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A 67-year-old man presented to the emergency department, reporting a first episode of light-headedness and palpitations upon standing up that morning. The patient had a history of hypertension, treated with carvedilol and lacidipine. He …

Molecular models of molecules of medical interest are discussed. The molecules added to the JCE Featured Molecules library this month include: 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine, Valium, Xanax, diludine, lacidipine, nifedipine, HMR 1794, hydantoin, phenytoin, spiro-thiohydantoin, 6-amino-penicillanic acid, a model penicillin, and penicillin G

The venom of the honeybee Apis mellifera induces cardiovascular dysfunction. As its effects on coronary arteries have not yet been described, we studied the effects of the whole honeybee venom (non-volatile part) in the isolated porcine left anterior descending coronary artery (LAD) and the influence of L-type Ca2+ channel blocker, lacidipine, upon the venom effects in LAD. The venom produced concentration dependent contractions (7-70 microg/ml) of the porcine LAD; maximal effect of the venom was approximately the same as the effect of 30 mM KCl. Lacidipine concentration dependently (0.1-10 microM) and significantly (Por = 0.05) decreased the venom-induced vasoconstriction. The results indicate the involvement of L-type Ca2+ channels in coronary contraction, induced by bee venom.

The main objective of this study was to evaluate well being and physical activity of two hundred and forty eight hypertensive patients, of which, one hundred and seventy seven were female, who had previously finished the Latin Amerícan Study on Lacidipine in Hypertension (LASTLHY). This was an open study carried out in twelve clinical centers situated in Argentina, Brazil, Colombia, Mexico and Venezuela, to compare, over a period of sixteen weeks, the antihypertensive actions of fixed-dose once daily oral monopharmacotherapy of 4 rng of lacidipine (n = 120) patients VS. 30 mg of nifedipine (n = 128) patients aged between 40-65 years old, with mild to moderate hypertension beginning at the end of a four weeks placebo run-in (end of week -1). Well being and physical activity were assessed through an experimental single questionnaire, which was administered taking into consíderation the physical and cultural diversities amongst the clinical centers and patients. The questionnaire included thirteen multiple-choice and eight contingent open questions. The score to each question was multiplied by a coefficient according to the importance of each question for each patient (semipersonal ization); the coefficient was evaluated from cultural and socioeconomic information collected at the time of enrollment. The semipersonalization was carried out by a blind psychological study with respect to the medication and had a high repeatability in the assignment of personalized coefficients to the score of each question. The scores of each question were added to obtain an overall weil being and activity scoring. The possible theoretical range for the overall scoring in this study was 10- 124.

With the aim of evaluating the effects on blood pressure, platelet function and insulin sensitivity of the dihydropiridines lacidipine and nifedipine GITS, a parallel double-blind study was carried out in a group of 20 patients with mild to moderate essential hypertension. They received a placebo for 4 weeks; then were divided at random into two groups of 10 patients each. Nifedipine GITS, 30 mg and lacidipine, 4 mg, were given during 16 weeks of active treatment. Blood pressure and heart rate were measured at the clinic in supine, sitting and standing positions, 24 +/- 1 h after the last dose. After the placebo and active phases were carried out, a platelet aggregation test was performed to determine platelet malondialdehyde production and a tolerance to 100 g of glucose by measuring glucaemia and plasma insulin. Both drugs reduced systolic and diastolic blood pressure at the same level, however there were observable differences in the rate of reduction. The nifedipine GITS reduced supine systolic blood pressure by 25 mm Hg in the first week, while the lacidipine did so by 11 mm Hg. At the end of the study period nifedipine reduced supine systolic blood pressure by 28 mm Hg and lacidipine by 20 mm Hg. Heart rate was increased slightly but significantly in the nifedipine GITS group only in the standing position. Both drugs reduced platelet aggregation ex vivo only marginally but they modified the malondialdehyde production, indicating an action on the arachidonic acid metabolic pathway.

Objective Lacidipine has already been demonstrated to reduce the expression of some adhesion molecules induced by pro-oxidant signals on endothelial cells. In order to verify if this effect is a peculiarity of this molecule, or belongs to other dihydropyridinic compounds (DHPs), the activity of lacidipine was compared with that of lercanidipine, amlodipine, nimodipine and nifedipine. Design and methods The compounds were incorporated in human umbilical vein endothelial cells (HUVECs) using native low-density lipoprotein as a carrier. The drug concentrations in HUVECs were measured by mass spectrometry. Human recombinant tumour necrosis factors was then incubated with HUVECs for 7 h at 37°C for adhesion molecule expression. Results The cellular amount of lacidipine, lercanidipine and amlodipine was similar, while nimodipine and nifedipine were almost undetectable or undetectable, respectively. Lacidipine, at any concentration, determined a dose-dependent significant decrease of the expression of intercellular adhesion molecule-1 (ICAM-1) ICAM-1, vascular cell adhesion molecule-1 (VCAM-1) VCAM-1 and E-selectin (P< 0.01). Lercanidipine and amlodipine determined variable decreases of adhesion molecules at the intermediate and highest concentrations. Nimodipine and nifedipine determined no effect on ICAM-1, VCAM-1 and E-selectin. The lowest IC 50 , i.e. the concentration determining the 50% reduction of ICAM-1, VCAM-1 and E-selectin expression was obtained with lacidipine for all the adhesion molecules considered (P < 0.01). Conclusions It is concluded that the effect of the DHPs used in this study on adhesion molecule expression is determined first by their lipophilicity and then by their intrinsic antioxidant activity.

Background and objective The European Lacidipine Study of Atherosclerosis (ELSA) is a prospective, randomized, double-blind, multi-national interventional trial to determine the effect of four-year treatment using the calcium antagonist lacidipine versus the beta-blocker atenolol on the progression of carotid atherosclerosis in 2259 asymptomatic hypertensive patients. B-mode ultrasound is used to measure the primary and secondary endpoints including the mean maximum intima-media thickness (IMT) of the carotid bifurcations and the common carotid arteries (CBM(max)), the mean maximum IMT of 12 standard carotid sites (M(max)) and the overall maximum IMT (T(max)). This paper reports the cross-sectional reproducibility of ultrasound measurements at baseline. Method To evaluate measurement reliability, each patient is scanned twice at baseline and again at four annual visits, with 80% of the replicate scans performed by the same sonographer and 20% by a different sonographer; 50% of the replicate scans are read by the same reader and the other 50% by different readers. Results The overall coefficient of reliability (R) was 0.859 for CBM(max), 0.872 for M(max) and 0.794 for T(max). The reliability for CBM(max) was stable during the 1 3/4-year baseline period (R = 0.848 to 0.953) and was uniform among the 23 field centres (R = 0.798 to 0.926). Intra- and inter-reader reliability were 0.915 and 0.872 respectively, and intra-sonographer reliability was 0.866. Conclusion The results demonstrate that by implementing standardized protocols and strict quality control procedures, highly reliable ultrasonic measurements of carotid artery IMT can be achieved in large multi-national trials.

