Efficacy & Biochemical Evaluation of Pharmaceutical Optimized Felodipine

Efficacy & Biochemical Evaluation of Pharmaceutical Optimized Felodipine 10mg (F-7) with Essential Hypertension

1. Saleem Khan 2. Noor Badshah 3. Samina 4. Asnad 5. Muhammad Ishaq

1. Asstt. Prof. of ENT, 2. Asstt. Prof. of Ophthalmology, 3. Asstt. Prof. of Gynecology, 4. Asstt. Prof. of Biochemistry, 5. Prof. of Surgery, Jinnah Medical College Peshawar

 

ABSTRACT

Objective: The objective of this double-blind, comparative study evaluating efficacy and biochemical effects of optimized felodipine 10mg (F-7) as monotherapy with comparison to placebo in adult patient with essential hypertension.

Study Design.  Double-blind, comparative study

Place and Duration of Study: This study was conducted at the Department of Biochemistry, University of Karachi from March 2011 to October 2011.

Materials and Methods: This was multicenter randomized, double-blind, comparative study.  Patients were randomized to receive once Felodipine (F-7) daily for 8 weeks and at the end of study efficacy and biochemical evaluation was done

Results: The patients treated with optimized Felodipine  10mg (F-7)alone, blood pressure reduction was lower, although significant; reaching values of  140.2 ± 11.3 /87.9 ± 5.5  mmHg (p < 0.05 versus Placebo) by the end of eight weeks of treatment. . No significant variation of blood glucose was observed and different parameters of lipid profile were also observed during the eight weeks of treatment with antihypertensive regimen used. Thus, the drug regimens used may be considered neutral as regards glucose and plasma lipid metabolism profile because   drug used at low doses.

Conclusion: We can suggest that the high antihypertensive efficacy, good tolerability and no biochemical effects of the optimized Felodipine 10mg (F-7)it is an excellent option for the treatment of hypertension in a wide range of hypertensive patients, with a high potential to reduce cardiovascular risks.

Key Words: Hypertension, Felodipine, Biochemical Effects


 

INTRODUCTION

Hypertension is one of the strongest modifiable risk factors for cardiovascular and kidney disease and has been identified as the leading risk factor for mortality1.In European countries the prevalence of hypertension in adults is estimated to be approximately 44%.2 Current guidelines for the management of hypertension recommend a target blood pressure of 140/90 mmHg, with a stricter target for patients who have a high risk of cardiovascular events (< 130/80 mmHg).3,4

Felodipine is a dihydropyridine calcium antagonist which is characterized by high vascular selectivity-that is, it is much more potent in its inhibition of contractile activity in vascular smooth muscle than in the myocardium. The in vitro ratio of vascular and myocardial potency for felodipine is greater than 118: 15 and felodipine plasma concentrations resulting in pronounced reductions in total peripheral resistance in

patients produce no negative ino tropic effects 6 and no effects on cardiac conduction7.' The efficacy and tolerability of felodipine in patients with congestive heart failure have been studied in several open8-10 and double blind placebo controlled phase II studies.11-13 Thus Dunselman et a1.12 and Timmis et a1. .14demonstrated improved exercise capacity with felodipine in patients with heart failure, while Tan et. a1.11  found no such improvement.   Comparative safety and efficacy trials indicate that angiotensin receptor blockers like olmesartan medoxomil have superior tolerability and antihypertensive efficacy15.  Similar investigation using olmesartan, medoxomil and amlodipine besylate showed great effectiveness and tolerance in patient with hypertension16. Combination therapies reduced B.P to a greater extent than with amlodipine besylate alone as indicated with benazepril hydrochloride with valsartan and with perindopril17, 18.

Therefore, the objective of this comparative study evaluating the efficacy and biochemical effects of optimized felodipine 10mg (F-7) with placebo in the treatment of patients with essential hypertension.

MATERIALS AND METHODS

This was multicenter, randomized, placebo-controlled, comparative study. Patient was randomized to receive optimized Felodipine 10mg (F-7) once daily and Placebo once daily for 8 weeks. The study was conducted in Department of Biochemistry, University of Karachi from   March 2011 to October 2011.Patients were selected from four different hospitals of orange Town and 80 patients were selected for the study. Therefore 80patients were effectively analyzed for efficacy and tolerability the analysis of antihypertensive efficacy and biochemical effects of a therapeutic regimen in the long term becomes important.  The primary efficacy variable was change from baseline in MSDP at the end of study. Secondary variable was change in mean sitting systolic blood pressure from baseline. Safety biochemical parameters (complete blood count, renal function, liver function, electrolytes, protein profile, and enzymes) and electrocardiogram at rest were also determined in all patients at the baseline (week O) and at the 8th week of antihypertensive treatment. At the same time points, glucose metabolism parameter values and plasma lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol, and triglycerides) were also recorded. Biochemical parameters were determined using an automated method.

