Ketanserin alone and in combination with enalapril in the treatment of essential hypertension: assessment of the haemodynamic effects.

The antihypertensive and haemodynamic efficacies of ketanserin and ketanserin plus enalapril were compared. The monotherapy phase of the study involved the oral administration of 40 mg ketanserin twice daily or 20 mg enalapril once daily for 12 weeks to 25 hypertensive patients. Systolic and diastolic blood pressures were significantly reduced by both drugs. Left ventricular function both at rest and during effort improved significantly with either drug. This was due to a reduction of end-systolic volume; end-diastolic volume decreased only with the use of enalapril. Combination therapy, involving 16 patients and both drugs given at the original dosage schedule for 12 weeks, resulted in further reductions in systolic and diastolic blood pressures, and an improvement in left ventricular function; indices of diastolic function were not modified. In conclusion, ketanserin and enalapril showed comparable antihypertensive and haemodynamic activities. A combination of ketanserin and enalapril increased the favourable characteristics of both drugs.

Effect of the selective 5-HT2 antagonist ketanserin on adenosine-induced bronchoconstriction in asthmatic subjects.

In eight asthmatic subjects a randomized, double-blind, placebo controlled study was performed to investigate the effect of inhaled ketanserin, a 5-HT2 receptor blocking agent, in a dose of 10 mg given 30 min before test, on adenosine-induced bronchospasm. The protective effect of ketanserin was significant in all patients, even though it altered basal bronchomotor tone in only two subjects. On the contrary, ketanserin did not inhibit histamine-induced bronchoconstriction in four of these eight asthmatics, even though it modified sensitivity and reactivity in one of them. The results suggest that ketanserin influence on adenosine bronchial reactivity and sensitivity was not due to the bronchodilator effect of ketanserin itself or to its antihistaminic activity. We have no certain explanation for the inhibition of adenosine-induced bronchoconstriction elicited by ketanserin. It is possible that 5-HT may play, at least in part, a role as mediator of adenosine-induced bronchoconstriction.

[Ridogrel, a new platelet antiaggregant molecule with a double mechanism of action. A pharmacological and clinical profile]. / Ridogrel, una nuova molecula antiaggregante piastrinica a doppio meccanismo d'azione. Profilo farmacologico e clinico.

Ridogrel has a double mechanism of action: it is a combined thromboxane A2 synthetase inhibitor and thromboxane A2/prostaglandin endoperoxide receptor blocker, demonstrated in vitro, as well as in vivo in animals and in man. In man, ridogrel is quickly absorbed after oral administration (30-60 min). The half-life is about 6-9 hours. At the oral dose of 300 mg b.i.d., the steady state has been reached at the third day of administration. Pharmacodynamic studies in healthy volunteers as well as in patients demonstrate a marked decrease in TXB2 serum level and an increase in 6ketoPGF1 alpha level. Moreover ridogrel inhibits the human platelet aggregation induced by U46619, collagen and arachidonic acid (thromboxane A2/prostaglandin endoperoxide receptor blocker). During the ridogrel treatment there have been neither variations of coagulative parameters (PTT, APTT, plasmatic fibrinogen) nor variations of other metabolic parameters except for those concerning the antiaggregant activity. To conclude, the preliminary data on about 100 healthy volunteers and more than 100 patients show that pharmacologic combined actions on enzyme and on receptors could be more efficacious than one single activity in eliminating circulatory flux resistance, in potentiating thrombolysis and in preventing or postponing vessels reocclusions. According to the above-mentioned results, ridogrel could have a good application in correction of thrombotic disorders due to platelet activation.

Acute respiratory and cardiovascular effects of inhaled ketanserin in chronic obstructive pulmonary disease. A comparative study with intravenously administered ketanserin.

In a double-blind, crossover study, nebulized ketanserin, a 5-HT2 receptor antagonist, and a placebo were given to eight patients with moderate to severe nonasthmatic COPD. Intravenous ketanserin had rapid onset of action and induced a longer lasting bronchial response than inhaled ketanserin. These results confirm that ketanserin acts as a mild bronchodilator in patients with COPD and demonstrate that the inhaled route has no advantage over the intravenous route in terms of effectiveness. Thus, 5-HT may play a role in bronchomotor tone, at least in patients with chronic airway obstruction.

