Continuous oral N-acetylcysteine treatment and development of nitrate tolerance in patients with stable angina pectoris.

The presence of sulfhydryl (SH) groups appears to be fundamental to nitrate-induced vasodilation and N-acetylcysteine (NAC), a sulfhydryl (SH)-donor substance, potentiates hemodynamic responsiveness to nitrates. We investigated the effect of simultaneous administration of NAC and isosorbide dinitrate (ISDN) on development of nitrate tolerance. In a double-blind, randomized, placebo-controlled cross-over study, seven patients with stable angina pectoris were treated for two 8-day periods with ISDN (40 mg four times daily, q.i.d.) together with NAC (controlled release 600 mg q.i.d.) or matching placebo. Bicycle exercise tests were performed before treatment was started, 1 h after treatment was started, and at day 8. After 8-day treatment with ISDN + placebo, responses determined by exercise testing were diminished as compared with responses obtained during acute therapy and did not differ from baseline values, suggesting development of tolerance to ISDN. During treatment with ISDN + NAC, time to 1-mm ST depression was significantly prolonged (441 +/- 44 vs. 381 +/- 40 s, mean +/- SEM) and total ST segment depression significantly reduced (1.9 +/- 0.7 vs. 3.5 +/- 0.8 mm) as compared with baseline values. The reduction in ST segment depression was significantly more pronounced during ISDN + NAC (46%) as compared with ISDN + placebo (23%). Although exercise time and time to angina pectoris were unaffected. NAC augmented the antiischemic effects of ISDN as assessed by ECG. This finding may suggest that development of nitrate tolerance is modified by chronic oral high-dose NAC administration.     

Efficacy of controlled-release isosorbide-5-mononitrate as adjunctive treatment to beta-blocking agents in patients with stable angina pectoris

Twenty-four patients with severe stable angina pectoris were included in a randomized, double-blind, placebo-controlled, cross-over study to assess the efficacy of a controlled-release preparation of isosorbide-5-mononitrate (ISMN-CR) 60 mg once daily or twice daily as adjunctive treatment to a beta blocker. In bicycle ergometer exercise tests performed 4 h after study drug intake, total exercise time and time until 1-mm ST-depression increased significantly during both regimens as compared with placebo (p less than 0.05). However, only the 60-mg once-daily regimen was significantly better than placebo with regard to time until angina pectoris. The results indicate that ISMN-CR 60 mg once daily is effective as adjunctive to beta-blocker treatment, and nitrate tolerance appeared to develop during the twice-daily regimen. In 10 of the patients, the effect of additional sublingual nitroglycerin (NTG) was studied. Exercise time after NTG remained remarkably constant throughout all study periods. Exercise time was significantly prolonged after additional NTG and independent of the dose level of ISMN-CR. This indicates that cross-tolerance to NTG was not induced during sustained treatment with ISMN-CR.     

Prevention and reversal of tolerance to nitroglycerine with N-acetylcysteine

A recent study demonstrated that the sulfhydryl donor N-acetylcysteine (NAC) potentiated hemodynamic responsiveness to nitroglycerine (NTG) in patients with ischaemic heart disease. The interaction between NTG and NAC in rings of bovine coronary artery was examined. Vasodilator responses to NTG were determined after elevation of tone with the thromboxane mimetic U46619 [(15S)-hydroxy-11 alpha, 9 alpha-(epoxymethano) prosta-5Z, 13E-dienoic acid]. NAC (1 microM-3 mM) induced no changes in tone of the preparation, but 10 microM NAC significantly potentiated responses to NTG (EC50 reduced from 0.69 +/- 0.19 microM to 0.22 +/- 0.06 microM; p less than 0.01). Increasing degrees of tolerance to NTG were produced at pH 7.4 by preincubating coronary rings with NTG in concentrations of 4.4 and 44 microM, and 0.22 mM. With 0.22 mM NTG, EC50 for subsequently administered NTG was increased to 11.0 +/- 1.8 microM (p less than 0.001 vs. control vessels). The degree of tolerance produced with this concentration of NTG was markedly attenuated by simultaneous (EC50 = 0.50 +/- 0.30 microM; p less than 0.001 vs. tolerant vessels) or subsequent (EC50 = 1.17 +/- 0.59 microM, p less than 0.001 vs. control vessels) incubation with 10 microM NAC. These data confirm that responses to NTG are modulated by sulfhydryl (or specifically cysteine) availability and suggest that in vitro tolerance to NTG is related to sulfhydryl (or cysteine) depletion. It is therefore possible that in vivo potentiation of NTG responses by NAC will be of clinical benefit in preventing or reversing loss of hemodynamic responsiveness to NTG.     

