Pittrow D B, Antlsperger A, Welzel D, Wambach G, Schardt W, Weidinger G
Department of Clinical Research, Novartis Pharma AG, Nürnberg, Germany.
Cardiovasc Drugs Ther. 1997 Nov;11(5):619-27. doi: 10.1023/a:1007774505445.
To investigate the concept of initiating therapy with low doses of a calcium antagonist and an ACE inhibitor, a fixed combination of isradipine 2.5 mg plus the ACE inhibitor spirapril 3 mg was compared with its components, with the full-dose monotherapies (isradipine 5 mg or spirapril 6 mg), and with placebo. After a 2-week wash out phase in pretreated patients and a subsequent 2-week placebo period, 405 patients with a diastolic blood pressure (DBP) between 100 and 114 mmHg were randomly allocated to 12-week once-daily double-blind treatment in one of the six treatment arms. In patients whose blood pressure was not normalized (defined as DBP< or =90 mmHg) after 6 weeks of treatment, the dosage of either medication was doubled or, in the placebo group, was switched to the fixed combination. After week 6, the mean reductions from baseline in sitting systolic/diastolic blood pressure 24 hours after dosing (trough) for the fixed combination or the monotherapies isradipine 5 mg, isradipine 2.5 mg, spirapril 6 mg, spirapril 3 mg, and placebo were 10.4/8.7, 10.0/9.4, 6.5/6.7, 10.0/8.3, 7.0/5.8, and 2.2/4.7 mmHg, respectively. The blood pressure changes obtained with the low-dose fixed combination were essentially identical to those observed with the full-dose monotherapies, thus showing an additive effect of low-dose isradipine and spirapril. In terms of tolerability, the lowest rate of any adverse events was found in the combination group. In this group, typical adverse events of calcium antagonists, such as headache, flushing, ankle edema, or palpitations, were observed only in 5%, 2%, 1%, and 0%, respectively, dry cough, considered typical for ACE inhibitors, was observed in only 1% of the combination group. In conclusion, the low-dose components isradipine 2.5 mg and spirapril 3 mg were shown to have an additive effect when combined, exerting a blood pressure-lowering effect comparable with the full doses and a trend to a better tolerability profile in comparison with the standard doses. Thus, low-dose combination therapy with these drugs appears to be a rational alternative to conventional monotherapy in the first-line treatment of hypertension.
为了研究低剂量钙拮抗剂和血管紧张素转换酶（ACE）抑制剂起始治疗的概念，将2.5毫克伊拉地平与3毫克ACE抑制剂螺普利的固定组合与其各成分、全剂量单药治疗（5毫克伊拉地平或6毫克螺普利）以及安慰剂进行比较。在对预处理患者进行2周的洗脱期及随后2周的安慰剂期后，将405例舒张压（DBP）在100至114毫米汞柱之间的患者随机分配至六个治疗组之一，进行为期12周的每日一次双盲治疗。在治疗6周后血压未恢复正常（定义为DBP≤90毫米汞柱）的患者中，两种药物之一的剂量加倍，或者在安慰剂组中改为固定组合治疗。在第6周后，固定组合或单药治疗的5毫克伊拉地平、2.5毫克伊拉地平、6毫克螺普利、3毫克螺普利及安慰剂在给药后24小时（谷值）时坐位收缩压/舒张压较基线的平均降低值分别为10.4/8.7、10.0/9.4、6.5/6.7、10.0/8.3、7.0/5.8及2.2/4.7毫米汞柱。低剂量固定组合获得的血压变化与全剂量单药治疗观察到的变化基本相同，从而显示出低剂量伊拉地平和螺普利的相加作用。在耐受性方面，联合治疗组中任何不良事件的发生率最低。在该组中，钙拮抗剂的典型不良事件，如头痛、潮红、踝部水肿或心悸，分别仅在5%、2%、1%和0%的患者中观察到，被认为是ACE抑制剂典型不良反应的干咳，在联合治疗组中仅在1%的患者中观察到。总之，2.5毫克伊拉地平和3毫克螺普利的低剂量成分联合使用时显示出相加作用，降压效果与全剂量相当，且与标准剂量相比有耐受性更好的趋势。因此，在高血压一线治疗中，这些药物的低剂量联合治疗似乎是传统单药治疗的合理替代方案。
