Comparison of Efficacy and Safety of Benidipine With

Home , Benidipine, Nimodipine

DISSERTATION ON

“COMPARISON OF EFFICACY AND SAFETY OF BENIDIPINE WITH

AMLODIPINE IN PATIENTS WITH UNCOMPLICATED HYPERTENSION

- A PROSPECTIVE STUDY”

Dissertation submitted to

THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSITY

In partial fulfillment of the requirement

For the award of the degree of

M.D. BRANCH-VI

IN PHARMACOLOGY

Submitted By

Registration Number: 201716452

KARPAGA VINAYAGA INSTITUTE OF MEDICAL SCIENCES

AND RESEARCH CENTRE, MADURANTHAGAM

THE TAMILNADU Dr. M.G.R. MEDICAL UNIVERSITY, CHENNAI

TAMILNADU

MAY-2020 CERTIFICATE

This is to certify that Dr. S. SRINATH, a Post Graduate student in the

Department of Pharmacology has carried out the work titled “Comparison of efficacy and safety of Benidipine with Amlodipine in patients with uncomplicated hypertension” under the guidance of Dr. P. JACOB VERGHESE, M.D.,

PROFESSOR, Department of Pharmacology, towards the partial fulfillment of regulations laid down by The Tamilnadu Dr. M.G.R Medical University, Guindy,

Chennai, Tamilnadu, India for the award of Doctor of Medicine (M.D.,) in

Pharmacology.

Dr.P. JACOB VERGHESE, M.D., DR. S. VIJAYALAKSHMI, M.D., PROFESSOR, PROFESSOR & HOD, Karpaga Vinayaga Institute of Karpaga Vinayaga Institute of Medical Medical Sciences & Research Centre, Sciences & Research Centre,

Chinnakolambakkam, Chinnakolambakkam, MaduranthagamTk, MaduranthagamTk,

Kancheepuram District– 603 308, Kancheepuram District– 603 308, Tamilnadu, India. Tamilnadu, India.

DR. SUFALA SUNIL VISHWASRAO,

PRINCIPAL, Karpaga Vinayaga Institute of Medical Sciences & Research Centre, Chinnakolambakkam, Maduranthagam Tk, Kancheepuram District– 603 308, Tamilnadu, India.

DECLARATION

I declare that dissertation entitled “Comparison of efficacy and safety of

Benidipine with Amlodipine in patients with Uncomplicated Hypertension” submitted by me for the degree of M.D., is the record work carried out by me under the guidance of Dr. P. JACOB VERGHESE, Professor of Pharmacology,

Karpaga Vinayaga Institute of Medical Sciences and Research Centre and has not formed the basis of any Degree, Diploma, Fellowship, titles in this or any other

University or other similar Institution of Higher learning.

Place: Chinnakolambakkam Signature of the Candidate

Date: DR. S. SRINATH

SIGNATURE OF GUIDE SIGNATURE OF HOD Dr.P. JACOB VERGHESE, M.D., DR. S. VIJAYALAKSHMI, M.D., PROFESSOR, PROFESSOR & HOD, Karpaga Vinayaga Institute of Karpaga Vinayaga Institute of Medical Medical Sciences & Research Centre, Sciences & Research Centre, Chinnakolambakkam, Chinnakolambakkam, MaduranthagamTk, MaduranthagamTk, Kancheepuram District– 603 308, Signature of the Guide Kancheepuram District– 603 308, Tamilnadu, India. Tamilnadu, India.

ACKNOWLEDGEMENTS

At the outset I express my sincere thanks to my esteemed guide Dr. P. JACOB

VERGHESE M.D., Professor in the Department of Pharmacology, Karpaga

Vinayaga Institute of Medical Sciences and Research Centre for his encouragement and valuable guidance in the topic given from time to time for the successful completion of study.

I am extremely thankful to our Managing Director, Dr. ANNAMALAI, MS,

MCH, Our Principal Dr. SUFALA SUNIL VISHWASRAO, M.D., our Medical

Director Dr. SATHIYANARAYANAN, Karpaga Vinayaga Institute of Medical

Sciences and Research Centre for providing me all the facilities to conduct this study.

I express my deep and sincere gratitude to Dr. S. VIJAYALAKSHMI, M.D.,

Professor and Head, Department of Pharmacology, Karpaga Vinayaga Institute of

Medical Sciences and Research Centre for being my mentor and support at all levels.

I profusely thank my Co-guide Dr. S. APPANDRAJ, M.D., Professor,

Department of General Medicine, Karpaga Vinayaga Institute of Medical Sciences and Research Centre for having permitted to conduct this study and the constant support he extended throughout the study.

I thank Dr. R. KAVITHA, MD., Professor in the Department of

Pharmacology, KarpagaVinayaga Institute of Medical Sciences and Research Centre for her kind guidance and encouragement during the course of this study.

I express my deep and sincere gratitude to Dr. B. PRATHAP, M.D., Associate

Professor, Department of Pharmacology, Karpaga Vinayaga Institute of Medical

Sciences and Research Centre for his guidance and support at all levels.

My heartfelt thanks to my Assistant Professors, Dr. E. SESHATHRI,M.D., and Dr. SUNIL M VISHWASRAO, M.D., in guiding me through the course of the study.

I owe my sincere thanks to Dr. N. CHANDRAN, B.V.Sc., and AH for encouraging me towards this research.

I thank my Senior and Junior Post Graduate colleagues for their greatest help and support throughout the course.

I sincerely thank our bio-statistician GLADIUS JENIFER for her guidance during my dissertation.

I am immensely grateful to the staffs at the Department of Pharmacology and

Department of General Medicine, Karpaga Vinayaga Institute of Medical Sciences and Research Centre for having provided me technical support throughout the study.

Last but no means the least, I am greatly indebted to all the patients who had taken part in this study without whom the study could not have been completed.

Finally, my dissertation would have not been accomplished without the support of my father Mr. Samraj, My wife Dr. Radheka and my other family members.

Above all I thank my Almighty for his blessings. CONTENTS

CHAPTER PARTICULARS PAGE NO.

1 INTRODUCTION 1

2 AIMS AND OBJECTIVES 4

3 REVIEW OF LITERATURE 6

4 DRUG PROFILE 28

5 PLAN OF WORK 34

6 MATERIALS AND METHODS 36

7 OBSERVATION AND RESULTS 45

8 DISCUSSION 66

9 SUMMARY 73

10 CONCLUSION 76

11 BIBLIOGRAPHY 78

12 ANNEXURES 91

LIST OF TABLES

S.NO TITLE PAGE NO

1 Classification of blood pressure in adults 8

2 Descriptive analysis of study group in study population 46

3 Comparison of mean age between study groups 46

4 Comparison of gender between study groups 48

Comparison of SBP at before drug treatment between study 5 49 groups Comparison of SBP at after drug treatment between study 6 51 groups Comparison of DBP at before drug treatment between study 7 53 groups Comparison of DBP at after drug treatment between study 8 55 groups

9 Comparison of ankle edema between study groups 57

Comparison of mean of serum creatinine between study 10 58 groups

11 Comparison of urine albumin between study groups 60

12 Comparison of mean difference of SBP between study groups 61

13 Comparison of mean difference of DBP between study groups 62

Comparison of SBP within groups before and after time 14 63 periods Comparison of DBP within groups before and after time 15 64 periods

16 Incidence of side effects 65

LIST OF FIGURES

S.NO TITLE PAGE NO

Systems involved in development and maintenance of blood 1 9 pressure

2 JNC 8 treatment guidelines for hypertension 15

Comparative error bar chart of comparison of mean age 3 47 between study groups

4 Stacked bar chart of comparison of gender between groups 48

Comparative error bar chart of comparison of SBP at before 5 50 drug between study groups

Comparative error bar chart of comparison of SBP at after 6 52 drug between study groups

Comparative error bar chart of comparison of DBP at before 7 54 drug between study groups

Comparative error bar chart of comparison of DBP at after 8 56 drug between study groups

Stacked bar chart of comparison of ankle edema between the 9 57 study groups

Comparative error bar chart of comparison of serum 10 59 creatinine between study groups

Stacked bar chart of comparison of urine albumin between 11 60 study groups

LIST OF ABBREVIATIONS

CCBs Calcium channel blockers

JNC Joint national committee

BP Blood pressure

SBP Systolic blood pressure

DBP Diastolic blood pressure

CAD Coronary artery disease

RAS Renin Angiotensin system

CVA Cerebrovascular accident

DHP Dihydropyridine

IHD Ischemic heart disease

LSM Life style modification

CKD Chronic kidney disease

CVD Cardiovascular disease

ACE Angiotensin converting enzyme

ARB Angiotensin receptor blocker

FDC Fixed dose combination

GFR Glomerular filtration rate

SPSS Statistical package for the social sciences

IQR Interquartile range

1. INTRODUCTION

Hypertension, a chronic medical condition which is more prone to cause cardiovascular diseases remains a global burden. Around 1.13 billion people worldwide are affected by hypertension till 20151, which is expected to be growing by

2020.Around 29.8% population in India are suffering from hypertension2. Since it is a major risk factor for cardiovascular mortality and other non-communicable diseases3, treatment studies on hypertension are effectively to be made. Dietary and lifestyle modifications may improve blood pressure control, but along with drug treatment there is major decline in the complications that are associated with hypertension.

All major classes of antihypertensive like diuretics, CCBs, beta blockers,

ACEIs, ARBs are most suited for long term therapy either in combination or alone4.Inspite of advent of many drugs for the control of hypertension, it remains the most common aggravating factor for cardiovascular diseases and controlling blood pressure effectively still remains a milestone in medical research4.

Calcium channel blockers (CCB) are nowadays widely used in the treatment of hypertension according to the JNC guidelines as a first choice because of their ability to reduce blood pressure effectively with minimal cost. CCBs disrupt the movement of calcium ions through calcium channels in the large vessels, thereby reducing their arterial stiffness which makes them an ideal choice for elevated systolic blood pressure.

Among the Dihydropyridine group of calcium channel blockers, Amlodipine has remarkable pharmacokinetic and pharmacodynamic profile5.Amlodipine blocks

2 the L-type calcium channels in peripheral blood vessels, thereby it has increased potency in lowering blood pressure but with few adverse effects like tachycardia and ankle edema which are remarkable. Incidence of ankle edema with Amlodipine is found to be around 1.7%-32% in various clinical studies6. The major drawback of using Amlodipine is its side effect ankle edema7.This may lead to dose reduction, poor compliance or even withdrawal of drug Amlodipine by the patient.

A new generation calcium channel blocker, Benidipine has more favorable outcomes on hypertension with good renoprotective effects8. Benidipine has the potency to block L, T & N type calcium channels9. It also acts as antagonist on mineralocorticoid receptor8. Benidipine has been recently launched in Indian market for the treatment of hypertension which shown promising end organ protection effect in recent investigational studies.

Moreover, Comparative studies of efficacy and safety among this group of drugs are few10and previous studies were done in all stages of hypertension along with pre-existing co-morbidities11. In our study we compared the safety and efficacy of

Benidipine with Amlodipine in patients of uncomplicated hypertension. Treatment of uncomplicated hypertension is associated with a reduction in forthcoming cardiovascular mortality12.

2. AIMS & OBJECTIVES

2. AIMS AND OBJECTIVES

AIM:

This study was aimed to assess and compare the efficacy and safety of

Benidipine with Amlodipine in patients with uncomplicated hypertension.

OBJECTIVES:

Primary objective:

To evaluate the efficacy of Benidipine over Amlodipine in patients of uncomplicated hypertension by reducing systolic and diastolic blood pressure less than 140/90mmHg.

Secondary objective:

To evaluate the safety of Benidipine compared to Amlodipine in patients of uncomplicated hypertension by assessing the renal parameters and incidence of ankle edema.

