Comparative Pharmacokinetic Profiles of a Novel Low-dose Micronized-isotretinoin 32 mg Formulation and Lidose-isotretinoin 40 mg in Fed and Fasted Conditions: Two Open-label, Randomized, Crossover Studies in Healthy Adult Participants.

Two open-label, crossover studies compared the bioavailability of Micronized-isotretinoin 32 mg and Lidose-isotretinoin 40 mg in healthy adults. In the fed bioequivalence/food-effect study, participants (n = 71) received single doses of fed-state Micronized-isotretinoin 32 mg, fed-state Lidose-isotretinoin 40 mg and fasted-state Micronized-isotretinoin 32 mg. In the fasting study, participants (n = 18) received single doses of fasted-state Micronized-isotretinoin 32 mg and fasted-state Lidose-isotretinoin 40 mg. Bioavailability was assessed by isotretinoin LnAUC0­t, LnAUC0­∞ and LnCmax in blood samples taken pre-dosing and over 96 h post-dosing. The 90% confidence intervals for baseline-adjusted least squares geometric mean ratios for LnAUC0­t, LnAUC0­∞ and LnCmax fell within the 80­125% range for bioequivalence for fed-state Micronized-isotretinoin 32 mg vs. fed-state Lidose-isotretinoin 40 mg. Fasted-state Micronized-isotretinoin 32 mg had ~2 times higher bioavailability than fasted-state Lidose-isotretinoin 40 mg. Food had no effect on the rate and a marginal effect on the extent of absorption of Micronized-isotretinoin 32 mg.

Pharmacokinetic comparison and bioequivalence evaluation of losartan/ hydrochlorothiazide tablet between Asian Indian and Japanese volunteers.

OBJECTIVES: To demonstrate the bioequivalence between the test and reference formulations of losartan/hydrochlorothiazide 50 + 12.5 mg tablet and evaluate the effect of ethnicity on pharmacokinetics properties of losartan, losartan carboxylic acid and hydrochlorothiazide on healthy Asian Indian and Japanese volunteers. METHODS: Randomized, open-label, crossover, bioavailability studies were conducted separately in healthy Asian Indian and Japanese volunteers. One tablet either of test or of reference product was administered after 10 hours of overnight fasting. After dosing, serial blood samples were collected for a period of 48 hours for both the studies. Plasma samples were analyzed for losartan, losartan carboxylic acid and hydrochlorothiazide by a validated liquid chromatographic and mass spectrometric method (LC-MS/MS). The pharmacokinetic parameters AUC0-t, AUC0-∞, Cmax, tmax, and other pharmacokinetics parameters were determined from plasma concentration-time profiles for both test and reference formulations of losartan/hydrochlorothiazide 50 + 12.5 mg tablets. Statistical evaluations were done to evaluate bioequivalence between generic test formulation (EPR0001) and Japanese reference product (Preminent®). RESULTS: Losartan, losartan carboxylic acid and hydrochlorothiazide were well tolerated by subjects in all periods of each study under fasted conditions. No serious adverse events were observed. The ratios of least square means for AUC0-t and Cmax and the affiliated 90% confidence intervals were within acceptance range recommended by PMDA. Marginal differences were observed in pharmacokinetic values of Asian Indian and Japanese volunteers. CONCLUSIONS: The results of these bioavailability studies indicate that the test formulation of losartan/hydrochlorothiazide 50 + 12.5 mg (EPR0001) tablets is bioequivalent to marketed Preminent® reference formulation in Asian Indian and Japanese volunteers, when administered under fasting conditions. Both test and reference formulations were well tolerated as a single oral dose when administered to healthy adult subjects under fasted conditions. Although Asian Indian and Japanese volunteers are ethnically different, results of these studies indicate that pharmacokinetic parameters of Asian Indian and Japanese volunteers are comparable to each other in terms of bioavailability of losartan, losartan carboxylic acid and hydrochlorothiazide. Similar least square means ratios were obtained in Asian Indian and Japanese volunteers demonstrating that a bioequivalence study conducted on Japanese volunteers seems to be substituted by Asian Indian volunteers' studies.

Bioequivalence of oxycodone hydrochoride extended release tablets to marketed reference products OxyContin® in Canada and US.

