Effect of Fixed-Dose Combination of Efonidipine + S(-) Metoprolol in Indian Hypertensive Patients

Aim: To evaluate the antihypertensive efficacy and safety of the fixed-dose combination (FDC) of Efonidipine and S (-) Metoprolol in adult patients with hypertension. Study Design: Multicentric, double-blind, randomized, parallel, comparative Phase III trial. Methodology: This clinical trial was conducted at five geographically distributed sites across India and enrolled 240 hypertensive patients. They were randomized (1:1) to receive either FDC of Efonidipine 40 mg + S (-) Metoprolol 25 mg tablet (E+S(-)M group) or FDC of Cilnidipine 10 mg + Metoprolol 50 mg tablet (C+M group) once daily for 90 days. Patients were evaluated for changes in their blood pressure (BP) from baseline to Day 30, 60 and 90. The study site staff, investigator and patients were blinded to the treatment allocation. Blood pressure was recorded as the mean of 3 consecutive measurements taken in a sitting position. Patients achieving target BP (<140/90 mmHg) were evaluated and the safety and tolerability were assessed based on the incidences of adverse events (AEs). Results: This study focused on evaluating the mean Systolic BP (SBP) and Diastolic BP (DBP) reduction from baseline to Day 30, 60 and 90. At baseline, patients had a mean (±SD) SBP and DBP of 154.60 (±11.33) mmHg and 98.68 (±8.18) mmHg respectively. After 30 days of the E+S(-)M treatment, the mean SBP/DBP was 136.06±10.55/ 86.68±5.51 mmHg (p<0.0001) and on Day 60 it was 129.48±10.51/ 84.17±5.51mmHg (P <0.0001), corresponding to mean reductions in SBP/DBP of 18.09/11.66 and 24.78/14.17 mmHg, respectively. There was a statistically significant (p <0.0001) reduction to 123.59 ± 15.21 mmHg in SBP and 82.38 ± 5.05 mmHg in DBP observed on Day 90 as compared to baseline. Post-treatment with E+S(-)M group, SBP/DBP reduction of 31.01/16.29 mmHg in hypertensive patients was observed. A total of 95% of the patients achieved a pre-defined target BP <140/90 mmHg on the administration of E+S(-)M. Furthermore, it was observed that 93% of Stage I and 96% of Stage II hypertensive patients achieved the target BP goal. A total of 5.78% of patients experienced adverse events (AEs) in the E+S(-)M group which was similar to that of C+M group. All AEs were mild in severity and resolved without any sequelae at the end of the study. No unexpected adverse events were reported, and the E+S(-)M dosage regimen was well tolerated by the patients. Both the treatment groups were non-inferior to each other. Conclusion: The study results demonstrated clinically meaningful reductions in blood pressure after administration of FDC of Efonidipine 40 mg + S(-) Metoprolol 25 mg over a period of 90 days. The treatment was efficacious, safe, and well?tolerated in the study population.

Forced degradation study of efonidipine HCl ethanolate, characterization of degradation products by LC-Q-TOF-MS and NMR

Efonidipine HCl Ethanolate is an antihypertensive drug with 1,4 dihydropyridine and phosphinane derivative. Forceddegradation study was performed in Efonidipine as per the guidelines by International Conference on Harmonization(ICH) Q1A (R2). Extensive degradation and slight degradation were observed in alkaline and photolytic conditions,respectively, whereas acidic, oxidative, and thermal conditions did not show any degradation. Degradation productswere separated on Thermo Hypersil BDS C18 column (250 × 4.6 mm, 5 µ), mobile phase in gradient mode usingammonium acetate buffer and acetonitrile with detection at a wavelength of 254 nm. Six degradation products in alkalinecondition and four degradation products in photolytic condition were identified by HPLC and characterized by massspectrometry using LC-Q-TOF-MS, and degradation pathway was proposed. This is the typical case of degradation,where co-solvent methanol reacts with Efonidipine to form pseudo degradation products such as DP1, DP4, DP5, andDP6. Three degradation products DP1, DP3, and DP4 in alkaline condition were isolated by preparative HPLC andwere characterized by LC-Q-TOF-MS, 1H/13C NMR, and IR techniques. By characterization with these techniques,DP1 is characterized as 3-2-(N-benzylanilino)ethyl 3-oxo-2,2-dimethylpropyl hydrogen 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl) pyridin-3-yl-3-phosphonate, DP3 is characterized as 2-(N-benzyl-N-phenylamino) ethanol, and DP4is characterized as 3-methoxy-2,2-dimethylpropyl hydrogen 1,4-dihydro-2,6-dimethyl-5-methyloxycarbonyl-4-(3-nitro)phenylpyridin-3-yl-3-phosphonate. The developed method was validated as per guidelines by ICH with respectto linearity, accuracy, precision, limit of detection, and robustness.

