A Review on Development and Validation of Analytical Methods for Estimation of Calcium Channel Blocker

Abstract

In order to determine the amounts of cilnidipine and lisinopril dihydrate, the Dual Wavelength Spectroscopic approach that was proposed was successfully utilized. The method that was created was verified in accordance with ICH Q2 (R1) without any deviations, and based on the findings, it was determined that the current method has the potential to be utilized for the routine examination of raw materials as well as in the formulation of pharmaceuticals. According to the findings of the linearity investigation, the suggested approach was able to produce linear results throughout the concentration range of 4–24 and 10–60 ?g/mL for lisinopril dihydrate and cilnidipine, respectively. It was determined that the proposed method was accurate based on the findings of the precision data and the low levels of the relative standard deviation (RSD). Both the LOD and LOQ values for cilnidipine and lisinopril dihydrate were determined and established. It was discovered that the recovery for lisinopril dihydrate was 98.82%, and the recovery for cilnidipine was 100.24%. The low values of the relative standard deviation (RSD) demonstrate that the procedure was accurate within the range that was defined. The suggested approach was found to be linear, sensitive, exact, and accurate for the simultaneous estimation of lisinopril dihydrate and cilnidipine in bulk and pharmaceutical formulations. This conclusion was reached as a consequence of the successful completion of the validation research and the findings that were discovered.

Keywords

Introduction

       
           
       
 Fig: 2 The contractile action of smooth muscle cells is modified by a number of different factors. KLF4 stands for Kruppel-Like Factor 4, TGs stands for triglycerides, and UPR stands for unfolded protein response. Ox-LDL stands for oxidised low-density lipoprotein.

Water-sodium retention

       
           
       
Fig: 3 When a person consumes a lot of salt, the gut flora causes them to have high blood pressure.

The underlying mechanisms for intestinal flora to lead to increased BP are still under investigation. There is evidence that high-salt intake depleted Lactobacillus to induce T helper 17 cells and to promote hypertension (34). Another study demonstrated that high-salt dietry reduced the levels of B. fragilis and arachidonic acid in the intestine, which increased intestinal-derived corticosterone production and corticosterone levels in serum and intestine, thereby promoting BP elevation (32). In deoxycorticosterone acetate (DOCA)–salt mice model of hypertension, short-chain fatty acids released by the fermentation of fiber from the intestinal flora are associated with lower BP levels, and this may be closely related to the increase in Bacteroides acidifaciens (35). Notably, the intestinal flora is not only involved in salt sensitivity, it also participate in other underlying mechanisms of hypertension (36), including RAAS (37–39), vascular endothelium (40), and renal dysfunction (41) etc. A recent large intestinal flora sequencing study demonstrated the role of intestinal flora in human was extremely complex (42). Intestinal flora also has the potential to be an independent mechanism of essential hypertension.

Angiotensin-converting enzyme inhibitors and angiotensin II type I receptor blockers

ACEIs and ARBs have been the cornerstone of RAAS inhibition for years and are key therapeutic options in patients with hypertension (HTN), reducing cardiovascular morbidity and mortality and improving renal outcomes. In the HOPE (Heart Outcomes Prevention Evaluation) ⁵, MICRO-HOPE (The Microalbuminuria, Cardiovascular, and Renal Outcomes in HOPE) ⁶, EUROPA (European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease) ⁷, SOLVD (Studies of Left Ventricular Dysfunction) ⁸, and Captopril Prevention Project ⁹ studies, ACEIs were beneficial in reducing rates of death, myocardial infarction, stroke, coronary revascularization, cardiac arrest, and heart failure, complications related to diabetes and heart failure. Both the RENAAL ¹⁰ and IDNT ¹¹ trials demonstrated a renoprotective effect of RAAS inhibition in nephropathy due to diabetes. ACEIs and ARBs are considered to be equally beneficial on the basis of studies such as ONTARGET ¹², which compared telmisartan and ramipril, and DETAIL ¹³, which compared telmisartan with enalapril and found no difference in progression of diabetic nephropathy. Azilsartan, a novel ARB, has been shown to have superior efficacy in reducing blood pressure (BP) when compared with olmesartan or valsartan ^14– 16. Azilsartan 80 mg reduces BP more efficaciously than the optimal and highest tolerated dosage of both olmesartan (40 mg) and valsartan (320 mg) using 24-hour ambulatory BP monitoring and without increase in adverse effects ¹⁴. A recent analysis of a German registry confirmed these results; among 3,849 patients with essential HTN, 61% of patients who initiated therapy with azilsartan achieved a BP target of less than 140/90 mmHg compared with 56% of those who were started on an ACEI ¹⁷. Azilsartan may be more effective at lowering BP because of its more potent ability to block AT ₁ receptors ¹⁸. However, only a prospective, randomized, dose-escalation study can truly test whether azilsartan is superior to other ARBs at lowering BP.