Antianginal efficacy and safety of ivabradine compared with amlodipine in patients with stable effort angina pectoris: a 3-month randomised, double-blind, multicentre, noninferiority trial

BACKGROUND AND OBJECTIVE: Current medical therapies for the symptoms of angina pectoris aim to improve oxygen supply and reduce oxygen demand in the myocardium. Not all patients respond to current antianginal monotherapy, or even combination therapy, and a new class of antianginal drug that complements existing therapies would be useful. This study was undertaken to compare the antianginal and anti-ischaemic effects of the novel heart-rate-lowering agent ivabradine and of the calcium channel antagonist amlodipine. PATIENTS AND METHODS: Patients with a >/=3-month history of chronic, stable effort-induced angina were randomised to receive ivabradine 7.5mg (n = 400) or 10mg (n = 391) twice daily or amlodipine 10mg once daily (n = 404) for a 3-month, double-blind period. Bicycle exercise tolerance tests were performed at baseline and monthly intervals. The primary efficacy criterion was the change from baseline in total exercise duration after 3 months of treatment. Secondary efficacy criteria included changes in time to angina onset and time to 1mm ST-segment depression, rate-pressure product at trough drug activity, as well as short-acting nitrate use and anginal attack frequency (as recorded in patient diaries). RESULTS: At 3 months, total exercise duration was improved by 27.6 +/- 91.7, 21.7 +/- 94.5 and 31.2 +/- 92.0 seconds with ivabradine 7.5 and 10mg and amlodipine, respectively, both ivabradine groups were comparable to amlodipine (p-value for noninferiority < 0.001). Similar results were observed for time to angina onset and time to 1mm ST-segment depression. Heart rate decreased significantly by 11-13 beats/min at rest and by 12-15 beats/min at peak of exercise with ivabradine but not amlodipine, and rate-pressure product decreased more with ivabradine than amlodipine (p-value vs amlodipine <0.001, at rest and at peak of exercise). Anginal attack frequency and short-acting nitrate use decreased substantially in all treatment groups with no significant difference between treatment groups. The most frequent adverse events were visual symptoms and sinus bradycardia with ivabradine (0.8% and 0.4% withdrawals, respectively) and peripheral oedema with amlodipine (1.5% withdrawals). CONCLUSIONS: In patients with stable angina, ivabradine has comparable efficacy to amlodipine in improving exercise tolerance, a superior effect on the reduction of rate-pressure product (a surrogate marker of myocardial oxygen consumption) and similar safety.     

曲美他嗪治疗稳定型心绞痛的疗效观察

目的:观察曲美他嗪辅助治疗稳定型心绞痛的疗效和安全性。方法:选择稳定型心绞痛患者110例,随机分为两组,对照组(52例)为常规心绞痛用药,曲美他嗪组(58例)在常规用药基础上加用曲美他嗪20mg,口服,每日3次,连续8周。结果:曲美他嗪组治疗总有效率高于对照组,差异有显著性(P<0.05);两组均无不良反应发生。结论:在常规药物治疗基础上加用曲美他嗪能更有效地缓解心绞痛,使运动耐量增加,且耐受性好,因此曲美他嗪是辅助治疗心绞痛安全、有效的药物。     

Antianginal effects of atenolol and pindolol in patients with stable effort angina pectoris

A double blind, randomised crossover study with 20 patients was performed to compare the antianginal effects of atenolol 100 mg once daily and pindolol 5 mg thrice daily. After a placebo run-in period, 2 treatments were given for 2 wk each. The number of anginal attacks and the nitroglycerin (NTG) consumption were determined. During bicycle exercise testing, the systolic blood pressure (BP), heart rate (HR), double product and exercise tolerance were measured. Both drugs reduced the number of anginal attacks and NTG consumption relative to the placebo, with atenolol being more effective than pindolol. During exercise, both beta-blockers produced a slight increase in BP and HR compared to the placebo. HR attained with atenolol was lower than pindolol at the same workload. The total duration of exercise and the maximal tolerated workload were greater in atenolol than pindolol experiment. The special properties of beta-blockers, such as cardioselectivity or intrinsic sympathomimetic activity (ISA), may have clinical importance in the treatment of angina pectoris.     

