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The liquid chromatography mass spectrometry (LC-MS) compatible, stability-indicating, specific, linear, accurate, sensitive with less run-time related impurities reversed phase high-performance liquid chromatography (RP-HPLC) related impurities method has been developed for olmesartan medoxomil (OLM), chlorthalidone (CHLR), and cilnidipine (CIL) drug combinations, and the method has been validated according to ICH and US-FDA guidelines. The chromatographic separation was performed by using Hypersil-BDS Thermo-Scientific, C18 (12.5 cm, 4.6 mm, 5 microns particle size) column. Mobile phase-A was prepared by mixing 3.85 gm ammonium acetate in HPLC water and adjust pH 5.0 by using diluted acetic acid. Acetonitrile was taken as mobile phase-B. Initial mobile phase ratio (55:45 v/v) was adjusted for mobile phase-A: mobile phase-B followed by gradient program. Other chromatographic conditions such as column temperature 25 degrees, flow rate 1.0 mL/minutes with the detection wavelength at 260 nm. The retention time for CHLR impurity A, olmesartan (OL), OLM impurity A, were found about 2.7, 3.3, and 7.2 minutes respectively, with a total run time of 18.0 minutes. The linearity calibration plot was performed and found linear relationship over the concentration range of 1.25 limit of quantitation (LoQ)–18.75 μg/mL, 3.6 LoQ–60.0 μg/mL, 3.6 LoQ– 60.0 μg/mL respectively for CHLR impurity A, OL and OLM impurity A respectively. The limit of detection (LoD) and LoQ were found 0.4 ppm (μg/mL) and 1.2 ppm (μg/mL), 1.2 ppm (μg/mL) and 3.5 ppm (μg/mL), 1.1 ppm (μg/mL) and 3.3 ppm (μg/mL) for CHLR impurity A, OL and OLM impurity A respectively. The accuracy was determined by recovery studies and was found between 90.0–110.0%. The developed analytical method has been validated for LoD-LoQ, specificity, linearity, accuracy, precision, robustness, and ruggedness, which were well within the acceptance limit as per ICH guidelines. All the degradation products generated by stress conditions were found to be well separated from one another (all drug components and impurities). The developed method with shorter runtime was successfully implemented for routine quality control and stability analysis to check the quality of OLM, CHLR, and CIL drug combinations.
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Background: Diabetic kidney disease is a life threatening and disabling complication of uncontrolled diabetes mellitus. Clinical proteinuria is a well-established marker of renal dysfunction. A dual L/N-type calcium channel blocker cilnidipine dilates the afferent and efferent arterioles of the glomerulus decreasing the intraglomerular pressure and showing antiproteinuric effects. The present study was conducted to assess the antiproteinuric efficacy of cilnidipine in patients of diabetic kidney disease.Methods: This interventional study was conducted on 50 patients of both genders aged 18 years and above with diabetic nephropathy (stage-2 to stage 4) visiting the medicine OPD at HIMS, Dehradun over a period of six months, the patients were given tablet cilnidipine (5-20 mg) once or twice a day. Baseline urine protein creatinine ratio (UPCR), serum creatinine and the estimated glomerular filtration rate (eGFR) was recorded at baseline and repeated after a period of 12 weeks. The end point was the decrease in UPCR after a period of 12 weeks. Students-paired T test was used for analysing the intragroup data.Results: After 12 weeks of treatment with cilnidipine, a significant reduction was observed in the urinary protein creatine ratio (mean盨D) from 3.2�23 at baseline to 3.09�09 respectively (p<0.05). Along with this there was also a reduction in the in serum creatinine which was significant (p<0.05) as well as an increase in the eGFR value which was also statistically significant (p<0.001).Conclusions: Cilnidipine reduces the UPCR as well as improves the kidney function in patients with diabetic kidney disease.
