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Background: Factor Xa (FXa) is known to play a central role in blood coagulation cascade and considered to be one of the most attractive targets for oral anticoagulants of new generation., Objective: Our approach for the development of directly acting oral anticoagulants (DOAC), FXa inhibitors was demonstrated in this work., Method: Chemical synthesis is the base of our approach for the development of potential inhibitors. In this work, the substances like R1-(CONH)-R2-(CONH)-R3 are being developed, using previously described docking and screening methods, where R1, R2 and R3 are some chemical groups and (CONH) are amide bonds connecting R1, R2 and R3. The direction of amide bond (CONH) could be arbitrary for R1, R2 and R2, R3., Results: Chemical modifications were made in the frame of the results, taking into account the structure of FXa, chemical synthesis capabilities, as well as patentability of the target compounds. Subnanomolar potency of several developed compounds was achieved. Several analyzers and various testing-suites have been used to measure the concentration that doubled the prothrombin time (PTx2). Moreover, in human plasma the PTx2 concentration of the compound 217 (DD217) turned out to be 80±20 nM. The compound efficacy has proved by in vivo assays including oral administrations in rats, rabbits and monkeys., Conclusion: The pharmacodynamic profile of DD217 for oral administration in cynomolgus monkeys proves the efficacy of the compound, which makes it promising for the future preclinical trials., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Introduction: This article presents the results of an international, multicenter, randomized, double-masked, placebo-controlled clinical study of Visomitin (Mitotech LLC, Moscow, Russian Federation) eye drops in patients with dry eye syndrome (DES). Visomitin is the first registered (in Russia) drug with a mitochondria-targeted antioxidant (SkQ1) as the active ingredient., Methods: In this multicenter (10 sites) study of 240 subjects with DES, study drug (Visomitin or placebo) was self-administered three times daily (TID) for 6 weeks, followed by a 6-week follow-up period. Seven in-office study visits occurred every 2 weeks during both the treatment and follow-up periods. Efficacy measures included Schirmer's test, tear break-up time, fluorescein staining, meniscus height, and visual acuity. Safety measures included adverse events, slit lamp biomicroscopy, tonometry, blood pressure, and heart rate. Tolerability was also evaluated., Results: This clinical study showed the effectiveness of Visomitin eye drops in the treatment of signs and symptoms of DES compared with placebo. The study showed that a 6-week course of TID topical instillation of Visomitin significantly improved the functional state of the cornea; Visomitin increased tear film stability and reduced corneal damage. Significant reduction of dry eye symptoms (such as dryness, burning, grittiness, and blurred vision) was also observed., Conclusion: Based on the results of this study, Visomitin is effective and safe for use in eye patients with DES for protection from corneal damage., Funding: Mitotech LLC.

Aim: Selection of optimal dosage regimen, length of treatment course (frequency of administration), safety, tolerance and clinical effectiveness evaluation of the medical preparation fortepren in patients with chronical recurrent herpes virus infection of genital localization., Materials and Methods: The medical product of antiviral and immune modulating effect--fortepren (sodium polyprenyl phosphate) as a 4 mg/ml solution for injections combined with the base course of acyclic nucleoside acyclovir, 400 mg tablets, held studies. 40 male and female patients participated in the study. After a 10-day acyclovir course (400 mg x 3 times a day) for removing the acute phase, 4 groups of 10 individuals were formed: 1--5 ml (20 mg) of fortepren i/m once at day 13 ± 2 after the start of the study after the completion of the treatment of the acute phase of the disease; 2--5 ml (20 mg) fortepren i/m 3 times at an interval of 21 days; 3--2 ml (8 mg) fortepren i/m 3 times at an interval of 21 days; 4 (control)--5 ml of placebo i/m at remission stage 3 times at an interval of 21 days. Increase of the duration of inter-recurrence period, decrease of the severity of the recurrences, state of skin and mucous damage elements, improvements of immunologic parameters were considered during effectiveness evaluation., Results: Significant differences in the frequency of recurrences of genital herpes were shown for 3 months of observation in experimental and control groups. A significant reduction of genital herpes recurrence frequency from 3.52 ± 0.09 (before treatment) to 2.89 ± 0.08 (after treatment) was noted in patients of group 3 (p < 0.001). The frequency of recurrences in the control group was 3.84 ± 0.10, that was higher than the parameters in all the experimental groups. A significant reduction of the rash area was noted in group 3, moreover, a redution of frequency of detection of clinical manifestations of genital herpes in the form of vesicle elements after treatment in groups 2 (p = 0.02) and 3 (p = 0.005) was found. Evaluation of local symptoms has established that burning have caused minimal discomfort for patients of groups 3 and 4 and itch and soreness--of groups 1 and 3. The least pronounced exacerbations were noted in patients of group 3. Intramuscular administration of fortepren preparation was established to result in the increase of titers of leukocyte virus-induced interferon for the whole duration of treatment., Conclusion: An intramuscular dose of 2 ml (8 mg) at recurrence stage 3 times at an interval of 21 days after the completion of the 10-day base course of treatment of the acute phase of chronical recurrent herpes virus infection of genital localization using acyclovir was accepted as an optimal dosage regimen. Analysis of the obtained results has shown an acceptable safety profile and a good level of tolerance for fortepren preparation.