Effect of Efonidipine on Proteinuria in Patients with Chronic Kidney Disease Receiving RAS Blockade / 대한신장학회지

PURPOSE: Efonidipine, which inhibits both T- and L-type calcium channels, has been shown to be effective in reducing proteinuria and preserve renal function. This study was conducted to compare the effects of efonidipine versus amlodipine on the management of hypertension and proteinuria in patients with chronic kidney disease (CKD) receiving ACE inhibitors or ARB. METHODS: This study included 41 CKD patients who were at stages 2-4 and had a urine spot protein/ creatinine ratio of >0.5. Patients were administered amlodipine (5 mg/day) and efonidipine (40 mg/ day) for 3 months in a cross-over design. Blood pressure and spot urine protein/creatinine ratio were compared before and after the cross-over treatment. RESULTS: There were 24 male patients and 17 female patients. The mean age of the patients was 55.9+/-12.9 years. When the patients' medication was changed to eponidifine, we obtained the following results. First, there were no significant changes in blood pressure and serum creatinine. Second, the urine spot protein/creatinine ratio was significantly decreased (before the cross-over, 2.9+/-2.6; after the cross-over, 2.3+/-1.9 g/g; p=0.02). Finally, the reduction rate of proteinuria was significantly higher in patients with CKD at stages 2-3 than in those with CKD at stage 4 after the cross-over (stage 2, - 26.1%; stage 3, -17%; stage 4, +12.8%; p=0.03). CONCLUSION: It is concluded that efonidipine may significantly decrease proteinuria compared with amlodipine in CKD patients receiving ACE inhibitors or ARB. Further double-blind clinical trials with a larger sample size are needed to confirm our results.

Spectroscopic studies on the interaction of efonidipine with bovine serum albumin

Efonidipine hydrochloride is an antihypertensive and antianginal agent with fewer side effects and is better tolerated in the treatment of hypertension with renal impairment. Its interaction with bovine serum albumin (BSA) is of great use for the understanding of the pharmacokinetic and pharmacodynamic mechanisms of the drug. The binding of efonidipine to BSA was investigated by fluorescence spectroscopy and circular dichroism. BSA fluorescence was quenched by efonidipine, due to the fact that efonidipine quenched the fluorescence of tryptophan residues mainly by the collision mode. The thermodynamic parameters ÄH0 and ÄS0 were 68.04 kJ/mol and 319.42 J·mol-1·K-1, respectively, indicating that the hydrophobic interactions played a major role. The results of circular dichroism and synchronous fluorescence measurements showed that the binding of efonidipine to BSA led to a conformational change of BSA. The fraction of occupied sites (è) for the 8-anilino-1-naphthalein-sulfonic acid (ANS)-BSA system is 85 percent, whereas for the NZ-105-BSA system, it is 53 percent, which suggests that the interaction of ANS with BSA is stronger than that of NZ-105 with BSA. Binding studies in the presence of ANS indicated that efonidipine competed with ANS for hydrophobic sites of BSA. The effects of metal ions on the binding constant of the efonidipine-BSA complex were also investigated. The presence of metal ions Zn2+, Mg2+, Al3+, K+, and Ca2+ increased the binding constant of efonidipine_BSA complex, which may prolong the storage period of NZ-105 in blood plasma and enhance its maximum effects.