The atypical ß-blocker S-oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model.

BACKGROUND: Beta-blockers and selected stereoisomers of beta-blockers, like bisoprolol and S-pindolol (ACM-001), have been shown to be effective in preclinical cancer cachexia models. Here, we tested the efficacy of stereoisomers of oxprenolol in two preclinical models of cancer cachexia-the Yoshida AH-130 rat model and the Lewis lung carcinoma (LLC) mouse model. METHODS AND RESULTS: In the Yoshida AH130 hepatoma rat cancer cachexia model and compared with placebo, 50 mg/kg/d S-oxprenolol (HR: 0.49, 95% CI: 0.28-0.85, P = 0.012) was superior to 50 mg/kg/d R-oxprenolol (HR: 0.83, 95% CI 0.38-1.45, P = 0.51) in reducing mortality (= reaching ethical endpoints). Combination of the three doses (12.5, 25 and 50 mg/kg/d) that had a significant effect on body weight loss in the S-oxprenolol groups vs the same combination of the R-oxprenolol groups lead to a significantly improved survival of S-oxprenolol vs R-oxprenolol (HR: 1.61, 95% CI: 1.08-2.39, P = 0.0185). Interestingly, there is a clear dose dependency in S-oxprenolol-treated (5, 12.5, 25 and 50 mg/kg/d) groups, which was not observed in groups treated with R-oxprenolol. A dose-dependent attenuation of weight and lean mass loss by S-oxprenolol was seen in the Yoshida rat model, whereas R-oxprenolol had only had a significant effect on fat mass. S-oxprenolol also non-significantly reduced weight loss in the LLC model and also improved muscle function (grip strength 428 ± 25 and 539 ± 37 g/100 g body weight for placebo and S-oxprenolol, respectively). However, there was only a minor effect on quality of life indicators food intake and spontaneous activity in the Yoshida model (25 mg/kg/S-oxprenolol: 11.9 ± 2.5 g vs placebo: 4.9 ± 0.8 g, P = 0.013 and also vs 25 mg/kg/d R-oxprenolol: 7.5 ± 2.6 g, P = 0.025). Both enantiomers had no effects on cardiac dimensions and function at the doses used in this study. Western blotting of proteins involved in the anabolic/catabolic homoeostasis suggest that anabolic signalling is persevered (IGF-1 receptor, Akt) and catabolic signalling is inhibited (FXBO-10, TRAF-6) by S-pindolol, but not he R-enantiomer. Expression of glucose transporters Glut1 and Glut 4 was similar in all groups, as was AMPK. CONCLUSIONS: S-oxprenolol is superior to R-oxprenolol in cancer cachexia animal models and shows promise for a human application in cancer cachexia.

Comparative efficacy of ß-blockers on mortality and cardiovascular outcomes in patients with hypertension: a systematic review and network meta-analysis.

The differential efficacy of lipophilic and hydrophilic ß-blockers on clinical outcomes has not been investigated. We sought to compare the effects of lipophilic and hydrophilic ß-blockers on mortality and cardiovascular outcomes by conducting a comprehensive systematic review and network meta-analysis. MEDLINE/PubMed, EMBASE, and the Cochrane Database were searched for all dates to January 5, 2015, for randomized trials with comparisons between all ß-blockers or between ß-blockers and other antihypertensive agents. Mortality and cardiovascular outcomes were also reported. Characteristics of each study and associated clinical outcomes were extracted, including all-cause mortality, coronary heart disease, stroke, and cardiovascular death. Thirteen trials with 90,935 participants were included, focusing on lipophilic ß-blockers (metoprolol, propranolol, and oxprenolol) and a hydrophilic ß-blocker (atenolol). In this review, lipophilic ß-blockers showed a significant reduction for the risk of cardiovascular mortality (odds ratio [OR] 0.72, 95% confidence interval [CI; 0.54-0.97]) compared with hydrophilic ß-blocker, and lipophilic ß-blockers showed decreased trend for the risk of all-cause mortality (OR 0.86, 95% CI [0.72-1.03]) and coronary heart disease (OR 0.88, 95% CI [0.64-1.23]). When the risk of stroke was evaluated using age stratification, lipophilic ß-blockers showed a significant reduction in the risk of stroke (OR 0.63, 95% CI [0.41-0.99]) compared with hydrophilic ß-blocker in patients aged <65 years.

