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Natural (RRR-) α-tocopherol (αT) is more bioactive than synthetic (all racemic, all rac-) αT, but not enough is known about the tissue kinetics of the 2 αT sources. We examined the time-course bioaccumulation of natural versus synthetic αT in tissues of young, marginally vitamin E-deficient mice using 13C-RRR-αT or 13C-all rac-αT tracers. In experiment 1, 3-week old male wild-type mice were fed a vitamin E-deficient diet for 0, 1, 2, or 3 weeks (n = 5/time point). Tissue αT levels were analyzed by HPLC-PDA. Feeding a vitamin E-deficient diet for up to 3 weeks decreased total αT concentrations in all analyzed tissues except the brain, which maintained its αT level. In experiment 2, a 2-week αT-depletion period was followed by administration of a single oral dose of 0.5 mg of 13C-RRR-αT or 13C-all rac-αT. At 12 hr, 1, 2, and 4 days post-dose, serum and multiple tissues were collected (n = 3/time point). αT was quantified by HPLC-PDA, and 13C-αT enrichment was determined by LC-MS. Both sources of 13C-αT reached maximum serum levels at 12 hr post-dose. 13C-RRR-αT levels were significantly higher than 13C-all rac-αT in serum at 1 d post-dose, and in heart, lungs, and kidney at 2d post-dose. In brain, 13C-RRR-αT concentrations were significantly higher than 13C-all rac-αT at 2 and 4 d post-dose. At 4 d post-dose, 13C-αT levels were similar between the 2 sources in examined tissues except for brain and adipose tissue where 13C-RRR-αT was higher. In conclusion, αT bioaccumulation over time varied substantially depending on αT source and tissue type.

The efficacy of two locally produced oxfendazole (OFZ) formulations against cysticercosis at 22,5% and 10%, versus a commercial formulation (Synanthic 9,06%) was evaluated in twenty-two naturally infected pigs that received a single oral dose of 30 mg/kg. Pigs were sacrificed at eight weeks post-treatment to evaluate the cysts found in their carcasses, and to determine the cysticidal efficacy, which was defined as the proportion of degenerated cysts over total cysts. Only degenerated cysts were found in muscle, heart, and tongue of pigs treated with OFZ in all groups, which shows an efficacy of 100%. Viable and degenerated cysts were found in brains, being the efficacy lower in all groups (65% [commercial OFZ], 47% [local OFZ 22.5%] and 31% [local OFZ 10%], p = 0.355). Locally produced OFZ formulations were similarly effective to the commercial formulation and may provide a practical alternative for the treatment of porcine cysticercosis. Se evaluó la eficacia de dos formulaciones de oxfendazol (OFZ) contra cisticercosis producidas localmente, al 22,5% y 10% en comparación con una formulación comercial (Synanthic 9,06%) en 22 cerdos naturalmente infectados, que recibieron una dosis oral de 30 mg/kg. Los cerdos fueron sacrificados a las ocho semanas postratamiento para evaluar quistes en en sus carcasas, y se determinó la eficacia cisticida a través de la proporción de quistes degenerados sobre el total. Solo se encontraron quistes degenerados en la musculatura, corazón y lengua de los cerdos tratados con OFZ en todos los grupos, lo cual muestra una eficacia del 100%. En los cerebros se encontraron quistes viables y degenerados, con una eficacia menor en todos los grupos (65% [OFZ comercial], 47% [OFZ local 22,5%] y 31% [OFZ local 10%], p = 0,355. Las formulaciones de OFZ producidas localmente fueron igual de efectivas que la formulación comercial y pueden proporcionar una alternativa para el tratamiento de la cisticercosis porcina

Qian Zhang,1,2 Zhiqiang Wang,1– 3 Jingying Wu,1,2 Zhen Zhou,3 Renpeng Zhou,1,2 Wei Hu1,2 1Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Anhui Provincial Institute of Translational Medicine, Hefei, People’s Republic of China; 3Menzies Institute for Medical Research, University of Tasmania, Hobart, Tasmania, AustraliaCorrespondence: Renpeng Zhou; Wei Hu Email zhourenpeng@ahmu.edu.cn; huwei@ahmu.edu.cnBackground: Regorafenib is an oral multi-kinase inhibitor approved for the treatment of solid tumours, but the pharmacokinetic profile of regorafenib in the Chinese population is unclear.Objective: The aim of this study was to examine the pharmacokinetics, bioequivalence, and safety of two formulations of regorafenib 40 mg in healthy Chinese volunteers under fed and fasting conditions.Methods: A single-centre, randomised, open-label, two-period, two-way crossover phase 1 trial was conducted by randomising a single oral dose of test (T) or reference (R, Stivarga®) regorafenib (40 mg) to healthy Chinese volunteers under both fasting and fed conditions (high-fat and high-calorie diet). Pharmacokinetic parameters were calculated using non-compartmental methods. Adverse events were recorded to assess drug safety.Results: Sixty-six participants were enrolled for both fasting and fed treatments. The 90% CIs geometric least-square means of ratioT/R for regorafenib were completely contained within the equivalence margin of 80– 125% under both fasting and fed conditions. Both formulations displayed similar and generally good safety profiles.Conclusion: Single oral dose of the T (40 mg) and R (40 mg) regorafenib was bioequivalent under fasting and fed conditions and had similar favourable safety profiles among healthy Chinese volunteers.Keywords: regorafenib, phase 1, pharmacokinetic, bioequivalence, Chinese healthy volunteers

We previously found that a single dose of B-type procyanidin mixture increase in skeletal muscle blood flow (BF). We compared BF changes following administration of (-)-epicatechin (EC, monomer) and the B-type procyanidins procyanidin B2 (B2, dimer), procyanidin C1 (C1, trimer), and cinnamtannin A2 (A2, tetramer). Each chemical was administered orally to rats, followed by BF measurement in cremaster arteriole for 60 min. About 10 and 100 µg/kg of B2 and C1 elicited BF increase, the effect was potent at 100 µg/kg. BF also increased significantly after administration of 10 µg/kg A2, but not with the administration at 100 µg/kg. EC yielded no BF changes. Co-treatment with the nonselective adrenaline blocker carvedilol attenuated the BF increase seen with 10 µg/kg A2 treatment. This outcome suggested the involvement of sympathetic nerve activation in the BF increase by this dose of A2. Co-treatment of 100 µg/kg A2 with the α2 blocker yohimbine exhibited an increase of BF significantly. The α2 adrenaline receptor in the vasomotor centre is an inhibitory receptor and it regulates hemodynamics. This result suggested that high doses of A2 did not alter BF because of activating the α2 adrenergic receptor. Phosphorylation of aortic endothelial nitric oxide synthase (eNOS) increased with 10 µg/kg A2 alone or co-treatment with 100 µg/kg A2 and yohimbine, but not with co-treatment of 10 µg/kg A2 and carvedilol or 100 µg/kg A2 alone. These results imply that A2 does not directly activate eNOS, but that shear stress from the increased BF might be associated with eNOS phosphorylation.

Beraprost sodium (BPS), an orally administrable prostaglandin I2 derivative, is used for the treatment of chronic arterial occlusion and pulmonary arterial hypertension and has potential efficacy in nephropathy. Beraprost sustained release (beraprost SR) is an oral sustained-release formulation of BPS. To confirm the dose rationale reported in a multi-regional study of nephropathy patients in Asia, this open-label study evaluated ethnic differences in the pharmacokinetic profiles of BPS and its active diastereomer (BPS-314d) after beraprost SR administration among healthy Japanese, Chinese, and Korean adult males. Twelve healthy subjects in each ethnic group were enrolled. Subjects received a single oral dose of 120 μg beraprost SR under fasting conditions. The geometric mean ratio (90% confidence interval) of the maximum plasma concentration (Cmax) and area under the plasma concentration–time curve from time 0 to time of the last quantifiable concentration (AUClast) of BPS was 1.12 (0.85–1.48) and 1.40 (1.05–1.86) in Chinese, and 1.18 (0.90–1.55) and 1.18 (0.89–1.58) in Korean compared to Japanese subjects. These differences were not clinically relevant. Similarly, differences in the Cmax and AUClast of BPS-314d were also small among the ethnic groups. Urinary excretion of BPS and BPS-314d was limited in all ethnic groups. Together, these findings indicate that the pharmacokinetics of beraprost SR are not affected by ethnic background. There were no clinically meaningful ethnic differences in the pharmacokinetics of BPS and BPS-314d following beraprost SR administration among Japanese, Chinese and Korean populations.

