Primeros casos autóctonos de hepatitis e en Uruaguay / First autochthonous hepatitis E cases in Uruguay

Con el objetivo de describir los primeros casos autóctonosde Hepatitis E se realizó un estudio descriptivo. La población,9 enfermos, se identificó en el periodo noviembre 2009a julio 2010. Se seleccionaron por IgG e IgM específicaspara VHE y se realizó búsqueda de ARN viral en suero porRT-PCR. Presentaron una media de 51 años, 8 del sexo masculino, educación terciaria, nivel socioeconómico medio alto, atención en el sector privado y residencia urbana. La clínica fue similar a Hepatitis A, con transaminasas elevadas por encima de 1500 (mU/ml), la glutamicopiruvica convalores máximos de 5270 (mU/ml). Todos presentaron hiperbilirrubinemia a predominio directa, aumento de lagamaglutamil transferasa y de Fosfatasa Alcalina. Se demostrócirculación en Uruguay del VHE con manifestaciones clínicas, lo que traduce la presencia de una enfermedad emergente. Se plantea introducir el diagnostico del VHE en forma protocolizada en pacientes sin diagnostico etiológico de hepatitis.

In order to describe the first autochthonous Hepatitis E cases, we carried out a descriptive study. The population, 9 patients, was identified from November 2009 to July 2010. They were selected by specificIgG and IgM for HEV and we made viral RNA search in serum by RT-PCR. Patients average age was 51 years old, 8 male, tertiary education, upper middle socioeconomic level, health attention in private sector and urban residence. Clinic results similar to hepatitis A, with elevated transaminases over 1500 (mU/ml) and glutamic pyruvic with maximum values of 5270 (mU/ml). All patients presented hyperbilirubinemia (direct predominance) and increased gamma glutamyl transferase and alkaline phosphatase. Circulation of HEV with clinical manifestations was demonstrated in Uruguay, this showsthe presence of an emergent disease. We suggest introducing a formalized HEV diagnosis in patients without etiologic diagnosis of hepatitis.

Cigarette smoking is independently associated with markers of endothelial dysfunction and hyperinsulinaemia in nondiabetic individuals with coronary artery disease.

BACKGROUND: Oxidative stress and endothelial dysfunction have been introduced as a unifying pathological mechanism for early atherosclerotic disease. They are caused by a variety of stimuli including cigarette smoking (environmental) and type 2 diabetes (disease factor). However, the role of hyperinsulinemia, a marker of insulin resistance, as a risk factor for atherosclerosis remains to be clarified. STUDY OBJECTIVES: To study the relationship of smoking, hyperinsulinaemia and biochemical markers of oxidative stress and endothelial dysfunction, in patients with coronary artery disease. DESIGN: Case-control study of 5-year survivor status in smokers, former smokers and nonsmokers with angiographically documented stable coronary artery disease classified by self-reporting of smoking status together with plasma cotinine measurements. SETTING: Cardiology and cardiac surgery unit of a tertiary care referral centre. PATIENTS AND METHODS: Plasma levels of vitamins C, E and selenium, and the adhesion molecules E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) were assessed in 214 patients at baseline together with the glucose and insulin response to an oral glucose challenge. Sixty known or newly diagnosed type 2 diabetic patients (28%) were identified and excluded from further analysis. RESULTS: E-selectin and ICAM-1, serving as markers of endothelial dysfunction, significantly correlated with hyperinsulinaemia (p < 0.05). Circulating immunoreactive insulin was elevated in active smokers and former smokers as compared to non-smokers after an oral glucose load (p < 0.05 for the area under the insulin time curve), despite a similar glucose response. Smoking was associated with a decrease in antioxidant vitamins C (p = 0.02) and E (p = 0.03), and an increase of E-selectin (p < 0.05) and ICAM-1 (p < 0.001). Low baseline ICAM-1 and high vitamin C levels emerged as the most significant multivariate predictors of 5-year survival (p < 0.001). CONCLUSIONS: Hyperinsulinaemia in smokers is linked with markers of endothelial dysfunction. Impaired vascular reactivity can thus be a new possible mechanism linking insulin resistance and smoking.

Concomitant administration of the alpha-glucosidase inhibitor voglibose (AO-128) does not alter the pharmacokinetics of glibenclamide.

