Diabetes

Diabetes is a life-long disease marked by high levels of sugar in the blood.

Causes, incidence, and risk factors

Diabetes can be caused by too little insulin (a hormone produced by the pancreas to control blood sugar), resistance to insulin, or both. To understand diabetes, it is important to first understand the normal process of food metabolism. Several things happen when food is digested:
A sugar called glucose enters the bloodstream. Glucose is a source of fuel for the body.
An organ called the pancreas makes insulin. The role of insulin is to move glucose from the bloodstream into muscle, fat, and liver cells, where it can be used as fuel.
People with diabetes have high blood sugar. This is because their pancreas does not make enough insulin or their muscle, fat, and liver cells do not respond to insulin normally, or both.
There are three major types of diabetes:
Type 1 diabetes is usually diagnosed in childhood. The body makes little or no insulin, and daily injections of insulin are needed to sustain life.
Type 2 diabetes is far more common than type 1 and makes up most of all cases of diabetes. It usually occurs in adulthood. The pancreas does not make enough insulin to keep blood glucose levels normal, often because the body does not respond well to the insulin. Many people with type 2 diabetes do not know they have it, although it is a serious condition. Type 2 diabetes is becoming more common due to the growing number of older Americans, increasing obesity, and failure to exercise.
Gestational diabetes is high blood glucose that develops at any time during pregnancy in a woman who does not have diabetes.
Diabetes affects more than 20 million Americans. About 54 million Americans have prediabetes. There are many risk factors for diabetes, including:
1. A parent, brother, or sister with diabetes
2. Obesity
3. Age greater than 45 years
4. Some ethnic groups (particularly African Americans, Native Americans, Asians, Pacific Islanders, and Hispanic Americans)
5. Gestational diabetes or delivering a baby weighing more than 9 pounds
6. High blood pressure
7. High blood levels of triglycerides (a type of fat molecule)
8. High blood cholesterol level
9. Not getting enough exercise
The American Diabetes Association recommends that all adults over age 45 be screened for diabetes at least every 3 years. A person at high risk should be screened more often.
Symptoms
High blood levels of glucose can cause several problems, including frequent urination, excessive thirst, hunger, fatigue, weight loss, and blurry vision. However, because type 2 diabetes develops slowly, some people with high blood sugar experience no symptoms at all.
Symptoms of type 1 diabetes:

Increased thirst

Increased urination
Weight loss in spite of increased appetite
Fatigue
Nausea
Vomiting
Patients with type 1 diabetes usually develop symptoms over a short period of time, and the condition is often diagnosed in an emergency setting.
Symptoms of type 2 diabetes:
Increased thirst
Increased urination
Increased appetite
Fatigue
Blurred vision
Slow-healing infections
Impotence in men

Signs and tests
A urine analysis may be used to look for glucose and ketones from the breakdown of fat. However, a urine test alone does not diagnose diabetes. The following blood glucose tests are used to diagnose diabetes:
Fasting blood glucose level -- diabetes is diagnosed if higher than 126 mg/dL on two occasions. Levels between 100 and 126 mg/dl are referred to as impaired fasting glucose or pre-diabetes. These levels are considered to be risk factors for type 2 diabetes and its complications.
Random (non-fasting) blood glucose level -- diabetes is suspected if higher than 200 mg/dL and accompanied by the classic symptoms of increased thirst, urination, and fatigue. (This test must be confirmed with a fasting blood glucose test.)
Oral glucose tolerance test -- diabetes is diagnosed if glucose level is higher than 200 mg/dL after 2 hours (This test is used more for type 2 diabetes.)