3. REVIEW OF LITERATURE

3.REVIEW OF LITERATURE

 Hypertension- definition

 Classification of hypertension

 Pathophysiology of hypertension

 Management of hypertension

 Role of CCBs in hypertension

 Relevant studies

HYPERTENSION DEFINITION:

Hypertension, a common medical disorder is defined as the sustained increase in arterial blood pressure of 140/90 mmHg or higher13. Hypertension is the primary cause of stroke, CAD and a major etiological factor to renal insufficiency, heart failure and dissecting aneurysm of aorta13. Hence the goal is focused on treating hypertension to prevent cardiovascular problems. Effective pharmacological treatment of patients with hypertension decreases morbidity and mortality from cardiovascular disease, heart failure, CAD and risk of strokes14.

STAGES OF HYPERTENSION:

Joint national committee on prevention, detection, evaluation and treatment of hypertension (JNC), a team of experts assembled by the heart, blood and lung institute classified the stages of hypertension based on 2 or more blood pressure recordings in sitting posture completed in 2 or more clinical visits15.

Table-1 JNC new guidelines for Classification of Blood Pressure in adults

SYSTOLIC BP DIASTOLIC BP CLASSIFICATION (mmHg) (mmHg) Normal BP <120 <80

Prehypertension 120-139 80-89

Stage 1 hypertension 140-159 90-99

Stage 2 hypertension >160 >100

PATHOPHYSIOLOGY OF HYPERTENSION:

The pathophysiology of hypertension is multifactorial which involves multiple organs and independent mechanisms. Various influential factors like genetics, neurohumoral mechanisms, obesity and dietary salt intake plays an important role in pathogenesis of hypertension16.

Arterial blood pressure is the combined effect of cardiac output and peripheral vascular resistance. Arterial blood pressure lowering drugs exerts their action on peripheral resistance, cardiac output or both13,14,16. Drugs decreasing cardiac output may do so by inhibiting myocardial contractility or by decreasing ventricular filling pressure. Drugs that decreasing peripheral resistance exerts their action by acting on vascular smooth muscle to cause relaxation of resistance vessels or by interfering with the sympathetic nervous system & RAS that produce constriction of resistance vessels. Drug effects are mediated not only by the variation in peripheral resistance but also via the effects on large artery stiffness17.

COMPLICATIONS OF HYPERTENSION:

Due to persistent elevated blood pressure, various clinical outcomes results, which are justified as the complications of hypertension. It is an independent and predisposing factor for various disorders. Hypertension if not promptly controlled in time, leads to target organ damage including heart18, brain19, kidney20, arteries21, eye22 etc.

TARGET ORGAN DAMAGE18-22: HEART:

1) Myocardial infarction

2) Angina pectoris

3) Hypertensive cardiomyopathy

4) Heart failure

BRAIN:

1) CVA- Stroke

2) Hypertensive encephalopathy

KIDNEY:

1) Hypertensive nephropathy

2) Chronic renal failure

ARTERIES:

1) CAD

2) Peripheral arterial disease

EYE:

1) Hypertensive retinopathy

UNCOMPLICATED HYPERTENSION:

A condition of increased blood pressure greater than or equal to 140/9023 without end organ damage and other related clinical disorders. Uncomplicated hypertension is usually asymptomatic with devoid of any symptoms of hypertension like nausea, headache, blurring of vision and dizziness24 but if left unchecked leads to target end organ damage. Hence routine checkup of blood pressure is mandatory to avoid untoward complications.

In our study we chose uncomplicated hypertensive patients to foresee the outcome of our study drugs in keeping the blood pressure under control so that major complications resulting from increased blood pressure can be put aside and allowing one to lead a healthy life.

MANAGEMENT OF HYPERTENSION:

The main objective in treating hypertension is to achieve the maximum reduction in the cardiovascular morbidity and mortality. Treatment of arterial blood pressure to achieve target level is related with decrease in cardiovascular complications. This also includes 35%–40% mean reduction in stroke incidence,

20%–25% mean reduction in myocardial infarction and >50% mean reduction in heart failure25.

There are several strategies for achieving therapeutic goal, most common is lifestyle modifications and pharmacological treatment.

NON - PHARMACOLOGICAL TREATMENT:

Healthy life style adoption decreases the occurrence of hypertension. Life style modifications not only decrease the blood pressure but also enhances the antihypertensive drug efficacy26. Life style modification (LSM) includes various activities

1) To maintain normal body weight27

2) To consume a diet rich in vegetables, fruits and low fat dairy products28

3) To reduce sodium intake in diet less than 2.4 g/day29

4) To engage in aerobic physical activity regularly for 30 minutes a day30

PHARMACOLOGICAL TREATMENT:

Patients who are not able to adopt life style modifications or not in strict control of blood pressure even after adopting LSM may switch over to pharmacological treatment.

Drugs used in treatment of hypertension can be classified according to their sites and mechanism of action. Selection of particular antihypertensive either alone or in combination with other groups depends upon co-existing morbidities and the patient response to the drug. Identifying an ideal antihypertensive drug for a patient imposes a great challenge nowadays in clinical practice.

An ideal antihypertensive drug should31:

1) be highly effective in decreasing arterial blood pressure with increased duration

of action to allow for once-daily dosing

2) not produce any untoward metabolic effects or induce adverse reaction

3) be able to promote the reversal of target organ damage.

At present, there is no single drug, or class of drugs, that possesses all these desirable effects but all classes have variable combinations of them.

CLASSES OF ANTIHYPERTENSIVE DRUGS:

DIURETICS:

1) Thiazides and related agents

2) Loop diuretics

3) K+ sparring diuretics

SYMPATHOLYTIC DRUGS:

1) Beta blockers

2) Alpha blockers

3) Mixed alpha & beta blockers

4) Centrally acting sympatholytic agents

RENIN ANGIOTENSIN ANTAGONISTS:

1) ACE inhibitors

2) Angiotensin II receptor blockers

3) Direct renin inhibitors

VASODILATORS:

1) Arterial

2) Arterial and venous

CALCIUM CHANNEL BLOCKERS:

1) Dihydropyridines

2) Non-dihydropyridines

In patients without complications of hypertension or any compelling indications, treatment is started with thiazide type of diuretics initially but recent JNC

8 guidelines suggested treatment modality is based on the race, age and associated co- morbidities. Either individual drug or in combination of the thiazide diuretic or CCBs are used in treatment of black people.

In patients with compelling indications associated with hypertension like

IHD32, Heart failure32, Diabetes mellitus33, Chronic renal failure34 and cerebrovascular disease35, choice of drug varies accordingly to their mechanism and site of action.

CALCIUM CHANNEL BLOCKERS (CCBs):

The calcium channel blockers are the most preferred group of drugs for the treatment of hypertension either alone or in combination with other group of drugs used in the treatment of hypertension36. Since 2014, JNC 8 has officially recommended the use of CCBs as first line therapy in treatment of hypertension.

Hence prior importance is given to the development of new calcium channel blockers in order to overcome the existing side effects with older generation CCBs.

PHARMACOLOGY OF CCBs:

Calcium channel blockers (CCBs) are group of drugs that disrupt the movement of calcium (Ca2+) through calcium channels. Most of the desired actions of CCBs are via voltage gated calcium channels37. CCBs are smooth muscle dilators and have a negative inotropic effect on heart. CCBs mostly bind to the alpha-1 subunit of the L- type calcium channel and exerts their action but at distinct sites38.

CALCIUM CHANNELS- PHYSIOLOGY:

Intracellular free calcium is important for regulation of cell function. Calcium channels serves as important mechanisms for calcium influx into the cells, enabling their physiological function. Various classes of calcium channels are recognized in our body.

Important Classes:

 Voltage gated calcium channels

 Ligand gated calcium channels

Voltage gated calcium channels are significant transducers of membrane potential changes which leads to initiation of many physiological events39. Voltage gated calcium channels are further designated to have different subtypes40.

 L- type (Long lasting)

 N- type (Neural)

 T-type (Transient)

 P/Q- type (Purkinje)

 R- type (Residual)

Apart from these types they have different subunits41 as α1 (pore forming unit),

α2δ (binding site), β, γ. Most of the calcium channel blockers bind to high voltage gated

L- type calcium channels42 which are mostly situated in the vascular smooth muscle, skeletal muscle and cardiac tissue. Thus, they prevent the influx of calcium ions intracellularly which leads to relaxation of the specific tissue.

CCBs possess two specific functions i.e. either they relax the vascular smooth muscle in the arteriole thereby decreasing peripheral resistance, ultimately decreased blood pressure or produces negative inotropic effect in heart. All CCBs exerts these two principal actions but their ratio differs according to their types43.

CCBs subtypes44:

Dihydropyridines:

 Ultra-short acting: Clevidipine

 Short acting: Nifedipine, Nicardipine, Nimodipine

 Intermediate acting: Nisoldipine, Nitredipine, Cilnidipine, Lercanidipine

 Long acting: Felodipine, Benidipine, Amlodipine

Non-dihydropyridines:

 Phenylalkylamines: Verapamil

 Benzothiazepines: Diltiazem

Dihydropyridines (DHP):

Dihydropyridines are potent vasodilators by blocking the influx of calcium ions thereby inducing relaxation of vascular smooth muscle leading to vasodilation. CCBs has become one of the most important first line agent in beginning antihypertensive therapy either alone or in combination45. This led to the development of newer dihydropyridines as they have fewer side effects and provides benefits beyond hypertension control46.

Hence development of new Ca2+ channel antagonists have been introduced recently with high efficacy and less side effect profile, especially in the DHP compounds which has much vascular selectivity, slower onset and longer half- life than their prototype compound nifedipine. Those more lipophilic DHP CCBs reach their

receptor, the L-type Ca2+ channel, then they bind and accumulate in the membrane lipid bilayer leading to diffusion within the membrane to its receptor site47.

DHPs like Nifedipine and Nicardipine have proven efficacy against hypertension. However, because of their quick onset and short half-life, they are likely to be associated with adverse effects mainly baroreflex sympathetic activation which led to their limitation in usage clinically48. Long acting DHPs like Amlodipine exhibit more lipophilic with good pharmacokinetic profile48 but their blockage of calcium channels includes only L- type.

The newer generation Benidipine (L/N/T-type49 CCB) are highly lipophilic

DHPs and now available to provide a real degree of therapeutic comfort in terms of stable activity, reduced adverse effects and a broad therapeutic spectrum, especially in cardiac failure and renal diseases. More over ankle edema is a troublesome side effect while using long acting CCB like Amlodipine for a long time due to the precapillary dilatation50.

On the other hand, Benidipine causes less ankle edema due to precapillary and postcapillary dilatation51. Benidipine was launched on the Japanese market more than a decade back with very few side effects have been reported so far, suggesting that it is a drug with good safety and possess long-acting pharmacological effects51.

With this background, this study was undertaken to assess the efficacy and safety of Benidipine and Amlodipine in patients with uncomplicated hypertension.

Our literature review focused on the pharmacological potential of Calcium channel blockers Benidipine and Amlodipine. Such literature reviews describe what has been written about the area, the major research findings across studies, and the major debates in terms of substantive and methodological issues.

 Prabhakar adake et al in 2015 in mangalore conducted a study on clinical efficacy

and pedal edema incidence of Amlodipine compared to Cilnidipine. He

highlighted the occurrence of pedal edema and its poor compliance of patients

while adhering to Amlodipine and concluded that Amlodipine as an

antihypertensive drug has higher incidence of pedal edema compared to other

calcium channel blockers7.

 Cheng xue et al in japan in 2011 studied the effect of Benidipine and

hydrochlorothiazide in Fosinopril treated hypertensive patients with chronic

kidney disease. The study concluded that Benidipine as an antihypertensive drug

controls hypertension via L&T-channel blockade and good safety profile on

renal system with least ankle edema incidence52.