OBJECTIVE: Voglibose is a new and potent inhibitor of alpha-glucosidases used for treatment of diabetes mellitus. It increases gastro-intestinal motility and could thus affect absorption of other concurrently administered antidiabetic drugs. The aim of this study was to investigate whether or not voglibose modifies the pharmacokinetics of glibenclamide, a widely used oral antidiabetic, and the glibenclamide-induced decrease in fasting serum glucose. METHODS: Twelve healthy male subjects were included in this double-blind cross-over study and received a single 1.75-mg dose of glibenclamide on the 8th day of continuous administration of either placebo (reference) or voglibose 5 mg t.i.d. (test). Blood samples were taken to determine the pharmacokinetic characteristics of glibenclamide and the test/reference ratios were evaluated according to bioequivalence criteria. Additional blood samples were taken to measure serum glucose on the same day. RESULTS: The concentration-time course of glibenclamide under concomitant voglibose administration was similar to that under placebo. The equivalence ratio (test/reference) for the pharmacokinetic characteristics AUCnorm was 1.03 (geometric mean; 0.95-1.11, 90% confidence interval) and Cmax.norm 1.01 (0.94-1.08). The parameters were within the accepted range of 0.8-1.25 (AUC) or 0.7-1.43 (Cmax), thus fulfilling equivalence criteria and indicating no effect of voglibose on glibenclamide kinetics. The glibenclamide-induced decrease in fasting serum glucose concentration was similarly independent of placebo or voglibose co-administration. CONCLUSIONS: Voglibose did not interact with glibenclamide on a pharmacokinetic level. Concomitant treatment was well tolerated and has been proven to be safe for further clinical use.

The alpha-glucosidase inhibitor voglibose (AO-128) does not change pharmacodynamics or pharmacokinetics of warfarin.

OBJECTIVE: Voglibose is a new and potent inhibitor of alpha-glucosidases and is used for the treatment of diabetes mellitus. Since voglibose increases gastrointestinal motility and could thus affect absorption of concomitantly administered drugs, it was investigated whether or not voglibose modifies the pharmacodynamics and pharmacokinetics of warfarin, an oral anticoagulant frequently used in cardiovascular disorders likely to arise in diabetic patients. METHODS: Twelve healthy male subjects were given individually adjusted doses of warfarin to reduce prothrombin time (Quick's method) to a value of about 30-40% of the normal range within the first 8 days. Then, the individuals maintenance dose, given in the morning, was maintained until day 15. On study days 11-15, voglibose was co-administered per os in a dose of 5 mg t.i.d. The prothrombin time was determined on days 10 and 11 (reference) and on days 15 and 16 (test), and the steady-state pharmacokinetic characteristics of the warfarin enantiomers were determined on days 10 (reference) and 15 (test). The ratios test/reference were evaluated according to bioequivalence criteria. RESULTS: The equivalence ratio (test reference) for the pharmacodynamic parameter prothrombin time was 0.97 and for the pharmacokinetic characteristics AUC0-24 h.t.ss: S-(-)-warfarin, 1.05; R-(+)-warfarin, 1.01; and Cmax.ss: S-(-)-warfarin, 1.08; R-(+)-warfarin, 1.04. All parameters were within the predetermined accepted range of 0.7-1.43 (pharmacodynamics) or 0.8-1.25 (pharmacokinetics), thus fulfilling equivalence criteria. CONCLUSIONS: Voglibose modified neither the pharmacodynamics nor the pharmacokinetics of warfarin under steady-state conditions. Concomitant treatment was well tolerated and has been proven to be safe for further clinical use.

Effect of four lansoprazole dose levels and one dosage regimen of omeprazole on 24-hour intragastric pH in healthy subjects.