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This investigation aimed to prepare Cilnidipine Nanoparticles by nanoprecipitation ultrasonication method and to study the significance of processing variables by applying quality by design. Cilnidipine is fourth-generation dual L/N-type Ca2+ channel blocker used for the management of hypertension. It is BCS class-II drug exhibiting lower aqueous solubility, which tends to lower bioavailability. The combination of Poloxamer 188 and Tween 80 was used as a stabilizer. The design of the experiment is one of the tools of Quality by design. Plackett -Burman design was applied for the screening of processing variables, which are significant for the method. The processing variables screened were stirring speed, antisolvent ratio, drug concentration, polymer concentration, stabilizer concentration. The effect of each parameter evaluated by particle size, entrapment efficiency, and drug release at 10 minutes of prepared Nanoparticles of Cilnidipine. Analysis of variance and Pareto-plot of Plackett-Burman design were utilized to find the significance of the factor and extent of the effect. The surface morphology of Cilnidipine Nanoparticles was studied by SEM. The Pareto plot, as well as statistical analysis of design, had shown that the Concentration of drug, solvent: antisolvent ratio and concentration of poloxamer 188 were the significant parameters for the method. The stabilizer concentration, the stirring speed, and the antisolvent ratio had a negative effect of while the concentration of drug has a positive effect on the particle size of Nanoparticles and drug release at 10 minutes and positive effect of entrapment efficiency of Cilnidipine Nanoparticles. The Cilnidipine Nanoparticles were characterized by FTIR and DSC analysis.
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Background: Chronic kidney disease (CKD) is an emerging health problem and is one of the major causes of mortality. Hypertension is closely linked with CKD and both these conditions cause severe cardiovascular events. Hence blood pressure control is pertinent in all stages of CKD. This plays a major role in preventing its progression to end stage kidney disease and death. The objectives of the study were to analyse the class, dosing schedule of antihypertensive prescribed in Chronic Kidney Disease and the incidence of monotherapy and combination therapy.Methods: This study designed as a cross sectional study was conducted in Nephrology department of a tertiary care center and antihypertensive prescription pattern of 364 CKD patients was analyzed. Demographic details, the co-morbid factors and the details of drugs received by each patient were recorded from their outpatient/ inpatient charts. Data collected were entered in MS excel sheet and descriptive analysis done using SPSS software.Results: Calcium Channel Blocker (CCB) was the most commonly prescribed antihypertensive (70.6%) in all stages and the most common CCB was Cilnidipine (54%) with the dosing schedule of 20mg twice daily (56.4%). Incidence of combination therapy was 71.7% and CCB+AA (Alpha agonist) was the commonest combination prescribed in all stages except stage 1.Conclusions: CCBSs were widely prescribed as antihypertensive in CKD irrespective of the stages. Cilnidpine was the routinely prescribed CCB and seemed to be well tolerated by the patients. The protocol followed in this tertiary care center was in accordance with the standard guidelines by Kidney Disease Improving Global outcomes 2012.
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Background: Blood flow, metabolic rate and oxygenrequirements of an organ guide the extent of oxidativestress experienced by any tissue in response to chronichypoxia. Currently cilnidipine is used in themanagement of hypertension and its antioxidant actionsare gaining wide interest. Aim and Objectives: Toevaluate the tissue specific effects of chronic sustainedhypoxia with regards to oxidative stress in the contextof cilnidipine. Material and Methods: Twenty fouradult male Wistar strain albino rats were randomlyassigned into four groups: group 1, control, normoxia(21% O ); group 2, chronic hypoxia (CH) (10% O ) for 2 221 days; group 3, normoxia + cilnidipine (Cil) for 21days; group 4, chronic hypoxia + cilnidipine (CH+Cil)for 21 days. Following 21 days of intervention bloodwas collected and animals were sacrificed and liver,lung and heart were collected. Serum MDA and MDAin tissue homogenate of liver, lung and heart wereestimated. Results: Our results demonstrate theelevated serum MDAlevels in chronic hypoxia exposedrats (group 2). We also observed increased MDAin liverfollowed by lung and least in the heart in chronichypoxia exposed rats (group 2). Treatment withcilnidipine reduced serum MDA and heart MDA levelsin cilnidipine treated chronic hypoxia exposed rats(group 4). However cilnidipine did not have anyinfluence on MDA levels in the liver and lung in samegroup of rats. Conclusion: The results demonstratetissue specific effects of chronic sustained hypoxia withthe highest oxidative stress observed in the liverfollowed by the lung. Although oxidative stress is alsoobserved in the heart it is the least in comparison to theliver and the lung. Cilnidipine, a dual L/N type calciumchannel blocker demonstrated beneficial antioxidantactions only in the heart supporting the cardioprotectiverole of cilnidipine
