Wine

Uses

Numerous clinical and epidemiological studies document an inverse relationship between red wine consumption and the incidence of coronary disease. Wine has also been linked to inhibitory effects on various stages of tumor development and may be associated with neuroprotection in many neurodegenerative conditions.

Dosing

In a clinical trial, red wine was administered to determine its effects on hypertension at 250 mL daily and as a resveratrol 500 mg capsule. A red wine extract was studied for its effect on low-density lipoprotein (LDL) oxidation at 1 g daily. Red wine extract and resveratrol supplements are available in numerous dosages and dosage forms. The most common dosage regimen listed by manufacturers is resveratrol 500 mg capsules. Some commercial products contain resveratrol from other sources, such as Polygonum cuspidatum . The recommended dosage of resveratrol is 1 capsule per 23 kg (50 lbs) of weight per day.

Contraindications

Avoid use if allergic to any of the ingredients in red wine because anaphylactic reactions have been documented. Alcohol consumption is contraindicated in patients with viral hepatitis (eg, hepatitis B and C).

Pregnancy/Lactation

Avoid use during pregnancy and lactation because of the risk of birth defects and fetal alcohol syndrome. Over-the-counter supplements should also be avoided because of the lack of clinical data.

Interactions

Red wine is reported to be a reversible inhibitor, but weak irreversible inhibitor, of CYP3A4 activity; therefore, caution is warranted when taking other medications. The inhibition of the enzyme by red wine is comparable in magnitude with that of erythromycin. Red wine may increase drug concentrations of cisapride but decrease drug concentrations of cyclosporine in some subjects. Red wine may interact with monoamine oxidase inhibitors (MAOIs); however, because of the severity of the potential interaction, patients should avoid red wine if taking MAOIs and for at least 4 weeks after discontinuation of therapy.

Adverse Reactions

Adverse reactions to pure wine are rare; however, the vast majority of commercially prepared wines now contain sulfites as preservatives. Individuals sensitive to these chemicals may develop severe allergic reactions, including wheezing and tachycardia. Resveratrol is structurally similar to the synthetic estrogen diethylstilbestrol and has weak estrogenic activity. Headaches following the ingestion of some wines have been associated with histamine or tyramine content.

Toxicology

A number of toxicity studies in mice and rats using large doses of resveratrol have demonstrated renal toxicity.

Wine is an agricultural product created by the natural fermentation of sun-ripened grape juice. Yeast-induced fermentation converts endogenous sugars to alcohol, and the flavors associated with each wine depend on the grape variety, harvesting, and fermentation conditions. While most wines are derived from grapes, fermentation of other fruits and vegetables has yielded wine-like alcoholic beverages. Wine production includes a series of steps, including extraction of juice, fermentation, clarification, and aging. 1 , 2

History

Wine has played an important role in societal development for thousands of years. The first cultivated grapes were grown in Asia Minor around 6,000 BC. Archaeologists have uncovered the remains of a 2,600-year-old winery in Israel. 1 Egyptian accounts of wine-making date back to 2,500 BC. The Bible makes reference to raising grapes to make wine. 2 Hippocrates (450 to 370 BC) was said to be the first physician to understand the healing value of wine. 3 The Romans disseminated information about the science and art of making wine throughout much of the world, and Europe subsequently became the center of wine-making expertise. Wine-making techniques were preserved during the Early Middle Ages by the clergy.

Early fermentation procedures produced heavy wines that often were exceedingly sweet. Refinement of the fermentation process resulted in the development of numerous varieties of wines, each with unique flavors and alcohol content. Wine has had a role in societal interactions and many religious ceremonies. The growth of the American wine industry during the 20th century was halted by Prohibition (1919 to 1933) but has risen steadily since. Today, wine is produced throughout the United States, with boutique wineries accounting for a proportional increase in production. 1 , 2 Several historical articles have been written discussing the history of wine and its use in the practice of medicine. 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13

Chemistry

The chemical composition of wine is complex. A typical wine contains more than 300 components in addition to alcohol, often including minerals and vitamins not found in other fermented beverages. 1 Alcohol concentrations may vary from 10% to 14% for table wines and up to 20% for certain aperitifs. While the prevalent alcohol is ethanol, glycerol and more than a dozen other alcohols have been isolated from wines. 14