Obese individuals are prone to vitamin D deficiency because of sequestration of vitamin D in their body fat. We planned to evaluate the rise in serum 25(OH)D levels in vitamin D–deficient obese vs normal body mass index(BMI) children, after administration of identical single dose of vitamin D. Twenty-two obese and 22 normal BMI children with serum 25 (OH)D

Amenamevir (ASP2151), a herpesvirus helicase-primase inhibitor, is currently used for the treatment of herpes zoster in Japan. Amenamevir is mainly metabolized in the liver, and urinary excretion of amenamevir is approximately 10% in healthy adults. The increase of systemic exposure in non-dialysis patients with severe renal impairment was much less than that associated with nucleoside antiviral agents. The aim of this study was to evaluate the pharmacokinetics and dialyzability of a single oral dose (400 mg) of amenamevir in hemodialysis patients.This was a single-arm, open-label, multicenter clinical pharmacology study. Nine patients aged 20-80 years with end-stage kidney disease and undergoing maintenance hemodialysis three times weekly were enrolled. Pharmacokinetics and dialyzability were investigated by serial collection of blood samples until 48 h post-dose during the study.The maximum plasma concentration and time to reach maximum plasma concentration during 24 h post-dose were 1585 ng/mL and 6.2 h, respectively. The area under the plasma concentration-time curve (AUC) from time zero to 24 h was 23,890 ng h/mL. The median terminal elimination half-life within 24 h before, during, and after hemodialysis was 14.7, 15.2, and 12.4 h, respectively. The AUC in hemodialysis patients was approximately double that in healthy adults. This increase in AUC was much less than that reported in nucleoside antiviral agents. The hemodialysis clearance, elimination fraction percentage, and amount of amenamevir removed were 37.8 mL/min, 28.1%, and 132.0 μg, respectively. The amount of amenamevir removed by hemodialysis was minimal. None of the hemodialysis parameters were associated with serum albumin. This study revealed no clinically relevant safety concerns.There were no clinically relevant safety concerns when 400 mg of amenamevir was administered as a single dose to hemodialysis patients without dose adjustment and/or modification of the dosing schedule.JapicCTI-184242.

Fedratinib is an oral, selective Janus kinase 2 inhibitor that is approved in the United States for the treatment of patients with intermediate-2 or high-risk myelofibrosis. Pharmacokinetics and tolerability of fedratinib in subjects with renal impairment (RI) and hepatic impairment (HI) were evaluated in two separate studies. In the renal study, male and female subjects with stable, chronic mild, moderate, and severe RI, as well as those with end-stage renal disease, were included. The hepatic study included subjects with stable, chronic mild HI. Both were phase 1, multicenter, open-label, single-dose studies, and included matched healthy subjects. Subjects received a single oral dose of fedratinib 300 mg on day 1, were discharged on day 4, returned for clinical visits on days 5–12, and had their end-of-study visit between days 14 and 16. Thirty-six and 17 subjects were included in the renal and hepatic studies, respectively. In the renal study, fedratinib area under the plasma concentration–time curve from time 0 to infinity (AUCinf) was 1.9- and 1.5-fold higher in subjects with severe and moderate RI, respectively, than in matched healthy subjects. In the hepatic study, fedratinib AUCinf did not appreciably differ between subjects with mild HI and matched healthy subjects. Overall, most treatment–emergent adverse events were gastrointestinal and mild. Mild RI and HI do not necessitate fedratinib dosage adjustments. Subjects with moderate RI should be monitored (with dosage adjustments made as necessary), whereas those with severe RI should receive a daily dose of 200 mg, reduced from the indicated dose of 400 mg.

Objectives: The objective of this study was to investigate the effect of pimobendan on echocardiographic parameters of right ventricular and atrial function in healthy cats. Animals: Eleven privately owned, healthy adult cats. Material and methods: Each cat underwent five echocardiographic examinations: the first and second examinations were performed 1 h apart on day 0. On day 1, the third examination served as baseline, whereas the fourth and fifth examinations were performed one and 6 h after administration of a single oral dose of pimobendan (1.25 mg/cat), respectively. Parameters of right ventricular and atrial morphology and function were collected and compared among time points. Results: Pimobendan administration produced a change in some echocardiographic variables. Specifically, heart rate, right ventricular fractional shortening and peak velocity of systolic lateral tricuspid annular motion increased (P = 0.032, P = 0.002 and P < 0.001, respectively), whereas right ventricular end-systolic internal diameter and right atrial maximum and minimum internal diameters decreased (P = 0.004, P = 0.025 and P = 0.01, respectively). Right ventricular fractional area change and tricuspid annular plane systolic excursion did not change. Conclusions: This novel study showed that pimobendan had positive effects on right ventricular and right atrial function in healthy cats. Further studies are needed to determine whether pimobendan has similar effects in cats with cardiac diseases.

Background and Objective This study measured and compared the exposure and safety of peficitinib (ASP015K), a novel oral Janus kinase inhibitor, in subjects with normal and impaired renal function after a single oral, clinically relevant peficitinib dose. Methods This was an open-label, parallel-group study conducted at two centres in Japan. Subjects with normal and mildly, moderately, or severely impaired renal function received a single oral dose of peficitinib (one 150 mg tablet) under fasting conditions in a hospital setting. Blood samples were collected prior to administration and up to 72 h post-dose for pharmacokinetic assessment. Safety was assessed up to 7 days post-dose. Results Peficitinib plasma concentration–time profiles were similar between those with normal and impaired renal function. In subjects with impaired renal function, area under the plasma concentration–time curve and maximum concentration were 0.8- to 1.1-fold those in subjects with no impairment. Two subjects (one in the normal group and one in the mildly impaired group) each experienced a treatment-emergent adverse event (TEAE). There were no serious TEAEs, deaths or TEAEs leading to treatment withdrawal. Conclusions Peficitinib exposure and TEAEs were similar in subjects with and without renal impairment after a single oral 150 mg dose. Based on these findings, it is not expected that peficitinib dose adjustment will be required in clinical practice, according to the degree of renal impairment. ClinicalTrials.gov identifier NCT02603497.

