T. J. Cleophas

T-Channel-Selective Calcium Channel Blockade: A Promising Therapeutic Possibility, Only Preliminarily Tested So Far

Basic studies as well as short-term clinical trials of the T-channel-selective calcium channel blocker, mibefradil, are reviewed. The compound reduced afterload and was effective for the symptomatic treatment of hypertension and stable angina pectoris. It did not display any relevant negative inotropic or positive chronotropic effect. Mibefradil has been withdrawn by the manufacturer because of drug interaction at the cytochrome P-450 3A4 enzyme. It is hoped that new T-channel-selective calcium channel blockers will be developed to explore further this promising but so far only preliminarily tested therapeutic possibility.

Nitrate-Induced Headache in Patients with Stable Angina Pectoris: Beneficial Effect of Starting on a Low Dosage

Background: Nitrates, although important for the management of angina pectoris, cause significant headache in many patients. Methods: In a randomized, double-blind, crossover study, 89 patients with stable angina pectoris were studied to compare two different dosage strategies of isosorbide-5-monon itrate (5-ISMN). Patients were randomized to either 60 mg 5-ISMN once daily (od) for two weeks or to 30 mg 5-ISMN od for one week followed by 60 mg 5-ISMN od for one week. Then, there was a two-week placebo washout, after which the alternative treatment was given. The authors assessed the occurrence of angina pectoris and headache by diary cards while taking into account the numbers of isosorbide dinitrate sublingual puffs and paracetamole tablets required. Data were assessed for carryover and time effects. Results: The two dosage regimens were equally efficient for the relief of angina pectoris without development of tolerance. Thirty percent of the patients never experienced headache from the given dosages. In the remainder of them there was a highly significant time effect: the overall numbers of headache attacks in the first period of active treatment versus the second were 2,380 vs 1,400 (P < 0.003). Yet significantly fewer patients had headache on low dosage than on high dosage (45 vs 57, P < 0.02). Conclusions: (1) Starting on a low dosage was associated with a reduced frequency and severity of headache and did not notably influence the beneficial effect on angina pectoris. (2) One in 3 patients never experienced headache from the given dosages. (3) The overall number of headache attacks in the first period of active treatment was signif icantly higher than in the second period irrespective of the dosages given.

Comparison of 50-mg and 100-mg Sustained-Release Isosorbide Mononitrate in the Treatment of Stable Angina Pectoris: Effects on Quality-of-Life Indices

High-dosage nitrates are more effective for the management of anginal symptoms but produce more adverse effects, including development of tolerance and the zero-hour effect (rebound angina at the end of the dosing interval). Such effects may reduce the beneficial effect of treatment on quality of life. In a self-controlled, 6-month study, the effects on symptoms and quality of life of 50 mg and 100 mg sustained-release isosorbide mononitrate (SR ISMN), administered once daily, on anginal symptoms and quality of life (QOL) were assessed in 453 patients with stable angina pectoris. QOL was assessed by means of a test battery based on the Medical Outcomes Short-Form 36 Health Survey and the Angina Pectoris Quality of Life Questionnaire. The internal consistency and reliability of the multiitem scales were estimated by use of Cronbachs alpha coefficient. Based on their improvements in New York Heart Association (NYHA) angina classification, patients who received 100 mg daily showed greater improvement than those who received 50 mg daily; the mean difference between treatments was consistent with a significantly greater improvement of mobility and angina indices. Adverse effects, as estimated by side-effect index, including rebound angina at times of rest, and by patient compliance rating, differed slightly between the two treatment regimens and were even less problematic with the higher dosage than with the lower dosage. Psychological distress index and life satisfaction scores also were significantly higher with 100 mg than with 50 mg daily. The results of this study suggest that SR ISMN 100 mg once daily provided a better NYHA angina classification than SR ISMN 50 mg did and did not produce further adverse effects. In addition SR ISMN 100 mg improved various QOL indices more than SR ISMN 50 mg did, particularly the mobility index and certain life satisfaction scores, which are the most important indicators of QOL in this category of patients.

Chronic nitrate therapy in patients with angina with comorbidity

In a retrospective study from the Dutch Mononitrate Quality of Life (DUMQOL) Study Group, the authors found that patients with angina with concomitant diabetes or hypercholesterolemia derived more benefit from changing over to a once-daily nitrate treatment regimen than did patients without angina. The aim of this study was to assess this issue prospectively. In an open-label study, patients with stable angina pectoris from facilities in Germany, Portugal, and me Czech Republic were treated for 3 months with multiple daily doses and subsequently for 3 more months with once-daily isosorbide mononitrate/dinitrate. After the first and second 3-month periods, they were assessed by a validated QOL battery including domains for mobility, side effects, life satisfaction, anginal pain, and psychological distress. In the 1045 patients who participated in the study, the mean summary domain scores varied from 5 to 16 points and score improvements from 1.6 to 4.3 points. In the patients without concomitant hypertension and smokers, domain scores improved less than they did in the patients without, with differences in domain score improvements up to 1.0 points (P<0.001), which is substantial considering the range of improvement was between 1.6 and 4.3 points. In the patients with diabetes mellitus or hypercholesterolemia, a reverse pattern was observed with differences in domain score improvements up to 0.4 points (P<0.05). Patients with angina with diabetes or hypercholesterolemia derived more benefit from an asymmetric regimen of isosorbide mononitrate/dinitrate than did patients without. Patients with angina with hypertension and smokers benefited less. Differences in endothelial function may be involved.