Application and Research Progress of Crystal Forms of Dihydropyridine Antihypertensive Drugs / 医药导报

Dihydropyridine (DHP) calcium channel blockers drugs (dipine in drug names) are currently used in the treatment of hypertension clinically. In recent years, with the emergence of generic drugs, it has been found that the drug efficacy is quite different from that of the original drug, and the reason is closely related to the difference in the crystal forms of the oral preparations. This paper reviews the polymorphic phenomenon of some DHP calcium channel blockers in the domestic market, introduces the clinical application and research progress of the DHP drugs, analyzes the differences between different crystal forms of the same drugs. This work may provide references and ideas for the research and development of generic drugs or new crystalline drug of DHP drugs.

Key Influencing Factors of Stability of 1, 4-Dihydropyridine Drug Solutions / 中国药学杂志

OBJECTIVE: To study the stability of 1, 4-dihydropyridines solutions and the key influencing factors. METHODS: The stabilities of the solutions of several representative drugs, ie, benidipine hydrochloride, amlodipine besylate and nifedipine, were tested in six kinds of solvents of different pHs (pH 1.0, pH 1.2, pH 2.0 hydrochloric acid solutions, pH 4.0 acetic acid solution, pH 6.8 phosphoric acid solution, water) by HPLC method. The effects of several metal ions, Fe3+ concentration and different pH values on the stability of the drug solutions were also investigated. RESULTS: Fe3+could lead to rapid degradation of 1, 4-dihydropyridine drugs, the degradation rate was accelerated with the increase of Fe3+concentration, and the degradation rate was decreased with the increase of pH value. CONCLUSION: The aromatization of 1, 4-dihydropyridines by Fe3+is the main reason for the degradation of 1, 4-dihydropyridines.

Comparison of electrophysiological effects of calcium channel blockers on cardiac repolarization

Dihydropyridine (DHP) calcium channel blockers (CCBs) have been widely used to treat of several cardiovascular diseases. An excessive shortening of action potential duration (APD) due to the reduction of Ca2+ channel current (I(Ca)) might increase the risk of arrhythmia. In this study we investigated the electrophysiological effects of nicardipine (NIC), isradipine (ISR), and amlodipine (AML) on the cardiac APD in rabbit Purkinje fibers, voltage-gated K+ channel currents (I(Kr), I(Ks)) and voltage-gated Na+ channel current (I(Na)). The concentration-dependent inhibition of Ca2+ channel currents (I(Ca)) was examined in rat cardiomyocytes; these CCBs have similar potency on I(Ca) channel blocking with IC50 (the half-maximum inhibiting concentration) values of 0.142, 0.229, and 0.227 nM on NIC, ISR, and AML, respectively. However, ISR shortened both APD50 and APD90 already at 1 microM whereas NIC and AML shortened APD50 but not APD90 up to 30 microM. According to ion channel studies, NIC and AML concentration-dependently inhibited I(Kr) and I(Ks) while ISR had only partial inhibitory effects (<50% at 30 microM). Inhibition of I(Na) was similarly observed in the three CCBs. Since the I(Kr) and I(Ks) mainly contribute to cardiac repolarization, their inhibition by NIC and AML could compensate for the AP shortening effects due to the block of I(Ca).

Environmental biotoxicity screening of some pyrrole and 1,4-dihydropyridine heterocyclic derivatives.

Synthesis of pyrrole 1-3 and 1,4-dihydropyridine derivatives 4-6 were prepared from condensation method and synthesized compounds were screened for environmental biotoxicity such as Brine shrimp cytotoxicity, Ichthyotoxic, Larvicidal and Nematicidial activities. Among the compounds 3 and 6 shows that highly toxic (LD50: 8.72 and 12.30 μg/mL) against Brain shrimp cytotoxic screening and compound 3 and 6 was highly toxicity ( LD50 : 5.01 and 7.75 μg/mL) against Antifeedant screening (ichthyotoxic profile). The compounds 3 and 6 was highly active (LD50: 12.88 μg/mL, and 14.79 μg/mL) against Larvicidal activity and compound 3 and 6 was highly active (LD50 : 8.20 μg/mL, and 7.43 μg/mL) against Nematicidal activity.

Effects of Four Dihydropyridine Calcium Antagonists on CYP3 A4 Enzyme Activity Induced By Dexametha-sone in Female Rats / 中国药师

Objective:To study the inhibition effects of four dihydropyridine calcium antagonists felodipine, nicardipine, lercani-dipine and nifedipine on CYP3A4 enzyme to provide the theoretical basis for the understanding of the drug interactions between dihydro-pyridine calcium antagonists and other drugs. Methods:Using the probe drugs method, the SD female rats induced by 80 mg·kg-1 · d-1 dexamethasone for three days were divided into the negative control group, positive control group, four DHPs groups with six ones in each. Dapsone was used as the probe substrate, and the concentration was determined by HPLC. Data analysis software WinNonLin was used in the pharmacokinetic model fitting process and the paired t-test was used in the statistical analysis. Results: AUC0-24 and CL/F of dapsone in the negative control group showed statistically significant differences when compared with those in the four DHPs groups and the positive group (Pnicardipine > lercanidipine > felodipine, the difference was not statistically significant (P>0. 05). Cmax of dapsone in the DHPs groups and the positive group had no statistically significant difference when compared with that in the negative control group ( P>0. 05). Conclusion:Although there are different inhibition effects on CYP3A4 among the four DHPs, the differences are not significant in vivo, and there is no influence on the combination drugs which is not mainly metabolized by CYP3A4.

