Research of Russian physicians' opinions on tuberculosis pharmacogenetics.

BACKGROUND: There is currently no widespread implementation of pharmacogenetic testing (PGx) methods in the practice of phthisiology service. OBJECTIVE: The aim of this study is to determine how informed and prepared phthisiologists, residents, and postgraduate students of the Russian Medical Academy of Continuing Professional Education (RMACPE, Moscow) use PGx techniques in their work to improve treatment safety, predict the occurrence of adverse reactions (ADRs), and personalize therapy. METHODS: A survey was conducted among phthisiologists (n = 314) living in different regions of the Russian Federation and studying at RMACPE, such as residents and post-graduate students (n = 185). The survey was developed on the Testograf.ru web platform and had 25 questions for physicians and 22 for residents and post-graduate students. RESULTS: More than 50% of respondents are ready to use PGx in clinical practice and thus are aware of the method's possibilities. At the same time only a small part of participants were aware of the pharmgkb.org resource. The absence of PGx in clinical guidelines and treatment standards, according to 50.95% of phthisiologists and 55.13% of students of RMACPE, the absence of large-scale randomized clinical trials, according to 37.26% of phthisiologists and 43.33% of students, and the lack of physician knowledge on PGx, according to 41.08% of phthisiologists and 57.83% of students, are all factors that prevent the implementation of PGx in Russia. CONCLUSION: According to the survey, the overwhelming majority of participants recognize the importance of PGx and are willing to use the method in practice. However, there is a low level of awareness among all respondents about the possibilities of PGx and the pharmgkb.org resource. The implementation of this service could significantly increase patient compliance, lower ADRs, and enhance anti-tuberculosis (TB) therapy quality.

[Prospects of Pharmacogenetic Testing for Design of Algorithms for Personalized Treatment of Tuberculosis of Respiratory Organs in the Astrakhan Region].

In spite of the availability of many antituberculosis drugs all over the world the morbidity of tuberculosis does not lower. Often the tuberculosis therapy schemes are adapted to every particular patient which is mainly due to the therapy unfavourable effects requiring discontinuation of the drugs used. Polymorphism of the detoxication genes, as predictors of the response to the drug therapy, was shown to be of certain significance. The experimental data would allow to substantiate personalized management of tuberculosis patients and to increase its efficacy and safety.

[Prognostication of toxicity of a group of chemical compounds comprising anti-tuberculosis medicines by the quantitative structure-activity correlation method].

Balaban (J), Wiener (W), and Rouvray (R) topological indices as well as detour (Ip) and electropy (Ie) indices reflecting the structure of chemical substances were used to establish correlation between median lethal dose (LD50) of an anti-tuberculosis medicine and its molecular structure. Monocyclic compounds showed linear correlation between LD50 values and Balaban index (R = 0.93). Correlation between a maximum daily dose and electropy index was typical of the products having a more complicated structure. Results of this study open up prospects for the development of new anti-tuberculosis medicinal preparations characterized by reduced toxicity.

[The diagnosis and correction of impairments of microcirculation, central hemodynamics, and oxygen status in children with traumatic shock].

The paper presents the results of studies of microcirculation, central hemodynamics, and oxygen status in 120 children aged 2-14 years who had traumatic shock of various etiology (40 with burn injury, 50 with mixed injury, and 30 with brain injury). The following studies were used: biomicroscopy of conjunctival microvessels with photo recording and processing on a computer; central hemodynamic monitoring; studies of a thromboelastogram, acid-alkali balance, and blood gases. The authors found the previously unknown parallels of the impairments of microcirculation, the severity of traumatic injury, and the parameters of central hemodynamics, and oxygen status in the patient. Traumatic shock was characterized by spastic impairments of all the components (perivascular, vascular, and intravascular) of microcirculation progressing to spastic-and-atonic ones. The degree of microcirculatory disorders depended on the severity of shock and the nature of injury. The criteria for compensation and decompensation in the microcirculatory module were defined. The routine infusion therapy initiated in the compensation period promotes to a significant alleviation of microcirculatory disorders; however, the mentioned shifts long persist. In this connection, a package of additional measures (infucol GEC solutions, disaggregatory, antihypoxic, and antioxidant agents, and coenzymes of vitamins) has been developed.

[Infusion-transfusion therapy of acute blood loss during early surgeries in children with severe thermal trauma]. / Infuzionno-transfuzionnaia terapiia ostroi krovopoteri vo vremia rannikh operatsii u detei s tiazheloi termicheskoi travmoi.

Research results of the central hemodynamics, microcirculation and of oxygen status are described for 48 children (aged 8 months to 14 years) as observed during surgeries aggravated by massive hemorrhage in the routine infusion-transfusion therapy plus a 6% solution of INFUKOL GEK. Solution dosages of 6% were approved; the drug's positive effect on the central-hemodynamics condition, microcirculation and on the oxygen regime, as observed in the process of the infusion therapy made to compensate for a massive blood loss, was demonstrated; besides, the related shrinking of the infusion therapy total volume and the possibility to give up totally or to significantly reduce the blood-drug preparations, administered intraoperatively, were shown.