Effect of ketanserin, a new blocking agent of the 5-HT2 receptor, on airway responsiveness in asthma.

Most of the antihypertensive drugs have a liability for adverse effects in asthma. Since there are few available data on the effect of ketanserin, a new antihypertensive drug which is a type-2 serotonin receptor antagonist, on human respiratory function, we have tested whether this drug can modify bronchial hyperresponsiveness to methacholine in asthmatic patients. The protective effect of intravenous ketanserin (0.14 mg/kg) was small, but significant.

Ketanserin and captopril interaction in the treatment of essential hypertensives.

The aim of the study was to evaluate whether the combination of ketanserin with captopril exerts an additive antihypertensive effect, as compared with single drug treatment. Twelve patients with uncomplicated moderate essential hypertension received, according to a randomized, double-blind, crossover design, ketanserin (40 mg twice daily), captopril (50 mg twice daily), the combination of the two drugs at these dosages, and the corresponding placebo, each treatment being given for 1 month. Both ketanserin and captopril as monotherapy similarly and significantly reduced blood pressure as compared with placebo (p less than 0.001). The combination treatment of ketanserin plus captopril further and significantly reduced blood pressure when compared with single drug treatment (p less than 0.001). Moreover, the percentage of responders and patients whose blood pressure was normalized were significantly greater under the combined treatment than under ketanserin or captopril monotherapy (p less than 0.001). These data indicate that the combination of ketanserin plus captopril exerts a clear additive antihypertensive effect when compared with each treatment as monotherapy, a finding that suggests this combination can be usefully employed in the treatment of hypertensive patients.

Comparison of ketanserin and enalapril in the treatment of mild-to-moderate essential hypertension.

In a double-blind 3-month study in mild-to-moderate essential hypertensive patients over 50 years of age, ketanserin, a selective S2-serotoninergic antagonist with additional alpha 1-adrenergic blocking properties, has been compared with enalapril, an angiotensin-converting enzyme inhibitor. Supine and upright blood pressures and heart rates were recorded for placebo and during active treatment (-4, -2, 0, 2, 4, 6, 8, 10, and 12 weeks). Metabolic profile (plasma glucose, creatinine, sodium, potassium, total and HDL-cholesterol, triglycerides, uric acid) was monitored during treatment with placebo and at the end of the study. Mean blood pressure was equally and significantly (p less than 0.001) lowered by both drugs from 2 weeks of treatment, whereas no changes occurred in mean heart rate or in biochemical variables. Dizziness was observed in three patients on ketanserin and in one patient on enalapril, whereas headache occurred in only one patient on enalapril. These data indicate that ketanserin is as effective and well tolerated as enalapril in hypertensive patients over 50 years of age.

Ketanserin, hypertension, and chronic alcoholism: double-blind study in forty patients.

In a randomized double-blind trial involving 40 alcoholic hypertensive patients, the antihypertensive activity of ketanserin, a serotonin antagonist with high affinity for S2 serotonergic receptors, was compared with a placebo. Patients in both groups were matched for age, body weight, blood pressure, alcoholic consumption, and length of alcoholism. The administration of ketanserin significantly reduced (p less than 0.001) mean supine blood pressure from 167/106 mmHg (22.3/14.1 kPa) at baseline to 145/87 mmHg (19.3/11.6 kPa) after 90 days of treatment versus a slight non-significant reduction with the placebo. No significant changes in heart rate, body weight, or laboratory parameters occurred. The incidence of side-effects was low in both groups. The results of this study suggest the possible role of serotonin in the pathogenesis of alcohol-related hypertension and the potential treatment of the disease using S2-receptor antagonists such as ketanserin.

Ketanserin, a new blocking agent of serotonin S2-receptors. Respiratory functional effects in chronic obstruction of the airways.