Background Azithromycin is a broad-spectrum antibiotic that has moderate antimalarial activity and has been shown to reduce all-cause mortality when biannually administered to children under five in high mortality settings in sub-Saharan Africa. One potential mechanism for this observed reduction in mortality is via a reduction in malaria transmission. Methods We evaluated whether a single oral dose of azithromycin reduces malaria positivity by rapid diagnostic test (RDT). We conducted an individually randomized placebo-controlled trial in Burkina Faso during the high malaria transmission season in August 2020. Children aged 8 days to 59 months old were randomized to a single oral dose of azithromycin (20 mg/kg) or matching placebo. At baseline and 14 days following treatment, we administered a rapid diagnostic test (RDT) to detect Plasmodium falciparum and measured tympanic temperature for all children. Caregiver-reported adverse events and clinic visits were recorded at the day 14 visit. Results We enrolled 449 children with 221 randomized to azithromycin and 228 to placebo. The median age was 32 months and 48% were female. A total of 8% of children had a positive RDT for malaria at baseline and 11% had a fever (tympanic temperature ≥ 37.5 °C). In the azithromycin arm, 8% of children had a positive RDT for malaria at 14 days compared to 7% in the placebo arm (P = 0.65). Fifteen percent of children in the azithromycin arm had a fever ≥ 37.5 °C compared to 21% in the placebo arm (P = 0.12). Caregivers of children in the azithromycin group had lower odds of reporting fever as an adverse event compared to children in the placebo group (OR 0.41, 95% CI 0.18–0.96, P = 0.04). Caregiver-reported clinic visits were uncommon, and there were no observed differences between arms (P = 0.32). Conclusions We did not find evidence that a single oral dose of azithromycin reduced malaria positivity during the high transmission season. Caregiver-reported fever occurred less often in children receiving azithromycin compared to placebo, indicating that azithromycin may have some effect on non-malarial infections. Trial registration Clinicaltrials.gov NCT04315272, registered 19/03/2020

Background In lower resource settings, previous randomized controlled trials have demonstrated evidence of increased weight gain following antibiotic administration in children with acute illness. We conducted an individually randomized trial to assess whether single dose azithromycin treatment causes weight gain in a general population sample of children in Burkina Faso. Methods Children aged 8 days to 59 months were enrolled in November 2019 and followed through June 2020 in Nouna Town, Burkina Faso. Participants were randomly assigned to a single oral dose of azithromycin (20 mg/kg) or matching placebo. Anthropometric measurements were collected at baseline and 14 days and 6 months after enrollment. The primary anthropometric outcome was weight gain velocity in g/kg/day from baseline to 14 days and 6 months in separate linear regression models. Results Of 450 enrolled children, 230 were randomly assigned to azithromycin and 220 to placebo. Median age was 26 months (IQR 16 to 38 months) and 51% were female. At 14 days, children in the azithromycin arm gained a mean difference of 0.9 g/kg/day (95% CI 0.2 to 1.6 g/kg/day, P = 0.01) more than children in the placebo arm. There was no difference in weight gain velocity in children receiving azithromycin compared to placebo at 6 months (mean difference 0.04 g/kg/day, 95% CI − 0.05 to 0.13 g/kg/day, P = 0.46). There were no significant differences in other anthropometric outcomes. Conclusions Transient increases in weight gain were observed after oral azithromycin treatment, which may provide short-term benefits. Clinical trials registration ClinicalTrials.gov NCT03676751. Registered 19/09/2018.

Background: As WHO expresses, COVID-19 is the infectious disease caused by the most recently discovered coronavirus. This new virus and disease were unknown before the outbreak began in Wuhan, China, in December 2019. COVID-19 is now a pandemic affecting many countries globally. Antiviral agents play fundamental role in Covid-19 treatment. Favipiravir is one of the favored agents and it still draws attention of generic drug industry which is constitutional for drug accessibility. Objective: The aim of this study is to demonstrate the bioequivalence of a new Favipiravir tablet formulation as compared to the reference tablet formulation in healthy male subjects under fasting conditions.To prove the bioequivalence, a randomised, single oral dose, cross-over, two-period study was carried out in 30 healthy subjects under fasting conditions. Plasma Favipiravir levels were quantified by using an in-house-developed high performance Liquid Chromatography Coupled to Tandem Mass Spectrometry (LC-MS/MS) method. Results: The 90% CIs for the test/reference geometric mean ratios of the Cmax and AUC0-tlast were 92.92 – 119.89% and 94.00 – 99.77%, respectively. Conclusions: This single-dose study has shown that the test and reference Favipiravir products met the required bioequivalence criteria. Besides, both products were well tolerated and safe. *The data that support the findings of this study are available from the corresponding author upon reasonable request. Some data may not be made available because of privacy or ethical restrictions.

The plasma pool of the hormone 1,25-dihydroxyvitamin D (1,25(OH)2D) is increased throughout most of human pregnancy. Mechanisms behind this adaptation are unclear, in part due to limited data on vitamin D kinetics during pregnancy. Stable isotopes make it possible to study vitamin D kinetics in vulnerable study populations like pregnant women. We conducted a pilot study of vitamin D kinetics in nonpregnant and pregnant women. We evaluated a clinical protocol and developed analytical methods to assess the serum appearance and disappearance of trideuterated vitamin D3 (d3-vitamin D3) and trideuterated 25-hydroxyvitamin D3 (d3-25(OH)D3) after a single oral dose of 25 µg of [6,19,19-2H]-vitamin D3 (d3-vitamin D3). Blood was collected at baseline and 2, 4, 6, 24, 168, 264, and 456 hours post-dosing. We then described the serum kinetic profiles of d3-vitamin D3 and d3-25(OH)D3 in nonpregnant and pregnant women. Serum kinetic profiles of d3-vitamin D3 and d3-25(OH)D3 followed a time course in line with previous pharmacokinetic studies. There was marked variability between participants in the AUC of d3-25(OH)D3 over the 20-day study period. This AUC of d3-25(OH)D3 was positively correlated with the serum DBP concentration, which was higher in pregnant compared with nonpregnant women. The mean serum half-life of 25(OH)D3 was longer but not significantly different in pregnant women (18.8 days) compared with nonpregnant women (13.6 days). Our pilot study demonstrated that a single oral dose of 25 µg of d3-vitamin D3 can be used to study vitamin D kinetics. Serum DBP concentration is an important predictor of vitamin D kinetics, and more research is needed to fully understand the significance of elevated DBP concentration during pregnancy.

The data provided herein include flow-mediated vasodilation responses, represented by changes in arterial diameter, and blood pressure in young adults after a single oral dose of edible emu oil or placebo (cross-over design). Ten healthy men and 10 healthy women participated. Increased blood flow in the antebrachial region was induced by inflating a pressure cuff and subsequently releasing the pressure by deflating the cuff. After the release, the arterial diameter was continuously monitored for 110 sec using ultrasonic diagnostic equipment. The changes in the arterial diameter from 20 to 110 sec post-cuff deflation are described in line graphs and tables. In addition, systolic and diastolic blood pressure data are provided in a table.

The aim of this study was to evaluate myocardial changes in a short-haired guinea pig (Cavia porcellus L) after everyday use of energy drinks for 60 days. The experiments were carried out on 11 male gui- nea pigs, age of 2 months, with a mean weight of 220±0.2 g. The guinea pigs were randomly grouped into a control group of 5 guinea pigs and experimen- tal group of 6. Experimental group guinea pigs were orally administered energy drinks 4 ml per day as a single oral dose. After the 60 days experiment, the quantitatively evaluated structures of myocardial in- terstitial collagen in the left ventricle using automa- ted image analysis system, which was connected to Olympus BXx51 microscope. Assessment was per- formed with Image-Pro Plus 5.1 analysis system. We calculated volume and perimeter of the interstitial fibrillar collagen in the left ventricular myocardium, the number of separate fibers in the field of view were counted. In total, there was evaluated 100 fields of view in the control group and 120 fields of view in the experimental group. Statistical analysis was per- formed using statistical package SPSS Statistics 20 and Microsoft Excel. We used bifactorial analysis of variance (ANOVA) to compare histomorphometric parameters between the two groups. We assessed that the difference between parameters was up to 1% and the individual specific effect was counting for 50% (p < 0.05). Variation of the featu- res was much larger within the experimental group, when compared to the control group. Maximum ave- rage values of the fibrillar collagen volume, perimeter and the number of separate fibers in the field of view were 1.2 times larger in the experimental group than in the control group. Repeated energy drink consumption acts as external factor stimulating adaptive remodeling processes. Quantative structural changes of fibrillar collagen in left ventricle of experimental group animals are reaction to a stress factor. Unbalanced changes of fi- brillar collagen may determine inadequate remodeling and become a reason for pathogenesis.

