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OBJECTIVE To investigate the effects of a single oral dose of gabapentin on fear-based aggressive behaviors (FABs) in cats during veterinary examinations. ANIMALS 55 healthy pet cats (26 with and 29 without a history of FAB during veterinary visits [FAB and untreated control groups, respectively]). PROCEDURES A standardized 9-step clinical examination protocol (with patient compliance scored from 0 to 9 according to the highest completed step) was tested on untreated control group cats. The protocol was then used in a double-blind, randomized, placebo-controlled, crossover-design trial in which FAB-group cats received owner-administered gabapentin (100 or 200 mg/cat) or placebo capsules 2 hours before the first of 2 veterinary visits and received the alternate treatment before the second visit ≥ 1 day later. Ease of administration (scored from 1 [very difficult] to 4 [very easy]) and adverse effects were recorded. Compliance scores were compared between treatments for the FAB group and between FAB and untreated control groups. Changes in scores between treatments for the FAB group were used to investigate associations between selected variables and the outcome of interest. RESULTS FAB group compliance scores after gabapentin administration (median, 9; range, 0 to 9) were significantly higher than scores after placebo administration (median 0.5; range, 0 to 7) and did not differ from scores for the untreated control group. Owner scores indicated capsule administration was easy. Adverse effects (most commonly drowsiness, myorelaxation, and ataxia) resolved ≤ 10 hours after detection. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested oral administration of gabapentin to cats 2 hours before a veterinary visit can reduce FAB during physical examination, enabling more complete evaluation.

This study aimed to investigate pharmacokinetics of fluoxetine in horses and validate a method for liquid chromatography mass spectrometry analysis of serum levels. Fluoxetine pharmacokinetics were determined using 10 healthy, adult horses. Fluoxetine pharmacokinetics following a single oral dose (0.25 mg/kg) were determined using blood samples collected prior to and at several time points over 7 days following administration. Serum concentrations of fluoxetine and its bioactive metabolite norfluoxetine were measured using liquid chromatography coupled to an accurate mass/high-resolution mass spectrometer. Pharmacokinetic parameters were estimated using a noncompartmental model. Time to maximum serum concentration and serum half-life of fluoxetine was 1.5 and 15.6 h, respectively. Steady-state serum concentrations were evaluated using five horses each receiving fluoxetine (0.25 mg/kg, PO, q24hrs) for 8 weeks and were found to be 62.9 ± 25.5 ng/ml on average. Norfluoxetine was not detected in any sample.

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

The aim of the present research was to describe the consequences of hyperlipidemia (HL) on the pharmacokinetics of glibenclamide (Gb) in poloxamer 407-induced hyperlipidemic rats. Rats were given intraperitoneal dose of poloxamer 407 to cause hyperlipidemia. A single oral dose of Gb (10 mg/Kg) was given to normal and HL rats. The Cmax and tmax after oral dose of Gb in normal rats were 340.10 µg/ml and 3.67 h, respectively. Whereas, the Cmax and tmax after oral dose of Gb in HL rats were noted as 773.39 µg/ml and 2.50 h respectively. The AUC value of Gb was found considerably higher in the HL rats. While the plasma clearance (CL) after oral dose of Gb was 2.53 ml/h and 1.39 ml/h in normal and HL rats respectively. The improved plasma concentration of Gb following oral dosing in rats with HL seems to be due to a direct influence on hepatic clearance or metabolizing enzymes. In conclusion, the Gb pharmacokinetics was considerably affected by the HL in rats. Such findings play an important role for predicting the alterations in the pharmacokinetics of drugs including GB, in cases having hyperlipidemia.

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.

Five adult Saanen goats received a single oral dose of Heterophyllaea pustulata containing 42.25 μg/kg rubiadin (anthraquinone) and 3 adult goats were untreated controls. All goats were exposed to sunlight and sequential ear skin biopsies were collected before treatment and at 32 hours, 3 days, 8 days, and 15 days after treatment. Changes at 32 hours after dosing included epidermal spongiosis, single cell death and acantholysis, an increased BAX/BCL-2 protein ratio, and dermal edema. Lesions at day 3 included epidermal and adnexal necrosis, crust formation, and acanthosis. Acanthosis, hyperkeratosis, and dermal fibrosis and neovascularization were present at day 15. The pro-apoptotic (BAX)/anti-apoptotic (BCL-2) protein ratio increased at 32 hours, whereas epidermal and dermal PCNA immunolabeling increased between days 8 and 15 after treatment. The cutaneous lesions were consistent with sunlight-induced damage, and the occurrence in treated but not control goats indicates photosensitization.

Neomorphic mutations in isocitrate dehydrogenase 1 (IDH1) are oncogenic for a number of malignancies, primarily low-grade gliomas and acute myeloid leukemia (AML). We report a medicinal chemistry campaign around a 7,7-dimethyl-7,8-dihydro-2H-1λ(2)-quinoline-2,5(6H)-dione screening hit against the R132H and R132C mutant forms of isocitrate dehydrogenase (IDH1). Systematic SAR efforts produced a series of potent pyrid-2-one mIDH1 inhibitors, including the atropisomer (+)-119 (NCATS-SM5637, NSC 791985). In an engineered mIDH1-U87-xenograft mouse model; after a single oral dose of 30 mg/kg, 16 h post dose, between 16-48 h, (+)-119 showed higher tumoral concentrations that corresponded to lower 2-HG concentrations, when compared with the approved drug AG-120 (ivosidenib).

Nonsteroidal anti-inflammatory drugs (NSAIDs) are some of the most widely used drugs in existence. However, they can cause numerous side effects. Therefore, it is crucial to develop approaches to reducing the severity of their side effects. The purpose of this study is to investigate the effect of mexidol on the anti-inflammatory activity of NSAIDs, such as selective cyclooxygenase (COX)-2 inhibitor etoricoxib and nonselective COX inhibitor diclofenac sodium. Effect of a single oral dose of the drugs was evaluated in rats and mice with carrageenan-induced edema by measuring the severity of edema over a period of 4 and 6 h, respectively. Diclofenac sodium at doses of 1 and 10 mg/kg exhibits a dose-dependent antiexudative effect, the effect of etoricoxib at these doses is comparable, and mexidol at a dose of 25 mg/kg does not exhibit an antiexudative effect. In mice, the effect of a combination of diclofenac sodium at a dose of 1 mg/kg and mexidol at a dose of 25 mg/kg is noninferior to diclofenac sodium at a dose of 10 mg/kg and superior to the effect of diclofenac sodium at a dose of 1 mg/kg. In rats, the combination of diclofenac sodium and mexidol significantly reduces the severity of edema at 4 h after its induction compared with diclofenac sodium at a dose of 1 mg/kg only. In mice, a combination of etoricoxib at a dose of 1 mg/kg and mexidol at a dose of 25 mg/kg is more effective than etoricoxib at doses of 1 and 10 mg/kg. In rats, etoricoxib at a dose of 10 mg/kg and the combination of etoricoxib at a dose of 1 mg/kg and mexidol at a dose of 25 mg/kg have a comparable effect. Mexidol at a low dose (25 mg/kg) enhances the antiexudative effect of diclofenac sodium and etoricoxib. Therefore, a decrease in the dose of NSAIDs in combination with mexidol will help to reduce the side effects of these drugs.

