Evaluation of Pharmacokinetics of a BCS Class III Drug with Two Different Study Designs: Tenofovir Alafenamide Monofumarate Film-coated Tablet.

Tenofovir alafenamide (TAF) is a BCS Class III compound and an oral pro-drug of Tenofovir (TFV) with limited oral bioavailability. The bioavailability of the oral intake increases with food as a result of the low stability of the active substance in the stomach. The reference drug is "Vemlidy® 25 mg Film Tablet", which contains 25 mg of TAF in "hemifumarate" form, is under patent protection until 15.08.2032 by Gilead, and so the "monofumarate" form was used in the present study. At first, a pilot study was conducted involving 12 subjects under fed conditions. The results of the pilot study revealed the test and reference products were not bioequivalent, as a result of insufficient statistical power and high inter-subject variability. Secondly, a physiologically based pharmacokinetic (PBPK) simulation was performed based on the pilot study results and literature data. Finally, the power of the design was increased and the pivotal study design was optimized into a four-period, full-replicated, cross-over study with 34 subjects under fed conditions and it was concluded that the test and reference products were bioequivalent. In conclusion, the present study proved the importance of a correct study design with higher statistical power for a BCS Class III compound with high variability, to present the pharmacokinetics.

A Study to Compare Bioequivalence Approach Between FDA and EMA in a Highly Variable Drug: Pinaverium Bromide Film Tablets.

The aim of this study is to investigate pharmacokinetic parameters of test and reference film tablet formulations of a highly variable drug, pinaverium bromide, under fasting conditions and to assess their bioequivalence in accordance with the FDA and EMA criteria. A randomised open-label, single oral dose, three-sequence, three-period, semi-replicated, cross-over trial was conducted with 36 healthy subjects. The intrasubject variability of reference products for Cmax and AUC0-tlast was found to be more than 50%. While bioequivalence was proven according to the FDA reference scaled average bioequivalence approach with only 36 subjects, more than 200 subjects are required to demonstrate bioequivalence in accordance with the EMA bioequivalence guideline. It is believed that the EMA bioequivalence criteria are too stringent for highly variable drugs whose intrasubject variability are more than 30% for both Cmax and AUC0-tlast and that in consequence the EMA ought to revise their bioequivalence guidelines for such drugs in the future.

Synthesis, antimicrobial activity, density functional modelling and molecular docking with COVID-19 main protease studies of benzoxazole derivative: 2-(p-chloro-benzyl)-5-[3-(4-ethly-1-piperazynl) propionamido]-benzoxazole.

This study contains synthesis, antimicrobial activity, density functional modelling and molecular docking studies of benzoxazole derivative: 2-(p-chloro-benzyl)-5-[3-(4-ethly-1-piperazynl) propionamido]-benzoxazole. The synthetic procedure of investigated compound is given in detail. The newly synthesized benzoxazole compound and standard drugs were evaluated for their antimicrobial activity against some Gram-positive, Gram-negative bacteria and fungus C. albicans and their drug-resistant isolates. The benzoxazole compound has been characterized by using 1H-NMR, IR and MASS spectrometry and elemental analysis techniques. The molecular structure of the compound in the ground state has been modelling using density functional theory (DFT) with B3LYP/6-311++g(d,p) level. The molecular docking of 2-(p-chloro-benzyl)-5-[3-(4-ethly-1-piperazynl) propionamido]-benzoxazole with COVID-19 main protease has been also performed by using optimized geometry and the experimentally determined dimensional structure of the main protease (M-pro) of COVID-19.

Biological evaluation and docking studies of some benzoxazole derivatives as inhibitors of acetylcholinesterase and butyrylcholinesterase.

A series of 2,5-disubstituted-benzoxazole derivatives (1-13) were evaluated as possible inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The results demonstrated that the compounds exhibited a broad spectrum of AChE and BChE inhibitory activity ranging between 6.80% and 90.21% except one compound which showed no activity against AChE at the specified molar concentration. Another derivative displayed a similar activity to that of reference drug (galanthamine) for inhibition of AChE and BChE. In addition, molecular docking of the compounds into active site of AChE was performed using recombinant human AChE (PDB ID: 4ey6) in order to understand ligand-protein interactions.

A rare complication following laparoscopic Roux & Y gastric bypass: intussusception-case report.

Obesity is a growing health problem in most parts of the world. Currently only proven long term effective treatment of obesity is bariatric surgery. Roux & Y gastric bypass together with sleeve gastrectomy are the most employed surgical techniques with acceptable metabolic and surgical complication rates. In this paper we would like to present an unexpected complication of Roux & Y gastric bypass: a retrograde intussusception located in the common limb 17 months after the surgery. As intussusception in adults usually originates from a leading point, there is no such an explanation following Roux & Y gastric bypass.

Synthesis and antimicrobial evaluation of 2-(p-substituted phenyl)-5-[(4-substituted piperazin-l-yl)acetamido]-benzoxazoles.

