Chemoenzymatic synthesis of enantiomerically enriched diprophylline and xanthinol nicotinate.

A concise chemoenzymatic route toward enantiomerically enriched active pharmaceutical ingredients (API) - diprophylline and xanthinol nicotinate - is reported for the first time. The decisive step is an enantioselective lipase-mediated methanolysis of racemic chlorohydrin-synthon acetate, namely 1-chloro-3-(1,3-dimethyl-2,6-dioxo-1,2,3,6-tetrahydro-7H-purin-7-yl)propan-2-yl acetate, performed under kinetically-controlled conditions on a preparative 500 mg-scale. The best results in terms of reaction enantioselectivity (E = 14) were obtained for the enantiomers resolution performed with lipase type B from Candida antarctica immobilized on acrylic resin (CAL-B, Novozym 435) suspended in homophasic acetonitrile-methanol mixture. The elaborated biocatalytic system furnished the key chlorohydrin intermediate (in 71% ee and 38% yield), which was then smoothly converted into enantioenriched active agents: (R)-(-)-diprophylline (57% ee) and (S)-(+)-xanthinol nicotinate (65% ee). To support the assignment of absolute configurations of EKR-products as well as to confirm the stereochemical outcome of the remaining reaction steps, docking studies toward the prediction of enantiomers binding selectivity in CAL-B active site as well as the respective chemical correlations with enantiomerically enriched analytical standards obtained from commercially available (R)-(-)-epichlorohydrin, were applied. In addition, single-crystal X-ray diffraction (XRD) analyses were performed for the synthesized optically active APIs furnishing by this manner a first crystal structures of nicotinic acid salt of xanthinol.

Inhibited proliferation of human umbilical artery smooth muscle cells by xanthinol nicotinate.

Vascular smooth muscle cell proliferation is a key event in the development of hypertension, instant restenosis and other cardiac disorders. Inhibition of this proliferation could lead to better prevention and treatment of these diseases. This study was designed to investigate the effects and mechanisms of different concentrations of xanthinol nicotinate (XN) on human umbilical artery smooth muscle cell (HUASMC) proliferation in vitro. HUASMCs were cultured by the tissue adherent method, passaged three times, and then identified by immunohistochemistry. HUASMCs were then treated with different concentrations of XN (0, 2.76, 27.6 or 276 µM), and a 3-(4,5-dimethylthiazol-2yl)-2, 5-diphenyltetrazolium bromide (MTT) assay was used to detect the inhibition of HUASMC proliferation. The levels of platelet-derived growth factor receptor (PDGFR) mRNA and protein (PDGFR-ß) were detected on the cell membrane of these treated HUASMCs using RT-PCR and Western blot analysis, respectively. After culturing and passaging three times, 90 % of the cultured cells were identified as HUASMCs by immunohistochemistry. HUASMC proliferation was inhibited by XN in a dose-dependent manner (P < 0.05). Furthermore, XN dose-dependently decreased the PDGFR mRNA and PDGFR-ß levels on the cell membranes of HUASMCs (P < 0.05). Thus, the results suggest that XN could become a potent therapeutic agent for regulating VSMC-associated vascular disease such as cardiovascular disease and restenosis after angioplasty.

[TREATMENT OF THROMBOTIC COMPLICATIONS IN THE INJURED PERSONS IN POLYTRAUMA].

Comparative results of treatment of thrombotic complications in the injured persons with combined trauma of trunk in two groups were adduced. The scheme of prophylax3 is and treatment of thrombotic complications was proposed; application of this scheme have permitted to reduce their rate in 5 times, from 54.5 to 11.2%.

Intradermal Therapy (Mesotherapy) for the Treatment of Acute Pain in Carpal Tunnel Syndrome: A Preliminary Study