Diabetes Mellitus

A serious disorder caused by an absence of or insufficient amount of insulin in the bloodstream.
Insulin is a hormone produced by the pancreas in varying amounts, depending on the concentration of glucose (sugar). When the pancreas is unable to secrete enough insulin to maintain a normal concentration of glucose in the blood, the blood-glucose concentration becomes elevated. Large amounts of glucose are then excreted in the urine. Insulin allows glucose to be absorbed by the liver and fat cells, where it is stored as glycogen. In times of stress, exercise, or an emergency, the glycogen is reconverted back to glucose. It also sends glucose to the muscle cells where it is then converted to energy.
More than 12 million Americans are affected by diabetes. There is a 5-6% increase in the number of those affected each year by the disease, primarily due to the population's increased rate of longevity. A rising rate of obesity, a prime cause for incidences of diabetes over the age of 40, also contributes to the increasing frequency of diabetes. It is estimated that for each reported new case of diabetes, there is an unreported one because symptoms of the early stages of adult diabetes tend to go unrecognized. Symptoms usually progress from mild to severe as the disease progresses.
Approximately 300,000 deaths each year are attributed to diabetes. Its prevalence increases with age, from about 0.2% in persons under 17 years of age to about 10% in persons aged 65 years and over. Females have a higher rate of incidence for the disease, while higher income groups in the United States show a lesser incidence than lower income groups. The incident rate is markedly different among ethnic groups; it is 20% higher in non-Caucasians than in Caucasians. However, for reasons as yet unknown, the rate of diabetes in ethnic groups such as Native Americans, Latin Americans, and Asian Americans is especially high and continues to rise.
There are two forms of diabetes mellitus. Type I is called insulin-dependent and type II, non-insulin-dependent. (In June 1997, an Expert Committee of the American Diabetes Association recommended changing the categories of diabetes to Type 1 [formerly Type I-indulin-dependent diabetes mellitus] and Type 2 [formerly Type Il-non-insulin-dependent diabetes mellitus]. This essay uses the conventional terminology, which was widely used at the time of publication.)
Insulin-dependent diabetes (type I) generally starts in childhood, affects approximately 700,000 Americans, and is characterized by severe insulin deficiency. It is probably due to the destruction of the insulin-secreting cells of the pancreas, which is often caused by an autoimmune disorder. Without insulin, the person develops ketoacidosis, a condition where high levels of ketone bodies are present in the blood. When the body is deprived of glucose, which can occur as a result of insulin deprivation or fasting, the body begins to break down fat for fuel. Ketones are the result of this lipid metabolism. The resulting lowered blood pH value leads to the acidosis.
Ketoacidosis is a serious condition and can lead to confusion, unconsciousness, and death if not treated. It can be diagnosed by urine tests which detect ketones in the urine. Untreated or uncontrolled diabetes will lead to ketosis, but fasting or starvation also produces ketones. Other symptoms of ketoacidosis include vomiting, abdominal pain, loss of appetite, and nausea. A very high blood glucose level in insulin-dependent diabetes can also lead to heart failure and coma.
Genetics plays a major role in Type I diabetes. There is also some evidence that children infected with certain viruses—rubella and coxsackie B in particular—may be susceptible to the disease. Diabetes in newborns can result from low birth weight as well as genetic predisposition. Some infants experience temporary diabetes, which may recur later in life.
Non-insulin-dependent diabetes (type II) usually occurs in people over age 40, and affects approximately 15.3 million Americans. This group comprises about 80% to 85% of the diabetic population. Even though they may have more than normal levels of insulin, they are resistant to its action. Unlike those with type I diabetes, people with type II diabetes rarely have ketoacidosis. Instead, insulin action can be impaired by obesity. Therefore, people who gain too much weight and ethnic groups that have changed to higher carbohydrate diets appear to be particularly prone to type II diabetes.
Pregnancy can also elevate a woman's glucose level. This condition is known as gestational diabetes and complicates approximately four percent of all U.S. pregnancies. Although their glucose levels may return to normal after they give birth, these woman may be at risk of developing type II diabetes in the future.
For those people who are in a high risk group for getting diabetes (those who have had relatives with diabetes, adults over the age of 40 who are overweight, and women who have had babies weighing nine pounds or more at birth), there is a quick and simple screening test that requires a drop of blood from the finger and takes about one to two minutes to complete. The test shows if there is a high or low blood-sugar level in the blood. After the results of the screening test, other tests can be done, if necessary. If the screening test shows blood-sugar levels that are either too high or too low, a fasting plasma glucose test can be given. One or more samples of blood are taken after the individual fasts for 10 to 16 hours. Blood-glucose levels of less than 115 milligrams per decaliter (mg/dl) are normal. Fasting plasma glucose levels of more than 140 mg/dl indicate diabetes. The oral glucose tolerance test also starts with a fast but adds a glucose drink taken after the fasting plasma glucose is tested. It is followed by several other tests to determine blood glucose levels. There are other tests used to monitor the condition, including self-tests. The presence of circulating islet antibodies is a good predictor of insulin-dependent diabetes. Research is being done on genetic tests to predict the risk of developing diabetes.
Deaths from ketoacidosis and diabetic coma have decreased over the years. However, long-term complications from diabetes began to increase as diabetics' life span increased. Some of these complications are kidney failure, heart disease, blindness, and nervous system disorders, all of which are believed to be the results of elevated blood-glucose levels. Today, glucose levels are controlled by injecting a rapidly absorbed insulin just before each meal. Added to this dosage, the slowly absorbed insulin can then be injected or pumped in by a prosthetic implant device between meals to maintain low insulin concentrations. The amounts required are determined by frequent blood-glucose measurements.
For overweight, non-insulin-dependent diabetics, controlling diet, avoiding foods high in sugar and carbohydrates, and encouraging weight loss may be sufficient treatment. A regular program of physical exercise is also recommended as an important part of diabetes treatment. Exercise utilizes surplus blood glucose and helps a person to both lose and maintain weight. In addition, non-insulin-dependent-type oral drugs may stimulate the pancreas to secrete additional insulin. It may be necessary to give injections of insulin.
Diabetes can be particularly difficult to manage during adolescence, when elevated levels of certain growth hormones make controlling blood glucose levels difficult. In addition, adolescents sometimes resist the dietary restrictions and close monitoring necessary to maintain good health. The most serious problem diabetic children face is hypoglycemia, or low blood glucose. Common symptoms in young children include misbehavior and irritability, although symptoms can vary from episode to episode. Hypoglycemia is easily treated by eating a sweet food. Parents are advised to inform teachers about symptoms and to enlist their help in maintaining the routines necessary to manage diabetes, including frequent testing of blood glucose levels, eating snacks before exercise, careful diet, and close monitoring of insulin dosage.
A relatively new treatment for type II diabetes is the drug Glucophage (generic name: metformin). Glucophage affects how the body handles its own insulin, increasing its effectiveness. With only a few side effects (diarrhea, nausea, bloating) that fade after the body adjusts to the medication, Glucophage offers an alternative to those who don't respond to changes in diet and exercise