Lansoprazole is a potent proton pump inhibitor and blocks gastric acid secretion. The potency of many antibiotics in eradicating Helicobacter pylori may be considerably enhanced by increasing the intragastric pH due to a twice-daily coadministration of proton pump inhibitors. This double-blind crossover study was designed to compare the effect on intragastric pH of four dose regimens of lansoprazole (30 mg o.a.d., 30 mg b.i.d., 45 mg b.i.d., 60 mg b.i.d.) after 5 days of treatment and to investigate whether an increment of lansoprazole dose level leads to a more pronounced effect. Omeprazole 20 mg b.i.d. was administered as a reference drug. The study was carried out in 20 healthy male subjects. Intragastric pH was recorded by a nasogastric probe over 24 h. All dose regimens of lansoprazole were well tolerated and no unexpected drug-related adverse events were observed. The lowest lansoprazole dose level, 30 mg o.a.d. already increased intragastric pH considerably. This effect was even enhanced by increase of the lansoprazole dose as assessed by mean pH as well as percentage of time spent above different pH values. The increase in effect with lansoprazole dose increment from 30 mg b.i.d. to 60 mg b.i.d. was only very small. The time spent at pH values above or equal to 3 after b.i.d. administration was slightly higher with all lansoprazole dose levels compared to omeprazole. The time spent at intragastric pH values above or equal to 5 after b.i.d. oral administration of 30 mg, 45 mg and 60 mg lansoprazole was comparable to that observed after b.i.d. oral administration of 20 mg omeprazole, so that it may be recommended to use lansoprazole 30 mg b.i.d. as a treatment equivalent to omeprazole 20 mg b.i.d. for eradication of Helicobacter pylori in combination with antibiotics.

Voglibose (AO-128) is an efficient alpha-glucosidase inhibitor and mobilizes the endogenous GLP-1 reserve.

The alpha-glucosidase inhibitor voglibose (AO-128) was designed to prevent rapid postprandial blood glucose rises in non-insulin-dependent diabetics. We analyzed its effect on the entero-insular axis in 72 healthy volunteers in a double-blind study design before, after the 1st dose, and on the 7th day of a 7-day treatment protocol (3 daily loads). Six parallel groups of 12 volunteers received voglibose (0.5, 1.0, 2.0, or 5.0 mg) or placebo (two groups). Blood was drawn at regular intervals up to 180 min after a standardized breakfast to analyze the levels of glucose, insulin, C peptide, gastric inhibitory polypeptide, and glucagon-like peptide 1 (GLP-1). As expected, after ingestion of voglibose, slight to moderate gastro-intestinal discomfort but no severe side-effects were reported. In a dose-dependent manner, voglibose significantly reduced postprandial increases of blood glucose, insulin, and C peptide. At the lower loads (0.5 and 1 mg voglibose three times daily), these effects were more pronounced after 7 days. The postprandial increase of gastric inhibitory polypeptide was already reduced after the first load of 2 and 5 mg voglibose. In comparison to the placebo group, this inhibition became also significant for the lower loads after 7 days. Interestingly, GLP-1, originating from the lower intestines, was increasingly released under voglibose treatment. The first administration of 1 mg voglibose enhanced GLP-1 secretion > 80% above controls. Treatment with 1 mg voglibose three times daily over 7 days revealed a maximal mobilizing effect on endogenous GLP-1 (> 90% above controls) which was not further increased by 2- or 5-mg loads. We conclude that voglibose treatment effectively inhibits intestinal disaccharidases and thereby mobilizes the endogenous pool of insulinotropic GLP-1.

Discordance of anti-ischemic and hemodynamic effects of captopril in stable coronary artery disease.

