Introduction

This supplement to the Journal of Cardiovascular Pharmacology includes a series of reports summarizing results of the pivotal clinical studies on the basis of which lercanidipine has recently been introduced as antihypertensive treatment in many European countries. Lercanidipine is a new dihydropyridine calcium antagonist, which has been synthesized and developed by Recordati in Italy and has been investigated in 44 studies (12 pharmacokinetic and 32 clinical efficacy and tolerability studies) that included 2,196 subjects (87 healthy volunteers and 2,109 hypertensive patients, 1,575 of whom received lercanidipine in doses between 2.5 and 40 mg daily for periods of up to 12 months). There are similarities and differences not only among different subclasses of calcium antagonists (dihydropyridines, phenylalkylamines, and benzothiazepines) but also within the same subclass, e.g., that of dihydropyridines (1). First-generation dihydropyridines, such as nifedipine and nicardipine, are shor??-acting and their therapeutic use is limited by the need for multiple daily doses. For example, the initial report by Olivari et al. (2) describing the antihypertensive efficacy of nifedipine capsules showed that a reasonably continuous (although by no means smooth) antihypertensive effect required administration of 10 mg capsules at least four times daily. These multiple administrations constituted an annoying regimen that is known to reduce patients compliance and which often renders treatment less consistent and beneficial. Short-acting calcium antagonists also have another important limitation, of which clinical investigators and pharmaceutical companies were aware well before the recent debate on the safety of these agents was raised by Furberg et al. (3-5). The promptness and suddenness of the vasodilating and blood pressure-lowering effect is known to induce a number of disturbances as direct or reflex consequences of the sudden vasodilatation. Flushing, headache, and palpitations have frequently been described as causes of withdrawal from medication with short-acting dihydropyridines. Tachycardia, reflexively induced by a rapid decrease in blood pressure, is also an annoying side effect for many patients. It has been argued (3) that tachycardia and vasodilation in non-ischemic areas may represent a risk for hypertensive patients with simultaneous known or unknown cardiac ischemia, but the observational studies on which this hypothesis is based do not provide reliable evidence about the size or even the direction of the real treatment effects, due to possible confounding by indication and. probably, to publication bias (6-8). Nevertheless, it is obvious that any disturbances that might reduce patient compliance with treatment should be avoided when possible. Lercanidipine has been synthesized and developed with the aim of overcoming the limitations of first-generation calcium antagonists, while retaining the useful vasodilating and antihypertensive properties characteristic of the calcium antagonists and particularly of dihydropyridines. The lercanidipine molecule is highly lipophilic (with a partition coefficient of 6), is easily and almost totally absorbed by the intestine and, after having reached a maximal plasma concentration in 1.5 to 3 h (i.e. a time period at least twice as long as that of nifedipine), strongly binds to the lipid bilayer of cell membranes close to the calcium-channel receptor, from which it is slowly released over subsequent hours. This mechanism explains both the long duration of the pharmacologic and therapeutic actions of lercanidipine and the slow onset of these actions, with consequent absence or scarcity of the reflex disturbances typical of short-acting dihydropyridines (9). Ambulatory blood pressure monitoring demonstrates that lercanidipine given once daily at the usually recommended dose of 10 mg has a rather uniform blood pressure-lowering effect throughout the 24-h period, with a peak effect at 5 to 7 h and a trough-to-peak ratio above 80%. Particular care has been taken to assess the action of lercanidipine on heart rate. This has been done by clinical measurements in all patients included in clinical studies, the measurements being frequently performed not only after a few weeks of drug administration but also after the first dose, when reflex tachycardia is most likely to occur with shortacting dihydropyridines. Further accurate assessments have been performed in patients subjected to ambulatory blood pressure monitoring who also had automatic heart rate recording at each time blood pressure was taken throughout the day and night, and finally in a study (10) that used electrocardiographic Holter monitoring, thus providing beat-to-beat evaluation. Tachycardia was not usually observed in hypertensive patients receiving the dose of 10 mg once daily, and only occurred, although rarely and moderately, in patients who were given the larger dose of 20 mg, especially when this was used as the initial dose. Electrocardiograms recorded in 1,440 patients show that lercanidipine lacks any pro-ischemic effect. Electrocardiographic signs of possible myocardial ischemia appeared during treatment in 1.9% of patients treated with lercanidipine and disappeared in 4.0% of them. For comparison, in 2.1% of patients electrocardiographic signs of ischemia appeared during placebo treatment and disappeared in 1.4% of placebo-treated patients (11). Clinical studies with lercanidipine have explored a wide range of doses from 2.5 to 40 mg once daily, and most studies indicate that the 10-mg dose is not only significantly more effective than placebo in lowering blood pressure but is consistently as effective as other antihypertensive agents, such as β-blockers, diuretics (12), angiotensin-converting enzyme inhibitors, and other calcium antagonists (e.g., long-acting formulations of nifedipine and amlodipine) (13). The 10-mg dose has been remarkably well tolerated. The principal adverse events are those known to occur with dihydropyridine calcium antagonists, i.e., headache, flushing, dizziness, and palpitations. Particularly low has been the incidence of ankle edema, an adverse effect common with most dihydropyridines. In trials vs. placebo the 10-mg dose had an incidence rate of adverse effects superimposable to that of placebo. The 20-mg dose, when given after a few weeks of treatment with the 10-mg dose, also had a low adverse effect rate, although a more consistent incidence of flushing, edema, and palpitations was observed when 20 mg was administered as the initial dose. Lercanidipine 10 mg once daily was also found effective and was well-tolerated in elderly hypertensive patients. The advent of dihydropirydine compounds such as lercanidipine which, because of their lipophilicity, have a slow onset and long duration of action, represents real progress in antihypertensive therapy, by improving the benefits/risks ratio and by increasing patient compliance. The potential applications of the high lipophilicity and the powerful antioxidant properties of lercanidipine for prevention and treatment of atherosclerosis are a fascinating perspective to be explored by further basic and clinical investigation.