MicroActive® Resveratrol Clinical Evidence

Resveratrol Clinical Evidence

MicroActive® Resveratrol Powder (30%) In Vitro and In Vivo Studies MicroActive® Resveratrol Dissolution Test. Unpublished paper. June 2011.

Topic:
In comparison with a standard resveratrol preparation, how quickly is MicroActive® resveratrol released and how long does it remain bioavailable?

Background:
Resveratrol is a phytochemical, found in the skin of red grapes, with cardiovascular and other health benefits. Standard resveratrol supplements release quickly in the body, however, so that blood levels drop quickly after the supplement is consumed. Can MicroActive® resveratrol provide longer lasting bioavailability?

Study Type:
In vitro and pilot human clinical intervention study

Study Design:
Double-blind crossover. Two types of resveratrol were dissolved into a medium that predicts bioavailability. Later subjects took both kinds of resveratrol and levels of it were measured in their blood.

Dosage:
Single dose, equivalent to 500 mg

Subjects:
2 healthy subjects

Results:
In the in vitro portion of the study, the standard resveratrol dissolved completely in 4 hours. By contrast, the MicroActive® resveratrol was released over 12 hours (97% released). In the human portion of the study, the standard resveratrol was absorbed quickly, with a peak level reached at 2 hours. After this peak, levels declined sharply with a small rise at 9 hours. MicroActive® also reached a peak at 2 hours, but with a longer peak period. Blood levels of resveratrol remained high for 9 hours or longer.

Conclusions:
“The ratio of MicroActive® to control Resveratrol AUC was 2.54. Unformulated resveratrol is absorbed rapidly, metabolized extensively, and eliminated, resulting in trace amounts of unchanged resveratrol in of the study indicate that [MT1] MicroActive® sustained-release formulation of resveratrol extends the systemic exposure to higher levels of free resveratrol and its metabolites. The results warrant a larger clinical study for further validation.”

Cancer Prevention Research
Howells LM et al. Phase I randomized, double-blind pilot study of micronized resveratrol (SRT501) in patients with hepatic metastases—safety, pharmacokinetics, and pharmacodynamics. 2011 Sep; 4(9):1419–25.

Topic:
Can micronization improve absorption and availability of resveratrol for cancer patients?

Background:
Resveratrol has shown promise in treating cancer; however, its bioavailability is compromised by rapid metabolism. Micronization is the process of reducing the average diameter of the particles of any solid material, thus lengthening release time and increasing the body’s exposure to a substance.

Study Type:
Human clinical intervention pilot trial

Study Design:
Placebo-controlled. Subjects took micronized resveratrol and the blood concentrations of the phytochemical were measured.

Dosage:
5g/day for 14 days

Subjects:
Patients with colorectal cancer and hepatic (liver) metastases who were scheduled to undergo hepatectomy

Results:
SRT501 (micronized resveratrol) was well tolerated. A single dose resulted in blood concentrations of 1,942 ± 1,422 ng/mL, 3.6 times published results for nonmicronized resveratrol. Resveratrol was detectable in liver tissue and cleaved caspase-3, a marker of cell death in malignant liver tissue, increased by 39%, compared with patients in the placebo group.

Conclusions:
“SRT501 warrants further clinical exploration to assess its potential clinical utility.”

British Journal of Nutrition

Brasnyó P et al. Resveratrol improves insulin sensitivity, reduces oxidative stress and activates the Akt pathway in type 2 diabetes patients. 2011 Aug; 106(3):383–9.

Topic:
Can resveratrol improve insulin sensitivity in Type 2 diabetic patients? If so, how does it work?

Background:
Resveratrol has been widely studied, but its metabolic effects are not well known.

Study Type:
Human clinical intervention trial

Study Design:
Double-blind, placebo-controlled. Subjects took resveratrol or a placebo and their insulin resistance and levels of ortho-tyrosine (a measure of oxidative stress) were measured as well as the ratio of pAkt to Akt in blood cells. (Akt is a protein kinase that plays a role in glucose metabolism and insulin signaling.)

Dosage:
10 mg/day (in 2 5-mg doses) for 4 weeks

Subjects:
19 Type 2 diabetes patients

Results:
By the end of the study, resveratrol significantly reduced insulin resistance and levels of ortho-tyrosine in urine. The ratio of pAkt to Akt rose.

Conclusions:
“The present study shows for the first time that resveratrol improves insulin sensitivity in humans, which might be due to a resveratrol-induced decrease in oxidative stress that leads to a more efficient insulin signaling via Akt pathway.”

Cell Metabolism
Timmers S et al. Calorie restriction-like effects of 30 days of resveratrol supplementation on energy metabolism and metabolic profile in obese humans. 2011 Nov 2; 14(5):612–22.