 Abe M, Okada et al in japan, 2010 studied the efficacy of Benidipine with

additive effect like decreasing plasma aldosterone levels. The study proved that

Benidipine results in a greater reduction of plasma aldosterone and albuminuria

than Amlodipine8.

 Li x and Xang et al in japan in 2014 studied the systematic review and meta-

analysis on the effects of T-type calcium channel blockers on renal function and

aldosterone levels in patients with hypertension. The study showed that effects

of T-type calcium channel blockers enhances renal function compared to L-Type

channels53.

 Tani. s et al in japan in 2014 conducted a pilot study on the effects of T/L type

calcium channel blocker Benidipine on albuminuria and aldosterone levels. The

study suggested that T/L type calcium channel blocker, Benidipine may

contribute to renal protection in addition to lowering blood pressure54.

 Yao k et al in 2006 in japan conducted a study on pharmacokinetic and clinical

properties of a novel calcium channel blocker, Benidipine in hypertensive

patients. The study revealed that Benidipine is a drug with established safety and

long acting pharmacological effect55.

 Seino H et al in 2007 in japan studied the effect of long acting T-type calcium

channel blocker, Benidipine hydrochloride on blood pressure and renal function

in hypertensive patients with diabetes mellitus after switching from Cilnidipine.

They demonstrated that Benidipine has a more potent anti-hypertensive effect

and good renal protection than Cilnidipine56.

 S. V. Dange et al in 2017, India compared the effects of efficacy on clinical and

biochemical parameters in stage I hypertensive patients. In this study,

Amlodipine and Benidipine were found to have same efficacy in treatment of

hypertensive patients. But there was noteworthy lessening of proteinuria and

serum triglycerides in Benidipine group as equated to Amlodipine group. This

study concluded that Benidipine is a better alternative to existing calcium

channel blockers4.

 Nishida et al, 2017 in Japan, studied the long-term effects on estimated

glomerular filtration rate with 5 calcium channel blockers (CCBs), i.e.

amlodipine, benidipine, cilnidipine, nifedipine, azelnidipine and investigated the

clinical effects of treatment duration with glomerular filtration rate and serum

creatinine level in diabetic patients with hypertension. There was no substantial

relation between duration of treatment, eGFR and serum creatinine level among

the 5 CCBs. More over the study stressed that all the five CCBs can be used

safely for hypertensive patients with diabetes57.

 Nakamura et al, 2010, Japan conducted a study on the various effects of

Amlodipine and Benidipine on biochemical parameters like proteinuria,

inflammatory and atherosclerotic markers. 40 hypertensive CKD patients were

randomly assigned to Benidpine 8mg and Amlodipine 5mg for a year. The study

proved that Benidipine offers more renal protection and ameliorates

atherosclerosis than Amlodipine in mild CKD patients with hypertension58.

 Kita T et al, 2005, Japan, a long -term study was conducted to study the effects

of Benidipine over arterial stiffness. Patients with hypertension were treated with

Benidipine for almost 1 year. Then the drug was withheld for 2 weeks and

analyzed for blood pressure and pulse wave velocity. The study concluded that

arterial wall properties can be improved by Benidipine way beyond that we can

hope, which stresses that it offers a promising result for treatment of

hypertension in future59.

 Tomino Y et al, 2013, Japan, studied the effects of a calcium channel blocker,

Benidipine in chronic kidney disease patients with hypertension. The study

showed that Benidipine dilates efferent and afferent arterioles of glomerulus,

thereby it decreases glomerular pressure proving that it is superior to other

calcium channel blockers. The study also stressed that it can be a concomitant

drug if required apart from RAS inhibitors. Benidipine may be used as a first line

drug in such patients60.

 Suguno N et al, 2013, Japan studied the in-depth mechanism of the calcium

channel blockers in offering kidney protection. This study demonstrated that

CCBs use in kidney disease apart from hypertension by blocking of other

calcium channels, including T-type and N-type, provides renal protection

because of their advantageous action on glomerular capillary pressure,

sympathetic nerve activity, renal fibrotic process. It necessitates more wide-

ranging studies to elucidate whether the seemingly beneficial actions of these

CCBs are available clinically61.

 Takashi masuda et al, 2011, Japan noted the positive effects of CCBs on lipid

and glucose metabolism in hypertensive patients with diabetes. The study was

conducted with 77 hypertensive patients, who were divided into 2 groups

according to copresence of diabetes mellitus. In these groups, the effects of 2

calcium channel blockers on glucose and lipid metabolism were compared. The

study concluded that CCBs which posses a property of blocking multiple calcium

channels are far superior in treating hypertension with co-morbidities62.

 Kojima et al, 2004, Japan, compared the aspects of proteinuria in hypertensive

patients with renal diseases among Amlodipine and Cilnidipine. The study

suggested that multiple calcium channels blocking agents like cilnidipine

possess greater reduction in proteinuria and glomerular filtration rate than

Amlodipine which is a L type calcium channel blocker alone. Long term follow-

up of studies required to assess the renal functions among this group of drugs63.

 Sakata K et al, 1999, Japan, studied the effects of Cilnidipine and Amlodipine

on cardiac sympathetic nervous system and neurohormonal status in patients of

essential hypertension. The study showed that in essential hypertensive patients,

Cilnidipine suppressed cardiac sympathetic overactivity than Amlodipine.

Cilnidipine and other newer calcium channel blockers may provide a new

strategy for treatment of CVD with more sympathetic activity64.

 Umemoto S et al, 2017, Japan, studied the combined effects of Benidipine with

beta blocker, Benidipine with Thiazides and Benidipine with ARBs on

cardiovascular diseases with poor blood pressure. The study shown that the

incidence of cardiovascular events was merely same among the 3 drug

combination regimens. The Benidipine-Thiazide combination may provide

improved cardiovascular outcomes than the Benidipine-Beta blocker

combination even in patients with poor BP control65.

 Koshy S et al, 2000, Chicago, studied the effects of calcium channel blockers on

blood pressure control. The study shown that FDC of a calcium channel blocker

and ACE inhibitor offer the recompenses of harmonizing physiologic action,

improved permissibility, lower side-effect profile, enhanced beneficial effects on

target organs, better amenability, and lower cost. This article focused on the

subclasses of CCBs and their role in shifting the natural antiquity of both

cardiovascular and renal disease66.

 Rakugi H et al, 2011, Japan, conducted a randomized control trial with calcium

channel blockers combination-based therapies in patients with hypertension to

prevent cardiovascular diseases. The trial showed that when calcium channel

blocker is added with ARB, Thiazide or Beta blocker provided almost a similar

outcome in targeting blood pressure and thereby prevention of cardiovascular

outcomes67.

 Azizuki O et al, 2008, Japan, studied the effects of T-type calcium channel

blocker, Benidipine on human aldosterone secretion in cell lines. The study

proved that in pathophysiological conditions, aldosterone induces renal and

cardiovascular diseases. Benidipine inhibited angiotensin II-tempted aldosterone

production and showed improver effects when used in combination with the

ARB, Valsartan. T-type Ca2+ channels may subsidize to supplementary benefits

of this drug for treating renal and cardiovascular diseases, elsewhere its primary

anti-hypertensive effects from blocking L-type Ca2+ channels68.

 Peng T et al, 2009, China, compared the renoprotective effects of Valsartan and

Benidipine in hypertensive patients with proteinuria. 236 patients with primary

hypertension with no secondary complications were enrolled in the study. Then

they were randomly divided into two groups and were administered either

Benidipine or Valsartan. The changes in the glomerular filtration rate (GFR) and

proteinuria were compared between the two groups.

The results presented that Valsartan was impressively effective in lowering the levels of proteinuria in hypertensive patients during the early stages of nephropathy. The renoprotective effects of Benidipine is noninferior to Valsartan in hypertensive patients with proteinuria69.

4. DRUG PROFILE

DRUG PROFILE

AMLODIPINE:70-71

Amlodipine belongs to the dihydropyridine, L- type of calcium channel blocker.

FORMULA:

C20H25CL N2 O5

MOLECULAR MASS:

408.87 grams/mol

CHEMICAL STRUCTURE:

DOSE:

2.5 mg, 5 mg, 10 mg OD

DOSAGE FORM:

Tablet

TRADE NAME:

AMLOKIND 2.5 (Manufacturer- Mankind, INDIA)

MECHANISM OF ACTION:

Amlodipine inhibits influx of calcium ions into vascular smooth muscles and cardiac smooth muscle. Thereby preventing the contractile process of both muscle cells.

Selective inhibition of calcium channels occurs across cell membranes. Amlodipine selectively blocks L-type calcium channel alone present in vascular and cardiac smooth cells.

PHARMACOKINETICS:

Amlodipine via oral route provides a systemic bioavailability of around 60%.

Metabolism occurs in liver. The t1/2 is about 30-50 hours and steady state plasma concentrations are seen after 7-8 days during once daily dosing. Excretion is via renal route with 60% of administered dose recovered in urine as an inactive metabolite, pyridine.

ADVERSE EFFECTS:

Common: Peripheral edema and fatigue

Least: Blood disorders, impotence, depression, tachycardia, gingival enlargement.

CONTRAINDICATIONS:

Breast feeding, cardiogenic shock, hypotension, heart failure, severe aortic stenosis.

BENIDIPINE55, 59

Benidipine belongs to the dihydropyridine, L, N & T type calcium channel blocker.

FORMULA:

C28H31N3O6

MOLECULAR MASS:

507.57 grams/mol

CHEMICAL STRUCTURE:

DOSE:

4 mg, 8 mg OD

DOSAGE FORM:

Tablet

TRADE NAME:

BENGREAT 4 mg (Manufacturer- Mankind, INDIA)

MECHANISM OF ACTION:

Benidipine is a triple calcium channel blocker exerts its mechanism by inhibiting

L, N & T type calcium channel. It presents a very long-lasting activity that can be elucidated by its high attraction for cell membranes from the DHP binding site. The additional property of Benidipine is the vascular selectivity towards peripheral blood vessels. It dilates both afferent and efferent arterioles in the periphery. It also decreases the secretion of aldosterone.

PHARMACOKINETICS:

Benidipine is rapidly absorbed after oral administration reaching a maximum concentration within 2 hours. Benidipine is highly bound to plasma proteins which accounts for 98% of the administered dose. Benidipine is almost totally metabolized in the liver. From different reports, it is thought that Benidipine is mainly metabolized by

CYP3A of which the formed metabolites are N-desbenzyl Benidipine and dehydro

Benidipine. The percentage of urinary excretion after oral administration is of approximate 36% of the administered dose. Some of the remaining dose is excreted in feces, making bile excretion as the remaining elimination route. The duration of action is 12-16 hours.

ADVERSE EFFECTS:

1. Palpitation

2. Headache

3. Dizziness

4. Flushing

5. Elevated liver enzymes

6. Vomiting

CONTRAINDICATIONS:

Pregnancy and lactation

Benidipine possess more advantage compared to other generation calcium blockers both in efficacy and safety. Previous studies in Japan has shown more effective profile of Benidipine and incidence of ankle edema is declining with the judicious use of Benidipine. Hence we conducted a comparative study between routinely used CCB,

Amlodipine with Benidipine in terms of safety and efficacy in our population.

5. PLAN OF WORK

PLAN OF WORK

The present study was planned to conduct a randomized comparative study on clinical efficacy and safety of Amlodipine (2.5 mg/day) versus Benidipine (4 mg/day) in patients with uncomplicated hypertension.

The present study was conducted in Karpaga Vinayaga Institute of Medical

Sciences & Research Centre, Chinnakolambakkam, Kanchipuram District-603 308,

Tamil Nadu. Protocol was initially designed. After getting informed consent from the hypertensive patients, they were enrolled in the study for assessing safety and efficacy parameters.

6. MATERIALS AND METHODS

MATERIALS AND METHODS

 Study design: Comparative observational prospective study to assess the safety and

efficacy of Benidipine with Amlodipine in patients of uncomplicated hypertension.