[Potential possibilities of using adrenergic beta blockers in chronic heart failure]. / Potentsial'nye vozmozhnosti primeneniia beta-adrenoblokatorov pri khronicheskoi serdechnoi nedostatochnosti.

The study was undertaken to examine the efficacy of beta-adrenoblockers used in 26 patients with chronic heart failure which had been caused by coronary heart disease in 12 patients, by rheumatic heart disease in 8 patients, by dilated cardiomyopathy in 5 patients, and by chronic myocarditis in 1 patient. beta-Blockers such as oxprenolol, propranolol, and metoprolol were supplemented to the therapy of the patients with chronic heart failure who were resistant to cardiac glycosides, diuretics, and vasodilators. This resulted in functional class improvement by the New York Heart Association from 3.67 +/- 0.1 to 2.29 +/- 0.1. The authors defined the following predictors of the efficacy of beta-blockers in chronic heart failure: duration of the disease, diastolic pressure, cardiac rhythm, and left ventricular ejection fraction and discussed the mechanisms responsible for their positive effect in chronic heart failure.

Elevated serum activity of N-acetyl-beta-glucosaminidase in essential hypertension: diagnostic value and reversal to normal values after antihypertensive therapy.

Previous studies have shown that urinary N-acetyl-beta-glucosaminidase (NAG) is elevated in patients with hypertension, even without renal disease. To elucidate the value of measuring NAG, both in urine and serum of hypertensive patients, we measured NAG activity in the serum, plasma, and 24-hour urine by the fluorimetric method in 84 patients with uncomplicated essential hypertension before and after 6 months of effective treatment. NAG activities of these hypertensive patients were compared with those of 102 healthy normotensive subjects and 97 patients with various renal diseases and controlled hypertension. Serum NAG activity was clearly greater in patients with essential hypertension (427 +/- 124 U/mL) than in normotensive subjects (380 +/- 109 U/mL) or patients with renal disorders (393 +/- 115 U/mL) (P less than or equal to 0.004). The greater was the diastolic pressure in the hypertensive group, the greater was serum NAG activity (r = +0.30, P = 0.004). Hypertensive patients with high serum NAG activity were further characterized by a more exaggerated increase in systolic pressure (34 +/- 16 v 25 +/- 15 mm Hg, P = 0.051) and total peripheral resistance (19% +/- 18% v 12% +/- 13%, P = 0.042) in response to the cold pressor test and by a greater increase in systolic pressure (56 +/- 15 v 45 +/- 13 mm Hg, P = 0.009) and diastolic pressure (11 +/- 7 v 6 +/- 9, P = 0.043) in response to bicycle exercise testing than the group with low serum NAG activity. In contrast, urinary NAG activity tended to be only slightly higher in patients with essential hypertension than in the normotensive control group (33 +/- 31 v 23 +/- 29 U/mg creatinine [cr], P = 0.062), whereas patients with renal diseases had clearly increased urinary NAG activity (87 +/- 105 U/mg cr) (P less than 0.001). Following effective antihypertensive therapy, serum NAG activity decreased in patients with essential hypertension to values of normotensive control subjects (from 427 +/- 124 U/mL to 386 +/- 106 U/mL, P less than 0.01). A significant decrease in serum NAG activity was observed in patients with both initially high as well as low pretreatment serum NAG activities (P less than 0.001 and P less than 0.02, respectively). Urinary NAG activity overall was unchanged by antihypertensive treatment. We conclude that in patients with mild essential hypertension, serum NAG activity was already elevated (whereas urinary NAG activity was not) and was normalized by effective antihypertensive treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

[Nifedipine and gingival hypertrophy]. / Nifedipina ed ipertrofia gengivale.

Nifedipine-induced gingival hypertrophy is a rare side effect reported by the producers of this drug but, surely, not well known in all its aspects. In the present case report this pathology is studied in a patient treated with nifedipine for 30 months for cardiac angina, analyzing the histologic features, the therapy plain conducted for the hypertrophy and the most important pathogenetic theories formulated till now.

The influence of adrenoreactive preparations on clinical and haemodynamic parameters in patients with ischaemic heart disease.

