acute and dose-dependent effect on serum betaine and plasma homocysteine concentrations in healthy humans.

    PubMed

    Schwab, Ursula; Törrönen, Anneli; Meririnne, Esa; Saarinen, Markku; Alfthan, Georg; Aro, Antti; Uusitupa, Matti

    2006-01-01

    Betaine, i.e., trimethylglycine, is linked to homocysteine metabolism. A 3-mo daily betaine supplementation decreased even normal plasma total homocysteine (tHcy) concentrations in humans. The pharmacokinetic characteristics and metabolism of betaine in humans have not been investigated in detail. The aim of this study was to assess the pharmacokinetics of orally administered betaine and its acute effect on plasma tHcy concentrations. Healthy volunteers (n = 10; 3 men, 7 women) with normal body weight (mean +/- SD, 69.5 +/- 17.0 kg), 40.8 +/- 12.4 y old, participated in the study. The betaine doses were 1, 3, and 6 g. The doses were mixed with 150 mL of orange juice and ingested after a 12-h overnight fast by each volunteer according to a randomized double-blind crossover design. Blood samples were drawn for 24 h and a 24-h urine collection was performed. Orally administered betaine had an immediate and dose-dependent effect on serum betaine concentration. Single doses of 3 and 6 g lowered plasma tHcy concentrations (P = 0.019 and P < 0.001, respectively), unlike the 1-g dose. After the highest dose, the concentrations remained low during the 24 h of monitoring. The change in plasma tHcy concentration was linearly associated with betaine dose (P = 0.006) and serum betaine concentration (R2 = 0.17, P = 0.025). The absorption and elimination of betaine were dose dependent. The urinary excretion of betaine seemed to increase with an increasing betaine dose, although a very small proportion of ingested betaine was excreted via urine. In conclusion, a single dose of orally administered betaine had an acute and dose-dependent effect on serum betaine concentration and resulted in lowered plasma tHcy concentrations within 2 h in healthy subjects. PMID:16365055

  1. Clinical trial with Secnidazole in a single dose in Venezuelan children infected by Giardia intestinalis.

    PubMed

    Di Prisco, M C; Jiménez, J C; Rodríguez, N; Costa, V; Villamizar, J; Silvera, A; Carrillo, M; Lira, C; Zerpa, E; López, Y

    2000-09-01

    The aim of this work was to evaluate in an open, noncomparative study the use of secnidazole in oral suspension given to Venezuelan children infected with Giardia intestinalis, from a community in Carapita, a slum area in Caracas. Seventy children from 2 to 11 years old (38 males and 32 females) were treated with a single oral dose of secnidazole (30 mg/Kg of body weight), after clinical and parasitological evaluation to make the diagnosis of active giardiasis. The effectiveness of treatment was determined by clinical examination and parasitological evaluation of feces samples 15 days after treatment. The results showed 95% of clinical cure with a significant decrease of the frequency of gastrointestinal symptoms. The parasitological cure was 98%, there were 4 failures at the end of treatment. Side effects observed after treatment were of mild intensity, lasting only few hours. These results show that a simple dose of secnidazole in an oral suspension is an effective, safe and well tolerated treatment for giardiasis in children and that this drug may be used as a mass treatment in risk populations. PMID:11029834

  2. Oral heparins.

    PubMed

    Hiebert, Linda M

    2002-01-01

    The antithrombotic drug heparin is administered parenterally and believed not effective orally. Oral heparin would be most suitable for long term administration, often required for the prevention of thrombosis. Following parenteral administration, heparin is taken up by endothelial cells. Our laboratory has shown that heparin is similarly taken up by endothelium following oral administration, despite low plasma heparin concentrations. In a twenty-four hour period, endothelial heparin concentrations are greatest within 15 minutes of oral dosing although plasma levels never exceed one percent of dose. Endothelial uptake accounts for a considerable amount of absorption if the total body endothelium is considered. In support of oral heparin absorption, we demonstrated a dose-dependent decrease in thrombosis incidence in a rat jugular vein model following single oral doses of unfractionated heparins (bovine and porcine) or low molecular weight heparins (reviparin, logiparin and ardeparin). Low molecular weight heparins were effective at lower doses than unfractionated heparins where a fifty percent reduction in thrombosis was observed with 0.025 mg/kg reviparin, 0.1 mg/kg logiparin, versus 7.5 mg/kg bovine unfractionated heparin. These studies support the work of others demonstrating measurable systemic changes following oral heparin administration and suggest that heparin may be effective when administered by the oral route. It also indicates that the presence of heparin in plasma likely reflects a much greater amount associated with endothelium. PMID:11934211

  3. Pharmacokinetics of azithromycin in foals after i.v. and oral dose and disposition into phagocytes.

    PubMed

    Davis, J L; Gardner, S Y; Jones, S L; Schwabenton, B A; Papich, M G

    2002-04-01

    The properties of azithromycin suggest that it may be an alternative to erythromycin for treatment of Rhodococcus equi pneumonia in foals. To investigate this possibility, the disposition of azithromycin in plasma, polymorphonuclear leukocytes (PMN), and alveolar cells was examined after a single administration in foals. Azithromycin suspension was administered orally (p.o.) at a dose of 10 mg/kg to five healthy 2-3-month-old foals. Two weeks later, azithromycin for injection was administered by intravenous (i.v.) infusion at a dose of 5 mg/kg to the same foals. Plasma samples were collected after p.o. and i.v. administration. Peripheral blood PMN and bronchoalveolar lavage fluid and alveolar cells were collected after p.o. administration. Azithromycin concentrations were determined by reverse-phase high-performance liquid chromatography (HPLC) with coulometric electrochemical detection. Azithromycin p.o. absorption was variable with a mean systemic availability of 39% (+/-20%). The plasma half-life was 16 and 18.3 h after i.v. and p.o. administration, respectively. Azithromycin had a very large volume of distribution (V(d)) of 11.6 L/kg [V(d(ss))] and 12.4 L/kg [V(d(area))]. The large V(d) can be attributed to high tissue and intracellular concentrations, exhibited by the high concentration of azithromycin in PMN and alveolar cells. The PMN half-life was 49.2 h. Dosage of 10 mg/kg of azithromycin p.o. once daily for foals with R. equi pneumonia is recommended for further study. PMID:12000529

  4. Failure of antimony trioxide to induce micronuclei or chromosomal aberrations in rat bone-marrow after sub-chronic oral dosing.