Focal cerebral hypoperfusion is a common finding in uncomplicated hypertensives even in the absence of large vessel atherosclerosis, and neuropsychological deficits correlate with cerebral hypoperfusion in hypertensive patients with cerebral microangiopathy. We investigated the effects on cerebral perfusion of the dihydropiridine calcium antagonist lacidipine and of hydrochlorothiazide (HCTZ) in asymptomatic hypertensive patients with concomitant atherosclerosis of the carotid arteries. Fifteen essential hypertensives (including 13 males, aged 55-75 years) with at least one 30-60% stenosis of the internal carotid artery at echo-color Doppler examination were treated in a double-blind, randomized, parallel study with lacidipine (4-6 mg od) or HCTZ (25-50 mg od) for 3 months after a 4-week single-blind placebo period. Regional cerebral perfusion was assessed at baseline and at the end of the treatment period with HMPAO-SPECT. Relative perfusion of cortical and subcortical areas was calculated as the ratio between their tracer activity and that of the cerebellum. At baseline, mean relative perfusion (MRP) of the cortical and subcortical areas was similar in the stenotic and the contralateral side. Despite the fall in pressure, lacidipine increased MRP both in the cortical and in the subcortical areas, whereas HCTZ increased MRP only in the cortical areas. The mean change in local vascular resistance, adjusted for initial perfusion value, was -20 A.U. (arbitrary unit) with lacidipine and -12 A.U. with HCTZ (p < 0.001). These differential effects of antihypertensive drugs on subcortical perfusion may be of benefit in the long-term prevention of vascular dementia in hypertensive patients.

Abstract —Carvedilol and lacidipine have been shown to exert cardioprotective effects in rat models of chronic hypertension. We investigated their effects in an acute model of pressure overload produced by suprarenal aortic constriction, in which enhanced myocardial production of endothelin-1 could play a crucial role. In the absence of drug treatment, after 1 week, aortic banding provoked an increase in carotid pressure associated with left ventricular hypertrophy (29%; P P P −1 · d −1 to rats with aortic banding normalized carotid pressure and left ventricular weight as well as preproendothelin-1 and skeletal α-actin gene expression. Carvedilol at a lower dose (7.5 mg · kg −1 · d −1 ) and lacidipine 1 mg · kg −1 · d −1 had only moderate and nonsignificant effects on carotid pressure but largely prevented left ventricular hypertrophy ( P P −1 · d −1 ) tended to exert similar effects but insignificantly. These results show that the antihypertrophic properties of carvedilol and lacidipine are partly independent of their antihypertensive effects and may be related to their ability to blunt myocardial preproendothelin-1 overexpression. Moreover, carvedilol at a dose of 7.5 mg · kg −1 · d −1 did not prevent myocardial overexpression of skeletal α-actin, which suggests that, in this model, reexpression of a fetal gene can be activated by pressure overload independently of cardiac hypertrophy.

The calcium antagonist lacidipine has been shown to be highly vasoselective and to improve myocardial perfusion in hypertensive patients. However, its effects on coronary artery vasomotility and on post-stenotic coronary flow reserve in patients with atherosclerotic heart disease are unknown.This study was designed to investigate the acute direct effects of repeated infusions of lacidipine on epicardial coronary artery vasomotion and on post-stenotic coronary artery blood flow in patients with stable angina pectoris and angiographic evidence of coronary heart disease.In 8 patients with stable angina and moderate to severe stenosis of the left coronary artery, measurements of epicardial dimensions (quantitative angiography) and of coronary blood flow (Doppler guidewire) distal to a stenosis were performed at baseline and after 3 repeated intracoronary boluses of 12 microg of lacidipine. Results were compared with those obtained after 10 mg of intracoronary papaverine.The intracoronary administration of lacidipine was well tolerated, without any adverse effects. Lacidipine significantly increased the minimal luminal diameter of the lesion (peak relative increase of 43.7%), without significant changes in heart rate and systolic aortic pressure. Intracoronary lacidipine caused a dose-dependent increase in coronary flow reserve. Maximal vasodilatory effects were equivalent to those obtained with intracoronary papaverine.These results suggest that lacidipine acts directly as a potent vasodilator in stenotic epicardial vessels and improves myocardial perfusion distal to a moderately severe stenosis in patients with stable angina.

Calcium antagonists are uniquely suitable for managing hypertension by virtue of their efficacy, metabolic neutrality and their ability to countervail counter-regulatory adaptive changes, thereby enhancing blood pressure lowering. Recent evidence has accrued underscoring the concept that calcium antagonists are heterogeneous and consist of chemically dissimilar agents. The difference in formulations and pharmacokinetics affect clinical events including the effect on blood pressure, heart rate and the degree with which sympathetic activity is activated. Lacidipine is a new calcium antagonist that is the prototype of the lipophilic dihydropyridines. Of great importance, lacidipine has a slow onset of vasodilator/ antihypertensive effect and does not promote an excessive sympathetic drive. These attributes commend its selection as an antihypertensive agent.

The aim of this study was to investigate the therapeutic effectiveness of lacidipine in stroke-prone spontaneously hypertensive rat (SHRSP) with cerebrovascular lesions in comparison with nicardipine. SHRSP were fed 1% saline as drinking water. After the onset of stroke, saline was replaced with water and each drug was administered orally once a day for 3 weeks. In the drug-untreated group, recurrence of stroke was repeated, deterioration and amelioration of neurological deficits (ND) were repeated, and histological examination and measurement of regional blood flow (rBF) using nonradioactive colored microspheres performed at the end of treatment revealed severe damages and significantly decreased rBF in brain and kidney, respectively. In kidney, not only lacidipine (1 mg/kg) but also nicardipine (30 mg/kg) decreased vascular lesions and ameliorated low-rBF significantly. Both drugs also inhibited the recurrence of stroke completely even at a low dose that did not ameliorate severe hypertension. Neuronal damages and ND in each lacidipine-treated group were ameliorated significantly, whereas those in each nicardipine-treated group were slightly improved. Lacidipine at 1 mg/kg alone ameliorated the cerebral low-rBF significantly even at 24 hr after administration. These results suggest that a long-lasting improvement of low-rBF after stroke may be useful in the treatment of SHRSP with cerebrovascular lesions.

