The DPP-4 inhibitor vildagliptin: robust glycaemic control in type 2 diabetes and beyond.

Vildagliptin is a potent selective inhibitor of dipeptidyl peptidase-4 (DPP-4) that improves glycaemic control by increasing islet alpha-cell and beta-cell responsiveness to glucose. In patients with type 2 diabetes mellitus (T2DM), vildagliptin improves beta-cell function, measured as insulin secretory rate relative to glucose level, and reduces glucagon secretion and endogenous glucose production in the postprandial period, resulting in reduced glucose levels. In clinical trials in T2DM, vildagliptin 100 mg/day monotherapy is effective in reducing haemoglobin A1c (HbA1c) across the spectrum of hyperglycaemia and has maintained efficacy over long-term treatment with neutral effects on body weight and lipids. Vildagliptin is associated with a low risk of hypoglycaemia, and has an adverse event profile comparable to placebo, including a reduced rate of gastrointestinal adverse effects compared with metformin and a reduced rate of oedema compared with rosiglitazone. As add-on combination therapy, vildagliptin produces significant further reductions in HbA1c in patients receiving metformin, pioglitazone, glimepiride and insulin, and has been found to reduce frequency of hypoglycaemia as an add-on to insulin. Preliminary findings indicate that the improved islet cell function underlying the efficacy of vildagliptin in T2DM is also observed in patients with impaired glucose tolerance, with vildagliptin treatment resulting in reduced glycaemic excursions. The overall profile of vildagliptin and the preliminary evidence of beneficial effects in the prediabetic state suggest that DPP-4 inhibition could be an effective strategy to prevent or delay progression from the prediabetic state to overt T2DM.

Therapeutic applications of angiotensin II receptor antagonists.

The renin-angiotensin system (RAS) represents today one of the most strategic targets of the therapy of cardiovascular diseases. During the last 30 years a number of more or less successful approaches to inhibit the activity of the RAS have been attempted. In particular, the use of ACE-inhibitiors has led to significant improvments in the outcom/treatment of hypertension, congestive heart failure, ischemic heart disease and nephropathies. On the other hand, Ace-inhibitors are not specifically targeted to RAS since they interfere with an enzyme with multiple different substrates. Furthermore, the inhibition of ACE does not prevent the formation of angiotensin II through alternative pathways, and thus the inhibition of RAS is often incomplete, especially under pathologic conditions stimulating RAS. For these reasons, the recent discovery of angiotensin II receptors antagonists, which selectively inhibit the action of angiotensin II at the level of the AT1 subtype receptor, is particularly attracting. This article reviews the background, the rationale and some of the clinical findings and potential applications with this new class of compounds.

Role of angiotensin II AT1 and AT2 subtype receptors in the regulation of atrial natriuretic peptide expression in salt-restricted rats.

Previous studies have suggested that angiotensin II modulates ANP secretion and this action appears to be largely independent from its hemodynamic effects. In order to explore the contribution of angiotensin II AT1 (AT1r) and AT2 (AT2r) receptor subtypes in the regulation of cardiac ANP, we studied the effects of selective antagonists of these receptors on ANP mRNA levels in the cardiac chambers of salt-restricted rats. Thirty-one Sprague-Dawley rats (12 weeks-old) weighing 250-350 g were studied during a low salt regimen and randomly assigned to the following treatment groups: AT1r-blockade (losartan) (10 mg/kg/day) (n = 18), AT2r-blockade (PD123319) (50 microg/kg/min) (n = 6), Control (salt-restriction) (n = 7). Treatments were maintained for 7 days; subsequently, 12 rats from the AT1r-blockade group were subdivided in to two groups: AT1r/AT2r-blockade (losartan +PD123319) (n = 6) and AT1r-blockade/vehicle (losartan+vehible) (n = 6), and treated for 7 additional days. Systolic blood pressure was significantly reduced by AT1r-blockade (p < 0.001), while it was not affected by AT2r-blockade. Concomitant treatment with both antagonists (AT1r/AT2r-blockade) restored blood pressure values to baseline (p < 0.001 vs. AT1r-blockade, p = n.s. vs Control). Atrial ANP mRNA was reduced by AT1r-blockade (-42%, p < 0.05) and did not change during AT1r-blockade alone. On the contrary, concomitant treatment with both antagonists resulted in a further significant inhibition of ANP expression (-65% and -36% vs Control and AT1r-blockade, respectively, both p < 0.05). ANP expression in ventricles was not affected by any of these treatments. Our results demonstrate that angiotensin II tonically modulates cardiac ANP expression in our experimental model. In particular, angiotensin II receptor subtypes AT1r and AT2r regulate atrial ANP mRNA levels through a synergic action and independently from blood pressure changes.