Sources and Dietary Intakes

Antioxidants can be vitamins, minerals, enzymes or plant derived nutrients called phytonutrients. The major vitamin antioxidants are vitamin C, vitamin E, beta-carotene, while selenium is the major mineral antioxidant. Many researchers and nutritionists discuss and report on "antioxidants" as if these were the only sources of importance. A thorough examination of antioxidants and their importance to human health must include a much larger list of compounds that are present in healthy, varied diet. Recommendations by the National Cancer Institute, the U.S.D.A., other government agencies and nutrition experts are to eat a minimum of 5-13 servings of fruits and vegetables per day, depending on calorie needs. Based on these recommendations, a typical varied diet would provide approximately 200-600 mg of vitamin C and 10-20 mg (16,000-32,000 IU) of carotenoids.Overall, polyphenols are the most abundant antioxidants in the diet. Their total dietary intake could be as high as 1 gram/day in a mixed, varied diet of fruits, vegetables, grains, and beverages.Possible intakes of other phytonutrient antioxidants would be anthocyandins "2 oz black grapes 1,500 mg; proanthocyanidins" 100-300 mg/d red wine; catechins "50 mg day" tea (one cup brewed green tea" 240-320 mg catechins), chocolate, apples, pears, grapes, red wine; isoflavones "50 mg/day from soy foods; chlorogenic acid" as high as 800 mg/day coffee drinkers. Although it may seem reasonable that a consistently healthy and varied diet could provide high doses of antioxidants, the average American gets a total of just three servings of fruits and vegetables a day. The latest dietary guidelines call for five to thirteen servings of fruits and vegetables a day, depending on one's caloric intake. For a person who needs 2,000 calories a day to maintain weight and health, this translates into nine servings, or 4½ cups per day.The 2001-2002 NHANES survey of dietary intakes shows that 93% of Americans fail to get even the Estimated Average Requirement (EAR) for vitamin E, let alone the RDA. More than half of adults fail to get even the average requirement for vitamin A. About one-third of non-smokers and two-thirds of smokers fall short on minimum vitamin C requirements.If the governmental dietary recommendations are meant to be taken seriously, then it follows that it would be better for people to achieve recommended amounts of nutrients than to fall short. Obviously, since the average intake of 3 servings or less of fruits and vegetables fails to provide minimum levels of even basic vitamins, intakes of the numerous other antioxidants are sure to be well under optimal and beneficial levels.It has been established that a good multivitamin can fill in gaps in missing vitamins, but availability of broad spectrum antioxidant supplements has lagged behind. Although there is much to be learned about the characteristics of the literally hundreds of dietary antioxidants, it seems reasonable that providing supplements of various antioxidant classes may fill in nutritional gaps and provide many of the benefits missing from the typical American diet.

Safety of Multivitamins and Antioxidants

Nutritional supplements have been widely used and highly valued by American consumers ever since vitamins were discovered and commercialized, beginning in the early decades of the 1900's. According to recent national health survey, as many as 78 million Americans adults use multivitamins on a regular basis. Multivitamin/mineral supplements are an effective means of delivering adequate amounts of most essential nutrients to help people achieve recommended intakes. The great majority of dietary supplements, including multivitamins, are safe for regular use. Despite widespread usage, there have been no specific published reports of toxicity or adverse effects associated with the use of multivitamins.A series of well-publicized clinical trials conducted in diseased patients utilizing relatively high doses of single nutrients or combinations of nutrients (such as vitamin E and/or beta-carotene), have yielded disappointing results, and even suggested the presence of harm. However, those trials were conducted in patients with serious illnesses (ie. cancer or cardiovascular disease) who were on multiple medications or who were current heavy smokers. The results of these trials should be placed in context and are not applicable to the generally healthy population.Advanced levels of antioxidants are a common thread among nearly every population that is less prone to premature chronic degenerative disease. The Japanese have high levels of fruit, vegetables, green tea and soy as part of their traditional diet. Vegetarians have lower levels of heart disease and cancer, compared to the typical mixed diet, likely in part due to higher intakes of antioxidants. While high levels of single nutrients and foods may pose a risk of danger and toxicity, there is no known unsafe intake level of total antioxidants in normally healthy individuals.

Increased fiber intake protects against cardiovascular disease risk factors

Increasing dietary fiber intake to at least 25 grams per day from varied sources provides a significant protective effect against cardiovascular disease. Researchers presumed that fiber intakes of 30-35 grams per day would likely provide an even greater protective effect.Increased dietary fiber intake is associated with reduced levels of a number of cardiovascular disease risk factors. The results of a study published in the American Journal of Clinical Nutrition add to a growing body of evidence linking higher dietary fiber intake with a lower risk of heart disease. Nearly 6,000 men and women were selected from participants in an ongoing trial designed to evaluate the effect of antioxidants on cancer and heart disease incidence over an eight year period.The highest total of insoluble dietary fiber intakes were associated with reductions in the risks of overweight and elevated waist-to-hip ratio, blood pressure, cholesterol, triglycerides, and homocysteine. Fiber from cereals was associated with a lower body mass index, blood pressure, and homocysteine concentration; fiber from vegetables with a lower blood pressure and homocysteine concentration; and fiber from fruit with a lower waist-to-hip ratio and blood pressure. Fiber from dried fruit or nuts and seeds was associated with a lower body mass index, waist-to-hip ratio, and glucose concentrations.The findings of this study illustrate the significance of increasing fiber intake from various dietary sources. The results also indicate that 25 grams total dietary fiber per day is the minimum intake required to attain a significant protective effect against cardiovascular disease, and that total dietary fiber intakes of 30-35 grams/day will likely provide an even greater protective effect.American Journal of Clinical Nutrition, Vol. 82, No. 6, 1185-1194, December 2005