Direct renin inhibitors

Renin secretion, a rate-limiting step, is the first step of the RAAS cascade. Renin has a unique specificity for its substrate angiotensin. Inhibition of renin provides an attractive option to inhibit the RAAS from its origin. The development of DRI started more than 30 years ago ¹⁹, but there were issues with potency, bioavailability, and cost. Currently, aliskiren is the only approved DRI for use in HTN ²⁰, and a significant BP reduction has been demonstrated in patients with essential HTN ^21, 22. Aliskiren is well tolerated and has a similar dose-dependent BP reduction in hypertensive patients as ARBs and a safety profile similar to that of placebo ^23, 24. However, several recent studies have shown either no benefit or even harmful effects of aliskiren in certain populations. The ALTITUDE (Aliskiren Trial in Type 2 Diabetes Using Cardio-Renal Endpoints) ²⁵ trial randomly assigned patients with type 2 diabetes and chronic kidney disease (CKD) or with cardiovascular disease (or with all three) already receiving an ACEI or ARB to aliskiren or placebo. Although there was a lower BP in the aliskiren arm, there was no reduction in the primary composite outcome, which included cardiovascular and renal events and mortality (hazard ratio [HR] 1.08, 95% confidence interval [CI] 0.98–1.20). In the ATMOSPHERE ²⁶ trial (Aliskiren Trial to Minimize Outcomes in Patients with Heart failure), the addition of aliskiren to enalapril in patients with chronic heart failure was not associated with reduction in adverse outcomes (see “Recent clinical trials” section for details). Similarly, no improvement in coronary atherosclerosis in pre-hypertensive patients (AQUARIUS) ²⁷ or improvement in cardiovascular outcomes in patients hospitalized with heart failure (ASTRONAUT) ²⁸ was seen with aliskiren compared with placebo. Given the lack of demonstrated benefit and increased rates of adverse events such as hyperkalemia, hypotension, and renal impairment as seen in ASTRONAUT when combined with ACEIs or ARBs, the current use of aliskiren is limited ²⁸.

Mineralocorticoid receptor antagonists

MRAs competitively inhibit mineralocorticoid receptors and decrease the number of epithelial sodium channels in the distal renal tubule ²⁹. Spironolactone, an MRA, has long been used for the treatment of HTN; however, its non-specificity for mineralocorticoid receptors manifests as anti-androgenic and progestational effects ^30, 31. Spironolactone was found to be the most effective add-on anti-hypertensive drug when compared with doxazosin and bisoprolol in treating resistant HTN in the PATHWAY-2 trial ³². This trial supports the important role of sodium retention in resistant HTN. Eplerenone, an MRA with lower affinity to progesterone and androgen receptors than spironolactone ²⁹, has been shown to be efficacious even using ambulatory monitoring studies ³³ and safe in the management of HTN. When compared with enalapril ³⁴, losartan ³⁵, and amlodipine ³⁶, eplerenone monotherapy was as efficacious in treating HTN. Currently, third- and fourth-generation MRAs are being developed to have the potency of spironolactone and the selectivity of eplerenone ³⁷. Finerenone, a novel non-steroidal MRA, has a greater affinity to the mineralocorticoid receptor than does eplerenone ³⁸ and greater selectivity than does spironolactone ³⁹. The Mineralocorticoid Receptor Antagonist Tolerability Study (ARTS) showed that finerenone (2.5–10 mg per day), in patients with CKD and albuminuria, decreased albuminuria with lower rates of hyperkalemia compared with spironolactone ⁴⁰. With the recent development of patiromer, a non-absorbed potassium binder, a safe option for the treatment of chronic hyperkalemia is available, maintaining and using RAAS inhibitors including spironolactone, in CKD and heart failure ⁴¹. Patiromer has also been shown to decrease potassium and aldosterone levels in patients with CKD and hyperkalemia on RAAS inhibitors independent of renin activity ⁴². The recent ARTS-DN (Mineralocorticoid Receptor Antagonist Tolerability Study–Diabetic Nephropathy) study demonstrated greater reduction in albuminuria with the addition of finerenone to ACEI or ARB in patients with diabetic nephropathy compared with placebo.^43, 44.