 Study centre: General medicine outpatient department of karpaga vinayaga

institute of medical science & research centre.

 Study duration: 1 year

 Study period: 3 months

 Study population: people of age group between 18-70 of both sexes who are

detected as hypertension with no complications.

 Sample size and sampling: Sample size calculations were made by based on the

following formula and previous journals4,52.

=1.96 for 95% confidence level.

=1.28 for 90% power.

=pooled standard deviation of 2 samples (3.5x3.5=12.24)

=clinically significant difference. (2x2=4), Considering an error of 5% with a 95% confidence level and 90% of power, then the required sample size will be

65 on each arm. There was drop out in the study in both groups, we completed the study with 60 sample in each group

Sampling technique - One group comprising of 65 patients receiving Benidipine 4mg

once a day in the morning and other group of 65 patients receiving Amlodipine 2.5mg

once a day in the morning. “Block randomization” method was used for assigning equal

groups. Four letter blocks were prepared as: AABB, ABAB, ABBA, BAAB, BABA,

BBAA and patients were allocated accordingly. For example, if randomly selected

block would be ABBA then the first patient would go to group A, second and third

patient would go to group B and fourth patient would go to group A. In this way there

was equal distribution of subjects in each group. There was 5 drop outs in each group

at the end of the study.

INCLUSION & EXCLUSION CRITERIA:

 Inclusion criteria-

1. Patients diagnosed as uncomplicated hypertension with BP greater than or equal

to 140/90 mmHg of both gender in the age group of 18-70 years, attending

outpatient department of general medicine. For age ≥60, BP of ≥150/90 is taken

according to JNC 8 guidelines

2. Hypertensive patients diagnosed earlier but not taking medication for past 2

weeks.

3. Patient in mono antihypertensive therapy either with Amlodipine or Benidipine.

 Exclusion criteria-

1. Age<18 years and > 70 years

2. Patients with secondary hypertension and other associated complications

3. Pregnant and nursing women

4. Patients prescribed with other antihypertensive drugs

5. Patient taking drugs that can alter BP

6. Patient with known allergy to calcium channel blockers

7. Patients with pedal edema, hypoproteinemia, anemia

PARAMETERS:

EFFICACY:

1. Blood pressure measurement (systolic and diastolic).

SAFETY:

1. Adverse events like ankle edema.

2. Renal parameter-Serum creatinine.

3. Albuminuria-Urine albumin.

STUDY INSTRUMENTS:

 Questionnaire- pre-tested structured questionnaire designed with variables of

demographic profile of the patients, clinical history comprising of present and past,

personal and family history, co-morbidities if any.

 Clinical monitoring-

1. Blood pressure to be measured using a standard mercury sphygmomanometer

and stethoscope in the right arm, sitting posture by the auscultatory method. An

average of three BP readings was taken.

2. Ankle edema assessed by clinical method (physician) over the medial malleolus

of both legs.

 Lab parameters-

1. Serum creatinine

2. Urine albumin

ETHICAL CONSIDERATION:

All the investigational procedures and protocols used in this study were reviewed

& approved by the Institutional Ethical Committee (IEC Reference No: 91/2017) and were in accordance with the CONSORT guidelines.

DATA COLLECTION:

Duration of the study will be for one year. Patients who are diagnosed as uncomplicated hypertension of both gender of age group between 18 and 70 years with no co-morbidities are informed about the study in detail and voluntary participants after giving written informed consent were enrolled in the study. Patients were examined for blood pressure on every 2 weeks for a period of 3 months by the physician in the right arm, sitting posture by the auscultatory method. Mean of 3 recordings of blood pressure are taken with an interval of 10-15 mins by the same physician and presence of ankle edema is noted over the medial malleolus of both legs. Presence of edema on either of

the legs is considered as positive for ankle edema. Based on questionnaire, if suspicion of any complication, were screened and then enrolled in the study. Lab parameters were collected on 0(baseline), 6 weeks, 12 weeks and analyzed in laboratory in karpaga vinayaga institute of medical science and research center.

OPERATIONAL DEFINITION:

Uncomplicated hypertension-patients with arterial hypertension of systolic blood pressure greater than or equal to 140 and diastolic blood pressure greater than or equal to 90 with no complications. According to JNC 8 guidelines treatment for hypertension for 60 or more than 60 years are to be initiated if blood pressure is greater than or equal to 150/90.

DATA ANALYSIS:

Software- IBM SPSS version 22.0

Statistical analysis:

Blood pressure parameters (systolic and diastolic) were considered as primary outcome variables. Ankle Edema, Serum Creatinine (mg/dl), Urine Albumin were considered as Secondary outcome variables. Study group (Benidipine Vs Amlodipine) was considered as Primary explanatory variable.Descriptive analysis was carried out by mean and standard deviation for quantitative variables, frequency and proportion for categorical variables. Non normally distributed quantitative variables were summarized by median and interquartile range (IQR). Data was also represented using appropriate diagrams like bar diagram, pie diagram and box plots.

All Quantitative variables were checked for normal distribution within each category of explanatory variable by using visual inspection of histograms and normality

Q-Q plots. Shapiro- wilk test was also conducted to assess normal distribution. Shapiro wilk test p value of >0.05 was considered as normal distribution.

For normally distributed Quantitative parameters the mean values were compared between study groups using Independent sample t-test (2 groups). The change in the quantitative parameters, before and after the intervention was assessed by paired t test (In case of two time periods).

Categorical outcomes were compared between study groups using Chi square test /Fisher's Exact test (If the overall sample size was < 20 or if the expected number in any one of the cells is < 5, Fisher's exact test was used.)

P value < 0.05 was considered statistically significant. IBM SPSS version 22 was used for statistical analysis72.

TRAIL FLOW CHART

STUDY VISITS

0 week 2 weeks 4 weeks 6 weeks 8 weeks 10 weeks 12 weeks

BP BP BP BP BP BP BP

Sr. Creatinine Sr. Creatinine Sr. Creatinine

Urine albumin Urine albumin Urine albumin

Patients were advised to follow up every 2 weeks till 3 months for checking blood pressure and ankle edema, regarding serum creatinine and urine albumin, checked at 0, 6, 12 weeks.

7. OBSERVATION AND RESULTS

OBSERVATION AND RESULTS

Result:

A total of 120 subjects were included in the final analysis.

Table 2: Descriptive analysis of study group in the study population

(N=120)

Group Frequency Percentages

Benidipine 60 50.00%

Amlodipine 60 50.00%

In both the groups, equal number of population (n=60) was enrolled.

Table 3: Comparison of mean age between the study groups (N=120)

Study group

Parameter Benidipine (N=60) Amlodipine (N=60) P value

(Mean± SD) (Mean± SD)

Age 50.67 ± 7.19 50.85 ± 6.93 0.887

The mean age of subjects in Benidipine group was 50.67 ± 7.19 years and it was 50.85

± 6.93 years in Amlodipine group. The difference in the age between the two groups was statistically not significant (P Value 0.887). (Table 3 & Figure 3)

Figure 3: Comparative error bar chart of Comparison of mean age between the

study groups (N=120)

Table 4: Comparison of gender between group (N=120)

Study group Chi Gender Benidipine Amlodipine P-value square (N=60) (N=60)

Male 35 (58.33%) 25 (41.66%) 3.333 0.068 Female 25 (41.66%) 35 (58.33%)

In Benidipine group, 35 (58.33%) participants were male and 25 (41.66%) participants were female. In Amlodipine group, 25 (41.66%) participants were male and

35 (58.33%) participants were female. The difference in the proportion of gender between study groups was statistically not significant (P value 0.068).

(Table 4 & Figure 4)

Figure 4: Stacked bar chart of Comparison of gender between group

(N=120)

100.00% 90.00% 80.00% 41.66% 70.00% 58.33% 60.00% 50.00%

40.00% Percentage 30.00% 58.33% 20.00% 41.66% 10.00% 0.00% Benidipine Amlodipine Group Male Female

Table 5: Comparison of SBP at before drug between the two groups

(N=120)

95% CI SBP Parameter Mean difference P value (Mean ± SD) Lower Upper

Benidipine 154.73 ± 9.22

2.53 -0.64 5.71 0.116

Amlodipine 152.2 ± 8.31

The mean SBP at before drug of subjects in Benidipine group was 154.73 ± 9.22 and it was 152.2 ± 8.31 in Amlodipine group. The difference in the SBP at before between the two groups was statistically not significant (P Value 0.116). (Table 5 &

Figure 5)

Figure 5: Comparative error bar chart of Comparison of SBP at before drug

between the two groups (N=120)

Table 6: Comparison of SBP at after drug between the two groups

(N=120)

95% CI

Parameter Group (Mean± SD) Mean difference P value Lower Upper

Benidipine 127.5 ± 10.13

3.10 -0.74 6.94 0.113

Amlodipine 130.6 ± 11.12

The mean SBP at after drug of subjects in Benidipine group was 127.5 ± 10.13 and it was 130.6 ± 11.12 in Amlodipine group. The difference in the SBP at after drug between the two groups was statistically not significant (P Value 0.113). (Table 6 &

Figure 6)

Figure 6: Comparative error bar chart of Comparison of SBP at after drug

between the two groups (N=120)

Table 7: Comparison of DBP at before drug between the two groups

(N=120)

95% CI DBP at before drug Parameter Mean difference P value (Mean ± SD) Lower Upper

Benidipine 96.73 ± 4.94

0.33 -1.72 2.39 0.749

Amlodipine 96.4 ± 6.35

The mean DBP at before drug of subjects in Benidipine group was 96.73 ± 4.94 and it was 96.4 ± 6.35 in Amlodipine group. The difference in the DBP at before between the two groups was statistically not significant (P Value 0.749). (Table 7 &

Figure 7)

Figure 7: Comparative error bar chart of Comparison of DBP at before drug

between the two groups (N=120)

Table 8: Comparison of DBP at after drug between the two groups

(N=120)

95% CI DBP at after drug Parameter Mean difference P value (Mean ± SD) Lower Upper

Benidipine 81.53 ± 8.7

0.57 -2.64 3.78 0.727

Amlodipine 82.1 ± 9.05

The mean DBP at after drug of subjects in Benidipine group was 81.53 ± 8.7 and it was 82.1 ± 9.05 in Amlodipine group. The difference in the DBP at after between the two groups was statistically not significant (P Value 0.727). (Table 8 & Figure 8)

Figure 8: Comparative error bar chart of Comparison of DBP at after drug

between the two groups (N=120)

Table 9: Comparison of ankle edema between the study groups (N=120)

Study group Chi P- Ankle Edema Amlodipine square value Benidipine (N=60) (N=60)

Yes 3 (5%) 20 (33.33%) 15.545 <0.001 No 57 (95%) 40 (66.66%)

In Benidipine group, 3 (5%) participants had ankle edema. In Amlodipine group,

20 (33.33%) participants had ankle edema. The difference in the proportion of ankle edema between study group was statistically significant (P value <0.001). (Table 9 &

Figure 9)

Figure 9: Stacked bar chart of Comparison of ankle edema between the study

groups (N=120)

100% 90% 80% 70% 66.66% 60% 50% 95% 40% Percentage 30% 20% 33.33% 10% 0% 5% Benidipine Study group Amlodipine Yes No

Table 10: Comparison of mean of Serum Creatinine between the study groups

(N=120)

Study group

Parameter Benidipine (N=60) Amlodipine (N=60) P value

(Mean± SD) (Mean± SD)

Serum Creatinine (mg/dl) 0.88 ± 0.12 0.91 ± 0.12 0.180

The mean Serum Creatinine of subjects in Benidipine group was 0.88 ± 0.12 mg/dl and it was 0.91 ± 0.12 mg/dl in Amlodipine group. The difference in the serum creatinine between the two groups was statistically not significant (P Value 0.180).

