New Synthetic Thrombin Inhibitors: Molecular Design and Experimental Verification

BACKGROUND: The development of new anticoagulants is an important goal for the improvement of thromboses treatments. OBJECTIVES: The design, synthesis and experimental testing of new safe and effective small molecule direct thrombin inhibitors for intravenous administration. METHODS: Computer-aided molecular design of new thrombin inhibitors was performed using our original docking program SOL, which is based on the genetic algorithm of global energy minimization in the framework of a Merck Molecular Force Field. This program takes into account the effects of solvent. The designed molecules with the best scoring functions (calculated binding energies) were synthesized and their thrombin inhibitory activity evaluated experimentally in vitro using a chromogenic substrate in a buffer system and using a thrombin generation test in isolated plasma and in vivo using the newly developed model of hemodilution-induced hypercoagulation in rats. The acute toxicities of the most promising new thrombin inhibitors were evaluated in mice, and their stabilities in aqueous solutions were measured. RESULTS: New compounds that are both effective direct thrombin inhibitors (the best K(I) was <1 nM) and strong anticoagulants in plasma (an IC(50) in the thrombin generation assay of approximately 100 nM) were discovered. These compounds contain one of the following new residues as the basic fragment: isothiuronium, 4-aminopyridinium, or 2-aminothiazolinium. LD(50) values for the best new inhibitors ranged from 166.7 to >1111.1 mg/kg. A plasma-substituting solution supplemented with one of the new inhibitors prevented hypercoagulation in the rat model of hemodilution-induced hypercoagulation. Activities of the best new inhibitors in physiological saline (1 µM solutions) were stable after sterilization by autoclaving, and the inhibitors remained stable at long-term storage over more than 1.5 years at room temperature and at 4°C. CONCLUSIONS: The high efficacy, stability and low acute toxicity reveal that the inhibitors that were developed may be promising for potential medical applications

Laparoscopic Pediatric Pyeloplasty: Trends in Regions of the Russian Federation

Introduction. The use of minimally invasive surgery of urteropelvic junction obstruction was started in the in the mid-90s of the last century. Replacement rates of open surgery and methods of the minimally invasive surgery are different in various countries. We analyzed the spread of minimally invasive technologies in some regions of the Russian Federation.Purpose of the study. To study the dynamics of replacement of open pyeloplasty with laparoscopic pyeloplasty in certain regions of the Russian FederationMaterial and methods. Available data included the annual number of laparoscopic and open pyeloplasties, patient age, complications, and medium-term results. Our analysis screened 1581 pyeloplasties, which were performed during 2004‒2018 in eight regions of the Russian Federation. The patients were separated into two groups according to age. There were 566 infants and 1015 older children. A total 908 (57.4%) laparoscopic pyeloplasty (LP) and 673 (42,6%) open pyeloplasty (OP) were performed. Of those patients who underwent laparoscopic pyeloplasty, 274 (48.4%) were infants, while 624 (61.5%) were older children. The rates of LP and OP use were then assessed according to year of surgery. A binary logistic regression model was used to evaluate the statistical significance of the rate of LP use over time, to predict postoperative complications and to compare the effectiveness of LP in comparison with OP.Results. The use of LP increased remarkably during the study period. In regions with 5 years of LP experience, LP utilization rate was significantly higher. The rate of LP in infants has been associated with increasing experience in the LP. A total, 70% of older children and 59% of infants were operated with LP in 8 regions in 2018.Conclusion. In some regions of the Russian Federation, the rate of LP is markedly increased and almost replaces open surgery. In regions where LP has been introduced over the past 5 years, the replacement rate is higher than in regions where LP was introduced before

Practical Application of Augmented/Mixed Reality Technologies in Surgery of Abdominal Cancer Patients