Many pathophysiological processes can affect the pharmacokinetic properties of drugs in people with diabetes. The present study was deigned to evaluate the influence of diabetes mellitus (DM) on the pharmacokinetic parameters of metronidazole administered as single oral dose. Twelve healthy volunteers and twelve diabetic patients were enrolled in the present study. On day 1, a single oral dose of metronidazole 500 mg was administered orally to all participants at 9:00 am after a 10-hour fasting. Over the following 48 hours, blood samples were taken at frequent intervals and serum metronidazole concentrations were measured by a high-performance liquid chromatography method for assessment of pharmacokinetics of metronidazole. The data indicated that maximum serum concentration (Cmax) and Kelim were significantly decreased (P

A case of Taenia asiatica infection detected by small bowel series and colonoscopy is described. The patient was a 42-year-old Korean man accompanied by discharge of movable proglottids via anus. He used to eat raw pig liver but seldom ate beef. Small bowel series radiologic examinations showed flat tape-like filling defects on the ileum. By colonoscopy, a moving flat tapeworm was observed from the terminal ileum to the ascending colon. The tapeworm was identified as T. asiatica by mitochondrial DNA sequencing. The patient was prescribed with a single oral dose (16 mg/kg) of praziquantel.

Majority of reported studies so far developed correlation regression equations using the rat muscle-to-plasma drug concentration ratio (Kp-muscle) to predict tissue-to-plasma drug concentration ratios (Kp-tissues). Use of regression equations derived from rat Kp-muscle may not be ideal to predict the mice tissue-Kps as there are species differences. (i) To develop the linear regression equations using mouse tissue-Kps; (ii) to assess the correlation between organ blood flow and/or organ weight with tissue-Kps and (iii) compare the observed tissue-Kps from mice with corresponding predicted tissue-Kps using Richter’s rat-Kp specific equations. Disposition of 12 small molecules were investigated extensively in mouse plasma and tissues after a single oral dose administration. Linear correlation was assessed for each of the tissue with rest of the other tissues, separately for weak and strong bases. Newly developed regression equations using mice tissue-Kps, predicted 79% data points within twofold. As observed correlation r 2 range was 0.75–0.98 between Kp-muscle and Kp-brain, -spleen, -skin, -liver, -lung, suggesting superior correlation between the tissue-Kps. Order of tissue-Kps, showed that tissue concentrations were directly proportional to the organ blood flow and inversely to the organ weight. Further, the observed tissue-Kps from mice were compared with corresponding predicted tissue-Kps using Richter’s rat-Kp specific equations. Overall, 46, 54 and 63% data points were under predicted ( twofold) for skin and brain, respectively. These findings suggest that cross species extrapolation predictability is poor. All these findings together suggest that mouse specific regression equations developed under controlled experimental conditions could be most appropriate for predicting mouse tissue-Kps for compounds with wide range of volume of distribution.

OBJECTIVES: Measure total B12 and holotranscobalamin (Holo-TC) concentrations in serum to show vitamin B12 absorption following single oral doses of multivitamin (MVI) gummy and tablet. METHODS: This crossover clinical trial involved healthy adults randomized to either gummy or tablet multivitamins (MVI) containing vitamin B12 (60.8 mcg in gummy and 91.8 mcg in tablet) as cyanocobalamin in a single dose in Phase 1 with serial blood samples collected at pre-dose and at 0.5-, 1-, 2-, 4-, 6-, 8-, 9-, 10-, 24-, and 48-hrs after dosing, followed by a 2-week washout period. In Phase 2, participants then crossed over to receive MVI in the form not previously given, with blood draws at the same timepoints. Serum samples were measured for total B12 (n = 19) using an electrochemiluminescence immunoassay (ECLIA) and for Holo-TC (n = 14) using commercial Holo-TC ELISA kit. Measurements from groups of time points were averaged to estimate pre-absorptive (0 to 2 hours) and absorptive (6 to 10 hours) concentrations of total B12 and Holo-TC for each subject. The difference between pre-absorptive and absorptive concentrations for both analytes was calculated to estimate newly absorbed vitamin B12. RESULTS: Mean increases of about 15% in serum Holo-TC in absorptive phase over the pre-absorptive phase were observed for both the gummies and the tablets, which are statistically significant (p

Synthesis, manufacturing and clinical trials of sulfonamides during the Great Patriotic War is a glorious page of Russian pharmaceutical industry and clinical medicine. Sulfidine, the active sulfonamide, was synthesized in 1937 under the stewardship of I.Y.Postovsky. Sulfidine manufacturing was organized in 1942. Pharmacokinetics and pharmacodynamics of sulfidine were investigated in a number of studies of the time. Blood concentration of sulfidine reached 0.88 – 3.1 0 mg/dL within 4 h after a single oral dose of 1 – 3 g. The peak concentration was observed in 8 – 12 h and was held at this level within 8 – 16 h. To achieve clinical effect, researchers recommended maintaining sulfidine concentration ≥ 3 – 4 mg/dL during 3 or 4 days. The oral administration of sulfidine was associated with gastrointestinal adverse events in 31% of patients; skin rash in 7% of patients, and polyneuritis in one patient. Therefore, Soviet investigators developed intravenous formulation of sulfidine. Pneumonia treatment with i.v. sulfidine required 0.75 – 3.0 g of the drug compared to 24 g of oral formulation. I.v. sulfidine caused less adverse events and similar clinical effect compared to the oral route of administration. Sulfidine treatment of pneumonia led to outstanding results including dramatically decreased mortality from 30% to 4 – 6%. A valuable experience of development and implementation of antibacterial drugs during the Great Patriotic War could be used for revival of the Russian national pharmaceutical industry.

Purpose The aim of this study is to determine the pharmacokinetics (PK) and pharmacodynamics (PD) of a single 12.5- or 25-mg dose of alogliptin, a dipeptidyl peptidase-4 (DPP-4) inhibitor, in pediatric (children and adolescents) and adult subjects with type 2 diabetes mellitus (T2DM). Methods A randomized, open-label, multicenter study was conducted in pediatric and adult subjects. Subjects in two pediatric groups (children and adolescents) were randomized 1:1 to receive a single oral dose of alogliptin 12.5 or 25 mg, respectively; all gender- and race-matched adult subjects received alogliptin 25 mg. Blood and urine samples were collected at prespecified time points for PK/PD analyses. A PK/PD model was developed using data from the study for steady-state simulations. Safety was also assessed. Results In pediatric subjects receiving the 25-mg dose, the mean alogliptin peak plasma concentrations (Cmax) and AUC0-inf values were 26 and 23% lower, respectively, than in adults receiving the 25-mg dose, but maximum observed DPP-4 inhibition effect (Emax) and AUEC0–24 values were similar to those in adults. In pediatric subjects receiving the 12.5-mg dose, the mean alogliptin Cmax and AUC0-inf values were 58 and 54% lower, respectively, than those in adults, hence Emax and AUEC0–24 values were also lower by 11 and 17%, respectively. The PK/PD model simulated data were consistent with study results. No safety concern was found. Conclusions A 25-mg dose of alogliptin in pediatric subjects achieved alogliptin exposures and DPP-4 inhibition similar to those in adult T2DM patients without safety concerns; therefore, this dose is recommended for a pediatric phase 3 trial. Electronic supplementary material The online version of this article (doi:10.1007/s00228-016-2175-1) contains supplementary material, which is available to authorized users.