    PubMed

    Kirkland, David; Whitwell, James; Deyo, James; Serex, Tessa

    2007-03-01

    Antimony trioxide (Sb2O3, CAS 1309-64-4) is widely used as a flame retardant synergist in a number of household products, as a fining agent in glass manufacture, and as a catalyst in the manufacture of various types of polyester plastics. It does not induce point mutations in bacteria or mammalian cells, but is able to induce chromosomal aberrations (CA) in cultured cells in vitro. Although no CA or micronuclei (MN) have been induced after acute oral dosing of mice, repeated oral dosing for 14 or 21 days resulted in increased CA in one report, but did not result in increased MN in another. In order to further investigate its in vivo genotoxicity, Sb2O3 was dosed orally to groups of rats for 21 days at 250, 500 and 1000 mg/kg day. There were no clinical signs of toxicity in the Sb2O3-exposed animals except for some reductions in body-weight gain in the top dose group. Toxicokinetic measurements in a separate study confirmed bone-marrow exposure, and at higher levels than would have been achieved by single oral dosing. Large numbers of cells were scored for CA (600 metaphases/sex group) and MN (12,000 PCE/sex group) but frequencies of CA or MN in Sb2O3-treated rats were very similar to controls, and not biologically or statistically different, at all doses. These results provide further indication that Sb2O3 is not genotoxic to the bone marrow of rodents after 21 days of oral administration at high doses close to the maximum tolerated dose. PMID:17174592

  5. Inhibition of cytochrome bc1 as a strategy for single-dose, multi-stage antimalarial therapy.

    PubMed

    Stickles, Allison M; Ting, Li-Min; Morrisey, Joanne M; Li, Yuexin; Mather, Michael W; Meermeier, Erin; Pershing, April M; Forquer, Isaac P; Miley, Galen P; Pou, Sovitj; Winter, Rolf W; Hinrichs, David J; Kelly, Jane X; Kim, Kami; Vaidya, Akhil B; Riscoe, Michael K; Nilsen, Aaron

    2015-06-01

    Single-dose therapies for malaria have been proposed as a way to reduce the cost and increase the effectiveness of antimalarial treatment. However, no compound to date has shown single-dose activity against both the blood-stage Plasmodium parasites that cause disease and the liver-stage parasites that initiate malaria infection. Here, we describe a subset of cytochrome bc1 (cyt bc1) inhibitors, including the novel 4(1H)-quinolone ELQ-400, with single-dose activity against liver, blood, and transmission-stage parasites in mouse models of malaria. Although cyt bc1 inhibitors are generally classified as slow-onset antimalarials, we found that a single dose of ELQ-400 rapidly induced stasis in blood-stage parasites, which was associated with a rapid reduction in parasitemia in vivo. ELQ-400 also exhibited a low propensity for drug resistance and was active against atovaquone-resistant P. falciparum strains with point mutations in cyt bc1. Ultimately, ELQ-400 shows that cyt bc1 inhibitors can function as single-dose, blood-stage antimalarials and is the first compound to provide combined treatment, prophylaxis, and transmission blocking activity for malaria after a single oral administration. This remarkable multi-stage efficacy suggests that metabolic therapies, including cyt bc1 inhibitors, may be valuable additions to the collection of single-dose antimalarials in current development. PMID:25918204

  6. Inhibition of Cytochrome bc1 as a Strategy for Single-Dose, Multi-Stage Antimalarial Therapy

    PubMed Central

    Stickles, Allison M.; Ting, Li-Min; Morrisey, Joanne M.; Li, Yuexin; Mather, Michael W.; Meermeier, Erin; Pershing, April M.; Forquer, Isaac P.; Miley, Galen P.; Pou, Sovitj; Winter, Rolf W.; Hinrichs, David J.; Kelly, Jane X.; Kim, Kami; Vaidya, Akhil B.; Riscoe, Michael K.; Nilsen, Aaron

    2015-01-01

    Single-dose therapies for malaria have been proposed as a way to reduce the cost and increase the effectiveness of antimalarial treatment. However, no compound to date has shown single-dose activity against both the blood-stage Plasmodium parasites that cause disease and the liver-stage parasites that initiate malaria infection. Here, we describe a subset of cytochrome bc1 (cyt bc1) inhibitors, including the novel 4(1H)-quinolone ELQ-400, with single-dose activity against liver, blood, and transmission-stage parasites in mouse models of malaria. Although cyt bc1 inhibitors are generally classified as slow-onset antimalarials, we found that a single dose of ELQ-400 rapidly induced stasis in blood-stage parasites, which was associated with a rapid reduction in parasitemia in vivo. ELQ-400 also exhibited a low propensity for drug resistance and was active against atovaquone-resistant P. falciparum strains with point mutations in cyt bc1. Ultimately, ELQ-400 shows that cyt bc1 inhibitors can function as single-dose, blood-stage antimalarials and is the first compound to provide combined treatment, prophylaxis, and transmission blocking activity for malaria after a single oral administration. This remarkable multi-stage efficacy suggests that metabolic therapies, including cyt bc1 inhibitors, may be valuable additions to the collection of single-dose antimalarials in current development. PMID:25918204

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

    PubMed

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

    2014-08-14

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

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

    PubMed Central

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

    2014-01-01

    Proteasome inhibition is an effective treatment strategy for multiple myeloma. With improving survival, attention is increasingly focusing on ease of administration and toxicity profile. Ixazomib is an investigational, orally bioavailable 20S proteasome inhibitor. Sixty patients with relapsed and/or refractory multiple myeloma were enrolled on this phase 1 trial to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) of single-agent, oral ixazomib given weekly for 3 of 4 weeks. Upon MTD determination, patients were enrolled to 4 different cohorts based on relapsed/refractory status and prior bortezomib and carfilzomib exposure. The MTD was determined to be 2.97 mg/m2. Dose-limiting toxicities were grade 3 nausea, vomiting, and diarrhea in 2 patients, and grade 3 skin rash in 1 patient. Common drug-related adverse events were thrombocytopenia (43%), diarrhea (38%), nausea (38%), fatigue (37%), and vomiting (35%). The observed rate of peripheral neuropathy was 20%, with only 1 grade 3 event reported. Nine (18%) patients achieved a partial response or better, including 8 of 30 (27%) evaluable patients treated at the MTD. Pharmacokinetic studies suggested a long terminal half-life of 3.6 to 11.3 days, supporting once-weekly dosing. This trial was registered at www.clinicaltrials.gov as #NCT00963820. PMID:24904120

  9. Metabolite profiles of rats in repeated dose toxicological studies after oral and inhalative exposure.

    PubMed

    Fabian, E; Bordag, N; Herold, M; Kamp, H; Krennrich, G; Looser, R; Ma-Hock, L; Mellert, W; Montoya, G; Peter, E; Prokudin, A; Spitzer, M; Strauss, V; Walk, T; Zbranek, R; van Ravenzwaay, B

    2016-07-25

    The MetaMap(®)-Tox database contains plasma-metabolome and toxicity data of rats obtained from oral administration of 550 reference compounds following a standardized adapted OECD 407 protocol. Here, metabolic profiles for aniline (A), chloroform (CL), ethylbenzene (EB), 2-methoxyethanol (ME), N,N-dimethylformamide (DMF) and tetrahydrofurane (THF), dosed inhalatively for six hours/day, five days a week for 4 weeks were compared to oral dosing performed daily for 4 weeks. To investigate if the oral and inhalative metabolome would be comparable statistical analyses were performed. Best correlations for metabolome changes via both routes of exposure were observed for toxicants that induced profound metabolome changes. e.g. CL and ME. Liver and testes were correctly identified as target organs. In contrast, route of exposure dependent differences in metabolic profiles were noted for low profile strength e.g. female rats dosed inhalatively with A or THF. Taken together, the current investigations demonstrate that plasma metabolome changes are generally comparable for systemic effects after oral and inhalation exposure. Differences may result from kinetics and first pass effects. For compounds inducing only weak changes, the differences between both routes of exposure are visible in the metabolome. PMID:27153797