BACKGROUND: The carpal tunnel syndrome (CTS) is the most common cause of severe hand pain. In this study we treated acute pain in CTS patients by means of local intradermal injections of anti-inflammatory drugs (mesotherapy). METHODS: In twenty-five patients (forty-five hands), CTS diagnosis was confirmed by clinical and neurophysiological examination prior to mesotherapy. A mixture containing lidocaine 10 mg, ketoprophen lysine-acetylsalycilate 80 mg, xantinol nicotinate 100 mg, cyanocobalamine 1,000 mcg plus injectable water was used. Sites of injection were three parallel lines above the transverse carpal ligament and two v-shaped lines, one at the base of the thenar eminence, and the other at the base of the hypothenar eminence. RESULTS: The day after the treatment, all but four patients reported a significant reduction in pain and paresthesias. After 12 months, 17 patients had a complete pain relief, eight patients reported recurrence of pain and sensory symptoms and four out of them underwent surgical treatment. CONCLUSIONS: With the obvious limits of a small-size open-label study, our results suggest that mesotherapy can temporary relieve pain and paresthesias in most CTS patients and in some cases its effect seems to be long-lasting. Further controlled studies are needed to confirm our preliminary findings and to compare mesotherapy to conventional approaches for the treatment of CTS.

[Sudden hearing loss: our experiences in treatment with vasoactive and corticosteroid therapy].

INTRODUCTION: Sudden hearing loss is a clinical entity of ambiguously defined aetiology manifested by hearing loss of more than 30 dB on three contiguous frequencies occurring within 72 hours. The lack of standard therapy protocol led to the use of variety of different therapies, thus making difficult objective quantification of their effect. OBJECTIVE: The aim of the study was to present our experience in the treatment of sudden hearing loss with administration of vasoactive and corticosteroid therapy. METHODS: Our research included 59 hospitally treated patients with a sudden hearing loss. During the period 1995-2004, 37 patients were treated using vasoactive agents (xanthinol nicotinate and pentoxifylline), and from 2004-2009, 22 patients were treated using parenteral corticosteroids (dexamethasone). All patients had unilateral sensorineural hearing loss of different level at frequencies from 500-4000 Hz, while other diagnostic procedures (laboratory tests, internist and neurology examinations, X-ray) were within normal limits. Evaluation of therapy effect was done by follow-up of hearing threshold changes and subjective complaints. RESULTS: The results showed that full recovery was achieved in patients with a mild and not fully severe hearing loss, with the majority of those (73%) under corticosteroid treatment. In these patients recovery was also achieved more rapidly. A partial recovery of hearing was detected in patients with hearing loss of more than 80 dB, and mostly in patients treated with corticosteroids. CONCLUSION: Although statistical evaluation does not indicate significant differences between the application of vasoactive drugs or corticosteroids, clinical findings support advantages of corticosteroid therapy. Treatment of hearing loss, although controversial, requires change of some up-to-now used agents. Advantages should go in favour of contricosteroids.

[Role of low-dose acetylsalicylic acid in comprehensive postoperative treatment of patients with lower-limb chronic arterial insufficiency].

The study comprised a total of 107 patients (all men) after endured femoropopliteal bypass grafting above the genicular fissure with a synthetic stent graft manufactured by the Gore Company for stage IIB and III chronic arterial insufficiency of the lower extremities according to the Fontain-Pokrovsky classification. Group One I (control group) was composed of fifty-four patients permanently taking in the postoperative period at the out-patient stage pentoxiphylline (trental 400 mg 1 tablet 3 times daily) and xantinol nicotinate at a dose of 150 mg one tablet thrice daily. Group Two (Study Group) consisted of fifty-three patients taking after reconstructive vascular surgery at the out-patient stage in addition to pentoxiphylline and xantinol nicotinate acetylsalicylic acid (cardiomagnil 75 mg 1 tablet once daily). The Control Group patients within 3 to 6 months of follow up were found to have a considerable progressing improvement of the functional abilities of the microcirculatory bed requiring in 44 (81.5%) cases hospitalization to the Surgical Department for intensive vascular therapy. Despite this fact four (7.4%) patients within the time frame from 6 to 9 months after surgery developed thrombosis of the vascular implant requiring a repeat surgical intervention. In the Study Group patients, the degree of functional capabilities of the microcirculatory bed in the postoperative period was less considerable, reaching the maximum after 10-12 months of follow up, with eighteen (34.0%) patients requiring hospitalization for additional vascular therapy to perform. There were no cases of implants' thrombosis in the Study Group patients. Pathological alterations in the functional state of the peripheral vascular bed correlated with viscosimetric indices and activity of blood platelet aggregation. The addition of antithrombocytic agents to conservative postoperative therapy considerably improved the outcomes of surgical treatment.

[Peyronie's disease: comparative results of conservative treatment].