The aim of this study was to characterize the in-vitro vasoselectivity of lercanidipine (in comparison with lacidipine, amlodipine, nitrendipine and felodipine) by evaluating its functional calcium antagonistic activity on rabbit vascular (aorta) and cardiac tissues (heart ventricle). Although incubation with all the compounds tested elicited a concentration-dependent relaxant effect on vascular tissue precontracted with KCl (80 mM), 50% relaxation was reached at different times for each concentration and drug tested. At 10 nM concentration 50% relaxation was reached after 210 min with lercanidipine, 278 min with amlodipine, 135 min with lacidipine, 75 min with nitrendipine and 70 min with felodipine. The onset of the effect was, therefore, similar for lercanidipine, amlodipine and lacidipine, but faster for nitrendipine and felodipine. Similarly, all the compounds tested concentration-dependently reduced the force of cardiac contraction (negative inotropic activity). In this model, the time needed to reach 50% reduction in contractile force was also concentration-dependent, and the ranking order of the speed of onset of the effect (evaluated as the ratio of the IC50 values (the concentrations inhibiting contraction by 50%) calculated after 1 and 4h incubation) was lacidipine (3.8) > amlodipine (9.6) > felodipine (39) > lercanidipine (68) = nitrendipine (89). The vasoselectivity, expressed as the ratio of the IC50 values obtained on cardiac and vascular tissue, were (for 4 h incubation) 730, 193, 95, 6 and 3 for lercanidipine, lacidipine, amlodipine, felodipine and nitrendipine, respectively, showing that lercanidipine is the most vasoselective of the calcium-antagonists tested. The results show that lercanidipine reduces the inotropic force of the rabbit heart to a lesser extent than do other calcium antagonists, and that this drug had the best heart/vessel selectivity index among the compounds tested at all the times tested.

The effect of lacidipine (LA), a new calcium channel blocker with an antioxidant effect, has been studied on cyclosporine (CsA)-induced nephrotoxicity in male Wistar rats. Lacidipine (1 mg/kg BW) was administered orally 3 days before and 14 days concurrently with CsA (50 mg/kg BW orally). Urine volume, Na+, K+, Li+ and creatinine in urine, and blood urea, serum creatinine, lithium, plasma malondialdehyde (MDA) and CsA levels were estimated in blood after 14 days CsA treatment. Kidneys were examined using histological techniques. Blood urea and serum creatinine were increased by 305 and 211%, respectively, with CsA when compared to the saline-treated animals. Creatinine clearance (Ccr) and lithium clearance (Licr) were decreased and proximal tubule fractional reabsorption 1-(Licr/Ccr) was significantly increased with CsA. Lacidipine protected rats from CsA-induced nephrotoxicity. Changes in blood urea, serum creatinine, Ccr, Licr and proximal tubule fractional reabsorption induced by CsA were significantly prevented by LA. There was a 160% rise in MDA levels with CsA, which was significantly reduced equal to control with LA. Histomorphology showed microcalcification with CsA, while it was normal with LA. In rats treated with LA, CsA did not show any microcalcification. Our data suggest that supplementation of LA may be helpful to reduce CsA nephrotoxicity.

Atherosclerosis results from multiple factors and involves several mechanisms, including endothelial monocyte and smooth muscle cell (SMC) changes, cholesterol accumulation, plaque rupture and thromboembolism. Calcium ions play a role in the initial and chronic development of atherosclerotic lesions. Several studies in experimental animal models have demonstrated the potential direct antiatherosclerotic effects of calcium antagonists. In this study the antiatherogenic activity of lercanidipine, a new lipophilic, second-generation calcium antagonist, was investigated. Lercanidipine and its enantiomers inhibited the replication and migration of arterial myocytes in concentrations ranging from 10 to 50 microM. The antiproliferative effect of lercanidipine was dose dependent, with a potency similar to that of lacidipine and nifedipine, and was unrelated to the stereoselectivity of enantiomers to bind L-type calcium channels. Lercanidipine and its enantiomers (25 microM) decreased the serum-induced elevation of [Ca2+]i in SMC, with the (S)-enantiomer (69% inhibition) being 2.4-fold more active than the (R)-counterpart (29% inhibition). The studies performed with enantiomers of lercanidipine suggest that the observed effects are not related to the blockade of voltage-dependent Ca2+ channels and confirm, at least in vitro, the pharmacological potential of the compound to influence negatively the process of atherogenesis.

OBJECTIVE: To analyze the effect of the long-acting calcium channel blocker lacidipine on cardiovascular remodeling induced by salt loading in a genetic model of hypertension. DESIGN: We examined the influence of threshold doses of lacidipine, with little blood-pressure lowering effect, on cardiac weight and gene expression in stroke-prone spontaneously hypertensive rats (SHRSP). METHODS: SHRSPs (8-week-old) were randomly allocated to four groups: control, salt-loaded SHRSP and salt-loaded SHRSP treated with lacidipine at 0.3 and 1 mg/kg per day. Systolic blood pressure was measured by the tail-cuff method. At the end of 6 weeks of treatment, ventricles were collected and weighed. Ventricular messenger RNA was extracted and subjected to Northern blot analysis. RESULTS: Lacidipine (0.3 mg/kg per day) not only prevented the salt-dependent cardiac hypertrophy and the slight increase in systolic blood pressure induced by salt, but also prevented, largely or completely, salt-dependent increases in ventricular levels of several gene products: skeletal and cardiac alpha-actin, beta-myosin heavy chain (beta-MHC), type I collagen, long-lasting (L)-type calcium channel and preproendothelin-1. At a higher dose of 1 mg/kg per day, lacidipine further decreased systolic blood pressure below the level of control SHRSP, completely prevented salt-dependent overexpression of the beta-MHC gene and markedly attenuated salt-dependent overexpression of the transforming growth factor-beta1 gene. CONCLUSIONS: Lacidipine prevents the cardiac remodeling and enhanced gene expression induced by salt loading in SHRSP at doses that only minimally affect the high systolic blood pressure.

