madman
Super Moderator
New Nutraceutical Combination Reduces Blood Pressure and Improves Exercise Capacity in Hypertensive Patients Via a Nitric Oxide–Dependent Mechanism
Background-—High blood pressure (BP) has long been recognized as a major health threat and, particularly, a major risk factor for stroke, cardiovascular disease, and end-organ damage. However, the identification of a novel, alternative, integrative approach for the control of BP and cardiovascular protection is still needed.
Methods and Results-—Sixty-nine uncontrolled hypertension patients, aged 40 to 68 years, on antihypertensive medication were enrolled in 2 double-blind studies. Forty-five were randomized to placebo or a new nutraceutical combination named AkP05, and BP, endothelial function, and circulating nitric oxide were assessed before and at the end of 4 weeks of treatment. Twenty-four patients were randomized to diuretic or AkP05 for 4 weeks and underwent a cardiopulmonary exercise test to evaluate the effects of AkP05 on functional capacity of the cardiovascular, pulmonary, and muscular systems. Vascular and molecular studies were undertaken on mice to characterize the action of the single compounds contained in the AkP05 nutraceutical combination. AkP05 supplementation reduced BP, improved endothelial function, and increased nitric oxide release; cardiopulmonary exercise test revealed that AkP05 increased maximum O2 uptake, stress tolerance, and maximal power output. In mice, AkP05 reduced BP and improved endothelial function, evoking increased nitric oxide release through the PKCa/Akt/endothelial nitric oxide synthase pathway and reducing reactive oxygen species production via NADPH-oxidase inhibition. These effects were mediated by synergism of the single compounds of AkP05.
Conclusions-—This is the first study reporting positive effects of a nutraceutical combination on the vasculature and exercise tolerance in treated hypertensive patients. Our findings suggest that AkP05 may be used as an adjunct for the improvement of cardiovascular protection and to better control BP in uncontrolled hypertension.
Clinical Perspective
What Is New?
• This is the first demonstration that supplementation with a novel nutraceutical combination can improve functional capacity and cardiovascular protection in uncontrolled hypertensive patients on antihypertensive medication.
• AkP05 has a direct effect on blood pressure, endothelial function, circulating nitric oxide levels, and exercise tolerance in humans.
• The single components of AkP05 exert synergistic effects in maintenance of the redox axis for nitric oxide bioavailability, modulating oxidative stress status and enzyme activity
What Are the Clinical Implications?
• This novel nutraceutical combination is able to contribute to the reduction of blood pressure levels and to the improvement of endothelial function and exercise effort beyond classical pharmacological therapy.
• The characterization of the beneficial cardiovascular properties of a combination of multiple naturally derived compounds, named AkP05, may lay the foundation for the development of new, natural adjunct therapies aimed at improving cardiovascular protection and contributing to the achievement of target blood pressure levels.
Perspectives
Although more studies are needed to completely characterize the cardiovascular effects of AkP05, the blood pressure– lowering effect and increased effort tolerance evoked suggest that it could be used in cardiovascular disease prevention. Moreover, the identification of a novel nutraceutical combination able to improve NO production and bioavailability in the hypertensive condition may extend the clinician’s armamentarium of approaches for better control of BP.
Data S1.
Supplemental Materials and Methods
Study design
The study was conducted in accordance with the guidelines of the declaration of Helsinki and was approved by the Ethic Committee of CE Campania Sud, Italy, which registered the study protocol (n° 390-01587470-30081). Written informed consent was obtained from each subject. Systolic and diastolic BP were measured by standard sphygmomanometer after 5 min in the supine position, according to the guidelines of the European Society of Hypertension/European Society of Cardiology. Subjects of both sexes with diagnosis of essential hypertension were screened for the following exclusion criteria: previous cardiac or cerebrovascular event; heart failure; diabetes mellitus; history of atrial fibrillation or other severe arrhythmias; chronic kidney disease (defined as serum creatinine levels >1.4 mg/dL); pre-existing psychiatric disorders; neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, early onset/genetic Alzheimer’s disease, neuromuscular pathologies, epilepsy; dementia. In addition, patients requiring any pharmacological treatment beyond anti-hypertensive drugs, pregnant women, and women planning to conceive were also excluded from the study.
We performed two different studies in humans. The first was a randomized double blind placebo controlled study with a 4 week follow-up during which forty-five treated hypertensive patients with stable, unsatisfactory control of blood pressure were randomized to receive placebo or one pill of a nutraceutical preparation (Akp05, 1gr., Izzek®, Damor Farmaceutici, Italy) containing dry plant extract of 300 mg Bacopa Monnieri + 50 mg dry extract of Ginkgo biloba leaves + 25mg phosphatidylserine + 40 mg dry extract of green tea leaves. The company also produced the placebo, similar in appearance and organoleptic properties to the nutraceutical preparation.
Since there is no gold standard measurement system that fulfils the criteria for optimal medication-adherence monitoring, in this study, for monitoring of the medication compliance, we relied on patient self-reporting. For study drug monitoring, we delivered to each patient a container containing the number of exact capsules to be used for the entire duration of the treatment. Furthermore, they were required to return the container at the end of the treatment period.
Blood pressure, non-invasive endothelial function, as assessed reactive hyperemia index (RHI), and serum nitric oxide concentration were measured in control conditions and at the end of the follow-up period.
The second outcome was a 1:1 randomized since it represents a novel outcome of the study. For this outcome twenty-four patients who were not taking diuretics participated in a second study conducted according to a single blind active controlled protocol. They were randomized to take, in addition to their medication, either one pill of AkP05 or one pill of diuretic (Chlorothiazide, 1gr/day) and underwent 24-hour ambulatory blood pressure monitoring and a cardiopulmonary exercise test (CPET) at baseline and after 4 weeks of treatment.