The influence of anaprilin, oxprenolol, nonachlazine, prazosin and levodopa on the clinical course and haemodynamics was investigated in 138 patients with ischaemic heart disease in whom selective coronary angiography had revealed an up to 50 percent stenosis of one of coronary arteries. The clinical picture of IHD patients with a high tolerance of physical exercise was characterized by a preponderance of spontaneous angina pectoris accompanied by painless myocardial ischaemia. A certain role in the genesis of these disturbances is played by the relative increase in the activity of alpha 1-adrenoreceptors and decrease in beta-adrenoreceptor activity. Prazosin and nonachlazine in monotherapy reduced the number of anginal attacks and episodes of painless myocardial ischaemia.

[Electrocardiographic and echocardiographic changes during antihypertensive therapy]. / Modificazioni elettrocardiografiche ed ecocardiografiche durante terapia antipertensiva.

To investigate the changes of electrocardiographic and echocardiographic indexes of left ventricular hypertrophy (LVH) during antihypertensive therapy, 100 hypertensive patients, mean age 46 years, were studied in pretreatment condition and during 12 months of antihypertensive therapy. In pretreatment condition, 83 patients showed LVH by echocardiography (echo; left ventricular mass index greater than 130 g/m2) and 30 patients had LVH by electrocardiography (ECG) (Sokolow index greater than 35 mm). In comparison to echo index of LVH, Sokolow index showed a sensibility of 34% and a specificity of 88%. Both LV mass echo index and ECG index significantly decreased after 3 months but in different way. LV mass index mainly decreased after 12 months, whereas Sokolow index particularly decreased after 6 months, with no further changes in the subsequent months. After 12 months of therapy, the LV mass echo index normalized in 19% of the patients (16/83) and Sokolow index normalized in 57% (17/30). ECG sensibility and specificity, in comparison to LV mass echo, was 20% and 100%, respectively. Thus, ECG appears less sensitive than echo in the detection of LVH. During antihypertensive therapy ECG index of LVH normalized more precociously and to a greater extent than the echo index. However, the normalization of LVH by ECG does not necessarily mean that a complete anatomic regression of LVH has occurred.

Comparative effects of celiprolol, propranolol, oxprenolol, and atenolol on respiratory function in hypertensive patients with chronic obstructive lung disease.

The aim of the study was to compare the pulmonary effects of four beta-blockers with different ancillary properties: propranolol (non-beta 1 selective without ISA), oxprenolol (non-beta 1 selective with ISA), atenolol (beta 1 selective), and celipropol (beta 1 selective with mild beta 2-agonist and alpha 2-antagonist activity) in hypertensive patients with chronic obstructive lung disease. Ten asthmatic patients, all males, aged 50-66 years were studied. Entry criteria were a) DBP greater than or equal to 95 mmHg and less than or equal to 115 mmHg; b) FEV1 less than 70% of the theoretical values; c) FEV1 increase of at least 20% after salbutamol inhalation (200 micrograms). After a 2-week washout period on placebo, each patient received propranolol (80 mg/day), oxprenolol (80 mg/day), atenolol (100 mg/day), and celiprolol (200 mg/day) for 1 week, according to a randomized, cross-over design. At the end of the washout and of each treatment period, airway function, assessed by FEV1, FVC, and FEV1%, was evaluated by spirometry both in the basal condition and after salbutamol inhalation. Unlike propranolol and oxprenolol, which significantly reduced FEV1 and inhibited the bronchodilator response to inhaled salbutamol, atenolol and celiprolol did not significantly affect respiratory function and did not antagonize salbutamol effects. Celiprolol more closely approached placebo in its respiratory effects than did atenolol, although the differences were not statistically significant.

[Changes in lipid fractions of blood during the treatment of hypertension with prazosin and trasicor]. / Sdvigi fraktsii lipidov krovi pri korrektsii arterial'no'i gipertenzii prazozinom i trazikorom.