Biochemical and pharmacological interactions between nitroglycerin and thiols. Effects of thiol structure on nitric oxide generation and tolerance reversal

Co-administration of N-acetylcysteine (NAC) with nitroglycerin (NTG) has been shown to partially reverse nitrate tolerance and to potentiate the hypotensive effect of NTG in humans. However, a high clinical dose of NAC was required for this pharmacologic interaction resulting in the production of unwanted side-effects. Therefore, sulfhydryl compounds more active than NAC need to be identified if this interaction is to be exploited clinically. We previously suggested that the effect of sulfhydryl compounds on NTG may be mediated by the formation of S-nitrosothiol or nitric oxide (NO) extracellularly to the vascular smooth muscle cell (e.g. in plasma) (Fung et al., J. Pharmacol Exp Ther 245: 524-530, 1988). In an attempt to understand the structural features which govern this thiol-catalyzed NO generation from NTG, nineteen different aliphatic and ten aromatic sulfhydryl compounds were examined with respect to their catalytic activity to generate NO from NTG in plasma. Significantly enhanced production of NO was observed with most sulfhydryl compounds examined when compared to buffer control. Among the aliphatic thiols, only mercaptosuccinic acid was more potent than NAC (2x), whereas among the aromatic thiols, both thiosalicylic acid (TSA, 10x) and TSA-methyl ester (3x) were more potent than NAC. Comparative in vitro relaxation studies were carried out using isolated (and nitrate-tolerant) rat aortic rings with NTG/TSA and NTG/NAC, in the presence of 0.5% (v/v) plasma. Under these conditions, partial reversal of NTG tolerance could be achieved with TSA, but not with NAC. These data are consistent with the view that extracellular production of NO or S-nitrosothiol serves as a tolerance-reversing mechanism of thiols on NTG. TSA appears to be a more potent sulfhydryl compound than NAC in this biochemical and pharmacologic interaction.     

Nitrate tolerance A problem during continuous nitrate administration

The organic nitrates are effective agents in the management of patients with angina pectoris. They are the agents of choice in the treatment of acute episodes of angina pectoris and are useful in angina prophylaxis. While the organic nitrates are extremely effective in angina prophylaxis during acute therapy, there is increasing evidence that with many dosing regimens for oral and transdermal therapy, substantial attenuation of the antianginal effects develops. Thus, during acute therapy the organic nitrates improve exercise tolerance for many hours, but during sustained therapy designed to provide antianginal efficacy throughout the 24-h period there is significant attenuation of the beneficial effects. It has been documented that treatment regimens designed to provide a period of nitrate washout prevent or reverse nitrate tolerance, and such changes in dosing regimens have been shown to provide continued antianginal protection. It is clear that the objective of providing 24-h antianginal protection with the organic nitrates cannot be achieved. With appropriate dosing schedules, however, it is possible to improve exercise tolerance throughout the major portion of the 24-h dosing period.     

Bopindolol in chronic stable angina pectoris: duration and extent of antianginal action.

The effects of bopindolol, a new beta-adrenoceptor blocker, on the exercise tolerance of 12 in-patients, mean age 57 (5 years), with stable angina pectoris and documented coronary artery disease were evaluated. All patients received on 4 different days a single oral dose of bopindolol 0.5 mg, bopindolol 1.0 mg, bopindolol 2.0 mg and placebo according to a double-blind latin square design. Treadmill symptoms-limited exercise tests were performed using a Bruce protocol, 3, 12 and 24 h after dosing. Bipindolol improved (P less than 0.05) exercise tolerance in comparison with placebo (by a maximum of 33%, 52% and 26% after the 2.0 mg dose) with no adverse effect on ischaemia. The primary action of bopindolol appeared to be to reduce myocardial oxygen consumption (mainly by its negative chronotropic effect) for up to the 24th hour after oral administration. Eight (66%) patients were angina free at the 3rd, 12th and 24th h exercise test. The effects of bopindolol were not dose-related. A short period of inactivity due to hospitalization may have influenced the exercise performance and led us to underestimate the presence of a dose-response. The results of this report suggest that bopindolol has a long lasting effect in the treatment of patients with chronic stable angina pectoris.     