Topic:
Can resveratrol mimic the effects of calorie restriction in humans?

Background:
Previous research has demonstrated resveratrol induces metabolic changes similar to those seen when obese animals are put on calorie-restricted diets.

Study Type:
Human clinical intervention trial

Study Design:
Randomized, double-blind crossover study.

Dosage:
150 mg/day for 30 days

Subjects:
11 healthy obese men

Results:
Resveratrol increased levels and activation of several enzymes and proteins involved in metabolism. Resveratrol also improved mitochondrial respiration (mitochondria generate energy within cells). It elevated fat stored in muscle while lowering fat stored in the liver, blood sugar levels, triglycerides, alanine-aminotransferase (an enzyme that indicates liver damage), inflammation markers, and systolic blood pressure. HOMA index scores (a measure of insulin sensitivity) improved after supplementation with resveratrol. After meals, subjects taking resveratrol had lower levels of fatty acids and glycerol (a component of triglycerides) in their blood.

Conclusions:
“In conclusion, we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.”

 Nutrition, Metabolism and Cardiovascular Disease

Wong WH et al. Acute resveratrol supplementation improves flow-mediated dilation in overweight/obese individuals with mildly elevated blood pressure. 2011 Nov; 21(11):851–6.

Topic:
How does supplementation with resveratrol affect flow-mediated dilation (FMD) in overweight and obese subjects with mildly elevated high blood pressure? Is the effect dose-dependent?

Background:
FMD is a measure of how blood vessels dilate when blood flows through them and can be used to evaluate cardiovascular risk. Poor FMD is associated with hypertension and obesity. Polyphenols have been shown to improve FMD. Resveratrol is a polyphenol found in red wine.

Study Type:
Human clinical intervention trial

Study Design:
Double-blind, randomized, crossover study.

Dosage:
30, 90 and 270 mg, in three separate doses, taken a week apart

Subjects:
19 overweight or obese men and post-menopausal women with untreated borderline hypertension (14 men, 5 women)

Results:
Resveratrol increased FMD in a dose-dependent way. FMD increased from 4.1 ± .8% with placebo to 7.7 ± 1.5% with the highest dose. FMD also increased in a linear relationship with blood concentrations of resveratrol.

Conclusions:
“Acute resveratrol consumption increased plasma resveratrol concentrations and FMD in a dose-related manner. This effect may contribute to the purported cardiovascular health benefits of grapes and red wine.”

Journal of Clinical Endocrinology and Metabolism

Ghanim H. An anti-inflammatory and reactive oxygen species suppressive effects of an extract of Polygonum cuspidatum containing resveratrol. 2010 Sep; 95(9):E1–8.

Topic:
What is the effect of Polygonum cuspidatum extract (PCE) on oxidative and inflammatory stress in humans?

Background:
Previous in vitro and animal research has demonstrated that resveratrol has anti-inflammatory and anti-aging effects. Polygonum cuspidatum (Japanese knotweed) is a rich source of resveratrol.

Study Type:

Human clinical intervention trial

Study Design:
Placebo-controlled. Fasting blood samples were taken at base line, 1, 3, and 6 weeks and were analyzed for oxidative and inflammatory stress.

Dosage:
40 mg/day for 6 weeks

Subjects:
20 healthy, normal-weight subjects

Results:
Subjects taking PCE had significantly reduced generation of free radicals. Moreover, the expression or binding of multiple proteins and enzymes associated with inflammation was also significantly reduced, compared with base line and placebo. These include p47, nuclear factor-kappa, jun-N-terminal kinase-1, IKB kinase, and phosphototyrosine phosphatase 1B.  PCE also reduced blood concentrations of TNF-alpha (an immune signaling cell involved in inflammation), IL-6 (a protein that regulates inflammation), and C-reactive protein (a marker of inflammation).

Conclusions:
“The PCE-containing resveratrol has a comprehensive suppressive effect on oxidative and inflammatory stress.”

 American Journal of Clinical Nutrition

Kennedy DO. Effects of resveratrol on cerebral blood flow variables and cognitive performance in humans: a double-blind, placebo-controlled crossover investigation. 2010 Jun; 91(6):1590–97.

 Topic:
What is the effect of supplementation with resveratrol on cognitive performance and cerebral blood flow in humans?

Background:
Resveratrol is thought to boost the body’s antioxidant defenses, regulate the production of nitric oxide, and promote blood vessel dilation, which improves blood flow.

Study Type:
Human clinical intervention trial

Study Design:
Randomized, double-blind, placebo-controlled crossover study. Subjects took a dose of resveratrol and 45 minutes later took a series of cognitive tests for 36 minutes known to activate the frontal cortex. Cerebral blood flow and levels of oxygenated and deoxygenated hemoglobin were measured.