Aims To assess the duration and consistency of the pharmacological activity of the dihydropyridine calcium antagonist drug, lacidipine. Methods Eight healthy normotensive young males participated in a double-blind randomised crossover comparison of single and multiple doses (for 2 weeks) of lacidipine and placebo. The calcium antagonist effects were quantified at 2, 6 and 24 h post dose by the extent of the attenuation of the pressor responses to the intravenous administration of the vasoconstrictors angiotensin II and noradrenaline. Results After 2 weeks of treatment, lacidipine consistently and significantly attenuated the pressor responses to both agents at 2 h post dose. At 6 and 24 h post dose there was a significant and progressive decline in the effectiveness of lacidipine in attenuating the pressor responses and for the response to angiotensin II there was no statistically significant effect at either 6 or 24 h post dose. Conclusions These results indicate that there is an obvious ‘peak’ in the pharmacological activity of lacidipine at about 2 h post dose and that this activity is not fully and consistently maintained throughout 24 h.

Objectives To investigate the relative roles of angiotensin II, bradykinin, and calcium-dependent pathways in the genesis of mesenteric vascular hypertrophy in experimental diabetes. Design Streptozotocin-induced diabetic Sprague–Dawley rats were randomly allocated to these treatments for 24 weeks: no treatment; ramipril at a hypotensive dose; ramipril plus the bradykinin type 2 receptor blocker icatibant; icatibant alone; ramipril at a low dose; the angiotensin II type 1 receptor antagonist, valsartan; the dihydropyridine calcium antagonist, lacidipine; and the nondihydropyridine calcium antagonist mibefradil. Methods Systolic blood pressure was serially measured every 4 weeks by tail-cuff plethysmography. We assessed the vascular architecture in sections of mesenteric arteries obtained after in-vivo perfusion, which were stained with an antibody to a-smooth muscle actin. Results Both blood pressure and the mesenteric arterial wall: lumen ratio were reduced by administration of ramipril, at the high dose, either alone or in combination with icatibant, and also by valsartan. Treatment either with the low dose of ramipril or with the calcium antagonists lacidipine and mibefradil was associated with a decrease in the wall: lumen ratio of the mesenteric arteries without influencing blood pressure. Conclusions These findings demonstrate that blockade both of angiotensin II-dependent and of calcium-dependent pathways attenuates mesenteric vascular hypertrophy in experimental diabetes. Furthermore, the antitrophic effects of these antihypertensive agents may be independent of their hypotensive effects.

Interaction of the calcium-channel antagonist dihydropyridines (DHPs), lacidipine and nifedipine, with a phospholipid bilayer was studied using 600 ps molecular dynamic simulations. We have constructed a double layer membrane model composed of 42 dimirystoyl-phosphatidylcholine molecules. The DHP molecules locate at about 7 A from the centre of the membrane, inducing an asymmetry in the bilayer. While lacidipine did not induce significant local perturbations as judged by the gauche-trans isomerisation rate, nifedipine significantly decreased this rate, probably by producing a local rigidity of the membrane in the vicinity of the DHP.

We investigated the effects of lacidipine on focal cerebral ischemia in rats, and these effects were compared with those of nicardipine. Drugs were administered orally 5 min after middle cerebral artery occlusion (MCAO). Neurological scores as described by Bederson et al. (Stroke 17, 472-476, 1986) and cerebral infarct size (CIS) determined by the 2,3,5-triphenyltetrazolium chloride staining method were measured 24 hr after MCAO. Cerebral blood flow (CBF) and energy metabolites were determined by the hydrogen clearance method and an enzymatic method, respectively. In the drug-untreated group, we observed low-CBF of approximate 13 ml/100 g/min during 0.5-6 hr of occlusion and extensive cerebral infarction associated with severe neurologic deficits (ND). Lacidipine at 1 and 3 mg/kg, although it lowered blood pressure, improved low-CBF to approximate 20 ml/100 g/min during 1.5-6 hr of occlusion and increased tissue levels of ATP 6 hr after MCAO in a dose-dependent manner. Nicardipine at 30 mg/kg also improved low-CBF and increased tissue levels of ATP significantly. However, the improvement of low-CBF by nicardipine was transient. Lacidipine at 3 mg/kg reduced CIS and ameliorated ND significantly. In contrast, nicardipine at 30 mg/kg could not ameliorate ND in spite of a significant reduction of CIS similar to that of lacidipine (3 mg/kg). These results suggest that the improvement of focal cerebral ischemia by lacidipine may be partly due to long-lasting improvement of collateral blood supply to the ischemic area.

1. Isradipine and lacidipine, two new drugs that are members of the nitro-aryl-1,4-dihydropyridine family, produced inhibition of both growth cultures and oxygen consumption on epimastigotes of Trypanosoma cruzi Tulahuen strain, at micromolar concentrations. 2. Isradipine was found to be the most potent derivative in both, in growth cultures (I50 = 20.8 microM) and in vivo oxygen uptake (I50 = 31.1 microM). 3. Diltiazem and verapamil, two well-known calcium channel antagonists, lacked inhibitory activity, even at a 100 microM concentration. 4. The present findings indicate that the trypanocide effects exerted by isradipine and lacidipine are not related with a disruption of the calcium homeostasis of the parasite.

It is rather the rate of the vasodilator effect than its magnitude which determines the triggering of reflex tachycardia associated with dihydropyridine calcium antagonists (DHP-CA). We therefore compared the rate of the vasodilator effects of a series of CA (both DHP and non-DHP) in rat isolated mesenteric artery preparations (size 256 +/- 3 microns, length 2 mm) from male Wistar rats (weighing 300-350 g) in an isolated wire myograph according to Mulvany and Halpern [12]. The mean force of the KCl-induced contraction amounted to 2.3 +/- 0.1 mN/mm. Potency (given as IC50-values), differential time course of action and recovery of the contractile response of the vessels after wash-out were established. These three parameters adhere to the following sequences: (1. potency) barnidipine [corrected] > (S)-lercanidipine > barnidipine racemate [corrected]> amlodipine > nifedipine, lacidipine > (R)-lercanidipine > verapamil, mibefradil; (2. differential time course) lacidipine, amlodipine > (S)- and (R)-lercanidipine, barnidipine [corrected], barnidipine racemate [corrected] > mibefradil, verapamil, nifedipine; (3. recovery) nifedipine > verapamil, barnidipine [corrected], amlodipine > barnidipine, lacidipine > mibefradil, (R)-lercanidipine > (S)-lercanidipine. In conclusion, barnidipine [corrected] proved to be the most potent vasodilator agent; interestingly, barnidipine was 20 times less potent when applied as a racemic mixture. A slow onset of action in DHP is a very important mechanism in preventing reflex tachycardia. For non-DHP (verapamil, mibefradil) reflex tachycardia probably is prevented by a direct effect on the conductive tissue in the myocardium.

