Valor de la genética en la era de la terapia triple frente al virus de la hepatitis C / The Value Of Genetics In The Era Of Hepatitis C Triple Therapy

A pesar de la introducción de los inhibidores de la proteasa (IP) en el tratamiento de la hepatitis C, la sensibilidad al IFN continúa siendo fundamental para alcanzar la respuesta virológica (RVS) y erradicar la infección viral. En la actualidad, el interferón pegilado (IFNpeg) y la ribavirina (RBV) son necesarios para evitar la selección de mutantes resistentes a los IP. La probabilidad de obtener la RVS con biterapia en pacientes naives infectados con genotipo 1 varía entre el 40-50%. Es decir, en casi la mitad de este grupo de pacientes no sería preciso introducir un IP, evitando así los efectos adversos del mismo y disminuyendo considerablemente el coste del tratamiento. Identificar a estos potenciales respondedores a la doble terapia es uno de los mayores retos en la práctica clínica. La variabilidad genética del huésped constituye uno de los factores fundamentales en la sensibilidad al IFNpeg y, por tanto, en la respuesta al tratamiento actual. Otros factores basales relacionados con el huésped, con el virus y, sobre todo, los factores intratratamiento como la respuesta virológica rápida (RVR), se relacionan fuertemente con la probabilidad de alcanzar la RVS. La evidencia sobre la decisión de tratar con doble o triple terapia en función de los factores predictores de respuesta se basa en estudios retrospectivos o análisis posthoc de los estudios pivotales de los IP. El estudio de los polimorfismos del gen de IFNL3 (IL28B), ITPA, genes estimulados por IFN (ISG), TT/ΔG (ss469415590; IFNL4) y de transportadores de RBV son factores genéticos importantes que nos pueden ayudar a tomar la decisión de tratar con doble o triple terapia en pacientes naives

Despite the introduction of protease inhibitors (PI) in the treatment of hepatitis C, the sensitivity of interferon continues to be essential to achieve a sustained virological response (SVR) and to eradicate the viral infection. Currently, pegylated interferon (PEG-IFN) and ribavirin (RBV) are required to avoid selection of PI-resistance mutations. The likelihood of obtaining an SVR with dual therapy in treatment-naïve patients with genotype 1 infection varies from 40% to 50%. That is, almost half of these patients would not require a PI, thus avoiding their adverse effects and considerably reducing the cost of the treatment. Identifying which patients could potentially respond to dual therapy is one of the main challenges in clinical practice. The genetic variability of the host is one of the main factors affecting the sensitivity of PEG-IFN and therefore in the response to current treatment. Other baseline factors related to the host, the virus and, especially, to intratreatment factors such as rapid virological response (RVR) are strongly associated with the probability of achieving an SVR. The evidence on the decision to prescribe dual or triple therapy according to the factors predictive of response is based on retrospective studies or post-hoc analyses of pivotal studies on PI. Study of the polymorphisms of the IFNL3 gene (IL28B), ITPA, IFN-stimulated genes (ISGs), TT/ΔG (ss469415590; IFNL4)) and RBV transporters could help in the decision to prescribe dual or triple therapy in treatment naïve patients

[The riboxin treatment of workers in the electron vacuum tube industry suffering from dermatoses]. / Lechenie riboksinom rabochikh élektrovakuumnoi promyslennosti, stradaiushchikh dermatozami.

Analysis of the treatment results in 85 patients with occupational skin diseases, working at the Kineskop industrial amalgamation in Lvov, evidences that application of a liniment containing riboxin (10%) and dimexide (40-50%) results in a marked clinical effect and normalization of impaired protective-barrier function of the skin. The treatment is carried out on an outpatient basis without cessation of work.

[The efficacy of quinazopyrine, preparation E and riboxin in experimental myocardial infarct]. / Effektivnost' khinazopirina, preparata E i riboksina pri éksperimental'nom infarkte miokarda.

A study is presented of the carbohydrate energy metabolism and processes of peroxidation in rats with experimental pitutrin-isadrin myocardial infarction. Essential changes of these values were noted. It is concluded that quinasopyrin and preparation E normalize to a greater extent and riboxin to a smaller extent metabolic disorders in the ischemia-involved myocardium tissues.

