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Olive Leaf Extract

October 2014

By Life Extension

Which is the optimal antihypertensive combination in different diseases, a renin- angiotensin-aldosterone system inhibitor with a diuretic or with a calcium channel blocker?

Successful treatment of hypertension often requires the association of drugs from different classes. Combination therapy takes advantage of complementary mechanisms of action, in order to reach target blood pressure (BP) earlier and to minimize the side effects of medications. In the last decade, several randomized trials have demonstrated the efficacy of combining a renin-angiotensin-aldosterone system (RAAS) inhibitor with a calcium channel blocker (CCB) or with a diuretic in different populations. The ACCOMPLISH trial was the only large clinical trial that directly compared the two combination strategies. In hypertensive individuals at high cardiovascular risk, benazepril plus amlodipine was superior to benazepril plus hydrochlorothiazide in reducing the primary composite endpoint of cardiovascular events plus death from cardiovascular causes. Small randomized trials have evaluated the two combination therapies in surrogate endpoints, such as microalbuminuria, with contrasting results. Current European and American guidelines recommend combination therapy as first-line when BP is at least 20/10 mmHg above treatment goals. However, the choice of the best combination therapy is still debated: the National Institute for Health and Clinical Excellence guidelines recommend a RAAS inhibitor plus a CCB, while the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure guidelines underline the pivotal role of thiazide diuretics. The combination of a RAAS inhibitor with a CCB demonstrated the best efficacy in reducing cardiovascular endpoint. However, the combination of a RAAS inhibitor with a diuretic has shown beneficial results in particular subgroup of patients, such as patients with heart failure or with African American origin. This review will focus on the rationale and current evidences about combination therapy in the management of arterial hypertension.

Curr Pharm Des . 2013;19(21):3753-65.

Incidence of discontinuation of angiotensin-converting enzyme inhibitors due to cough, in a primary healthcare center in Singapore.

INTRODUCTION: The inci-dence of cough induced by angiotensin-converting enzyme (ACE) inhibitors has been reported to be 5%-20%, with less than half of affected patients requiring discontinuation due to persistent cough. However, the incidence in the local Asian population has not been studied. This study aimed to objectively evaluate the incidence of discontinuation of ACE inhibitors due to cough, in a primary healthcare center in Singapore. METHODS: We retrospectively reviewed the medical records, both electronic and written, of patients who attended Tampines Polyclinic to identify those who were newly prescribed ACE inhibitors. The written medical records were analyzed to identify patients who discontinued the use of ACE inhibitors and to find out the reasons for discontinuation. RESULTS: A total of 424 patients were identified during the study period. Out of the 424 patients, 129 (30.4%) discontinued the use of ACE inhibitors due to cough. Overall, 90 (21.2%) patients who were initially started on ACE inhibitors were eventually switched to angiotensin receptor blockers (ARBs). CONCLUSION: In our cohort, the incidence of discontinuation of ACE inhibitors due to cough is higher than most other studies. The relationship between ethnicity and tolerance of medications should not be underestimated. As there is a high incidence of discontinuation of ACE inhibitors due to cough in the local population, ARBs may be a reasonable substitute as a first-line medication, if clinically indicated.

Singapore Med J . 2014 Mar;55(3):146-9.

Comparative effectiveness of renin-angiotensin system blockers and other antihypertensive drugs in patients with diabetes: systematic review and Bayesian network meta-analysis.