The paper deals with the study into the benefits of prazosin and trasicor used in arterial hypertension. Their effects on the blood lipid composition were evaluated. With prazosin, the steady antihypertensive effect was reached in 81.0%, whereas with trasicor, it was attained in 46%. When prazosin was given, total cholesterol and triglycerides were statistically significantly decreased by 6.8 and 14.8%, respectively, while high density lipoproteins was increased by 9.1%. When trasicor was administered, no changes were observed in the spectrum of serum lipids. Thus, prazosin is effective in correcting two major risk factors for coronary heart disease, namely arterial hypertension and hyperlipoproteinemia, thereby reducing a risk for coronary heart disease.

Importance of quantitative analysis of ventricular arrhythmias for predicting the prognosis in low-risk postmyocardial infarction patients. European Infarction Study Group.

In 378 placebo patients enrolled in the European Infarction Study (EIS), a secondary prevention study after acute myocardial infarction, 24-h baseline Holter monitoring was done 14 to 31 days after MI, and the relationship of electrical (ventricular arrhythmias) and mechanical (clinical signs of ventricular dysfunction) risk factors was analysed on the basis of mortality during the subsequent 2 years of follow-up. There was a rather low overall 2-year mortality rate of 6.9%. Consecutive arrhythmias (ventricular pairs and runs of ventricular premature beats) and left-ventricular dysfunction alone were associated with a low mortality of 4.0% and 3.6%, respectively. However, the combination of both defined a high-risk group characterized by a 2-year mortality rate of 16.7%. Additionally, the risk of dying was dependent on the frequency of consecutive arrhythmias: 22.2% of the patients with greater than 10 ventricular pairs per day died during the follow-up period in contrast to 9.9% of those with only 1-10 ventricular pairs per day. Thus, only the combination of electrical and mechanical risk factors, and especially the frequency of consecutive VPB, is helpful in identifying a subgroup of postMI patients with poor clinical outcome. An intervention study should restrict itself to this risk population only.

Efficacy and tolerability of long term oxprenolol and chlorthalidone singly and in combination in hypertensive blacks.

Sixty two black patients who had confirmed but untreated hypertension participated in a double blind clinical trial of the efficacy and tolerability of slow-release oxprenolol in a daily dose of 160 mg initially and 320 mg subsequently versus chlorthalidone 50 mg daily. Thereafter, a combination of oxprenolol with chlorthalidone in an initial dose of 160 mg and 25 mg and a subsequent dose of 320 mg and 50 mg, respectively, was administered and the effects compared with those of the same drugs given singly. The trial lasted for 3 years, but each participant took active medication for 1 year. Oxprenolol as monotherapy had no effect on the blood pressure, irrespective of the dose. Chlorthalidone as monotherapy produced a significant fall in blood pressure (p less than 0.01). Combining the 2 drugs enhanced their blood pressure lowering effects (p less than 0.001). Oxprenolol as monotherapy and as part of combination therapy was well tolerated by all patients. Chlorthalidone as monotherapy was well tolerated by most patients while a fraction of the patients developed biochemical derangements. These results confirm the findings that a beta-blocker alone may be ineffective in lowering blood pressure in hypertensive blacks. The results also show that the efficacy and tolerability of a beta-blocker and a diuretic are enhanced by their combined administration. Finally, the results show that increasing the dose of a beta-blocker or a diuretic does not produce a further increase in its blood pressure lowering effect.

A randomized comparison of early with conservative use of antihypertensive drugs in the management of pregnancy-induced hypertension.

Two treatment strategies were compared in 155 women with pregnancy-induced hypertension who were also given comprehensive non-pharmacological care. The mean gestation at entry was 28 weeks. As long as the diastolic blood pressure (DBP) remained below 106 mmHg, oxprenolol, or oxprenolol plus dihydralazine, were given to the early treatment group, and matching placebos to the control group. Open antihypertensive treatment was provided for patients whose DBP rose above 105 mmHg. Proteinuria occurred in seven women in each group. In the early treatment group, 13 of the 78 women were delivered by caesarean section; the corresponding numbers in the control group were 27 of 76 (17 vs 36%, 95% confidence interval (CI) of difference: 5-33%); the sections included seven and 16 in the early treatment and control groups, respectively, for severe hypertension and/or fetal distress. There were five perinatal deaths, two in the early treatment group and three in the control group. Early treatment did not influence gestational age at birth or birthweight. Respiratory distress syndrome occurred in four infants in the early treated group and in 10 in the control group; 14 infants in the former group and 26 in the latter were in hospital for more than 10 days (18 vs 35%; 95% CI of difference 4-32%). These results indicate that early antihypertensive treatment with oxprenolol is safe for the fetus and newborn in pregnancy-induced hypertension, but has no advantage over non-pharmacological care in terms of fetal growth. However, it may prevent acute hypertension in late pregnancy and associated fetal distress, and thus reduce the number of caesarean sections.

