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.
The aim of the investigation was to assess the capabilities of combined application of multislice linear digital X-ray tomography (tomosynthesis) and ultrasound examination in diagnosing spinal tuberculous lesion.Materials and methods. 117 patients with tuberculous spondylitis (n=46) and hematogenous vertebral osteomyelitis (n=71), treated from 2010 to 2015 in the Research Institute of Phthisiopulmonology affiliated to I.M. Sechenov First Moscow State Medical University, were included into the study.Results. The main radiation signs of tuberculous spondylitis and hematogenous vertebral osteomyelitis using multislice linear X-ray tomography have been specified. The following is characteristic of tuberculous spondylitis: mixed lytic destruction of vertebral bodies (p=0.04), anterior wedge-shaped deformation of the 2/3 and more of the vertebral body height (p=0.04), a rare damage of the arches, transverse and/or spinous processes (p=0.05). A diagnostic efficacy of the standard roentgenography, CT, tomosynthesis and a combination of tomosynthesis and US examination in revealing inflammatory changes in paravertebral tissues in patients with spinal tuberculosis has been determined. The sensitivity of the methods was 71.6, 90.2, 80.0 and 88.5% respectively, specificity amounted to 79.2, 93.1, 84.0 and 81.8%, respectively. The analysis of the diagnostic significance of the radiation techniques in differential diagnosis of tuberculosis and spinal osteomyelitis estimated the best values of sensitivity in CT (89.7%) and multislice linear digital X-ray tomography (84.6%) compared to the standard roentgenography (82.2%). Specificity was equal to 84.0, 79.3 and 76.1%, respectively.Conclusion. The combination of multislice linear digital X-ray tomography and US examination enables a significant reduction of radiation dose during examination of patients suspected of tuberculous spondylitis.
A procedure involving ion pair HPLC combined with UV detection was developed for determination of the innovative antituberculosis drug perchlozone in human blood plasma and validated in terms of selectivity, calibration curve, accuracy, precision, sensitivity, and stability. The procedure enables determination of the perchlozone concentration in the blood plasmas of patients taking other antituberculosis medication and can be used for both pharmacokinetic investigations and therapeutic monitoring.
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