(Table 10 & Figure 10)

Figure 10: Comparative error bar chart of Comparison of mean of Serum

Creatinine between the study groups (N=120)

Table 11: Comparison of urine albumin between the study groups (N=120)

Group Urine Albumin Benidipine (N=60) Amlodipine (N=60)

Yes 0 (0%) 1 (1.66%)

No 60 (100%) 59 (98.33%)

* No statistical test was applied-due to 0 subjects in the cell

In Amlodipine group, only 1 (1.66%) participant had urine albumin. (Table 11

& figure 11)

Figure 11: Stacked bar chart of Comparison of urine albumin between the study

groups (N=120)

100% 90% 80% 70% 60% 50% 100% 98.33% 40%

30% Percentage 20% 10% 0% 0% 1.66% Benidipine Amlodipine Study group Yes No

Table 12: Comparison of mean difference of SBP between the study groups

(N=120)

95% CI

Parameter (Mean± SD) Mean difference P value Lower Upper

Benidipine 27.23 ± 10.45 5.63 1.89 9.38 0.004 Amlodipine 21.6 ± 10.28

The mean difference of SBP of subjects in Benidipine group was 27.23 ± 10.45 and it was 21.6 ± 10.28 in Amlodipine group. The difference (5.63) in the mean difference of SBP between the two groups was statistically significant (P Value 0.004).

(Table 12)

Table 13: Comparison of mean difference of DBP between the study groups

(N=120)

95% CI Parameter (Mean± SD) Mean difference P value Lower Upper

Benidipine 15.2 ± 9.43

0.90 -2.33 4.13 0.582

Amlodipine 14.3 ± 8.4

The mean difference of DBP of subjects in Benidipine group was 15.2 ± 9.43 and it was 14.3 ± 8.4 in Amlodipine group. The difference (0.90) in the mean difference of DBP between the two groups was statistically not significant (P Value 0.582).

(Table 13)

Table 14: Comparison of SBP within the group at before and after time periods

(N=120)

95% CI of mean SBP Mean P Parameter difference Mean ± STD Difference value Lower Upper

Before drug 153.47 ± 8.83

24.42 22.48 26.35 <0.001

After drug 129.05 ± 10.7

The mean of SBP before drug was 153.47 ± 8.83 and has decreases to 129.05 ±

10.7 in after drug, the difference (24.42) in between before and after drug within group was statistically significant (p value <0.001). (Table 14)

Table 15: Comparison of DBP within the group at before and after time periods

(N=120)

95% CI of mean

DBP Mean difference P Parameter Mean ± STD Difference value Lower Upper

Before drug 96.57 ± 5.67

14.75 13.14 16.36 <0.001

After drug 81.82 ± 8.85

The mean of DBP before drug was 96.57 ± 5.67 and has decreases to 81.82 ±

8.85 in after drug, the difference (14.75) in between before and after drug within group was statistically significant (p value <0.001). (Table 15)

Various side effects are seen in both the groups including ankle edema are as

follows:

Table 16: Incidence of side effects:

PERCENTAGE AMONG S.NO SIDE EFFECTS 120 PATIENTS

1 Ankle edema 19%

2 Urine albuminuria 1%

3 Headache 3%

4 Palpitations 2%

5 Constipation 1%

6 Light headedness 1%

7 Nausea 0

Among which ankle edema is seen predominantly in the Amlodipine group of patients.

8. DISCUSSION

DISCUSSION

Hypertension prevalence is increasing alarmingly and it is a major root cause of various cardiovascular morbidity and mortality73. Calcium channel blockers shown good results in treatment of various stages of hypertension. Newer CCBs offers promising results in terms of efficacy and safety. This study was undertaken to assess the efficacy and safety of Benidipine (B) versus Amlodipine (A). Two groups with equal number of participants were chosen and total 120 participants were recruited in the study.

Mean age among group A and group B were 50.85 and 50.67 years respectively which does not show any statistical significance. Maximum number of subjects were around 40- 60 years. Among 60 participants in Benidipine group, 58.33% were male,

41.66% were female. Among 60 participants in Amlodipine group, 41.66% were male and 58.33% were female. Sex distribution among both groups had no significant statistical difference.

Efficacy parameters were assessed by difference in the blood pressure readings before and after drug administration. Out of 120 patients, mean systolic blood pressure before starting treatment were 154.73 and 152.2 among Benidipine and Amlodipine groups respectively which was not statistically significant. Mean systolic blood pressure after drug treatment was 127.5 and 130.6 among Benidipine and Amlodipine groups respectively which was also statistically not significant. Similar results were seen in a study published by Nakamura74 and colleagues which was a comparative prospective study conducted among Amlodipine and Benidipine patients having

hypertension with chronic kidney disease. The study showed that systolic blood pressure was equally decreased in both groups.

Mean diastolic pressure before starting treatment were 96.73 and 96.4 among

Benidipine and Amlodipine group respectively which was not statistically significant.

Mean diastolic blood pressure after drug treatment was 81.53 and 82.1 among

Benidipine and Amlodipine group respectively. There was no significant statistical difference at the end of the treatment. Similar results were seen in the studies published by Dange4 and Nakamura74. Dange and colleagues conducted a comparative study among Benidipine and Amlodipine on clinical and biochemical parameters in hypertensive patients. They also showed that both Amlodipine and Benidipine have equal efficacy in reducing diastolic blood pressure and readings were statistically not significant.

The overall comparison of blood pressure in both the groups before drug and after drug time periods shown a greater reduction in systolic and diastolic BP which was 24.42 and 14.75 respectively. (Table 13 & 14).

The mean difference of systolic blood pressure in Benidipine and Amlodipine was 27.23 and 21.6. The difference in the mean difference of systolic BP is 5.63 which was statistically significant. Our study suggests there is greater reduction in mean difference of systolic blood pressure by Benidipine compared to Amlodipine. Similar results are noted by Mitsuru75 and his colleagues. They conducted a changeover study of Amlodipine to Benidipine on renoprotective effects in hypertensive patients. Their study also suggested that mean systolic blood pressure was much reduced by Benidipine

in comparing to Amlodipine proving the higher efficacy of triple calcium channel blocker.

The mean difference of diastolic blood pressure in Benidipine and Amlodipine was 15.2 and 14.3 respectively. The difference in the mean difference is 0.90 which was not statistically significant. This shows that there is no much difference in reduction of diastolic blood pressure in both groups. This varies with other studies like Mitsuru75.

Such similar results were seen in study conducted by Hoshide76 and his colleagues. The study showed that Amlodipine has similar effect in terms of efficacy compared to the other calcium channel blockers.

Safety parameters were assessed in terms of clinical evaluation of ankle edema over medial malleolus of both legs. Serum creatinine and urine albumin were assessed for renal protective effect.

Among 120 patients, after drug treatment 5% had ankle edema in Benidipine group, whereas 20% had ankle edema in Amlodipine group. This difference in proportion between both the groups are statistically significant which implies that

Benidipine has a lesser incidence of ankle edema compare to Amlodipine.

Previous studies conducted by Shetty77 also showed that Amlodipine has higher incidence of ankle edema compared to multiple calcium channels blocker (CCBs). The most likely mechanism78 involved in formation of ankle edema are increased capillary hydrostatic pressure, increased capillary permeability, decreased plasma oncotic pressure and hindrance of the lymphatic system.

Edema occurs due to alteration of fluids from intravascular to extravascular compartment. The external force is driven by the hydrostatic pressure in capillaries which is denoted by the vascular tone. The main reason for Amlodipine-induced ankle edema is increased hydrostatic pressure by pre- arteriolar dilation. The new L, T and N- type of calcium channel blocker, Benidipine causes pre and post capillary dilatation which neutralizes the hydrostatic pressure, resolving the edema.

The mean serum creatinine after drug treatment among Benidipine and

Amlodipine group were 0.88 and 0.91 respectively. There was no significant statistical difference in our study. Similar outcomes were seen in studies conducted by

Nakamura74 and Tomino60 showing the renoprotective effects while using calcium channel blockers. There was no noticeable albuminuria in both the groups which correlates study done by Ando79 and his colleagues. Benidipine effect on urine albumin was superior compared to other calcium channel blockers was shown by above study79.

Reno-protective effects of newer generation calcium channel blockers is due to the dilatation of afferent and efferent arterioles in glomerulus, thereby decreasing glomerular capillary pressure79. However our study was conducted in uncomplicated hypertensive patients which excludes renal disease, hence the effects of both calcium channel blockers are clear in not causing renal damage but their efficacy in improving renal disease is not done in our study.

Hypertension along with proteinuria are common risk factors for development of renal failure. There is recent evidence that control of both blood pressure and proteinuria slows the rate of evolution of renal disease. The calcium channel blockers

have unique pharmacological properties which may vary, but as a group they are effective antihypertensive agents in patients with good safety profile80.

In our study some patients experienced minor side effects like headache 3%, palpitations 2%, constipation 1%, lightheadedness 1% among 120 patients (table 16).

There was no hypotension in both the treatment groups. Safety profile was established in both the drugs except ankle edema which is predominantly seen in the Amlodipine group. This concern alerts the researchers to develop a new calcium channel blocker in the market to provide better patient compliance.

Most common reason for few patients experiencing headache and lightheadedness are probably due to vasodilation. Palpitations mostly occur due to reflex tachycardia but much less compared to nifedipine. Such side effects are mostly seen in patients of age over 45 in our study.

Benidipine on the other hand shown promising results both in efficacy and safety compared to Amlodipine. Drugs which are having property of blocking multiple calcium channels have much intensity in reducing blood pressure and minimizing side effects. Evolution of such group of drugs paves way for much advances in treatment of hypertension with less side effects. Further long-term studies will definitely provide a limelight over effective results of new generation calcium channel blockers in future.

STUDY LIMITATIONS:

The present study included some study limitations. Our selection of subjects was limited to hypertensive patients with no complications, so in patients with renal or cardiac problems, these drug effects are unknown. Our study was single center not multi-centric, single dose regimen in both the groups no escalation of high doses were tried, non-blinded, short duration study which is difficult to know the chronic side effects. In depth biochemical safety parameters regarding renal, cardiac and liver profile have not been enrolled in our study.

More-over we enrolled outpatients, so we are not able to concentrate on their diet and salt intake which may have some influence on the results. Our study was focused mainly on treating hypertensive patients in initial stages, thereby preventing complications and we have analyzed the data among the patients present in our outpatient department. However, a community based prospective study would further identify hypertensive cases earlier and prevent complications.

9. SUMMARY

SUMMARY

The present study outcomes focus mainly with the following highlights,

 The proportion of male and female hypertensive patients were 58.33% and 41.66%

in Benidipine group. In Amlodipine group, 41.66% and 58.33% were male and

female respectively which was not statistically significant.

 The overall mean age group of patients were 50.67% and 50.85% among Benidipine

and Amlodipine groups respectively which was not statistically significant.

 There was no significant statistical difference in systolic and diastolic blood pressure

values before and after drug treatment in comparing both the groups.

 The mean difference of systolic blood pressure between the two groups was

statistically significant (P value is 0.004).

 The mean difference of diastolic blood pressure between the two groups was not

statistically significant (P value is 0.582)

 There was significant statistical difference in change in SBP & DBP within the

groups of Benidipine and Amlodipine (P <0.001)- compared to the baseline data

(before and after time periods)

 The difference in proportion of ankle edema between the two study groups (5% in

Benidipine and 33.3% in Amlodipine) was statistically significant (P value <0.001)

 The difference in the serum creatinine between the two groups was not statistically

significant (P value is 0.180)

 The difference on urine albuminuria in both the groups are not comparable, there is

no albuminuria in Benidipine group and one albuminuria in Amlodipine group.

 Only few minor side effects like headache 3%, palpitations 2%, constipation 1%,

lightheadedness 1% among 120 patients were seen.