RESULTS

The patients treated with optimized Felodipine 10mg (F-7)alone, blood pressure reduction was lower, although significant; reaching values of 140.2 ± 11.3 /87.9 ± 5.5  mmHg (p < 0.05 versus Placebo) by the end of eight weeks of treatment. Variations in blood pressure measurement in the standing position during treatment were similar to those recorded in the sitting position, and no episode of orthostatic hypotension was reported in either of the therapeutic regimen.

Table No.1: Baseline characteristics

 

Felodipine
(F-7) (n=60)

Placebo (n=20)

Age (years)

50.2 + 9.3

51.5 + 9.8

Male / Female (%)

43.4 / 56.6

35.0 / 65.0

Body weight (Kg)

68.9 + 13.5

71.2 + 12.2

BMI (kg/m2)

27.5 + 3.8

27.8 + 3.4

SBP sitting (mmHg)

149.5 + 11.5

148.8 + 10.9

DBP sitting (mmHg)

95.7 + 7.4

94.9 + 7.8

Table No.2: Ambulatory blood pressure monitoring. Mean values of blood pressure

 

Felodipine (F-7) (n=60)

Placebo (n=20)

P-value

 

 

Systolic BP - 24 hours (mmHg)

 

 

Baseline

149.7 ± 11.2

149.4 ± 11.4

NS

Week 8

140.2 ± 11.3

148.9 ± 11.2

0.0074

 

Diastolic BP - 24 hours (mmHg)

 

 

Baseline

97.6 ± 7.4

95.4 ± 8.8

NS

Week 8

87.9 ± 5.5

94.9 ± 7.9

0.0003

NS: Non significant, p: probability

No significant variation in leg volume measurement was observed among the both groups studied during the eight weeks of treatment. No significant variations of blood glucose were observed and different parameters of lipid profile were also observed during the eight weeks of treatment with antihypertensive regimen used. Thus, the drug regimens used may be considered neutral as regards glucose and plasma lipid metabolism profile because   drug used at low doses.

Table No.3: Baseline Biochemical characteristics

 

 Felodipine (F-7) (n=60)

Placebo (n=20)

 

Fasting Blood Glucose(mg/dl)

 

Baseline

97.4 ± 11.5

99.1 ± 8.8

Week 8

95.5 ± 11.9

98.9 ± 9.2

 

Total Cholesterol (mg/dl)

 

Baseline

 

198.2 ± 43.1

195.2 ± 33.3

Week 8

199.7 ± 43.2

193.9 ± 34.1

 

LDL - Cholesterol (mg\dl)

 

Baseline

114.5 ± 34.2

117.8 ± 25.8

Week 8

114.9 ± 34.3

116.7 + 24.7

 

HDL - Cholesterol (mg\dl)

 

Baseline

53.2 ± 13.1

48.8 ± 11.7

Week 8

51.8 ± 12.8

48.7 ± 11.5

 

Triglycerides (mg\dl)

 

Baseline

136.2 ± 88.2

145.5 ± 88.1

Week 8

136.1 ± 89.3

144.2 ± 88.9

DISCUSSION

The baseline characteristics of the population included in the study are shown in Table no1. We can observe that the groups were not different in relation to age, body mass index and weight, heart rate, and systolic and diastolic pressure values .No significant variations of blood glucose and different parameters of lipid profile were observed during the eight-week of treatment with any of the three antihypertensive regimens used.  Thus, the drug regimens used may be considered neutral as regards glucose, plasma lipid metabolism. The results of this study showed that the optimized product Felodipine10mg (F-7)as a high antihypertensive efficacy that is sustained in the long term with a quite reduced percentage of loss of blood pressure control in table No.2 We observed that more than 71.8% of the patients treated with optimized product of Felodipine 10mg (F-7)remained with diastolic blood pressure levels equal to or lower than 90 mmHg, thus achieving the goals for the treatment of hypertension. The difficulty to achieve the goal of controlling systolic blood pressure explains why the international guidelines for studies on antihypertensive drugs still use criteria based on diastolic blood pressure to describe the antihypertensive efficacy of a drug, in spite of the fact that guidelines indicate the real need to control systolic blood pressure as well. It is important to point out that blood pressure reduction provided by the treatment with optimized product of Felodipine 10mg (F-7)did not cause any secondary Increase in sympathetic activity, since no significant variations of heart rate occurred. . In addition to a high efficacy in reducing blood pressure, keeping it at controlled levels, an antihypertensive drug should also have a good biochemical profile, since the presence of adverse effects may decrease the degree of compliance of the patient to the therapeutic regimen, thus ultimately leading to treatment dropout. Our results showed that the optimized product of Felodipine 10mg (F-7)at low doses has a very good biochemical profile with a low incidence of adverse events. The good biochemical profile of the optimized Felodipine 10mg (F-7)may be explained by the use of lower doses of each of the hypotensive drugs, since the existence of a strong relation between the dose of the hypotensive drug and the frequency of adverse events is known. However, some drugs used in the treatment of hypertension, such as diuretics and beta-blockers, are known to be able to promote harmful alterations in lipid metabolism, especially in glucose metabolism. In our study we observed that the use of the optimized Felodipine 10mg (F-7)did not change parameters of either glucose metabolism or plasma lipids, thus having a neutral biochemical profile even when used for 8 weeks. Table.No.3 Based on these results we can suggest that the optimized product Atenolol 10mg (F-7) is safe and adequate for the treatment of hypertension in patients with metabolic syndrome, diabetes mellitus and dyslipidemia.  Because alterations in these parameters are very frequently observed in hypertensive patients. Incidentally, hypertension is frequently associated to the metabolic syndrome; also, the frequency of this association increases with age. However, some drugs used in the treatment of hypertension, such as diuretics and beta blockers, are known to be able to promote harmful alterations in lipid metabolism, especially in glucose metabolism. Based on these results we can suggest that this therapeutic modality is safe and adequate for the treatment of hypertension in patients with metabolic syndrome, diabetes mellitus and dyslipidemia.