Background: Fenpropathrin, a synthetic pyrethroid (Type I/II) is commonly used as an insecticide in homes and in agriculture. The present study was planned to determine the median lethal dose (LD 50 ) of Fenpropathrin in adult Wistar rats, both male and female. Statistically, LD 50 is a first screening step to asses and evaluate the toxicity for a chemical that causes death of 50% population of test animals when given by a specified route as a single dose for a specific time period. Methods: The experimental rats were divided into 10 groups (5 of male and 5 of female rats) and ten rats were divided into each group. For each group of animals, a single oral dose of Fenpropathrin dissolved in corn oil was administered orally at 15, 30, 45, 60 and 75 mg/kg body weight (bw) concentrations. The animals were monitored up to 96 hours to assess the signs of toxicity and to calculate the LD 50 as per the graphical method procedure suggested by Miller and Tainter (1944)10. Result: Estimated LD 50 of Fenpropathrin was found to be 52.72±8.61mg/kg body weight in male rats and 48.08±8.13 mg/kg body weight in female rats. There were no toxic signs or behavioural changes in the single oral dose of Fenpropathrin at 10mg/kg body weight, thus it can be considered as No Observed Adverse Effect Level (NOAEL). Conclusion: It can beconcluded from the study that Fenpropathrin is highly toxic pyrethroid due to its low LD 50 value in Wistar rats.The result of this study may serve as a basis for dose administration for further research on Fenpropathrin toxicity.

As per Ayurveda symptoms of Rheumatoid arthritis resembles with Amavata disease. Action of Hinguleshwara rasa on Amavata is mentioned in the text of Rasatarangini in Ayurveda. In this study investigation was made to find out preventive & curative changes occurred in rat paw of Freuds Complete Adjuvant induced RA model. Indomethacin was kept as standard control and Hinguleshwar rasa as a treatment. After induction of arthritis with FCA on day 14, animals were treated up to 28th day of the study with indomethacin and Hinguleshwar rasa. After completion of 28 days of daily single oral dose administration of Hinguleshwar rasa and Indomethacin, animals were sacrificed. Ankle joints were severed and processed for histological studies. It was observed that the joints of Hinguleshwar rasa treated animals showed recovery towards normal histological architecture whereas all other joint samples of bones of rats were showing focal and minimal pathological changes, focal and minimal congestion of blood vascular tissue. Similar normal Histo-architecture was found in Indomethacin treated animals. However it was observed that, Hinguleshwar rasa showed better restoration of joint Histopathological changes occurred due to FCA damage. Hence the efficacy of Hinguleshwar rasa on Amavat (Rheumatoid arthritis) was better than Indomethacin treatment.

Background: Baloxavir marboxil (BM) is a novel drug with a cap-dependent endonuclease inhibitory action for influenza A or B; it is highly safe and requires just a single oral dose. Patients with severe heart failure use implantable ventricular assist device (iVAD) until transplantation, but they have an increased risk of thrombosis development. Their warfarin is administered based on point-of-care testing (POCT) with a strict control of prothrombin time-international normalized ratio (PT-INR). Case report: Here, we report a case of a patient with iVAD whose PT-INR was significantly increased from the target range after BM administration. The patient was a 45-year-old man and transplanted with iVAD; warfarin treatment was started when his PT-INR target range was 3.0–3.5. At home, he frequently self-measured PT-INR by POCT and precisely controlled the warfarin dose. He had a fever, was diagnosed with influenza A and was administered BM 40 mg. Thereafter, his PT-INR continued to increase, reaching 4.8 on day 12 of BM administration, exceeding his target range; warfarin was skipped for 1 day. In this case, based on the history of BM administration and clinical course, the increase in PT-INR could be due to BM. Considering the interaction between warfarin and BM, we suspected a possibility of competition for protein-binding sites. Increased PT-INR in the patient was detected early by POCT and thus severe bleeding was avoided. Conclusion: Strict monitoring of PT-INR when using BM in patients taking warfarin is of clinical importance.

Amongst numerous plants and plant products that find use in alternative healthcare as herbal medicines, Sarcocephalus latifolius has been attracting much attention as a plant whose different parts are invaluable for treatment and management of several disease conditions. This study was intended to evaluate the possible effects of a high single dose of Sarcocephalus latifolius root extract on liver enzymes, bilirubin, cholesterol, and triglyceride of rat serum. A total of thirty-six adult rats were used for the studies. The animals were divided into three sets of twelve rats each. Each set was subdivided into three groups (A, B, C) with each group consisting of four animals. The first set was used to study serum activities of alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyltransferase; the second set was used to evaluate the levels of serum bilirubin while the third set was used to assay serum concentration of cholesterol and triglyceride. For each set, the animals in group A orally received 2000mg/kg body weight single dose of the extract, and those in group B received 1500mg/kg single dose administered orally. Group C animals, fed normal diet and water were used as the control in all cases. All analyses were spectrophotometric. There were nonsignificant reductions (p > 0.05), in the activities of ALP, ALT and AST for both dose schedules, whereas statistically nonsignificant increases in activity were recorded for GGT for the two dose schedules. The total bilirubin was found to decrease nonsignificantly (p > 0.05), while conjugated bilirubin was found to decrease significantly (p < 0.05) for both doses when compared with the control. Both cholesterol and triglyceride were nonsignificantly decreased for both dose schedules. Thus, Sarcocephalus latifolius root extract has the potential to conserve the integrity of the liver (non-hepatotoxic), and possesses cholesterol-lowering potentials.