The medical literature documents numerous biological properties 15 for wine polyphenols, which include the phenolic acids p-coumaric, cinnamic, caffeic, gentisic, ferulic, and vanillic acids and the trihydroxy stilbenes polydatin and resveratrol. 12 , 16 Resveratrol has attracted the most attention because of its biological activity. 15

There is a wide range of phenol concentrations in selected wines. One Japanese report analyzes resveratrol and piceid and their isomers content in 42 different wines. The average stilbene content was 4.37 mg/L in red wines and 0.68 mg/L in white wines. 17 Red wines have higher concentrations of total phenols, flavonoids, flavanols, and anthocyanins than white or rosé wines. 18 Red wines have 6 times the concentration of trans -resveratrol than white wines, while white-grape variety wines contain higher concentrations of cis -resveratrol. 19 Red and white wines contain 0.12 to 0.06 mg/L of cis -resveratrol, while red wines contain a concentration of 12.68 mg/L of trans -resveratrol. 19 Wine flavonoids are also present (1 to 3 g/L in red, 0.2 g/L in white) and include flavonols, anthocyanins, flavanols (catechins, quercetin), oligomers (procyanidins), and polymers (tannins) of the catechins. 12 Anthocyanins are responsible for the color of wine. 20

Champagnes and sparkling wines contain approximately 1.5% carbon dioxide. Other wine components include carbonyl compounds, organic acids, tannins, carbohydrates, and esters. 1 , 14

Uses and Pharmacology

Numerous clinical and epidemiological studies report an inverse relationship between red wine consumption and the incidence of coronary disease. Its inhibitory effect on various stages of tumor development is also documented. Wine has neuroprotective effects on many neurodegenerative conditions. 21

Antiaging

Resveratrol may activate sirtuin 1 (SIRT1), which is part of the oxidized form of nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylases or sirtuins. The SIRT1 protein plays a critical biological role in response to DNA damage, metabolism, longevity, and carcinogenesis. 22 Additional potential mechanisms of action include antioxidant activity or suppression of mitogen-induced phosphorylation of S6K, which is associated with cell-size control. 23 Resveratrol may activate sirtuins for specific peptide substrates. 24

In vitro and animal data

Numerous studies have explored the molecular biology and antiaging activity of resveratrol. 25 , 26 Resveratrol was reported to slow aging and increase life span in simple organisms, such as yeast, 27 fish, 28 and mice. 29 The trans -resveratrol concentrations in plasma and tissues after oral administration of red wine to rats or humans are similar to concentrations that are active in vitro, usually in the range of 1 to 30 mM. 25

Anti-inflammatory
In vitro and animal data

In in vitro models, resveratrol inhibits synthesis and release of proinflammatory mediators, modifies eicosanoid synthesis, inhibits activated immune cells, and inhibits cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). 30 , 31 , 32 In a chronic experimental colitis rat model, resveratrol reduced neutrophil infiltration and proinflammatory cytokines, such as TNF-alpha. 33 , 34 COX-2 and NF-kappa B protein expression was also reduced.

Clinical data

Resveratrol inhibited basal release of the inflammatory cytokine IL-8 from alveolar macrophages in patients who smoke and in those with chronic obstructive pulmonary disease. 35

Cancer

Resveratrol is effective in blocking all 3 stages of carcinogenesis (ie, initiation, promotion, progression). 21 , 36 Numerous molecular mechanisms of anticancer activity 37 are associated with resveratrol: blocking carcinogen activation by inhibiting phase I enzymes, enhancing antioxidant capacity and inducing phase II carcinogen detoxifying enzymes, arresting cell proliferation by modulating cell cycle regulatory machinery, inducing apoptosis of damaged or transformed cells, turning off the angiogenic switches and blocking neovascularization in tumor tissues, suppressing invasion and metastasis, and sensitizing tumor cells for chemotherapy-induced apoptosis.

