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3,5-Dinitrobenzylsulfanyl tetrazoles and 1,3,4-oxadiazoles, previously identified as having high in vitroactivities against both replicating and nonreplicating mycobacteria and favorable cytotoxicity and genotoxicity profiles were investigated. First we demonstrated that these compounds act in a deazaflavin-dependent nitroreduction pathway and thus requirea nitro group for their activity. Second, we confirmed the necessity of bothnitro groups for antimycobacterial activity through extensive structure–activity relationship studies using 32 structural types of analogues, each in a five-membered series. Only the analogues with shifted nitro groups, namely, 2,5-dinitrobenzylsulfanyl oxadiazoles and tetrazoles, maintained high antimycobacterial activity but in this case mainly as a result of DprE1 inhibition. However, these analogues also showed increased toxicity to the mammalian cell line. Thus, bothnitro groups in 3,5-dinitrobenzylsulfanyl-containing antimycobacterial agents remain essential for their high efficacy, and further efforts should be directed at finding ways to address the possible toxicity and solubility issues, for example, by targeted delivery.

The nuclear constitutive androstane receptor (CAR, NR1I3) plays significant roles in many hepatic functions, such as fatty acid oxidation, biotransformation, liver regeneration, as well as clearance of steroid hormones, cholesterol, and bilirubin. CAR has been proposed as a hypothetical target receptor for metabolic or liver disease therapy. Currently known prototype high-affinity human CAR agonists such as CITCO (6-(4-chlorophenyl)imidazo[2,1-b][1,3]thiazole-5-carbaldehyde-O-(3,4-dichlorobenzyl)oxime) have limited selectivity, activating the pregnane X receptor (PXR) receptor, a related receptor of the NR1I subfamily. We have discovered several derivatives of 3-(1H-1,2,3-triazol-4-yl)imidazo[1,2-a]pyridine that directly activate human CAR in nanomolar concentrations. While compound 39regulates CAR target genes in humanized CAR mice as well as human hepatocytes, it does not activate other nuclear receptors and is nontoxic in cellular and genotoxic assays as well as in rodent toxicity studies. Our findings concerning potent human CAR agonists with in vivo activity reinforce the role of CAR as a possible therapeutic target.

Aim:We studied the influence of coffee consumption on the therapeutic effect of methotrexate (MTX) in patients with rheumatoid arthritis (RA) sorted according to ADORA2Agenotypes. Patients & methods:82 RA patients were dichotomized according to caffeine intake with a threshold of 700 mg/week. Disease activity score 28 (DAS28) was applied (>3.2: high; <3.2: low or remission). Patients were genotyped using quantitative PCR allelic discrimination. Results:We found significantly higher risk of RA in patients with higher caffeine intake and the CT genotype of ADOARA2Ars2298383, rs3761422 and rs2267076 SNPs. The CC genotype of ADORA2Ars2236624 SNP in patients with lower caffeine intake treated with MTX is significantly protective. Conclusion:ADORA2Agenotypes and coffee intake influence risk of RA and efficacy of it MTX treatment.

The main goal of the study was to determine the incidence and the character of drug related problems (DRPs) identified in chronic kidney disease patients by the clinical pharmacist at the nephrology department. As secondary objective, the aim was to identify the frequency and character of DRPs of selected high risk drugs in medication reviews. The clinical pharmacist reviewed patients' medication records and made drug therapy-related recommendations to physicians. The clinical pharmacists' interventions were categorized using an adaptation of the Pharmaceutical Care Network Europe. During the study period (January 2016 - June 2018) the clinical pharmacist performed 1192 interventions in 1870 adult patients admitted to the Nephrology Department. The most frequent DRP was untreated indication 324 (27.18%) of all interventions, and incorrect dose 248 (20.81%). Anti-infectives were identified as the drug category with the highest frequency of interventions. Almost 93% of all interventions were accepted by the attending physicians. Still within the second objectives, underdosing was observed as the most frequent problem for renally excreted drugs. It was found that an incorrect dose is a very frequent issue at the nephrology department. Surprisingly, the main problem was underdosing. In the category of renally excreted drugs, underdosing was observed in antithrombotics and antivirals. The above- mentioned results prove the need of a clinical pharmacist, preferably in sense of maximizing of the treatment effect and improving the care of patients.