Beta-blocking agent facilitating the spontaneous passage of ureteral stones.

Based on data from neurophysiological studies, the author checked the action of a beta-blocking agent facilitating spontaneous stone passage from the ureter. Experience has shown that, compared with the control group, the beta-receptor-blocking agents proved to be useful in the facilitation of a spontaneous discharge of stones located in the lower part of the ureter.

ACE-inhibitors and quality of life.

A review of the literature concerning quality of life aspects on ACE-inhibitors in hypertensive patients is given. In the first part of the eighties two prospective multi-center randomised trials were conducted to determine the effect of captopril in comparison to methyldopa or an unselective beta-blocker on the quality of life in patients with mild to moderate hypertension (Hill et al. and Croog et al.). Both studies revealed slight but significant positive effects on indices of quality of life in captopril treated patients compared to those who had methyldopa or an unselective beta-blocker. Later, another ACE-inhibitor, enalapril, has been compared with a selective beta-blocker (Edmonds et al. and Herrick et al.) with respect to side-effects and the quality of life. The measurements of the quality of life tended to favour enalapril, but the differences were small and the over-all tolerability of the two drugs was similar. In conclusion, comparisons with more long standing forms of antihypertensive therapy suggest a slightly more favourable effect of ACE-inhibitors on the quality of life.

Cardioprotection by beta-blockers: molecular and structural aspects in experimental hypertension.

This paper deals with some changes at the cardiac and aortic levels observed in normotensive rats and in hypertensive rats and turkeys by using two different beta-blockers, namely propranolol and oxprenolol. Chronic treatment with propranolol induced in the heart of normotensive rats a shift in the ventricular myosin pattern toward the "slow" V2 and V3 isoforms which are characterized by a reduced oxygen consumption. Oxprenolol treatment did not modify the blood pressure levels in the renal hypertensive rats nor in the spontaneously hypertensive turkeys. Nevertheless, in both experimental models a substantial modification of the media and intima, respectively, took place. In untreated hypertensive and normal rats the thickness of the aortic media was significantly higher than that of the treated ones, therefore suggesting a direct effect of oxprenolol on the smooth muscle cells of the aortic media. In the spontaneously hypertensive turkeys the atherosclerotic plaques appeared to be more frequent and thicker than those found in the oxprenolol-treated animals. These two experiments demonstrate that beta-blockers can prevent the development of hypertrophy of the media and decrease both the incidence and severity of intimal proliferations independently of blood pressure control. It therefore appears that the well-known myocardial protective effect played by beta-blockers, which mainly consists of a reduced myocardial oxygen consumption, is certainly obtained by reducing blood pressure and heart rate but also by changing the contractile protein pattern. In addition, an indirect myocardial protective effect could be exerted by beta-blockers at the vascular level by preventing medial hypertrophy and the development of atherosclerosis.

Efficacy of four antihypertensive drugs (clonidine, enalapril, nitrendipine, oxprenolol) on stress blood pressure.

The impact of 4 antihypertensive drug regimens on blood pressure (BP) during everyday life stress and on BP during experimental stress in the laboratory was examined in an open clinical study. Sixty middle-aged men with mild-to-moderate essential hypertension never previously treated were treated either with low-dose clonidine (n = 10), oxprenolol (n = 20), nitrendipine (n = 20) or enalapril (n = 10). Before therapy, all 4 groups did not differ in age, weight, degree of obesity, BP at work site and casual BP measured in the outpatient clinic. After 6 months of effective therapy (casual BP within the normotensive range), casual diastolic BP was identical among the 4 groups, whereas systolic BP was lower in patients treated with clonidine or oxprenolol than in those who received enalapril. A disparate pattern of antihypertensive efficacy among the 4 groups emerged when stress BP was compared, with average ambulatory BP higher in patients receiving clonidine or enalapril than in those who had oxprenolol or nitrendipine. During ambulatory BP monitoring, patients treated with oxprenolol had the lowest level at each level of physical activity and self-reported emotional arousal. During bicycle exercise, patients receiving clonidine had the highest increase in systolic BP and those administered oxprenolol the lowest, whereas the BP response during mental stress was similar among all 4 therapeutic groups. The analysis of the hemodynamic response pattern during mental stress unmasked further disparities. Oxprenolol provoked an abnormal hemodynamic response during mental stress tests (increase in total peripheral resistance), whereas nitrendipine and enalapril preserved the physiological hemodynamic profile (decrease of total peripheral resistance).(ABSTRACT TRUNCATED AT 250 WORDS)