Effect of felodipine on myocardial and renal injury induced by aldosterone-high salt hypertension in uninephrectomized rats

It has been recently shown that calcium channel blockers might have a protective effect on cardiac fibrogenesis induced by aldosterone. The objective of this study was to evaluate the protective effect of felodipine, a dihydropyridine calcium channel blocker, against heart and kidney damage caused by aldosterone-high sodium intake in uninephrectomized rats. Wistar rats were divided into three groups: CNEP (uninephrectomized + 1 percent NaCl in the drinking water, N = 9); ALDO (same as CNEP group plus continuous infusion of 0.75 µg/h aldosterone, N = 12); ALDOF (same as ALDO group plus 30 mg·kg-1·day-1 felodipine in the drinking water, N = 10). All results were compared with those of age-matched, untreated rats (CTL group, N = 10). After 6 weeks, tail cuff blood pressure was recorded and the rats were killed for histological analysis. Blood pressure (mmHg) was significantly elevated (P < 0.05) in ALDO (180 ± 20) and ALDOF (168 ± 13) compared to CTL (123 ± 12) and CNEP (134 ± 13). Heart damage (lesion scores - median and interquartile range) was 7.0 (5.5-8.0) in ALDO and was fully prevented in ALDOF (1.5; 1.0-2.0). Also, left ventricular collagen volume fraction ( percent) in ALDOF (2.9 ± 0.5) was similar to CTL (2.9 ± 0.5) and CNEP (3.4 ± 0.4) and decreased compared to ALDO (5.1 ± 1.6). Felodipine partially prevented kidney injury since the damage score for ALDOF (2.0; 2.0-3.0) was significantly decreased compared to ALDO (7.5; 4.0-10.5), although higher than CTL (null score). Felodipine has a protective effect on the myocardium and kidney as evidenced by decreased perivascular inflammation, myocardial necrosis and fibrosis.

TRPC3 cation channel plays an important role in proliferation and differentiation of skeletal muscle myoblasts

During membrane depolarization associated with skeletal excitation-contraction (EC) coupling, dihydropyridine receptor [DHPR, a L-type Ca2+ channel in the transverse (t)-tubule membrane] undergoes conformational changes that are transmitted to ryanodine receptor 1 [RyR1, an internal Ca2+-release channel in the sarcoplasmic reticulum (SR) membrane] causing Ca2+ release from the SR. Canonical-type transient receptor potential cation channel 3 (TRPC3), an extracellular Ca2+-entry channel in the t-tubule and plasma membrane, is required for full-gain of skeletal EC coupling. To examine additional role(s) for TRPC3 in skeletal muscle other than mediation of EC coupling, in the present study, we created a stable myoblast line with reduced TRPC3 expression and without alpha1SDHPR (MDG/TRPC3 KD myoblast) by knock-down of TRPC3 in alpha1SDHPR-null muscular dysgenic (MDG) myoblasts using retrovirus-delivered small interference RNAs in order to eliminate any DHPR-associated EC coupling-related events. Unlike wild-type or alpha1SDHPR-null MDG myoblasts, MDG/TRPC3 KD myoblasts exhibited dramatic changes in cellular morphology (e.g., unusual expansion of both cell volume and the plasma membrane, and multi-nuclei) and failed to differentiate into myotubes possibly due to increased Ca2+ content in the SR. These results suggest that TRPC3 plays an important role in the maintenance of skeletal muscle myoblasts and myotubes.