In vitro and animal data

Resveratrol induces differentiation and apoptosis in numerous human tumor lines, including leukemia, colon, breast, prostate, and esophageal cells. 21 Several review articles report extensive investigations of resveratrol's anticancer activity. 21 , 36 , 37 For example, resveratrol and trans -resveratrol induced cell-cycle arrest in the G1 phase or S-G2 phase transition, triggering apoptosis in a variety of cancer cells, including JB6 epidermal cells, human promyelocyte leukemia HL-60 cells, several colon cancer cell lines, 38 human mammary cancer cell lines, and human prostate cancer cells. 39 In an in vitro human hepatocellular carcinoma model, resveratrol inhibited TNF-alpha-mediated MMP-9 (enzymes critical for tumor progression) expression by downregulating NF-kappa B activity and blocking cell invasion. 40 Resveratrol induced neuronal differentiation of medulloblastoma cells by potentially altering STAT3 activation or production (ie, inhibition would lead to growth arrest and apoptosis of medulloblastoma cells). 41 Activity against mammary or breast cancer cells may be through antiestrogenic properties, downregulation of catalase, 42 or disruption of signaling mechanisms leading to enhanced cytotoxicity by resveratrol (ie, through the AC/PKA cascade). 43 Administration of 100 mg/kg daily of resveratrol resulted in a reduction in radiation-induced chromosome aberration frequency in mouse bone marrow cells. 44

Clinical data

A phase 1 clinical trial examined the plasma pharmacokinetics of resveratrol and its metabolites. 45 A single dose of resveratrol reached maximum drug concentrations (C max ) of 0.3 to 2.4 mmol/L as compared with in vitro experiments requiring a concentration greater than 5 mmol/L for cancer chemoprevention. Resveratrol 3-sulfate was the most abundant metabolite conjugate and was present in the plasma at the 4 to 14 mmol/L C max concentration range. It is unknown whether repeated dosing schedules may achieve higher systemic concentrations of resveratrol. The results of this trial in humans are consistent with experiments in rodents.

Coronary disease

Numerous mechanisms have been suggested for the beneficial cardiovascular effects of wine polyphenols, including nitric oxide production by vascular endothelium, defense against ischemic-reperfusion injury, promotion of vasorelaxation, protection and maintenance of intact endothelium, antiatherosclerotic properties, inhibition of LDL oxidation, suppression of platelet aggregation, and estrogen-like actions. 12 , 21 , 46

Animal data

The various cardioprotective mechanisms associated with dosing animals with resveratrol have been reviewed. 15 Resveratrol (5 to 25 mmol/L) may have antifibrotic activity as it inhibits growth paths stimulated by angiotensin-II, epidermal growth factor, or transforming growth factor-beta, all of which are essential in fibroblast proliferation and differentiation. 15 Red wine polyphenolic extract reduced the degree of hyperhomocysteinemia, an important vascular risk factor for atherosclerosis, in mice. 47 Resveratrol reduced infarct size and improved left systolic and diastolic function after myocardial ischemia in rats by potentially reducing atrial natriuretic peptide and transforming growth factor beta-1 (both protect the heart from detrimental remodeling). 48 Doses of resveratrol 2.5 and 5 mg/kg/day protected the heart from ischemic reperfusion injury by inducing a survival signal, which has also been documented in other studies. 49

Clinical data

World Health Organization data show that fat consumption is associated with coronary heart disease (CHD) mortality. However, certain populations in which daily consumption of wine is highest (eg, Italy, Switzerland, France) had high-fat intake but low CHD mortality rates. This has been termed the French paradox . 50 Researchers previously found a population-based association between CHD mortality and increased wine consumption. 51 Subsequent reports confirmed that moderate intake of wine lowers CHD mortality. 52 , 53 , 54

In one study, the yearly rate of CHD mortality per 1,000 men decreased from approximately 22 among those who did not drink alcohol to approximately 8 for those who had 2 drinks per day. 55 The Copenhagen City Heart Study (CCHS) (Copenhagen, Denmark), initiated in 1976, analyzed 13,329 patients 45 to 84 years of age for 16 years to determine risk of first stroke. Although this report did not address factors such as genetic diversity, existing risk factors, or type (red or white) or amount of wine consumed, it confirmed that wine has beneficial effects. It was concluded that compounds other than ethanol in wine are responsible for the protective effect on risk of stroke. 56 The National Stroke Association (NSA) has concluded that heavy drinking increases stroke risk, while modest consumption, such as a 4 ounce glass of wine per day, may lower stroke risk, provided that there is no other medical reason to avoid alcohol. 57 One drink of ethanol dilates the brachial artery but does not activate sympathetic outflow; however, 2 drinks increase the heart rate, cardiac output, sympathetic nerve firing rate, or cardiovascular risk factors. 58

