Improved bioavailability of Azelnidipine gastro retentive tablets-optimization and in-vivo assessment.

Azelnidipine, dihydropyridine based calcium channel blocker has been used for treating ischemic heart disease and cardiac remodeling after myocardial infarction but it is having a low bioavailability due to its poor solubility. The present study is to investigate the formulation and evaluation of floating tablets of Azelnidipine for controlled release and to increase bioavailability by increasing the gastrointestinal transit time and mucoadhesion of drug. The gastro retentive tablets were prepared by direct compression method using different concentrations of combination of Polyoxyethylene oxide WSR 303 as hydrophilic polymer and Potassium bicarbonate as gas generating agent. Main effects of the formulation variables were evaluated quantitatively using design approach showing that both independent variables have significant effects on floating lag time, % drug release at 1 h (D1 h) and time required to release 90% of the drug (t90). The statistically optimized formulation (F3) released 95.11 ±â€¯1.43% drug for 12 h followed K-Peppas drug release kinetics indicating release of drug by diffusion and erosion mechanism. Evaluation of the optimized formulation in vivo in human volunteers showed that the GFT was buoyant in gastric fluid and that its gastric residence time was enhanced. Pharmacokinetics studies carried out revealed significant (P < 0.05) equivalent Cmax, longer Tmax and higher AUC values for the optimized formula compared to the marketed oral product. From the results obtained it can be concluded that Azelnidipine Gastro retentive tablets with enhanced bioavailability and better release pattern is suitable for more effective treatment compared to marketed conventional tablets.

[Clinical cfficacy of calcium channel blockers slow the third generation of lercanidipine in the treatment of patients with arterial hypertension].

The review describes the classification, mechanisms of action, the effects of calcium channel blockers slow and the clinical benefits of dihydropyridine calcium antagonists, the third generation. Presented modern aspects of clinical pharmacology and research results on the efficacy, safety and organoprotective lercanidipine.

SMILES-based QSAR models for the calcium channel-antagonistic effect of 1,4-dihydropyridines.

The activity of 72 1,4-dihydropyridines as calcium channel antagonists was examined. The simplified molecular input-line entry system (SMILES) was used as representation of the molecular structure of the calcium channel antagonists. Quantitative structure-activity relationships (QSARs) were developed using CORAL software (http://www.insilico.eu/CORAL) for four random splits of the data into the training and test sets. Using the Monte Carlo method, the CORAL software generated the optimal descriptors for one-variable models. The reproducibility of each model was tested performing three runs of the Monte Carlo optimization. The obtained results reveal good predictive potential of the applied approach: The correlation coefficients (r(2) ) for the test sets of the four random splits are 0.9571, 0.9644, 0.9836, and 0.9444.

Structural model for dihydropyridine binding to L-type calcium channels.

1,4-Dihydropyridines (DHPs) constitute a major class of ligands for L-type Ca(2+) channels (LTCC). The DHPs have a boat-like, six-membered ring with an NH group at the stern, an aromatic moiety at the bow, and substituents at the port and starboard sides. Various DHPs exhibit antagonistic or agonistic activities, which were previously explained as stabilization or destabilization, respectively, of the closed activation gate by the portside substituents. Here we report a novel structural model in which agonist and antagonist activities are determined by different parts of the DHP molecule and have different mechanisms. In our model, which is based on Monte Carlo minimizations of DHP-LTCC complexes, the DHP moieties at the stern, bow, and starboard form H-bonds with side chains of the key DHP-sensing residues Tyr_IIIS6, Tyr_IVS6, and Gln_IIIS5, respectively. We propose that these H-bonds, which are common for agonists and antagonists, stabilize the LTCC conformation with the open activation gate. This explains why both agonists and antagonists increase probability of the long lasting channel openings and why even partial disruption of the contacts eliminates the agonistic action. In our model, the portside approaches the selectivity filter. Hydrophobic portside of antagonists may induce long lasting channel closings by destabilizing Ca(2+) binding to the selectivity filter glutamates. Agonists have either hydrophilic substituents or a hydrogen atom at their portside, and thus lack this destabilizing effect. The predicted orientation of the DHP core allows accommodation of long substituents in the domain interface or in the inner pore. Our model may be useful for developing novel clinically relevant LTCC blockers.

