[Mechanisms of the wound-healing action of native collagen type I in ischemic model full-thickness skin wounds on the example - medical devices Collost «(part I)]. / Mekhanizmy ranozazhivlyayushchego deistviya nativnogo kollagena I tipa v modeli ishemizirovannykh polnosloinykh ran kozhi na primere meditsinskogo izdeliya «Kollost¼. (Chast' I).

Active collagen type I successfully used in regenerative medicine. However, despite the large amount of material of cellular and molecular mechanisms underlying skin repair, the molecular mechanisms of wound healing with use collagen type I, not studied enough. PURPOSE OF THE STUDY: To study the mechanism of the native collagen type I wound-healing action of native type I collagen on the example of the medical device Collost (7% gel) in a model of the rats difficult-to-heal skin wounds. MATERIAL AND METHODS: Male rats in population SD (72 individuals) surgically formed an ischemic dorsal skin flap (3×10 cm) with two full-thickness skin wounds 6 mm in diameter.The trained animals divided into 2 groups: in the experimental group, medical device Collost (gel) applied once after the operation, in the control group - a standard medical device for comparison. The dynamics of wound healing assessed, the number of M2 macrophages, myofibroblasts, vascularization and expression of the main markers of the repair process in the wound tissues and time points for assessment were: after 3, 7 and 14 days after operation using macroscopic, immunohistochemical, and molecular methods. RESULTS: It has been established that the mechanism of action of native collagen type I is associated with the acceleration of the appearance of «progenitorous¼ M2-macrophages in the wound tissues, decrease in the severity of inflammation or reduction in the duration of the inflammatory stage of the repair process, change in the expression spectrum of number of growth factors, an acceleration of neovasculogenesis. CONCLUSION: In this work, on the modern experimental model shown regenerative efficiency of a medical device based on collagen type I and described the molecular and cellular processes of wound healing when using it It has been shown that the acceleration of wound healing processes occurs when using a medical device based on native collagen type 1, it is also accompanied by a better aesthetic closure of the damaged skin area.

[The main results of clinical trials of the efficacy, safety and pharmacokinetics of the perspective anti-tuberculosis drug makozinone (PBTZ169)].

Tuberculosis is a chronic infectious disease, usually localized in the respiratory system and representing one of the most important global social and biomedical health problems associated with the spread of therapy-resistant forms (multidrug-resistant and extensively drug-resistant tuberculosis). One of the most promising targets for the development of antimycobacterial drugs is the enzyme DprE1, which is involved in the synthesis of the cell wall of mycobacteria. In the series of DprE1 inhibitor drugs, the most advanced drug is PBTZ169 (INN maсozinone). Clinical trials (CT) of the efficacy and safety of macozinone are conducted by the pharmaceutical company LLC NEARMEDIC PLUS in the Russian Federation, and in other countries (Sponsors: Innovative Medicines for Tuberculosis Foundation, cole polytechnique fdrale de Lausanne and Bill and Melinda Gates Foundation). The publication describes results of completed I, IIa and Ib phases CT, conducted in the Russian Federation. AIM: The goal of phase I CT was to assess the safety, tolerability and pharmacokinetics (PK) of PBTZ169, 40 mg capsule, after single and multiple administration under fasting conditions in increasing doses in healthy volunteers. The goal of phase IIa CT was to study the efficacy (in terms of early bactericidal activity EBA), safety and PK of the drug PBTZ169, 80 mg capsules, in various doses, when used as monotherapy in patients with newly diagnosed respiratory tuberculosis with bacterial excretion and retained sensitivity to isoniazid and rifampicin. The purpose of phase Ib CT was to evaluate the safety, tolerability, PK of PBTZ169, 80 mg capsule, after single, double and multiple administration under fasting conditions in increasing doses, as well as the effect of food on its bioavailability in healthy volunteers. MATERIALS AND METHODS: The data of 100 healthy volunteers and 15 patients with newly diagnosed pulmonary tuberculosis, who received the study medication PBTZ169, capsules 40 mg and 80 mg, in the dose range 40 mg 1280 mg of PBTZ169, obtained during phase I, IIa and Ib CTs were analyzed. During I phases CTs, safety, tolerability, and PK of the drug after a single and multiple administration under fasting condition and after meals at rising doses were evaluated. The safety assessment included evaluation of AE/SAE, vital signs, ECG results, and laboratory tests results in the safety population. In the course of phase IIa CT, in addition to safety, tolerance, and PK evaluation, the efficacy of the drug (in terms of EBA) using sputum culture on agar with CFU/ml counting (main method) and quantitative PCR method (auxiliary method) was evaluated. RESULTS: During all CTs, a high safety and tolerability profile was shown, the main PK parameters of the drug and the efficacy were described. PBTZ169 demonstrated linear PK in the dosage range up to 640 mg after single and multiple administration, a statistically significant of EBA of the drug after monotherapy at the dose of 640 mg/day was demonstrate, and it was concluded that the preferred regimen of the drug PBTZ169 intake is administration after meals. Good tolerability and a favorable safety profile of the drug in the studied doses range were demonstrate during all the CTs. CONCLUSION: One of the most promising and currently studied drugs-inhibitors of DprE1, a new target for the cell wall of mycobacteria, is PBTZ169 or macozinone, which is being develop by the Russian pharmaceutical company NEARMEDIC PLUS ltd.