  10. Low-dose oral interferon modulates expression of inflammatory and autoimmune genes in cattle.

    PubMed

    Mamber, Stephen W; Lins, Jeremy; Gurel, Volkan; Hutcheson, David P; Pinedo, Pablo; Bechtol, David; Krakowka, Steven; Fields-Henderson, Rachel; Cummins, Joseph M

    2016-04-01

    While the safety and efficacy profiles of orally administered bovine interferon (IFN) alpha have been documented, the mechanism(s) that result in clinical benefits remain elusive. One approach to delineating the molecular pathways of IFN efficacy is through the use of gene expression profiling technologies. In this proof-of-concept study, different (0, 50, 200 and 800 units) oral doses of natural bovine IFN (type I) were tested in cattle to determine if oral IFN altered the expression of genes that may be pivotal to the development of systemic resistance to viral infections such as foot-and-mouth disease (FMD). Oral IFN was administered twice: Time 0 and 8h later. Blood was collected at 0, 8 and 24h after the first IFN administration, and DNA isolated from peripheral blood mononuclear cells (PBMCs) was employed in quantitative polymerase chain reaction (qPCR) microarray assays. Within 8h, 50 and 200 units of oral IFN induced significant (P<0.05) changes in expression of 41 of 92 tested autoimmune and inflammatory response-associated genes. These data suggest that orally administered IFN is a viable approach for providing short-term antiviral immunity to livestock exposed to viruses such as FMD virus (FMDV) until such a time that an effective vaccine can be produced and distributed to producers. PMID:27032505

  11. Effects of therapeutic and supratherapeutic doses of oral tedizolid phosphate on cardiac repolarisation in healthy volunteers: a randomised controlled study.

    PubMed

    Flanagan, Shawn; Litwin, Jeffrey; Fang, Edward; Prokocimer, Philippe

    2016-07-01

    Drug-induced prolongation of the QT interval on the electrocardiogram (ECG) infrequently results in Torsades de pointes, a potentially fatal arrhythmia. Therefore, thorough QT analysis of new drugs is a regulatory requirement. The objective of this phase 1 study was to assess the effects of oral tedizolid phosphate on the QT interval corrected with Fridericia's formula (QTcF) in healthy adult subjects. A single therapeutic dose (200 mg) and a supratherapeutic dose (1200 mg) of tedizolid phosphate were administered to characterise QTc changes following typical systemic exposure and with markedly higher exposures, respectively. This was a four-way crossover study with 48 subjects randomly assigned to receive therapeutic and supratherapeutic doses of tedizolid phosphate, moxifloxacin (positive control for QT interval prolongation) and placebo (negative control). A continuous 12-lead ECG was recorded from 1 h before drug administration to 23 h after administration. Adverse events, which were generally mild, occurred most frequently with moxifloxacin or with a supratherapeutic dose of tedizolid phosphate; however, all treatments were well tolerated. This study demonstrated that therapeutic or supratherapeutic doses of the antibacterial tedizolid had no clinically significant effect on QT interval in healthy adults [ClinicalTrials.gov registration no.: NCT01461460]. PMID:27342387

  12. Minimum Effective Dose of Cattle and Sheep BSE for Oral Sheep Infection

    PubMed Central

    McGovern, Gillian; Martin, Stuart; Jeffrey, Martin; Dexter, Glenda; Hawkins, Steve A. C.; Bellworthy, Sue J.; Thurston, Lisa; Algar, Lynne; González, Lorenzo

    2016-01-01

    The minimum dose required to cause infection of Romney and Suffolk sheep of the ARQ/ARQ or ARQ/ARR prion protein gene genotypes following oral inoculation with Romney or Suffolk a sheep Bovine spongiform encephalopathy (BSE)-derived or cattle BSE-derived agent was investigated using doses ranging from 0.0005g to 5g. ARQ/ARQ sheep which were methionine (M) / threonine (T) heterozygous or T/T homozygous at codon 112 of the Prnp gene, dosed ARQ/ARR sheep and undosed controls did not show any evidence of infection. Within groups of susceptible sheep, the minimum effective oral dose of BSE was found to be 0.05g, with higher attack rates following inoculation with the 5g dose. Surprisingly, this study found no effect of dose on survival time suggesting a possible lack of homogeneity within the inoculum. All clinical BSE cases showed PrPd accumulation in brain; however, following cattle BSE inoculation, LRS involvement within Romney recipients was found to be significantly lower than within the Suffolk sheep inoculated group which is in agreement with previous reports. PMID:26968011

  13. Minimum Effective Dose of Cattle and Sheep BSE for Oral Sheep Infection.

    PubMed

    McGovern, Gillian; Martin, Stuart; Jeffrey, Martin; Dexter, Glenda; Hawkins, Steve A C; Bellworthy, Sue J; Thurston, Lisa; Algar, Lynne; González, Lorenzo

    2016-01-01

    The minimum dose required to cause infection of Romney and Suffolk sheep of the ARQ/ARQ or ARQ/ARR prion protein gene genotypes following oral inoculation with Romney or Suffolk a sheep Bovine spongiform encephalopathy (BSE)-derived or cattle BSE-derived agent was investigated using doses ranging from 0.0005g to 5g. ARQ/ARQ sheep which were methionine (M) / threonine (T) heterozygous or T/T homozygous at codon 112 of the Prnp gene, dosed ARQ/ARR sheep and undosed controls did not show any evidence of infection. Within groups of susceptible sheep, the minimum effective oral dose of BSE was found to be 0.05g, with higher attack rates following inoculation with the 5g dose. Surprisingly, this study found no effect of dose on survival time suggesting a possible lack of homogeneity within the inoculum. All clinical BSE cases showed PrPd accumulation in brain; however, following cattle BSE inoculation, LRS involvement within Romney recipients was found to be significantly lower than within the Suffolk sheep inoculated group which is in agreement with previous reports. PMID:26968011

  14. Opioid use and dropout in patients receiving oral naltrexone with or without single administration of injection naltrexone

    PubMed Central

    Sullivan, Maria A.; Bisaga, Adam; Glass, Andrew; Mishlen, Kaitlyn; Pavlicova, Martina; Carpenter, Kenneth M.; Mariani, John J; Levin, Frances R.; Nunes, Edward V.