10. CONCLUSION

CONCLUSION

From our study, it was concluded that

 Both Amlodipine and Benidipine are equally efficacious antihypertensive agents

individually. However, Benidipine treated group showed much reduction in mean

difference in systolic blood pressure than Amlodipine treated group.

 Benidipine being L, N & T type CCB has lesser incidence of ankle edema than L

type CCB, Amlodipine. Both the groups had no significant change in levels of serum

creatinine and urine albumin.

11. BIBLIOGRAPHY

BIBLIOGRAPHY

1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL, Jr, et

al. The Seventh Report of the Joint National Committee on Prevention,

Detection, Evaluation, and Treatment of High Blood Pressure: The JNC 7

report. JAMA. 2003; 289:2560–72.

2. Anchala R, Kannuri NK, Pant H, Khan H, Franco OH, Di Angel antonio E, et al.

Hypertension in India: A systematic review and meta-analysis of prevalence,

awareness, and control of hypertension. J Hypertens.2014;32: 1170–7.

3. Stafylas PC, Sarafidis PA. Carvedilol in hypertension treatment. Vasc Health

Risk Manag. 2008; 4:23 –30.

4. DANGE, S. V. et al. Comparison of effects of Benidipine and Amlodipine on

clinical and biochemical parameters in hypertensive patients: an observational

study. International Journal of Basic & Clinical Pharmacology, [S. l.], v. 6, n. 9,

p. 2233-2236, aug. 2017

5. Abernethy DR. Pharmacokinetics and pharmacodynamics of Amlodipine.

Cardiology. 1992; 80 Suppl 1:31-6.

6. Patil PA, Kothekar MA. Development of safer molecules through

chirality. Indian J Med Sci. 2006; 60: 427–37.

7. Prabhakar Adake, H.S.Somashekar,P.K Mohammed Rafeeq, Dilshad Umar,

Bahija Basheer, Kusai Baroudi.J. Adv Pharm Technology Res. 2015 Apr-

Jun; 6(2): 81–85.

8. Abe M, Okada K, Maruyama T et al. Comparison of the antiproteinuric effects

of the calcium channel blockers Benidipine and Amlodipine administered in

combination with angiotensin receptor blockers to hypertensive patients with

stage 3–5 chronic kidney disease. Hypertension. Res 2009; 32:270–5.

9. Yamamoto E, Kataoka K, Dong YF, Nakamura T, Fukuda M, Nako H, Ogawa

H, Kim-Mitsuyama S. Benidipine, a dihydropyridine L-type/T-type calcium

channel blocker, affords additive benefits for prevention of cardiorenal injury in

hypertensive rats. J Hypertens. 2010 Jun;28(6):1321-9.

10. Hall WD, Reed JW, Flack JM, Yunis C, Preisser J, and the ISHIB Investigators

Group. Comparison of the Efficacy of Dihydropyridine Calcium Channel

Blockers in African American Patients With Hypertension. Arch Intern

Med. 1998; 158(18):2029–2034.

11. Liu J, Ma J, Wang J, Zeng DD, Song H, Wang L. et al. Comorbidity analysis

according to sex and age in hypertension patients in China. International journal

of medical sciences. 2016; 13:99.

12. Lee CJ, Hwang J, Oh J, Lee SH, Kang SM, Choi D, Kim HC, Park S. Treatment

of uncomplicated hypertension is associated with a reduction in cardiovascular

mortality: a Korean national cohort study. J Hypertens. 2017 May;35

13. Laurence L. Brunton, Randa Hilal-Dandan, Bjorn C. Knollman. Goodman and

Gilman’s The Pharmacology Basis of Therapeutics. 13th edn. New York: Mc

Graw Hill Medical: 2018

14. Rosendorff C, Lackland DT, Allison M, Aronow WS, Black HR, Blumenthal

RS, Cannon CP, de Lemos JA, Elliott WJ, Findeiss L, Gersh BJ, Gore JM, Levy

D, Long JB, O'Connor CM, O'Gara PT, Ogedegbe O, Oparil S, White WB;

American Heart Association, American College of Cardiology, and American

Society of Hypertension. Treatment of hypertension in patients with coronary

artery disease: A scientific statement from the American Heart Association,

American College of Cardiology, and American Society of Hypertension. J Am

Soc Hypertens. 2015 Jun; 9(6):453-98.

15. James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C,

Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, Smith SC

Jr, Svetkey LP, Taler SJ, Townsend RR, Wright JT Jr, Narva AS, Ortiz E. 2014

evidence-based guideline for the management of high blood pressure in adults:

report from the panel members appointed to the Eighth Joint National Committee

(JNC 8). JAMA. 2014 Feb 5; 311(5):507-20.

16. Hall JE, Granger JP, do Carmo JM, da Silva AA, Dubinion J, George E, Hamza

S, Speed J, Hall ME. Hypertension: physiology and pathophysiology. Compr

Physiol. 2012 Oct; 2(4):2393-442.

17. Franklin, S. S., Hypertension in Older People: Part 1. The Journal of Clinical

Hypertension, 2006; 8; 444-449.

18. Gaddam KK, Verma A, Thompson M, Amin R, Ventura H. "Hypertension and

cardiac failure in its various forms". The Medical Clinics of North America. May

2009; 93 (3): 665–80

19. Schrader J et al. "[Stroke and hypertension]". April 2009. 50 (4): 423–32.

20. Tylicki L, Rutkowski B. "[Hypertensive nephropathy: pathogenesis, diagnosis

and treatment]"; feb 2003; 14 (80): 168–73.

21. Gardner AW, Afaq A. "MANAGEMENT OF LOWER EXTREMITY

PERIPHERAL ARTERIAL DISEASE". Journal of Cardiopulmonary

Rehabilitation and Prevention.; 2008; 28 (6): 349–57.

22. Walsh JB et al. "Hypertensive retinopathy. Description, classification, and

prognosis". Ophthalmology; oct 1982; 89 (10): 1127–31.

23. Ma, Jun, and Randall S Stafford. “Screening, treatment, and control of

hypertension in US private physician offices, 2003-2004.” Hypertension

(Dallas, Tex: 1979) vol. 51, 5 (2008): 1275-81.

24. Sigurdsson JA, Bengtsson C. Symptoms and signs in relation to blood pressure

and antihypertensive treatment. A cross-sectional and longitudinal population

study of middle-aged Swedish women. Acta Med Scand 1983; 213: 183–190

25. European Society of Hypertension/European Society of Cardiology Guidelines

for the management of arterial hypertension. Journal of Hypertension, 2003,

21:1011–1053.

26. Cutler JA, Stamler J. Prevention of hypertension. In: Izzo JL Jr, Black HR, eds.

Hypertension primer: the essentials of high blood pressure: basic science,

population science, and clinical management, 3rd edition. Philadelphia,

Lippincott Williams and Wilkins, 2003.

27. Jiang SZ, Lu W, Zong XF, Ruan HY, Liu Y. Obesity and hypertension. Exp Ther

Med. 2016; 12(4):2395–2399.

28. Anne Cecilie K. Larstorp, Serena Tonstad, Effect of a Low fat Diet Intervention

on Blood Pressure and Hypertension: Rather Switch to a Mediterranean

Diet, American Journal of Hypertension, Volume 29, Issue 8, August 2016, 900

903

29. Ha SK. Dietary salt intake and hypertension. Electrolyte Blood Press. 2014;

12(1):7–18.

30. Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on blood pressure:

a meta-analysis of randomized, controlled trials. Ann Intern Med. 2002 Apr 2;

136(7): 493-503.

31. O’Brien E et al. European Society of Hypertension recommendations for

conventional, ambulatory and home blood pressure measurement. Journal of

Hypertension, 2003, 21:821–848.

32. Vasan RS et al. Impact of high-normal blood pressure on the risk of

cardiovascular disease. New England Journal of Medicine, 2001, 345:1291–

1297

33. Zanchetti A, Ruilope LM. Antihypertensive treatment in patients with type-2

diabetes mellitus: what guidance from recent controlled randomized trials?

Journal of Hypertension, 2002, 20:2099–2110.

34. Ohkubo T et al. Reference values for 24-hour ambulatory blood pressure

monitoring based on a prognostic criterion: the Ohasama Study. Hypertension,

1998, 32:255–259.

35. Alqadri SL, Sreenivasan V, Qureshi AI. Acute hypertensive response

management in patients with acute stroke. Curr Cardiol Rep 2013; 15:426

36. Wang, Angela L et al. “New generations of dihydropyridines for treatment of

hypertension.” Journal of geriatric cardiology: JGC vol. 14,1 (2017): 67-72.

37. Godfraind T. Discovery and Development of Calcium Channel Blockers. Front

Pharmacol. 2017; 8:286.

38. Striessnig J, Ortner NJ, Pinggera A. Pharmacology of L-type Calcium Channels:

Novel Drugs for Old Targets. Curr Mol Pharmacol. 2015;8(2):110–122.

39. Catterall WA. Voltage-gated calcium channels. Cold Spring Harb Perspect Biol.

2011; 3(8): a003947.

40. Cloues, R. K., Cibulsky, S. M. & Sather, W. A. Ion interactions in the high-

affinity binding locus of a voltage-gated Ca2+ channel. J. Gen. Physiol.

2000; 116, 569–586

41. Dolphin, A. C. (2016), Voltage‐gated calcium channels and their auxiliary

subunits: physiology and pathophysiology and pharmacology. J Physiol, 594:

5369-5390.

42. Nakayama H, Kuniyasu A. Identification of binding sites for calcium channel

antagonists. Jpn Heart J. 1996 Sep;37(5):643-50.

43. Katz AM. Pharmacology and mechanisms of action of calcium-channel

blockers. J Clin Hypertens. 1986 Sep; 2(3 Suppl):28S-37S.

44. H.L. Sharma and K.K. Sharma. The principles of Pharmacology; paras medical,

3rd edition, India

45. Wang JG, Kario K, Lau T, Wei YQ, Park CG, Kim CH, Huang J, Zhang W, Li

Y, Yan P, Hu D, Asian Pacific Heart Association. Hypertens Res. 2011 Apr;

34(4):423-30.

46. Kjeldsen SE, Aksnes TA, Ruilope LM Drugs R D. 2014 Jun; 14(2):31-43

47. Wang, Angela L et al. “New generations of dihydropyridines for treatment of

hypertension.” Journal of geriatric cardiology: JGC vol. 14,1 (2017): 67-72.

48. Coca A, Mazón P, Aranda P, Redón J, Divisón JA, Martínez J, Calvo C, Galcerán

JM, Barrios V, Roca-Cusachs I Coll A Expert Rev Cardiovasc Ther. 2013 Jan;

11(1):91-105.

49. Kosaka H, Hirayama K, Yoda N, Sasaki K, Kitayama T, Kusaka H, Matsubara

M. The L-, N-, and T-type triple calcium channel blocker Benidipine acts as

anantagonist of mineralocorticoid receptor, a member of nuclear receptor

family.Eur J Pharmacol. 2010 Jun 10; 635(1-3):49-55.

50. Makani H, Bangalore S, Romero J, Htyte N, Berrios RS, Makwana H, Messerli

FH. Peripheral edema associated with calcium channel blockers: incidence and

withdrawal rate--a meta-analysis of randomized trials. J Hypertens. 2011 Jul;

29(7):1270-80.

51. Yao K, Nagashima K, Miki H. Pharmacological, pharmacokinetic, and

clinicalproperties of Benidipine hydrochloride, a novel, long-acting calcium

channel blocker. J Pharmacol Sci. 2006 Apr; 100(4):243-61.

52. Xue C, Zhou C, Yang B, et al on Comparison of efficacy and safety between

Benidipine and hydrochlorothiazide in fosinopril-treated hypertensive patients

with chronic kidney disease: protocol for a randomised controlled trial. BMJ

Open 2017; 7: e013672.