左卡尼汀提高稳定型劳力性心绞痛病人运动耐量

目的 :比较左卡尼汀与曲美他嗪对心绞痛病人临床疗效及对运动耐量的影响。方法 :选择 6 0例冠心病稳定型心绞痛伴高脂血症病人 ,随机分为2组 ,分别予左卡尼汀 1.0 g ,po ,tid× 12wk及曲美他嗪 2 0mg ,po ,tid× 12wk ,比较每周心绞痛发作次数及硝酸甘油消耗量 ,运动耐量及血脂水平。结果 :左卡尼汀及曲美他嗪均减少心绞痛发作次数、硝酸甘油消耗量 ,运动至出现ST段压低 1mm所需时间、心绞痛所需时间、ST段缺血型下移之和明显减少 ,运动持续时间显著延长 ,左卡尼汀还降低总胆固醇、三酰甘油 ,升高高密度脂蛋白胆固醇。结论 :左卡尼汀及曲美他嗪均能缓解稳定型心绞痛病人症状 ,改善运动诱发的心肌缺血 ,提高运动耐量。左卡尼汀还可调节血脂水平     

Prazosin potentiates the acute hypotensive effects of nitroglycerin but does not attenuate nitrate tolerance in normal conscious rats

Sympathetic activation has been suggested as a mechanism of acute nitrate tolerance, but the available literature is not definitive. We investigated the effects of prazosin, an alpha1-adrenoceptor antagonist, on acute nitroglycerin (NTG) hemodynamics and tolerance development in normal conscious rats. The effect of prazosin bolus injection (300 microg/kg) on NTG hemodynamics was first determined after acute dosing. The extent of maximal mean arterial pressure (MAP) response and the duration of drug-induced hypotension to NTG bolus doses (5, 15, and 30 microg) were measured before and after prazosin. In separate studies, the effects of prazosin on NTG tolerance development were examined. Rats received either 10 microg/min NTG or vehicle infusion for 5 hours after predosing with prazosin (300 microg/kg). Maximal MAP response to the hourly 30-microg NTG i.v. bolus challenge dose (CD) was determined before and after prazosin, and during NTG or vehicle infusion. Our results showed that bolus doses of NTG (at 5, 15, and 30 microg) dose-dependently decreased maximal MAP by 20.8 +/- 5.8, 26.1 +/- 5.0, and 30.6 +/- 5.7 mm Hg, respectively. Prazosin caused an average of 16 mm Hg depression in MAP, and it only slightly potentiated the hypotensive effects of bolus doses of NTG both after acute dosing and during continuous infusion. Prazosin treatment prolonged the duration of NTG-induced MAP response by about 4-fold for all NTG doses examined (P < 0.01 versus corresponding dose before prazosin, ANOVA). In both prazosin-treated and untreated groups, NTG infusion significantly attenuated the MAP response of the NTG CD starting from 1 hour of infusion (P < 0.001 versus 0 hour response, ANOVA), confirming tolerance development. In the presence of NTG tolerance development, prazosin no longer enhanced the apparent duration of NTG action. The hypotensive effect produced by the 30-microg NTG CD lasted for 7 +/- 2 and 10 +/- 2 seconds for prazosin-treated and untreated groups, respectively (P > 0.05, ANOVA). Our results showed that, in both NTG-tolerant and control animals, prazosin only slightly potentiated the maximum hypotensive effects of a challenge NTG dose, but did not significantly alter the pharmacodynamics of NTG-induced hemodynamic tolerance. Thus, in our animal model, sympathetic blockade by prazosin neither prevented nor attenuated in vivo tolerance induced by NTG.     