INTRODUCTION: Oxycodone is a semisynthetic opioid agonist used for the relief of moderate to severe pain. A new generic oxycodone hydrochloride (HCl) extended release (ER) tablet is currently being developed by Ranbaxy Pharmaceutical Inc., New Brunswick, NJ, USA. OBJECTIVE: To assess relative bioavailability of a new generic (test) formulation of oxycodone hydrochloride (HCl) extended release (ER) tablets with that of marketed reference products, OxyContin®, in Canada and USA, in healthy adult subjects under fasting and fed conditions. METHODS: Five studies were conducted in all, three of which were designed to comply with the regulatory criteria for marketing a new generic formulation of OxyContin® in Canada and the remaining two to comply with regulatory criteria for marketing a new generic formulation of OxyContin® in the USA. Each study was a balanced, randomized two-period, two-treatment, two-sequence, crossover design. A single oral dose of test or reference product was given in Period 1, followed by a 7-day washout period, after which subjects received the alternative product in Period 2. In order to block the pharmacological effects of oxycodone, subjects were administered naltrexone HCl (1 × 50 mg tablet) 12 hours prior to oxycodone HCl administration, concurrent with oxycodone HCl administration, and 12 hours after oxycodone HCl administration. Throughout the confinement portion of the study, adverse events were closely monitored. Serial blood samples were collected, following which oxycodone in plasma was estimated using a validated analytical procedure. RESULTS: Oxycodone was well tolerated by subjects in both periods of each study under both fed and fasted conditions. No serious adverse events were observed. The ratios of geometric means for AUC0-t and Cmax and the affiliated 90% confidence intervals for AUC were within acceptance range recommended by Health Canada. These criteria were met for both the raw data as well as data corrected for measured drug content (potency). The ratios of geometric means and the 90% confidence intervals for AUC0-t, AUC0-∞ and Cmax were within acceptance range recommended by United States Food and Drug Administration (FDA). CONCLUSIONS: Results demonstrate that the test formulation of oxycodone HCl ER tablets is bioequivalent to marketed OxyContin® reference formulations in Canada and USA, when administered both under fasted and fed conditions. Additionally, oxycodone HCl ER tablets were well tolerated as a single oral dose when administered to healthy adult subjects under fasted and fed conditions.

Clinical safety and pharmacokinetic evaluation of aqueous extract of Cocculus hirsutus, an anti-viral phytopharmacetical drug as a potential for the treatment of dengue and COVID-19.

Background and aim: Dengue a worldwide concern for public health has no effective vaccine or drug available for its prevention or treatment. There are billions of people who are at risk of contracting the dengue virus (DENV) infections with only anti-mosquito strategies to combat this disease. Based on the reports, particularly in vitro studies and small animal studies showing anti-viral activity of aqueous extract of Cocculus hirsutus (AQCH), studies were conducted on AQCH tablets as a potential for the treatment of dengue and COVID-19 infections. The current study was part of the research on AQCH tablet formulation and was aimed to evaluate safety and pharmacokinetics in healthy human subjects. Materials and methods: Sixty healthy adult human subjects were divided into 5 groups (cohorts: I to V; n = 12 per cohort) and randomized in the ratio of 3:1 to receive active treatment or placebo in a blinded manner. Five doses 100 mg, 200 mg, 400 mg, 600 mg and 800 mg tablets were administered three times daily at an interval of 8 h for days 01-09 under fasting conditions and a single dose in morning on day 10. Safety assessment was based on monitoring the occurrence, pattern, intensity, and severity of adverse events during study period. Blood samples were collected for measurement of the bio-active marker Sinococuline concentrations by a validated LC-MS/MS method followed by pharmacokinetic evaluation. Results and conclusion: The test formulation was well tolerated in all cohorts. Sinococuline peak plasma concentration (Cmax) and total exposure of plasma concentration (AUC) demonstrated linearity up to 600 mg and saturation kinetics at 800 mg dose. There was no difference observed in elimination half-life for all the cohorts, suggesting absence of saturation in rate of elimination. Dose accumulation was observed and steady state was achieved within 3 days. The information on human pharmacokinetics of AQCH tablets would assist in further dose optimization with defined pharmacokinetic-pharmacodynamic relationship.