[Effect of physicochemical properties on the pharmacokinetic parameters of the new representative of benzothiazinones antituberculosis drug macozinonе].

INTRODUCTION: Tuberculosis (TB) is one of the top ten causes of death worldwide. Improvement of the treatment options via development of new drugs and treatment regimens that would be more convenient for patients is one of key options of improving the effecacy of the TB prevention and careis. Since the creation of new treatment regimens by minimizing the number of the drugs used and reducing the duration of treatment is the most promising and correct direction, macozinone, a new candidate of the benzothiazinone series, can become the basis for development of new chemotherapy regimens for drug-resistant forms of TB including the combination of macozinone with the most effective modern anti-TB drugs. AIM: Comparative evaluation of the pharmacokinetic properties of macozinone capsules 80 mg and the new dosage form a dispersible tablet for preparation of oral solution. MATERIALS AND METHODS: Solubility of the substance macozinone in biorelevant media in vitro, permeability of macozinone in the test Caco-2 in vitro, as well as pharmacokinetics of macozinone in dogs in vivo were evaluated. RESULTS: The solubility assessment in biorelevant media showed that the average limit of macozinone substance dissolution in the pH 5.0 acetate buffer solution was from 6 to 9 mg/l, in FaSSIF medium (fasted) from 2.5 to 4 mg/l, and in FeSSIF medium (after meals) from 16.8 to 29 mg/l. It is established that the cell permeability of the pharmaceutical substance macozinone in the CACO-2 test system is on average 2.510-6cm/s in the forward direction from the apical to basolateral cell membrane, and 1.510-6cm/s in the reverse direction, which corresponds to low permeability. The main pharmacokinetic parameters of macozinone dispersable tablets 160 mg, after dosing with food and on an empty stomach, as well as capsules 80 mg, when administered on an empty stomach in vivo studies in dogs are presented. DISCUSSION: The specific physicochemical properties of macozinone, the problems of developing the new dosage form, as well as ways of solving some of them are presented. CONCLUSION: In the process of new dosage forms development, the existing chemical properties of the macozinone substance should be considered. One of the promising ways of increasing bioavailability and, consiquently, efficacy is development a fundamentally new drug form with modified release within the absorption window.

2-(1-Hydroxypropyn-2-yl)-1-vinylpyrroles: the first successful Favorsky ethynylation of pyrrolecarbaldehydes.

1-Vinylpyrrole-2-carbaldehydes react with acetylene at atmospheric pressure in a NaOH/EtOH/DMSO system at 7-10 °C to afford 2-(1-hydroxypropyn-2-yl)-1-vinylpyrroles in 53-94% yield. Thus, the first base-mediated direct ethynylation of pyrrolecarbaldehydes with free acetylene under modified conditions of the Favorsky reaction has been implemented to pave an expedient route to important biomolecules containing a pyrrole ring.

[The effect of melatonin and mexamine on the human thyroid under in-vitro conditions]. / Vliianie melatonina i meksamina na shchitovidnuiu zhelezu cheloveka v usloviiakh in vitro.

