lacidipine and 1-4-dihydropyridine

Many 1,4-dihydropyridines (DHPs) possess redox properties. In this review DHPs are surveyed as protectors against oxidative stress (OS) and related disorders, considering the DHPs as specific group of potential antioxidants with bioprotective capacities. They have several peculiarities related to antioxidant activity (AOA). Several commercially available calcium antagonist, 1,4-DHP drugs, their metabolites, and calcium agonists were shown to express AOA. Synthesis, hydrogen donor properties, AOA, and methods and approaches used to reveal biological activities of various groups of 1,4-DHPs are presented. Examples of DHPs antioxidant activities and protective effects of DHPs against OS induced damage in low density lipoproteins (LDL), mitochondria, microsomes, isolated cells, and cell cultures are highlighted. Comparison of the AOA of different DHPs and other antioxidants is also given. According to the data presented, the DHPs might be considered as bellwether among synthetic compounds targeting OS and potential pharmacological model compounds targeting oxidative stress important for medicinal chemistry.

Topics: Amlodipine; Animals; Antioxidants; Azetidinecarboxylic Acid; Calcium Channel Blockers; Cattle; Dihydropyridines; Epithelial Cells; Humans; Hydrogen; Lipoproteins, LDL; Mice; Microsomes; Mitochondria; Niacinamide; Nifedipine; Nitrobenzenes; Oxidants; Oxidative Stress; Piperazines

Lacidipine (LAC) is a calcium antagonist used in the treatment of hypertension. It is a lipophilic drug containing dihydropyridine ring that is responsible for the activity. This review article gives an overview of various analytical techniques proposed for the determination of LAC in pharmaceutical dosage forms, in pure form, in biological fluids and to determine characteristics of LAC in modified release dosage forms. Ultra violet/visible spectrophotometric, spectroflourimetric, high performance liquid chromatography, high performance thin layer chromatography, electro-analytical, bioanalytical and miscellaneous methods such as microbiological assay, X-ray diffraction, differential scanning calorimetry, were discussed. Various parameters such as system suitability, selectivity, linearity, precision, accuracy, limit of detection, limit of quantification and robustness have been discussed for the employed methods.. Lay abstract Lacidipine (LAC) is a calcium channel blocker used to reduce blood pressure in hypertension. It has good hydrophobic interactions that gives high distribution of drug in the lipophilic membrane. Chemically, it is (E)-4-[2-[3-(1, 1-dimethylethoxy)-3-oxo-1-propenyl] phenyl]-1, 4-dihydro-2, 6-dimethyl-3,5 pyridine di-carboxylic acid diethyl ester that contains dihydropyridine ring responsible for antihypertensive activity. It is the most commonly used antihypertensive drug as it has high vascular selectivity, tolerability and large dose acceptability with negative ionotropic effects. In spite of anti-hypertensive activity, it shows anti-atherosclerotic, antibacterial and antioxidant effects such as Vitamin E. It has such an important role in treating the life-threatening cardiovascular disorders. The various formulations are available in the market pertaining to this drug. In order to assess the pharmacokinetic parameters, toxicological properties and to estimate the exact concentration of LAC, various analytical techniques are employed for the estimation of LAC in pharmaceutical dosage forms, biological matrices and for the physical characterization of LAC. Here these methods are described to give a clear glance for the future scientists to develop few more easily adoptable methods.

Topics: Calcium Channel Blockers; Dihydropyridines; Pharmaceutical Preparations; Spectrophotometry, Ultraviolet

Amlodipine and lacidipine, conventional antihypertensive drugs, inhibited Leishmania donovani infection in vitro and in BALB/c mice when administered orally. These 1,4-dihydropyridine derivatives functioned through dose-dependent inhibition of oxygen consumption, triggering caspase 3-like activation-mediated programmed cell death of the parasites.

Topics: Administration, Oral; Amlodipine; Animals; Antiprotozoal Agents; Dihydropyridines; Leishmania donovani; Leishmaniasis, Visceral; Macrophages, Peritoneal; Mice; Mice, Inbred BALB C; Parasitic Sensitivity Tests; Treatment Outcome

Dihydropyridines (DHPs), synthetic molecules used as antihypertensive agents, bind to plasma membrane receptors following diffusion through the hydrophobic phase. In this study, MRS technique has been used to clarify the interactions of the dihydrophyridines Nifedipine and Lacidipine within the lipid bilayer. 1D and 2D 1H MRS at high field have been employed to examine the behavior of unilamellar dimyristoyl-phosphatidylcholine liposomes when the two drugs have been inserted in the bilayer. In particular, the study represents an innovative application of 2D 1H NOESY technique to clarify different mechanisms of interactions of small molecules inside model membranes. On the other hand, 31P measurements have been performed in multilamellar dimyristoyl-phosphatidylcholine lipsomes to detect alterations of lipid polymorphic phases. The experiments show that the two dihydropyridines interact with the lipids by different modalities. Lacidipine undergoes a very strong interaction with lipids, possibly inducing a phase segregation of lipid molecules into the bilayer, while self-association seems to be the prevalent interaction of Nifedipine inside the bilayer.