Background-—High blood pressure (BP) has long been recognized as a major health threat and, particularly, a major risk factor for stroke, cardiovascular disease, and end-organ damage. However, the identification of a novel, alternative, integrative approach for the control of BP and cardiovascular protection is still needed.
Methods and Results-—Sixty-nine uncontrolled hypertension patients, aged 40 to 68 years, on antihypertensive medication were enrolled in 2 double-blind studies. Forty-five were randomized to placebo or a new nutraceutical combination named AkP05, and BP, endothelial function, and circulating nitric oxide were assessed before and at the end of 4 weeks of treatment. Twenty-four patients were randomized to diuretic or AkP05 for 4 weeks and underwent a cardiopulmonary exercise test to evaluate the effects of AkP05 on functional capacity of the cardiovascular, pulmonary, and muscular systems. Vascular and molecular studies were undertaken on mice to characterize the action of the single compounds contained in the AkP05 nutraceutical combination. AkP05 supplementation reduced BP, improved endothelial function, and increased nitric oxide release; cardiopulmonary exercise test revealed that AkP05 increased maximum O2 uptake, stress tolerance, and maximal power output. In mice, AkP05 reduced BP and improved endothelial function, evoking increased nitric oxide release through the PKCa/Akt/endothelial nitric oxide synthase pathway and reducing reactive oxygen species production via NADPH-oxidase inhibition. These effects were mediated by synergism of the single compounds of AkP05.
Conclusions-—This is the first study reporting positive effects of a nutraceutical combination on the vasculature and exercise tolerance in treated hypertensive patients. Our findings suggest that AkP05 may be used as an adjunct for the improvement of cardiovascular protection and to better control BP in uncontrolled hypertension.
Clinical Perspective
What Is New?
• This is the first demonstration that supplementation with a novel nutraceutical combination can improve functional capacity and cardiovascular protection in uncontrolled hypertensive patients on antihypertensive medication.
• AkP05 has a direct effect on blood pressure, endothelial function, circulating nitric oxide levels, and exercise tolerance in humans.
• The single components of AkP05 exert synergistic effects in maintenance of the redox axis for nitric oxide bioavailability, modulating oxidative stress status and enzyme activity
What Are the Clinical Implications?
• This novel nutraceutical combination is able to contribute to the reduction of blood pressure levels and to the improvement of endothelial function and exercise effort beyond classical pharmacological therapy.
• The characterization of the beneficial cardiovascular properties of a combination of multiple naturally derived compounds, named AkP05, may lay the foundation for the development of new, natural adjunct therapies aimed at improving cardiovascular protection and contributing to the achievement of target blood pressure levels.
Perspectives
Although more studies are needed to completely characterize the cardiovascular effects of AkP05, the blood pressure– lowering effect and increased effort tolerance evoked suggest that it could be used in cardiovascular disease prevention. Moreover, the identification of a novel nutraceutical combination able to improve NO production and bioavailability in the hypertensive condition may extend the clinician’s armamentarium of approaches for better control of BP.
Data S1.
Supplemental Materials and Methods
Study design
The study was conducted in accordance with the guidelines of the declaration of Helsinki and was approved by the Ethic Committee of CE Campania Sud, Italy, which registered the study protocol (n° 390-01587470-30081). Written informed consent was obtained from each subject. Systolic and diastolic BP were measured by standard sphygmomanometer after 5 min in the supine position, according to the guidelines of the European Society of Hypertension/European Society of Cardiology. Subjects of both sexes with diagnosis of essential hypertension were screened for the following exclusion criteria: previous cardiac or cerebrovascular event; heart failure; diabetes mellitus; history of atrial fibrillation or other severe arrhythmias; chronic kidney disease (defined as serum creatinine levels >1.4 mg/dL); pre-existing psychiatric disorders; neurodegenerative diseases such as multiple sclerosis, amyotrophic lateral sclerosis, Parkinson’s disease, early onset/genetic Alzheimer’s disease, neuromuscular pathologies, epilepsy; dementia. In addition, patients requiring any pharmacological treatment beyond anti-hypertensive drugs, pregnant women, and women planning to conceive were also excluded from the study.
We performed two different studies in humans. The first was a randomized double blind placebo controlled study with a 4 week follow-up during which forty-five treated hypertensive patients with stable, unsatisfactory control of blood pressure were randomized to receive placebo or one pill of a nutraceutical preparation (Akp05, 1gr., Izzek®, Damor Farmaceutici, Italy) containing dry plant extract of 300 mg Bacopa Monnieri + 50 mg dry extract of Ginkgo biloba leaves + 25mg phosphatidylserine + 40 mg dry extract of green tea leaves. The company also produced the placebo, similar in appearance and organoleptic properties to the nutraceutical preparation.
Since there is no gold standard measurement system that fulfils the criteria for optimal medication-adherence monitoring, in this study, for monitoring of the medication compliance, we relied on patient self-reporting. For study drug monitoring, we delivered to each patient a container containing the number of exact capsules to be used for the entire duration of the treatment. Furthermore, they were required to return the container at the end of the treatment period.
Blood pressure, non-invasive endothelial function, as assessed reactive hyperemia index (RHI), and serum nitric oxide concentration were measured in control conditions and at the end of the follow-up period.
The second outcome was a 1:1 randomized since it represents a novel outcome of the study. For this outcome twenty-four patients who were not taking diuretics participated in a second study conducted according to a single blind active controlled protocol. They were randomized to take, in addition to their medication, either one pill of AkP05 or one pill of diuretic (Chlorothiazide, 1gr/day) and underwent 24-hour ambulatory blood pressure monitoring and a cardiopulmonary exercise test (CPET) at baseline and after 4 weeks of treatment.
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