53. Li, Xue, and Mao Sheng Yang. “Effects of T-Type Calcium Channel Blockers

on Renal Function and Aldosterone in Patients with Hypertension: A Systematic

Review and Meta-Analysis.” Ed. Ryuichi Morishita. PS ONE 9.10 (2014):

e109834. PMC. Web. 25 Oct. 2017.

54. Tani S, Takahashi A, Nagao K, Hirayama A. Effects of the T/L-type calcium

channel blocker Benidipine on albuminuria and plasma aldosterone

concentration. A pilot study involving switching from L-type calcium channel

blockers to Benidipine. Int Heart J. 2014;55(6):519-25

55. Nagashima K, Miki H. Pharmacological, pharmacokinetic, and clinical

properties of a novel, long-acting calcium channel blocker. J Pharmacol Sci.

2008 Apr; 100(5):241-65.

56. Seino H, Miyaguchi S, Yamazaki T, Ota S, Yabe R, Suzuki S. Effect of

Benidipine hydrochloride, a long-acting T-type calcium channel blocker, on

blood pressure and renal function in hypertensive patients with diabetes mellitus.

Analysis after switching from cilnidipine to Benidipine. Arzneimittel

forschung.2007; 57(8):526-31.

57. Nishida, Y., Takahashi, Y., Tezuka, K. et al. Drugs R D (2017) 17: 403.

58. Nakamura, Tsukasa Ueda, Yoshihiko Sugaya, Takeshi Yamagishi,

ShoichiYamada, ShingoKoide, Hikaru et al. The American Journal of the

Medical Sciences, Volume 339, Issue 2, 157 – 163

59. Kita T, Suzuki Y, Eto T, Kitamura K: Long-term anti-hypertensive therapy with

Benidipine improves arterial stiffness over blood pressure lowering. Hypertens

Res 2005; 28: 959–964

60. Tomino Y. Renoprotective effects of the L/T-type CCB, Benidipine in patients

with hypertension. Cur Hypertens Rev.2013, May; 9(2):108-14.

61. Sugano N, Hayashi K, Hosoya T, Yokoo T. Mechanistic view of renal protective

action of calcium channel blockade. Curr Hypertens Rev2013; 9: 187–192.

62. Masuda T, Ogura MN, Moriya T, Takahira N, Matsumoto T, Kutsuna T, et al.

Beneficial Effects of L‐and N‐type Calcium Channel Blocker on Glucose and

Lipid Metabolism and Renal Function in Patients with Hypertension and Type

II Diabetes Mellitus. Cardiovascular therapeutics. 2011 Feb 1; 29(1):46-53.

63. Kojima S, Shida M, Yokoyana H. Comparison between Cilnidipine and

Amlodipine besilate with respect to proteinuria in hypertensive patients with

renal diseases. Hypertens Res. 2004; 27:379-85

64. Sakata K, Shirotani M, Yoshida H, Nawada R, Obayashi K, Togi K, et al. Effects

of Amlodipine and cilnidipine on cardiac sympathetic nervous system and

neurohormonal status in essential hypertension. Hypertension. 1999 Jun

1;33(6):1447-52

65. Umemoto S, Ogihara T, Matsuzaki M, et al. Effects of calcium channel blocker

Benidipine-based combination therapy on target blood pressure control and

cardiovascular outcome: a sub-analysis of the COPE trial. Hypertens Res.

2017;40(4):376–384

66. Koshy S, Bakris GL. Therapeutic approaches to achieve desired blood pressure

goals:focus on calcium channel blockers. Cardiovasc Drugs Ther 2000; 14:295–

301

67. Rakugi H, Ogihara T, Umemoto S, Matsuzaki M, Matsuoka H, Shimada K,

Higaki J, Ito S, Kamiya A, Suzuki H, Ohashi Y, Shimamoto K, Saruta T;

Combination Therapy of Hypertension to Prevent Cardiovascular Events Trial

Group. Combination therapy for hypertension in patients with CKD: a

subanalysis of the Combination Therapy of Hypertension to Prevent

Cardiovascular Events trial. Hypertens Res. 2013 Nov; 36(11):947-58.

68. Akizuki O, Inayoshi A, Kitayama T, Yao K, Shirakura S, Sasaki K, Kusaka H,

Matsubara M. Blockade of T-type voltage-dependent Ca2+ channels by

Benidipine, a dihydropyridine calcium channel blocker, inhibits aldosterone

production in humanadrenocortical cell line NCI-H295R. Eur J Pharmacol. 2008

Apr 28; 584(2-3):424-34.

69. Peng T, Hu Z, Xia Q, Jiang B, Li X, Yang X. A comparative study of the

renoprotective effects of Benidipine and valsartan in primary hypertensive

patients with proteinuria. Arzneimittelforschung. 2009; 59(12):647-50.

70. J.-Y. Park, K.-A. Kim, G.-S. Lee et al., “Randomized, open-label, two-period

crossover comparison of the pharmacokinetic and pharmacodynamic properties

of two Amlodipine formulations in healthy adult male Korean subjects,” Clinical

Therapeutics, vol. 26, no. 5, pp. 715–723, 2004.

71. Fares H, DiNicolantonio JJ, O'Keefe JH, Lavie CJ. Amlodipine in hypertension:

a first-line agent with efficacy for improving blood pressure and patient

outcomes. Open Heart. 2016; 3(2): e000473.

72. IBM Corp. Released 2013. IBM SPSS Statistics for Windows, Version 22.0,

Armonk, NY; IBM CORP

73. Zhou D, Xi B, Zhao M, Wang L, Veeranki SP. Uncontrolled hypertension

increases risk of all-cause and cardiovascular disease mortality in US adults: the

NHANES III Linked Mortality Study. Sci Rep. 2018; 8(1):9418.

74. Nakamura T, Sato E, Fujiwara N, Kawagoe Y, Ueda Y, Sugaya T, Yamagishi S,

Yamada S, Koide H. Comparative effects of Benidipine and Amlodipine on

proteinuria, urinary 8-OHdG, urinary L-FABP, and inflammatory and

atherosclerosis markers in early-stage chronic kidney disease. Am J Med Sci.

2010 Feb;339(2):157-63

75. Mitsuru ohishi, Takashi T, Norihisa ito: Renal-Protective Effect of T-and L-Type

Calcium Channel Blockers in Hypertensive Patients: An Amlodipine-to-Benidipine

Changeover (ABC) Study. Hypertension Research volume30, pages797–

806 (2007)

76. Hoshide S, Kario K, Ishikawa J, Eguchi K, Shimada K: Comparison of the

effects of cilnidipine and Amlodipine on ambulatory blood pressure. Hypertens

Res 2005; 28: 1003–1008.

77. Shetty, Kiran & Shetty, Ranjan & Reddy, Rohit & Nayak, Vidhya. (2015).

Calcium channel blockers induced pedal edema; mechanism and treatment

options: Review. International Journal of Sciences & Applied Research. 2. 27-

33.

78. Sica D a. Calcium Channel Blocker-Related Peripheral Edema: Can It Be

Resolved? J Clin Hypertens 2003; 5(4):291–5.

79. Ando K, Nitta K, Rakugi H, Nishizawa Y, Yokoyama H, Nakanishi T, Kashihara

N, Tomita K, Nangaku M, Takahashi K, Isshiki M, Shimosawa T, Fujita T.

Comparison of the Antialbuminuric Effects of Benidipine and

Hydrochlorothiazide in Renin-Angiotensin System (RAS) Inhibitor-Treated

Hypertensive Patients with Albuminuria: the COSMO-CKD

(COmbination Strategy on Renal Function of Benidipine or Diuretics TreatMent

with RAS inhibitOrs in a Chronic Kidney Disease Hypertensive Population)

Study. Int J Med Sci 2014; 11(9):897-904.

80. Derwa A, Peeters P, Vanholder R. Calcium channel blockers in the prevention

of end stage renal disease: a review. Acta Clin Belg. 2004 Jan-Feb; 59(1):44-56.

12. ANNEXURES

ANNEXURE - IA

PATIENT INFORMATION SHEET

 We are conducting a study on apparently hypertensive individuals attending

Karpaga Vinayaga Institute of Medical Sciences, Kancheepuram District-603 308

and for that your BP measurement, blood sample and urine sample may be valuable

to us.

 The purpose of this study is to compare the safety and efficacy of Benidipine with

Amlodipine in patients with Uncomplicated Hypertension- A Prospective study,

with the help of hypertensive volunteers with no complications.

 We are selecting certain cases of hypertension and if you are found to be eligible,

we will enroll you in our study and provide you hypertensive treatment with any of

our above drugs for a period of 3 months, we may be using your BP measurement

records, blood sample, urine sample for evaluation of both the drug safety and

efficacy periodically.

 The privacy of the patients in the research will be maintained throughout the study.

In the event of any publication or presentation resulting from the research, no

personally identifiable information will be shared.

 Taking part in this study is voluntary. You are free to decide whether to participate

in this study or to withdraw at any time; your decision will not result in any loss of

benefits to which you are otherwise entitled.

Signature of investigator Signature of participant

Date:

ANNEXURE – IB

PATIENT CONSENT FORM

Title of the study: Comparison of safety and efficacy of Benidipine with Amlodipine in patients with Uncomplicated Hypertension- A Prospective study.

Name: Date :

Age/sex: OP No :

Phone : Individual ID No:

The details of the study have been provided to me in writing and explained to me in my own language.

I confirm that I have understood the above study and had the opportunity to ask questions.

I understand that my participation in the study is voluntary and that I am free to withdraw at any time, without giving any reason, without the medical care that will normally be provided by the hospital being affected.

I agree not to restrict the use of any data or results that arise from this study provided such a use is only for scientific purpose(s).

I have been given an information sheet giving details of the study.

I fully consent to participate in the above study.

Signature

ANNEXURE II A

QUESTIONNAIRE (HYPERTENSION GROUP)

Patient ID Number: ______

1. Sex

i. Male

ii. Female

2. Age (years) ______

3. Home region ______

4. How long have you been in this region?

i. < 1 year

ii. 1-5 years

iii. > 5 years

iv. All my life

v. Just came for treatment

5. Address ______

6. Tel number ______

7. Referred from

i. Fast track clinic

ii. Normal clinic

iii. District

iv. Others ______

8. Marital status

i. Single

ii. Married

iii. Separated

iv. Divorced

v. Widowed

9. Employment status

i. Employed

ii. Self employed

iii. Petty business

iv. Housewife

v. Peasant

vi. Others ______

10. Level of education

i. No formal education

ii. Primary education

iii. O-level education

iv. A-level education

v. University education

11. Are you a current smoker?

i. Yes

ii. No

12. Are you taking alcohol?

i. Yes

ii. No

13. What level of physical activities do you have while at work?

i. Light

ii. Moderate

iii. Active

14. What level of physical activities do you have while commuting to and from work?

i. Using motorized transportation, or no work (0min of walking or cycling)

ii. Walking or cycling 1-29min

iii. Walking or cycling >30min

15. What level of activities do you have during your leisure time?

i. Low

ii. Moderate

iii. High

16. Personal history of hypertension

i. present

ii.absent

17. When were you diagnosed to have Hypertension?

i. <1 month

ii. 1 month – 1year

iii. >1 year ago

18. Do you have any close relative who is/was suffering from hypertension?

i. Yes

ii. No

19. If the answer is yes, who is this person?

i. Father

ii. Mother

iii. Sibling

iv. Father’s sibling

v. Mother’s sibling

vi. Child

vii. Father’s parents

viii. Mother’s parents

ix. Sibling’s child

20. Have you ever suffered from any of the following conditions?

i. Diabetes Mellitus

ii. High Cholesterol

iii. Angina

iv. TIA/Stroke

v. Intermittent claudication

vi. Poor vision

vii. Kidney disease

ANNEXURE II B

PROFORMA FOR PATIENT DETAILS

Name: Op No:

Gender: Individual Id No:

Age: Address:

H/O Hypertension: H/O Any Associated

Complications:

General Examination:

Height: Weight:

Ankle Edema: BMI:

Blood Pressure: Pulse:

(Sitting Posture-Right Arm)

Systemic Examination:

CVS: Abdomen:

RS: CNS:

Investigation:

Serum Creatinine: Urine Albumin:

Diagnosis:

PATIENT FOLLOW UP CHART

PATIENT ID:

GROUP: A (Amlodipine)

B (Benidipine)

S.NO DATE VISIT BLOOD ANKLE SERUM URINE

(weeks) PRESSURE EDEMA CREATININE ALBUMIN

1 0

2 2

3 4

4 6

5 8

6 10

7 12

ANNEXURE III

100

ANNEXURE IV

101

ANNEXURE IV A

102

ANNEXURE IV B

PLAGIARISM CERTIFICATE

This is to certify that this dissertation work titled “Comparison of safety and efficacy of Benidipine with Amlodipine in patients of uncomplicated hypertension-

A Prospective study of the candidate Dr. S. Srinath with registration number

201716452 for the award of Doctor of Medicine degree in the branch of Pharmacology.