The study was designed to investigate whether a long-acting dihydropyridine calcium antagonist has additional antihypertensive effect when combined with currently used low-dose thiazide diuretic therapy. After 6 weeks with open chlorthalidone monotherapy at 25 mg daily, hypertensive patients with trough diastolic BP 90-115 mm Hg were randomly assigned to receive double-blind lacidipine, 4 mg daily or matching placebo for 4 weeks, while continuing to receive background chlorthalidone. Then patients crossed over to the alternative regimen for a second 4-week period. Clinic and 24-h ambulatory blood pressure (BP) were measured on the final day of chlorthalidone monotherapy and on the final day of each double-blind treatment. Seventeen patients completed the study [mean age, 51.0 +/- 6.9 (SD) years]. Clinic BP was lower with lacidipine versus placebo (systolic, p < 0.01; diastolic, p < 0.05). Daytime ambulatory BP was reduced with lacidipine (p < 0.05), whereas nighttime BP was unchanged. Mean 24-h ambulatory diastolic BP also was reduced on lacidipine (p < 0.05). Heart rate was increased on lacidipine during both daytime (p < 0.01) and nighttime (p < 0.05). In conclusion, when added to chlorthalidone, lacidipine produced a significant reduction in clinic and ambulatory BP during daytime but not nighttime. This was associated with increased heart rate. Modem long-acting dihydropyridines may produce small but clinically significant additive antihypertensive effects in patients uncontrolled on low-dose thiazide monotherapy.

The generation of free radicals has been implicated in the pathologies of a number of cardiovascular diseases like infarction, stroke and atherosclerosis. Free radicals initiate lipid peroxidation, which leads to the impairment of membrane function and finally cell death. This often results in irrecoverable tissue damage. Therefore, potentially useful drugs would be those that not only have effects on the symptoms of the disease, but also demonstrate antioxidant and free radical scavenging properties. Some calcium entry blockers (CEBs) of the dihydropyridine (DHP) family (e.g. lacidipine, amlodipine, nifedipine) have been shown to possess radical scavenging activity in addition to their potent vasorelaxant properties. Some DHPs are active in inhibiting the autoperoxidation of rat cortical membranes. The order of potency was lacidipine>nimodipine>nifedipine, with lacidipine having an activity comparable to vitamin E. Lacidipine was also potent in protecting cells from the marked impairment of calcium homeostasis caused by oxidative stress induced by H2O2. Similarly, in the isolated rabbit heart electrolysis of the perfusion medium increases coronary artery pressure and this is antagonised by prior treatment with lacidipine. In vivo marked protection has been seen in animal models of vascular damage. In the stroke-prone spontaneously hypertensive rat lacidipine, at doses that do not block the development of hypertension, prevent mortality and tissue damage to brain and kidney, organs at risk in this model. Lacidipine also blocked the development of arterial lesions in two animal models of atherosclerosis : the hypercholesterolaemic rabbit and the hypercholesterolaemic hamster. These actions can be at least partially ascribed to mechanisms other than simple blood pressure reduction and might well relate to antioxidant activity.

Abstract Essential hypertension is characterized by impaired endothelium-dependent vasodilation. The present study was designed to test whether antihypertensive treatment with the calcium antagonist lacidipine can improve endothelium-dependent vasodilation in essential hypertensive patients. In 12 normotensive subjects (mean age, 47.8±8.6 years; blood pressure, 118.6±4.2/76.7±3.9 mm Hg) and 19 hypertensive patients (mean age, 49.4±10.2 years; blood pressure; 153.5±13.3/101.3±6.4 mm Hg), we studied forearm blood flow modifications (strain-gauge plethysmography) induced by intrabrachial infusion of acetylcholine (0.15, 0.45, 1.5, 4.5, and 15 μg/100 mL per minute) and bradykinin (5, 15, and 50 ng/100 mL per minute), two endothelium-dependent vasodilators that act through different receptors and signal transduction pathways, and sodium nitroprusside (1, 2, and 4 μg/100 mL per minute), an endothelium-independent vasodilator. In essential hypertensive patients, vascular reactivity was repeated during prolonged (8 weeks of oral treatment at 6 mg/d) lacidipine administration and 2 weeks after withdrawal of chronic (32-week) treatment. Hypertensive patients showed significantly ( P P

Objective To evaluate the modifications of the morphology of mesenteric small resistance vessels in spontaneously hypertensive rats (SHR) induced by lacidipine treatment Methods Lacidipine was administered at three different dosages, 20, 10, and 0.3 mg/kg per day. Fifty rats were studied. Nine SHR and 11 Wistar-Kyoto (WKY) rats were not treated. Each lacidipine dose was administered to 10 SHR. The drug and the placebo were administered by gavage from age 4 to age 12 weeks. The blood pressure was measured noninvasively every week. The animals were killed when they were aged 13 weeks, and the relative left ventricular mass (left ventricular weight plus septum weight/body weight) was calculated. Small mesenteric resistance vessels were dissected and mounted on a micromyograph (Mulvany's technique), and morphological parameters of the vessels were studied (media thickness and media: lumen ratio). Results The systolic blood pressure of SHR administered 20 and 10 mg/kg lacidipine per day was reduced significantly during the treatment period, whereas that of rats treated with 0.3 mg/kg lacidipine per day did not change. A significant reduction in media: lumen ratio was observed for all three groups of treated rats, including those to which 0.3 mg/kg lacidipine per day had been administered, and no reduction in systolic blood pressure could be detected. The relative left ventricular mass was reduced significantly only in rats to which 20 and 10 mg/kg lacidipine per day had been administered. Conclusion A significant reduction in magnitude of vascular structural alterations was observed even in SHR treated with a low, nonhypotensive dose of lacidipine.