[Characteristics of anesthesia in trauma surgery in children with severe burn injuries]. / Osobennosti anesteziologicheskogo obespecheniia pri travmatichnykh operatsiiakh u detei s tiazheloi ozhogovoi travmoi.

The authors analyze total anesthesia in 347 children with thermal injuries, subjected to traumatic operations involving massive blood loss. A characteristic feature of total anesthesia in children subjected to early necrectomies was a lower dose or refusal from cholinolytics for premedication, endotracheal multicomponent narcosis with ketamine, fentanyl (promedole) in the minimal doses in parallel with inhalation anesthesia by fluothane traces and a nitrous oxide-oxygen mixture with at least 50% oxygen. The optimal initial dose of nondepolarized myorelaxants in burnt children is 30-50% higher than the recommended dose and is determined by the size and depth of injury. For controlled myoplegia, the doses of nondepolarized myorelaxants for subsequent injections should be 1.5-2.5 times lower than the initial dose. The duration of pancuronium and arduan effects depended on hepatorenal function. Tracrium provided regulated myorelaxation in children with burns even in cases with hepatorenal dysfunction. A high rate of massive blood loss and early development of multiple organ failure in children with thermal injuries prompted us to develop infusion-transfusion therapy for traumatic operations involving massive blood loss. The volume of blood loss is estimated from the area of necrotic tissues removed and the type of necrectomy. Qualitative composition of transfusion mixture and the rate of transfusion is determined by the rate and volume of blood loss, level of hemoglobin and hematocrit, and metabolic disorders during the operation. Prolonged ventilation of the lungs is recommended for children with thermal injuries after operations involving blood loss of 1 circulating blood volume or more. These measures decreased the incidence and severity of complications involving the hemodynamics, oxygen status and metabolism in tissues, and improved the reparation.

[The characteristics of the action of nondepolarizing myorelaxants during operations on children with thermal injuries]. / Osobennosti deistviia nedepoliarizuiushchikh miorelaksantov vo vremia operatsii u detei s termicheskoi travmoi.

Effects of nondepolarizing myorelaxants pancuronium, arduan, and tracrium were studied during surgery in 347 children with thermal injuries aged from several months to 15 years. Nondepolarizing myorelaxants are drugs of choice for providing myoplegia in children operated on for thermal injuries. The optimal initial dose of these agents in children with burns is 30-50% higher than the recommended dose and depends on the size of the lesion. For controllable myoplegia, the doses of subsequent injections are to be 1.-5-2 times lowered in comparison with the initial dose. The effects of pancuronium and arduan depend on the hepatorenal function. Tracrium ensures sufficient controllable myorelaxation in children with burns even in cases with hepatorenal dysfunction.

[Anesthesia in surgery involving blood loss of different volume in children]. / Anesteziologicheskoe obespechenie pri operatsiiakh s razlichnoi velichinoi krovopoteri u detei.

Three variants of narcosis were compared in order to choose the optimal anesthesia for traumatic surgery involving blood loss of 15, 15 to 30, and more than 30% of the due volume of circulating blood. Microcirculation of the eye conjunctiva, central hemodynamics, hemostasis system, and lipid peroxidation were studied. Calypsol-based non-inhalation multicomponent intravenous anesthesia including neuroleptanalgesia and seduxen was found to be the least toxic and indicated for patients subjected to traumatic surgery involving blood loss of more than 30%.

[The basic mechanisms of microcirculatory disorders before and during operations in children with developmental defects of the kidneys and urinary tract]. / Osnovnye mekhanizmy narushenii mikrotsirkuliatsii do i vo vremia operatsii u detei s porokami razvitiia pochek i mochevyvodiashchikh putei.

The authors studied biomicroscopic picture of microcirculation in the vessels of bulbar conjunctiva, renal hemodynamics, blood cell metabolism in 50 patients aged 3-12 with renal and ureteral defects. By morphology of the kidneys assessed at aortography, computer renangiography and other tests 2 groups of children were identified: bilateral congenital urological disorder combined with severe advanced dysplasia of the renal tissue and the ureter, low renal function (group 1); light or moderate disorder of renal function, minimal dysplasia of the renal tissue. In children with renal and urinary defects with renal dysfunction there was systemic abnormal microcirculation (group 1) characterized by severe capillarotrophic insufficiency in the form of unusual winding of all the microvessels, formation of vascular loops and balls, narrowing of capillary lumen, etc. in the presence of acute arteriolar spasm and rheological alterations in microvessels. In addition to functional changes in arteriolar tone, mechanisms of microcirculatory disturbances in children with congenital surgical disorders of the kidneys and urinary tracts involve membrane-destructive processes. Changes in phospholipids level and their spectrum in plasma and red cell membranes, a rise in the activity of phospholipase A and C in the serum and red cell membranes exhibit close correlation with microhemodynamic impairment. Instructions are provided for conduction of preoperative preparation and multicomponent anaesthesia with allowances for principal mechanisms of microcirculatory disorders in children with severe congenital renal and urinary affections.

