[Controlled study of the effect of dihydroergocristine on organic brain psychosyndrome]. / Kontrollierte Studie zur Wirkung von Dihydroergocristin beim hirnorganischen Psychosyndrom.

The aim of this study was to verify long-term therapeutic efficacy and tolerance of dihydroergocristine (DHEC, CAS 17479-19-5) in a double blind placebo controlled study, in elderly patients with psychosyndrome characterized by memory and behaviour impairment. Two hundred patients, aged more than 65 years, were randomly divided into two groups of one hundred each. The first group received one 6-mg DHEC tablet daily for four months and the other group received placebo. The evaluation parameter for efficacy was the neuropsychological test SCAG (Scale of Clinical Assessment for Geriatrics), administered before and after 30, 60 and 120 days. The results showed a significant difference between DHEC and placebo with regard to total and partial scores of SCAG as well as to single items (mental alertness, recent memory, disorientation, anxiety, mood depression, emotional lability, motivation, uncooperativeness, fatigue, headache, tinnitus). After as few as thirty days of DHEC treatment the severity of mental and psychological symptoms was markedly decreased (p vs placebo < 0.01), as documented by significant positive changes of SCAG items. The four-month double blind period was followed by a two-month single blind period, during which patients of both groups received placebo. At the end of these two months, SCAG total score was unfavourably increased in patients previously administered DHEC, although scores were still significantly lower both versus baseline and versus previous placebo patients. Safety was good (placebo: one case of diarrhea; DHEC: one case of gastralgia and dizziness). Nine patients dropped out for reasons unrelated to treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of a vasodilating beta-blocker and a cardioselective beta-blocker in long-term treatment of hypertension: a European multicentre study.

The therapeutic effectiveness and safety of indenolol, a vasodilating beta-blocker with beta 2-agonism, was compared with that of atenolol, a cardioselective beta-blocker, in a 1-year double-blind trial. A total of 143 hypertensive patients (diastolic blood pressure 95-115 mmHg after 1 month of placebo) were randomly allocated to either atenolol, 50 mg/day, or indenolol, 60 mg/day. If the target diastolic blood pressure (less than or equal to 90 mmHg) was not reached after 1 month, the beta-blocker was doubled. If the target was still not reached, a diuretic was added after 2 months and doubled after 4 months. There was a higher overall responsiveness and monotherapy was more effective in the atenolol group, but at the lower dose indenolol was more effective than atenolol; however, no differences between drugs were significant. Although the drop-out rate was higher with indenolol, withdrawals due to side effects were similar in both groups. Indenolol was as effective and safe as atenolol in long-term antihypertensive therapy.

Changes in left ventricular anatomy and systemic hemodynamics induced by antihypertensive therapy with indenolol.

In 20 patients with mild or moderate essential hypertension who responded favorably to indenolol antihypertensive therapy, echocardiography was performed in the basal condition and 6 and 12 months after the beginning of permanent antihypertensive treatment. Indenolol induced a significant decrease in blood pressure, from a basal value of 170 +/- 3/100 +/- 8 mmHg to 142 +/- 4/87 +/- 2 mmHg after 6 months (p less than 0.01) and to 133 +/- 4/84 +/- 2 mmHg after 1 year (p less than 0.01), and in heart rate, from 72 +/- 5 to 61 +/- 3 bpm after 6 months (p less than 0.01) and to 60 +/- 2 bpm after 1 year (p less than 0.01). Simultaneously, there was a significant reduction in cardiac output (from 6.3 +/- .4 to 5.7 +/- .2 liters/min after 6 months, p less than 0.05, and to 5.6 +/- .2 liters/min after 1 year, p less than 0.01), due to a reduction in heart rate, increased stroke volume, and improved left ventricular performance after indenolol. Total peripheral resistance was also reduced, although statistical significance was not attained. However, a significant inverse correlation was found between the initial value of cardiac output and total peripheral resistance and the changes in these parameters induced by indenolol treatment (cardiac output: r = -0.824 and -0.855, total peripheral resistance: r = -0.876 and -0.899 at 6- and 12-month controls, respectively, all p less than 0.001). Finally, there was a parallel decrease in left ventricular wall and septal thickness and estimated left ventricular mass in patients with left ventricular hypertrophy, whereas no change in left ventricular anatomy could be detected in patients with normal left ventricular mass.