The aim of this study was to investigate the effects of paroxetine, a potent inhibitor of CYP2D6, on the pharmacokinetics of atomoxetine and its two metabolites, 4-hydroxyatomoxetine and N-desmethylatomoxetine, in different CYP2D6 genotypes. Twenty-six healthy subjects were recruited and divided into CYP2D6*wt/*wt (*wt=*1 or *2, n = 10), CYP2D6*wt/*10 (n = 9), and CYP2D6*10/*10 groups (n = 7). In atomoxetine phase, all subjects received a single oral dose of atomoxetine (20 mg). In paroxetine phase, after administration of a single oral dose of paroxetine (20 mg) for six consecutive days, all subjects received a single oral dose of atomoxetine with paroxetine. Plasma concentrations of atomoxetine and its metabolites were determined up to 24 h after dosing. During atomoxetine phase, there were significant differences in Cmax and AUC0−24 of atomoxetine and N-desmethylatomoxetine among three genotype groups, whereas significant differences were not found in relation to CYP2D6*10 allele after administration of paroxetine. AUC ratios of 4-hydroxyatomoxetine and N-desmethylatomoxetine to atomoxetine were significantly different among three genotype groups during atomoxetine phase (all, P

A 6-week, randomized, open-label, active-controlled clinical trial was conducted to evaluate the influence of a low-dose curcumagalactomannosides (CGM) (400 mg once daily) in OA subjects. The treatment was compared with a standard combination of 500 mg glucosamine hydrochloride (GLN) and 415 mg chondroitin sulphate (CHN), supplied as a single oral dose twice a day. Out of 84 subjects randomized, 72 subjects who have completed the study were evaluated for the safety and efficacy of the treatments at baseline and subsequent visits (day 28 and 42), by measuring walking performance, VAS, KPS, and WOMAC scores. CGM exhibited 47.02, 21.43, and 206% improvement in VAS, KPS, and walking performance, respectively, compared to the baseline. Similarly, there was 31.17, 32.93, 36.44, and 35% improvement in the pain, stiffness, physical function, and total WOMAC scores. CGM also caused a substantial reduction in the serum inflammatory marker levels. The results indicate that a short-term supplementation of a low dosage CGM exerted superior beneficial effects than a high-dosage CHN-GLN combination in alleviating the pain and symptoms of OA subjects. Further clinical trials of extended duration in a larger population is required to substantiate the efficacy of CGM in the long-term management of OA.

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.

Ethiopian Aloe species were used for diverse traditional medicines but some species have been reported for potential toxicity. Therefore, oral acute toxicity test were done from leaf exudates of 17 Aloe species using Swiss albino mice (n = 5/cage). A single oral dose of 300 and 2000 mg/kg body weight at a rate of 1 mL/100 gm administered and major toxicity symptoms were monitored; and relative body and organs weights were measured daily until day 14. Data were analyzed using one-way ANOVA followed by Tukey’s post hoc test for multiple comparisons. Groups treated with exudates of Aloe calidophila, A. trichosantha subsp. longiflora, A. megalacantha subsp. alticola, A. megalacantha subsp. megalacantha, A. otallensis, A. pubescens, A. rivae, A. rugosifolia, A. secundiflora, A. tewoldei and A. yavellana did not showed any signs of toxicity at both dose levels. These groups showed no significance difference (P > .05) in percentage body weight, relative organs weight and food and water consumption compared to control group and Median Lethal Oral Dose (LD50-value) was estimated to be > 2000 mg/kg body weight. Groups treated with A. harlana, A. mcloughlinii, A. pirottae and unidentified/AHU53 showed overt signs of toxicity and significance difference (P 300 mg/kg body weight. This acute oral toxicity test revealed the importance of safety concern while using Aloe species in traditional medicines.

Fedratinib is an oral and selective kinase inhibitor with activity against wild type and mutationally activated Janus kinase 2 and FMS-like tyrosine kinase 3, for the treatment of adult patients with intermediate-2 or high-risk primary or secondary myelofibrosis. This open-label mass balance study in healthy subjects investigated the excretion balance and systemic exposure of radioactivity after oral administration of [14C]-fedratinib; and the pharmacokinetics of fedratinib and its contribution to overall exposure of radioactivity. Six healthy males received a single oral dose of 200 mg [14C]-fedratinib base (2.775 MBq, 75 μCi) as a solution. Blood, urine and feces samples were collected for up to 35 day postdose. Urine and feces samples were collected until the 24-h excretion of radioactivity fell below 0.5% of administered dose (at least 14 day postdose). Expired air was collected up to 8-h postdose. Total radioactivity (blood, plasma, urine, feces, and expired air) and fedratinib concentrations (plasma) were measured. Approximately 77% (23% unchanged) of fedratinib derived radioactivity was excreted in feces and 5% (3% unchanged) was excreted in urine. Excretion via expired air was negligible. The time to maximum concentration for both total radioactivity and parent drug was similar, with unchanged drug representing the majority of the circulating radioactivity. The ratio of blood to plasma concentration of radioactivity ranged from 0.615 to 0.753 indicating limited distribution of fedratinib and/or its metabolites into red blood cells. Fedratinib derived radioactivity was primarily excreted in feces following a single oral dose of radiolabeled fedratinib to healthy subjects.

We have previously reported that prenatal alcohol exposure (PAE) in the 2nd trimester-equivalent of gestation is associated with increased N-methyl- d -aspartate (NMDA)-induced generalized tonic-clonic seizures (GTCSs) prevalence in postpartum developing rats. Whether the 1st trimester-equivalent of gestation is also a vulnerable period for developing GTCSs following PAE is unknown. Here, we investigated the effects of a single episode of PAE at embryonic day 8 (E8, in the 1st trimester-equivalent) or E18 (in the 2nd trimester-equivalent) on NMDA-induced seizures in developing rats at postnatal day 7 (P7, the equivalent of preterm newborns) and P15 (the equivalent of term infants). Pregnant Sprague–Dawley rats were given a single oral dose of ethanol (5 g/kg body weight) at E8 or E18 and the postpartum rats were tested for the susceptibility to NMDA-induced seizures at either P7 or P15. NMDA-induced seizures consisted of wild running-like behavior (WRLB), flexion seizures (FSs), clonic seizures (CSs), GTCSs, and tonic seizures (TSs); these seizures were observed in both control-treated and PAE-treated, male and female, P7 and P15 rats. Quantification reveals that the overall prevalence of CSs, GTCSs and TSs occurrence were significantly increased in the E18-PAE group compared to E8-PAE group, adjusting for sex and postnatal day. Furthermore, the overall prevalence of FSs and TSs occurrence was significantly increased in PAE-treated males compared to females, adjusting for embryonic stage and postnatal day. The overall prevalence of WRLB and FSs occurrence was also increased in PAE-P7 rats compared to PAE-P15 rats, adjusting for sex and embryonic stage. We conclude that the susceptibility to develop GTCSs was higher when PAE occurred in the 2nd rather than in the 1st trimester-equivalent of gestation.