High Antioxidant Levels are Associated with a Reduced Risk of Periodontitis

Periodontitis is an inflammatory disease that affects the supporting tissues of the teeth and is associated with an increased risk of stroke, type-2 diabetes, and heart disease. A new study reveals that increased serum antioxidant concentrations are associated with a reduced risk of periodontitis, even in people who have never smoked.

Periodontitis is an inflammatory condition of the tissue surrounding the teeth which has been linked with an increased risk of stroke, type-2 diabetes, and heart disease. A new report published in the Journal of Nutrition revealed that higher serum antioxidant levels are associated with a reduction in the risk of periodontitis.

The current research examined data from 11,480 participants in the Third National Health and Nutrition Examination Survey (NHANES III), for whom periodontal measurements and serum levels of several antioxidants had been recorded. These antioxidants included alpha-carotene, beta-carotene, selenium, lutein, beta-cryptoxanthin, vitamins A, C and E, and total antioxidant levels.

Mild periodentitis was found in 14% of the subjects and 5% had severe disease. Higher vitamin C and total antioxidant levels were associated with a lower incidence of periodontitis, especially with severe disease. Individuals whose vitamin C levels were in the top 20% of participants had a 39% lower risk of periodontitis than participants with the lowest intakes. For subjects who had never smoked, those with the highest intake of vitamin C experienced only half the risk of periodontitis compared to those with the lowest vitamin C levels.

Vitamin C has a role in collagen synthesis and maintenance of connective tissue, which may explain its benefit in protecting against periodontitis. In addition, it is known as a potent antioxidant that may also help reduce inflammation.

Journal of Nutrition Vol. 137, 657-664, March 2007.

Herbal Medicine for the Treatment of Arrhythmia

In traditional Chinese medicine, arrhythmias are categorized by the characteristic symptoms of palpitations and abnormal pulse. Numerous Chinese herbal medicines are identified to have antiarrhythmic effects, such as xin bao, ci zhu wan, bu xin dan, and several others. However, few clinical trials have been conducted to study their effects and safety. Xin bao is one agent that has begun to be examined. The mechanism of action of xin bao is thought to be through its stimulation and increased excitability of the sinuatrial node. In one observational study, the effects of xin bao were documented in 87 patients with sick sinus syndrome. Xin bao was administered orally 2 to 3 times per day for 2 months. Patients with major symptoms of sick sinus syndrome, which included dizziness, palpitations, and chest pressure, improved significantly after treatment. No serious adverse effects were noted. This study suggests a possible role of xin bao in the treatment of sick sinus syndrome. However, more scientific research on xin bao and other antiarrhythmic Chinese herbs mentioned previously are necessary before any recommendations can be made for their routine use in patients with sick sinus syndrome or other arrhythmias.

