The Pharmacological Properties of Red Grape Polyphenol Resveratrol: Clinical Trials and Obstacles in Drug Development
Abstract
:1. Introduction
Resveratrol Bioavailability and Metabolism
2. Resveratrol: Pharmacology and Therapeutic Potential
2.1. Resveratrol in Cardiovascular Health
2.2. Resveratrol for the Treatment and Prevention of Cancer
2.3. Resveratrol in Diabetes
2.4. Resveratrol in Neuroprotection
3. Human Clinical Trials of Resveratrol
4. Resveratrol as an Adjuvant
5. Resveratrol Based Nanoformulations
6. Toxicity and Adverse Effects of Resveratrol
7. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Pharmacology | Reference |
---|---|
Anticancer | [54,55,56] |
Analgesic and Anti-inflammatory | [57,58,59] |
Anti-diabetic | [60,61,62] |
Neuroprotection | [63,64,65] |
Antiviral | [66,67,68] |
Anti-obesity | [69,70,71] |
Cardioprotection | [72,73,74] |
Antioxidant | [75,76,77] |
Anti-aging | [78,79,80] |
Nephroprotection | [81,82,83] |
Clinical Condition | Cohort Size (Numbers) | Resveratrol Dose and Duration | Principal Outcomes of Resveratrol Treatment | Reference |
---|---|---|---|---|
Atherosclerosis | Individuals diagnosed with nonalcoholic fatty liver disease were randomly assigned to either a placebo (n = 25) or resveratrol (n = 25) group | 600 mg/day, 84 days | Plasma ox-LDL, LDL-C/HDL-C, and LDL-C/ox-LDL levels showed no changes | [111] |
Individuals in good health were randomly assigned to either a resveratrol (n = 24) or a calorie restriction (n = 24) group | 500 mg/day, 30 days | A rise in plasma TC and non-HDL cholesterol but no change in plasma TG, HDL-C, LDL-C, or apolipoprotein A1 | [112] | |
Randomized groups of patients with carotid stenosis >70% and a request for surgical intervention were given either Cardioaspirin® and Aterofisiol® (n = 107) or Cardioaspirin® and placebo (n = 107) | 20 mg/day, 25 days | Decreased dry weight of lipid and cholesterol in removed plaques (0.232 ± 0.018 vs. 0.356 ± 0.022; 0.036 ± 0.006 vs. 0.053 ± 0.007 mg/mg dry weight, respectively) | [113] | |
Randomized placebo (n = 28) and resveratrol (n = 28) groups of patients with type 2 diabetes mellitus and coronary heart disease | 500 mg/day, 30 days | No change in plasma TG, TC, or LDL-C; HDL-C plasma levels increased; TC/HDL-C plasma levels dropped | [114] | |
Stable coronary artery disease patients (n = 10) were given placebo or resveratrol treatments | 330 mg/day, 3 days | Coronary artery bypass graft patients had higher FMD than those who had undergone percutaneous coronary intervention, whereas percutaneous coronary intervention patients showed no difference in FMD | [115] | |
Hypertension | Patients with hypertension (n = 24) given a placebo or resveratrol | 300 mg, acute supplementation | Increased FMD in women and individuals with higher LDL-C | [116] |
Patients with hypertension (n = 18) given a placebo or isolated phytochemicals | 60 mg/day, 28 days | Decreased diastolic blood pressure | [117] | |
Peripheral artery disease patients were split into two groups and given either a standard balloon angioplasty (n = 75) or a resveratrol drug-coated balloon (n = 78) | 0.9 µg/mm2, 728 days | Target lesion revascularization was reduced, and patients were able to walk further after treatment than those who received standard balloon angioplasty | [118] | |
Diabetes | A prospective, open-label, randomized controlled experiment involving 62 patients with type 2 diabetes | 250 mg/day, 90 days | Decreases in hemoglobin A1c, systolic blood pressure, total cholesterol, and total protein indicate better glycemic control | [119] |
Placebo-treated (n = 38) and resveratrol-treated (n = 38) patients with type 2 diabetes | 1000 mg/day, 56 days | Changes in plasma HDL-C, TG, TC, and LDL-C were not significant, whereas plasma glucose was reduced | [120] | |