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OBJECTIVE:To optimize the formulation of Cilnidipine sustained-release tablet,and study its drug-release mecha-nism. METHODS:Solvent method was adopted to prepare the cilnidipine solid dispersion,then Cilnidipine sustained-release tablet was prepared by using hypromellose K4M(HPMC K4M)as release material. Using comprehensive scores of cumulative release de-gree in 2,6,12 h as indexes,single factor method and Box-Behnken response surface method were used to screen the amounts of HPMC K4M and ethyl cellulose (EC),lactose-microcrystalline cellulose (MCC) ratio in formulation of Cilnidipine sustained-re-lease tablet,and verification test was conducted. The drug-release mechanism of Cilnidipine sustained-release tablet was investigat-ed by model fitting way. RESULTS:The optimal formulation was as follow as 25％ of cilnidipine solid dispersion,30％ of HPMC K4M,10％ of EC,lactose-MCC ratio of 1:1(m/m). The adhesive was 5％ PVPP ethanol solution and the lubricant was 0.5％magnesium stearate. The cumulative release degrees of prepared sustained-release tablet in 2,6,12 h were(21.4±3.3)％,(62.9± 2.8)％,(85.4±0.5)％(n=3),relative error of which to predicted value 25％,60％,90％were 14.4％,4.8％and 5.1％. Release curve showed the highest fitting degree with the first-order release model,conforming to non-Fick diffusion. CONCLUSIONS:Cil-nidipine sustained-release tablet with sustained-release effect is successfully prepared by optimized formulation.
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OBJECTIVE: To study the dissolution behavior of cilnidipine tablets, evaluate the consistency of dissolution behavior between three domestic products and the original tablets, and develop a new dissolution method with discriminatory power for prescription process. METHODS: The dissolution media were hydrochloric acid solution (pH 1.2), acetate buffer (pH 4.0), phosphate buffer (pH 6.8) and water, all containing 0.4% SDS. Using original tablets as the reference preparation, the dissolution curve of the test and reference preparations was compared by the similarity factor method. Apparatus 2 was used for the new method of dissolution test, using 900 mL phosphate buffer with 0.5% SDS (pH 6.8) as the dissolutive medium,at the rate of 75 r·min-1. The dissolution solution was taken at 60 min and analyzed by HPLC. The dissolution limit was set at 70%. RESULTS: For the three domestic pharmaceutical products, only one had consistent dissolution curves in the four dissolution media with the original product from Japanese Ajinomoto Co.. The new method of dissolution test could distinguish the products manufactured by advanced technology from those by process of general level. CONCLUSION: The new dissolution method has discriminatory power for prescription process of insoluble cilnidipine tablets when using phosphate buffer (pH 6.8) as the dissolutive medium, and the quality of the product can be effectively controlled.
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Hypertension is a prevalent condition. Improving blood pressure control would depend on understanding concerns and limitations of physicians. Objective: Understanding practice of calcium channel blockers use among physicians. Material and methods: A cross-sectional, observational paper based questionnaire survey among 218 Indian physicians. Results: According to 55.83% of physicians (n=218), prevalence of hypertension ranges between 21-40%. Sixty percent physicians get referred cases mostly from the general physicians (69.48%). More than 20% patients have concomitant illness according to 33.81% physicians, most common being diabetes (33.44%).According to 96.30% physicians, due to asymptomatic nature, hypertension remains undiagnosed, untreated and uncontrolled. Stress (32.35%), obesity (23.13%), physical inactivity (22.78%) and smoking (20.52%) are responsible for sympathetic over activity. Calcium channel blockers (CCBs) (37.19%), beta blockers (30.43%), angiotensin receptor blocker (ARB) (12.14%) and angiotensin converting enzyme (ACE) inhibitors (4.02%) are used as first choice in patients with sympathetic over activity. Ischemic event, stroke, heart failure and renal failure occur due to ignoring sympathetic over activity according to 30.91%, 25.39%, 20.97% and 22.30% physicians respectively. According to 51.63% of physicians, patient compliance to antihypertensive therapy is > 70%. Lack of awareness (40.5%) and dosage frequency (24%) are two most common reasons for noncompliance. According to 89.72% of physicians, the current CCBs primarily inhibit L-type calcium channels but cause sympathetic over activity. A total of 48.34% physicians, >10% patients complain of pedal edema with amlodipine. In physicians opinion, blockage of L and N type of calcium channels (56.47%), unique mode of action (11.76%), arteriolar and venous dilation (9.41%) and inhibition of reninangiotensin- aldosterone (RAS) system (7.06%) are responsible for less pedal edema with cilnidipine. A total of 98.7% and 99.54% physicians rated efficacy and safety of cilnidipine as “good-very good” compared to other CCB respectively. Conclusion: In hypertension, sympathetic over activity may cause many complications. As per the physicians opinion survey, cilnidipine because of its unique mechanism of action offers multiple benefits in hypertensive patients and can be preferred over amlodipine.