Introduction: Lacidipine (LCDP) is chemically a 1, 4-dihydropyridine derivative Ca+ 2 channel blocker used as an antihypertensive. Type and extent of packaging have a strong influence on the photo-stability of the 1,4-dihydropyridine derivatives. In standard, light protection of drug substance/drug product can be obtained either by use of an opaque additive in the formulation that competitively absorbs or reflects light reaching the sample and/or by blocking the access of light to the drug through external protection by packaging. Materials and Methods: External protection by covering tablets with an opaque film coating involving a light-reflecting inorganic pigment such as titanium dioxide and/or by using an opaque impermeable packaging material was an appropriate suitable option for establishing photo-stability. Thus, the main objective of the present study was to optimize the % level of film coating in LCDP core tablets, and selection of a final packaging material and its respective extent, that is, primary, secondary and/or tertiary packaging, for LCDP tablets. Results and Conclusion: The main objective (% level of film coating) was optimized by directly exposing core tablets, 1% w/w, 2% w/w and 3% w/w film-coated tablets, to a light source as per Option-2 of ICH Q1B and its comparative analysis at the end of light exposure testing. The other objective (extent of drug product packaging) was established successfully by assessing whether or not an acceptable change has occurred at the end of the light exposure testing of the LCDP film-coated tablets in a direct exposure study or a primary immediate pack and/or secondary marketing pack.

1. 1. The calcium-channel blocking activity of lacidipine has been studied compared with that of nifedipine and verapamil on the isolated rabbit heart and aorta. 2. 2. All the compounds induced a dose-dependent negative inotropic effect (10 −8 -10 −5 M); although lacidipine showed less, but longer lasting, activity. 3. 3. Lacidipine showed a weak negative chronotropic effect and nifedipine was ineffective. Only verapamil strongly decreased the heart rate. 4. 4. The three calcium antagonists abolished vasopressin-induced coronary spasm and inhibited partially metoxamine-induced coronary spasm. Only lacidipine reduced basal coronary pressure. 5. 5. In the aortic strips, all the compounds antagonized KC1-induced contractions, and they exerted a partial effect on noradrenaline-and angiotensin II-induced contractions.

We investigated the effect of NO/cyclic GMP pathway on the action of calcium antagonists (isradipine, nisoldipine, lacidipine, verapamil, diltiazem) in rat aorta exposed to 100 mM KCl. For this purpose constitutive NO synthase was blocked by using 100 microM N omega-nitro-L-arginine (L-NNA). The steady-state contractile response evoked by 100 mM KCl was enhanced when the basal NO release had been blocked. The combined effects of basal NO release and calcium antagonists resulted in an inhibition greater than additive. Concentrations of calcium antagonists producing 50% inhibition of contraction were about 3-fold lower in the presence of the basal NO release than in its absence (P < 0.01). 45Ca2+ influx stimulated by 100 mM KCl was not affected by the basal NO release, but was inhibited by isradipine and verapamil regardless of NO blockade. Thus, the facilitation of the action of calcium antagonists by NO/cyclic GMP pathway seemed not to be accompanied by a modification of their action on L-type calcium channels. To confirm this, we measured the contractile tension and the calcium signal in fura-2 loaded rings, pretreated with either verapamil or verapamil plus 8-bromo cyclic GMP (BrcGMP), and further exposed to increasing concentrations of extracellular Ca2+ ([Ca2+]o) in 100 mM KCl solution. The increase in cytosolic Ca2- ([Ca2+]cyt) evoked by increasing ([Ca2+]o) in rings pretreated with verapamil alone was not different from rings pretreated with verapamil plus BrcGMP. In contrast, the [Ca2+]o-contraction curve was significantly shifted to the right in rings pretreated with verapamil plus BrcGMP. These results show that the NO/cyclic GMP pathway facilitates the inhibitory effect of calcium antagonists on 100 mM KCl-evoked contraction. This phenomenon is not related to a modification of calcium channel blockade, but could result from the reduction of the sensitivity of contractile machinery to Ca2+ by cyclic GMP.

This paper reports on some interactions of calcium antagonists with nitric oxide and endothelin. It reviews evidence showing that the vasorelaxant action of calcium antagonists is facilitated by nitric oxide and describes the mechanism of this modulation. The interaction of calcium antagonists with endothelin is examined considering functions and production of the peptide. Among the functions examined, attention is drawn to the potentiation of responses to vasoconstrictors evoked by low threshold concentrations of endothelin, an action that could be important in pathology. The production of endothelin is increased by a high-salt diet in spontaneous hypertensive stroke-prone rats, this increased production, related to the overexpression of prepro ET-1mRNA, is responsible for cardiovascular hypertrophy and is blunted, in a blood pressure-unrelated manner, by the calcium antagonist lacidipine. At the same dosage regimen, lacidipine inhibits the hypertrophy of the cardiovascular system evoked by a high-salt diet.

METHODS OF CURRENT TRIALS: Several ongoing trials are investigating the anti-atherosclerotic effects of antihypertensive drugs in hypertensive patients. Changes in carotid intimal-medial thicknesses and atherosclerotic plaques are being explored by a sensitive quantitative B-mode ultrasound technique. MULTICENTER ISRADIPINE/DIURETIC ATHEROSCLEROSIS STUDY (MIDAS): The results from this pioneering study indicated a slower progression, at least in the first 6 months, of carotid plaques in isradipine-treated patients than in diuretic-treated patients. MIDAS has been particularly valuable in giving information on the rate of growth of intimal-medial thickness in hypertensive patients and on the best end-point to use in carotid ultrasound trials. EUROPEAN LACIDIPINE STUDY ON ATHEROSCLEROSIS (ELSA) AND VERAPAMIL IN HYPERTENSION AND ATHEROSCLEROSIS STUDY (VHAS): Baseline data from these two ongoing studies have provided evidence of the very high prevalence of carotid lesions among hypertensive patients: the prevalence of plaques (defined as a carotid intimal-medial thickness of > or = 1.3 mm) was 83% in ELSA, while in VHAS, in which plaques were defined as an intimal-medial thickness of > 1.5 mm), the plaque prevalence was 37%. These observations emphasize the importance of evaluating the atherosclerotic action of antihypertensive agents. PLAQUE HYPERTENSION LIPID-LOWERING ITALIAN STUDY (PHYLLIS): This trial is using a factorial design to explore the anti-atherosclerotic action of an angiotensin converting enzyme (ACE) inhibitor (fosinopril) versus a diuretic, and also intends to evaluate the possible benefits of associating antihypertensive therapy with a statin to induce lipid-lowering to prevent the progression of carotid atherosclerosis.