Effect of indenolol treatment on beta-adrenergic receptors of polymorphonucleates in essential hypertension.

Indenolol is a new antihypertensive agent, whose beta 1-adrenoceptor antagonist properties combined with beta 2-adrenoceptor agonist properties have been shown by experimental studies in animals. Our previous work reported that in vivo beta-adrenoceptor blocking drugs markedly increase the beta-adrenoceptor (BAR) number, without increasing BAR affinity. The aim of this study was to evaluate BAR density and affinity before and after indenolol therapy in membranes of polymorphonucleates (PMN) of patients with essential hypertension. Polymorphonuclear binding parameters were studied in 12 hypertensives (WHO stages I and II) after 14 days of placebo and after 21 days of indenolol therapy (120 mg once daily orally). Indenolol did not increase BAR number but significantly decreased (P less than 0.01) BAR affinity. On the basis of these data it is concluded that indenolol does not induce the same changes in PMN's BAR as previously observed with oxprenolol, propranolol and labetalol. This phenomenon may account for the absence of rebound effect after withdrawal of indenolol in hypertensives.

Indenolol kinetics versus pharmacodynamics in hypertension.

A kinetic model has been employed to compare the duration of the antihypertensive activity of indenolol to its plasma half-life both after single administration and at steady-state. After a 14 day run-in period with placebo, 60 or 120 mg indenolol were given to hypertensive patients I or II grade, according to W.H.O. guidelines, once a day for 14 days. Blood samples were drawn and blood pressure recorded at intervals after the first dose, during treatment and after the last dose of the compound. Both plasma concentration and mean arterial pressure difference curves were fitted by a first order input-output model, where plasma half-life was 4 h, while pharmacological half-life was 24 h for both dose-levels tested. Therefore, with once-a-day dose regimen an accumulation of the antihypertensive effect of indenolol was demonstrated, with 99% steady-state of blood pressure reached after 7 days, while the drug did not accumulate in the central compartment.

Indenolol: a new antihypertensive agent: efficacy, toxicity, and hemodynamic effects in a crossover double-blind study with metoprolol.

The antihypertensive efficacy of a new agent, indenolol, was compared with that of the well-established antihypertensive drug, metoprolol, and its hemodynamic effects were investigated using echocardiography. Eighteen hypertensives completed a double-blind, crossover, randomized study using indenolol and metoprolol. Two four-week courses with indenolol or metoprolol were preceded and followed by a two-week placebo period; the total duration of the study was 14 weeks. Indenolol proved to be significantly more effective than metoprolol in decreasing blood pressure values at rest (P less than .05). Furthermore, three patients that failed with metoprolol were successfully treated with indenolol. Both drugs induced a significant decrease in cardiac output that was mediated mainly through a reduction in heart rate, because stroke volume, left ventricle circumferential fiber shortening velocity, and ejection fraction were not significantly reduced by either drug. However, after indenolol, a significant direct relationship was found between the basal values of both cardiac output (r = .809) and total peripheral resistance (r = .800), and the reduction of these parameters. On the contrary, after metoprolol only, the correlation between the basal value of cardiac output and its reduction was significant (r = .790).

Indenolol pharmacokinetics and pharmacodynamics after single and repeated daily doses.

The relationship between indenolol (an investigational agent) plasma levels and the drug's effect on blood pressure and heart rate was investigated after single and repeated once daily administration at two dosage levels (60 mg and 120 mg) in two different groups of patients with first or second stage hypertension, according to the World Health Organization classification. The pharmacokinetic data were indicative of a first order absorption-elimination curve; time of maximum plasma levels was 1.5 to two hours, and elimination half-life was four hours. The drug did not accumulate in the central compartment after repeated administrations. A long-lasting decrease of both resting and isometric exercise systolic pressure values was recorded after acute indenolol administration. Diastolic pressure was affected only by repeated administrations. The lower dose (60 mg daily) of indenolol did not affect heart rate, whereas the higher dose (120 mg daily) decreased this parameter. A steady state of pressure values and heart rate was reached after 14 days of once daily treatment.