I personally verified the urkund.com website for the purpose of plagiarism check. I found that the uploaded thesis file contains from introduction to conclusion pages and results show 5% (percentage) of plagiarism in the dissertation.

Guide/ Supervisor sign with seal

103

MASTER SHEET

SBP Before SBP After DBP Before DBP Ankle Serum Creatinine Urine S. no Name Group Age Sex Drug Drug Drug After Drug Edema (Mg/Dl) Albumin 1 Valliamma Benidipine 52 Female 160 132 100 80 No 0.8 No 2 Karuppasamy Benidipine 50 Male 162 140 96 90 No 0.8 No 3 Vasanthi Benidipine 45 Female 140 124 90 78 No 0.7 No 4 Anbuselvan Benidipine 58 Male 160 138 110 90 Yes 0.8 No 5 Ulaganathan Benidipine 52 Male 170 120 90 80 No 0.7 No 6 Sundari Benidipine 50 Female 140 124 90 78 No 0.7 No 7 Dhanalakshmi Benidipine 42 Female 140 120 110 80 No 0.7 No 8 Deviga Benidipine 43 Female 140 126 90 78 No 0.8 No 9 Seethalaksmi Benidipine 49 Female 144 136 90 86 No 0.8 No 10 Tiripurasundari Benidipine 50 Female 146 120 96 78 No 1.0 No 11 Moogambikai Benidipine 51 Female 140 136 90 86 No 0.9 No 12 Balraj Benidipine 45 Male 140 130 90 90 No 0.7 No 13 Soundarajan Benidipine 48 Male 142 128 90 80 No 0.7 No 14 Mathi Benidipine 60 Female 150 130 100 90 No 0.9 No 15 Muttaiah Benidipine 50 Male 160 124 100 86 No 0.9 No 16 Chinnaiah Benidipine 44 Male 150 130 96 90 No 0.7 No 17 Srinivasan Benidipine 62 Male 166 136 96 86 No 0.9 No 18 Selvi Benidipine 44 Female 170 130 90 90 No 0.9 No 19 Kanni Benidipine 70 Female 160 130 100 80 No 1.1 No 20 Vasudevan Benidipine 50 Male 170 140 100 90 No 0.9 No 21 Murali Benidipine 40 Male 150 110 90 70 No 1.1 No 22 Malathi Benidipine 56 Female 150 130 100 90 No 1.0 No 23 Chitra Benidipine 62 Female 152 130 100 90 No 1.0 No 24 Murugan Benidipine 59 Male 152 130 96 84 No 0.9 No 25 Ganesh Benidipine 48 Male 150 120 94 90 No 0.8 No 26 Kumar Benidipine 46 Male 152 120 96 90 No 0.8 No 27 Narayanan Benidipine 50 Male 150 120 94 70 No 0.6 No 28 Mani Benidipine 45 Male 148 110 90 70 Yes 0.8 No 29 Rajarajan Benidipine 49 Male 160 100 100 70 No 1.0 No 30 Deepa Benidipine 44 Female 150 126 100 90 No 1.0 No 31 Mala Benidipine 50 Female 160 140 100 90 No 1.0 No 32 Velvizhi Benidipine 42 Female 150 130 96 70 No 0.9 No 33 Annam Benidipine 49 Female 160 130 90 90 No 0.8 No 34 Settu Benidipine 60 Male 156 130 96 70 No 1.0 No

104

35 Muthulakshmi Benidipine 50 Female 158 130 96 60 No 0.9 No 36 Mari Benidipine 52 Male 160 130 90 90 No 0.7 No 37 Murugan Benidipine 38 Male 170 150 100 90 No 1.0 No 38 Subburayan Benidipine 52 Male 150 120 100 80 No 0.9 No 39 Kannan Benidipine 70 Male 160 130 100 80 No 1.0 No 40 Sadashir Benidipine 45 Male 160 130 100 80 No 0.9 No 41 Sasikumar Benidipine 48 Male 150 126 100 98 No 0.9 No 42 Udayappa Benidipine 55 Male 160 130 90 80 No 0.9 No 43 Vani Benidipine 40 Female 150 130 100 70 No 0.8 No 44 Iyappan Benidipine 42 Male 150 130 100 80 No 0.9 No 45 Balan Benidipine 58 Male 166 130 100 70 No 1.0 No 46 Parthiban Benidipine 45 Male 154 110 100 70 No 1.0 No 47 Shanthi Benidipine 40 Female 160 114 100 80 No 1.0 No 48 Vadivel Benidipine 55 Male 140 100 90 60 No 1.1 No 49 Leelavathy Benidipine 46 Female 140 110 90 70 No 0.8 No 50 Mahalakshmi Benidipine 50 Female 152 130 100 70 Yes 1.0 No 51 Vanitha Benidipine 52 Female 150 136 100 82 No 0.8 No 52 Kumaresan Benidipine 48 Male 158 120 96 90 No 1.0 No 53 Viragesan Benidipine 52 Male 160 120 100 90 No 0.8 No 54 Kadhir Benidipine 46 Male 156 120 96 90 No 0.8 No 55 Samaraj Benidipine 62 Male 164 136 100 82 No 1.0 No 56 Yuvaraj Benidipine 60 Male 160 130 100 90 No 1.0 No 57 Sekar Benidipine 54 Male 166 150 104 70 No 0.9 No 58 Vanaja Benidipine 65 Female 180 140 96 80 No 1.0 No 59 Mani Benidipine 50 Male 160 140 100 80 No 0.8 No 60 Vennila Benidipine 50 Female 160 138 100 90 No 0.9 No 61 Madasamy Amlodipine 48 Male 150 136 96 90 Yes 0.8 No 62 Punniyavathy Amlodipine 54 Female 148 136 96 76 No 1.0 No 63 Punnagai Amlodipine 45 Female 140 136 90 88 Yes 0.8 No 64 Neelammal Amlodipine 55 Female 148 136 104 90 Yes 0.7 No 65 Radhakrishnan Amlodipine 45 Male 140 138 90 86 Yes 0.8 No 66 Sarathy Amlodipine 43 Male 150 140 80 70 No 0.9 No 67 Malliga Amlodipine 48 Female 140 130 80 60 No 0.8 No 68 Amudhavani Amlodipine 47 Female 140 110 80 70 No 0.8 No 69 Shanthi Amlodipine 42 Female 140 128 88 84 No 0.7 No 70 Swarnalaksmi Amlodipine 46 Female 154 144 102 80 Yes 1.0 No 71 Sundaramurthy Amlodipine 44 Male 152 124 94 60 Yes 0.6 No 72 Syed Amlodipine 45 Male 140 110 90 80 No 0.7 No

105

73 Rajendiran Amlodipine 48 Male 146 120 96 90 Yes 1.0 No 74 Umapathy Amlodipine 48 Male 160 140 100 90 No 0.9 Yes 75 Chinnaponnu Amlodipine 50 Female 150 140 100 90 Yes 1.0 No 76 Moorthy Amlodipine 51 Male 166 140 100 90 No 0.7 No 77 Swetha Amlodipine 45 Female 150 140 100 90 No 0.9 No 78 Mahalakshmi Amlodipine 42 Female 144 110 98 70 Yes 0.8 No 79 Chitra Amlodipine 52 Female 150 100 100 70 No 1.0 No 80 Kuppusamy Amlodipine 52 Male 148 120 100 90 No 0.8 No 81 Saravanavel Amlodipine 62 Male 152 130 110 90 No 0.8 No 82 Akila Amlodipine 59 Female 140 130 78 72 No 0.9 No 83 Anand Amlodipine 53 Male 142 140 90 90 No 0.9 No 84 Saravanan Amlodipine 47 Male 158 138 90 82 No 0.9 No 85 Ajay Amlodipine 59 Male 152 120 96 90 Yes 0.9 No 86 Karuppasamy Amlodipine 55 Male 154 120 96 90 No 0.8 No 87 Dhanam Amlodipine 48 Female 146 110 96 70 Yes 0.8 No 88 Rajalakshmi Amlodipine 54 Female 148 110 98 70 Yes 0.9 No 89 Sargunam Amlodipine 54 Female 160 138 100 90 No 1.1 No 90 Kannama Amlodipine 52 Female 142 120 98 90 No 0.9 No 91 Karthik Amlodipine 52 Male 170 130 100 90 No 0.9 No 92 Subbulakshmi Amlodipine 48 Female 156 136 102 90 No 1.1 No 93 Marthandam Amlodipine 50 Male 154 140 100 80 No 0.9 No 94 Vijaya Amlodipine 44 Female 160 136 100 86 No 0.9 No 95 Rajendiran Amlodipine 52 Male 164 140 100 90 No 1.2 No 96 Veeraya Amlodipine 64 Male 150 138 100 90 Yes 1.3 No 97 Minnal Amlodipine 49 Female 160 140 100 90 Yes 1.0 No 98 Chidambaram Amlodipine 50 Male 150 140 90 76 No 0.8 No 99 Usha Amlodipine 42 Female 160 134 100 76 Yes 1.0 No 100 Mariraja Amlodipine 36 Male 160 130 100 90 No 0.9 No 101 Muthuraj Amlodipine 50 Male 164 140 104 80 No 0.9 No 102 Kanniammal Amlodipine 59 Female 148 140 102 90 Yes 0.8 No 103 Bahadhur Amlodipine 42 Female 160 126 90 80 No 0.9 No 104 Unnamalai Amlodipine 50 Female 160 130 100 70 Yes 0.9 No 105 Muthumari Amlodipine 44 Female 160 130 100 70 No 0.9 No 106 Meena Amlodipine 48 Female 150 130 90 70 Yes 1.0 No 107 Munusamy Amlodipine 53 Female 140 130 92 90 No 1.0 No 108 Saai Mahima Amlodipine 42 Female 150 130 92 70 No 1.0 No 109 Archana Amlodipine 62 Female 150 130 100 90 No 1.0 No 110 Kumar Amlodipine 45 Male 140 110 90 70 No 1.0 No

106

111 Karthik Amlodipine 48 Male 150 110 100 80 No 0.9 No 112 Umadevi Amlodipine 48 Female 156 144 96 92 No 1.0 No 113 Vijayarani Amlodipine 52 Female 160 140 100 90 Yes 0.9 No 114 Selvaraj Amlodipine 64 Male 170 140 100 86 No 0.9 No 115 Chandrammaal Amlodipine 70 Female 160 138 100 80 No 0.9 No 116 Murali Amlodipine 59 Female 170 150 100 90 Yes 1.1 No 117 Gowri Amlodipine 50 Female 160 144 100 86 No 1.1 No 118 Devaraj Amlodipine 65 Male 150 120 100 70 No 1.0 No 119 Varalakshmi Amlodipine 59 Female 150 130 100 90 No 1.0 No 120 Rekha Amlodipine 50 Female 150 126 100 76 No 0.9 No

107