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.

Introduction This study characterized the pharmacokinetics (PKs) of a donepezil patch formulation currently under development, using mixed effect modeling analysis, and explored optimal patch dosing regimens in comparison with the donepezil oral formulation. Methods PK data used in this analysis were from 60 healthy Korean male subjects participating in two Phase I studies, where subjects received single or multiple doses of donepezil of 43.75, 87.5, and 175 mg via patches, and 12 of them received a single oral dose of 10 mg of donepezil, followed by a single dose of donepezil via a patch. Donepezil PKs were analyzed by nonlinear mixed effect modeling using NONMEM software. Results A well-stirred model with two-compartment distribution and delayed absorption was chosen as the best model for the oral formulation. The PKs of donepezil after the patch applications were best described by a two-compartment linear model with zero-order absorption (D2) and absorption delay. The relative bioavailability (BA) of donepezil after the patch application compared with oral dosing was described to be affected by the duration of patch application. Conclusion PK simulations based on the chosen PK models suggested that, overall, donepezil exposure in plasma is similar whether with 10 mg of oral donepezil every 24 h or a 175 mg patch every 72 h, and likewise with 5 mg of oral donepezil every 24 h or an 87.5 mg patch every 72 h.

Homeovox, a multicomponent homeopathic treatment for laryngitis of various etiologies, was tested for allergenic properties and immunotoxicity.Methods. 80 male albino guinea pigs and 180 male СВА, C57BL/6 and F1 hybrid (CBAхС57BL/6) mice were used in the study. In order to assess immunotoxicity, Homeovox was administrated orally to mice for 14 days at doses of 100 mg/kg and 1 000 mg/kg. To assess the allergenic properties of Homeovox, albino guinea pigs were also given the drug at doses of 100 mg/kg and 1 000 mg/kg according to the standard immunization schedules.Results. Oral administration of Homeovox to mice for 14 days at doses of 100 mg/kg and 1 000 mg/kg did not cause significant changes in the main characteristics of immune response compared to controls. When assessing allergenicity, Homeovox at doses 100 mg/kg and 1 000 mg/kg administered according to the standard immunization schedules did not induce systemic anaphylaxis or active skin anaphylaxis in albino guinea pigs. The immunization of guinea pigs by Homeovox at the same doses in a mixture with Freund's complete adjuvant caused no delayed allergic reactions. Homeovox at a single oral dose of 1 000 mg/kg significantly decreased concanavalin A-induced inflammation in CBA mice by 58.4 %.Conclusion. Within the dosage range investigated, Homeovox does not induce immunotoxicity, immediate- or delayed-type allergic or pseudoallergic reactions.

Fedratinib is an orally administered Janus kinase 2-selective inhibitor that is indicated for the treatment of adult patients with intermediate-2 or high-risk myelofibrosis in the United States. Fedratinib is metabolized by multiple cytochrome P450s (CYPs) in vitro, with the predominant contribution from CYP3A4. The primary objective of this study was to evaluate the effects of 14-day repeated 200 mg twice daily (BID) oral doses of a strong CYP3A4 inhibitor, ketoconazole, on a sequential ascending single oral dose of fedratinib in healthy male subjects. An open-label, fixed-sequence, two-treatment cross-over study was conducted. Two cohorts of healthy adult males received two single doses of fedratinib (50 mg in Cohort 1 and 300 mg in Cohort 2) with one dose administered alone on Day 1 of Period 1 and the other dose coadministered with ketoconazole in the morning of Day 6 of Period 2. Subjects in both cohorts received 200-mg BID (Days 1–14) ketoconazole during Period 2. Coadministration of repeated 200-mg BID oral doses of ketoconazole for 14 days increased fedratinib exposure by 3.85- and 3.06-fold for area under the plasma concentration–time curve from time zero to infinity following a single oral dose of fedratinib of 50 and 300 mg, respectively. Oral administration of a single dose of 50 or 300 mg of fedratinib, administered alone or coadministered with steady-state ketoconazole, was safe and tolerable in the healthy male subjects. These results serve as the basis for fedratinib dose reduction when fedratinib is coadministered with strong CYP3A4 inhibitors.

The objective of this study was to assess the anti-inflammatory effects of ribes rubrum oil at three different doses (5, 10 and 15 ml/kg b.w/day) in adult male albino rats with indomethacin-induced stomach ulcers (IND). Forty rats (135±5g) categorized into 5 groups (n=8), for 45 days. Group (1) normal control, thirty-two rats were gavaged IND as single oral dose (30mg/Kg b.w) resulted in gastric ulcer, then distributed to four groups, group (2) IND-intoxicated control, Groups 3, 4 and 5 were administrated ribes rubrum oil at levels of (5, 10 & 15 ml/kg b.w) respectively. Administrated levels of ribes rubrum oil found to have remarkable elevation in food conversion efficiency in experimental rats, gastric juice pH, in compared to the drunken control group, gastric prostaglandin E2 and gastric cytochrome P450 reductase levels were lower. The levels of pro-inflammatory cytokines NO, TNF-, and IL-1 were dramatically reduced, which was related with an increase in blood hemoglobin (Hb), packed cell volume (PCV), and red blood cells (RBCs)in ulcerogenic rats compared to intoxicated control. Data showed that, the main components of ribes rubrum oil are β-Pinene, γ-linolenic and Linalool oxide levels (25.9 %, 23.10 % and 10.5%, respectively) for their antioxidant activity. Findings showed that administrate ribes rubrum oil at dose 15 ml/kg followed by 10 ml/kg had the best results against ulcerogenic rats. In conclusion, the outcomes are consistent with the concept that ribes rubrum oil had a gastroprotective and antisecretory effects against gastric ulcer that may be attributed to the antioxidant properties of the oil that ameliorates the damage occur in gastric of rats.