The role played by serotonin (5-HT) in the regulation of bronchomotor tone has up to now been a much debated question, although there is good evidence that it induces intense bronchoconstriction after inhalation in asthmatic patients. Serotonin has been found to contract the tracheobronchial smooth muscle of different animals. Some data suggest that tracheobronchial contraction due to serotonin is mediated by its interaction with the S2-receptor. The blockade of this receptor by ketanserin, a serotoninergic antagonist which primarily binds to S2-serotoninergic receptors, produces bronchodilation. The respiratory effects of intravenously administered ketanserin (10 mg) or placebo were compared in a double-blind crossover study in 14 patients with chronic obstruction of the airways. The forced expiratory volume in one second (FEV1) and the instantaneous forced expiratory flow after 50 percent of the forced vital capacity has been exhaled (FEF50%) did not change after placebo, but they increased significantly after administration of ketanserin. The results suggest that in patients with chronic obstructive pulmonary disease, serotonin may play a role in the development of obstruction of the airways, even if the mechanism remains undefined.

Clinical experience with ketanserin in the treatment of hypertension.

Ketanserin (K), a selective and specific S2-receptor antagonist, has been compared with metoprolol (M), a cardioselective beta-blocker, in a double-blind study in order to assess its efficacy and safety in the treatment of essential hypertension. After a placebo run-in period of 4 weeks, hypertensive patients [supine diastolic blood pressure (DBP) greater than or equal to 100 mmHg] were treated with K, 40 mg twice daily (n = 18), or with M, 100 mg twice daily (n = 14). Systolic pressure (SBP) and DBP, both supine and standing, were significantly reduced from the first month of treatment by both drugs and remained stable for the whole study period (12 weeks). About two-thirds of the patients treated with K responded to the therapy (drop in DBP of at least 10%) and half were normalized (DBP less than or equal to 90 mmHg). In the M group, 50% of patients responded and 30% were normalized. A significant decrease in the heart rate was observed with M, but not with K. Ten patients treated with K were followed for 1 year. The antihypertensive effect of K was maintained throughout the study with evidence of tolerance. No serious adverse reaction was observed.

Ketanserin (S2-receptor blocking agents), hypertension and chronic alcoholism.

Ketanserin is a pure antagonist of serotonin S2-receptors, in blood vessels, platelets and bronchial tissue. Ketanserin has been suggested as hypotensive drug in man, but it shows as well a specific activity on platelet aggregation. An increased incidence of hypertension, of unknown origin, has been found in patients with chronic alcoholism: hypotheses have been made upon an increased incretion of catecholamines and a greater sensitivity of blood vessels' receptors to their action. The data from the present study of eleven patients show that these subjects had an increased platelet activity and ketanserin administration was effective in allowing both the blood pressure levels and platelet activity to resume their normal range. This drug is thus suggested, for its pharmacological properties, as an elective medication for hypertensive patients with chronic alcoholism.

Flunarizine, cerebral blood flow and reversion of experimental atherosclerosis in rabbit.

Flunarizine is a calcium entry blocker active in the treatment of peripheral vascular disease. The present study was performed to evaluate the effect of flunarizine on cerebral blood flow (CBF) and lipidic patterns in rabbits with dietary experimental atherosclerosis. Since it is well known that there is only a slight correlation between the severity of atheromatous lesions ascertained at necroscopy and the severity of clinical symptoms of cerebral vascular disease, the effect of the drug was assessed by measuring the CBF and compartmental distribution of blood flow in unanaesthetized rabbits by the intracarotid Xe-133 clearance method; blood pressure, plasma lipids and tissue fat infiltration were also checked. An atherogenic diet brings about significant impairment of CBF. Flunarizine is inactive in normal rabbits if chronically administered at the daily dose of 10 mg/kg p.o. In atherosclerotic rabbits chronic treatment with flunarizine induced a pronounced increase in cerebral haemodynamic parameters. Arterial pressure and blood pCO2 were not significantly modified. Lipidic patterns were not markedly improved by flunarizine treatment in comparison with values for atherosclerotic animals. These data demonstrate that flunarizine treatment counteracts the haemodynamic effects of cerebral atherosclerosis. The pronounced activity on the cerebral vessels is accompanied by a weak antilipaemic effect.