Assessment of the effects of L- and N-type Ca2+ channel blocking drugs using canine blood-perfused papillary muscle preparations.

It is important to accurately and conveniently assess the effects of L- and N-type Ca(2+) channel blocking drugs, which are commonly used for treatment of hypertension, but no method is available to simultaneously assess the effects of them in the same preparation. We have therefore designed an ex vivo method to measure the changes in contractile response of anterior papillary muscle of right ventricle and myocardial interstitial norepinephrine (NE) level using canine blood-perfused papillary muscle preparations. Papillary muscle-developed tension (PMDT) induced by an electronic stimulator was measured with force transducer. Myocardial interstitial NE effluent was collected by microdialysis fiber, which was implanted at the base of the papillary muscle, and measured with high performance liquid chromatography. Cilnidipine, a typical L- and N-type Ca(2+) channel blocker, was used to prove the efficiency of this method. First, to assess the effects of drugs on L-type Ca(2+) channel, the changes in basal PMDT were measured. Cilnidipine and nicardipine, a selective L-type Ca(2+) channel blocker, but not omega-conotoxin GVIA (omega-CTX), a selective N-type Ca(2+) channel blocking peptide, decreased basal PMDT dose-dependently. Second, to assess the effects of drugs on N-type Ca(2+) channel, the changes in PMDT and myocardial interstitial NE level by intracardiac sympathetic ganglion stimulation were measured. Cilnidipine and omega-CTX, but not nicardipine, dose-dependently reduced sympathomimetic increases in PMDT and myocardial interstitial NE level. These results indicate that our method is efficient to assess the effects of various L- and N-type Ca(2+) channel blocking drugs in the same papillary muscle preparation.

Assessment of long-term antihypertensive treatment by clinic and ambulatory blood pressure: data from the European Lacidipine Study on Atherosclerosis.

OBJECTIVES: Information on the features of long-term modifications of clinic and 24-h ambulatory blood pressure (ABP) by treatment is limited. The present study aimed to address this issue. METHODS: Ambulatory BP monitoring and clinic BP (CBP) measurements were performed at baseline and at yearly intervals over a 4-year follow-up period in 1523 hypertensives (56.1 +/- 7.6 years) randomized to treatment with lacidipine or atenolol in the European Lacidipine Study on Atherosclerosis (ELSA). RESULTS: CBP was always greater than ABP, while reductions in all BP values (greater for CBP than for ABP) were on average maintained throughout 4 years, CBP changes showing limited relationship with ABP changes (r = 0.14-0.27). BP reductions by treatment during daytime and night-time were correlated (r = 0.63-0.73). BP normalization was achieved in a greater percentage of patients for CBP (41.7%) than for ABP (25.3%), with systolic BP control being always less common than diastolic BP control. BP normalization was more frequent at single yearly visits than throughout the 4 years. Twenty-four-hour BP variability was reduced by treatment over 4 years in absolute but not in normalized units. CONCLUSIONS: The present study provides the best evidence available on long-term effect of antihypertensive treatment on both ABP and CBP. On average, ABP was sustainedly reduced by treatment throughout the follow-up period, but 24-h BP was more difficult to control than CBP. In several patients, ABP control was unstable between visits, the percentage of patients under control over 4 years being much less than that of those controlled at each year. Treatment induced a reduction in absolute but not in normalized BP variability estimates. This has clinical implications because of the prognostic importance of ABP mean values and variability.

Synthesis of mono- and bisdihydrodipyridopyrazines and assessment of their DNA binding and cytotoxic properties.