[Comparative analysis of different premedication methods in minor surgery in children]. / Sravnitel'nyi analiz razlichnykh metodik premedikatsii pri malykh khirurgicheskikh vmeshatel'stvakh u detei.

Oxygen regimen, hemodynamics, hemocoagulation, vegetative status, and immune status of patients subjected to multiple surgical interventions under anesthesia are analyzed. Three premedication schemes are considered. Routine fluothane anesthesia with nitrogen oxide + oxygen or calypsol after standard premedication is inadequate in children when used repeatedly. Tramal, a new analgesic, used in premedication, is highly effective, causes no side effects, and ensures sufficiently deep and prolonged analgesia. Use of neurovegetative blocking for premedication is a new and most physiological method of analgesia to be used in multiple minor surgical interventions in patients with burns.

[Therapeutic form of doxycycline hydrochloride for intravenous administration in the treatment of suppurative-septic diseases]. / Lekarstvennaia forma doksitsiklina gidrokhlorida dlia vnutrivennogo vvedeniia pri lechenii gnoino-septicheskikh zabolevanii.

Efficacy of doxycycline hydrochloride administered intravenously was studied in treatment of severe purulent inflammatory diseases such as pneumonia, lung abscesses, pyothorax, skin and soft tissue infections, peritonitis, purulent cholangitis, etc.. Doxycycline showed significant advantages over tetracyclines: prolonged action, higher efficacy and good tolerance. Favourable results were observed in 85 per cent of the cases.

[Drug dosage during balanced anesthesia in children with urinary tract diseases]. / Dozirovanie preparatov dlia sbalansirovannoi anestezii pri operatsiiakh u detei s zabolevaniiami mochevyvodiashcei sistemy.

To determine principles of choosing individual fentanyl and ketamin doses the data on the course of general anesthesia in 120 children were processed by regression analysis. It has been established that individual anesthetic dose titration should take into consideration the child's age, efficacy of premedication, renal function and circulatory pattern The infusion rate is determined with regard to anesthesia-induced circulatory changes. Regression analysis made it possible to work out formulas which enable individual dose titration and determination of the infusion rate.

[The polymorphism of the pharmacological effects of calcium channel blockers]. / Polimorfizm farmakologicheskikh éffektov blokatorov kal'tsievykh kanalov.

In experiments on mice and rats it was shown that the studied calcium channel blockers--verapamil (finoptin, isoptin), nifedipine (corinfar), sensit (phendilin), cinnarizine (stugeron), diltiazem--are heterogeneous by their pharmacological properties. No relationships between the antiarrhythmic, anticonvulsant and cholinolytic effects of the compounds were revealed. It was supposed that the cholinolytic activity of nifedipine and diltiazem in arecoline salivation test reflects not their competitive relations with acetylcholine on the active surface of the receptor, but rather is realized at the level of the signal transmembrane transmission systems.

[Relation between disorders of systemic microcirculation and chemotactic activity of macrophages in children with appendicular peritonitis]. / Vzaimosviaz' narushenii sistemnoi mikrotsirkuliatsii i khemo- taksicheskoi aktivnosti makrofagov u detei s appendikuliarnym peritonitom.

As many as 58 children aged 3 to 14 years operated on for destructive forms of appendicitis complicated by diffuse peritonitis were examined for microcirculation of eye conjunctiva microvessels using biomicroscopy and for chemotactic++ activity of macrophages in an area of aseptic inflammatory reaction. The correlation analysis made it possible to reveal specific dependence of macrophagal chemotaxis on primary derangement in one or another component of the microcirculatory bed, the extent of diminution of the arteriolar, capillary and venular lumen as well as on the impairment of blood aggregation in microvessels. Detoxication therapy contributed to the improvement of microcirculation and the growth of the release of macrophages to the area of aseptic inflammatory reaction.

[Microcirculatory disorders in the acute period of craniocerebral injuries in children]. / Narusheniia mikrotsirkuliatsii v ostrom periode cherepno-mozgovoi travmy u detei.

The authors analyzed the results of the biomicroscopy examination of the microcirculation in patients aged 2.5 to 15 years in the acute period of craniocerebral trauma. It was established that the changes in the condition of the conjunctival microvessels reflect the general cerebral microcirculation impairments following craniocerebral injury, their severity depending on the degree of brain involvement. They are characterized by spastic arterioles, distended venules as well as the development of the sludging phenomenon and the disruption of the capillary blood flow depending on the severity of craniocerebral trauma.