Novel corona virus (COVID-19); Global efforts and effective investigational medicines: A review.

Coronavirus disease-2019 (COVID-19), associated with the outbreak of deadly virus originating in Wuhan, China, is now a global health emergency and a matter of serious concern. Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is rapidly spreading worldwide, and WHO declared the outbreak of this disease a pandemic on March 11, 2020. Though some of the countries have succeeded in slowing down the rate of the spread of this pandemic, most the countries across the globe are still continuing to experience an increasing trend in the growth and spread of this deadly disease. Hence, in the current scenario, is has now become essential to control and finally irradicate this deadly disease using an effective vaccine. One can expect the prominent role of already available antivirals, antibodies and anti-inflammatory drugs in the market, in this pandemic. Immunomodulatory and biological therapeutics are also in the high expectations to combat COVID-19. RNA based vaccines might be more advantageous over traditional vaccines, to deal with the pandemic threat. Aiming towards this direction, clinical trials for SARS-CoV-2 vaccine are currently underway all across the globe. Currently, about 150 health related organizations and research labs are in the progress for the evolution of COVID-19 vaccines, globally. The initial aim of these clinical trials is to assess vaccine's safety, which is tested in Phase I/II/III studies where the primary outcomes typically examine the frequency of adverse effects. The vaccine is about to undergo phase III testing in several countries such as India, USA, South Africa, Brazil and England. US Government, under Operation Wrap Speed is even ready to sponsor three candidates, namely-The University of Oxford and AstraZeneca's AZD1222; Moderna's mRNA-1273; and Pfizer and BioNTech's BNT162 for Phase III trials.

Comparison of Analgesic Efficacy of Dexmedetomidine and Midazolam as Adjuncts to Lignocaine for Intravenous Regional Anesthesia.

BACKGROUND: Intravenous regional anesthesia (IVRA) is safe, technically simple, and cost-effective technique compared to general anesthesia with success rates of 94-98% for upper and lower limb surgeries. The main disadvantage of this procedure is its limited duration for surgery, lack of postoperative analgesia, and tourniquet pain. To overcome this disadvantage, various adjuvants to lignocaine have been studied from time to time. AIM: To compare the analgesic efficacy of dexmedetomidine and midazolam as adjuncts to lignocaine for IVRA for forearm and hand surgeries. SETTING AND DESIGN: The study was conducted by the Department of Anaesthesia of Medical College and patients posted for elective as well as the emergency forearm and hand surgeries were included in the study. It was a prospective comparative study. MATERIALS AND METHODS: Sixty patients of either sex belonging to the American Society of Anesthesiologists Class I and II, in the age range of 18-65 years, scheduled for upper limb orthopedic surgery, either elective or emergency, were included in the study. All patients were administered IVRA in this prospective, double-blind, randomized study. Patients enrolled in the study were randomly divided into two groups of thirty each. Group M-received 40 ml of 0.5% lignocaine with midazolam 50 µg/kg and Group D-received 40 ml of 0.5% lignocaine with dexmedetomidine 1 µg/kg. Time of onset of sensory block, duration of analgesia, total dose of fentanyl given, intraoperative blood pressure, oxygen saturation, heart rate, postoperative analgesia, and adverse effects were recorded and compared between the groups. STATISTICAL ANALYSIS USED: The statistical evaluation was performed using SPSS version 17.0 software. All values were calculated with a 95% confidence interval. The parameters were expressed as mean ± standard deviation and t-test was used for comparing demographic and clinical data. For comparisons, P < 0.05 was considered statistically significant. RESULTS: Mean duration of analgesia was 93 ± 28 min in dexmedetomidine group and 84 ± 28 min in midazolam group, and onset of sensory block was comparable in both groups. CONCLUSION: Dexmedetomidine and midazolam, when used as adjuvants to lignocaine for IVRA, significantly improve the intraoperative conditions by providing superior quality of block. The superiority of one over the other could not be established as midazolam produced the early onset of block and less requirement of fentanyl, whereas dexmedetomidine when added to IVRA provided longer duration of analgesia (93 ± 28 min) in comparison to midazolam (84 ± 28 min).