Aminoalkyl-substituted monomeric and dimeric dihydrodipyridopyrazines have been synthesized and evaluated as antitumor agents. Potent cytotoxic compounds were identified in both series. Biochemical and biophysical studies indicated that all these compounds strongly stabilized the duplex structure of DNA and some of them elicited a selectivity for GC-rich sequences. Sequence recognition by of the dimeric dihydrodipyridopyrazines is reminiscent of that of certain antitumor bisnaphthalimides. Compared to monomers, corresponding dimeric derivatives showed higher affinity for DNA. This property was attributed to a bisintercalative binding to DNA. This assumption was indirectly probed by electric linear dichroism and DNA relaxation experiments. DNA provides a bioreceptor for these dihydrodipyridopyrazine derivatives, but no poisoning of human topoisomerases I or II was detected. Most of the compounds efficiently inhibited the growth of L1210 murine leukemia cells and perturbed the cell cycle progression (with a G2/M block in most cases). A weak but noticeable in vivo antitumor activity was observed with one of the dimeric compounds. This studies identifies monomeric and dimeric dihydrodipyridopyrazines as a new class of DNA-targeted antitumor agents.

Lacidipine: a review of its use in the management of hypertension.

UNLABELLED: Lacidipine (Caldine, Lacimen, Lacipil, Midotens, Motens) is a once-daily, orally-administered, lipophilic dihydropyridine calcium antagonist with an intrinsically slow onset of activity, resulting in a lack of reflex tachycardia. It has a long duration of action and a high degree of vascular selectivity. In addition to calcium channel-modulated vasodilation, lacidipine displays antioxidant activity greater than that of other dihydropyridine calcium antagonists. In randomised, well-controlled trials, lacidipine 2-6 mg orally once daily had antihypertensive efficacy similar to that of other long-acting dihydropyridine calcium antagonists, thiazide diuretics, atenolol (a beta-blocker) and enalapril (an ACE inhibitor). Lacidipine was effective in elderly patients (including those with isolated systolic hypertension), African Nigerian patients and patients with concurrent type 2 diabetes mellitus. During long-term treatment for 4 or 5 years in patients with isolated systolic hypertension or essential hypertension, the incidence of cardiovascular events and mortality with lacidipine was similar to that with chlorthalidone or atenolol. The European Lacidipine Study on Atherosclerosis (ELSA), in which 2334 patients with hypertension were randomised to 4 years of therapy with lacidipine 4-6 mg/day or the beta-blocker atenolol 50-100 mg/day, demonstrated significantly lower atherosclerotic progression and plaque formation with lacidipine compared with atenolol in patients completing the full 4 years of the study. Between-group differences in favour of lacidipine for the primary efficacy variable (mean change in carotid artery intima-media thickness) did not reach statistical significance in the intent-to-treat population. The tolerability profile of lacidipine (headache, flushing, pedal oedema, dizziness and palpitations) is similar to that of other dihydropyridine calcium antagonists, but with a lower incidence of peripheral oedema. Data from the ELSA study suggest that the incidence of serious adverse events during long-term lacidipine therapy is similar to that with atenolol. CONCLUSION: Lacidipine is an effective, well tolerated, once-daily, oral antihypertensive agent that can be used in a wide variety of patients. As with other members of its class, lacidipine has shown potentially beneficial antiatherosclerotic effects, although definitive data with respect to possible superiority over other drug classes are still required. Therefore, lacidipine is an attractive therapy for the long-term management of essential hypertension.

[Evaluation of psychosomatic symptomatology in hypertensive patients treated with lercanidipine (LERCAPSICO study)]. / Valoración de la semiología psicosomática en hipertensos tratados con lercanidipino (estudio LERCAPSICO).

