Pharmaceutical Chemistry Journal

Zolpidem was determined quantitatively in blood using a GC/MS method with an internal standard of imipramine hydrochloride. The multiple regression coefficient for the obtained calibration curve was r = 0.999. Metrological assessment of the method used eight statistical parameters. The extraction efficiencies of zolpidem at three concentrations were determined in model blood. Yields of 96 – 99% of the test compound were observed. The method was validated for specificity, detection limit (DL), limit of quantitation (LOQ), linearity, analytical range, accuracy, and precision (repeatability and intralaboratory precision). Statistically processed results were within acceptance limits. The DL for zolpidem in blood was 24 ng/mL; LOQ, 72.7 ng/mL

Literature data and domestic and foreign methodological documentation for preclinical studies of the safety and toxicokinetics of pharmaceuticals are analyzed. According to Marketing Authorization and Assessment Rules for Medicinal Products in the EAEU, a developer must include in a General Technical Document information on toxicokinetic studies that is evaluated during a review of preclinical test results. The main approaches to expert evaluation of drug toxicokinetic studies are formulated. The main content of the expert analysis includes the methodological basis and results of the research, safety profile characteristics, extrapolation of preclinical data, risk factor characteristics, and predicted clinical patient safety profile. The inclusion of toxicokinetic studies in a program of preclinical toxicological studies is important in principle for an adequate extrapolation of experimental data and prediction of the safety of pharmaceuticals in humans. Expert analysis of toxicokinetic data allows toxicology study results, drug toxicity profile characteristics, and the risk of toxic side effects to be interpreted correctly.

Three series of substituted sydnone sulfonamide derivatives were synthesized wherein 3-(4-methylphenyl)-4-(chlorosulfonyl)sydnone (5) was linked by a sulfonamide linkage with various thiazole, benzothiazole and quinazoline groups. The structures of the compounds were confirmed by IR and NMR spectroscopy and elemental analysis. The synthesized compounds were evaluated for their antibacterial, antifungal, antiproliferative and anti-HIV activities. Anti-HIV activity was determined against human immunodeficiency virus HIV-1 (III-B) and HIV-2 (ROD) in MT-4 cells. Inhibition of cytomegalovirus and varicella-zoster virus (VZV) replication was measured in human embryonic lung (HEL) cells.

Using abacavir sulfate substance and medicinal formulations as an example, this being an agent used as an active pharmaceutical substance (APS) protected by a series of patents, we demonstrate that additional patenting has occurred because its physicochemical properties and the laws of chemistry have been ignored and professional terminology has been applied inappropriately. Eurasian patent No. EA 001809 includes substitution of the correct chemical name of the patented substances with an erroneous synonym, and the statement of claim, along with lack of novelty of the data on the properties of the patented substances, includes contradictory and unreliable information irrelevant to the item subject to the patent. This approach to prolonging the period of legal protection of a substance used as an APS is not acceptable either from the scientific or from the ethical points of view. Our x-ray diffraction study of abacavir sulfate (USP RS) showed that this substance and abacavir hemisulfate are identical, on the basis of published data on the structure of abacavir hemisulfate crystals. Each of these substances is a neutral salt and each has the atomic formula (C14H19N6O)2SO4 and a molecular weight of 670.76. Thus, repatenting a known APS (i.e., abacavir sulfate) as a new substance under a name incorrect for a neutral salt, i.e., (1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]cyclopent-2-en-1-methanol hemisulfate, is unjustified.