A review of 30 population studies suggests a correlation between alcohol consumption and a decrease in cardiovascular risk but also emphasizes that the effect of alcohol on cardiovascular risk is highly dependent on other risk factors. Alcohol as a “heart medicine” was deemed inefficacious in this report. 59 A later study agrees that alcoholic intake is associated with lower CHD risks, but found that mortality can be influenced by lifestyle characteristics (eg, smoking, obesity). 60

Red wine phenolic compounds have positive effects on plasma antioxidant capacity. 61 Antioxidants prevent the oxidation of LDL cholesterol into plaque, which is known to clog arteries and lead to cardiovascular disease. 62 The most potent antioxidants for LDL are the phenolics epicatechin, catechin, and resveratrol. 63

Wine flavonoids and phenolics inhibit clotting by platelet and monocyte aggregation inhibition, 21 , 64 apparently caused by inhibition of either oxygenase enzymes 65 or thromboxane synthesis. 12

Purple grape juice may have the same effects as red wine in reducing heart disease risk. 66 Fruit consumption has also correlated highly with reduced CHD mortality. 54 White wine provides cardiovascular protection similar to that of red wine if it contains tyrosol and hydroxytyrosol. 67

Neurodegenerative conditions

Most evidence supports resveratrol's role in activating the SIRT1/PGC-1 pathway, which improves mitochondrial function. 68

In vitro and animal data

In a cerebral ischemia rat model, resveratrol induced relaxation of smooth muscle in the wall of the basilar artery and may provide protection through antioxidant and vasodilatory activity. 69 Red wine polyphenolic compounds equivalent to approximately one-twentieth of a glass of red wine reduced brain injury in rats from the onset of cerebral ischemia by decreasing the release of amino acids, increasing the release of free radical scavengers, and improving blood flow restoration and cerebral energy metabolism. 70 Resveratrol protected C6 glioma cells against oxidative DNA damage. 71 Chronic treatment with red wine in rats led to an increase in hippocampal aromatase activity. 72

Alzheimer disease

Alheimer disease is associated with intracellular neurofibrillary tangles, extracellular amyloid-b (Ab) peptides, synaptic failure, and mitochondrial dysfunction. 21 In rats, resveratrol and SIRT1 treatment reduced NF-KB signaling involved in neuronal death stimulated by Ab. Treatment with resveratrol may provide multiple benefits leading to reduced inflammation because of its antioxidant activity, activation of SIRT1, and modulation of NF-kB signaling. 73 Resveratrol may not inhibit Ab production. 74 Instead, it may activate numerous molecular transcription factors, leading to enchanced gene expression of antioxidant molecules and DNA repair. 75

Huntington disease

Several studies support resveratrol's role in improving motor and cognitive impairment through its antioxidant activity. 21 , 76 Resveratrol's activity partially protects against the mitochondrial dysfunction and oxidative damage often seen in Huntington disease. 77

Parkinson disease

Parkinson disease is associated with a depletion of dopamine, often resulting in an imbalance between cholingeric and dopaminergic neurons. 21 Administration of resveratrol in mice protected against a neurotoxin used to induce Parkinsonism or motor coordination impairment, hydroxyl radical overloading, and neuronal loss. 78 , 79 Dopamine-induced cytotoxicity in neuroblastoma cells was partially reversed by resveratrol. Other studies with resveratrol found cell proliferation at low concentrations versus apoptosis at high concentrations. 80

Other pharmacologic effects
Gastrointestinal

Wine may help relieve achlorhydria and related gastric disorders and malabsorption syndromes. 14 , 51 Certain substances in wine promote better absorption of minerals such as calcium, magnesium, phosphorus, and zinc. The aroma and taste of wine stimulate the appetite, especially in elderly and debilitated patients. 2 , 14 In addition, white wine shortens gastric emptying time. 81

Psychological

A large body of evidence has accumulated regarding the benefits of moderate wine intake in the management of other conditions, including emotional tension, anxiety, and inability to relax. The pharmacology of ethanol has been well characterized, including its effects on the CNS and smooth and skeletal muscles. 2 , 14

Wound healing

Wine may be of benefit when used topically in stimulating wound healing and improving rheumatoid skin ulcerations. 82