Baloxavir marboxil, a novel influenza therapeutic agent, is a prodrug rapidly metabolized into its active form, baloxavir acid, which inhibits cap‐dependent endonuclease. This study evaluated the pharmacokinetics (PKs) and safety of baloxavir acid in healthy Korean subjects and compared them with published data in Japanese subjects. This open‐label and single‐ascending dose study was conducted in 30 Korean male subjects, with a single oral dose of baloxavir marboxil (20, 40, or 80 mg) administered to eight subjects each; additionally, 80 mg was administered to six subjects (body weight >80 kg). Noncompartmental and population PK analyses were performed, and results were compared with those of Japanese subjects. Appropriateness of the body weight‐based dosing regimen was evaluated by simulation. PK profiles of baloxavir acid revealed multicompartment behavior with a long half‐life (80.8–98.3 h), demonstrating a dose‐proportional increase. Baloxavir acid reached peak plasma concentration from 3.5 to 4.0 h postdosing. Body weight was identified as a significant covariate of apparent oral clearance and apparent volume of distribution, which was similar to that observed in Japanese subjects. Body weight‐adjusted analysis revealed that exposure to baloxavir acid did not significantly differ between Korean and Japanese subjects. Simulated exposures to baloxavir acid demonstrated that the body weight‐based dosing regimen for baloxavir marboxil was appropriate. Based on a PK study, clinical data including dosing regimen developed in Japan were adequately extrapolated to Korea, supporting the approval of baloxavir marboxil in Korean as a new treatment option for influenza.

Little information on the human metabolism and urinary elimination of hydrafinil (9-fluorenol) exists. In order to support preventive anti-doping activities concerning compounds such as hydrafinil, a pilot elimination study was conducted with three healthy male volunteers receiving a single oral dose of 50 mg of hydrafinil. Urine samples were collected prior to and up to 72-h post-administration and were subjected to both gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry, which allowed for the identification of the intact drug as well as Phase I and Phase II metabolites, primarily hydroxylated and/or glucuronidated or sulfo-conjugated hydrafinil. The identity of these metabolites was corroborated by high-resolution/high-accuracy tandem mass spectrometry, and the applicability of routine doping control workflows for the detection of hydrafinil and its main metabolites was assessed. Therefore, two findings of hydrafinil and its metabolites were recorded, which concerned out-of-competition doping control samples and, hence, were not pursued with confirmatory analyses. Yet, the initial testing procedure results indicate that hydrafinil might require consideration in sports drug testing programs to ensure its detection, if classified as prohibited by the World Anti-Doping Agency (WADA).

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 Subtilisin QK is a serine protease in the subtilisin family, and is fermented by Bacillus subtilis QK02. The fibrinolytic activity of subtilisin QK was measured by detecting low molecular weight degradation products using a spectrophotometric method developed by Japan Bio Science Laboratory Co., Ltd. Subtilisin QK powder can maintain its fibrinolytic activity for more than 24 months when it is stored at room temperature and protected from light. Our previous results showed that subtlisin QK directly degraded cross-linked fibrins in the fibrin plate assay and effectively inhibited thrombosis in the mouse thrombus model. The aim of this study was to determine the acute toxicity, potential subchronic toxicity, and safety pharmacology of subtilisin QK in Sprague–Dawley (SD) rats. Methods In the acute toxicity study, a single oral dose of 100,000 FU/kg was administered to 10 female and 10 male SD rats. In the 28-day subchronic toxicity, 60 female and 60 male SD rats were randomly assigned to four experimental groups (daily oral dose of 0, 2500, 7500 and 25,000 FU/kg). In the safety pharmacology study, 20 female and 20 male SD rats were randomly assigned to four experimental groups (single oral dose of 0, 500, 1500 and 5000 FU/kg). Results No death occurred and no adverse effects were observed in the acute toxicity study at a dose of 100,000 FU/kg. In the 28-day subchronic toxicity study, several hematological and blood biochemical parameters showed increases or decreases; however, due to the lack of a dose–response relationship, these differences were considered unrelated to treatment. In the safety pharmacology study, no adverse effects were observed on the central nervous of SD rats post-administration up to a dose of 5000 FU/kg subtilisin QK. Conclusion The results showed that oral consumption of subtilisin QK is of low toxicological concern. No adverse effects were observed at doses of 2500, 7500, and 25,000 FU/kg in the 28-day subchronic toxicity, and the no-observed-adverse-effect level (NOAEL) of subtilisin QK was 25,000 FU/kg.

Ponazuril, a novel coccidiocidal triazinetrione, has shown promise in addressing apicomplexan diseases in mammals and birds. This study describes the pharmacokinetics of ponazuril in healthy adult Indian peafowl (Pavo cristatus) following a single oral dose administered at two different dosages. Peafowl (four males and four females) were administered compounded ponazuril at 20 or 40 mg/kg orally in a double crossover design, with a 2-wk washout period. Blood was collected from each bird at 2, 4, 8, 24, 48, 72, 96, and 120 h after administration for plasma concentration of ponazuril using high-pressure liquid chromatography. Fecals were evaluated for coccidial shedding for 3 consecutive d prior to the ponazuril trial, 1 wk after the first dose of ponazuril, and 1 wk after the second dose of the trial. After the first trial, one peafowl administered 20 mg/kg ponazuril was shedding coccidia, but no coccidia were detected by the end of the second trial. Ponazuril reached peak concentrations (Tmax) at 21.38 h + 5.25 and 22.04 h + 7.39, and peak concentration (Cmax) were 11.82 µg/ml + 3.01 and 18.42 µg/ml + 4.13, for 20 and 40 mg/kg doses, respectively. Ponazuril was detected at 120 h with a concentration of 9.48 µg/ml + 2.59 and 12.25 µg/ml + 2.89 and a half-life of 219.4 + 58.7 h and 186.7 + 58.7 h, for and 40 mg/kg doses, respectively. Ponazuril in peafowl was well absorbed orally, plasma concentrations increased with dose, and elimination was slower than current dosages for birds would suggest. No obvious adverse effects were observed at either dosage.

International audience; Anxiety appears among the most frequent psychiatric disorders. During recent years, a growing incidence of anxiety disorders can be attributed, at least in part, to the modification of our eating habits. To treat anxiety disorders, clinicians use benzodiazepines, which unfortunately display many side effects. Herein, the anxiolytic-like properties of two natural products (αS1–casein hydrolysate and Gabolysat®) were investigated in rats and compared to the efficacy of benzodiazepine (diazepam). Thus, the conditioned defensive burying test was performed after a unique oral dose of 15 mg/kg, at two time-points (60 min and then 30 min post oral gavage) to show potential fast-onset of anxiolytic effect. Both natural products proved to be as efficient as diazepam to reduce the time rats spent burying the probe (anxiety level). Additionally, when investigated as early as 30 min post oral gavage, Gabolysat® also revealed a fast-anxiolytic activity. To date, identification of bioactive peptide, as well as how they interact with the gut–brain axis to sustain such anxiolytic effect, still remains poorly understood. Regardless, this observational investigation argues for the consideration of natural compounds in care pathway.