A cross-over study comparing the efficacy of a combination of atenolol and nifedipine at different doses in angina pectoris

Summary

Although the combined administration of atenolol and nifedipine has been shown to be effective in the treatment of angina pectoris the optimum dosage level of the combination has not yet been established. A double-blind, randomly assigned three period cross-over study was carried out therefore to investigate the effects of different daily doses of a fixed combination of 50?mg atenolol and 20?mg sustained-release nifedipine per capsule. Twenty-one patients with stable angina pectoris were randomized, after a 2-week run-in period, to receive treatment for 4 weeks with either 1 capsule twice daily (A), 2 capsules in the morning and 1 in the evening (B), or 2 capsules twice daily (C). A treadmill exercise tolerance test was performed together with a clinical evaluation after the run-in and each of the three treatment periods. Analysis of the results from the 19 patients who completed the study revealed there were no significant differences between the three treatment periods with respect to the general exercise test parameters, number of anginal attacks per week or nitrate consumption. Few side-effects were reported and were only mild in nature. On these findings, therefore, there would appear to be little justification for increasing the dose of the combination above the equivalent of treatment A.     

Lack of negative inotropic effects of the new calcium antagonist Ro 40-5967 in patients with stable angina pectoris.

We screened the antiischemic, hemodynamic, and inotropic effects of different dosages of the new calcium channel blocker Ro 40-5967 in 65 patients with stable effort-induced angina pectoris. In a double-blind way, patients were randomized to recieve a single oral dose of 50, 100, or 200 mg Ro 40-5967 or placebo, given as a drinking solution. Left ventricular ejection fraction (LVEF), blood pressure (BP), and heart rate (HR) were measured at rest and during a supine bicycle exercise test on day 0 (baseline) and 2 h after drug intake on day 1. Twenty-four hours later, the bicycle exercise test was repeated. Ro 40-5967 improved exercise duration and resting LVEF. After 200 mg, exercise time increased significantly from 8.4 +/- 0.8 min (mean +/- SEM) to 9.6 +/- 0.7 min (p = 0.018), and LVEF at rest increased from 54.5 +/- 2.2 to 58.1 +/- 2.6% (p = 0.045). Time to 0.1 mV ST-segment depression increased significantly from 4.3 +/- 0.8 to 5.5 +/- 0.9 min in the 100-mg group (p = 0.013) and from 4.3 +/- 1.3 to 5.4 +/- 1.5 min in the 200-mg group (p = 0.027). Maximum ST-segment depression decreased significantly at all dose levels (p = 0.01), with the maximum decrease noted in the 200-mg group (from 0.21 +/- 0.03 to 0.15 +/- 0.02 mV, p = 0.004). BP, HR, and rate-pressure product did not change significantly at rest or at maximum exercise. A single dose of Ro 40-5967 has antiischemic properties in patients with stable angina pectoris, with maximum effects obtained after 200 mg. No signs of negative inotropy were noted, and the drug was well tolerated.     

Efficacy and Tolerability of Nisoldipine Coat-Core vs Diltiazem Retard in Combination with a Beta-Blocker in Patients with Stable Exertional Angina Pectoris

A randomised, double-blind, placebo-controlled, parallel-group trial with forced titration study to investigate possible equivalence of efficacy and tolerability between nisoldipine coat-core (CC) 40mg once daily, and diltiazem retard 120mg twice daily, was carried out in 176 patients with stable angina pectoris who were already receiving beta-blocker therapy. A total of 164 patients were included in the tolerability analysis and 135 patients were evaluable for efficacy (nisoldipine CC, n = 69; diltiazem retard, n = 66). During bicycle exercise tolerance tests, time to 1mm ST-segment depression, total exercise time, and time to angina were assessed at baseline and at the end of the treatment period. The number of angina attacks and of consumed nitroglycerin tablets were recorded in weekly diaries. Time to onset of 1mm ST-segment depression increased by 69.4 +/- 100.0 seconds with nisoldipine CC and by 65.9 +/- 87.6 seconds with diltiazem retard. The two treatment regimens were equally effective in time to onset of 1mm ST-segment depression, time to angina pectoris, and in exercise duration. A beneficial effect on angina attacks and nitroglycerin consumption was achieved with both treatments. Patient compliance, as assessed by the number of returned tablets, was high, at over 80%. Six patients withdrew from the treatment because of adverse events. Mild and transient adverse events were reported by 24 patients during treatment. One patient experienced a severe circulatory shock on the combination of diltiazem retard and atenolol. Peripheral oedema and headache were more common on nisoldipine CC. We concluded that the two treatments were equally efficacious and tolerated in patients with stable angina pectoris.     