OBJECTIVE: To assess the effects of different classes of antihypertensive treatments, including monotherapy and combination therapy, on survival and major renal outcomes in patients with diabetes. DESIGN: Systematic review and Bayesian network meta-analysis of randomized clinical trials. DATA SOURCES: Electronic literature search of PubMed, Medline, Scopus, and the Cochrane Library for studies published up to December 2011. STUDY SELECTION: Randomized clinical trials of antihypertensive therapy (angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), a blockers, b blockers, calcium channel blockers, diuretics, and their combinations) in patients with diabetes with a follow-up of at least 12 months, reporting all cause mortality, requirement for dialysis, or doubling of serum creatinine levels. DATA EXTRACTION: Bayesian network meta-analysis combined direct and indirect evidence to estimate the relative effects between treatments as well as the probabilities of ranking for treatments based on their protective effects. RESULTS: 63 trials with 36,917 participants were identified, including 2,400 deaths, 766 patients who required dialysis, and 1,099 patients whose serum creatinine level had doubled. Compared with placebo, only ACE inhibitors significantly reduced the doubling of serum creatinine levels (odds ratio 0.58, 95% credible interval 0.32 to 0.90), and only b blockers showed a significant difference in mortality (odds ratio 7.13, 95% credible interval 1.37 to 41.39).Comparisons among all treatments showed no statistical significance in the outcome of dialysis. Although the beneficial effects of ACE inhibitors compared with ARBs did not reach statistical significance, ACE inhibitors consistently showed higher probabilities of being in the superior ranking positions among all three outcomes. Although the protective effect of an ACE inhibitor plus calcium channel blocker compared with placebo was not statistically significant, the treatment ranking identified this combination therapy to have the greatest probability (73.9%) for being the best treatment on reducing mortality, followed by ACE inhibitor plus diuretic (12.5%), ACE inhibitors (2.0%), calcium channel blockers (1.2%), and ARBs (0.4%). CONCLUSIONS: Our analyses show the renoprotective effects and superiority of using ACE inhibitors in patients with diabetes, and available evidence is not able to show a better effect for ARBs compared with ACE inhibitors. Considering the cost of drugs, our findings support the use of ACE inhibitors as the first line antihypertensive agent in patients with diabetes. Calcium channel blockers might be the preferred treatment in combination with ACE inhibitors if adequate blood pressure control cannot be achieved by ACE inhibitors alone.

BMJ . 2013 Oct 24;347:f6008.

Olive (Olea europaea L.) leaf polyphenols improve insulin sensitivity in middle-aged overweight men: a randomized, placebo-controlled, crossover trial.

BACKGROUND: Olive plant leaves (Olea europaea L.) have been used for centuries in folk medicine to treat diabetes, but there are very limited data examining the effects of olive polyphenols on glucose homeostasis in humans. OBJECTIVE: To assess the effects of supplementation with olive leaf polyphenols (51.1 mg oleuropein, 9.7 mg hydroxytyrosol per day) on insulin action and cardiovascular risk factors in middle-aged overweight men. DESIGN: Randomized, double-blinded, placebo-controlled, crossover trial in New Zealand. 46 participants (aged 46.4 ± 5.5 years and BMI 28.0 ± 2.0 kg/m(2)) were randomized to receive capsules with olive leaf extract (OLE) or placebo for 12 weeks, crossing over to other treatment after a 6-week washout. Primary outcome was insulin sensitivity (Matsuda method). Secondary outcomes included glucose and insulin profiles, cytokines, lipid profile, body composition, 24-hour ambulatory blood pressure, and carotid intima-media thickness. RESULTS: Treatment evaluations were based on the intention-to-treat principle. All participants took >96% of prescribed capsules. OLE supplementation was associated with a 15% improvement in insulin sensitivity (p = 0.024) compared to placebo. There was also a 28% improvement in pancreatic b-cell responsiveness (p = 0.013). OLE supplementation also led to increased fasting interleukin-6 (p = 0.014), IGFBP-1 (p = 0.024), and IGFBP-2 (p = 0.015) concentrations. There were however, no effects on interleukin-8, TNF-a, ultra-sensitive CRP, lipid profile, ambulatory blood pressure, body composition, carotid intima-media thickness, or liver function. CONCLUSIONS: Supplementation with olive leaf polyphenols for 12 weeks significantly improved insulin sensitivity and pancreatic b-cell secretory capacity in overweight middle-aged men at risk of developing the metabolic syndrome.

PLoS One . 2013;8(3):e57622.

Vasorelaxant activity of extracts obtained from Apium graveolens: possible source for vasorelaxant molecules isolation with potential antihypertensive effect.