We report herein the discovery of 3,5-dinitrophenyl 1,2,4-triazoles with excellent and selective antimycobacterial activities against Mycobacterium tuberculosisstrains, including clinically isolated multidrug-resistant strains. Thorough structure–activity relationship studies of 3,5-dinitrophenyl-containing 1,2,4-triazoles and their trifluoromethyl analogues revealed the key role of the position of the 3,5-dinitrophenyl fragment in the antitubercular efficiency. Among the prepared compounds, the highest in vitro antimycobacterial activities against M. tuberculosisH37Rv and against seven clinically isolated multidrug-resistant strains of M. tuberculosiswere found with S-substituted 4-alkyl-5-(3,5-dinitrophenyl)-4H-1,2,4-triazole-3-thiols and their 3-nitro-5-(trifluoromethyl)phenyl analogues. The minimum inhibitory concentrations of these compounds reached 0.03 μM, which is superior to all the current first-line anti-tuberculosis drugs. Furthermore, almost all compounds with excellent antimycobacterial activities exhibited very low in vitro cytotoxicities against two proliferating mammalian cell lines. The docking study indicated that these compounds acted as the inhibitors of decaprenylphosphoryl-β-d-ribofuranose 2′-oxidase enzyme, which was experimentally confirmed by two independent radiolabeling experiments.

Introduction:Due to their multiple effects, glucocorticoids (GCs) have versatile medical uses. They can regulate many xenobiotic-metabolizing enzymes of the cytochrome P450 (CYP) superfamily, and thus, influence pharmacotherapy.Areas covered:The aim of this paper is to summarize the molecular effects of GCs on CYP as well as the available clinical evidence on drug–drug interactions (DDIs) between GCs and other drugs in which GCs influence the metabolism of other medicines through modifying CYP activity. We used the factographic database DRUGDEX® along with bibliographic searches.Expert opinion:Most of the literature reported CYP3A4 induction by GCs, but this was not proved in all research. As the conclusions on these DDIs are conflicting, there are several issues to be considered like the dosage of GCs, the length of GCs treatment and concomitant therapy, all of which can have an additive inducing effect. Further, in designing a DDI study, crossover studies are preferred. A literature search of the abovementioned information resources provided dissimilar results.

Stereoselective aspects of pharmacokinetics and metabolism of a chiral nonsteroidal antiinflammatory drug, flobufen, 4-(2', 4'-difluorobiphenyl-4-yl)-2-methyl-4-oxobutanoic acid, were studied in male guinea pigs after p.o. administration of racemic flobufen (rac-flobufen) at a dose of 10 mg/kg. Blood samples were collected at intervals over 16 h after the administration of rac-flobufen for the quantification of flobufen enantiomers and their respective metabolites in plasma by chiral high-performance liquid chromatography (HPLC). Compartmental pharmacokinetic analysis was used to determine pharmacokinetic parameters of R- and S-flobufen. The plasma concentrations of the S- and R-enantiomers differed significantly during the experimental period. The S/R-enantiomeric ratio in 7plasma reached a maximum value of 10.1 at 240 min postdose. The oral clearance value of R-flobufen was five times higher than S-flobufen. The other pharmacokinetic parameters (Ke, T1/2, VSS/F, MRT) of the enantiomers also differed substantially. All four stereoisomers of the dihydrometabolite of flobufen were detected in plasma with varying concentrations. Metabolite 17203 [4-(2,4-difluorophenyl)-phenylacetic acid] exhibited a relatively longer residence time compared to that noted for the enantiomers of the parent compound. Pharmacokinetics of the flobufen enantiomers were stereoselective in guinea pigs. The metabolism of flobufen was complex. However, metabolite 17203 seemed to be the main metabolite of flobufen that may be responsible for its relatively long-lasting antiphlogistic and immunomodulatory effects. Chirality 15:724–729, 2003. © 2003 Wiley-Liss, Inc.