Subject(s)
Adult , Blood Pressure/physiology , Calcium Channel Blockers/administration & dosage , Calcium Channel Blockers/therapeutic use , Dihydropyridines/administration & dosage , Dihydropyridines/analogs & derivatives , Dihydropyridines/therapeutic use , Humans , Hypertension/drug therapy , India , Middle Aged , Physicians , Surveys and Questionnaires , Sympathetic Nervous System/physiologyABSTRACT
A simple and economical dual wavelength spectrophotometric method has been developed for the simultaneous estimation of Cilnidipine and Olmesartan Medoxomil in their tablet dosage form. The principle for dual wavelength method is “the absorbance difference between two points on the overlain spectra is directly proportional to the concentration of the component of interest”. From the UV absorption spectrum of Cilnidipine, three wavelengths were selected, which were 282.99, 337.85 and 352.92 nm. At 352.92 nm only Cilnidipine has reasonable absorbance, so it was selected for the estimation of it from combination drug product. At these two wavelengths absorbance for Cilnidipine was found to be same i.e. absorbance difference was zero for any concentration, while for Olmesartan Medoxomil concomitantly increase in absorbance difference with increase in its concentration. So, 282.99 and 337.85 nm wavelengths were selected for the estimation of Olmesartan Medoxomil from its combination drug product. The method involved solving of an equation based on measurement of absorbances at two wavelengths 282.99 and 337.85 nm. Regression analysis of Beer’s plots showed good correlation in concentration range of 10-60 μg/ml for Cilnidipine and 20-120 μg/ml for Olmesartan Medoxomil. The suitability of this method was for quantitative determination of Cilnidipine and Olmesartan Medoxomil was proved by validation and recovery study. The proposed method was found to be simple, rapid, economical, accurate and reproducible for the routine analysis of both drugs in tablet dosage forms.
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Background: Hypertension is a widespread public health problem and a major risk factor. Amlodipine, a calcium channel blocker is frequently used in the treatment of hypertension. Since Amlodipine primarily L-type calcium channel blocker (CCB) and thus reduces blood pressure, it stimulates sympathetic nerve activity leading to reflex increase in heart rate. Cilnidipine, a new type of CCB which can inhibit L- type calcium channels but also N-type calcium channels. We compare the clinical effectiveness of Amlodipine and Cilnidipine on blood pressure, heart rate, proteinuria and lipid profile in hypertensive patients. Methods: The study was a prospective, randomized, open label comparison, total ninety five patients were recruited for study in which 45 patients received 5-10mg Amlodipine and other 55 patients of same age groups received 10-20mg Cilnidipine. 15 patients in Amlodipine group and 18 patients in Cilnidipine group were diabetic, whereas 12 and 14 patients were proteinuric in Amlodipine and Cilnidipine group respectively. Results: Both the groups were well matched in term of age, weight, clinical findings and laboratory values. Both the drug significantly reduced both systolic (SBP) and diastolic blood pressure (DSP). In the Amlodipine group the pulse rate (PR) after treatment tended to be higher than those before treatment. In the Cilnidipine group there was decrease in PR after treatment. Unlike Amlodipine, Cilnidipine decreased urinary protein excretion and in diabetic patients reduced serum triglyceride. Conclusions: The study indicates that unlike Amlodipine, Cilnidipine which inhibits L-and N-type calcium channels will be useful for patients with hypertension and cardiovascular disease, diabetes mellitus or renal disease and proves to be a better alternative to existing calcium channel blockers.