OBJECTIVE: To investigate vasorelaxant effect of organic extracts from Apium graveolens (A. graveolens) which is a part of a group of plants subjected to pharmacological and phytochemical study with the purpose of offering it as an ideal source for obtaining lead compounds for designing new therapeutic agents with potential vasorelaxant and antihypertensive effects. METHODS: An ex vivo method was employed to assess the vasorelaxant activity. This consisted of using rat aortic rings with and without endothelium precontracted with norepinephrine. RESULTS: All extracts caused concentration-dependent relaxation in precontracted aortic rings with and without endothelium; the most active extracts were Dichloromethane and Ethyl Acetate extracts from A. graveolens. These results suggested that secondary metabolites responsible for the vasorelaxant activity belong to a group of compounds of medium polarity. Also, our evidence showed that effect induced by dichloromethane and ethyl acetate extracts from A. graveolens is mediated probably by calcium antagonism. CONCLUSIONS: A. graveolens represents an ideal source for obtaining lead compounds for designing new therapeutic agents with potential vasorelaxant and antihypertensive effects.

Asian Pac J Trop Biomed . 2013 Oct;3(10):776-9.

Antihypertensive effect of celery seed on rat blood pressure in chronic administration.

This study investigated the effects of different celery (Apium graveolens) seed extracts on blood pressure (BP) in normotensive and deoxycorticosterone acetate-induced hypertensive rats. The hexanic, methanolic, and aqueous-ethanolic extracts were administered intraperitoneally and their effects on BP and heart rate (HR) were evaluated in comparison with spirnolactone as a diuretic and positive control. Also, the amount of n-butylphthalide (NBP), as an antihypertensive constituent, in each extract was determined by HPLC. The results indicated that all extracts decreased BP and increased the HR in hypertensive rats, but had no effect on normotensive rats. The data showed that administration of 300 mg/kg of hexanic, methanolic, and aqueous-ethanolic (20/80, v/v) extracts of the celery seed caused 38, 24, and 23 mmHg reduction in BP and 60, 25, and 27 beats per minute increase in the HR, respectively. Also, the HPLC analysis data revealed that the content of NBP in the hexanic extract was 3.7 and 4 times greater than methanolic and aqueous-ethanolic extracts. It can be concluded that celery seed extracts have antihypertensive properties, which appears to be attributable to the actions of its active hydrophobic constitutes such as NBP and can be considered as an antihypertensive agent in chronic treatment of elevated BP.

J Med Food . 2013 Jun;16(6):558-63.

A Pilot Study to Evaluate the Antihypertensive Effect of a Celery Extract in Mild to Moderate Hypertensive Patients

Objective: To evaluate the efficacy of a standardized extract of celery seed, 150 mg/d, supplying 85% 3-n-butylphthalide (3nB) in mild to moderate hypertensive patients. Study Design: A single-arm study of 30 mild to moderate hypertensive patients given the test medication following a 7-day wash out period. The primary clinical assessment was the effect on blood pressure at week 3 and week 6. Secondary measures were fasting blood levels of total cholesterol, LDL cholesterol, HDL cholesterol, VLDL cholesterol, free fatty acids, and serum electrolytes (i.e., sodium, potassium, calcium). Results: There was statistically significant decrease in both systolic blood pressure (SBP) and diastolic blood pressure (DBP) at week 3 and week 6 compared to baseline. The change at week 6 for the SBP was 8.2 mmHg (SD=3.6, P<0.005) and for the DBP was 8.5 mmHG (SD=2.9, P<0.005). Conclusions: The results from this pilot study suggest that celery seed extract may have clinically relevant blood pressure–lowering effects, indicating that additional clinical research is warranted.

Natural Medicine Journal. 2013;4(4):1-3.

Prevalence of hypertension and circadian blood pressure variations in patients with obstructive sleep apnea-hypopnea syndrome.

OBJECTIVE: To investigate the prevalence of hypertension and circadian blood pressure (BP) variations in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). METHODS: Patients referred to a sleep clinic underwent polysomnography with measurement of BP at four time points. They were classified into four groups (control, and mild, moderate or severe sleep apnea) using the apnea-hypopnea index (AHI). Circadian variation was assessed using night-time to daytime mean BP (R N/D) and morning to evening mean BP (R M/E) ratios. RESULTS: Hypertension was significantly more common in patients with OSAHS (50.5%) than in controls (30.4%). AHI was positively correlated with hypertension after controlling for related confounders. Mean BP values at all four time points rose with increasing AHI. The increase in night-time and morning values was more pronounced than the increase in daytime and evening values in patients with OSAHS, resulting in loss of the normal BP diurnal rhythm. The R N/D and R M/E ratios increased with increasing AHI. Daytime BP was significantly correlated with AHI and the lowest oxygen saturation value. CONCLUSION: OSAHS was shown to be an independent risk factor for hypertension. It was also associated with loss of the normal BP diurnal rhythm.