Herbal Medicine for the Treatment of Venous Insufficiency

The seeds of horse chestnut, Aesculus hippocastanum, have long been used in Europe to treat venous disorders such as varicose veins. The saponin glycoside aescin from horse chestnut extract (HCE) inhibits the activity of lysosomal enzymes thought to contribute to varicose veins by weakening vessel walls and increasing permeability, which result in dilated veins and edema. In fact, recent research has shown that A hippocastanum inhibits only against hyaluronidase but not elastase, and this activity is linked mainly to the saponin escin. In animal studies, HCE, in a dose-dependent fashion, increases venous tone, venous flow, and lymphatic flow. It also antagonizes capillary hyperpermeability induced by histamine, serotonin, or chloroform. This extract has been shown to decrease edema formation of lymphatic and inflammatory origin. Horse chestnut extract has antiexudative properties, suppressing experimentally induced pleurisy and peritonitis by inhibiting plasma extravasation and leukocyte emigration, and its dose-dependent antioxidant properties can inhibit in vitro lipid peroxidation. Randomized, double-blind, placebo-controlled trials with HCE show are eduction in edema, measured using plethysmography.
In another recent randomized, placebo-controlled study, the efficacy and safety of class 2 compression stockings and dried HCE were compared. Both HCE and the compression stockings decreased lower leg edema after 12 weeks of therapy; the results showed an average 43.8-mL reduction with HCE and 46.7-mL with compression stockings, while the placebo group showed an increase of 9.8 mL. Both HCE and compression therapy were well tolerated, with no serious adverse effects. This study may indicate that both of these modalities are reasonable alternatives for the effective treatment of patients with chronic venous insufficiency. Also, HCE has been shown to markedly improve other symptoms associated with chronic venous insufficiency, such as pain, tiredness, itching, and tension in the swollen leg, in a case-observation study. Aside from effects on venous insufficiency, prophylactic use of HCE has been thought to decrease the incidence of thromboembolic complications of gynecological surgery. However, since this issue is still controversial, this does not appear to be the case.
Standardized HCE is prepared as an aqueous alcohol extract of 16% to 21% of triterpene glycosides, calculated as aescin. The usual initial dosage is 90 to 150 mg/d of aescin, which may be reduced to 35 to 70 mg/d if clinical benefit is seen. Standardized HCE preparations are not available in the United States, but nonstandardized products may be available.
Some manufacturers promote the use of topical preparations of HCE for treatment of varicose veins as well as hemorrhoids; however, at least one study has demonstrated poor aescin distribution at sites other than the skin and muscle tissues underlying the application site. Moreover, the involvement of arterioles and veins in the pathophysiology of hemorrhoids makes the effectiveness of HCE doubtful, since HCE has no known effects on the arterial circulation. For now, research studies have yet to confirm any clinical effectiveness of topical HCE preparations.
Although adverse effects are uncommon, HCE may cause gastrointestinal irritation. Parenteral aescin has produced isolated cases of anaphylactic reactions, as well as hepatic and renal toxic effects. In the event of toxicity, aescin can be eliminated via dialysis, with elimination dependent on protein-binding. Horse chestnut extract is also one of the components of venocuran, a drug marketed as a treatment for venous disorders. In 1975, venocuran was determined to cause a pseudolupus syndrome characterized by recurrent fever, myalgia, arthralgia, pleuritis, pulmonary infiltrates, pericarditis, myocarditis, and mitochondrial antibodies in the absence of nuclear antibodies after prolonged treatment. Venocuran has since been withdrawn from the market; however, the nature of its pathophysiologic action is still unknown.
Like A hippocastanum, Ruscus aculeatus (butcher's broom) is also known for its use in treating venous insufficiency. Ruscus aculeatus is a short evergreen shrub found commonly in the Mediterranean region. Two steroidal saponins, ruscogenin and neurogenin, extracted from the rhizomes of R aculeatus are thought to be its active components. In vivo studies on hamster cheek pouch reveal that topical Ruscus extract dose dependently antagonizes histamine-induced increases in vascular permeability. Moreover, topical Ruscus extract causes dose-dependent constriction of venules without appreciably affecting arterioles. Topical Ruscus extract's vascular effects are also temperature dependent and appear to counter the sympathetic nervous system's temperature-sensitive vascular regulation: venules dilate at a lower temperature (25°C), constrict at near physiologic temperatures (36.5°C), and further constrict at higher temperatures (40°C); arterioles dilate at 25°C, are unaffected at 36.5°C, and remain unaffected or constrict at 40°C, depending on Ruscus concentration. Based on the influence of prazosin, diltiazem, and rauwolscine, the peripheral vascular effects of Ruscus extract appear to be selectively mediated by effects on calcium channels and 1-adrenergic receptors with less activity at 2-adrenergic receptors. Also, R aculeatus exhibits strong antielastase activity and has little effect on hyaluronidase in direct contrast to A hippocastanum. This activity may contribute to their efficacy in the treatment of venous insufficiency since these enzyme systems are involved in the turnover of the main components of the perivascular amorphous substance.
Several small clinical trials using topical Ruscus extract support its role in treating venous insufficiency. One randomized, double-blind, placebo-controlled trial involving 18 volunteers showed a beneficial decrease in femoral vein diameter (median decrease, 1.25 mm) using duplex B-scan ultrasonography. The decrease was measured 2.5 hours after applying 4 to 6 g of a cream containing 64 to 96 mg of Ruscus extract. In another small trial (N = 18) it was shown that topical Ruscus extract may be helpful in reducing venous dilation during pregnancy. Oral agents may be useful as topical drugs for venous insufficiency, although the evidence is less convincing. Although capsule, tablet, ointment, and suppository (for hemorrhoids) preparations of Ruscus extract are available in Europe, only capsules are available in the United States. These capsules contain 75 mg of Ruscus extract and 2 mg of rosemary oil. Aside from occasional nausea and gastritis, adverse effects from using R aculeatus have rarely been reported, even in high doses. Nevertheless, one should be wary of any drug that has not been thoroughly tested. Although there is ample evidence to support the pharmacological activity of R aculeatus, there is still a relative deficiency of clinical data to establish its actual safety and efficacy. Until more studies are completed, no recommendations regarding dosage can be offered.