Topics: Dihydropyridines; Dimyristoylphosphatidylcholine; Lipid Metabolism; Lipids; Liposomes; Magnetic Resonance Spectroscopy; Molecular Structure; Nifedipine

Calcium-channel blockers (CCBs) reduce systolic blood pressure and stroke-related mortality in stroke-prone spontaneously hypertensive rats (SPSHR). Brain ischemia is associated with loss of intracellular antioxidants. Increased formation of oxygen radicals and oxidation of LDL may enhance arterial vasoconstriction by various mechanisms. CCBs that also exert antioxidative properties in vitro may therefore be particularly useful. To investigate such antioxidant effects in vivo, we determined several parameters of LDL oxidation in SPSHR treated with two 1,4-dihydropyridine-type (1,4-DHP) CCBs of different lipophilic properties and compared them with antioxidant-treated and untreated controls. We also tested whether these drugs decrease the formation of oxidation-specific epitopes in arteries.. Five groups of 9 to 14 SPSHR each (aged 8 weeks) were treated with 80 mg/kg body wt per day nifedipine, 1 mg or 0.3 mg/kg body wt per day lacidipine, vitamin E (100 IU/d), or carrier for 5 weeks. A group of Wistar-Kyoto rats was used as normotensive control. Plasma samples were taken, and LDL was isolated by ultracentrifugation. Then LDL was exposed to oxygen radicals generated by xanthine/xanthine oxidase reaction (2 mmol/L xanthine+100 mU/mL xanthine oxidase), and several parameters of oxidation were determined. The presence of native apolipoprotein B and oxidation-specific epitopes in the carotid and middle cerebral arteries was determined immunocytochemically.. 1,4-DHP CCBs completely prevented mortality. Normotensive Wistar-Kyoto rats showed less oxidation than control SPSHR. Plasma lipoperoxide levels were 0.87+/-0.27 micromol/L in control SPSHR, 0.69+/-0.19 and 0.63+/-0.20 micromol/L in the groups treated with 0.3 and 1 mg lacidipine, respectively, and 0.68+/-0.23 micromol/L in nifedipine-treated animals (P<0.05 versus control SPSHR for all values). Both CCBs significantly decreased formation of conjugated dienes and prolonged the lag time in LDL exposed to oxygen radicals. Similarly, lipoperoxides and malondialdehyde were significantly reduced (P<0.05). Reduced relative electrophoretic mobility and increased trinitrobenzenesulfonic acid reactivity of LDL from treated rats (P<0.01) also indicated that fewer lysine residues of apolipoprotein B were oxidatively modified in the presence of 1,4-DHP CCBs. Finally, these drugs reduced the intimal presence of apolipoprotein B and oxidized LDL (oxidation-specific epitopes) in carotid and middle cerebral arteries.. In the SPSHR model, 1,4-DHP CCBs reduce plasma and LDL oxidation and formation of oxidation-specific epitopes and prolong survival independently of blood pressure modifications. Our results support the concept that the in vivo protective effect of these drugs on cerebral ischemia and stroke may in part result from inhibition of oxidative processes.

Topics: Animals; Antioxidants; Apolipoproteins B; Arteries; Calcium Channel Blockers; Cerebrovascular Disorders; Dihydropyridines; Epitopes; Genetic Predisposition to Disease; Immunohistochemistry; Lipoproteins, LDL; Male; Oxidation-Reduction; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Reference Values; Vitamin E

The time-course of dihydropyridine receptor occupancy by lacidipine and its relationship with pharmacological activity has been studied in spontaneously hypertensive rat (SHR), as measured by the inhibition of specific (+)-[3H]PN 200-110 binding in-vivo. After oral administration of doses active in reducing blood pressure, lacidipine did not show tissue target differences in respect to binding sites labelled by (+)-[3H]PN 200-110 in cerebral cortex, heart, ileum, bladder and thoracic aorta. The relative occupancy of receptors in heart 60 min after oral administration of 1 mg kg-1 lacidipine was 75%. After 12 h, when lacidipine was still effective in reducing blood pressure in SHR, a low (15%) but detectable proportion of receptors was still occupied by the drug. The percentage decrease of blood pressure was linear with the percentage of receptor occupancy obtained by different doses of lacidipine; that is, there was a close correspondence between ED25 for decrease in blood pressure (0.33 mg kg-1) and ED25 for inhibition of (+)-[3H]PN 200-110 specific binding in the heart (0.36 mg kg-1). The long-lasting effect of lacidipine on blood pressure might be explained by its selective interaction with dihydropyridine binding sites labelled in-vivo by (+)-[3H]PN 200-110.

Topics: Administration, Oral; Animals; Antihypertensive Agents; Aorta, Thoracic; Binding Sites; Brain; Calcium Channel Blockers; Cerebral Cortex; Dihydropyridines; Dose-Response Relationship, Drug; Drug Interactions; Heart; Ileum; Injections, Intravenous; Isradipine; Male; Myocardium; Rats; Rats, Inbred SHR; Tritium; Urinary Bladder