Triatomines are vectors of American Trypanosomiasis also known as Chagas´ disease where several reservoirs including dogs are involved in the transmission cycle of the causal agent (Trypanosoma cruzi). Considering that the prevalence of American trypanosomiasis in dogs is higher than in humans and that dogs in addition are susceptible of this disease, and are involved in peridomestic transmission to humans, the search for new alternatives for vector control of the triatomines responsible for transmission in dogs is required. Over the 20 weeks the study lasted, 600 individual female, adult of Rhodnius prolixus were offered to the 15 dogs treated with a single oral dose of Fluralaner (Bravecto®, MSD). Feeding pattern of triatomines was not affected by the treatment during the whole study. The fluralaner-induced mortality of R. prolixus had a significant effect until week 12 at which time 100% mortality was observed. Mortality decreased to 67.5% at week 16 to practically nil 0.8% on week 20. Fluralaner achieved 100% mortality of triatomines between 12- and 48-h post-feeding. It was demonstrated that a single oral dose of fluralaner in dogs is highly effective in producing mortality in adult R. prolixus for the time guaranteed by the manufacturer for other blood-sucking insects, with a considerable effective residual effect for up to 16 weeks. Due to this high efficacy, fluralaner could be considered in strategies to control the transmission vectors of Chagas disease in dogs and in turn decrease the peri-domestic transmission cycle, particularly in hyperendemic areas.

Purpose The aim of this study is to assess the bioequivalence of a new generic formulation and the branded formulation of levocetirizine dihydrochloride in healthy Chinese volunteers under fasting and fed conditions, and food-intake effect on the pharmacokinetic properties is also evaluated. Patients and methods Volunteers were randomly allocated into two groups to receive a single oral dose of generic formulation and branded formulation under fasting or fed conditions, respectively. Blood samples were collected at designated time points. Plasma concentrations of levocetirizine were determined by UFLC-MS/MS. Safety evaluations were carried out through the study. The main pharmacokinetic parameters of the two formulations of levocetirizine were calculated using non-compartmental analysis incorporated in WinNonlin® 7.0 software. Results Forty-nine volunteers were enrolled; 46 completed the studies. Under fasting and fed conditions, the 90% confidence intervals for the geometric mean of generic/branded ratios were in the range of 94.75–107.24% and 99.98–114.69% for the maximum observed concentration, and 97.13–102.50% and 98.36–103.98% for the area under the concentration–time curve. As a result of food intake before administration, the reduced rate and extent of absorption of levocetirizine were observed. Both formulations were generally well tolerated, with no serious adverse reactions reported. Conclusion The two formulations demonstrated essentially identical pharmacokinetic profiles and were all well within the FDA/CFDA bioequivalence standards. Meanwhile, food intake can delay the absorption rate and reduced the bioavailability of levocetirizine in healthy Chinese volunteers., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/-Xhw5uFbQfw

We evaluated single oral dose of delafloxacin versus single intramuscular ceftriaxone in participants with uncomplicated urogenital gonorrhea (primary objective). Secondary objectives included the efficacy, safety, and tolerability of delafloxacin versus ceftriaxone for uncomplicated urogenital, rectal, and/or pharyngeal gonorrhea.In this open-label, multicenter study, 460 participants at 25 study centers were randomized (2:1) to receive a single 900-mg oral dose of delafloxacin or 250-mg intramuscular ceftriaxone. Neisseria gonorrhoeae culture, nucleic acid amplification test, and clinical responses were evaluated. The primary efficacy end point was the urogenital microbiological cure in the urogenital microbiological intention-to-treat population; noninferiority (NI) was assessed using a 10% NI margin.In the urogenital microbiological intention-to-treat population, urogenital cure rates for delafloxacin were 85.1% (194/228) versus 91.0% (91/100) for ceftriaxone (95% confidence interval, -13.18% to 1.36%). Because the lower bound of the confidence interval exceeded the prespecified -10% NI margin, delafloxacin did not demonstrate NI to ceftriaxone. Treatment failures were more often associated with N. gonorrhoeae with higher delafloxacin minimum inhibitory concentration (MIC) values. In microbiologically evaluable participants, failure occurred in 1 (0.6%) of 177 urogenital infections caused by isolates with delafloxacin MICs0.008 μg/mL and 31 (64.6%) of 48 infections caused by isolates with delafloxacin MICs ≥0.008 μg/mL. Gastrointestinal adverse events were common with 900-mg of delafloxacin and typically included mild to moderate diarrhea, flatulence, nausea, and vomiting. The most common adverse event was diarrhea in both treatment groups.A single 900-mg dose of delafloxacin is not a reliable treatment of uncomplicated urogenital gonorrhea. Treatment failures were common in infections caused by N. gonorrhoeae with delafloxacin MICs ≥0.008 μg/mL. Additional testing with alternative dosing regimens could be considered.ClinicalTrials.gov Identifier: NCT02015637.

Aims: To determine the median lethal dose (LD50) of crude ethanolic leaf extract of Phyllanthus amarus and evaluate its sub-chronic oral toxicity in experimental mice (BALB/C strain). Study Design: One-factor, one-control, one-test group experimental design. Place and Duration of Study: Department of Medical Biochemistry, Delta State University, Abraka, Nigeria, between December, 2014 and November, 2015. Methodology: Crude ethanolic leaf extract of P. amarus was prepared as previously described and twenty (20) Swiss albino mice (BALB/C strain) were randomly and equally divided into two (2) groups and administered 2000 mg/kg body weight (Group A) and 5000 mg/kg body weight (Group B) of the prepared extract as single oral dose in line with the limit dose method of determining LD50. For the sub-chronic oral toxicity study, ten (10) mice were assigned into control (n=5) and experimental (n=5). The control animals were given placebo-normal saline, but the experimental mice were administered with nocebo – 300 mg/kg body weight of P. amarus crude ethanolic extract for twenty one (21) days. Thereafter, the animals in each group were sacrificed and then, serum and liver homogenate were obtained for the assay of total antioxidant capacity (TAC) and oxidative damage (Malondialdehyde-MDA) Using documented methods. Liver tissue was also processed for histopathological examination using H&E stain. Results: Data showed LD50 of the extract to be greater than 5000 mg/kg. Assessment of the herb’s sub-chronic oral toxicity indicates that the leaf extract significantly (P=.03) enhanced total antioxidant capacity (TAC) in both serum (Control: TAC = 0.10±0.03 mM, Experimental: TAC = 0.33±0.05 mM) and liver (Control: TAC = 0.12±0.09 mM, Experimental: TAC = 0.34±0.06 mM) but reduced (P = .01) the biomarker for liver tissue damage (Control: MDA = 41.89±3.36 µM, Experimental: MDA = 4.67±4.04 µM). In addition, hepatic cells were invigorated by P. amarus treatment as suggested by the histopathological features. Conclusion: Collectively, P. amarus crude ethanolic leaf extract possesses high degree of tolerance and hepatic tonic potential with no identifiable toxic or side effects.