Herbal Medicine for the Treatment of Cerebral and peripheral Vascular Disease

Having existed for more than 200 million years, Ginkgo biloba (maidenhair tree) was apparently saved from extinction by human intervention, surviving in Far Eastern temple gardens while disappearing for centuries in the West. It was reintroduced to Europe in 1730 and became a favorite ornamental tree. Although the root and kernels of G biloba have long been used in traditional Chinese medicine, the tree gained attention in the West during the 20th century for its medicinal value after a concentrated extract of G biloba leaves was developed in the 1960s. At least 2 groups of substances within G biloba extract (GBE) demonstrate beneficial pharmacological actions. The flavonoids reduce capillary permeability as well as fragility and serve as free radical scavengers. The terpenes (ie, ginkgolides) inhibit platelet-activating factor, decrease vascular resistance, and improve circulatory flow without appreciably affecting blood pressure. Continuing research appears to support the primary use of GBE for treating cerebral insufficiency and its secondary effects on vertigo, tinnitus, memory, and mood; also, GBE appears to be useful for treating peripheral vascular disease, including diabetic retinopathy and intermittent claudication.
In a randomized, placebo-controlled, double-blind study, EGb 761, which is a standardized extract of G biloba with respect to its flavonol glycoside and terpene lactone content, was shown to significantly decrease the areas of ischemia as measured by transcutaneous partial pressure of oxygen during exercise. Because of its rapid anti-ischemic action, EGb 761 may be valuable in the treatment of intermittent claudication and peripheral artery disease in general.
Also, studies have been examining the cardioprotective efficacy of EGb 761 in regard to its anti–free radical action in myocardial ischemia–reperfusion injury. In vitro studies with animal models have shown that this compound may exert such an effect. A clinical study of 15 patients undergoing coronary bypass surgery demonstrated that oral EGb 761 therapy may limit free radical–induced oxidative stress occurring in the systemic circulation and at the level of the myocardium during these operations. It remains to be studied whether extracts of G biloba may be used as pharmacological adjuvants to limit tissue damage and metabolic alterations following coronary bypass surgery, coronary angioplasty for acute myocardial infarctions, or even in managing coronary thrombosis.
Although approved as a drug in Europe, Ginkgo is not approved in the United States and is instead marketed as a food supplement, usually supplied as 40-mg tablets of extract. Since most of the investigations examining the efficacy of GBEs used preparations such as EGb 761 or LI 1370, the bioequivalence of other GBE products has not been established. The recommended dosage in Europe is one 40-mg tablet taken 3 times daily with meals (120 mg/d). Adverse effects due to GBE are rare but can include gastrointestinal disturbances, headache, and allergic skin rash.
Known mostly as a culinary spice and flavoring agent, Rosmarinus officinalis (rosemary) is listed in many herbal sources as a tonic and all-around stimulant. Traditionally, rosemary leaves are said to enhance circulation, aid digestion, elevate mood, and boost energy. When applied externally, the volatile oils are supposedly useful for arthritic conditions and baldness.
Although research on rosemary is scant, some studies have focused on antioxidant effects of diterpenoids, especially carnosic acid and carnosol, isolated from rosemary leaves. In addition to having antineoplastic effects, antioxidants in rosemary have been credited with stabilizing erythrocyte membranes and inhibiting superoxide generation and lipid peroxidation. Essential oils of rosemary have demonstrated antimicrobial, hyperglycemic, and insulin-inhibiting properties. Rosemary leaves contain high amounts of salicylates, and its flavonoid pigment diosmin is reported to decrease capillary permeability and fragility. Despite the conclusions derived from in vitro and animal studies, the therapeutic use of rosemary for cardiovascular disorders remains questionable, because few, if any, clinical trials have been conducted using rosemary. Because of the lack of studies, no conclusions can be reached regarding the use of the antioxidants of rosemary in inhibiting atherosclerosis. Although external application may cause cutaneous vasodilation from the counterirritant properties of rosemary's essential oils, there is no evidence to support any prolonged improvement in peripheral circulation. While rosemary does have some carminative properties, it may also cause gastrointestinal and kidney disturbances in large doses. Until more studies are done, rosemary should probably be limited to its use as a culinary spice and flavoring agent rather than as a medicine.