[The effect of riboxin on lipid peroxidation in patients with acute myocardial infarct]. / Vliianie riboksina na perekisnoe okislenie lipidov u bol'nykh ostrym infarktom miokarda.

A study of 64 patients with acute myocardial infarction revealed an elevated concentration of peroxidation radicals in the blood, a reduction of the antioxidant system. Three hours after i/v administration of riboxin the content of peroxidation radicals reduced. After discontinuation of intravenous riboxin peroxidation of lipids increased again.

Synthesis and biological properties of purine and pyrimidine 5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl analogues of AMP, GMP, IMP, and CMP.

Methyl 2,3-O-isopropylidene-D-ribofuranoside (1) was converted to 1-O-acetyl-5-bromo-5-deoxy-2,3-di-O-benzoyl-D-ribofuranose (6) in five steps with good yield. The Arbuzov condensation of compound 6 with triethyl phosphite resulted in the synthesis of 1-O-acetyl-2,3-di-O-benzoyl-5-deoxy-5-(diethoxyphosphinyl)-D-ribofuranos e (7). Compound 7 was used for direct glycosylation of both purine and pyrimidine bases. The glycosylation was accomplished with the dry silylated heterocyclic base in the presence of trimethylsilyl triflate. Deblocking of the glycosylation products gave exclusively the beta anomer of the 5'-phosphonate analogues of 9-[5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl]adenine (13), 9-[5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl]guanosin e (16), 9-[5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl]hypoxant hine (17), and 9-[5'-deoxy-5'-(dihydroxyphosphinyl)-beta-D-ribofuranosyl]cytosine (15), described here for the first time. The target compounds as well as their intermediates showed no in vitro antiviral or antitumor activity, although phosphorylation of 15 and 16 to di- and triphosphate analogues was demonstrated with use of isolated cellular enzymes.

[The results of the use of riboxin in the combined treatment of patients with pulmonary tuberculosis]. / Rezul'taty ispol'zovaniia riboksina v kompleksnoi terapii bol'nykh tuberkulezom legkikh.

Studies with infected animals showed that riboxine (inosine) having anabolic, antifibrotic, immunostimulating, antihypoxic and hepatoprotective activities, by the level of its therapeutic effect was not inferior to levamisole or sodium oxybutyrate and exceeded methyluracil. The evidence of the riboxine therapeutic effect mostly correlated with the antihypoxic activity. The use of riboxine at the early stages in the treatment of new cases with infiltrative destructive tuberculosis of the lungs of lobar and polysegmental extent promoted normalization of gaseous metabolism, significant improvement of capillary blood flow in the destructive zone, earlier and more frequent arresting of intoxication signs, sputum abacillation and elimination of the destructive cavities.

[The clinical efficacy and outlook for the use of new drugs for metabolic therapy in dermatology]. / Klinicheskaia éffektivnost' i perspektivy primeneniia nekotorykh novykh sredstv metabolicheskoi terapii v dermatologii.

Based on the literature data and their own findings, the authors give grounds for the use of phosphaden, riboxin, and dipromonium in psoriasis, eczema, and atrophic lichen. Prospects in the application of vitamin synthetic analogues and of coenzymic preparations are shown.

[Influence of kordaron, anaprilin, dimedrol and riboxin on the hemodynamic effects of strophanthin in experimental heart failure]. / Vliianie kordarona, anaprilina, dimedrola i riboksina na gemodinamicheskie éffekty strofantina pri éksperimental'noi serdechnoi nedostatochnosti.

In experiments on 183 rats it was shown that cordarone, anapriline, dimedrol and riboxine increasing in experimental cardiac insufficiency tolerance to the cardiotoxic effect of strophanthin differ significantly by their influence on the hemodynamic effects of this cardiac glycoside. Cordarone increased intensity of the hemodynamic effects of strophanthin and accelerated their development. Under the action of anapriline and dimedrol the stimulating effect of strophanthin on hemodynamics decreased to a much lesser degree than its cardiotoxicity. Riboxine virtually abolished the hemodynamic effects of strophanthin.