In in vitro study of the human euthyroid and thyrotoxic thyroid gland melatonin (N-acetyl-5-methoxytryptamine) and, to a lesser measure mexamine (5-methoxytryptamine) had a dose-dependent inhibiting effect on thyroxine secretion. Moreover, melatonin weakened the TSH stimulating effect in relation to the secretory process in the thymus while mexamine did not. Despite the similarity in the quality of the effect of both methoxyindoles on the release of thyroxine, the mechanism of its realization differs: the action of melatonin is mediated by the adenylate-cyclase-cAMP system, but in the action of mexamine the cAMP-dependent mechanism does not take part. Maintenance of the sensibility of the human thyroid to the effect of TSH is an obligatory condition for realization of the action of both methoxyindoles on the secretory process in it.

[Epiphysis cerebri-thyroid interrelations. Distorting effect of partial thyroidectomy on the antithyroid action of epiphyseal methoxyindoles in animal experiments]. / Epifizarno-tireoidnye vzaimootnosheniia. Izvrashchaiushchii éffekt chastichnoi tireoidéktomii na kontratireoidnoe vliianie épifizarnykh metoksiindolov v éksperimente.

The effect of pineal methoxyindoles (MI) on hypothalamus-hypophysis-thyroid gland system was studied in intact and partially thyroidectomized male Wistar rats in conditions of a short light day (winter). Melatonin administration for 10 days suppressed 131I uptake by the thyroid gland and decreased the levels of T3, T4 and thyrotropic hormone (TTH) in the blood serum of intact animals, with TTH reaction to thyroid hormone (TH) retained. 5-methoxytryptamine administration was less effective. Partial thyroidectomy distorted the direction of MI effect: melatonin and to a lesser extent 5-methoxytryptamine caused a marked normalization of a decreased TH content and an increased TTH level in the blood serum of partially thyroidectomized rats. TTH-TH reaction also corresponded to the control. A predominantly modulating character or pineal MI effect on thyroid system is suggested.

Effect of single neonatal melatonin treatment on in vitro thyroxin secretion and TSH or melatonin-modified cAMP level of one-month-old rats.

At the age of one month, incubation with melatonin of the thyroid glands of rats having received a single melatonin treatment at the age of three days resulted in increased thyroxine production. TSH was unable to enhance the thyroxine production of animals treated with melatonin neonatally, while its considerable increase could be observed in the case of control animals. Simultaneous TSH and melatonin treatment applied in vitro at the age of one month resulted in an approximately twofold increase of thyroid T4 production in rats having received neonatal melatonin treatment. In vitro alteration of the cyclic AMP level of the thyroid glands of intact and neonatally melatonin treated rats ran practically parallel, except that in the melatonin treated animals the cAMP level was higher after TSH administration. At the same time the cAMP level decreased in the thyroid gland of animals treated with TSH + melatonin. There was no exact correlation between the alterations of cAMP and T4 levels in the given experimental system.

[Seasonal characteristics of the effect of melatonin on thyroid function]. / Sezonnye osobennosti vliianiia melatonina na funktsiiu shchitovidnoi zhelezy.

Changes in pituitary-thyroid axis sensitivity to bioactive component of pineal gland, melatonin, have been detected. In winter (short days) melatonin (100 micrograms/100 g of rat body weight) decreased T3 T4, TSH content and 131I uptake by thyroid tissue. However, it was noted that in summer (long photoperiod) the same injection caused suppression of T3 plasma level and 131I uptake ability of the thyroid gland, with T4 and TSH blood levels remaining significantly increased.

[Comparative experimental study of the effect of melatonin and 5-methoxytryptamine on the thyroid gland of rats]. / Sravnitel'noe izuchenie vliianiia melatonina i 5-metoksitriptamina na shchitovidnuiu zhelezu krys v eksperimente.

The authors studied the reactivity of the pituitary-thyroid system as influenced by melatonin and mexamine at varying times of photoperiod. It is concluded that the drugs under study had uncertain effects on rat thyroid function. It is assumed that different components of the hypothalamus-pituitary-thyroid system experience seasonal alterations in the sensitivity to the action of pineal gland methoxyindoles.