    2015-01-01

    Background Adherence to oral naltrexone has been poor and can be improved somewhat with behavioral therapy. We compared Behavioral Naltrexone Therapy (BNT) to Compliance Enhancement (CE) and tested efficacy of single-dose injection naltrexone (XR-NTX; 384 mg) with behavioral therapies at further improving aherence to oral naltrexone. Methods A 24-week, randomized, placebo-controlled trial (N=125) compared four treatment conditions following inpatient detoxification and oral naltrexone induction: (1) BNT+XR-NTX; (2) BNT+ placebo injection; (3) CE+ XR-NTX; and (4) CE+placebo injection. All participants were maintained on oral naltrexone throughout the trial. Primary outcome was retention in treatment. Results Of 89 randomized participants, 78.7% (70/89) completed 4 weeks, 58.2% (54/89) completed 8 weeks, 47.2% (42/89) completed 12 weeks, and 25.8% (23/89) completed 24 weeks. A Cox proportional hazards regression modeled time to dropout as a function of treatment condition, baseline opioid dependence severity (bags per day of heroin use), and their interaction. Interaction of conditions by baseline severity was significant (X23 = 9.19, p = .027). For low-severity patients (<6 bags/day), retention was highest in the BNT-XRNTX group (60% at 6 months), as hypothesized. For high-severity (> 6 bags/day) patients, BNT-XR-NTX did not perform as well, due to high early attrition. Conclusion For low-severity heroin users, single-dose XR-NTX improved long-term treatment retention when combined with behavioral therapy. In higher-severity opioid-dependent patients, XR-NTX was less helpful, perhaps because, combined with oral naltrexone, it produced higher blood levels and more withdrawal discomfort. When cost considerations recommend oral naltrexone following XR-NTX, the latter should be phased in slowly. PMID:25555621

  15. Disposition of 2-mercaptobenzothiazole and 2-mercaptobenzothiazole disulfide in rats dosed intravenously, orally, and topically and in guinea pigs dosed topically

    SciTech Connect

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

    1989-01-01

    To determine the metabolic disposition of (14C)-2-mercaptobenzothiazole (MBT) and (14C)-2-mercaptobenzothiazole disulfide (MBTS), male and female rats were dosed topically. Topical doses were 36.1 micrograms/animal for (14C)MBT and 33.6 micrograms/animal for (14C)MBTS. Although more MBT passed through the skin than MBTS and although, relative to rats, guinea pigs absorbed a greater percentage of the dose (33.4% compared to 16.1-17.5% of the MBT and 12.2% compared to 5.94-7.87% for MBTS), the disposition of radioactivity derived from the two compounds was similar. Washing of the skin removed more of the radioactivity from guinea pigs than from rats. For both sexes of rats dosed intravenously with (14C)MBT or (14C)MBTS, disposition of the compounds was similar. In 72 h, 90.9-101% of the dose appeared in the urine and 3.79-15.1% in the feces. At this time, a small portion of the administered radioactivity remained associated with erythrocytes. Oral dosing of rats for 14 d with unlabeled MBT prior to a single dose of (14C)MBT or with unlabeled MBTS prior to a single dose of (14C)MBTS (0.730 mg/kg). For both sexes, disposition of the compounds was similar. At 96 h after dosing, a small portion of the administered radioactivity remained associated with erythrocytes, most of which was bound to the membranes. For both compounds and sexes, 60.8-101% of the radioactivity administered appeared in the urine and 3.46-9.99% in the feces in 96 h. At the time, only trace amounts of radioactivity remained in tissues other than blood. Of these tissues, thyroid contained the highest concentration. In the urine, there was a detectable MBT or MBTS, but there were two metabolites, one of which was identified as a thioglucuronide derivative of MBT. The other was possibly a sulfonic acid derivative of MBT.

  16. Efficacy of a single high dose versus multiple low doses of LLLT on wounded skin fibroblasts

    NASA Astrophysics Data System (ADS)

    Hawkins, Denise H.; Abrahamse, Heidi

    2007-07-01

    Background/purpose: In vivo studies have demonstrated that phototherapy accelerates wound healing in the clinical environment; however the exact mechanism is still not completely understood. The main focus of this study was to use in vitro laboratory results to establish an effective treatment regimen that may be practical and applicable to the clinical environment. This in vitro study aimed to compare the cellular responses of wounded fibroblasts following a single exposure of 5 J/cm2 or multiple exposures of low doses (2.5 J/cm2 or 5 J/cm2) on one day of the week to a single application of a higher dose (16 J/cm2) on day 1 and day 4. Methodology: Cellular responses to Helium-Neon (632.8 nm) laser irradiation were evaluated by measuring changes in cell morphology, cell viability, cell proliferation, membrane integrity and DNA damage. Results: Wounded cells exposed to 5 J/cm2 on day 1 and day 4 showed an increase in cell viability, increase in the release of bFGF, increase in cell density, decrease in ALP enzyme activity and decrease in caspase 3/7 activity indicating a stimulatory effect. Wounded cells exposed to three doses of 5 J/cm2 on day 1 showed a decrease in cell viability and cell proliferation and an increase in LDH cytotoxicity and DNA damage indicating an inhibitory effect. Conclusion: Results indicate that cellular responses are influenced by the combination of dose administered, number of exposures and time between exposures. Single doses administered with sufficient time between exposures is more beneficial to restoring cell function than multiple doses within a short period. Although this work confirms previous reports on the cumulative effect of laser irradiation it provides essential information for the initiation of in vivo clinical studies.

  17. A comparison in young and elderly subjects of the pharmacokinetics and pharmacodynamics of single and multiple doses of benazepril.

    PubMed Central

    Macdonald, N J; Elliott, H L; Hughes, D M; Reid, J L

    1993-01-01

    1. The pharmacokinetics and pharmacodynamics of single and multiple oral doses of the ACE inhibitor benazepril were investigated in young and elderly normotensive subjects. 2. Following multiple doses the trough concentrations were significantly higher in the elderly and the areas under the plasma concentration-time curves (AUC0-24) were significantly greater, by approximately 23%. 3. The fall in blood pressure tended to be greater in the elderly subjects but this is likely to be attributable to their higher initial blood pressures, although it may reflect the small differences in pharmacokinetics. 4. The age related differences in kinetics and dynamics following multiple dosing are quantitatively similar to those obtained with single doses. However, there appears to be a quantitative difference between benazepril and other ACE inhibitors in that the age related increases were of a relatively smaller magnitude. PMID:9114904

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

    SciTech Connect

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

    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.

  19. 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

  20. Oral dosing of chemical indicators for in vivo monitoring of Ca2+ dynamics in insect muscle.

    PubMed

    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

  1. Radiation damage in single-particle cryo-electron microscopy: effects of dose and dose rate

    PubMed Central

    Karuppasamy, Manikandan; Karimi Nejadasl, Fatemeh; Vulovic, Milos; Koster, Abraham J.; Ravelli, Raimond B. G.

