Waller D G
Southampton General Hospital, United Kingdom.
J Cardiovasc Pharmacol. 1999 Aug;34 Suppl 2:S21-7; discussion S29-31. doi: 10.1097/00005344-199908002-00005.
During long-term prophylaxis of angina with oral nitrates, sustained high plasma nitrate concentrations produce partial or complete tolerance to both the haemodynamic and the clinical effects of the drug. There is substantial evidence that this can be prevented by an adequate nitrate-free or nitrate-low period during each 24 h dosing interval. However, a nitrate-free interval carries the risk of a rebound increase in myocardial ischaemia. Once-daily formulations of isosorbide mononitrate deliver high plasma nitrate concentrations that improve exercise tolerance in patients with angina for at least 12 h after dosing. During the remainder of the dosage interval, plasma nitrate concentrations fall but are sufficient to protect against coronary artery spasm overnight. Myocardial ischaemia has a marked circadian rhythm. All ischaemic events (total ischaemic burden, myocardial infarction and sudden cardiac death) are most frequent in the hours immediately after waking. Oral anti-ischaemic prophylaxis should ideally provide protection during this critical period, in order to minimize symptoms, maximize exercise capacity and perhaps also to reduce the risk of clinical events. The ideal long-acting nitrate formulation should therefore provide a rapid rise in plasma nitrate concentration as well as maintaining prolonged efficacy throughout the dosing interval. Elantan LA is a sustained-release capsule formulation of isosorbide mononitrate for once-daily dosing. This capsule contains pellets which release 30% of the dose immediately, while 70% is released slowly to maintain the therapeutic response. The pharmacokinetic profile of this formulation prevents the development of tolerance, while also conferring long-term anti-anginal efficacy. Patients reported an improvement in both severity of angina and quality of life indices when their therapy was changed from multiple daily dosing with isosorbide dinitrate to once-daily dosing with Elantan LA (50 mg). The anti-anginal effect of Elantan LA is attained rapidly after dosing. Within 30 min of ingestion, there are clinically significant improvements in exercise tolerance, comparable with the speed of onset after an immediate-release formulation of isosorbide mononitrate. Elantan LA is an effective once-daily prophylaxis for angina which also produces a rapid onset of therapeutic effect. The release profile of this formulation maximizes protection against the morning surge in myocardial ischaemia.
在使用口服硝酸盐类药物长期预防心绞痛期间，持续的高血浆硝酸盐浓度会导致机体对药物的血流动力学效应和临床效应产生部分或完全耐受性。有大量证据表明，通过在每24小时给药间隔内设置足够的无硝酸盐或低硝酸盐期，可以预防这种情况。然而，无硝酸盐间期存在心肌缺血反跳性增加的风险。单硝酸异山梨酯的每日一次剂型可使血浆硝酸盐浓度升高，从而在给药后至少12小时内提高心绞痛患者的运动耐量。在其余的给药间隔期内，血浆硝酸盐浓度会下降，但足以防止夜间冠状动脉痉挛。心肌缺血具有明显的昼夜节律。所有缺血事件（总缺血负荷、心肌梗死和心源性猝死）在醒来后的数小时内最为频繁。理想情况下，口服抗缺血预防性治疗应在这一关键时期提供保护，以减轻症状、最大化运动能力，并可能降低临床事件的风险。因此，理想的长效硝酸盐制剂应能使血浆硝酸盐浓度迅速升高，并在整个给药间隔期内维持长效疗效。依兰特LA是一种单硝酸异山梨酯的缓释胶囊制剂，每日给药一次。该胶囊含有小丸，可立即释放30%的剂量，而70%则缓慢释放以维持治疗反应。这种制剂的药代动力学特征可防止耐受性的产生，同时还具有长期抗心绞痛疗效。当患者的治疗从每日多次服用二硝酸异山梨酯改为每日一次服用依兰特LA（50毫克）时，患者报告心绞痛严重程度和生活质量指标均有所改善。依兰特LA给药后抗心绞痛作用迅速起效。摄入后30分钟内，运动耐量有临床上的显著改善，与单硝酸异山梨酯速释制剂后的起效速度相当。依兰特LA是一种有效的每日一次心绞痛预防性药物，其治疗效果起效迅速。这种制剂的释放特性可最大程度地预防早晨心肌缺血的激增。