Objective: Pharmacokinetic evaluation of montelukast sodium chronomodulated capsules (sustained-release solid dispersion of drug enclosed in pH-sensitive film-coated hard gelatin shell) and marketed tablets has been carried out in this study. Methods: A single oral dose of prepared capsules and marketed conventional tablets was administered in healthy male Dunkin-Hartley albino guinea pigs. Blood samples were collected at different time intervals and plasma concentration of drug was determined by reversed-phase high-performance liquid chromatography. Different pharmacokinetic parameters were assessed from plasma drug concentration-time profile by one-compartment model, first-order kinetics. Results: Pharmacokinetic parameters such as time to reach maximum concentration, elimination rate constant, elimination half-life, and mean residence time data indicates that drug release from chronomodulated capsules is significantly prolonged with initial release lag time of 3.5–4 h in comparison with marketed conventional tablets. However, maximum drug plasma concentration, area under the concentration-time curve, and apparent volume of distribution values show non-significant difference between capsules and marketed tablets. Conclusion: The findings specified that capsules were providing time controlled delivery of drug at a desired rate for prolonged time, which may be helpful for the prevention of episodic attack of asthma in early morning hours.

Purpose. We evaluated potential drug-drug interactions between cilostazol and simvastatin, both CYP3A substrates, in healthy subjects. Methods. An open-label, two-period, fixed-sequence clinical study was conducted. Seventeen subjects were given a single oral dose of simvastatin 40 mg on day 1 and multiple oral doses of cilostazol 100 mg twice daily on days 2 to 5 followed by a single dose of cilostazol and simvastatin on day 6. Plasma concentrations of simvastatin and its active metabolite, simvastatin acid, were measured using liquid chromatography-tandem mass spectrometry for pharmacokinetic assessment. Moreover, serum lipid profiles under fasting conditions were determined. Results. The geometric mean ratios of the area under the plasma concentration-time curve from time zero to time infinity of simvastatin combined with cilostazol to that of simvastatin alone were 1.64 (90% CI, 1.38-1.95) for simvastatin and 1.31 (1.04-1.66) for simvastatin acid. In addition, coadministration with cilostazol significantly increased the maximum concentration of simvastatin and simvastatin acid, up to 1.8-fold and 1.6-fold, respectively. However, the effects of a single dose of simvastatin on serum lipid profiles were not affected notably when simvastatin was coadministered with cilostazol. Conclusions. Multiple doses of cilostazol increased the systemic exposure of simvastatin and simvastatin acid following a single dose of simvastatin.

OBJECTIVE: To determine the pharmacokinetics of a single oral dose of trazodone and its effect on the activity of domestic pigeons (Columba livia). ANIMALS: 6 healthy adult male domestic pigeons. PROCEDURES: During the first of 3 experiments, birds received orally administered trazodone at doses ranging from 3 to 30 mg/kg to determine the dose for subsequent experiments. During the second experiment, each bird received 1 dose of trazodone (30 mg/kg, PO). Blood was collected for determination of plasma trazodone concentration before and at predetermined times for 24 hours after drug administration. Pharmacokinetic parameters were calculated by noncompartmental analysis. During experiment 3, birds were instrumented with ultralightweight accelerometers and received orally administered trazodone (30 mg/kg) or an equal volume of water twice at a 48-hour interval. Activity of birds was monitored for 24 hours after administration of each treatment. RESULTS: No adverse effects were observed. Mean ± SD terminal half-life of trazodone was 5.65 ± 1.75 hours. Plasma trazodone concentrations remained > 0.130 μg/mL for approximately 20 hours. Trazodone did not affect the activity of birds during the first 2 and 15 hours after administration. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that oral administration of 1 dose (30 mg/kg) of trazodone to healthy pigeons was safe and resulted in plasma drug concentrations that were similar to those considered therapeutic in humans and dogs for up to 20 hours. Further research is necessary to characterize the pharmacokinetics for repeated doses as well as the clinical effects of trazodone in birds with behavior problems.

Introduction and objectives: Adhesive bowel obstruction is considered one of the commonest causes of intestinal obstruction managed in daily practice, medical schools differ in management plans from conservative to interventional measures with increased morbidity and mortality with recurrent surgical interventions, the aim of our study is to evaluate the therapeutic role of oral water soluble contrast (urographin) in treatment of early adhesive intestinal obstruction. Patients and methods: All pediatric patients presented at our units in the period from December 2016 to December 2017 by early adhesive intestinal obstruction were included in this study. All patients were given conservative treatment for 24 hours (nothing per mouth, insertion of nasogastric tube, and intravenous fluids). Patients with failure of improvement after 24 hours were divided to 2 groups in the first group we continued the same conservative measures for 48 hours, in the second group we used single oral dose of urographin. Follow up of the patients was done clinically and radiologically for another 48 hours. Demographic data, type of first surgery, results, complications, and outcome all were collected and statistically analyzed. Results: The study included 35 patients, oral urographin was used in 14 patients, and we continued traditional measures in 21 patients. The mean duration of hospital stay in the urographin group was 3.36 ± 0.49 while in the conservative group was 6.24 ± 0.89 with P value

LC/MS quantification of leukotoxin (LTX) and leukotoxin diol (LTXdiol) in plasma has been previously reported, however large sample volumes are required for achieving stated assay Lower Limit of Quantification (LLOQ). Reported here is a fit-for-purpose LC/MS method that reduces plasma volume from 700 to 25 µL and omits pre-concentration steps. These improvements make for a method with increased utility in mouse studies offering limited sample volumes. Additionally, omitting pre-concentration steps streamlines sample processing, which can now be completed in under 10 min. This method can be used to quickly answer if the ratio of LTX to LTXdiol changes with the dose of the therapeutic drug so this could be used as a potential biomarker for correlating PK/PD effects. No extensive assay characterization was performed before application to an exploratory in-life study. Basal levels of LTX and LTXdiol in plasma were quantified by LC-MRM across 10 individual mice, and the average signal-to-noise was 36 for LTX and 3039 for LTXdiol, with CVs of 29.4% and 15.2%, respectively. Addition of LTX and LTXdiol reference standard at 5, 25, and 75 ng/mL into pooled mouse plasma was quantifiable within 30% relative error using a surrogate matrix calibration curve ranging from 0.8 to 200 ng/mL. The average ratio of LTX to LTXdiol across the 10 mice was 0.32, consistent with previous reports. Finally, the method was applied to a mouse PK/PD study to monitor LTX/LTXdiol kinetics after a single oral dose of a soluble epoxide hydrolase inhibitor. The mean plasma ratio of LTX to LTXdiol increased up to 10-fold by 3 h post-dose followed by a decrease to near pre-dose levels by 24 h, consistent with transient inhibition of sEH-mediated conversion of LTX to LTXdiol. The method improvements described here will make subsequent quantification of LTX and LTXdiol in mouse studies significantly easier.