Effect of 9-beta-D-arabinofuranosyladenine 5'-monophosphate and 9-beta-D-arabinofuranosylhypoxanthine 5'-monophosphate on experimental herpes simplex keratitis.

Treatment of established experimental keratitis caused by herpes simplex virus with 9-beta-d-arabinofuranosyladenine 5'-monophosphate (Ara-AMP) or 9-beta-d-arabinofuranosylhypoxanthine 5'-monophosphate (Ara-HxMP) showed that the Ara-AMP, in a concentration of 2 or 20%, had a significant effect on the keratitis but that 0.4% Ara-HxMP showed only minimal activity. Ara-AMP was also effective in the treatment of idoxuridine-resistant keratitis. No local toxicity with a high concentration (20%) of Ara-AMP was seen, but the duration of therapy was brief.

Prevention of increased hemoglobin-oxygen affinity in open-heart operations with inosine-phosphate-pyruvate solution.

In a control group of 32 patients undergoing open-heart operation, erythrocyte 2,3-diphosphoglycerate (2,3-DPG) declined progressively during the course of perfusion from a prebypass mean of 17.00 to 11.29 mu M per gram of hemoglobin at the end of bypass. The decrease was greater than that attributable merely to dilution of the patients' cells with the 2,3-DPG-deficient donor cells used to prime the pump oxygenator circuit. Administration of 300 mg of allopurinol, to prevent the conversion of inosine to uric acid, every 8 hours during the 24 hours prior to operation in 11 patients did not prevent the 2,3-DPG decrease during heart-lung bypass: prebypass, 18.31; postbypass, 13.56 mu M/gm Hgb. The mean P50 for both these groups combined decreased from a prebypass mean of 25.7 to a postbypass level of 21.9 torr. A solution of 0.1 M inosine, 0.1 M pyruvate, and 0.066 M phosphate (IPP) in a dosage of 7.5 ml per kologram of body weight prevented the 2,3-DPG decrease: prebypass, 15.74; postbypass, 14.85. Administration of 15 ml per kilogram of IPP in 15 patients preserved 2,3-DPG: prebypass, 18.09; postbypass, 18.52. The P50 remained unchanged in this last group. The method of providing for myocardial oxygen requirements during bypass was not standardized, and therefore the protective effect of IPP against ischemic damage in patients undergoing aortic valve replacement or myocardial revascularization could not be evaluated. No deleterious effects of IPP were noted.

Inhibition of experimental deoxyribonucleic acid virus-induced encephalitis by 9-beta-D-arabinofuranosylhypoxanthine 5'-monophosphate.

9-beta-d-Arabinofuranosylhypoxanthine 5'-monophosphate (ara-HxMP) significantly controlled the development of encephalitis produced by deoxyribonucleic acid viruses in mice. In most experiments the activities of ara-HxMP and 9-beta-d-arabinofuranosyladenine (ara-A) were determined simultaneously. In the intracerebral (target organ) and intravenous therapy experiments, ara-HxMP had a pronounced advantage over ara-A since the water solubility of ara-HxMP enabled it to be used in much higher concentrations. In experiments where the two drugs were administered intraperitoneally or orally they exhibited similar activity. In several intraperitoneal therapy experiments ara-HxMP was tested alone, using various treatment schedules and dosages. In these experiments, efficacy was observed in groups that had treatments initiated as late as 72 h after virus inoculation.

Efficacy of 9-beta-D-arabinofuranosylhypoxanthine 5'-monophosphate in therapy of equine abortion virus-induced hepatitis in hamsters.

Equine abortion virus (EAV)-induced hepatitis in hamsters presents an interesting animal model for the evaluation of drugs possessing anti-deoxyribonucleic acid virus activity. These experiments demonstrate that 9-beta-d-arabinofuranosylhypoxanthine 5'-monophosphate (ara-HxMP), a new synthetic, water-soluble, antiviral agent, effectively controls this disease in hamsters with a therapeutic index of approximately 60. Ara-HxMP prevented hepatitis-associated deaths in hamsters, reduced the titer of EAV developing in hamsters, and inhibited the increase of serum glutamic pyruvic transaminase in EAV-infected hamsters.