Long-term clinical experience with conservative treatment of Peyronie's disease has demonstrated that clinical efficacy of this therapy comprises maily anesthesia while erectile problems are not solved. Introduction of the drugs into the fibrous plaque is not adequate and hard to perform. Some drugs affect only some components of pathogenesis. For stabilization of the process it is recommended to use transdermal electrophoresis or phonophoresis. The search for new effective drugs and methods continues.

Use of Xanthinol Nicotinate as a co-treatment for radio- and chemo-therapy in experimental tumors.

The tumor micro-environment plays a key role in the tumor resistance to cytotoxic treatments. It has been demonstrated that it is possible to modulate the tumor microenvironment to potentiate anti-cancer therapy. Here, we made the hypothesis that the vasoactive agent xanthinol nicotinate (XN) could be an important modulator of the tumor perfusion and oxygenation. Using functional non invasive techniques (in vivo EPR oximetry and dynamic contrast enhanced MRI), we were able to define a time window in which tumor oxygenation, flow and permeability were significantly increased in the TLT tumor model implanted in muscles of mice. As a consequence of the alleviation of tumor hypoxia, we found out that XN was able to radiosensitize the tumors when applying 10 Gy of X-Rays during the reoxygenation of the tumors (enhancement in radiation response of 1.4). Moreover, the administration of cyclosphosphamide (50 mg/kg) used as a chemotherapeutic agent was more efficient when applying the treatment after XN administration (enhancement in response to chemotherapy of 2.7). These results show the importance of the dynamic evolution of the tumor microenvironment on the response to treatments, and that XN is an efficient modulator of the tumor hemodynamics that may potentiate cytotoxic treatments.

Novel inhibitors of HIV discovered among existing classes of pharmaceutical compounds indicated for unrelated clinical indications.

In vitro screening of 307 drugs with various clinical indications (cardiotropic, neurotropic, antibacterial, etc.) has revealed 6 compounds which displayed remarkable antiretroviral activity. Three of these drugs had a tendency to have undesirable side effects and were thus excluded from further consideration. Remaining three, i.e., Xantinol Nicotinate, Tardiferon, and Trental may become valid candidates for inclusion into antiviral regimens such as HAART. In vitro tests have shown that xantinol and trental display synergistic effect with azidothymidine, inhibit the replication AZT-resistant strains of HIV, and have no competing undesirable activities. These compounds should be evaluated in safety studies to determine optimal doses for patients with HIV. If these studies confirm in vitro results these compounds may become valid candidates as safe and affordable means to be added into the arsenal of antiretroviral drugs.

Development and validation of a liquid chromatography-tandem mass spectrometry method for the determination of xanthinol in human plasma and its application in a bioequivalence study of xanthinol nicotinate tablets.

A sensitive, rapid liquid chromatographic-electrospray ionization mass spectrometric method for the determination of xanthinol in human plasma was developed and validated. Xanthinol nicotinate in plasma (0.5 mL) was pretreated with 20% trichloroacetic acid for protein precipitation. The samples were separated using a Lichrospher silica (5 microm, 250 mm x 4.6 mm i.d.). A mobile phase of methanol-water containing 0.1% formic acid (50: 50, v/v) was used isocratically eluting at a flow rate of 1 mL/min. Xanthinol and its internal standard (IS), acyclovir, were measured by electrospray ion source in positive selected reaction monitoring mode. The method demonstrated that good linearity ranged from 10.27 to 1642.8 ng/mL with r=0.9956. The limit of quantification for xanthinol in plasma was 10.27 ng/mL with good accuracy and precision. The mean plasma extraction recovery of xanthinol was in the range of 90.9-100.2%. The intra- and inter-batch variability values were less than 4.8% and 7.9% (relative standard deviation, R.S.D.), respectively. The established method has been successfully applied to a bioequivalence study of two xanthinol nicotinate tablets for 20 healthy volunteers.

[Sudden hearing loss--our experience in treatment with vasoactive therapy].