1. The in vivo antiatherogenic activity of the calcium antagonist, lacidipine, was investigated in two different types of atherosclerotic lesions (proliferative and fatty lesions) induced in rabbits. 2. The proliferative lesion was obtained by positioning a hollow silastic collar around one carotid artery, while aortic fatty lesions were induced by cholesterol feeding. Cholesterol (1%) and lacidipine (1, 3, and 10 mg kg-1) were given daily mixed with standard diet for 8 weeks to White New Zealand rabbits. The intimal hyperplasia (proliferative lesion) was induced 6 weeks after dietary and drug treatment started. 3. The neointimal formation was determined by measuring cross sectional thickness of intimal (I) and medial (M) tissue of fixed arteries. In untreated animals (n = 5), 14 days after collar positioning an intimal hyperplasia was clearly detectable: the arteries with no collar (sham) showed an I/M tissue ratio of 0.03 +/- 0.02, whereas in the carotid with collar the ratio was 0.62 +/- 0.12. In lacidipine-treated animals a significant and dose-dependent effect on proliferative lesions at all three doses tested, was observed. I/M ratios were 0.47 +/- 0.02, 0.40 +/- 0.09, 0.32 +/- 0.02 for doses 1, 3, and 10 mg kg-1 day-1, respectively (P < 0.05). 4. The fatty lesion extent was significantly reduced by lacidipine at the 10 mg kg-1 day-1 dose, although a trend was also observed with lower dosage. 5. These results suggest a direct antiatherosclerotic effect of lacidipine, independent of modulation of risk factors such as hypercholesterolaemia and/or hypertension. Furthermore, the proliferative lesions are apparently more sensitive to lacidipine than are lipid-rich lesions.

Objective-To evaluate the efficacy and safety of the second generation dihydropyridine calcium channel blocker lacidipine in patients with heart failure. Design-Placebo controlled, parallel group, double blind study over 8 weeks. Setting-General community hospital in Breda, The Netherlands. Patients-A random sample was studied of 25 outpatients with symptoms of mild to moderate heart failure, despite treatment with diuretics, digoxin, and angiotensin converting enzyme inhibitors. Their mean age was 65 years, with mean left ventricular ejection fraction of 0.24 and a peak oxygen consumption of 14.4 ml/min/kg. Two patients dropped out on lacidipine, one patient on placebo. Intervention-Treatment with lacidipine 4 mg once daily or placebo for eight weeks. Main outcome measure-Cardiopulmonary exercise testing, invasive haemodynamics, and plasma neurohormones. Results-Treatment with lacidipine 4 mg once daily, as compared to placebo treatment, significantly improved peak oxygen consumption (P

In physiological or pathophysiological conditions, vascular tone is regulated by various neural, endocrine, paracrine, and autocrine factors that may exert immediate or delayed effects. In this chapter, we report experiments undertaken to characterize immediate effects by examining the role of endothelium-derived relaxing factors (EDRFs) and of endothelin. We also summarize studies on long-term effects by examining calcium channels and regulation of vascular tone in hypertension, considering comparison of contractile properties of arteries from normotensive and hypertensive rats and their relation with calcium channels. We discuss the following points: differences in postcontraction tone, in response to Cat+-channel activator, in the effect of amlodipine added in vitro on the Bay K 8644 concentration—effect curve, and in dihydropyridine-binding sites. We show the influence of salt loading on the cardiac and renal preproendothelin-1mRNA expression and on its consequences in stroke-prone spontaneously hypertensive rats, and report its blood pressure-independent inhibition by lacidipine, a long-lasting calcium antagonist.

GUIDELINES ON DRUG SAFETY: Recent European Union draft guidelines for the safety evaluation of drugs intended for long-term use state that during drug development the safety profile of the new compound should be assessed over a period of time consistent with intended usage. This is in reasonable agreement with guidelines prepared by other regulatory authorities. CLINICAL DRUG DEVELOPMENT: Satisfactory preclinical data on a new compound are used to obtain authorization for human testing from the National Committees on Safety of Medicines. Clinical trials are performed in four phases, ranging from phase I studies performed on healthy volunteers (n = 20-50) to postmarketing (phase IV) studies. The latter are of great importance as they cover large patient populations (n = 2000 to > or = 10,000) and allow detection of rare adverse drug reactions. ADVERSE DRUG REACTIONS: Type B reactions are serious, unpredictable reactions to a drug that necessitate treatment withdrawal. Type A reactions are dose-dependent, and represent the majority of adverse reactions. They are often managed by dose reduction rather than drug withdrawal. ADVERSE REACTIONS TO ANTIHYPERTENSIVE AGENTS: Examples of type B adverse reactions to antihypertensives are the cutaneous and ocular reactions to practolol, and angioneurotic oedema associated with angiotensin converting enzyme inhibitors. Lacidipine, a second-generation calcium antagonist, is an example of a modern antihypertensive agent with a favourable safety profile. The adverse reactions associated with lacidipine are mild to moderate and of the A type, the major ones being those typical of calcium antagonists (headache, flushing and pedal oedema due to vasodilation.

Aims To assess the benefits of the calcium antagonist lacidipine on the prevention of cardiovascular events and the prevention of organ damage in two long-term clinical trials. SYSTOLIC HYPERTENSION IN THE ELDERLY LONG-TERM LACIDIPINE (SHELL) TRIAL: In the SHELL trial, the efficacy of lacidipine-based treatment is to be compared with that of thiazide-like diuretic (chlorthalidone)-based treatment in elderly patients with isolated systolic hypertension. The incidence of cardiovascular mortality and cardiovascular morbidity over a 5-year period are endpoints. European lacidipine study on atherosclerosis (elsa) trial In the ELSA trial, the effects of lacidipine-based treatment and beta-blocker (atenolol)-based treatment on the development and progression of carotid atherosclerosis are to be assessed in hypertensive patients. The primary endpoint of this study is the rate of change in the thickness of the carotid artery wall, measured with B-mode ultrasound.