A randomized, placebo-controlled, double-blind investigation of 19 patients with type 2 diabetes | 5 mg twice daily, 30 days | Glucose and insulin levels dropped, glucose spikes after meals were postponed, and ortho-tyrosine was excreted in the urine | [121] | |
Nonalcoholic fatty liver disease patients who were overweight and randomly assigned to either a placebo (n = 8) or resveratrol (n = 8) group | 1500 mg/day, 180 days | Very low-density lipoprotein TG secretion. Oxidation, and clearance rates were not affected, neither at baseline nor in response to insulin | [122] | |
Type 2 diabetes patients in whom the disease is under control (n = 17) were given either placebo or resveratrol | 150 mg/day, 30 days | Insulin sensitivity in the liver and the rest of the body did not change, nor did the amount of fat stored in the liver | [123] | |
Placebo- and resveratrol-treated patients with type 2 diabetes (n = 14) | 1000 mg/day, 35 days | Glycemic control and glucagon-like peptide 1 secretion did not vary | [124] | |
Treatment with resveratrol or a placebo in elderly people with glucose intolerance (n = 30) | 2–3 g/day, 42 days | Reactive hyperemia index rises, but blood pressure and plasma lipid levels remain unchanged | [125] | |
Diabetic patients at high risk (n = 8) treated with placebo and resveratrol | 150 mg/day, 34 days | There was no difference in the absorption of 18F-fluorodeoxyglucose or the inflammation of arteries | [126] | |
Obesity | Children and adolescents with obesity were split into two groups: those who took a resveratrol supplement (n = 16) and those who took a placebo (n = 11) | 20 mg/day, 180 days | Enhanced hyperemic delta flow 6 months after post-occlusive release | [127] |
Obese older people (n = 22) were divided into two groups: those given placebo or resveratrol with curcumin | 200 mg, 30 min before consuming the high-fat meal | Post-meal soluble vascular cell adhesion molecule-1 response was reduced, but other inflammatory indicators and adhesion molecules in the blood were unaffected | [128] | |
Placebo (n = 10), 300 mg (n = 10), and 1000 mg (n = 9) resveratrol groups were used to test the effects of resveratrol on the weight and health of older, overweight persons | 300 and 1000 mg/day, 90 days | The 1000 mg resveratrol group had higher levels of soluble vascular cell adhesion molecule-1 and total plasminogen activator inhibitor than the 300 mg resveratrol and placebo groups | [129] | |
Neurodegenerative diseases | 102 people with early-onset Huntington’s disease (HD) | 40 mg twice a day, 365 days | Not known yet | [130] |
120 patients with mild to moderate dementia most likely due to Alzheimer’s disease (AD) | 500 mg/day with dose escalation of up to 1000 mg twice/day, 365 days | Nausea, weight loss, and diarrhea are the only reported side effects of resveratrol, which is safe and well-tolerated. CSF Aβ40 and Aβ42 biomarkers show no improvement. Enhanced decline in brain volume | [131] | |
27 people with mild to moderate AD | Resveratrol, glucose, and malate supp. delivered in grape juice, 365 days | At modest doses, resveratrol is safe and well-tolerated. The Mini-Mental State Exam and the AD Assessment Scale for Cognition scores did not significantly change | [130] | |
Cancer | 14 patients with prostate cancer | 500, 1000, 2000, 3000, or 4000 mg of MPX. Every 500 mg MPX has 4.4 μg resveratrol, 60–930 days (depending on the patient) | Increased PSADT | [132] |
A single-center, randomized, placebo-controlled trial of 66 people with prostate cancer | 150 mg or 1000 mg daily, 120 days | A drop in androstenedione, and dehydroepiandrosterone (DHEAS). The PSA and prostate size remained unchanged | [133] | |
Phase 1 trial of nine patients with colorectal cancer; randomized, placebo-controlled, double-blind | 5.0 g SRT501, 14 days before surgery | Elevated levels of activated caspase-3 (apoptosis) | [134] | |
Cases of colorectal cancer in 20 patients | 500 or 1000 mg, 8 days prior to surgery | Ki-67 staining decreases, indicating a decrease in tumor cell growth | [135] | |