CONCLUSION

In brief, the results of this multicenter study demonstrated that the optimized Felodipine 10mg (F-7)has a high antihypertensive efficacy, allowing approximately 72.3% of the patients treated to achieve and maintain for eight weeks. We can suggest that the high antihypertensive efficacy, good tolerability and no biochemical effects of the optimized Felodipine 10mg (F-7) it is an excellent option for the treatment of hypertension.

REFERENCES

1.       Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ. For the Comparative Risk Assessment Collaborating Group. Selected major risk factors and global and regional burden of disease.  Lancet 2002;360:1347–60. 

2.       Wolf-Maier K, Cooper RS, Banegas JR, Giampaoli S, Hense HW, Joffres M, et al. Hypertension and blood pressure levels in 6 European countries, Canada, and the US. JAMA 2003;289:2363–9. 

3.       Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003;42: 1206 – 1252.

4.       Ogihara T, Kikuchi K, Matsuoka H, et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2009). Hypertens Res 2009;32:3-107.

5.       Ljung B, Nordlander M. Pharmacodynamic properties of felodipine. Drugs 1987;34(suppl 3):
7-15.

6.       Culling W, Ruttley MS, Sheridan DJ. Acute hemodynamic effects of felodipine during beta blockade in patients with coronary artery disease. Br Heart3' 1984;52 (4):431-4.

7.       Amlie JP, Endresen K, Sire S. The effect of felodipine on the sinus and atrioventricular node in patients with ischaemic heart disease. J Cardiovasc Pharmacol 1990;15 (suppl 4):S25.

8.       Emanuelsson H, Hjalmarson A, Holmberg S, Waagstein F. Acute haemodynamic effects of felodipine in congestive heart failure. Eur J Clin Pharmacol 1985;28:489-93.

9.       Tweddel AC, Martin W, McGhie AI, Hutton I. Sustained haemodynamic effects of felodipine in patients with chronic cardiac failure. Br J Clin Pharmacol 1988;25:689-94.

10.    Timmis AD, Smyth P, Kenny JF, Campbell S, Jewitt DE. Effects of vasodilator treatment with felodipine on haemodynamic responses to treadmill exercise in congestive heart failure. Br Heart J 1984;52:314-20.

11.    Tan LB, Murray RG, Larsson Y, Littler WA. Felodipine in patients with chronic heart failure: discrepant haemodynamic and clinical effects. Br Heart J 1987;58:122-8.

12.    Dunselman PHMJ, Kuntze CEE, van Bruggen A, Hamer H, Wesseling H, Lie KI. Felodipine in heart failure: double blind placebo controlled study in 23 patients. Circulation 1987;76(suppl 4):IV-179.

13.    Kassis E, Amtorp O, Waldorff S, Fritz-Hansen P. Efficacy of felodipine in chronic congestive heart failure: a placebo controlled haemodynamic study at rest and during exercise and orthostatic stress. Br Heart J 1987;58:505-11.

14.    Timmis AD, Campbell S, Monaghan MJ, Walker L, Hewitt DE. Acute haemodynamic and metabolic effects of felodipine in congestive heart failure. Br Heart J 1984;51:445-51.

15.    Steven GC, Michael M, Sulekha K, James L, Reinilde H. The combination of olmesartan medoxomil  and amlodipine besylate  in controlling high blood pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study.  Clin Therapeut 2008; 30: 587-604.

16.    Bernard RC, Carl JP, John OP, Jaroslav Sl, Galina C, Jerzy K, et al. Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina. JAMA 2004;291:309-316. 

17.    Khalida B, Najaf AG, Naheed A. Comparative studies of cimetidine derivative “temalastine” for potential energy calculation by Kitaigorodskii and lennard-jones functions.  Pak J Biochem Mol Biol 2010;43:81-86.

18.    Afshan N, Naheed A, Khalida B, Najaf AG, Farhat B. Conformational analysis geometry optimization of nucleosidic  antitumor antibiotic showdomycin by Arguslab  4 software. Pak J Pharmacol 2009; 22:78-82.