Stereoselective aspects of pharmacokinetics and metabolism of a chiral nonsteroidal antiinflammatory drug, flobufen, 4‐(2′, 4′‐difluorobiphenyl‐4‐yl)‐2‐methyl‐4‐oxobutanoic acid, were studied in male guinea pigs after p.o. administration of racemic flobufen (rac‐flobufen) at a dose of 10 mg/kg. Blood samples were collected at intervals over 16 h after the administration of rac‐flobufen for the quantification of flobufen enantiomers and their respective metabolites in plasma by chiral high‐performance liquid chromatography (HPLC). Compartmental pharmacokinetic analysis was used to determine pharmacokinetic parameters of R‐ and S‐flobufen. The plasma concentrations of the S‐ and R‐enantiomers differed significantly during the experimental period. The S/R‐enantiomeric ratio in 7plasma reached a maximum value of 10.1 at 240 min postdose. The oral clearance value of R‐flobufen was five times higher than S‐flobufen. The other pharmacokinetic parameters (Ke, T1/2, VSS/F, MRT) of the enantiomers also differed substantially. All four stereoisomers of the dihydrometabolite of flobufen were detected in plasma with varying concentrations. Metabolite 17203 [4‐(2,4‐difluorophenyl)‐phenylacetic acid] exhibited a relatively longer residence time compared to that noted for the enantiomers of the parent compound. Pharmacokinetics of the flobufen enantiomers were stereoselective in guinea pigs. The metabolism of flobufen was complex. However, metabolite 17203 seemed to be the main metabolite of flobufen that may be responsible for its relatively long‐lasting antiphlogistic and immunomodulatory effects. Chirality 15:724–729, 2003. © 2003 Wiley‐Liss, Inc.

The transfer kinetics of cyclosporine across the dually perfused rat placenta in the maternal to fetal direction and a possible involvement of P-glycoprotein were investigated. The transplacental clearance of cyclosporine in the materno–fetal direction was found to be dependent on the maternal inflow concentration of cyclosporine. Coadministration of cyclosporine with an excess of quinidine or chlorpromazine into the maternal compartment revealed 1.7- and 1.9-fold increase in cyclosporine concentration in the fetal compartment. In the experiments where quinidine was present both in the maternal and fetal compartments, cyclosporine appeared in the fetal compartment significantly faster, and its amount was three times higher when compared with controls. Conversely, quinidine or chlorpromazine did not affect the transplacental passage of L-[³H]-glucose. The interference of quinidine with the metabolism of cyclosporine in the placenta was excluded because only traces of M-1 and M-17 metabolites were found in the fetal solutions. Sodium azide, a mitochondrial respiratory inhibitor, was found to double the rate of cyclosporine, but not L-[³H]-glucose, passage across the placenta. Our findings indicate that P-glycoprotein pumps cyclosporine out of the trophoblast cells of the rat placenta in the ATP-dependent manner and restricts the passage of cyclosporine across the placental barrier. © 2001 Wiley-Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1583–1592, 2001

The transfer kinetics of cyclosporine across the dually perfused rat placenta in the maternal to fetal direction and a possible involvement of P‐glycoprotein were investigated. The transplacental clearance of cyclosporine in the materno–fetal direction was found to be dependent on the maternal inflow concentration of cyclosporine. Coadministration of cyclosporine with an excess of quinidine or chlorpromazine into the maternal compartment revealed 1.7‐ and 1.9‐fold increase in cyclosporine concentration in the fetal compartment. In the experiments where quinidine was present both in the maternal and fetal compartments, cyclosporine appeared in the fetal compartment significantly faster, and its amount was three times higher when compared with controls. Conversely, quinidine or chlorpromazine did not affect the transplacental passage of L‐[3H]‐glucose. The interference of quinidine with the metabolism of cyclosporine in the placenta was excluded because only traces of M‐1 and M‐17 metabolites were found in the fetal solutions. Sodium azide, a mitochondrial respiratory inhibitor, was found to double the rate of cyclosporine, but not L‐[3H]‐glucose, passage across the placenta. Our findings indicate that P‐glycoprotein pumps cyclosporine out of the trophoblast cells of the rat placenta in the ATP‐dependent manner and restricts the passage of cyclosporine across the placental barrier. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:1583–1592, 2001

Streptococcal cell wall mucopep–tide administered intravenously to experimental animals provoked marked circulatory changes. A fall of arterial blood pressure and a decrease of cardiac output were observed. These changes are similar to those reported after the administration of bacterial lipopoly–saccharide. Some evidence suggests that both a direct effect of mucopeptide on sensitive structures and a release of pharmacologically active substances may play a role in the hemodynamic disturbances. On the other hand, the central nervous system probably plays no important role in the circulatory effect of the mucopeptide.

Summary Measurement of the cardiac output by dilution of a thermal indicator is considered theoretically under both generalized and specific conditions. The practical aspects of the measurement show that only a part of derived equations is available for the calculation of flow from recorded thermodilution curves. A real dilution process, as it is detected, deviates from the theoretically required conditions in more respects.