Herbal Medicine for the Treatment of Cerebral and peripheral Vascular Disease

Having existed for more than 200 million years, Ginkgo biloba (maidenhair tree) was apparently saved from extinction by human intervention, surviving in Far Eastern temple gardens while disappearing for centuries in the West. It was reintroduced to Europe in 1730 and became a favorite ornamental tree. Although the root and kernels of G biloba have long been used in traditional Chinese medicine, the tree gained attention in the West during the 20th century for its medicinal value after a concentrated extract of G biloba leaves was developed in the 1960s. At least 2 groups of substances within G biloba extract (GBE) demonstrate beneficial pharmacological actions. The flavonoids reduce capillary permeability as well as fragility and serve as free radical scavengers. The terpenes (ie, ginkgolides) inhibit platelet-activating factor, decrease vascular resistance, and improve circulatory flow without appreciably affecting blood pressure. Continuing research appears to support the primary use of GBE for treating cerebral insufficiency and its secondary effects on vertigo, tinnitus, memory, and mood; also, GBE appears to be useful for treating peripheral vascular disease, including diabetic retinopathy and intermittent claudication.
In a randomized, placebo-controlled, double-blind study, EGb 761, which is a standardized extract of G biloba with respect to its flavonol glycoside and terpene lactone content, was shown to significantly decrease the areas of ischemia as measured by transcutaneous partial pressure of oxygen during exercise. Because of its rapid anti-ischemic action, EGb 761 may be valuable in the treatment of intermittent claudication and peripheral artery disease in general.
Also, studies have been examining the cardioprotective efficacy of EGb 761 in regard to its anti–free radical action in myocardial ischemia–reperfusion injury. In vitro studies with animal models have shown that this compound may exert such an effect. A clinical study of 15 patients undergoing coronary bypass surgery demonstrated that oral EGb 761 therapy may limit free radical–induced oxidative stress occurring in the systemic circulation and at the level of the myocardium during these operations. It remains to be studied whether extracts of G biloba may be used as pharmacological adjuvants to limit tissue damage and metabolic alterations following coronary bypass surgery, coronary angioplasty for acute myocardial infarctions, or even in managing coronary thrombosis.
Although approved as a drug in Europe, Ginkgo is not approved in the United States and is instead marketed as a food supplement, usually supplied as 40-mg tablets of extract. Since most of the investigations examining the efficacy of GBEs used preparations such as EGb 761 or LI 1370, the bioequivalence of other GBE products has not been established. The recommended dosage in Europe is one 40-mg tablet taken 3 times daily with meals (120 mg/d). Adverse effects due to GBE are rare but can include gastrointestinal disturbances, headache, and allergic skin rash.
Known mostly as a culinary spice and flavoring agent, Rosmarinus officinalis (rosemary) is listed in many herbal sources as a tonic and all-around stimulant. Traditionally, rosemary leaves are said to enhance circulation, aid digestion, elevate mood, and boost energy. When applied externally, the volatile oils are supposedly useful for arthritic conditions and baldness.
Although research on rosemary is scant, some studies have focused on antioxidant effects of diterpenoids, especially carnosic acid and carnosol, isolated from rosemary leaves. In addition to having antineoplastic effects, antioxidants in rosemary have been credited with stabilizing erythrocyte membranes and inhibiting superoxide generation and lipid peroxidation. Essential oils of rosemary have demonstrated antimicrobial, hyperglycemic, and insulin-inhibiting properties. Rosemary leaves contain high amounts of salicylates, and its flavonoid pigment diosmin is reported to decrease capillary permeability and fragility. Despite the conclusions derived from in vitro and animal studies, the therapeutic use of rosemary for cardiovascular disorders remains questionable, because few, if any, clinical trials have been conducted using rosemary. Because of the lack of studies, no conclusions can be reached regarding the use of the antioxidants of rosemary in inhibiting atherosclerosis. Although external application may cause cutaneous vasodilation from the counterirritant properties of rosemary's essential oils, there is no evidence to support any prolonged improvement in peripheral circulation. While rosemary does have some carminative properties, it may also cause gastrointestinal and kidney disturbances in large doses. Until more studies are done, rosemary should probably be limited to its use as a culinary spice and flavoring agent rather than as a medicine.