Experimental and theoretical studies on inhibition of mild steel corrosion by some synthesized polyurethane tri-block co-polymers.

Polyurethane based tri-block copolymers namely poly(N-vinylpyrrolidone)-b-polyurethane-b-poly(N-vinylpyrrolidone) (PNVP-PU) and poly(dimethylaminoethylmethacrylate)-b-polyurethane-b-poly(dimethylaminoethylmethacrylate) (PDMAEMA-PU) were synthesized through atom transfer radical polymerization (ATRP) mechanism. The synthesized polymers were characterized using nuclear magnetic resonance (NMR) spectroscopy and gel permeation chromatography (GPC) methods. The corrosion inhibition performances of the compounds were investigated on mild steel (MS) in 0.5 M H2SO4 medium using electrochemical measurements, surface analysis, quantum chemical calculations and molecular dynamic simulations (MDS). Potentiodynamic polarization (PDP) measurements revealed that the polymers are mixed-type corrosion inhibitors. Electrochemical impedance spectroscopy (EIS) measurements showed that the polymers inhibit MS corrosion by adsorbing on MS surface to form pseudo-capacitive interface. The inhibitive effects of the polymers increase with increasing concentration and decrease with increasing temperature. The adsorption of both the polymers on MS surface obey the Langmuir adsorption isotherm and involves both physisorption and chemisorption mechanisms. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) analyses showed that the polymers formed protective film on MS surface and shield it from direct acid attack. Quantum chemical calculations and molecular dynamic simulations studies corroborate experimental results.

Plasma pharmacokinetics and milk levels of ceftriaxone following single intravenous administration in healthy and endometritic cows.

Pharmacokinetics and milk levels of ceftriaxone were studied in healthy and endometritic cows following single intravenous administration. The drug was detected up to 8 h of dosing in plasma of healthy and endometritic cows and the drug disposition followed three-compartment open model. The values of Vd(area), AUC, t(1/2beta), Cl(B), MRT and P/C ratio were 0.50 +/- 0.19 L.kg(-1), 62.2 +/- 23.3 microg.ml(-1).h, 1.02 +/- 0.07 h, 0.30 +/- 0.09 L.kg(-1).h(-1), 1.55 +/- 0.25 h and 0.52 +/- 0.27, respectively, in healthy and 1.55 +/- 0.52 L.kg(-1), 37.0 +/- 17.1 microg.ml(-1).h, 1.56 +/- 0.25 h, 0.56 +/- 0.14 L.kg(-1).h(-1), 2.14 +/- 0.34 h and 1.44 +/- 0.60, respectively, in endometritic cows. The drug was detected in milk for 36 h after administration. For MIC(90) of 0.5 microg.ml(-1) the most appropriate dosage for ceftriaxone, would be 9.0 mg.kg(-1) repeated at 6 h intervals for the treatment of endometritis in cows.

Two-way crossover bioequivalence study of alendronate sodium tablets in healthy, non-smoking male volunteers under fasted conditions.

This study was conducted in order to assess the bioequivalence of two different formulations containing 70 mg alendronate sodium (CAS 121268-17-5) under fasted conditions. One hundred twenty-two healthy male volunteers were enrolled in an open label, randomized, crossover design with a wash-out period of 20 days in one study center. Urine samples were collected up to 36 h post-dose, and the concentrations of alendronic acid were determined using a high performance liquid chromatographic method with pre-derivatization and fluorescence detection (HPLC/FL) method. The mean Ae(0-t) were 604.24 +/- 348.73 microg and 627.36 +/- 327.99 microg, while the mean R(max) were 193.87 +/- 114.68 microg/h and 202.00 +/- 107.83 microg/h for the test and reference formulations, respectively. The T(max) of the test and reference tablets were 1.26 +/- 0.58 h and 1.26 +/- 0.51 h, respectively. No significant differences of pharmacokinetic parameters between the two studied formulations were found. The 90% confidence intervals for the primary target parameters, intra-individual ratios for Ae(0-t) and R(max) of alendronic acid, were between 0.86-1.00 and 0.85-1.01, respectively, and thus within the acceptance range for bioequivalence criteria. In the light of the present study it can be concluded that the test formulation is bioequivalent to the reference formulation.