The aim of this study is to evaluate four drug regimens for treatment of scabies as regard their efficacy, acceptability and cost effectiveness. Two hundred cases with ordinary scabies were randomized into four groups. First group received ivermectin 200 μg/kg body weight single oral dose, repeated after one week. The second received benzyl benzoate 20% cream. The third received permethrin 2.5%-5% lotion, whereas the fourth group received 5-10% sulfur ointment. Topical treatments were applied for five consecutive nights. Patients were followed up for two weeks for cure rate and adverse effects. At the end of the study, permethrin provided a significant efficacy of 88% and acceptability in 100% of cases, but had higher cost to treat one case (20.25 LE). Ivermectin provided efficacy and acceptability rates of 84% and 96%, respectively, and had a cheaper cost (9.5 LE). Benzyl benzoate provided 80% for both rates and was the cheapest drug. Sulfur ointment provided the least rates, and it was the most expensive. Treatment choice will depend on the age, the general condition of cases, patient compliance to topical treatment and his ability to stick to its roles, and the economic condition of the patient.

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.

6054 Background: Niraparib is approved for the maintenance treatment of adult patients (pts) with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy, or with similar cancers but advanced, associated with homologous recombination deficiency (HRD) and have been treated with ³3 prior chemotherapy regimens. Niraparib is extensively metabolized in the liver and eliminated via both hepatobiliary and renal routes. Objectives of this study included characterization of niraparib pharmacokinetics (PK) and safety in pts with normal hepatic function vs. pts with moderate hepatic impairment. Methods: This phase I, open-label, parallel-group, single-dose study enrolled pts with advanced solid tumors into 2 groups: normal hepatic function and moderately impaired hepatic function, defined as bilirubin >1.5 to 3 times the upper limit of normal and any aspartate aminotransferase elevation. Pts received a single 300-mg dose and underwent PK sampling for 7 days. Exposure parameters included maximum concentration (Cmax), area under the concentration-time curve calculated to last measured concentration (AUClast), and extrapolated to infinity (AUCinf). PK parameters were determined using a non-compartmental analysis in WinNonlin. Results: Seventeen pts were enrolled; 9 with normal hepatic function and 8 with hepatic impairment. Niraparib Cmax was 7% lower in pts with moderate hepatic impairment compared with pts with normal hepatic function (Table). Overall exposure was increased in pts with moderate hepatic impairment, with niraparib AUClast and AUCinf increased 45% and 60%, respectively. Safety data during the PK phase of the study is consistent with the known profile for niraparib. Conclusions: Pts with moderate hepatic impairment experienced increased niraparib exposure which did not noticeably alter the toxicity profile in this population. Clinical trial information: NCT03359850. [Table: see text]

Understanding the physiological fluctuations in the corrected QT (QTc) interval is important to accurately interpret the variations in drug-induced prolongation. The present study aimed to define the time course of the effect of moxifloxacin on the QT interval to understand the duration of the responses to moxifloxacin. This retrospective analysis was performed on data taken from a thorough QT 4-way crossover study with 40 subjects. Each period consisted of a baseline electrocardiogram (ECG) day (day -1) and a treatment day (day 1). On both days, ECGs were recorded simultaneously using 2 different systems operating in parallel: a bedside ECG and a continuous Holter recording. The subjects were randomized to 1 of 4 treatments: 5 mg and 40 mg of intravenous amisulpride, a single oral dose of moxifloxacin (400 mg), or placebo. Standardized meals, identical in all 4 periods, with similar nutritional value were served. Bedside ECG results confirmed that the moxifloxacin peak effect was delayed in the fed state and showed that the Fridericia corrected QT prolongation induced by moxifloxacin persisted until the end of the 24-hour measurement period. The use of continuous Holter monitoring provided further insight, as it revealed that the moxifloxacin effect on QTc was influenced by diurnal and nocturnal environmental factors, and hysteresis effects were noticeable. The findings suggested that moxifloxacin prolongs QTc beyond its elimination from the blood circulation. This is of relevance to current concentration-effect modeling approaches, which presume the absence of hysteresis effects.

Foods contain natural vitamin B12 forms, such as hydroxo&ndash, B12 (HO&ndash, B12), whereas vitamin pills contain the synthetic cyano&ndash, B12 (CN&ndash, B12). Recent studies in rats showed different tissue distributions of CN&ndash, B12 and HO&ndash, B12 24 h after oral administration. Here, we investigate whether these differences are sustained or leveled out with time in both B12-deplete and -replete rats, thereby assessing if the two forms are equally good at maintaining a normal B12 status. Male Wistar rats were fed diets with low (n = 16) or high (n = 12) B12 content for 17 days. At day 10, the rats received a single oral dose of [57Co]-labeled CN&ndash, B12 or HO&ndash, B12 (n = 6 and n = 8, respectively, in each diet group). The rats were sacrificed on day 17 and endogenous B12 and [57Co]&ndash, B12 were measured in liver, kidney, and plasma. We found that the low-B12 diet introduced a B12-deplete state as judged from medians of endogenous B12 compared to rats on a (high-B12 diet): Plasma (565 (1410) pmol/L), liver (28.2 (33.2) pmol/g), and kidneys (123 (1300) pmol/g). One week after oral administration, the labeled B12 was distributed as follows: HO&ndash, B12 &gt, CN&ndash, B12 (liver) and CN&ndash, HO&ndash, B12 (kidneys, plasma). The tissue/plasma ratios showed different equilibriums for labeled CN&ndash, B12 in the B12-deplete and -replete groups. The equilibrium of endogenous B12 resembled [57Co]CN&ndash, B12 in replete rats but differed from both [57Co]CN&ndash, B12 and [57Co]HO&ndash, B12 in deplete rats. The data suggest long-term differences in tissue utilization of the two B12 forms and warrant further studies concerning the possible benefits of consuming HO&ndash, B12 instead of CN&ndash, B12 in oral B12 replacement.

Eldecalcitol (ED-71) is a novel active vitamin D3 derivative, used for the treatment of osteoporosis. This is the first clinical study to investigate the pharmacokinetics and safety of eldecalcitol in Chinese subjects. This was an open, single-center, randomized, two-dose level, two-period crossover phase I study in 24 healthy Chinese adult males. Eligible subjects received a single oral dose of eldecalcitol capsule 0.5 or 0.75 μg at period 1 or period 2, monitored over a 144-h observation period for pharmacokinetics and a 14-day observation period for safety. The wash-out time was 14 days. The data observed in this study were compared with historical data in Japanese subjects to evaluate the inter-ethnic differences in pharmacokinetics. After single doses of 0.5 and 0.75 μg eldecalcitol, the maximum serum concentration (Cmax) of eldecalcitol was reached within 3.0–4.0 h (Cmax was 0.0638 ± 0.0076 ng/ml in the 0.5-μg group and 0.0944 ± 0.0126 ng/ml in the 0.75-μg group, area under the concentration-time curve from 0 to 24 h (AUC(0-24h)) was 1.02 ± 0.15 ng·h/mL in the 0.5-μg group and 1.57 ± 0.26 ng·h/mL in the 0.75-μg group). The pharmacokinetic parameters was similar between the Chinese and Japanese subjects; both Cmax and partial AUCs could be considered to be dose-proportional over the tested dose range of 0.5–0.75 µg in Chinese subjects, which was in line with previously published results on eldecalcitol linear pharmacokinetics (range 0.1–1.0 µg) in Japanese subjects. Alanine aminotransferase increase was the most common adverse event (AE). No drug-related serious AEs were reported. All of the drug-related AEs of eldecalcitol were mild in severity. Pharmacokinetic exposure (Cmax and partial AUCs) was dose-proportional over the tested dose range of 0.5–0.75 µg in healthy Chinese adult males. The pharmacokinetic character of eldecalcitol in Chinese subjects was similar to historical data from Japanese subjects. Eldecalcitol was well tolerated at doses ranging from 0.5 to 0.75 µg, with no new safety signals identified. This study was registered at the China Food and Drug Administration (Registration number: 2014L02212 and 2014L02213), and also registered at http://www.chinadrugtrials.org.cn (No. CTR20160430).