    2011-01-01

    combined with an improved understanding of the effects of dose and dose rate will aid single-particle cryo-electron microscopists to have better control of the outcome of their experiments. PMID:21525648

  2. Radiation damage in single-particle cryo-electron microscopy: effects of dose and dose rate.

    PubMed

    Karuppasamy, Manikandan; Karimi Nejadasl, Fatemeh; Vulovic, Milos; Koster, Abraham J; Ravelli, Raimond B G

    2011-05-01

    an improved understanding of the effects of dose and dose rate will aid single-particle cryo-electron microscopists to have better control of the outcome of their experiments. PMID:21525648

  3. Genetic testing to guide warfarin dosing: Impact of direct oral anticoagulants.

    PubMed

    Lentz, S R

    2016-08-01

    Despite rapid growth in the use of direct oral anticoagulants (DOACs), warfarin remains a widely prescribed anticoagulant drug. It is likely that the overall use of warfarin will continue to decline, but not completely disappear, as indications for DOACs expand. This changing anticoagulation landscape, along with the likelihood that personalized genomic information will become increasingly available, has several implications for the future of warfarin dosing strategies. PMID:27178490

  4. Role of sulfite additives in wine induced asthma: single dose and cumulative dose studies

    PubMed Central

    Vally, H; Thompson, P

    2001-01-01

    BACKGROUND—Wine appears to be a significant trigger for asthma. Although sulfite additives have been implicated as a major cause of wine induced asthma, direct evidence is limited. Two studies were undertaken to assess sulfite reactivity in wine sensitive asthmatics. The first study assessed sensitivity to sulfites in wine using a single dose sulfited wine challenge protocol followed by a double blind, placebo controlled challenge. In the second study a cumulative dose sulfited wine challenge protocol was employed to establish if wine sensitive asthmatics as a group have an increased sensitivity to sulfites.
METHODS—In study 1, 24 asthmatic patients with a strong history of wine induced asthma were screened. Subjects showing positive responses to single blind high sulfite (300 ppm) wine challenge were rechallenged on separate days in a double blind, placebo controlled fashion with wines of varying sulfite levels to characterise their responses to these drinks. In study 2, wine sensitive asthmatic patients (n=12) and control asthmatics (n=6) were challenged cumulatively with wine containing increasing concentrations of sulfite in order to characterise further their sensitivity to sulfites in wine.
RESULTS—Four of the 24 self-reporting wine sensitive asthmatic patients were found to respond to sulfite additives in wine when challenged in a single dose fashion (study 1). In the double blind dose-response study all four had a significant fall in forced expiratory volume in one second (FEV1) (>15% from baseline) following exposure to wine containing 300 ppm sulfite, but did not respond to wines containing 20, 75 or 150 ppm sulfite. Responses were maximal at 5 minutes (mean (SD) maximal decline in FEV1 28.7 (13)%) and took 15-60 minutes to return to baseline levels. In the cumulative dose-response study (study 2) no significant difference was observed in any of the lung function parameters measured (FEV1, peak expiratory flow (PEF), mid phase forced expiratory

  5. PHARMACOKINETIC PROPERTIES OF A SINGLE ADMINISTRATION OF ORAL GABAPENTIN IN THE GREAT HORNED OWL (BUBO VIRGINIANUS).

    PubMed

    Yaw, Taylor J; Zaffarano, Bianca A; Gall, Andrew; Olds, June E; Wulf, Larry; Papastavros, Efthimia; Coetzee, Johann F

    2015-09-01

    Gabapentin (1-[aminomethyl] cyclohexane acetic acid) is a γ-aminobutyric acid analogue that has been shown to be efficacious for neuropathic pain control in humans. Plasma gabapentin concentrations >2 μg/ml are considered effective in treating epilepsy in humans and are suggested to provide analgesia for neuropathic pain. This study investigated the pharmacokinetics of a single oral dose of gabapentin suspension (11 mg/kg) in great horned owls ( Bubo virginianus ). Plasma gabapentin concentrations were determined in six healthy birds for 48 hr using high-performance liquid chromatography with mass spectrometric detection. Plasma gabapentin concentrations were estimated by noncompartmental pharmacokinetic analysis. The harmonic mean (±SD) maximum concentration (Cmax), time to maximum concentration (Tmax), and elimination half-life (tv2λZ) for gabapentin (11 mg/kg) were 6.17±0.83 μg/ml, 51.43±5.66 min, and 264.60±69.35 min, respectively. In this study, plasma gabapentin concentrations were maintained above 2 μg/ml for 528 min (8.8 hr), suggesting that gabapentin administered orally every 8 hr may be appropriate in great horned owls. PMID:26352959

  6. Pharmacokinetic profiles of meloxicam in turtles (Trachemys scripta scripta) after single oral, intracoelomic and intramuscular administrations.

    PubMed

    Di Salvo, A; Giorgi, M; Catanzaro, A; Deli, G; della Rocca, G

    2016-02-01

    Meloxicam is an anti-inflammatory and analgesic drug used to treat many pathological conditions in turtles. With the aim to fill the lack of data about its pharmacokinetic in this species, eighteen turtles (Trachemys scripta scripta) were divided in three groups and treated with a single dose of meloxicam (0.2 mg/kg) by intramuscular, intracoelomic and oral route, respectively. At scheduled time points, blood samples were collected and meloxicam concentrations were determined by HPLC. Pharmacokinetic parameters were calculated from the obtained concentration-time curves. After intramuscular treatment, a plasma peak of meloxicam equal to 1590.03 ± 1845.32 ng/mL (mean ± SD) and a Tmax of 1.17 ± 0.45 h were reached, indicating a quick absorption of the drug. The intracoelomic administration brought to the largest AUC (12621.04 ± 6203.79 h*ng/mL) and to a Cmax and a Tmax equal to 1154.52 ± 662.78 ng/mL and 2.82 ± 1.39 h, respectively. Following oral treatment, the plasma concentrations of meloxicam were very low indicating a scarce absorption. Further studies are warranted to determine the effective plasma concentration of meloxicam in turtles and, consequently, the dosage regimen. PMID:26789011

  7. CHANGES IN IN VITRO BRAIN AND SPINAL CORD PROTEIN PHOSPHORYLATION AFTER A SINGLE ORAL ADMINISTRATION OF TRI-O-CRESYL PHOSPHATE TO HENS

    EPA Science Inventory

    The effect of a single oral 750 mg/kg dose of tri-o-cresyl phosphate (TOCP) on the endogenous phosphorylation of brain and spinal cord proteins was assessed in hens during the development of and recovery from delayed neurotoxicity. Crude membrane and cytosolic fractions were prep...

  8. High-Dose Oral Ibuprofen in Treatment of Patent Ductus Arteriosus in Full-Term Neonates

    PubMed Central

    Pourarian, Shahnaz; Rezaie, Mehrdad; Amoozgar, Hamid; Shakiba, Ali-Mohammad; Edraki, Mohammad-Reza; Mehdizadegan, Nima

    2015-01-01

    Background: Patent ductus arteriosus (PDA) is an important risk for heart failure due to left to right shunt in term neonates. Objectives: In this study, we evaluated the effect of high dose ibuprofen in closure of PDA in term neonates. Patients and Methods: We used double dose ibuprofen (20 mg/kg, 10 mg/kg, and 10 mg/kg) for 3 - 30 day old term neonates with PDA who were admitted in the neonatal wards of Shiraz University of Medical Sciences. The results of this study were compared to the data of the previous study in our center which used the low dose of ibuprofen (10 mg/kg, 5 mg/kg, and 5 mg/kg). Results: 29 full term neonates received high-dose ibuprofen, in 18 neonates, PDA was closed after 4 days (62.1% versus 43.3% for the standard dose and 4.7% for the control group in the previous study) (P = 0.001). The results showed no significant correlation between the closure rate and gestational age, postnatal age, sex, and weight. In the 4th day of treatment, size of the pulmonic end of ductus arteriosus decreased from 2.09 mm to 0.77 mm compared to 1.68 mm to 0.81 mm in the standard dose of oral ibuprofen and 2.1 mm to 1.4 mm in the control group (P = 0.046). Conclusions: This study indicated that high-dose oral ibuprofen was more effective in closing or decreasing the size of PDA. PMID:26396694

  9. A pharmacokinetic study of patchouli alcohol after a single oral administration of patchouli alcohol or patchouli oil in rats.