Aldosterone synthase inhibitors

Another way of blocking the effects of mineralocorticoid receptor activation is to inhibit aldosterone formation. LCI699 is a potent first-in-class aldosterone synthase inhibitor. In patients with primary aldosteronism, LCI699 (up to 1.0 mg twice a day) caused modest reduction in 24-hour systolic BP (SBP) and office SBP compared with placebo ⁴⁵. One mg of LCI699 was not superior to eplerenone 50 mg in reducing ambulatory SBP in patients with stage 1 or 2 HTN ⁴⁶. LCI699 significantly lowered office and ambulatory BP in patients with primary HTN, but 20% of the patients on LCI699 developed blunted cortisol release ⁴⁶. Because of this non-specificity, the development of LCI699 has been stopped in favor of developing more specific inhibitors.

Aminopeptidase A inhibitor

Functional RAAS may be present in the brain ⁴⁷, and several animal models have demonstrated that hyperactivity of brain RAAS may contribute to HTN ^48, 49. Brain aminopeptidase A (APA) converts angiotensin II to angiotensin III. APA inhibition by EC33 has been shown to be a novel anti-hypertensive agent in animals ^50– 52. QGC001, an orally active prodrug of EC33, was tolerated in healthy normotensive human males but with no changes in renin, aldosterone, BP, or heart rate ^53– 56. This study demonstrates that QGC001, the first drug in its class, can be safely administered to humans, but further studies are required to assess the safety and efficacy of QGC001 in patients with HTN. Additional research on novel ways to block the RAAS, including development of prorenin blockade, gene- and vaccine-based strategies, and targeting ACE2, is being developed but has not yet translated into the clinic. 

CONCLUSION

Although there is regional variability in the outlook for hypertension over the next 5 to 10 years, It is clear overall that the prevalence of hypertension and, therefore, the associated global burden attributable to hypertension, will increase. Global population growth and aging will largely contribute to this increase – 1.5 billion people are expected to be affected by 2025– which will be focused in low and middle income countries. However, these adverse trends in disease burden will be variably offset by improvements in prevention, awareness and treatment. The size of improvements in each of these 3 areas will vary from non-existent (-hypertension prevention could even worsen in some parts of the world, as exposure to factors that promote raised BP increases) to substantially large and important elsewhere in the world. Overall, prevention will probably contribute least to any improvement in BP-associated disease burden. This is because 80% of the world is in the process of developing, which hitherto has inevitably been associated with increased exposure to the main environmental determinants of raised BP such as excess intake of calories, alcohol and salt. Food and drink industries, governments and education systems would be required to cooperate in order to reverse this pattern. Implementation of preventive strategies has largely been limited to high income countries. Despite reasonably compelling evidence to the contrary, recommendations that the general population should restrict salt intake have been questioned on the basis of largely suboptimal observational data Such confusion worsens an already very difficult public health challenge. Data show that only approximately half of people with hypertension are aware of their condition, and the Lancet Commission on hypertension identified improving awareness of hypertension is a critical action needed to improve the current disease burden. The global BP awareness campaign promoted by the International Society of Hypertension whereby World Hypertension Day was extended to become May Measurement Month (MMM) in 2017 could contribute substantially to improving rates of routine BP screening around the world. Over 1.20 million adults (?18 years) from >100 countries were screened as part of MMM and the ensuing data allied to health-economic analyses will be used to persuade policy makers in each country that enhanced local BP screening and treatment facilities are wise financial investments.

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