This study was performed to investigate the intrapulmonary penetration of lascufloxacin in humans. Thirty healthy adult male Japanese subjects, allocated into five groups, received lascufloxacin in a single oral dose of 75 mg. Bronchoalveolar lavage and blood sampling were performed simultaneously in each subject at 1, 2, 4, 6, or 24 h after administration, and lascufloxacin concentrations in plasma, epithelial lining fluid, and alveolar macrophages were determined. Lascufloxacin was rapidly distributed to the epithelial lining fluid with a time to maximum drug concentration ( T max ) of 1 h, which was identical to that in plasma. The maximum concentration of drug ( C max ) values in plasma, epithelial lining fluid, and alveolar macrophages were 0.576, 12.3, and 21.8 μg/ml, respectively. The corresponding area under the concentration-time curve from 0 to 24 h (AUC 0–24 ) values were 7.67, 123, and 325 μg · h/ml. The mean drug concentrations in the epithelial lining fluid and alveolar macrophages were much higher than those in plasma at all time points examined, and the average site-to-free plasma concentration ratios fell within the ranges of 57.5 to 86.4 and 71.0 to 217, respectively. Drug levels in epithelial lining fluid and alveolar macrophages exceeded the MIC 90 values for common respiratory pathogens. (This study was registered at JAPIC under registration number JapicCTI-142547.)

Objective Maraviroc (MVC) is a potential candidate for 'on demand' preexposure prophylaxis. In the present study, we evaluated the efficacy of a single oral dose of MVC to prevent ex-vivo HIV-1 infection of rectal tissue in humans. Design and methods Eight HIV-1-negative healthy volunteers received a single oral dose of MVC (300 or 600 mg), and two additional volunteers received tenofovir disoproxil fumarate/emtricitabine (TDF/FTC, 300/200 mg) for 10 days. Rectal biopsies were performed prior to the ex-vivo challenge (day 0), at day 7 (4 h after MVC) or after 10 days with TDF/FTC. Rectal biopsies were infected ex-vivo, and viral inhibition and CCR5 occupancy was analyzed. MVC concentration in plasma and rectal tissue was measured just after biopsy and after viral incubation. Results Ex-vivo rectal tissue protection with MVC was incomplete in all but two participants, whereas TDF/FTC avoided ex-vivo infection in the two controls. Median dose-normalized concentration of MVC was significantly higher in rectal tissue than in plasma (561.1 and 155.1 ng/ml, respectively). A significant loss of MVC during the virus incubation (about 60%) and a low CCR5 occupancy (approximately 45%) were detected in rectal cells. Conclusions An ex-vivo challenge with a single oral dose of MVC does not prevent ex-vivo infection of human rectal mucosa. The lack of prophylactic efficacy observed suggests that 'on demand' MVC preexposure prophylaxis would not prevent rectal HIV-1 transmission.

Objective The aim of this study was to investigate and compare the pharmacokinetics of trantinterol and its active amphoteric carboxylic acid metabolite (1-carbonyl trantinterol) between the healthy elderly and young subjects. Methods This was a single-center, open-label, parallel-group study completed by 22 healthy subjects (≥65 years (the elderly group); 18-45 years (the young group); 9 males and 2 females per age group) receiving single oral dose of 50 μg trantinterol tablets. Blood samples were taken at intervals up to 48 hours post-dose. Results In both groups, maximum plasma concentration of trantinterol was researched at 0.9 hours, while the tmax of 1-carbonyl trantinterol differed slightly. Trantinterol Cmax and AUClast were higher in the elderly group than the young group, by 27% (90% CI, 0.95-1.69) and 77% (90% CI, 1.25-2.51), respectively. For 1-carbonyl trantinterol, Cmax, and AUClast were also higher, by 36% (90% CI, 1.04-1.78) and 71% (90% CI, 1.27-2.30), respectively, in the elderly group. The CL/F and V/F of trantinterol and 1-carbonyl trantinterol were significantly lower in the elderly group, while t1/2 of both did not show significant differences. CL/F of trantinterol and 1-carbonyl trantinterol were found to significantly correlate inversely with age, and positively with the baseline creatinine clearance. Conclusions A single dose of 50 μg trantinterol was well tolerated. Significant changes in Cmax and AUC of trantinterol and 1-carbony trantinterol were seen in the elderly and may be clinically important.

Rosuvastatin is used to treat dyslipidemia and its use is quite frequent among postmenopausal women. Menopause significantly affects the pharmacokinetics of drugs, and altered drug response and therapeutic efficacy may be anticipated in postmenopausal women compared with premenopausal women. The current study is based on assessment of differences in pharmacokinetics of rosuvastatin between pre- and postmenopausal women of Asian ethnicity. Volunteers were administered a single oral dose of rosuvastatin 40 mg in an open-label and non-controlled pharmacokinetic study. A reversed-phase HPLC method was applied for quantification of rosuvastatin in plasma samples. Student’s t test was used to compare the pharmacokinetic parameters of rosuvastatin between pre- and postmenopausal women at the 95 % confidence interval. The C max (premenopausal = 58.2 ± 29.1, postmenopausal = 12.2 ± 3.1 ng/ml), $$[{\text{AUC}} ]_{0}^{8}$$ (premenopausal = 272.6 ± 107.3 ng·h/ml, postmenopausal = 58.8 ± 16.6 ng·h/ml), and $$[{\text{AUC}} ]_{0}^{\infty }$$ (premenopausal = 366.1 ± 169, postmenopausal = 66.4 ± 12.9 ng·h/ml) of rosuvastatin were significantly higher (p

Made available in DSpace on 2020-12-12T01:06:05Z (GMT). No. of bitstreams: 0 Previous issue date: 2019-12-01 Freitas, MC, Cholewa, JM, Gerosa-Neto, J, Gonçalves, DC, Caperuto, EC, Lira, FS, and Rossi, FE. A single dose of oral ATP supplementation improves performance and physiological response during lower body resistance exercise in recreational resistance-trained males. J Strength Cond Res 33(12): 3345-3352, 2019-The aim of this study was to investigate the acute effect of adenosine-5'-triphosphate (ATP) supplementation on performance and physiological responses during resistance exercise in recreationally resistance-trained males. Eleven men (age = 27.5 ± 5.5 years, mass = 83.4 ± 9.8 kg, height = 182 ± 0.04 cm) completed 2 randomized, double-blind trials: ATP supplement condition (ATP = 400 mg) or a placebo condition. Thirty minutes after supplement consumption, subjects performed 4 sets of half-squats until momentary muscular failure at 80% of the 1 repetition maximum with 2 minutes of recovery between sets. The total number of repetitions, blood pressure, heart rate, blood lactate, and oxygen consumption were evaluated. The total weight lifted were higher for the ATP condition compared with placebo (Placebo = 3,995.7 ± 1,137.8, ATP = 4,967.4 ± 1,497.9 kg; p = 0.005). Heart rate was higher at set-4 for ATP compared with placebo (p < 0.001) and oxygen consumption during exercise was greater for ATP (p = 0.021). There were no differences between conditions for lactate and blood pressure. In summary, a single oral dose of ATP supplementation improved lower-body resistance training performance and energy expenditure in recreational resistance-trained males. Exercise and Immunometabolism Research Group Department of Physical Education São Paulo State University (UNESP) Department of Kinesiology Coastal Carolina University Biosciences Department Federal University of São Paulo UNIFESP Human Movement Laboratory University São Judas Tadeu Immunometabolism of Skeletal Muscle and Exercise Research Group Department of Physical Education Federal University of Piauí (UFPI) PI Exercise and Immunometabolism Research Group Department of Physical Education São Paulo State University (UNESP)

The effects of a single oral dose of liothyronine (L-T3) on thyroid stimulating hormone (TSH) and other related thyroid system parameters are partly understood despite therapeutic use of this hormone over many decades. We characterize individualized responses of the hypothalamus-pituitary-thyroid (HPT) axis and its related temporal hormonal profile using an electrical network model. Based on thyroid hormone responses from blood samples using a single 50[Formula: see text][Formula: see text]g oral dose of liothyronine in healthy persons with a normal operating euthyroid feedback HPT system, we derived an equivalent electrical circuit model for the system’s responses. The mathematical model was tested with a circuit simulator and validated with individualized clinical data. This signal processing technique makes the evaluation of bioequivalence and bioavailability of various preparations of liothyronine at an individualized level a feasible endeavor for clinical application.