Exercise tolerance in patients with angina pectoris after pentaerythritol trinitrate and alprenolol studied by two different methods

Summary Exercise tolerance has been studied by two different methods, heart-rate-controlled exercise and stepwise increased load, in 12 patients with angina pectoris. The response to a beta-adrenergic blocking agent, alprenolol, and an alkyl nitrate derivative, pentaerythritol trinitrate (PETRIN) was studied by the two methods after double-blind administration of the drugs. Rating scales were used to quantitate the degree of dyspnoea, angina pectoris and tiredness in the legs. After PETRIN both methods showed significant increases in exercise tolerance (19 and 21 per cent). The heart-rate-controlled test showed a significant increase (33%) after alprenolol, but the change was not significant by the other method. In the patients studied, heart-rate-controlled exercise discriminated between active drug and placebo better than the stepwise increased load test, what might have been due to more optimal matching of the loads obtained in the heart-rate-controlled test. Indications are given about how to design an exercise study in patients with angina pectoris.     

Assay of plasma isosorbide dinitrate and its metabolites after oral administration of immediate and delayed-action forms

This paper describes a kinetic comparative study of plasma concentrations of isosorbide dinitrate (ISDN) and its mononitrate derivatives (2-ISMN or 5-ISMN) after oral administration of a sustained release form of ISDN or a (non) sustained release form of 5-ISMN. The blood extracts determinations were performed by electron capture gas chromatography which is an accurate and sensitive method suitable for the quantitation of concentrations in the nanogram per ml range. The results are in good agreement with those of the literature. The standard form of 5-ISMN is rapidly absorbed. The Tmax value is approximately 1H with a corresponding Cmax value close to 400 ng/ml. For the sustained release drugs, the Tmax increases to 6H and Cmax is nearly half the 5-ISMN standard form value. Considering the administered dose, it seems better to use 5-ISMN than ISDN. For a long lasting treatment of angina pectoris and ischaemic cardiac diseases, both forms can be used.     

Comparison of the safety and efficacy of bisoprolol versus atenolol in stable exercise-induced angina pectoris: a Multicenter International Randomized Study of Angina Pectoris (MIRSA).

Bisoprolol 10 mg and atenolol 100 mg once daily were compared regarding efficacy and safety in stable effort angina in a 12-week, multicenter, double-blind, randomized, parallel-group study. Efficacy was evaluated with angina pectoris diaries and bicycle exercise tests. Spontaneously mentioned complaints and side effects were recorded at each visit. In 11 centers, 147 patients completed the study; 76 received bisoprolol 10 mg, and 71 received atenolol 100 mg. After 12 weeks, weekly anginal attack rate was reduced significantly (p less than 0.05) with bisoprolol (5 +/- 0.5 to 2 +/- 0.6) and with atenolol (4 +/- 0.4 to 1 +/- 0.2). Peak exercise capacity (in W x min) increased significantly (p less than 0.05) with bisoprolol (772 +/- 47 to 878 +/- 52) and with atenolol (891 +/- 46 to 986 +/- 53). Rate pressure product (RPP) at peak exercise (in beats/min x mm Hg) decreased significantly (p less than 0.05) with both bisoprolol (25,003 +/- 692 to 20,116 +/- 637) and atenolol (26,544 +/- 557 to 21,603 +/- 576) (all values are mean +/- SE). The differences between the groups were not statistically significant. There were no significant differences regarding nature and incidence of adverse events between the groups. Thus, bisoprolol 10 mg once daily and atenolol 100 mg once daily are equipotent in their effects on stable effort angina. Both regimens were comparable with respect to incidence and nature of side effects.     

Acute effects of nisoldipine, propranolol, and their combination in patients with chronic stable angina: a double-blind, randomized, cross-over, placebo-controlled study.