Dosage

Wine has been administered in a clinical trial for its effects on hypertension at 250 mL daily and as a resveratrol 500 mg capsule. A red wine extract was studied for its effect on LDL oxidation at 1 g daily. 83 , 84 Red wine extract and resveratrol supplements are available in numerous dosages and dosage forms. The most common dosage regimen listed by manufacturers is resveratrol 500 mg capsules. The recommended dosage is 1 capsule per 23 kg (50 lb) of body weight per day. As a nutraceutical, resveratrol is commercially available in the United States and Europe. 45 The reported antiaging activity of resveratrol has been promoted in skin care formulation marketing. 85

Pregnancy/Lactation

Avoid use during pregnancy and lactation because of the risk of birth defects and fetal alcohol syndrome. Over-the-counter supplements should be avoided because of the lack of clinical data.

Interactions

Because red wine is reported to be a reversible inhibitor but weak irreversible inhibitor of CYP3A4 activity, caution is warranted when taking with medications. 86 , 87 The inhibition of the enzyme by red wine is comparable with that of erythromycin. 87

Blood pressure medications

Red wine may cause dose dumping of calcium antagonists (eg, extended-release felodipine) in certain populations. 86

Cisapride

In a randomized, crossover study in 12 healthy men, cisapride 10 mg taken with 250 mL of red wine doubled the area under the plasma concentration-time curve (AUC) and peak plasma concentration of cisapride in 1 subject. 88

Cyclosporine

Red wine may reduce cyclosporine concentrations, decreasing the pharmacologic effect and increasing the risk of transplant rejection. In 12 healthy subjects, 177 mL of red wine consumed 15 minutes before ingestion of cyclosporine 8 mg/kg and a second 177 mL consumed with cyclosporine and for 15 minutes following administration, decreased the AUC and peak plasma concentration of cyclosporine 30% and 38%, respectively. 89

Insulin

Caution may be warranted because resveratrol reduced glucose levels in diabetic rats. 90

Monoamine oxidase inhibitors

Sudden and severe hypertensive responses after the ingestion of food or beverages high in tyramine or other pressor amines have occurred in patients taking MAOIs. 91 , 92 , 93 However, because of headaches associated with red wine in some individuals, this reaction may have been erroneously implicated as occurring with ingestion of red wine (eg, chianti) and MAOIs. 91 A causal relationship has not been established with red wine and MAOIs.

Adverse Reactions

Individuals who are allergic to any of the ingredients in red wine should avoid use, because anaphylactic reactions have been documented. 94 Alcohol consumption is contraindicated in patients with viral hepatitis (eg, hepatitis B and C).

Adverse reactions to pure wine are rare; however, the vast majority of commercially-prepared wines contain sulfites as preservatives, and those sensitive to these chemicals may develop severe allergic reactions, including wheezing and tachycardia. Sensitivity to yeasts may result in allergies to some wines. While a glass of wine before bedtime has long been an accepted treatment for temporary insomnia, a larger amount may be counterproductive due to repressed respiration resulting in sleep apnea. 95

Patients with gastroesophageal reflux should ingest wine cautiously because wine may cause additional reflux. 96 , 97

A direct association has been made between increased wine consumption and the rate of ovarian cancer in women in Italy. 98 Excessive wine consumption has been associated with a reversible rise in systolic blood pressure levels. 99 Resveratrol is structurally similar to the synthetic estrogen diethylstilbestrol and has estrogenic activity. 100

Toxicology

The dangers of drinking too much wine is available in a concise summary. 2 In addition, a report on the management of heavy drinkers is referenced. 101

A number of toxicity studies using resveratrol at large doses (2,000 and 4,000/3,000 mg/kg in mice, and 3,000 mg/kg in rats) have shown renal toxicity. A daily dose of 20 mg/kg in rats was not renally toxic. A daily dose of resveratrol 100 mg/kg did not induce chromosome aberrations after 30 days of ingestion. 44 Resveratrol suppressed inflammation and inhibited lipid peroxidation in glycerol-induced renal injury in rats. 102

Absorption of resveratrol is at least 70% in humans, while oral bioavailability is almost zero due to extensive metabolism. 103 Resveratrol metabolites in urine may be potential biomarkers of wine consumption in epidemiologic and clinical assays and in intervention studies. 104

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