Oestrogens and the heart.

The incidence of cardiovascular disease is lower in women before the menopause compared with men, while menopausal women have an incidence of coronary disease similar to that of men of the same age. This is mainly dependent upon oestrogen deficiency. Large-scale epidemiological studies have demonstrated that oestrogen replacement therapy leads to approximately 50 per cent reduction of cardiovascular disease in women taking hormones, compared with untreated women. Multiple mechanisms have been proposed to explain the cardiovascular risk reduction observed in women on oestrogen therapy. Oestrogens positively affect plasma lipids and exert a beneficial effect upon carbohydrate metabolism and the haemocoagulation profile. Oestrogens may also have anti-atherogenic properties. Recent in vitro studies have demonstrated that oestrogens may positively influence all the steps involved in the formation of the atherosclerotic plaque (accumulation of cholesterol in the arterial wall, arterial smooth muscle cell proliferation, platelet aggregation, collagen and elastin production). Angiographic studies conducted in humans have demonstrated that women on oestrogens have significantly less coronary disease and less severe occlusion scores compared with women not taking hormone replacement therapy. Animal and human studies have shown that oestrogens act as vasodilating substances. Endothelium-dependent mechanisms have been identified and imply that oestrogens act through the endothelial release, mainly, of nitric oxide, a potent vasodilating substance which has been identified with EDRF (endothelium derived relaxing factor). More recently, oestrogens have been shown to affect also the vascular tone in the absence of the endothelium. Therefore, endothelium-independent mechanisms could be involved in the pathogenesis of the oestrogens' vascular effects. There is evidence that oestrogens have calcium antagonistic properties; this mechanism may be responsible for the reduction of peripheral vascular resistance observed in women on hormone replacement therapy and may slow the progression of coronary artery disease. The menopausal age is characterized by an imbalance of the neurohormonal system. Sudden increases of plasma catecholamines are evident when women have hot flushes, a typical clinical sign of the menopausal period. The abnormal release of catecholamines may reduce coronary flow reserve and increase peripheral vascular resistance and, therefore, may be dangerous for the heart. It has been shown, by means of the study of heart rate variability, that oestrogens are effective in modulating the neurohormonal system. The reduction of sympathetic tone has beneficial effects on coronary flow reserve and may be important in explaining the cardioprotective effect of oestrogens. Peripheral and coronary vasodilation observed in women on hormone replacement therapy might be also due to the inhibition of the release of vasoconstrictor factors such as endothelin-1 by oestrogens. Therefore, oestrogens protect the heart against coronary artery disease and they are now regarded as being as important as aspirin and antihypertensive drugs were in the past. Hormone replacement therapy should be considered in every menopausal woman to possibly prevent the occurrence of cardiovascular disease or, if already present, to slow its progression.

Cardiovascular pharmacology of hormone replacement therapy.