Objective : Spontaneous cyclic vasomotor activity can occur in small resistance arteries in vitro after precontraction with a vasoconstrictor. Calcium and potassium channels and nitric oxide synthesis or release seem to be involved in the genesis of this vasomotor activity. We therefore investigated the effects of chronic antihypertensive therapy with calcium antagonists and angiotensin converting enzyme (ACE) inhibitors on the amplitude and frequency of cyclic vasomotor activity in vitro in spontaneously hypertensive rats (SHR). Materials and methods : SHR were treated with fosinopril at 25 mg/kg per day or lacidipine at 10 mg/kg per day or nitrendipine at 30 mg/kg per day, from the age of 4 to 12 weeks. Data were compared with those obtained in untreated SHR and Wistar-Kyoto (WKY) rats. Half the rats were killed at 13 weeks of age, and the remaining half were killed at 38 weeks of age. The mesenteric small resistance arteries were dissected, mounted on a micromyograph and then contracted submaximally with noradrenaline. Acetylcholine was then added to the organ bath. Results : More than 50% of the vessels showed cyclic vasomotor activity. The frequency and amplitude of this activity were greater in SHR than WKY rats after noradrenaline and after acetylcholine. At 13 weeks of age (but not at 38 weeks of age), treatment with a calcium antagonist (either lacidipine or nitrendipine) significantly reduced the frequency and amplitude of the vasomotor activity, probably by interfering with calcium entry. No change was observed after fosinopril. Conclusions : Antihypertensive treatment with different drugs may affect cyclic vasomotor activity differently, probably by interfering with cellular mechanisms involved in its genesis. The effects of calcium antagonists on cyclic vasomotor activity are still present after short-term but not after long-term treatment withdrawal.

The automation and validation of the HPLC-radioimmunoassay (RIA) method for the determination of lacidipine are reported. The solid-phase extraction step was automated by the introduction of the ASPEC system. A two-column system was adopted for the HPLC purification. The RIA was converted from heterogeneous to homogeneous by the scintillation proximity assay system and automated using an automatic dilution system. All characteristics in terms of accuracy, precision, specificity, and linearity resulted similar to the manual version. The quantification limit was set to 40 pg/ml. The new version of the method increased the number of samples assayed per month two- to three-fold.

In this single-blind crossover study the antihypertensive efficacies of two dihydropyridine calcium antagonists, sustained-release isradipine and lacidipine, were compared using clinic and ambulatory blood-pressure measurements. After a 2-week placebo wash-out, 34 patients (19 men, 15 women, mean age 49 years) with mild to moderate hypertension (diastolic blood pressure range 95 – 110 mmHg) were treated with 5 mg sustained-release isradipine for 4 weeks and 4 mg lacidipine for 4 weeks in a random order. Medications were taken once daily at 08.00 h. Clinic and ambulatory blood pressures were recorded at the end of each placebo or treatment period. Two patients stopped isradipine and six lacidipine because of severe adverse effects. Clinic systolic and diastolic blood pressures decreased by an average of 17/14 mmHg with isradipine and 17/13 mmHg with lacidipine, compared with placebo ( P < 0.01 in both cases), without a change in heart rate. Mean ambulatory 24-h and daytime systolic and diastolic blood pressure were significantly reduced by sustained-release isradipine and lacidipine ( P < 0.05 and P < 0.01, respectively). At night systolic blood pressure fell compared with placebo ( P < 0.05 with both drugs) whereas the reduction in diastolic blood pressure was not statistically significant. Mean 24-h heart rate remained unchanged. Blood-pressure variability did not differ significantly between the two drugs or between either drug and the placebo. The antihypertensive effects of sustained-release isradipine and lacidipine were similar, but the tolerability of isradipine appears to be greater since it caused fewer withdrawals.

Calcium channel blockers are increasingly used in ophthalmology, for instance in patients with visual field defects caused by vasospasm. Endothelin is a new vasoactive peptide which also has been implicated in hypoperfusion of the ophthalmic circulation. This study investigated the effects of the calcium channel blockers on the response to endothelin-1, bradykinin and sodium nitroprusside in isolated porcine ciliary arteries (diameter 200-250 microns). Isolated porcine ciliary arteries were suspended in myograph systems filled with modified Krebs-Ringer solution (37 degrees C; 95% O2/5% CO2) for isometric tension recording. Endothelin-1 (10(-12) -10(-7) M) induced potent concentration-dependent contractions of porcine ciliary arteries (PD50 = 8.3 +/- 0.1; n = 7). Lacidipine (10(-5) -10(-7) M) and nifedipine (10(-5) M) significantly reduced the contractions and decreased the sensitivity to endothelin-1 as compared to control (P < 0.03). On the other hand, endothelium-dependent relaxations to bradykinin (10(-10) -10(-6) M) and endothelium-independent relaxations to sodium nitroprusside (10(-10) -10(-4) M) remained unaffected by the calcium channel blocker. These findings demonstrate that in porcine ciliary arteries, the calcium channel blockers selectively inhibit endothelin-1-induced contractions, while leaving endothelium-dependent and endothelium-independent relaxations unaffected. This property of calcium channel blockers may contribute to the clinical efficacy of this class of drugs in patients with ocular vasospasms.

For more than two decades calcium antagonists (CEBs) have been widely used for the treatment of myocardial ischaemia (angina pectoris). Amongst the classes of CEBs, the 1,4-dihydropyridines (DHPs), like nifedipine, have been used for this indication because of their haemodynamic and electrophysiological properties. The ability of nifedipine to reduce afterload and to induce coronary vasodilation, as well as to increase collateral blood supply, has supported its extensive use in the treatment of angina pectoris. However, its short duration of action also provokes reflex tachycardia, which often limits its beneficial effect and may actually precipitate pain. The newer DHPs, such as amlodipine and lacidipine, are endowed with slow onset and long duration of vasodilatory activity; they are able to reduce coronary resistance with little or no effect on heart rate. The more lipophilic DHP, lacidipine, shows also a pronounced vascular protection, on both smooth muscle and endothelium, and is able to reduce the formation of atheroma plaque in animal models at therapeutic doses. This protective activity might be explained in terms of both the effective CEB activity of lacidipine together with antioxidant properties that this DHP has shown.