Rilpivirine is a non-nucleoside reverse transcriptase inhibitor, used for the treatment of human immunodeficiency virus type-1 infection. An open label study was conducted to investigate the pharmacokinetics (PK) and safety of a single oral dose of rilpivirine 25 mg in Japanese healthy adult subjects. No adverse events were reported. The mean Cmax (144.3 ng/mL) and AUCinf (4542 ng h/mL) in Japanese subjects were approximately 30 % higher than those reported from a similar study in Caucasian healthy subjects, whereas the median tmax and mean t1/2 values were comparable between studies. A simple physiologically based PK model was developed to characterize the rilpivirine PK profile. The model adequately described rilpivirine PK profiles, and well-predicted drug-drug interactions. With exploration using the model, body size and CYP3A4 abundance were identified as factors which explained the observed inter-ethnic difference in rilpivirine exposure. The inter-ethnic difference in rilpivirine exposure was however considered not clinically relevant, since inter-individual variabilities of those intrinsic factors are larger than inter-ethnic ones; and the observed AUCinf in Japanese subjects was within the range of AUCtau associated with efficacy and safety in Phase 3 studies. This study results support the use of rilpivirine without dose modification specific to Japanese patients.

This experimental challenge study assessed immune protection 1 year after a single dose of live-attenuated oral Bordetella bronchiseptica (Bb) vaccine in dogs. Forty Bb-seronegative 7-9-week-old puppies were randomly assigned at Day 0 to receive a single oral dose of either Bb vaccine (n = 20; vaccinated group) or sterile water (n = 20; control group). Groups were housed separately until comingling 1 day pre-challenge (Day 365). Challenge with virulent aerosolized Bb occurred at Day 366. Clinical scores were obtained at Days 1-7, and 366-380. Bb microagglutination test (MAT) titers were obtained at Days -7, 0, monthly post-vaccination, and Days 358, 365, and 380. Nasal swabs were collected for microbiological assessment at Days -7, 0, 365, and 367-380. Oral Bb vaccination was not associated with side effects. Pre-challenge, vaccinated dogs developed persistent Bb MAT titers and control dogs remained seronegative. Post-challenge, duration of cough was longer in control dogs (least square means [LSM], 8.6 days) than vaccinated dogs (LSM, 1.5 days; P0.0001), with more control dogs having cough on 2 or more consecutive days (control group, n = 17/19, 89.5%; vaccinated group, n = 3/19, 15.8%; P = 0.0011). Post-challenge, Bb shedding occurred in all control dogs and 5/19 (26%) vaccinated dogs. Average duration of Bb shedding was longer in the control group (11.9 days vs. 0.6 days; P0.0001) and nasal Bb loads were higher in the control group (P0.00001). Orally administered Bb vaccine stimulated immunity that was still protective against virulent Bb challenge after 1 year.

Objectives The anti-inflammatory activity of Boswellia serrata extracts (BSE) is well known. BSE comprises boswellic acids (BA) such as 3-O-acetyl-11-keto-beta-boswellic acid (AKBA) and 11-keto-boswellic acid (KBA) as major constituents. One of the limitations of BAs is their poor oral bioavailability. The aim of the study was to prepare solid lipid particles of Boswellia serrata extract (SLBSP) to enhance the bioavailability of BAs. Methods The pharmacokinetic profile of BAs was studied in 10 healthy human volunteers following a single oral dose of 333 mg of SLBSP. Pharmacokinetic blood samples were collected at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, and 12 h post drug administration. Plasma KBA and AKBA levels were measured using a validated LC-MS/MS method. Pharmacokinetics parameters were estimated using Pheonix WinNonlin (Build 6.4.0.768) software. Results Ten healthy human volunteers were included and peak plasma concentration was achieved in 1.5 and 2.3 h for AKBA and KBA respectively. Maximum plasma concentration (C max) was 8.04 ± 1.67 ng/mL for AKBA and 23.83 ± 4.41 ng/mL for KBA whereas the corresponding area under the concentration-time curve (AUC) was 136.7 ± 56.77 ng/mL*h and 165.7 ± 24.5 ng/mL*h respectively. The elimination half-life (t 1/2) of AKBA and KBA was 6.8 ± 3.0 h and 2.45 ± 0.3 h respectively. Conclusions The SLBSP formulation of BSE showed enhanced oral bioavailability of BAs compared with historically reported data of unformulated BSE.

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 The aim of study was to evaluate the single oral dose and 28 day repeated oral administration toxicity profile of the synthetic compound Gαq-RGS2 signaling inhibitor, (1-(5-chloro-2-hydroxyphenyl)-3-(4-(trifluoromethyl)phenyl)-1 H-1,2,4-triazol-5(4 H)-one) as per OECD guideline 425 (2008a) and 407 (2008b), respectively. Results In acute toxicity study, a single oral dose administration of Gαq-RGS2 signaling inhibitor did not show any mortality at doses of 5, 50, 300 and 2000 mg/kg within 24 h and 14 days. The treatment of Gαq-RGS2 signaling inhibitor at dose 10 and 100 mg/kg for 28 days did not show any mortality, significant changes in the increase of body weight, various organ damage markers, hematological parameters, relative organ/body weight ratio and microscopic anatomical texture of essential organs as compared to vehicle and normal control. Conclusions A single oral administration of Gαq-RGS2 signaling inhibitor up to dose of 2000 mg/kg in mice and repeated administration of Gαq-RGS2 signaling inhibitor at higher dose 100 mg/kg for 28 days in the rats is safe.

Objective To assess the effect of green tea intake on the pharmacokinetics of the β-blocker celiprolol. Materials and method In an open-label crossover study, 3 healthy subjects were given water or a green tea beverage daily for 3 days. On day 4, each subject received a single oral dose of 200 mg celiprolol with water or green tea. Serum and urinary concentrations of celiprolol were measured for up to 24 hours. Results Green tea intake decreased the area under the serum concentration-time curve and urinary excretion of celiprolol by 98.6 and 98.0%, respectively. Conclusion Green tea intake might have a negative impact on the clinical effectiveness of celiprolol.