To evaluate secnidazole as a single oral dose treatment for bacterial vaginosis in a phase 2 randomized, double-blind, placebo-controlled study.In a phase 2, randomized, double-blind, dose-ranging, placebo-controlled study, women with bacterial vaginosis who met all Amsel criteria (discharge; pH 4.7 or greater; 20% or greater clue cells; positive whiff test) were randomized one to one to one at 24 U.S. centers to 1 or 2 g secnidazole compared with placebo. The primary endpoint was clinical cure (normalization of discharge, amine odor, and clue cells) 21-30 days after treatment. Secondary endpoints included microbiologic cure, defined as a Nugent score of 0-3, and therapeutic cure, defined as meeting criteria for both clinical and microbiologic cure. The modified intent to treat was used for efficacy analyses and included all randomized patients who met the enrollment criteria. Assuming a clinical cure rate of 40% in the active groups and 15% in the placebo group, a sample size of 52 patients per group provided approximately 80% power to detect a significant difference between groups (.05 level [two-sided]) using a Cochran-Mantel-Haenszel test.Between May and September 2014, 215 patients were enrolled. In the intent-to-treat population, the clinical cure rate was 65.3% for the 2-g group, 49.3% for the 1-g group, and 19.4% for the placebo group. The modified intent-to-treat population included 188 women (median age 33 years; 32% with four or more bacterial vaginosis episodes in the previous year; 54% black) with baseline Nugent scores 4 or greater. Clinical, microbiologic, and therapeutic cure rates were 67.7%, 40.3%, and 40.3% for 2 g secnidazole and 51.6%, 23.4%, and 21.9% for 1 g secnidazole compared with 17.7%, 6.5%, and 6.5% for placebo, respectively (P.05 for secnidazole compared with placebo; all endpoints). Both doses were well-tolerated.Oral granules containing 1 and 2 g secnidazole were superior to placebo in bacterial vaginosis treatment (P.001 for both groups). These data support the development of secnidazole for bacterial vaginosis treatment.ClinicalTrials.gov, NCT02147899.

The brain level of perfluorododecanoic acid (PFDoA) was compared with those of perfluorooctanoic acid (PFOA) and perfluorodecanoic acid (PFDA) in rats 9 days after a single oral dose (50 mg/kg). The PFDoA level in the brain was 44.0 ± 2.0 µg/g, which was higher than that in the serum (24.4 ± 1.0 µg/ml). In contrast, the concentrations of PFOA and PFDA in the brain were low (

Background: Many of flavonoid rich natural products found to have a significant influence on postprandial hyperglycemia, a major risk factor for diabetic complications. Enhancement of insulinotropic gut hormones by inhibition of dipeptidyl peptidase-IV (DPP-IV) are among the newest strategies for treatments of Type 2 diabetes which thought to be the underlying action through which flavonoid can reduce postprandial hyperglycemia. Aim: This study aim was designed to investigate the potential role of standardized grape seed proanthocyanidin in controlling postprandial hyperglycemia by enhancing the regulatory incretin effect of gut hormones in response to oral and intraperitoneal (I.P) glucose load in healthy rats. Materials and Methods: Five groups of animals each of six rats were used in this study, which was conducted in March 2013. Groups (II and V) treated with single oral dose of proanthocyanidin (50 mg/kg), Group III received single oral dose of sitagliptin (40 mg/kg) and Groups (I and IV) treated with vehicle serve as control groups. All treatments were given 30 min before oral or I.P glucose load. Blood glucose was estimated over 2 h duration at (0, 30, 60, 90, and 120) min from glucose load. Result: Both proanthocyanidin and sitagliptin significantly improve hyperglycemia induced by oral glucose load relative to control. While non-significant changes were achieved by proanthocyanidin after I.P glucose challenge compared to untreated control group. Conclusion: The result of this study indicated that proanthocyanidin may possess an enhancement of incretin effect of gut peptides, which could be responsible for some of its action on glucose homeostasis. This finding may provide an opportunity for further pharmacological studies using more specific models to clarify the possible action of proanthocyanidin as a natural DPP-IV inhibitor.

Background. CDRI 97/78 has shown efficacy in animal models of falciparum malaria. The present study is the first in-human phase I trial in healthy volunteers. Methods. The study was conducted in 50 healthy volunteers in a single, ascending dose, randomized, placebo-controlled, double blind design. The dose ranges evaluated were from 80 mg to 700 mg. Volunteers were assessed for clinical, biochemical, haematological, radiographic, and electrocardiographic parameters for any adverse events in an in-house facility. After evaluation of safety study results, another cohort of 16 participants were administered a single oral dose of 200 mg of the drug and a detailed pharmacokinetic analysis was undertaken. Results. The compound was found to be well tolerated. MTD was not reached. The few adverse events noted were of grade 2 severity, not requiring intervention and not showing any dose response relationship. The laboratory and electrocardiographic parameters showed statistically significant differences, but all were within the predefined normal range. These parameters were not associated with symptoms/signs and hence regarded as clinically irrelevant. Mean values of T1/2, MRT, and AUC0-∞ of the active metabolite 97/63 were 11.85±1.94 h, 13.77±2.05 h, and 878.74±133.15 ng·h/mL, respectively Conclusion. The novel 1,2,4 trioxane CDRI 97/78 is safe and will be an asset in malarial therapy if results are replicated in multiple dose studies and benefit is shown in confirmatory trials.

Sulfolane is a ground water contaminant near refinery sites. The objective of this work was to investigate the toxicokinetics and bioavailability of sulfolane in male and female Harlan Hsd:Sprague Dawley® SD® rats and B6C3F1/N mice following a single oral administration of 10, 30, or 100 mg/kg. Sulfolane was rapidly absorbed in rats with the maximum plasma concentration, C(max), reached at ≤ 1.47 h. Although C(max) increased proportionally to the dose, the half-life of elimination increased with the dose and the area under the concentration versus time curve (AUC) increased more than proportionally to the dose. In male and female rats, plasma elimination half-life increased with the dose from 1.97 to 6.33 h. Absorption of sulfolane in mice following oral administration was more rapid than in rats with C(max) reached at ≤ 0.55 h. In addition, mice had a shorter half-life (≤ 1.25 h) and a lower AUC than rats. In male and female mice, both C(max) and AUC increased more than proportionally to the dose. Bioavailability of sulfolane was higher in rats (81–83%) than mice (59–63%) at 10 mg/kg; at 30 and 100 mg/kg, bioavailability > 100% in both species and sexes suggesting that the saturation of metabolism and clearance processes of sulfolane may begin at a single oral dose of ~30 mg/kg. There was no apparent sex difference in toxicokinetic parameters of sulfolane in rats and mice. These data demonstrate that sulfolane was well-absorbed following oral administration with high bioavailability in rats and mice with some species differences, but no sex difference.

