OPC‐13340, a New Potent and Long‐Acting Dihydropyridine Calcium Antagonist

Abstract

Key Words: OPC-13340-€alcium antagonist-Hypertension-EDRF-Cerebral blood flow.OPC-13340 is a new dihydropyridine calcium antagonist that is now under clinical trials as a long-acting antihypertensive and an antianginal agent. OPC-13340 was found to have the most potent and the longest hypotensive action among six compounds (OPC-13340, nifedipine, nitrendipine, nisoldipine, nicardipine, and diltiazem) tested in various hypertensive rat and dog models. Its hypotensive action is more specific for hypertensive than for normotensive animals. In normotensive conscious rats, OPC-13340 increased cerebral blood flow more than nicardipine or nimodipine. Also, in the aged spontaneously hypertensive rat (SHR) model, OPC-13340 did not decrease cerebral blood flow during severe hypotension. OPC-13340 has a unique action on endothelium-dependent relaxation in isolated rat aorta, namely it prolongs the duration of endothelium-dependent relaxation, while other calcium antagonists tested did not have such an effect at a clinically relevant concentration range. The following review summarizes preclinical and clinical experience with this compound to date. CHEMISTRY

Effects of pranidipine, a new calcium antagonist, on circulation in the choroid, retina and optic nerve head

“…The dose of pranidipine was determined according to experimental findings in the dog. 15,16 The duration of the drug or vehicle injection is 1 s and it began at t = 0 in Figure 1. The NB ONH and NB choroid were recorded immediately before and every 5 min for 90 min after the injection.…”

“…In dogs, pranidipine increased arterial blood flow in various vascular beds, including vertebral arteries; it has a longer duration of action than nicardipine or nifedipine. 16 2) Because the lipophilicity of pranidipine was the highest among the tested compounds (nisoldipine, nicardipine, nitrendipine, and nifedipine 17 ), this drug might have a higher access rate to vascular smooth muscle cells of the retina or ONH vessels through the blood-retinal or blood-neural barrier.…”

“…15,16 4) Pranidipine has a unique action on endothelium-dependent relaxation in isolated rat aorta, namely it prolongs the duration of endothelium-dependent relaxation, whereas other calcium antagonists (nifedipine, nitrendipine, nicardipine, diltiazem, and verapamil) do not have this effect at a clinically relevant concentration range. 16,18 To study the potential of pranidipine as a vasodilator in ocular tissues such as the retina, ONH, or choroid, the time course of changes in the circulation of these tissues was monitored after systemic administration of pranidipine in rabbits, using the noninvasive laser speckle method. [19][20][21] …”

Pranidipine, a novel calcium antagonist, once daily, for the treatment of hypertension: A multicenter, double-blind, placebo-controlled dose-finding study

“…The effect of once-daily administration of pranidipine on circadian rhythm has also been studied; the drug did not alter circadian rhythm, and the duration of the blood pressure-lowering effect was 24 hours. Numerous studies have been performed both in normotensive volunteers [1] and in patients with essential hypertension to assess its prolonged hypotensive effect, as evidenced by 24 hour invasive blood pressure monitoring [2]. The safety and tolerability of pranidipine have also been demonstrated [1].…”

“…Numerous studies have been performed both in normotensive volunteers [1] and in patients with essential hypertension to assess its prolonged hypotensive effect, as evidenced by 24 hour invasive blood pressure monitoring [2]. The safety and tolerability of pranidipine have also been demonstrated [1]. In order to gain additional insight into the hypotensive action of this calcium channel blocker, dose-range finding studies are required.…”