    PubMed

    Zhang, Ruoqi; Yan, Peiao; Li, Yunxia; Xiong, Liang; Gong, Xiaohong; Peng, Cheng

    2016-08-01

    Pogostemonis herba is used in traditional Chinese medicine to remove dampness, relieve sunstroke, stop vomiting and increase appetite. Patchouli alcohol, an ingredient in pogostemonis herba, has the potential to treat inflammation as well as bacterial and fungal infections. The essential oil of pogostemonis herba (patchouli oil) is commonly given orally in clinical settings; however, no pharmacokinetic studies have examined its oral administration. The goal of this study was to investigate the pharmacokinetic behavior of patchouli alcohol following single-dose oral administration in rats; the influence of other patchouli oil components on the pharmacokinetic profile of patchouli alcohol was also examined. In this study, a simple and selective GC/MS method was developed and validated to measure the level of patchouli alcohol in rat plasma. The study revealed that the pharmacokinetics profile was linear in both the patchouli alcohol and patchouli oil groups. The C max and AUC0-t of patchouli alcohol were greater in all three doses of patchouli alcohol compared to corresponding patchouli oil doses. Additionally, the T max values were significantly greater in the patchouli oil group. These results suggest that the other ingredients in patchouli oil influence the pharmacokinetic behavior of patchouli alcohol during its absorption. The results provide a meaningful basis for evaluating the clinical application of patchouli oil and patchouli alcohol. PMID:25753831

  10. Pharmacokinetics of acteoside following single dose intragastric and intravenous administrations in dogs.

    PubMed

    Zhang, Wei; Huo, Shi-Xia; Wen, Yan-Li; Xing, Han; Zhang, Qing; Li, Ning; Zhao, Di; Sun, Xiao-Lin; Xu, Jie; Yan, Ming; Chen, Xi-Jing

    2015-08-01

    Acteoside (verbascoside), a phenylethanoid glycoside widely distributed in various plants, has been shown to have potential activity against Alzheimer's disease, attracting great attentions recently. The present study was designed to develop a selective and sensitive LC-MS/MS method for the determination of acteoside in biological samples and carry our a pharmacokinetic (PK) study in beagle dogs. The PK parameters were calculated using non-compartmental models. Following a single-dose oral administration, acteoside was rapidly absorbed and eliminated, with Tmax being between 30 to 45 min and terminal half-life being about 90 min. The areas under the time-concentration curve (AUC) were 47.28 ± 8.74, 87.86 ± 13.33, and 183.14 ± 28.69 mg · min · L(-1) for oral administration of 10, 20, and 40 mg · kg(-1), respectively, demonstrating that the exposure of acteoside proportionally increased with the dose level. The absolute bioavailability of acteoside was around 4%. For all the PK parameters, there were large variations between individual dogs. In conclusion, the pharmacokinetic characteristics observed in the present study can be of great value to help better understand the pharmacological properties of acteoside and to improve the outcome of its clinical use. PMID:26253497

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

    PubMed Central

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

    1999-01-01

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

  12. Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein

    PubMed Central

    Boettcher, Michael-Friedrich; Heinig, Roland; Schmeck, Carsten; Kohlsdorfer, Christian; Ludwig, Matthias; Schaefer, Anja; Gelfert-Peukert, Sabine; Wensing, Georg; Weber, Olaf

    2012-01-01

    AIMS To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60–5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). METHODS The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20–45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60–5521 (n = 28) or were treated with a placebo (n = 10). RESULTS In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60–5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h. CONCLUSIONS BAY 60–5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated. PMID:21838789

  13. 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

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

    SciTech Connect

    de Haan, R.A.; van Aken, J. )

    1990-08-01

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

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

    PubMed

    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

  16. Single- and repeated-dose toxicities of aloe fermentation products in rats

    PubMed Central

    Kim, Hyun-Kyoung; Baik, Soon-Ok; Choi, Soo-Young; Lee, Jae-Young

    2011-01-01

    In this study, aloe fermentation products were derived from mycelia from 3 mushrooms: Ganoderma lucidum (AG), Hericium erinaceum (AH), and Phellinus linteus (AP). Levels of aloin A and B increased with fermentation time. The highest levels were measured on the fifth day of fermentation. β-Glucan levels decreased with fermentation time. The safety of aloe fermentation products were examined in male and female Sprague-Dawley rats. Rats were orally administered the three aloe fermentation products at dose levels of 1, 2 or 5 g/kg for single-dose toxicity test and 0.5, 1, or 2 g/kg for repeated-dose toxicity test. There were no significant differences in body weight gain between vehicle control and AG-, AH- or AP-treated rats. Also, significant changes in daily feed intake and water consumption were not observed. In hematological analysis, none of the parameters were affected by aloe fermentation products with mushroom mycelia. This suggests that there are no negative effects on homeostasis and immunity. In blood biochemistry analysis, none of the markers were affected by feeding rats with AG, AH or AP. Similarly, there were no significant effects on markers for liver, kidney, skeletal and heart muscle functions. No remarkable lesions were observed in these organs at histopathology. Since there were no adverse effects of AG, AH and AP in single- or repeated-dose toxicity tests, even at higher doses than normal, we conclude that the aloe fermentation products with mushroom mycelia possess long-term safety and could be candidates as multifunctional nutrients for the improvement of intestinal function and immunity. PMID:21998613

  17. Effect of single and repeat doses of casopitant on the pharmacokinetics of CYP450 3A4 substrates midazolam and nifedipine

    PubMed Central

    Zamuner, Stefano; Johnson, Brendan M; Pagliarusco, Sabrina; Fina, Paolo; Peroni, Michela; Fiore, Monica; Adams, Laurel M; Fernandes, Sofia A

    2010-01-01

    AIM To evaluate the impact of single and repeated doses casopitant on the pharmacokinetics of single dose midazolam and nifedipine (CYP3A substrates) in healthy subjects. The effect on debrisoquine metabolism (CYP2D6 substrate) was also assessed. METHODS Three open-label studies were conducted in healthy subjects. In the first study subjects received single dose 50 or 100 mg oral casopitant, single dose 5 mg oral midazolam and single dose 10 mg oral debrisoquine. In the other two studies subjects received repeated doses of 10 mg (study 2), 30, or 120 mg oral casopitant and single doses of 5 mg oral midazolam (study 2) and single doses of 10 mg oral nifedipine (study 3). Plasma concentration–time data were analyzed using standard non-compartmental methods. The effect of casopitant on all probes was assessed using geometric means ratios and corresponding 90% confidence intervals (CIs). RESULTS The AUC(0,∞) of midazolam was increased 1.44-fold (90% CI 1.35, 1.54) and 1.52-fold (90% CI 1.41, 1.65) after co-administration with a single dose of 50 or 100 mg casopitant, respectively. Debrisoquine metabolism was unchanged. After 3 days of casopitant administration, midazolam AUC(0,∞) was increased 1.45- (90% CI 1.32, 1.59), 2.02- (90% CI 1.75, 2.32), and 2.67-fold (90% CI 2.18, 3.27) after co-administration with 10, 30 or 120 mg casopitant, respectively. After 14 days of casopitant administration, midazolam AUC(0,∞) was increased 1.51- (90% CI 1.40, 1.63) to 3.49-fold (90% CI 2.98, 4.08). After 3 days of casopitant administration, nifedipine AUC(0,∞) was increased 1.56- (90% CI 1.37, 1.78) and 1.77-fold (90% CI 1.54, 2.04) after co-administration with 30 or 120 mg casopitant, respectively. Similar increases in nifedipine exposure were observed after 14 days of casopitant administration. CONCLUSIONS Casopitant is a dose- and duration-dependent weak to moderate inhibitor of CYP3A. PMID:20840445