Randomized, double-blind, placebo-controlled clinical study for breast cancer in 39 people | 5 or 50 mg twice daily, 90 days | Decreased RASSF-1α methylation | [136] |
Nanoformulation Method | Study Model | Outcome | Reference |
---|---|---|---|
Resveratrol medication delivery systems based on self-emulsification | In vitro, in vivo (rats) | Enhanced pharmacokinetics, decreased metabolism, and enhanced solubility | [161] |
Micellar solubilization of resveratrol | Twelve healthy volunteers (oral administration) | Increased oral bioavailability | [162] |
Suspension of free resveratrol, resveratrol-filled nanoparticles, and layer-by-layer nanoparticles | In vivo (Wistar rats, oral administration, 20 mg/kg) | Systemic exposure was increased when resveratrol was encapsulated in layer-by-layer nanoparticles with resveratrol nanocores | [163] |
Nanoparticle delivery method based on oat-shellac proteins | In vitro, in vivo (rat model) | Resveratrol was buffered in the stomach acid and released gradually into the small intestine. Transport and absorption by cells are enhanced relative to free resveratrol. Enhancement in bioavailability | [164] |
Resveratrol nanoencapsulation in casein | In vitro, in vivo (rats) | Oral administration in rats: remained in the gut and reached intestinal epithelium. Produced high plasma levels of resveratrol (sustained for at least 8 h) and similar results for its metabolites. Oral bioavailability was 10 times higher compared to an oral solution of resveratrol | [165] |
Trans-resveratrol nanocrystals | In vitro, in vivo (rats) | Increased oral bioavailability | [166] |
Nanoparticles of human serum albumin coupled with glycyrrhizic acid and loaded with resveratrol | In vivo (rats; single-dose tail vein injection) | The absorption rate of resveratrol was increased. High levels of resveratrol were found in most of the rats’ vital organs. The highest levels were found in the liver, suggesting that a delivery method that focuses on the liver could be effective | [167] |
Trans-resveratrol-loaded mixed micelles | In vivo (rats; intravenous administration) | Enhanced pharmacokinetic parameters. Improved brain targeting | [168] |
Resveratrol bovine serum albumin nanoparticles (RES-BSANP) | In vivo (nude mice; intraperitoneal injection) | Enhanced dilution and soluble in water. Cancer development was suppressed in hairless mice bearing human ovarian primary tumors | [169] |
Folate-conjugated HSA nanoparticles | HePG2 liver cancer cells | Showed decreased resveratrol release and increased cytotoxicity | [170] |
Piperine-loaded mixed micelles | MCF-7 breast cancer cells | Improved cytotoxicity | [171] |
Sericin nanoparticles | Caco-2 cells colorectal cancer cells | Strong cytotoxic against Caco-2 cells | [172] |
Folic acid-targeted micelles | MCF-7 breast cancer cells | Increased cytotoxicity was achieved due to the sustained release of encapsulated resveratrol provided by the nano-formulation. | [173] |
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Farhan, M.; Rizvi, A. The Pharmacological Properties of Red Grape Polyphenol Resveratrol: Clinical Trials and Obstacles in Drug Development. Nutrients 2023, 15, 4486. https://doi.org/10.3390/nu15204486
Farhan M, Rizvi A. The Pharmacological Properties of Red Grape Polyphenol Resveratrol: Clinical Trials and Obstacles in Drug Development. Nutrients. 2023; 15(20):4486. https://doi.org/10.3390/nu15204486
Chicago/Turabian StyleFarhan, Mohd, and Asim Rizvi. 2023. "The Pharmacological Properties of Red Grape Polyphenol Resveratrol: Clinical Trials and Obstacles in Drug Development" Nutrients 15, no. 20: 4486. https://doi.org/10.3390/nu15204486
APA StyleFarhan, M., & Rizvi, A. (2023). The Pharmacological Properties of Red Grape Polyphenol Resveratrol: Clinical Trials and Obstacles in Drug Development. Nutrients, 15(20), 4486. https://doi.org/10.3390/nu15204486