We studied the short-term effects of oral administration of nisoldipine (10 mg) and propranolol (80 mg) alone and in combination in 14 patients with chronic exertional angina pectoris in a double-blind, randomized, cross-over study. The 14 patients (13 men and 1 woman, mean age 56 +/- 7 years) performed symptoms-limited bicycle exercise stress test 3 h after placebo or active substance administration. Maximal work load, exercise duration, and time to 1-mm ST segment depression were significantly increased and ST depression at peak exercise was significantly decreased by drugs alone and in combination. Propranolol and nisoldipine alone improved exercise duration similarly and as well as the combination; however, a different response to the three pharmacologic interventions was found in patients treated with single drugs. The improvement in exercise tolerance was associated with rate-pressure product values at peak exercise, unchanged after nisoldipine and significantly reduced after both propranolol alone and in combination. After placebo, all patients had exercise-induced angina, in 9, 8, and 4 patients after nisoldipine, propranolol, and the combination of the two drugs, respectively. Nisoldipine is effective in the treatment of effort angina and its combination with propranolol may be useful and superior in patients who show poor response to monotherapy.     

Anti-anginal effect of fasudil,a Rho-kinase inhibitor,in patients with stable effort angina: a multicenter study

Rho-kinase plays an important role in calcium sensitization for vascular smooth muscle (VSMC) contraction and may be involved in the inappropriate coronary vasoconstriction during exercise-induced myocardial ischemia. In this multicenter phase II study, the anti-anginal effect of fasudil, which is metabolized to a specific Rho-kinase inhibitor hydroxyfasudil after oral administration, was examined in patients with stable effort angina. In the phase IIa trial, after a 2-week washout period of anti-anginal drugs, 45 patients received increasing doses of fasudil (5, 10, and 20 mg TID for every 2 weeks). The fasudil treatment significantly prolonged the maximum exercise time and the time to the onset of 1-mm ST segment depression on treadmill exercise test (both p < 0.01), whereas blood pressure and heart rate during exercise were unchanged before and after the treatment. Higher doses of fasudil (20 and 40 mg TID) were subsequently tested in 22 patients in the same manner with similar positive results. In the phase IIb trial, after a 2-week washout period of anti-anginal drugs, 125 patients were assigned, in a double-blind manner, to a 4-week oral treatment with a different dose of fasudil (5, 10, 20, or 40 mg TID) and treadmill exercise test was performed before and after the treatment. Again, both maximum exercise time and time to the onset of 1-mm ST segment depression were prolonged in all groups. A significant dose-response relation was noted across the treatment groups for the exercise tolerance index that was determined by the combined effect of exercise time and ST segment depression (p = 0.006). Fasudil was well tolerated in both trials without any serious adverse reactions. These results suggest the efficacy and adequate safety profile of fasudil, the first drug in a novel class of vasodilators, for the treatment of stable effort angina.     

Echo-dipyridamole stress test evaluation of isosorbide-5-mononitrate efficacy and tolerance in patients with coronary heart disease: interplay with sympathetic activity

In 22 patients with stable myocardial ischemia, we prospectively studied the short- and long-term effects of isosorbide-5-mononitrate (5-ISMN) on dipyridamole-induced myocardial ischemia, the ability of dipyridamole-stress echocardiography to evaluate nitrate tolerance, and the role of activation of the neurohumoral system in nitrate tolerance development, assessed by modifications of catecholamines plasma levels and heart rate variability. After brief treatment with 5-ISMN, dipyridamole-stress echocardiography was negative in 19 of 22 patients (p < 0.001 vs. placebo). During the sustained phase, dipyridamole-stress echocardiography was positive after both placebo and active drug (p = NS vs. placebo). Heart rate variability showed significantly higher values in power of the low frequency (LF) band and low- to high-frequency ratio (L/H), as well as significantly lower values of the power of the high-frequency (HF) band (all p < 0.001) during brief but not during sustained administration of 5-ISMN. Norepinephrine plasma levels were significantly higher (p < 0.001) during short-term 5-ISMN administration but not during the sustained phase. Our results indicate that short-term administration of 5-ISMN antagonizes dipyridamole-induced myocardial ischemia and show the loss of antiischemic efficacy in 95% of patients during sustained treatment, demonstrating that dipyridamole-stress echocardiography is a useful tool to assess the presence of nitrate tolerance. Spectral analysis of heart rate variability and norepinephrine values confirm that brief nitrate administration increases sympathetic activity, a possible crucial trigger event in the development of nitrate tolerance, whereas prolonged nitrate treatment is not associated with prolonged neurohumoral activation.