OBJECTIVE: To value the grade of anxiety and psychosomatic semiology in hypertensive patients treated with lercanidipine and to analyse their evolution. A secondary objective is to carry out a pharmacovigilance study with lercanidipine. MATERIAL AND METHODS: Prospective multicentre observational 6 month study in primary hypertensive patients with SBP between 140-180 mm Hg and/or 90-110 mm Hg DBP. After a washout period of 10 days, treatment with 10 mg (1-0-0) lercanidipine is initiated. If BP is not controlled treatment with ramipril 2.5 mg/day is instaured. Clinical check-ups are carried periodically with measurements of BP, Heart Rate, objective valuation of tolerance to the drug and observance. At the initiation and end of the study biochemical check-ups are carried out, the level of anxiety is measured using the STAI questionnaire (Trait subscale) (Evaluation in decatipes 0-4 without ansiety 4-7 moderate ansiety, 7-10 high ansiety) and the psychosomatic profile with a questionnaire designed by this group. (Scale 0-18; 0 large semiology, 18 without semiology). Clinical tolerance to the drug is valued both subjectively and objectively. RESULTS: On included 538 patients. On registred 54 drop out, with side effects (3.75/). Completed the study 484 (237 M, 247 F), 429 of them with Lercanidipine in monotherapy (88.6/). Mean age 60.9 +/- 10.7. Mean BMI 29.1 +/- 5. The grade of anxiety did not alter during the study passing from 4.6 +/- 1.7 at the beginning of the study to 4.5 +/- 1.7 at the end of the study (valuation in decatypes) (ns). The psychosomatic semiology changed favourably from 10.7 +/-4.2 to 12.5 +/- 3.7 (p<0.00005). The evolution according to sex is similar. The mean SBP decreased from 165.6 +/- 12.2 mm Hg to 137.9 +/- 10.4 mm Hg (p<0.00005) and the mean DBP decreased from 96.5 +/- 8.1 mm Hg to 81.0 +/- 6.1 mm Hg (p<0.00005). Clinical tolerance was very good. Biochemical parameters were modified substantially: initial cholesterolemia 227.7 mg/dl and final cholesterolemia 213.6 mg/dl (p<0.00005); initial glucose 108.4 mg/dl and final glucose 105.7 mg/dl (p<0.00005). CONCLUSIONS: The mean level of anxiety in the group studied is confirmed not to vary during the length of the study. Psychosomatic semiology is reduced being statistically significant. Lercanidipine is shown to be very effective as antihypertensive and well tolerated. 164

Renal adenosine A3 receptors in the rat: assessment of functional role.

The functional roles of adenosine A3 receptors in the rat kidney were assessed for the first time with respect to A1 receptor-mediated responses. Utilizing a chronically instrumented conscious rat preparation, we tested renal excretory responses to acute administration of the A3 receptor antagonists 3-ethyl-5-benzyl-2-methyl-6-phenyl-4-phenylethynyl-1 ,4-(+)-dihydropridine-3,5-dicarboxylate (MRS-1191) and 9-chloro-2-(2-furyl)-5-phenylacetylamino-[1,2,4]-triazolo[1,5-c]qu inazoline (MRS-1220) with reference to the effects of the A1 receptor antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX). The intravenous administration of DPCPX resulted in significant increases in fluid and sodium excretions without affecting glomerular filtration rate (GFR). This suggests that DPCPX-induced diuretic and natriuretic responses are related to decreased tubular reabsorption. However, neither MRS-1191 nor MRS-1220 alone affected fluid or sodium excretions, or GFR, indicating lack of an effect of either compound on renal function. On the other hand, the co-administration of MRS-1220 with DPCPX abolished both the diuretic and natriuretic responses to DPCPX, being suggestive of antagonism between these two compounds. MRS-1191, however, did not affect the DPCPX-induced fluid and sodium excretions. Neither the A1 nor the A3 receptor antagonists altered potassium excretion individually or in combination. The data suggest that while adenosine A1 receptors are involved in the regulation of renal fluid and sodium transport, A3 receptors do not appear to have a major role in regulation of renal excretory function under baseline physiological conditions.

In vitro assessment for vascular selectivity of a new dihydropyridine derivative, NB-818.