INTRODUCTION: A specific title "sudden hearing loss" refers to illness which is characterized by a sudden, rapid sensoneural hearing loss mostly in one ear without obvious causes, accompanied with dizziness, and without vestibular symptomatology. It is defined as a hearing loss for more than 30 dB on 3 or more successive frequencies which appear in 72 hours. OBJECTIVE: The main goal of our paper was to estimate success of implementation of vasoactive method in patients with sudden hearing loss of senso-neural type in different ranges in hospital conditions. METHOD: Our research covered 37 patients hospitalized because of a sudden hearing loss of sensoneural type in different ranges. Diagnosis, in all patients, was established by clinical ORL examination, audiology and vestibular examination. R including CT and MR, neurological, internist and laboratory examinations were used in order to exclude other aetiology. In monitored patients, we started treatment with vasoactive therapy, ampules of xanthinol nicotinate (one ampule of 2 ml, 300 mg) or ampules of pentoxiphylline (one ampule of 5 ml, 100 mg) in form of infusions with addition of vitamins with an everyday gradual increase of dosage up to 12 ampules of xanthinol nicotinate and up to 5 ampules of pentoxiphylline. Then we started with an everyday decrease of dosage down to the first one. RESULTS: After the complete curing protocol, we found out that in patients with light and medium senso-neural damages of hearing sense (23 or 62%), hearing recovery was complete. In patients with heavy damage of hearing (9 or 24%), partial success was evidenced. The most difficult cases, with complete hearing loss, heavy buzzing and vertiginous problem (5 or 14%) responded to therapy, so buzzing and vertiginous problems disappeared but hearing was not improved. CONCLUSION: Usage of vasoactive medicaments in hospital conditions in treatment of sudden hearing loss gives good results and it is the closest to aetiological therapy.

[Pathogenetic basis for using prodectin and teonicol, redergin and aescuzan in complex treatment of chronic gastritis]. / Patogeneticheskie osnovy primeneniia prodektina i teonikola, redergina i éskuzana pri kompleksnom lechenii khronicheskogo gastrita.

The study of the microvessels in bioptates of gastric mucosa and micro haemocirculation in the conjunctiva of 254 patients with chronic gastritis revealed that exacerbation of the gastric process is going on the background of hard terminal bloodstream disorders. They have the generalized character and picture of the typical chronic relapsing trombohaemorrhagic syndrome. The use of Prodectin (250 mg), Teonicolum (150 mg), Redergin (1 tab.) and Aescuzan (25 dr.) 4 times per day during 3 weeks helps to eliminate the microcirculatory disorders and exacerbation of the chronic gastritis.

[Determination of xanthinol nicotinate in drug preparations using capillary isotachophoresis]. / Stanovení obsahu xanthinoliumnikotinátu v lécivých prípravcích metodou kapilární izotachoforézy.

Cationic capillary isotachophoresis (ITP) with coductimetric detection has been used for separating and determination of xanthinol in two commercial mass-produced preparations. The optimized ITP electrolyte system consisted of 5 mM potassium picolinate + 5 mM picolinic acid (pH 5.21) as the leading electrolyte and 10 mM formic acid as the terminating electrolyte. The driving and detection currents were 50 microA (for 380 s) and 10 microA, respectively. The analysis took about 8 min. According to the validation procedure based on the reference UV spectrophotometric method, the ITP method gave practically the same results.

The role of xanthine oxidase and the effects of antioxidants in ischemia reperfusion cell injury

During last years considerable interest has been devoted to understand the role of oxugen radicals in the inschemia induced cell injury associated with reperfusion. In the brain and in others tissues, free radicals play a role as modulators of vascular tone as well as a cytotoxic role as part of the ischemia associated pathology. This review discusses methods for free radical detection in brain and in other tissues, mechanisms of radical production in the course of the ischemia reperfusion process, and the efficacy of potential antioxidant agents in post ischemia therapy, especially with respect to allopurinol, an inhibitor of xanthine oxidase, and the role of taurine and its derivatives as antioxidants in different organs including the brain.

The role of xanthine oxidase and the effects of antioxidants in ischemia reperfusion cell injury

During last years considerable interest has been devoted to understand the role of oxugen radicals in the inschemia induced cell injury associated with reperfusion. In the brain and in others tissues, free radicals play a role as modulators of vascular tone as well as a cytotoxic role as part of the ischemia associated pathology. This review discusses methods for free radical detection in brain and in other tissues, mechanisms of radical production in the course of the ischemia reperfusion process, and the efficacy of potential antioxidant agents in post ischemia therapy, especially with respect to allopurinol, an inhibitor of xanthine oxidase, and the role of taurine and its derivatives as antioxidants in different organs including the brain. (AU)

Thrombolytic and antiplatelet action of xanthinol nicotinate (Sadamin): possible mechanisms.