It has been about 15 years since the introduction of the rechargeable mitochondria-targeted antioxidants (RMA). Two major groups have been developing RMA of the MitoQ and SkQ types independently, and many additional trials have been done by other researchers. This has provided solid preclinical evidence of RMA efficacy in various models. Human trials of systemic MitoQ were not followed by further advances, but the safety of MitoQ and, most likely, other RMA in humans has been demonstrated. A prooxidant effect at higher concentrations of RMA was described. For RMA of the SkQ type, a large window between anti- and prooxidant concentrations was observed, which makes SkQs promising as potential medicines. Significant RMA-induced improvements in many diseases that do not have an accepted treatment have been described. This justifies further clinical trials of RMA., (© 2014 Elsevier Inc. All rights reserved.)

Plastoquinone, a very effective electron carrier and antioxidant of chloroplasts, was conjugated with decyltriphenylphosphonium to obtain a cation easily penetrating through membranes. This cation, called SkQ1, is specifically targeted to mitochondria by electrophoresis in the electric field formed by the mitochondrial respiratory chain. The respiratory chain also regenerates reduced SkQ1H(2) from its oxidized form that appears as a result of the antioxidant activity of SkQ1H(2). SkQ1H(2) prevents oxidation of cardiolipin, a mitochondrial phospholipid that is especially sensitive to attack by reactive oxygen species (ROS). In cell cultures, SkQ1 and its analog plastoquinonyl decylrhodamine 19 (SkQR1) arrest H(2)O(2)-induced apoptosis. When tested in vivo, SkQs (i) prolong the lifespan of fungi, crustaceans, insects, fish, and mice, (ii) suppress appearance of a large number of traits typical for age-related senescence (cataract, retinopathies, achromotrichia, osteoporosis, lordokyphosis, decline of the immune system, myeloid shift of blood cells, activation of apoptosis, induction of β-galactosidase, phosphorylation of H2AX histones, etc.) and (iii) lower tissue damage and save the lives of young animals after treatments resulting in kidney ischemia, rhabdomyolysis, heart attack, arrhythmia, and stroke. We suggest that the SkQs reduce mitochondrial ROS and, as a consequence, inhibit mitochondria-mediated apoptosis, an obligatory step of execution of programs responsible for both senescence and fast "biochemical suicide" of an organism after a severe metabolic crisis.

Functional derangements in the brain during the acute period of ischemic hemispheric stroke (IS) were assessed in terms of the severity of the motor neurological deficit in the acute period of IS and neurophysiological measures of motor evoked potentials (MEP) using transcranial magnetic stimulation (TCMS). A total of 52 patients (23 women, 29 men, mean age 58.5 +/- 8.7 years) were studied. Patients were divided into two subgroups: group 1 consisted of 29 patients with good functional outcomes from the acute period; group 2 consisted of 23 patients with poor functional outcomes. The use of TCMS for recording MEP demonstrated increases in the latency of the M response both after stimulation of the projection of the motor area of the cortex of the lesioned hemisphere and after stimulation of the spinal cord. There were increases in the central motor conduction time (CMCT) in the lesioned hemisphere of the brain and a negative correlation was seen between the severity of the neurological defect and CMCT on the one hand (r = -0.65 to -0.78; p < 0.001) and, on the other, the latency of the M response in TCMS of the motor zone of the cortex on the side of the hemispheric stroke (r = -0.65 to -0.79; p < 0.001). The increases in the latency of the M response and CMCT have prognostic significance for early assessment of the outcome of IS.

Mutant alleles CYP2D63 and CYP2D64 were detected by PCR in 33 individuals. All examinees were given 50 mg methoprolol (orally). Plasma concentrations of the drug and its major metabolite was determined by high performance liquid chromatography and arterial pressure and heart rate were monitored. The rate of methoprolol metabolism was significantly lowered in subjects with CYP2D64 mutation. This determined blood pressure decrease and bradycardia in these subjects after drug intake.

Beams at the output of an axially symmetric multimode fiber were produced with mostly positive or negative values of angular index m through skew illumination of the input end of the fiber. In this way rays with predominantly positive or negative helicity were excited inside the fiber. The output cw speckle field at the wavelength lambda = 632.8 nm contained large densities N(+) and N(-) of wave-front dislocations, or optical vortices, of both positive and negative sign. Vorticity was defined as V = N(+) - N(-) , was expressed analytically through the Wigner function of the field, and was found experimentally to be in good agreement with theory.

A new method for the measurement of the phase shift between second-harmonic light generated by a bulk glass and the injected second-harmonic seed is presented. A linearly polarized pump and a second-harmonic seed with noncollinear polarizations were used for preparation of cerium-doped lead-silica glass. Independence of the phase shift from the angle between the polarizations of the recording waves is demonstrated, and a phase shift value close to 90 degrees is observed, i.e., the X((2)) grating was in phase with the real ?E(EE)?.