The incidence of cardiovascular disease in women is negligible before natural or surgically-induced menopause, and increases after menopause. Epidemiological data suggest that estrogen replacement therapy reduces the occurrence of coronary artery, and possibly cerebrovascular, disease by 25 to 50% in treated women compared with non-users. These findings are supported by the evidence that estrogens have a beneficial effect on cholesterol metabolism and deposition, contributing to the inhibition of atherosclerotic plaque formation in arterial walls. Early reports suggested that up to 60% of the protective effect of estrogens on coronary artery disease was attributable to favourable changes in plasma lipids. Reanalysis of the data indicated that the lipid changes probably account for approximately 25% of the cardioprotective effect of estrogens and that other effects are, therefore, likely to be important. The influence of estrogens on carbohydrate metabolism, atheroma formation and cardiovascular haemodynamics may also play an integral role in the overall beneficial effect of the hormones. Animal and human studies have shown that the administration of estrogens leads to a restoration of endothelial function, an increase in cardiac output, an increase in arterial flow velocity, a decrease in vascular resistance, and a decrease in systolic and diastolic blood pressure. Recent studies on hormone replacement regimens have shown that estrogens may favourably affect fibrinolysis and reduce plasma fibrinogen to premenopausal levels. Despite these effects of estrogens the recent Heart and Estrogen/Progestin Replacement Study (HERS) failed to show a cardioprotective effect of hormone replacement therapy (HRT) in elderly women with coronary artery disease. However, the HERS study has several limitations and stands alone against the large body of evidence that suggest that HRT may reduce cardiovascular mortality and morbidity.

Acute anti-ischemic effect of testosterone in men with coronary artery disease.

BACKGROUND: The role of testosterone on the development of coronary artery disease in men is controversial. The evidence that men have a greater incidence of coronary artery disease than women of a similar age suggests a possible causal role of testosterone. Conversely, recent studies have shown that the hormone improves endothelium-dependent relaxation of coronary arteries in men. Accordingly, the aim of the present study was to evaluate the effect of acute administration of testosterone on exercise-induced myocardial ischemia in men. METHODS AND RESULTS: After withdrawal of antianginal therapy, 14 men (mean age, 58+/-4 years) with coronary artery disease underwent 3 exercise tests according to the modified Bruce protocol on 3 different days (baseline and either testosterone or placebo given in a random order). The exercise tests were performed 30 minutes after administration of testosterone (2.5 mg IV in 5 minutes) or placebo. All patients showed at least 1-mm ST-segment depression during the baseline exercise test and after placebo, whereas only 10 patients had a positive exercise test after testosterone. Chest pain during exercise was reported by 12 patients during baseline and placebo exercise tests and by 8 patients after testosterone. Compared with placebo, testosterone increased time to 1-mm ST-segment depression (579+/-204 versus 471+/-210 seconds; P<0. 01) and total exercise time (631+/-180 versus 541+/-204 seconds; P<0. 01). Testosterone significantly increased heart rate at the onset of 1-mm ST-segment depression (135+/-12 versus 123+/-14 bpm; P<0.01) and at peak exercise (140+/-12 versus 132+/-12 bpm; P<0.01) and the rate-pressure product at the onset of 1-mm ST-segment depression (24 213+/-3750 versus 21 619+/-3542 mm Hgxbpm; P<0.05) and at peak exercise (26 746+/-3109 versus 22 527+/-5443 mm Hgxbpm; P<0.05). CONCLUSIONS: Short-term administration of testosterone induces a beneficial effect on exercise-induced myocardial ischemia in men with coronary artery disease. This effect may be related to a direct coronary-relaxing effect.

[The efficacy of vibration and traction in correcting contractures of the joints (an experimental study)]. / Effektivnost' vibrotraktsii pri korrektsii kontraktur sustavov (éksperimental'noe issledovanie).

The experiments on rabbits with modelled articular contracture established a marked corrective effect of simultaneous exposure of the rabbits to vibration and traction. Clinical trials in patients with traumas of the peripheral nerves complicated by articular contractures provided evidence for high efficacy of combined rehabilitation including vibration and traction methods.

Role of spectral measures of heart rate variability as markers of disease progression in patients with chronic congestive heart failure not treated with angiotensin-converting enzyme inhibitors.