Dosage:
Single dose of 250 or 500 mg

Subjects:
22 healthy adults

Results:
Resveratrol induced a dose-dependent increase in cerebral blood flow during cognitive tasks. Hemoglobin deoxygenation increased, suggesting improved extraction of oxygen. However, cognitive function was not improved.

Conclusions:
“These results showed that single doses of orally administered resveratrol can modulate cerebral blood flow variables.”

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Molecular Nutrition and Food Research
Almeida L et al. Pharmacokinetic and safety profile of trans-resveratrol in a rising multiple-dose study in healthy volunteers. 2009 May; 53 Suppl 1:S7–15. 

Topic:
How quickly is trans-resveratrol metabolized in different doses? Are high doses safe?

Background:
Resveratrol has been studied for its cardiovascular and other health benefits. How does the body process this substance at different doses?

Study Type:
Human clinical intervention trial

Study Design:
Double-blind, randomized, placebo-controlled.

Dosage:
25, 50, 100, or 150 mg 6 times a day up to 13 doses

Subjects:
10 healthy adults

Results:
Blood concentrations of trans-resveratrol rose in a dose-dependent way, ranging from 3.89 ng/mL for the lowest dose to 63.8 ng/mL for the highest one. The half-life of trans-resveratrol (or the time needed for peak blood concentration to be halved) was 1–3 hours for the first dose and 2–5 hours for subsequent doses. Bioavailability was better after morning dosing. Side effects were mild and similar across different doses.

Conclusions:
“In conclusion, repeated administration was well tolerated but produced relatively low plasma concentrations of trans-resveratrol, despite the high doses and short dosing interval used.”

 Cancer Research

Brown VA et al. Repeat dose study of the cancer chemopreventive agent in healthy volunteers: safety, pharmacokinetics, and effects on the insulin-like growth factor axis. 2010 Nov 15; 70(22):9003–11.

 Topic:
Can resveratrol lower levels of insulin-like growth factor (IGF) in humans? Are there any side effects?

Background:
High levels of IGF have been associated with cancer. Animal studies have shown resveratrol can downregulate IGF.

Study Type:
Human clinical intervention trial

Study Design:
Subjects took different doses of resveratrol. Blood concentration of resveratrol and its metabolites was measured, as were levels of IGF-1 and IGF-3.

Dosage:
.5, 1, 2.5, or 5 g/day for 29 days

Subjects:
40 healthy subjects

Results:
Resveratrol  was safe, but the two highest doses caused mild to moderate gastrointestinal symptoms. Ingestion of resveratrol  decreased IGF-1 and IGF-3 in all subjects. The 2.5-g dose was most effective.

Conclusions:
“The observed decrease in circulating IGF-I and IGFBP-3 might contribute to cancer chemopreventive activity.”

 Annals of the New York Academy of Sciences

Edwards JA et al. Safety of resveratrol with examples for high purity trans-resveratrol, resVida(®). 2011 Jan; 1215:131–7.

Topic:
What is the acceptable daily intake (ADI) for resveratrol?

Background:
Previous research has shown that trans-resveratrol has low toxicity.

Study Type:
Review paper

Dosage:
Varied by study

Summary:
The ADI for resveratrol has been set at 450 mg/day, based on a 13-week study of a 750 mg/kg/day in which no adverse effects were noted. Very high doses (2,000–3,000 mg/kg/day) introduced into the kidney and bladder by tube have been administered to animals. Studies in rabbits and rats have ranged from 4 weeks to 6 months. Short-term studies show no genotoxicity (damage to DNA), and a 6-month mouse study showed no increase in tumors.

Conclusions:
“Clinical data support an ADI of at least 450 mg/day, and kinetic data from the DSM 13-week toxicity study also support the expectation of no increase in toxicity with longer term intake.”

 

 

Mechanism of Action
Initially, it was thought resveratrol exerted its effects by directly activating sirtuin 1, a protein associated with healthy metabolism and insulin sensitivity. However, recently it was found that resveratrol attaches to and inhibits phosphodiesterases (PDEs), enzymes that inactivate cAMP and cGMP, both of which are important for various metabolic processes.

 A study published in 2012 found that the primary target for resveratrol is PDE4 in skeletal cells. Resveratrol inhibits PDE4, which initiates a cascade of events that ultimately indirectly activate sirtuin

1. As a result, resveratrol has multiple actions, from increasing insulin sensitivity to improving blood vessel dilation to reducing inflammation.

 http://www.nutraceuticalsworld.com/issues/2012-03/view_industry-news/study-suggests-resveratrols-mechanism-of-action/