Efficacy of a new antihypertensive agent (indenolol) assessed by ambulatory blood pressure monitoring.

The effects of two-week treatment periods with indenolol (I) and metoprolol (M) were examined by 24-hour mean blood pressure (BP) monitoring in control conditions and during exercise stress test in 7 patients with essential hypertension, using the Oxford method. Both drugs induced a significant reduction in mean BP and heart rate (HR) as compared to pretreatment values (mean BP: from 117 +/- 3 mmHg to 106 +/- 4 after I, p less than 0.05 and to 102 +/- 3 after M, p less than 0.01; HR: from 78 +/- 2 bpm to 66 +/- 2 after I, p less than 0.01 and to 67 +/- 2 after M, p less than 0.01). I and M induced a significant reduction in systolic and diastolic BP throughout the day and most of the night. During bicycle ergometer the basal and peak values of systolic and diastolic BP were significantly lower after both treatments as compared to the pretreatment values (both p less than 0.01). Our data suggest that I once a day possesses a substantial and consistent antihypertensive action, effective over most of the 24 hours.

Haemodynamic effects of indenolol at rest and after a submaximal workload in essential hypertension.

The effect of indenolol on heart rate and blood pressure at rest and after submaximal workload has been studied in 19 patients with established essential hypertension. A stepwise increase from moderate to submaximal exercise was chosen to mimic challenges normally occurring in daily life. After 4 weeks of once a day indenolol therapy a significant, gradual reduction in the following cardiovascular parameters was observed: heart rate at rest fell by 20%, 30% after exercise and 31% after recovery; systolic blood pressure showed a fall of 15% at rest, 19% after workload and 14% after recovery; the reduction in diastolic blood pressure was 15% at rest, 11% after exercise and 12% after recovery. The rate-pressure product was decreased by 32% at rest, 43% after exercise and 42% after recovery. It is concluded that the most important pharmacological effect of indenolol is the significant decrease in myocardial oxygen demand. In patients with essential hypertension indenolol not only produces a definite antihypertensive effect, but it also increases workload tolerance and decreases subjective symptoms during physical activity. Compliance was good and no severe side effects were observed.

Computerized echocardiographic study of left ventricular function and cardiodynamic investigation with a new antihypertensive agent (indenolol).

Indenolol hydrochloride is a recently introduced antihypertensive substance. Although it has beta-adrenoceptor blocking activity, its action is due to total peripheral resistance reduction. We investigated the effects of indenolol therapy on left ventricular performance in 15 patients with essential hypertension. Assessments were made using systolic time intervals and computerized echocardiography. The echocardiographic and mechanocardiographic tracings were recorded three times: at the beginning of the trial, after seven days of placebo, and after three weeks of indenolol treatment. The indenolol therapy significantly decreased (P less than 0.001) systolic and diastolic blood pressures and heart rate in all patients, both in supine and standing positions. After three weeks of treatment, systolic time intervals and echocardiographic determinants of left ventricular function were substantially unchanged in comparison with the basal and placebo evaluations. We conclude that indenolol exerted a marked effect on chronotropism but no demonstrable negative effect on inotropism in patients with essential hypertension. No clinical signs of heart failure were recorded. Side effects were absent, and patient compliance was good in all cases.

Indenolol in hypertension.

After a complete washout 14 hypertensive inpatients were given placebo for 3 days. Undistinguishable 30- or 60-mg indenolol tablets were then given twice daily for 14 days in a double-blind, randomized manner. Supine and standing arterial pressure and heart rate were measured at rest three times a day. Indenolol decreased systolic and diastolic arterial pressure as well as heart rate in subjects in supine and standing positions. Placebo had no effect. The effect of indenolol on systolic arterial pressure was dose and time related, but independent of the intensity of hypertension. No dose-effect relationship was found on diastolic arterial pressure. Decrease of heart rate was dose and time related, although bradycardia was never noted. Indenolol was well tolerated.