Measures of heart rate variability in the frequency domain quantify autonomic activity. However, the relation of these measures to the severity of ventricular dysfunction in patients with congestive heart failure remains uncertain. We applied spectral analysis of heart rate variability to 24-hour Holter monitor recordings obtained from 20 patients with congestive heart failure who were not treated with angiotensin-converting enzyme inhibitors to determine whether significant changes in parameters of heart rate variability reflect the progression of symptoms in patients with ventricular failure. Both total and low-frequency heart rate spectral power were seen to decrease with worsening New Heart Associate (NYHA) functional class. A significant (p = 0.04) higher total power was noted in NYHA class II than in class III patients (3.0 x 10(-3) +/- 3.6 10(-4) and 2.5 x 10(-3) +/- 5.9 x 19(-4) [beats/min]2, respectively). Similarly, low-frequency heart rate spectral power was significantly (p = 0.008) higher in class II than in class III patients (1.7 x 10(-3) +/- 4.6 x 10(-4) and 1.1 x 10(-3) +/- 3.5 x 10(-4) [beats/min]2, respectively). Only the low-frequency component of the spectrum was directly correlated with left ventricular ejection fraction (LVEF) (r = 0.40) with a trend toward statistical significance (p = 0.07). Measures of heart rate variability and the changes in autonomic tone that they reflect may therefore serve as markers of the extent of disease progression in patients with congestive heart failure.

Assessment of autonomic tone over a 24-hour period in patients with congestive heart failure: relation between mean heart rate and measures of heart rate variability.

Patients with congestive heart failure (CHF) are characterized by an imbalance of the autonomic nervous system, which may contribute to the progression of circulatory failure and influence survival. However, it is still unclear whether CHF is characterized by a suppression of the diurnal variation in autonomic tone that is observed in normal subjects. To characterize the circadian variation in autonomic tone in patients with ventricular failure, ambulatory 24-hour Holter monitor recordings were obtained in 20 patients with CHF; 4-minute epochs of data from every hour of each 24-hour recording were selected. For each epoch we calculated the mean heart rate (HR) and, by applying spectral analysis of heart rate variability (HRV), we quantified the magnitude of the total (0.02 to 0.9 Hz), sympathetically governed low frequency variability (0.02 to 0.1 Hz), and parasympathetically mediated high-frequency variability (0.1 to 0.9 Hz). These areas were also expressed as a ratio to total variability and a ratio of high to low variability. A highly significant change in the mean HR over 24 hours was observed (p = 0.0001); no changes in the measures of HRV were obtained (p < 0.3). No significant correlation was found between mean HR and any frequency domain measures. We conclude that the sustained imbalance of autonomic tone over a 24-hour period, as shown by the spectral analysis of HRV, may promote the progression of circulatory failure and predispose patients with CHF to malignant ventricular arrhythmias and sudden cardiac death.(ABSTRACT TRUNCATED AT 250 WORDS)

Survival of hog cholera virus (HCV) in sausage meat products (Italian salami).

Survival of hog cholera virus (HCV) was determined in several sausage meat products (Italian salami) prepared with meats from experimentally infected hogs slaughtered at the peak of disease. Meats were processed following the technology applied by the main factories of the typical Italian production. The survival of HCV was assessed through inoculation in both PK 15 cell monolayers and fully susceptible piglets. In all types of sausages examined HCV was detected up to 75 days of curing by piglet inoculation. This technique was much more sensitive than use of cell culture.

Exercise hyperventilation chronic congestive heart failure, and its relation to functional capacity and hemodynamics.

The ventilatory response to exercise was evaluated in 26 normal sedentary men and 68 patients with chronic heart failure using the slope of the relation between minute ventilation (VE) and carbon dioxide production (VCO2). All subjects underwent maximal upright bicycle cardiopulmonary exercise testing; 33 patients also underwent right-sided cardiac catheterization. The slope of VE/VCO2 was calculated by linear regression analysis using data from all the exercise tests and the first 60% of exercise duration; a high correlation was seen between these results (r = 0.83; p less than 0.001). The slope of VE/VCO2 was significantly, though weakly, related to peak exercise work load, oxygen consumption and ventilatory threshold (r = -0.49, -0.56 and -0.49, respectively), several peak exercise hemodynamic parameters and peak exercise dead space/tidal volume ratio (r = 0.70). With use of multivariate analysis, the only independent determinants of the slope were peak exercise dead space/tidal volume ratio and cardiac index. Thus, in patients with heart failure, exercise hyperventilation can contribute to the impairment of functional capacity and can be considered a compensatory response to abnormal hemodynamics and lung blood distribution in order to keep blood gas concentrations normal.