Here we report on thrombolytic and hypotensive actions of Xanthinol nicotinate (Sadamin) in rats and on its anti-platelet and fibrinolytic effects in patients with peripheral arterial obliterative disease (PAOD). Special consideration was given to a proposal of new mechanisms of anti-platelet and thrombolytic actions of Sadamin. We conclude that the mechanism of anti-platelet and thrombolytic activity of Sadamin partly consists of a simultaneous release of endogenous prostacyclin and nitric oxide by the nicotinate component of Sadamin, whereas the theophylline component is responsible for enhancement of physiological actions of these endothelial mediators at the level of cyclic nucleotides which are their second messengers.

Drug monitoring studies as a method of analyzing response criteria.

Two multicenter drug monitoring studies are presented. Some methodological problems are dealt with and the validity of such studies is discussed in terms of differential indication. In a first study (Lehmann et al., 1993) the results of a 12-week xanthinol niacinate treatment (500 to 3000 mg daily) in a cohort of 10,134 outpatients suffering from cerebrovascular insufficiencies were recorded systematically by nonreactive evaluation methods. The therapy was found to be most successful in patients with the target symptoms vertigo, tiredness, lack of concentration, affective disorder, and disturbances of vigilance and vitality. The most frequent side-effects were flush or heat sensations in 9.1% of the patients and gastrointestinal complaints in 3.3%. In a second study (Klieser et al., 1994) we systematically collected data from 219 patients with Major Depressive Disorder during five weeks of treatment with fluoxetine (20 mg daily). The results showed that depressively inhibited, anxious patients with a depression of minor severity, who showed a relatively marked improvement within the first week of treatment, profited the most from this therapy. The first study was designed to use nonreactive evaluation methods. Correlation analyses helped to identify the types of patient with a good response to treatment. The second study was organized on the model of conventional controlled pharmacological studies with the application of commonly used scales. The differential indication was to be inferred from the uni- and multivariate comparison of responders and nonresponders. In the light of these two studies, the problems of target definition, sample design, target variables, practicability, statistical analysis, and validity are discussed.

[New method of atherosclerotic macular dystrophies treatment]. / Novyi metod lecheniia ateroskleroticheskikh makulodistrofii.

The authors analyze the results of treating atherosclerotic maculodystrophies by direct laser phoresis. The method consists in insertion of a collagen infusion system in Tenon's space. Drugs (nicotinic acid or xanthinol nicotinate) are delivered to the posterior compartment of the eye through this system. Then a light guide is inserted in the tube and a 2-min session of low-intensity He-Ne laser exposure is performed at a wavelength of 630 nm, and 10 mWt/cm2 flow power density (7 to 10 sessions per course). Clinical studies showed that vision acuity increased by an average of 0.08 diopters, or by 40% of the initial level, in 72% of cases. The peripheral visual field extended by an average of 51.4 degrees for 8 meridians in 95% of patients. The index of critical frequency of flashings fusing and the frequency-contrast characteristics improved in 85% of cases. The rheography improved by 34.5% of the initial level. A stable improvement was observed for 12 months after a course of direct laser phoresis in 97.5% of patients. Hence, the new method is simple and recommended for the treatment of atherosclerotic maculodystrophies.

[The efficacy of using antiaggregants in chronic glomerulonephritis with grade-I chronic kidney failure]. / Efektivnist' vykorystannia antyahrehantiv pry khronichnomu hlomerulonefryti z I stupenem khronichnoï nyrkovoï nedostatnosti.

Both short-term and long-term effectiveness of xantinole nicotinate as well as trentale and combinations thereof with dipyridamole has been demonstrated in patients with chronic glomerulonephritis presenting with grade 1 chronic renal insufficiency, which fact can be accounted for by their vasoactive and antiaggregant actions. Particular regimens have been developed to treat the medical condition in question with the above drug preparations, comparative evaluation was done of their effects on the clinical course of the illness as well as on the effective renal plasma flow, concentration of nitrogenous remainder in blood and urine, concentration of medium size molecules in blood. It is advisable that antiaggregants be administered long term (from several months to several years).