INHIBITION OF TRYPANOSOMA CRUZI GROWTH IN MAMMALIAN CELLS BY NIMODIPINE, WITH LOW CYTOTOXICITY TO HOST CELLS

An in vitro infection system of <I>Trypanosoma cruzi</I> and HeLa cells was used to measure the anti-<I>T. cruzi</I> activities of various calcium antagonists classified into dihydropyridines, diphenylalkylamines, and benzothiazepines and of allopurinol and benznidazole as medium and highly effective reference compounds, respectively. Six dihydropyridines (10 μM each), i. e. nifedipine, nicardipine, nimodipine, nisoldipine, nitrendipine, and amlodipine, decreased the rates of infection of HeLa cells from 11.7% (control) to 5.8, 0.9, 1.2, 3.6, 5.9, and 1.7%, respectively. Nicardipine and amlodipine were highly toxic to HeLa cells, causing detachment of cells from coverslips. Nimodipine was thus the most effective inhibitor tested against <I>T. cruzi</I> infection in HeLa cells. Verapamil and gallopamil (diphenylalkylamines), diltiazem and midazolam (benzothiazepines), and allopurinol (positive control) were less effective than nimodipine. IC<SUB>50</SUB> values, the concentrations of compounds that elicited a 50% reduction in the infection rates of HeLa cells, were 2.5, 2.6, 1.3, 2.1, and 1.7 μM for nicardipine, nimodipine, amlodipine, verapamil, and benznidazole, respectively, while the values for nifedipine, diltiazem, and allopurinol were much higher. Nicardipine, amlodipine, and verapamil again showed significant cytotoxicities to HeLa cells. When Swiss 3T3 fibroblasts replaced HeLa cells, nimodipine markedly lowered the host-cell-infection rate, with an IC<SUB>50</SUB> value of 8.3 nM. Thus, nimodipine is expected to be a highly effective anti-<I>T. cruzi</I> lead compound, with low cytotoxicity to mammalian cells. Structural formulas of nimodipine and nicardipine in relation to their low and high cytotoxicities, respectively, against HeLa cells are discussed.

Analysis of Calcium Antagonists Used in Some Hospitals of Guangdong Province from 2002 to 2004 / 中国药房

OBJECTIVE:To evaluate the status quo and the tendency of calcium antagonists used in Guangdong Province.METHODS:The consumption sum,DDDs and the average daily expenses of calcium antagonists in Guangdong Province from2002to2004were analyzed statistically.RESULTS:The consumption sum of calcium antagonists from2002to2004increased year by year,with amlodipine leading the list of consumption sum and nifedipine leading the list of DDDs.CONCLUSIONS:Dihydropyridine calcium antagonists dominate Guangdong market.

Thyroid hormone-induced alterations of ryanodine and dihydropyridine receptor protein expression in rat hear

Thyroid hormone-induced cellular dysfunctions may be associated with changes in the intracellular Ca2+ concentration. The ryanodine receptor, a Ca2+ release channel of the SR, is responsible for the rapid release of Ca2+ that activates cardiac muscle contraction. In the excitation-contaction coupling cascade, activation of ryanodine receptors is initiated by the activity of sarcolemmal Ca2+ channels, the dihydropyridine receptors. In hyperthyroidism left ventricular contractility and relaxation velocity were increased, whereas these parameters were decreased in hypothyroidism. The mechanisms for these changes have been suggested to include alterations in the expression and/or activity levels of various proteins. In the present study, quantitative changes of ryanodine receptors and the dihydropyridine receptors, and the functional consequences of these changes in various thyroid states were investigated. In hyperthyroid hearts, (3H)ryanodine binding and ryanodine receptor mRNA levels were increased, but protein levels of ryanodine were not changed significantly. However, the above parameters were markedly decreased in hypothyroid hearts. In case of dihydropyridine receptor, there were a significant increase in the mRNA and protein levels, and (3H)nitrendipine binding, whereas no changes were observed in these parameters of hypothyroid hearts. Our findings indicate that hyperthyroidism is associated with increases in ryanodine receptor and dihydropyridine receptor expression levels, which is well correlated with the ryanodine and dihydropyridine binding. Whereas opposite changes occur in ryanodine receptor of the hypothyroid hearts.

A Clinical Study of Antihypertensive Effects of Amlodipine(Norvasc(R)) in Essential Hypertension

BACKGROUND: To evaluate the safety and the efficacy of amlodipine, a dihydropyridine calcium antagonist, monotherapy in the treatment of moderate essential hypertension. METHOD: Amlodipine 5mg once a day was administered as a starting dose in 30 patients with essential hypertension in the morning and a one step upward titration was performed (amlodipine 10 mg once a day) was done at the end of 4weeks treatment. Final evaluation was done at 12weeks with laboratory test and echocardiogram. RESULT: Within 4weeks treatment with dose of 5mg amlodipine once a day, the systolic blood pressure (SBP) was decreased(184.5+/-23.3/150.5+/-16.0mmHg,p<0.000), and the diastolic blood pressure(DBP) was also decreased significantly (109.9+/-04.6/92.3+/-11.5mmHg, P<0.001). After 12 weeks of treatment with a mean dosage of 6.6mg once a day, SBP and DBP was maintained comparing with basal level (147.0+/-15.8/88.1+/-0.9mmHg, respectively). The efficacy of amlodipine treatment was noted an excellent in 16 patients(53.3%), good in 4 patient(13.3%), fair in 4 patients(13.3%), and failed in 2 patients(6.7%). There was no significant change in heart rate before and after amlodipine treatment. (80.0+/-2.3/80.9+/-10.4 beats/minute n.s). Amlodipine had not significant effects on laboratory findings such as serum creatinine, BUN, ALT/AST, hemoglobin, leukocyte count,platelet and lipid profiles. There was facial flushing 2 patients, but no need to discontinue administration of amlodipine and all patients completed for 12weeks therapy. CONCLUSION: It is concluded that amlodipine is an effective antihypertensive agent, as monotherapy once a day in patients with moderate essential hypertension.