J Int Med Res . 2014 Mar 20;42(3):773-780.

Olive (Olea europaea) leaf extract effective in patients with stage-1 hypertension: comparison with Captopril.

A double-blind, randomized, parallel and active-controlled clinical study was conducted to evaluate the anti-hypertensive effect as well as the tolerability of Olive leaf extract in comparison with Captopril in patients with stage-1 hypertension. Additionally, this study also investigated the hypolipidemic effects of Olive leaf extract in such patients. It consisted of a run-in period of 4 weeks continued subsequently by an 8-week treatment period. Olive (Olea europaea L.) leaf extract (EFLA(®)943) was given orally at the dose of 500 mg twice daily in a flat-dose manner throughout the 8 weeks. Captopril was given at the dosage regimen of 12.5 mg twice daily at start. After 2 weeks, if necessary, the dose of Captopril would be titrated to 25 mg twice daily, based on subject’s response to treatment. The primary efficacy endpoint was reduction in systolic blood pressure (SBP) from baseline to week-8 of treatment. The secondary efficacy endpoints were SBP as well as diastolic blood pressure (DBP) changes at every time-point evaluation and lipid profile improvement. Evaluation of BP was performed every week for 8 weeks of treatment; while of lipid profile at a 4-week interval. Mean SBP at baseline was 149.3±5.58 mmHg in Olive group and 148.4±5.56 mmHg in Captopril group; and mean DBPs were 93.9±4.51 and 93.8±4.88 mmHg, respectively. After 8 weeks of treatment, both groups experienced a significant reduction of SBP as well as DBP from baseline; while such reductions were not significantly different between groups. Means of SBP reduction from baseline to the end of study were -11.5±8.5 and -13.7±7.6 mmHg in Olive and Captopril groups, respectively; and those of DBP were -4.8±5.5 and -6.4±5.2 mmHg, respectively. A significant reduction of triglyceride level was observed in Olive group, but not in Captopril group. In conclusion, Olive (Olea europaea) leaf extract, at the dosage regimen of 500 mg twice daily, was similarly effective in lowering systolic and diastolic blood pressures in subjects with stage-1 hypertension as Captopril, given at its effective dose of 12.5-25 mg twice daily.

Phytomedicine . 2011 Feb 15;18(4):251-8.

Food supplementation with an olive (Olea europaea L.) leaf extract reduces blood pressure in borderline hypertensive monozygotic twins.

Hypertension is a harmful disease factor that develops unnoticed over time. The treatment of hypertension is aimed at an early diagnosis followed by adequate lifestyle changes rather than pharmacological treatment. The olive leaf extract EFLA943, having antihypertensive actions in rats, was tested as a food supplement in an open study including 40 borderline hypertensive monozygotic twins. Twins of each pair were assigned to different groups receiving 500 or 1,000 mg/day EFLA943 for 8 weeks, or advice on a favourable lifestyle. Body weight, heart rate, blood pressure, glucose and lipids were measured fortnightly. Blood pressure changed significantly within pairs, depending on the dose, with mean systolic differences of < or =6 mmHg (500 mg vs control) and < or =13 mmHg (1000 vs 500 mg), and diastolic differences of < or =5 mmHg. After 8 weeks, mean blood pressure remained unchanged from baseline in controls (systolic/diastolic: 133 +/- 5/77 +/- 6 vs 135 +/- 11/80 +/- 7 mmHg) and the low-dose group (136 +/- 7/77 +/- 7 vs 133 +/- 10/76 +/- 7), but had significantly decreased for the high dose group (137 +/- 10/80 +/- 10 vs 126 +/- 9/76 +/- 6). Cholesterol levels decreased for all treatments with significant dose-dependent within-pair differences for LDL-cholesterol. None of the other parameters showed significant changes or consistent trends. Concluding, the study confirmed the antihypertensive and cholesterol-lowering action of EFLA943 in humans.

Phytother Res. 2008 Sep;22(9):1239-42.