The vascular selectivity of NB-818 (isopropyl methyl 2-carbamoyloxymethyl-6-methyl-4-(2,3-dichlorophenyl)-1,4-dihydropyridine -3, 5-dicarboxylate), a newly synthesized dihydropyridine derivative, was evaluated in in vitro experiments. NB-818 and nifedipine concentration dependently caused a relaxant effect in rabbit femoral arteries precontracted with 60 mM K+, a negative inotropic effect in guinea-pig papillary muscles, and a negative chronotropic effect in guinea-pig right atria. The onset of these inhibitory effects of NB-818 was much slower than that of nifedipine when compared at concentrations producing the same inhibition. The relaxant effect of NB-818 was about 10 times more potent than that of nifedipine, while the negative inotropic effect of NB-818 was about 100 times less potent than that of nifedipine. As a result, NB-818 showed about 300 times higher vascular selectivity than nifedipine. The two drugs exhibited a similar potency for the negative chronotropic effect. In a whole-cell configuration with voltage clamp, the blocking effect of NB-818 on L-type Ca2+ current (ICa) in guinea-pig ventricular cells appeared much more slowly than that of nifedipine and was hardly washed out. The potency of NB-818 to block ICa was markedly enhanced under depolarized conditions (i.e. at a holding potential of -30 mV) compared to that under polarized conditions (i.e. at a holding potential of -70 mV). Such a voltage-dependent blocking action on ICa was less pronounced for nifedipine. These results indicate that NB-818 is a slow-acting Ca2+ channel antagonist with much high vascular selectivity. Its vascular selectivity may be at least in part related to the marked voltage-dependent inhibition of ICa.

An assessment of lacidipine and atenolol in mild to moderate hypertension.

1. The aim of this randomised, double-blind four way crossover study was to assess the interaction between the new calcium antagonist, lacidipine and atenolol, in patients with mild to moderate hypertension. 2. Sitting blood pressure at 4 h post-dosing with lacidipine (4 mg) and atenolol (100 mg) alone was significantly lower compared with placebo (137/89 +/- 3/3 mmHg; 142/89 +/- 5/3 mmHg; and 154/98 +/- 5/3 mmHg respectively; P < 0.001). Co-administration of both drugs produced a significant additive effect compared with atenolol and lacidipine alone (124/80 +/- 4/2 mmHg; P < 0.002). 3. Heart rate on treatment with lacidipine alone was significantly greater at 4 h compared with placebo (86 +/- 1 beats min-1 and 74 +/- 2 beats min-1 respectively; P < 0.001). When both drugs were used in combination, there was a significant decrease in pulse rate compared with lacidipine alone (58 +/- 1 beats min-1 and 86 +/- 1 beats min-1 respectively; P < 0.001). 4. Home blood pressure recordings confirmed the statistically significant reduction in blood pressure on co-dosing (120/82 +/- 10/2 mmHg) compared with lacidipine (140/92 +/- 5/3 mmHg) and atenolol (146/90 +/- 6/3 mmHg) given alone (P < 0.05). 5. Lacidipine alone produced a significant exercise tachycardia compared with atenolol alone and the atenolol/lacidipine combination (97 +/- 8 beats min-1; 65 +/- 4 beats min-1 and 75 +/- 7 beats min-1 respectively; P < 0.001). Exercise tolerance was not adversely affected by the co-administration of both lacidipine and atenolol.

Assessment of Ca(2+)-antagonistic effect of SM-6586 and its isomers, novel 1,4-dihydropyridine derivatives, by radioligand binding assay.

The Ca(2+)-antagonistic effects of the 1,4-dihydropyridine derivative (+/-)SM-6586 and its optical isomers were compared with those of its two derivatives ((+/-)SM-7297 and (+/-)SM-7548) and other Ca(2+)-antagonists using a radioligand binding assay. The Ca(2+)-antagonistic effects of the optical isomers of SM-6586 were in the order of (+) greater than (+/-) greater than (-)SM-6586 in both rat brain and heart. The pKi value of (+)SM-6586 was comparable to those of nimodipine, nicardipine, nifedipine and nitrendipine. The pA2 value for (+)SM-6586 was the highest among the SM-6586 isomers, thus suggesting that (+)SM-6586 has a potent Ca(2+)-antagonistic effect.