A series of 2-(p-substituted phenyl)-5-(2-{4-[(p-chloro-fluorophenyl)/phenyl] piperazin-1-yl}acetamido)-benzoxazoles were synthesized and tested for their antimicrobial activities. The structures of the new derivatives were elucidated by spectral techniques. The minimum inhibitory concentrations (MIC) of the new benzoxazoles, along with those of previously synthesized analogues, were determined against standard bacterial and fungal strains and drug-resistant isolates, and compared with those of several reference drugs. The new benzoxazole derivatives were found to possess a broad spectrum of antimicrobial activity with MIC values of 32-1024 µg/ml. Although the standard drugs were more active against the tested pathogens, the activities of the new benzoxazoles and the reference drugs were largely similar against the drug-resistant isolates.

Synthesis, FT-IR investigation and computational study of 5-[(4-Bromophenyl)acetamido]-2-(4-tert-butylphenyl) benzoxazole.

The synthesis and antimicrobial properties of 5-[(4-Bromophenyl)acetamido]-2-(4-tertbutylphenyl) benzoxazole are reported in the present work. The optimized molecular structure, (1)H NMR, vibrational frequencies, corresponding vibrational assignments of 5-[(4-Bromophenyl)acetamido]-2-(4-tert-butylphenyl) benzoxazole have been investigated experimentally and theoretically using Gaussian09 software package. Potential energy distribution of the normal modes of vibrations was done using GAR2PED program. The HOMO and LUMO analysis is used to determine the charge transfer within the molecule. The stability of the molecule arising from hyper-conjugative interaction and charge delocalization has been analyzed using NBO analysis. MEP was performed by the SDD method and the predicted infrared intensities have also been reported. The calculated geometrical parameters are in agreement with that of similar derivates. The first hyperpolarizability is high and the title compound is suitable for further NLO studies. Microbiological results indicated that the title compound possessed a broad spectrum activity against the tested Gram-positive, Gram-negative bacteria.

Novel benzoxazoles: synthesis and antibacterial, antifungal, and antitubercular activity against antibiotic-resistant and -sensitive microbes.

A new series of 5-(p-substituted benzamido/phenylacetamido)-2-(p-tert-butylphenyl)benzoxazole derivatives were synthesized and evaluated for their antibacterial, antifungal, and antimycobacterial activities against antibiotic-resistant and -sensitive Staphylococcus aureus, Enterococcus faecalis, Escherichia coli, Klebsiella pneumoniae, and Mycobacterium tuberculosis as well as against Candida albicans and Candida krusei. The compounds possessed broad-spectrum activity against all of the tested Gram-positive and Gram-negative bacteria and yeasts, their minimum inhibitory concentrations (MICs) ranging between 16-128 microg/ml. One compound exhibited significant antibacterial activity (16 microg/ml) against an antibiotic-resistant Enterococcus faecalis isolate, having twice the potency of the compared standard drugs vancomycin and gentamycin sulfate. The compounds also showed moderate antitubercular activity with MIC values between 8-128 microg/ml against Mycobacterium tuberculosis and its clinical isolate.

Synthesis and antimicrobial activity of novel benzoxazoles.

A series of 2-(p-substituted-benzyl)-5-[[4-(p-chloro/fluoro-phenyl)piperazin-1-yl]acetamido]-benzoxazoles were synthesized in need of new compounds for the fight against microbial pathogens. Their structures were elucidated by spectral techniques. These new derivatives, along with previously synthesized 2-(p-substituted-benzyl)-5-substituted-benzoxazoles, were evaluated for their antibacterial and antifungal activities against standard strains and drug-resistant isolates in comparison with ampicillin, gentamicin sulfate, ofloxacin, vancomycin, fluconazole, and amphotericin B trihydrate. The minimum inhibitory concentration (MIC) of each compound was determined by a two-fold serial dilution technique. The compounds were found to possess a broad spectrum of antimicrobial activities with MIC values of 32-256 microg/ml. Although standard drugs were more active against the pathogenes employed in this study, the activities of the new benzoxazoles and reference drugs against drug-resistant isolates of the microorganisms were largely similar.

Synthesis, antimicrobial activity, pharmacophore analysis of some new 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl)carboxamido]benzoxazoles.

The synthesis and antimicrobial activity of a new series of 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl)carboxamido]benzoxazole derivatives 3-12 were described. The in vitro antimicrobial activity of the compounds was determined against some Gram-positive, Gram-negative bacteria and fungi and their drug-resistant isolates in comparison with standard drugs. Antimicrobial results indicated that the synthesized compounds possessed a broad spectrum of activity with MIC values 500-15.625 microg/ml. In the series, the most active compound against Candida krusei and Candida albicans isolate is 8 with MIC value 31.25 microg/ml. However, it is one dilution less potent than the compared fluconazole. Some of the screened compounds exhibit significant activity, having MIC value as 31.25 microg/ml in Pseudomonas aeruginosa having same activity as Rifampicin. Furthermore, considering the worth of developing new antibacterial agents against drug-resistant P. aeruginosa the present study explores the structure-activity relationship analysis of 2-(substitutedphenyl/benzyl)-5-[(2-benzofuryl)carboxamido]benzoxazoles using 3D-common features pharmacophore hypotheses approach.