The purpose of this research was to describe the pharmacokinetic parameters of β-hydroxyphosphocarnitine (β-HPC; CAS No. 1220955-20-3) after a single oral dose in rats and rabbits as well as to assess the impact of 14 weeks of β-HPC (100 mg/kg) treatment on the serum metabolites and liver enzymes, body weight, and hepatic steatosis of lean and obese Zucker fa/fa rats. In the case of the rat and rabbit study, the β-HPC area under the curve, biological half-life, and clearance were 2,174.4 versus 3,128 μg∙h/ml, 23.7 versus 8.87 h, and 13.9 versus 151.1 ml/h in the rats versus the rabbits, respectively. The values for the time of maximal concentration were 0.58 versus 1.53 h, for the maximal concentration, they were 62.4 versus 221.4 μg/ml, and for the absorption rate constant 0.02 versus 2.40 h-1, respectively. In the case of the Zucker fa/fa rat study, β-HPC administered orally once a day reduced insulin, triglyceride, and cholesterol levels in the liver and serum; it also reduced weight gain and decreased liver steatosis in obese rats after 14 weeks. β-HPC could therefore potentially be used in the treatment of metabolic syndrome.

We aimed to investigate the effect of induced hepatic and renal failure on the pharmacokinetics of topiramate (TPM) in rats. Twenty-four Sprague-Dawley rats were used in this study. Renal or hepatic failure was induced by a single i.p. dose of 7.5 mg/kg cisplatin (n=8) or 0.5 mL/kg carbon tetrachloride (CCl4) (n=8), respectively. Three days after cisplatin dose or 24 h after CCl4dose, the rats were administered a single oral dose of 20 mg/kg TPM. The plasma samples were quantified by LC-MS/MS method. Compared to control, plasma concentration-time profile in CCl4-treated and, to a lesser extent, in cisplatin-treated rats decreased more slowly particularly in the elimination phase. TPM oral clearance (CL/F) in CCl4-treated group was significantly lower than that in control (P<0.001), whereasAUC0−∞, T1/2, and Vd/F were significantly higher in CCl4-treated rats compared to the control (P<0.01). The CL/F was not significantly different between cisplatin-treated rats and control (P>0.05). However, in cisplatin-treated rats, the T1/2 and Vd/F were significantly higher than that in the control group (P<0.01). Both conditions failed to cause a significant effect onCmaxorTmax. The present findings suggest that induced hepatic or renal failure could modify the pharmacokinetic profile of TPM in the rat.

Macitentan is under development for the treatment of pulmonary arterial hypertension (PAH). Patients with PAH may suffer from comorbidities such as renal or hepatic impairment. Two prospective, single-center, open-label studies evaluated the pharmacokinetics of macitentan and its metabolites (pharmacologically active ACT-132577 and inactive ACT-373898) in healthy subjects and in subjects with mild, moderate, and severe hepatic impairment or severe renal function impairment (SRFI). After administering a single oral dose of 10 mg macitentan the pharmacokinetic parameters including area under the curve from zero to infinity (AUC∞) were derived from plasma concentration-time profiles. Exposure to macitentan and ACT-132577 was lower in hepatically impaired versus healthy subjects, with no correlation with the degree of hepatic impairment. Exposure to ACT-373898 was lower in subjects with moderate hepatic impairment only. Plasma concentration-time profiles for macitentan and ACT-132577 (active) were similar in healthy subjects and subjects with SRFI. AUC∞ of ACT-373898 (inactive) was 7.3-fold higher in subjects with SRFI versus healthy subjects. No safety concerns were raised in either study. Based on these observations, pharmacokinetic alterations of macitentan due to hepatic or renal function impairment are not considered clinically relevant and no dose adjustment is necessary in these patients.

AIMS: This study aimed to find out the efficacy of single oral dose 150mg of fluconazole in treatment of acute vulvovaginal candidiasis, to evaluate its safety assessment and the clinical and mycological efficacy assessment. MATERIALS AND METHODS: This study is carried out in department of obstetrics and gynaecology Gandhi medical college sultania hospital Bhopal and with the help of microbiology department Gandhi medical college Bhopal over a period of one year. It is a hospital based clinical prospective study. RESULTS: Maximum age incidence was found between 2130years. Mostly patients belonged to low socioeconomic status and were uneducated. Maximum patients were married (98%) and multiparous (92%), nulliparous formed the smallest group (8%). In factors predisposing to candidiasis, contraceptive methods were found to be important in which maximum incidence was found in patients using oral contraception about 32% and 12% of IUCD users were affected. Other factors were antibiotic treatment (5%) and diabetes (2%). Vaginal discharge and pruritis were the two commonest symptoms found. Among the signs vaginal discharge and white plaques was the commonest sign. On follow up visits 88 cases had complete clinical cure and only 6 cases showed failure and 9 recurrences. In mycological assessment maximum 135 cases showed complete cure, 6 were failure and 9 recurrence. In overall results, excellent results were found in 88cases, good in 38 cases, fair in 9 cases and recurrence in 9 cases. Recurrences were mainly due to rectal carriers. CONCLUSION: In conclusion fluconazole was found effective as a systemic single oral dose therapy for acute vulvovaginal candidiasis. It is proved safe in terms of tolerance and preferred by patients. So in view of its favourable patients acceptability and compliance profile, it is considered as a first line therapeutic choice for treatment of women with vaginal candidiasis.

Introduction:The purpose of this study was to evaluate the effect of atorvastatin on the structure of skeletal muscles in male albino rats and the possibility of recovery of any changes in the muscles. Drug used: Atorvastatin (Lipitor 20mg) tablets.The daily single oral dose was 1.6 mg /kg body weight. Experimental animals: Twenty five adult local strain male albino rats with average weight of 160 gm were chosen, divided into five equal groups and fed on ordinary rat diet: Group I (control group), Group II treated with atorvastatin (1.6 mg/kg/b.wt/day) for two weeks, Group III treated with atorvastatin for two weeks then stopped receiving treatment for two weeks (recovery group 1), Group IV treated with atorvastatin for four weeks and Group V treated with atorvastatin for four weeks then stopped receiving treatment for four weeks (recovery group II). Results: Administration of atorvastatin for long duration resulted in some sort of myotoxic structural changes and apoptosis as evident by deformity in the mitochondria , lack of striation , degeneration of nuclei and splitting of muscle fibres in the adult male albino rat skeletal muscle. Conclusions:Atorvastatin (statin) has many adverse effects on the skeletal muscle tissues with treatmant for long duration (Group IV). So, patients should avoid the possible side effects.

Carrying the apoE ε4 allele (E4+) is the most important genetic risk for Alzheimer's disease. Unlike non-carriers (E4 − ), E4+ seem not to be protected against Alzheimer's disease when consuming fish. We hypothesised that this may be linked to a disturbance inn-3 DHA metabolism in E4+. The aim of the present study was to evaluate [13C]DHA metabolism over 28 d in E4+v.E4 − . A total of forty participants (twenty-six women and fourteen men) received a single oral dose of 40 mg [13C]DHA, and its metabolism was monitored in blood and breath over 28 d. Of the participants, six were E4+ and thirty-four were E4 − . In E4+, mean plasma [13C]DHA was 31 % lower than that in E4 − , and cumulative β-oxidation of [13C]DHA was higher than that in E4 − 1–28 d post-dose (P≤ 0·05). A genotype × time interaction was detected for cumulative β-oxidation of [13C]DHA (P≤ 0·01). The whole-body half-life of [13C]DHA was 77 % lower in E4+ compared with E4 − (P≤ 0·01). In E4+ and E4 − , the percentage dose of [13C]DHA recovered/h as13CO2correlated with [13C]DHA concentration in plasma, but the slope of linear regression was 117 % steeper in E4+ compared with E4 − (P≤ 0·05). These results indicate that DHA metabolism is disturbed in E4+, and may help explain why there is no association between DHA levels in plasma and cognition in E4+. However, whether E4+ disturbs the metabolism of13C-labelled fatty acids other than DHA cannot be deduced from the present study.