BACKGROUND: The role of angiotensin converting enzyme (ACE) inhibition in patients with coronary artery disease without concomitant disease such as heart failure or hypertension has not been elucidated. In this double-blind, cross-over, randomized trial of the ACE inhibitor captopril, its antianginal and anti-ischemic effects were studied during monotherapy and in the presence of an organic nitrate. METHODS: Thirty-seven patients (34 men, three women) with stable coronary artery disease and exercise-induced ST-segment depression were enrolled. After a washout phase without medication they received placebo, isosorbide dinitrate (ISDN) 20 mg twice daily, captopril 12.5 mg twice daily, and the combination of both for 1 week each, after which exercise tolerance, blood pressure and heart rate (supine, standing and 24 h profile), and peripheral arterial vasodilatation (finger pulse plethysmography) were assessed. RESULTS: Thirty-three patients completed all phases of the study. Exercise-induced anginal symptoms occurred in 17 patients, and asymptomatic ischemia was seen in the other 16 men. In comparison with ISDN, the anti-ischemic effects of captopril were minimal, despite a similar reduction in blood pressure. Compared with baseline, 1 week of placebo reduced the sum of ST-segment depression, the main efficacy parameter, by 10% (NS), captopril by 19% (NS), ISDN by 37% (P < 0.001) and the combination of captopril and ISDN by 42% (P < 0.001; NS versus ISDN). No patient remained completely free of exercise-induced angina during treatment with captopril; however, three patients after ISDN and seven patients after the combination did (P < 0.05). Blood pressure at rest decreased at peak effect by 9-10% systolic (P < 0.001) with monotherapy and by up to 7% diastolic (P < 0.001), and during combined therapy with captopril and ISDN by 18% systolic (P < 0.001) and 12% diastolic (P < 0.001). Significantly enhanced circulatory effects of captopril plus ISDN versus ISDN were found for blood pressure (P < 0.001) and peripheral arterial vasodilation (P < 0.01). The reflex tachycardia induced by ISDN in the upright position (5 beats/min) was not blocked by captopril during combined therapy. CONCLUSIONS: The antianginal and anti-ischemic effects of captopril alone were marginal, despite significant circulatory effects after short-term administration. Although captopril in combination with ISDN resulted in a significant further blood-pressure-lowering effect and increased peripheral arterial vasodilatation, the magnitude of potentiation of the anti-ischemic nitrate effects was, in contrast, small. Only exercise-induced angina was further improved by the use of the combination. No paradoxical worsening of ischemia or angina was seen after captopril. Thus, although captopril has no place as first-line therapy for ischemia, its use in combination with ISDN could be advantageous for long-term prognosis.

[Effect of low-dosage intravenous nitrate therapy on the anticoagulant effect of heparin]. / Einfluss einer niedrigdosierten intravenösen Nitrattherapie auf die antikoagulatorische Wirkung von Heparin.

BACKGROUND AND AIM: Controversial studies concerning the fact that simultaneous i.v. administration of heparin and glyceroltrinitrate (GTN) might reduce the anticoagulatory effect of heparin have been published. In a controlled and comparative study we therefore investigated the influence of the nitrates GTN or isosorbide dinitrate (ISDN) in comparison to placebo on the anticoagulatory effect of a constant heparin infusion in patients with CAD. PATIENTS AND METHODS: 22 stable and mobile inpatients (two female, 20 male; aged 47 to 80; documented CAD in 20 patients, one patient with atrial fibrillation, one patient with suspected CAD), kept on a therapeutic heparin infusion for several days (prolongation of the partial thromboplastin time [PTT] by 1.5 to two-fold), were included. Study course: Day 1: Discontinuation of nitrate medication, optimization of heparin therapy and fixation of the heparin dose (mean dose 33,800 E/24 h in the GTN group and 32,700 E/24 h in the ISDN group). Day 2: Intravenous simultaneous administration of 0.9% NaCl solution as placebo (3 ml/h) with heparin over 24 hours. Day 3: Substitution of NaCl solution by randomised single-blind intravenous administration of GTN (n = 10; 0.1%, solved in NaCl; dose 2.8 +/- 0.5 mg/h) or ISDN (n = 12; 0.1%, solved in NaCl, dose: 4.8 +/- 0.8 mg/h) for 24 hours. Day 4: Discontinuation of nitrates. RESULT: As compared to placebo, the intravenous simultaneous administration of GTN or ISDN and heparin over 24 hours had no influence on the anticoagulatory effect of heparin when the areas under the curve of PTT values on days 2 and 3 were compared (PTT measurements at 8, 10 a.m., 1, 3, 6, 11 p.m.; Mann-Whitney test). After GTN or ISDN had been discontinued, no change in PTT values was seen during the following five hours. CONCLUSION: There is no indication of a pharmacodynamic relevant interaction between heparin and low-dose intravenous nitrate therapy in patients with CAD.

Triple balloon-on-a-wire or "ménage à trois" coronary angioplasty.

We have described here the triple balloon or "ménage à trois" technique of coronary angioplasty of trifurcation lesions or closely approximated bifurcation lesions. Although the need for this technique is uncommon on anatomic grounds, it can facilitate excellent angiographic results.

Brachial approach directional coronary atherectomy of right coronary artery saphenous vein bypass grafts.

We describe here a technique for performing directional coronary atherectomy to right coronary artery saphenous vein bypass grafts from the brachial approach using a long introducer sheath system. This technique has the advantages of 1) avoiding femoral artery trauma and 2) ease of access into the bypass graft, avoiding occasional problems with guide catheter kinking or non-coaxial alignment.