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

    PubMed

    Haney, J

    2015-02-01

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

  19. [Current perspectives on the repackaging and stability of solid oral doses].

    PubMed

    Lagrange, F

    2010-11-01

    Which are the guidelines and scientific aspects for repackaged oral solid medications in France in 2010 whereas it develops? The transient or definitive displacement of the solid oral form from the original atmosphere to enter a repackaging process, sometimes automated, is likely to play a primary role in the controversy. However, the solid oral dose is to be repackaged in materials with defined quality. Considering these data, a review of the literature for determination of conditions for repackaged drug stability according to different international guidelines is presented in this paper. Attention is also paid to the defined conditions ensuring the conservation and handling of theses drugs throughout the repackaging process. However, there is lack of scientific published stability data. Nevertheless, recent alternatives may be proposed to overcome the complexity of studying stability in such conditions. Then, the comparison of the moisture barrier properties of the respective package, a galenic model of hygroscopic molecules, or light sensitive molecules or stability data obtained during the industrial preformulation phase could also secure the list of drugs to be reconditioned. Similarly, a wise precaution will be to get stability data for the industrial blisters and unit doses undergoing the real conditions of the medication use process in hospitals and other healthcare settings. By now, reduction of dispensing errors and improvement of the compliance aid put a different perspective on the problem of repackaged drugs. To date, the pharmacist is advised to carry out its analysis of the risks. PMID:21073993

  20. Cardiac Safety of Diclofenac at a Single Dose in Ram

    PubMed Central

    Er, Ayse; Dik, Burak

    2013-01-01

    Nonsteroidal anti-inflammatory drugs are frequently prescribed drug group in human and veterinary medicine. However, diclofenac, a traditional nonsteroidal anti-inflammatory drug, related to cardiotoxicity is reported, and blood cardiac damage markers may increase within the first hours after damage. The aim of the current research was to determine the effect of diclofenac on the blood cardiac damage markers. Single dose of diclofenac (2.5 mg/kg, IM) was injected to 6 rams. Blood samples were collected in before (0 hour, control) and 6 hours after injection. Specific (troponin I, and creatine kinase-MB) and nonspecific (lactate dehydrogenase, aspartate aminotransferase) blood cardiac damage marker concentrations, routine biochemical (hepatic damage, renal damage, lipid metabolism, glucose, and phosphorus) parameters, and hemogram values were measured. Diclofenac increased (P < 0.05) specific (troponin I) and nonspecific cardiac (lactate dehydrogenase, aspartate aminotransferase), hepatic (aspartate aminotransferase, alkaline phosphatase, and alanine aminotransferase), and muscular (creatine kinase) damage markers and high density lipoprotein level, while it decreased (P < 0.05) low density lipoprotein level. Moreover, diclofenac decreased (P < 0.05) white blood cell counts and increased (P < 0.05) red blood cell counts. In conclusion, it may be stated that diclofenac shows slight cardiotoxicity, whereas it may show potent hepatic and muscular damage effects at an intramuscularly single dose in sheep. Thereby, repeated injections of diclofenac may be more harmful in sheep. PMID:24228015

  1. 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

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

    PubMed

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

    2005-04-01

    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 (1 mg kg(-1) per day) resulted in significant inhibition of disease progression. This effective dose is lower than the dose usually associated with psychotropic effects of THC. Furthermore, we detected the CB2 receptor (the main cannabinoid receptor expressed on immune cells) in both human and mouse atherosclerotic plaques. Lymphoid cells isolated from THC-treated mice showed diminished proliferation capacity and decreased interferon-gamma secretion. Macrophage chemotaxis, which is a crucial step for the development of atherosclerosis, was also inhibited in vitro by THC. All these effects were completely blocked by a specific CB2 receptor antagonist. Our data demonstrate that oral treatment with a low dose of THC inhibits atherosclerosis progression in the apolipoprotein E knockout mouse model, through pleiotropic immunomodulatory effects on lymphoid and myeloid cells. Thus, THC or cannabinoids with activity at the CB2 receptor may be valuable targets for treating atherosclerosis. PMID:15815632

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

    PubMed Central

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

    2012-01-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. 4,496 MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance and volume of the central compartment were 24.2 L/hr and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA clearance by 33.8%. The optimal LSS was immediately before and at 0.25, 1.25, 2, and 4hr after oral MMF administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. PMID:23382105

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

    PubMed

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

    2013-04-01

    We sought to create a population pharmacokinetic model for total mycophenolic acid (MPA), to study the effects of different covariates on MPA pharmacokinetics, to create a limited sampling schedule (LSS) to characterize MPA exposure (i.e., area under the curve or AUC) with maximum a posteriori Bayesian estimation, and to simulate an optimized dosing scheme for allogeneic hematopoietic cell transplantation (HCT) recipients. Four thousand four hundred ninety-six MPA concentration-time points from 408 HCT recipients were analyzed retrospectively using a nonlinear mixed effects modeling approach. MPA pharmacokinetics was characterized with a two-compartment model with first-order elimination and a time-lagged first-order absorption process. Concomitant cyclosporine and serum albumin were significant covariates. The median MPA clearance (CL) and volume of the central compartment were 24.2 L/hour and 36.4 L, respectively, for a 70 kg patient receiving tacrolimus with a serum albumin of 3.4 g/dL. Dosing simulations indicated that higher oral MMF doses are needed with concomitant cyclosporine, which increases MPA CL by 33.8%. The optimal LSS was immediately before and at 0.25 hours, 1.25 hours, 2 hours, and 4 hours after oral mycophenolate mofetil administration. MPA AUC in an individual HCT recipient can be accurately estimated using a five-sample LSS and maximum a posteriori Bayesian estimation. PMID:23382105

  5. Prescription and consumption of solid oral drugs dispensed as unitary doses in a third level hospital

    PubMed Central

    Calderón-Guzmán, David; Juárez-Olguín, Hugo; Hernández-García, Ernestina; Medina-Andrade, Alejandro; Juarez Tapia, Belen

    2015-01-01

    Background: The knowledge about the pattern of prescription and consumption of solid oral drugs dispensed as unitary doses (UD) in Mexico is sparing. Purpose: The aim of this study was to describe the pattern of prescription and consumption of solid oral drugs dispensed as unitary doses (UD) in a third level private hospital of Mexico. A retrospective study of a 60-month period (from 2007 to 2011) was carried out to know the pattern of drugs dispensed as UD in a third level hospital. Results: Among the principal drugs consumed were analgesic, antihypertensive, antibiotic, anti-inflammatory, antiepileptic, and diuretics. The dispensation of drugs per year was as follows: 181 drugs with 85,167 UD in 2007; 199 with 90,519 UD in 2008; 193 with 101,479 UD in 2009; 195 with 100,798 UD in 2010; and 198 with 103,913 UD in 2011. Conclusion: The findings confirmed that prescription and consumption of unitary doses in the hospitalization service increased, and revealed the extensive use of analgesics as the principal prescribed drug in this kind of hospital. PMID:27013914

  6. Single- and multiple-dose tolerability and pharmacokinetics of the CRTH2 antagonist setipiprant in healthy male subjects.