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The present study was designed to establish comparatively the inhibitory effects of cilnidipine (CNP), nifedipine (NIF), and omega-conotoxin GVIA (CTX) on the release of CA evoked by cholinergic stimulation and membrane depolarization from the isolated perfused model of the rat adrenal medulla. CNP (3 micrometer), NIF (3 micrometer), and CTX (3 micrometer) perfused into an adrenal vein for 60 min produced greatly inhibition in CA secretory responses evoked by ACh (5.32 x 10(-3) M), DMPP (10(-4) M for 2 min), McN-A-343 (10(-4) M for 2 min), high K+ (5.6 x 10(-2) M), Bay-K-8644 (10(-5) M), and cyclopiazonic acid (10(-5) M), respectively. For the CA release evoked by ACh and Bay-K-8644, the following rank order of potency was obtained: CNP > NIF > CTX. The rank order for the CA release evoked by McN-A-343 and cyclopiazonic acid was CNP > NIF > CTX. Also, the rank orders for high K+ and for DMPP were NIF > CTX > CNP and NIF > CNP > CTX, respectively. Taken together, these results demonstrate that all voltage-dependent Ca2+ channels (VDCCs) blockers of cilnidipine, nifedipine, and omega-conotoxin GVIA inhibit greatly the CA release evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors and the membrane depolarization without affecting the basal release from the isolated perfused rat adrenal gland. It seems likely that the inhibitory effects of cilnidipine, nifedipine, and omega-conotoxin GVIA are mediated by the blockade of both L- and N-type, L-type only, and N-type only VDCCs located on the rat adrenomedullary chromaffin cells, respectively, which are relevant to Ca2+ mobilization. It is also suggested that N-type VDCCs play an important role in the rat adrenomedullary CA secretion, in addition to L-type VDCCs.
Subject(s)
Animals , Rats , (4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride , 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester , Adrenal Glands , Adrenal Medulla , Calcium Channels , Calcium Channels, L-Type , Calcium Channels, N-Type , Chromaffin Cells , Dimethylphenylpiperazinium Iodide , Membranes , Nifedipine , omega-Conotoxin GVIA , omega-Conotoxins , VeinsABSTRACT
The present study was attempted to investigate the effect of cilnidipine (FRC-8635), which is a newly synthesized novel dihydropyridine (DHP) type of organic Ca2 channel blockers, on secretion of catecholamines (CA) evoked by acetylcholine (ACh), high K, DMPP and McN-A-343 from the isolated perfused rat adrenal gland. Cilnidipine (1~10microM) perfused into an adrenal vein for 60 min produced relatively dose- and time-dependent inhibition in CA secretory responses evoked by ACh (5.32 10 3 M), DMPP (10 4 M for 2 min) and McN-A-343 (10 4 M for 2 min). However, lower dose of cilnidipine did not affect CA secretion by high K (5.6 10 2 M), higher dose of it reduced greatly CA secretion of high K. Cilnidipine itself did fail to affect basal catecholamine output. In the presence of cilnidipine (10microM), the CA secretory responses evoked by Bay-K-8644 (10microM), an activator of L-type Ca2 channels and cyclopiazonic acid (10microM), an inhibitor of cytoplasmic Ca2 -ATPase were also inhibited. Moreover, omega-conotoxin GVIA (1microM), a selective blocker of the N-type Ca2 channels, given into the adrenal gland for 60 min, also inhibited time-dependently CA secretory responses evoked by Ach, high K, DMPP, McN-A-343, Bay-K-8644 and cyclopiazonic acid. Taken together, these results demostrate that cilnidipine inhibits CA secretion evoked by stimulation of cholinergic (both nicotinic and muscarinic) receptors from the isolated perfused rat adrenal gland without affecting the basal release. However, at lower dose, cilnidipine did not affect CA release by membrane depolarization while at larger dose inhibited that. It seems likely that this inhibitory effect of cilnidipine is exerted by blocking both L- and N-type voltage-dependent Ca2 channels (VDCCs) on the rat adrenomedullary chromaffin cells, which is relevant to inhibition of both the Ca2 influx into the adrenal chromaffin cells and intracellular Ca2 release from the cytoplasmic store. It is thought that N-type VDCCs may play an important role in regulation of CA release from the rat adrenal medulla.