The technology of augmented and mixed reality (AR/MR) is useful in various areas of modern surgery. We considered the use of augmented and mixed reality technologies as a method of preoperative planning and intraoperative navigation in abdominal cancer patients. Practical use of AM/MR raises a range questions, which demand suitable solutions. The difficulties and obstacles we encountered in the practical use of AR/MR are presented, along with the ways we chose to overcome them. The most demonstrative case is covered in detail. The three-dimensional anatomical model obtained from the CT scan needed to be rigidly attached to the patient’s body, and therefore an invasive approach was developed, using an orthopedic pin fixed to the pelvic bones. The pin is used both similarly to an X-ray contrast marker and as a marker for augmented reality. This solution made it possible, not only to visualize the anatomical structures of the patient and the border zone of the tumor, but also to change the position of the patient during the operation. In addition, a noninvasive (skin-based) marking method was developed that allows the application of mixed and augmented reality during operation. Both techniques were used (8 clinical cases) for preoperative planning and intraoperative navigation, which allowed surgeons to verify the radicality of the operation, to have visual control of all anatomical structures near the zone of interest, and to reduce the time of surgical intervention, thereby reducing the complication rate and improving the rehabilitation period

New Opportunities for Complex Therapy in Patients with Dry Eye Syndrome of Various Etiologies

The purpose: to evaluate the effectiveness of the Delfanto® in the complex therapy of patients with dry eye syndrome of various etiologies and severity of the clinical course.Patients and methods. 114 patients (228 eyes) with dry eye syndrome of various etiologies were examined: 72 patients with chronic meibomian blepharitis and dysfunction of the meibomian glands (xerosis due to increased evaporation of the tear film), 33 women with perimenopause (a mixed form of xerosis with a predominant decrease in the production of components of the tear film) and 9 persons with Syegren syndrome (xerosis due to a pronounced decrease in tear production). All patients received individually selected tear replacement therapy over the past weeks and the drug was not replaced throughout the study. At the same time, patients with mild and moderate clinical course of SSG for 30 days received Delfanto® at a dosage of 60 mg, and with severe course — 120 mg per day.Results. All patients on the background of complex therapy showed a significant decrease in the severity of subjective manifestations of the dry eye syndrome, an increase in the of the tear film stability and indicators of tear production. At the same time, the dynamics of changes in these parameters of the course of the xerotic process increased as the therapy continued, reaching a maximum by the 30th day. The maximum effect of Delfanto® in the complex therapy of patients with dry eye syndrome was observed in patients with chronic meibomian blepharitis. Moreover, patients with a mild clinical course of cornealconjunctival xerosis were the most susceptible to the therapy.Conclusion. The effectiveness of the complex therapy for patients with dry eye syndrome can be significantly increased by prescribing Delfanto® in a daily dose of 60 mg for mild and moderate xerosis and 120 mg — for severe disease. Delfante® can be recommended for widespread clinical use in complex treatment of patients with various clinical and pathogenetic forms of dry eye syndrome

A Molecular Phylogeny of <i>Stylodipus</i> (Dipodidae, Mammalia): A Small Genus with a Complex History

A range-wide phylogenetic/phylogeographic study of the three-toed jerboas of the genus Stylodipus is conducted using the mitochondrial cytb gene and fragments of several nuclear genes. The genus has been believed to include three species: S. telum (W Central Asia, SE Europe), S. andrewsi (E Central Asia), and S. sungorus (Dzungar basin). Our data support the dichotomy between S. andrewsi and the other taxa forming S. telum species group. Within the latter, both mtDNA and nuclear loci indicate a species-level divergence between S. telum and the S. t. birulae lineage (Zaisan depression, NE Kazakhstan), previously considered a subspecies of S. telum and here elevated to full species. S. sungorus is recovered as a close sister group to S. birulae on the basis of nuclear data but clustered with S. telum in the mitochondrial tree. The latter taxon is the most variable and includes two closely related eastern and western sublineages, separated by the Volga-Ural sands and joined by a more divergent S. t. karelini lineage (E Kazakhstan). The observed mitonuclear discordance is hypothesized to occur due to mtDNA introgression resulting from hybridization between S. sungorus and S. t. karelini, which highlights the important role of reticulations in the evolution of Dipodidae