Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcium-channel antagonist drugs of the 1,4-dihydropyridine type have been shown to bind to the L-type calcium channel. These drugs are not only amphiphilic, but new molecular designs have become increasingly lipophilic and can readily transport across cell membranes, accessing both hydrophilic and hydrophobic environments, despite becoming more soluble in the membrane bilayer. This biophysical understanding appears not only to define the molecular pathways for drug binding to the calcium-channel receptor, but also to explain differences in the overall clinical pharmacokinetics observed for different drugs in this class. The pharmacokinetic profile of calcium antagonists, although influenced to some degree by interactions with their target calcium-channel receptor, appears to be largely dictated by their interactions with cell membranes at the molecular level. There appears to be a correlation between the duration of action of such membrane-active drugs and the membrane partition coefficient in conjunction with the washout rate. This class of drugs has evolved from a drug such as amlodipine, with a long duration of action related to prolonged plasma half-life, to lercanidipine, which has the shortest plasma half-life relative to its intrinsically long duration of action. Recently, it was discovered that membrane cholesterol reduces the amount of calcium-channel antagonist that can partition into the membrane. Atherosclerotic disease results in increased levels of membrane cholesterol in smooth muscle cells. Latest generation calcium antagonist, which have a long duration of action, can better overcome this negative effect. Lercanidipine has now been shown to have one of the highest measured tolerances to cholesterol, which may indicate its ability to treat a broad range of hypertensive patients with varying degrees of progressive atherosclerotic disease. On what criteria should the effectiveness of calcium antagonists be evaluated? A good calcium antagonist needs to exhibit a placebo-like side-effect profile, thus ensuring good patient compliance. However, an intrinsically long-lasting, once-a-day dose is also pharmacokinetically desirable. To be a truly optimal calcium antagonist, it should function and be efficacious over a broad range of hypertensive patients. It should be able to control blood pressure in light of other complications such as progressive atherosclerotic disease. Recent studies indicate that during the progression of atherosclerosis, cholesterol levels within cell membranes of the arterial wall increase, a process that can reduce the effective concentration of calcium antagonists in these membranes. What is needed is a calcium antagonist that is slow acting to reduce vasodilatory induced side-effects and intrinsically long lasting to ensure once-a-day dosage, and that possesses a high cholesterol tolerance factor to overcome the molecular and compositional changes taking place in the arterial wall, so that it can treat effectively a broad range of hypertensive patients.
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PMID:Lercanidipine: short plasma half-life, long duration of action and high cholesterol tolerance. Updated molecular model to rationalize its pharmacokinetic properties. 985 Apr 37

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.
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PMID:The new calcium antagonist lercanidipine and its enantiomers affect major processes of atherogenesis in vitro: is calcium entry involved? 985 Apr 38

Lercanidipine is a lipophilic, dihydropyridine calcium antagonist with a long receptor half-life. Its slow onset of action helps to avoid reflex tachycardia associated with other dihydropyridines (DHPs). It produces even and sustained blood pressure lowering with once-daily dosing. It has equivalent antihypertensive efficacy to many other agents and is effective as initial monotherapy or in combination. Efficacy has been demonstrated in elderly as well as younger patients and also in the presence of other risk factors. Lercanidipine is well tolerated with DHP-associated adverse effects occurring early in treatment. The incidence of pedal edema and subsequent withdrawals has been found to be lower with lercanidipine than with amlodipine or nifedipine gastrointestinal transport system. Preclinical and preliminary clinical findings suggest lercanidipine may have beneficial effects on atherosclerosis and left ventricular hypertrophy. The efficacy and tolerability profiles of lercanidipine make it a suitable choice for treating hypertension in a wide range of affected patients.
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PMID:Lercanidipine in hypertension. 1731 3