Disparities in blood pressure control under various antihypertensive regimens.

Ambulatory blood pressure recordings and stress blood pressures during exercise were compared among hypertensive patients effectively treated with oxprenolol, nitrendipine, enalapril or low-dose clonidine. After 6 months of therapy, the means of blood pressure at rest and casual diastolic pressure were nearly identical among the four therapeutic groups. Although all pressures fell to within the normotensive range, casual systolic pressures were lower in patients treated with sympatholytic agents than in those taking enalapril. In contrast, average ambulatory blood pressure was less controlled in patients given clonidine or enalapril than in those given oxprenolol or nitrendipine. During physical stress patients taking clonidine showed the highest stress blood pressures and those taking oxprenolol the lowest pressures. The study demonstrated that although blood pressure was reduced to within the normotensive range in all four therapeutic groups, analysis of values of ambulatory blood pressure and stress blood pressure during physical activity showed a disparate pattern of antihypertensive efficacy.

Effects of chlorthalidone, oxprenolol, and their combination in hypertensive blacks: a randomized double-blind crossover study.

One hundred twenty black patients with mild to moderate essential hypertension participated in a double-blind placebo-controlled crossover study of the efficacy and tolerability of slow release oxprenolol versus chlorthalidone singly and in combination. Oxprenolol as monotherapy produced no effect on blood pressure as compared with placebo even after doubling the dose. Chlorthalidone as monotherapy produced a significant decrease in blood pressure (p less than 0.01). Combining oxprenolol with chlorthalidone yielded hypotensive effects in excess of those of either of the components given singly. Oxprenolol produced a significant decrease in plasma renin activity (PRA) whereas chlorthalidone produced a significant increase in PRA. These results indicate that a beta-blocking agent alone is ineffective in lowering blood pressure in hypertensive blacks, even when the dose is high. Oxprenolol may increase the hypotensive effect of chlorthalidone by counteracting the hypokalemic effect of the diuretic and by attenuating the diuretic-induced increase in plasma renin activity.

[Type A behavior and psychological characteristics of hypertensive patients undergoing antihypertensive treatment]. / Comportamento di "tipo A" e caratteristiche psicologiche dell'iperteso in trattamento antiipertensivo.

The aim of this study was to evaluate the presence of "type A" behaviour and possible psychological distress in 373 hypertensive patients. One-hundred and ninety-five males, 56.2 +/- 6.2 years old and one-hundred and seventy-eight females, 57.1 +/- 6.2 years old, coming from the IPPPSH and still under double-blind treatment with or without a beta-blocker (oxprenolol 160 mg SR), were studied by means of the Jenkins Activity Survey form C and several tests from the Cognitive Behavioural Assessment Battery (CBA-2.0). Seventy-four point eight percent of the patients showed a "type A" pattern, and 25.5% were in the extreme predictive interval for coronary heart disease according to WCGS. "Type A" pattern was not influenced by variables such as age, sex, education, job or previous pharmacological treatment. The patients studied did not show any particular psychological distress at the psychometric evaluation. However, special social and cultural characteristics and different therapies influenced some symptoms, such as anxiety, depression and somatic lamentation. According to this study: "type A" behaviour seems to be a steady feature of the hypertensive patient; furthermore, it seems to be due to a "biological imprinting" which can be considered a cause of hypertension; psychological distress depends on a particular set of environmental stimuli. In the first case an accurate prevention is needed while, in the second case adequate pharmacological and/or psychological therapies are needed.