    PubMed

    Sidharta, Patricia N; Diamant, Zuzana; Dingemanse, Jasper

    2014-12-01

    Chemoattractant receptor-homologous molecule expressed on T helper (Th) 2 cells (CRTH2) is a G-protein-coupled receptor for prostaglandin D2 (PGD2), a key mediator in inflammatory disorders such as asthma and allergic rhinitis. In this study, we investigated the single- and multiple-dose tolerability and pharmacokinetics (PKs) of setipiprant, an orally active, potent, and selective CRTH2 antagonist. This randomized, double-blind, placebo-controlled study was performed in two parts in healthy male subjects. In study Part A, single oral doses of up to 2000 mg setipiprant or placebo were given to sequential groups of eight subjects each. Additionally, the impact of food on the PKs was investigated in one-dose group. In study Part B, two groups of subjects received 500 or 1000 mg setipiprant or placebo b.i.d. during 5.5 days. At regular intervals, tolerability variables and plasma and urine levels of setipiprant were determined. Setipiprant was well tolerated after single- and multiple-dose administration. Headache was the most frequently reported adverse event. No treatment effect on tolerability variables was observed. After single- and multiple-dose administration, setipiprant was rapidly absorbed and followed a biphasic elimination pattern with an elimination half-life between 10 and 18 h. Steady-state conditions were reached after 2-3 days and setipiprant did not accumulate. Exposure to setipiprant was lower in the presence of food. Urinary excretion of unchanged setipiprant did not exceed 7% of the administered dose. In this entry-into-human study, setipiprant showed good tolerability and a favorable PK profile, thus warranting its development in the treatment of inflammatory disorders. PMID:24734908

  7. Activity of the human carcinogens benzidine and 2-naphthylamine in triple- and single-dose mouse bone marrow micronucleus assays: results for a combined test protocol.

    PubMed

    Mirkova, E

    1990-01-01

    The activities of the human bladder carcinogens benzidine and 2-naphthylamine in the mouse bone marrow micronucleus assays using a limited test protocol (oral dosing to male mice, sampling 24 h later) have recently been established. As a contribution to the International Collaborative Study on the evaluation of the sensitivity of the triple-dose micronucleus test protocol it was decided to re-evaluate benzidine and 2-naphthylamine using a combined triple- and single-dose test protocol. Benzidine gave a clear positive response in male mice 24 h after 3 daily doses of 150 and 300 mg/kg. A single dose of 900 mg/kg of benzidine gave a weaker response 24 h after dosing. In the case of 2-naphthylamine a stronger positive response was observed 24 h after a single dose of 600 mg/kg as compared to 3 daily doses of 200 or 400 mg/kg. There was no significant difference in the increased positive response observed for a single dose of 30 mg/kg of cyclophosphamide compared with 3 successive daily doses of 10 mg/kg. Based on the present data the combined triple/single-dose micronucleus test protocol is strongly supported. PMID:2366784

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

    PubMed

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

    2013-10-01

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

  9. Population pharmacokinetics of single-dose riociguat in patients with renal or hepatic impairment

    PubMed Central

    2016-01-01

    Abstract This population pharmacokinetics (PK) analysis characterized the PK of the oral soluble guanylate cyclase stimulator riociguat in patients with renal or hepatic impairment and determined whether smoking affects riociguat dosing. Two phase 1 studies were performed in patients with renal impairment (n = 72, of whom 11 were smokers), and two were performed in those with hepatic impairment (n = 64, of whom 12 were smokers). Plasma and urine samples were collected after a single oral dose of riociguat 1.0 or 0.5 mg. Nonlinear mixed-effects modeling was used to develop a combined, two-compartment population PK model for riociguat and its main metabolite, M1. Riociguat and M1 clearance was split into renal and nonrenal parts; the nonrenal part for riociguat was divided into metabolism to M1 and a metabolic (nonrenal) part. Total clearance of riociguat was 1.912 L/h. The main route of riociguat clearance is metabolism to M1 (1.2 L/h). In this model, hepatic function biomarkers or Child-Pugh classification had no significant effect on riociguat or M1 clearance. Nonrenal (nonmetabolism) riociguat clearance was similar in all groups. Renal clearance (0.242 L/h) contributed less to riociguat total clearance, mainly determined by glomerular filtration (0.174 L/h). Renal impairment reduced riociguat and M1 clearance. Hepatic or renal impairment had limited effects on total exposure to riociguat. However, individual dose adjustment of riociguat should be administered with particular care in patients with moderate hepatic or renal impairment. Riociguat is not recommended in severe hepatic or renal impairment. Smoking reduced riociguat exposure by significantly increasing metabolism to M1. PMID:27162631

  10. Single-Dose Pharmacokinetics of the CCR9 Receptor Antagonist Vercirnon in Healthy US and Japanese Subjects.

    PubMed

    Haberer, Lynda J; Hacquoil, Kimberley; Ino, Hiroko; Sakamoto, Takashi; Kanemoto, Noriaki; McSherry, Iain; Hirama, Toshiyasu

    2013-10-01

    Two randomized, single-dose, crossover studies were carried out to assess different formulations and doses of the CCR9 receptor antagonist vercirnon in healthy subjects. US study (n = 24): a five-period crossover study in healthy US subjects to assess the bioavailability of four new GlaxoSmithKline formulations compared with a "reference" formulation. Each subject received a single 500 mg dose of each of the five vercirnon formulations in a fed state. Primary pharmacokinetic (PK) endpoints were maximum plasma concentration, (Cmax ), and exposure as assessed by area under the curve (AUC). There was no significant difference in PK parameters and bioavailability between the formulations tested. Japanese study (n = 30): a four-period crossover study in healthy Japanese male subjects to assess PK and dose proportionality following single, ascending, oral doses of 250, 500, and 1,000 mg vercirnon under fasted and fed conditions. Vercirnon Cmax and AUC parameters in the fasted state increased in a less than dose proportional manner and were on average 20% higher in fed subjects compared with fasted subjects. Overall, these results support the premise that vercirnon has similar PK/safety profiles within US and Japanese populations. There was no evidence to preclude the use of the new vercirnon formulation in future studies. PMID:27121943