[A comparative evaluation of the immunological efficacy of ADPT vaccine and ADT-M anatoxin in the immunization of children against diphtheria and tetanus]. / Sravnitel'na otsenka immunologicheskoi éffektivnosati AKDS-vaktsiny i ADS-M-anatoksina pri immunizatsii detei protiv difterii i stolbniaka.

Comparative study of the immunological effectiveness of adsorbed diphtheria-pertussis-tetanus (DPT) vaccine and adsorbed diphtheria-tetanus toxoid with reduced antigen content (adsorbed DT toxoid R) in the immunization of children, carried out in accordance with the vaccination schedule, was made. Immune response to the injection of adsorbed DPT vaccine was higher than after immunization with adsorbed DT toxoid R, as evidenced by antibody titers. It was probably due to differences in the number of injections constituting the course of immunization: it consisted of 3 injections and 1 booster injection for adsorbed DPT vaccine and 2 injections and 1 booster injection for adsorbed DT toxoid R. Immunization with adsorbed DPT vaccine produced immunity which was retained for a longer period. These results are indicative of the expediency of the primary immunization of children with adsorbed DT toxoid R introduced in three injections in order to ensure more stable and prolonged postvaccinal (mainly antidiphtheria) immunity.

Potency assessment of foot-and-mouth disease vaccines in cattle by means of antibody assays.

A tendency has emerged for some years to replace the challenge infection of cattle for the assessment of foot-and-mouth disease (FMD) vaccine potency. This can be actually evaluated by means of antibody assays on cattle sera, at about 3/4 weeks after the vaccination. Serological results can be worked out as single titres (to be compared with a pre-determined threshold level) or as mean antibody titres induced by different vaccine dilutions. However, the assessment of FMDV-specific antibody titres would not fully depict the extent and the efficacy of the immune response of cattle; moreover, the antibody response would not be proportional if potent vaccines are used (greater than or equal to 10-12 PD50). Thus, a particular approach is suggested for the serological procedures, which enable credible estimates of potent FMD vaccines to be formulated.

Survival of foot-and-mouth disease virus in sausage meat products (Italian salami).

Determination of the survival of foot- and-mouth disease virus (FMDV) in fresh meat from experimentally infected swine and in several types of sausage meat (Italian salami) produced according to the technology widely applied by the principal Italian producers has been carried out. The purpose of the experiment was to assess if typical Italian salami can be considered safe with regard to the spread of FMD through international trade. The results obtained showed: (a) high titers of FMDV were detected in both muscle and fat tissues from animals slaughtered at the peak of the experimental disease; and (b) FMDV was not detectable in the above tissues 72 h after slaughtering and the same applies to the different types of salami tested 7 days after production. The above results were obtained in tissue cultures and confirmed through piglet inoculation.

[Epidemiologic characteristics of hepatitis A morbidity among children from one of the districts of Moscow in 1982-1986]. / Epidemiologicheskaia kharakteristika zabolevaemosti gepatitom A sredi detei odnogo iz raionov Moskvy v 1982-1986 gg.

By the epidemic features, the district under study may be classified as a territory with moderate epidemic activity of hepatitis A (HA). The highest incidence was observed in children of 3-6 years of age. Annually, the seasonal wave in the district was started in school children. As a rule, the first case of the disease in preschool children's institutions (PCI) was due to infection contracted from schoolchildren or from adults. The further spread of the infection in PCI was due to breaks in the sanitary-hygienic regimen or principles of isolation of the quarantine group. When these principles and the sanitary-hygienic regimen were observed, the incidence in foci was limited to 1-3 cases of HA. In instances of late introduction of the infection into PCI with crude breaks in the sanitary-hygienic regimen or principles of isolation of the quarantine group "nonseasonal" (February or April) rises in HA incidence occurred in the district.