Herbal Medicine for the Treatment of Atherosclerosis

In addition to its use in the culinary arts, garlic (Allium sativum) has been valued for centuries for its medicinal properties. Garlic is one of the herbal medicines that has been examined more closely by the scientific community. In recent decades, research has focused on garlic's use in preventing atherosclerosis. Garlic, like many of the other herbal medicines discussed previously, has demonstrated multiple beneficial cardiovascular effects. A number of studies have demonstrated these effects that include lowering blood pressure, inhibiting platelet aggregation, enhancing fibrinolytic activity, reducing serum cholesterol and triglyceride levels, and protecting the elastic properties of the aorta.
Consumption of large quantities of fresh garlic (0.25 to 1.0 g/kg or about 5-20 average sized 4-g cloves in a person weighing 78.7 kg) has been shown to produce the beneficial effects mentioned earlier. In support of this, a recent double-blind cross-over study was conducted on moderately hypercholesterolemic men that compared the effects of 7.2 g of aged garlic extract with placebo on blood lipid levels. This study found that there was a maximal reduction of 6.1% in total serum cholesterol levels and 4.6% in LDL cholesterol levels with garlic compared with placebo.
However, despite positive evidence from numerous trials, some investigators have been hesitant to outright endorse the routine use of garlic for cardiovascular disease because many of the published studies had methodological shortcomings, perhaps because constituent trials were small, lacking statistical power. Also, inappropriate methods of randomization, lack of dietary run-in period, short duration, or failure to undertake intention-to-treat analysis may explain the cautious acceptance of previous meta-analyses. In fact, one recent study found no demonstrable effect of garlic ingestion on lipid and lipoprotein levels. This study used a cross-over design protected by a washout period to reduce between-subject variability as well as close assessment and reporting of dietary behavior, which had been lacking in previous trials. Another study found no effect of garlic on cholesterol absorption, cholesterol synthesis, or cholesterol metabolism. As is evident, the precise extent of garlic's impact on atherosclerosis remains controversial; larger, more rigorously designed trials may be necessary to better determine its utility in preventing cardiovascular disease.
Garlic has also been studied in hypertensive patients as a blood pressure–lowering agent. Similar to its lipid effects, no conclusive studies have been conducted and many methodological shortcomings exist in study designs. The results of one meta-analysis that considered 8 different trials suggest some clinical use for patients with mild hypertension, but there is insufficient evidence to recommend its use as routine clinical therapy. Garlic has also been shown to possess antiplatelet activity. In the past, this action was mostly documented in vitro. A new study examined the effect of the consumption of a fresh clove of garlic on platelet thromboxane production and showed that after 26 weeks, serum thromboxane levels were reduced about 80%.This may prove to be beneficial in the prevention of thrombosis in the future. Recently, the effect of long-term garlic intake on the elastic properties of the aorta was also studied. Participants in the trial (limited to those aged 50-80 years) consumed 300 mg/d of standardized garlic powder for more than 2 years. The results showed that the pulse-wave velocity and standardized elastic vascular resistance of the aorta were lower in the garlic group than in the control group. Consequently, long-term garlic powder intake may have a protective effect on the elastic properties of the aorta related to aging. In these ways, garlic has shown numerous beneficial cardiovascular effects that need to be investigated further to determine its therapeutic utility.
Intact cells of garlic bulbs include an odorless, sulfur-containing amino acid known as allinin. When garlic is crushed, allinin comes into contact with allinase, which converts allinin to allicin. Allicin has potent antibacterial properties, but it is also highly odoriferous and unstable. Ajoenes, self-condensation products of allicin, appear to be responsible for garlic's antithrombotic activity. Most authorities now agree that allicin and its derivatives are the active constituents of garlic's physiological activity. Fresh garlic releases allicin in the mouth during the chewing process. Dried garlic preparations lack allicin but contain allinin and allinase. Since allinase is inactivated in the stomach, dried garlic preparations should be coated with enteric so that they pass through the stomach into the small intestine where allinin can be enzymatically converted to allicin. Few commercial garlic preparations are standardized for their allicin yield based on allinin content, hence making their effectiveness less certain. However, one double-blind, placebo-controlled study involving 261 patients for 4 months using one 800-mg tablet of garlic powder daily, standardized to 1.3% allinin content, demonstrated significant reductions in total cholesterol (12%) and triglyceride levels (17%).
Aside from a garlic odor on the breath and body, moderate garlic consumption causes few adverse effects. However, consumption in excess of 5 cloves daily may result in heartburn, flatulence, and other gastrointestinal disturbances. Some people have reported allergic reactions to garlic, most commonly allergic contact dermatitis. Patch testing with 1% diallyl disulfide is recommended when garlic allergy is suspected Because of its antithrombotic activity, garlic should be used with caution in people taking oral anticoagulants concomitantly.
The resin of Commiphora mukul (gugulipid), a small, thorny tree native to India, has long been used in Ayurvedic medicine to treat lipid disorders. The primary mechanism of action of gugulipid is through an increase in the uptake and metabolism of LDL cholesterol by the liver. In a double-blind, cross-over study completed in 125 patients taking gugulipid compared with 108 patients taking clofibrate, the average decrease in serum cholesterol and triglyceride levels was 11% and 16.8%, respectively, with gugulipid compared with 10% and 21.6%, respectively, with clofibrate. In general, hypercholesterolemic patients responded more favorably to gugulipid therapy than hypertriglyceridemic patients. Moreover, it was shown in another randomized, double-blind trial that C mukul also decreased LDL cholesterol levels by 12.5% and the total cholesterol–high-density lipoprotein cholesterol ratio by 11.1%, whereas the levels were unchanged in the placebo group.
Besides being potentially as effective in lowering blood lipid levels as modern hyperlipidemic drugs, gugulipid may even be safer. In the trial mentioned previously, compliance was greater than 96%, with only the adverse effects of headache, mild nausea, and hiccups noted. However, it has been shown that gugulipid may affect the bioavailability of other cardiovascular drugs, namely, propranolol hydrochloride and diltiazem hydrochloride. Gugulipid significantly reduced the peak plasma concentration and area under the curve of both these drugs, which may lead to diminished efficacy or nonresponsiveness. Undoubtedly, gugulipid is a natural lipid-lowering drug with potential for therapeutic use, but rigorous, larger clinical trials will be necessary to further evaluate its safety and efficacy before it can be endorsed as an alternative therapy for hyperlipidemia and prevention of atherosclerosis.
Maharishi amrit kalash-4 and Maharishi amrit kalash-5 are 2 complex herbal mixtures with significant antioxidant properties that have been shown to inhibit LDL oxidation in patients with hyperlipidemia. In experimental studies, the herbal mixtures have also been shown to inhibit enzymatic- and nonenzymatic-induced microsomal lipid peroxidation and platelet aggregation.

Herbal Medicine for the Treatment of Angina Pectoris

Crataegus hawthorn, a name encompassing many Crataegus species (such as Crataegus oxyacantha and Crataegus monogyna in the West and Crataegus pinnatifida in China) has acquired the reputation in modern herbal literature as an important tonic for the cardiovascular system that is particularly useful for angina. Crataegus leaves, flowers, and fruits contain a number of biologically active substances, such as oligomeric procyanins, flavonoids, and catechins. From current studies, Crataegus extract appears to have antioxidant properties and can inhibit the formation of thromboxane as well.
Also, Crataegus extract antagonizes the increases in cholesterol, triglyceride, and phospholipid levels in low-density lipoprotein (LDL) and very low-density lipoprotein in rats fed a hyperlipidemic diet; thus, it may inhibit the progression of atherosclerosis. This hypocholesterolemic action may be due to an up-regulation of hepatic LDL receptors resulting in greater influx of plasma cholesterol into the liver. Crataegus also prevents cholesterol accumulation in the liver by enhancing cholesterol degradation to bile acids, as well as suppressing cholesterol biosynthesis.
According to another study, Crataegus extract, in high concentrations, has a cardioprotective effect on ischemic-reperfused hearts without causing an increase in coronary blood flow. On the other hand, oral and parenteral administration of oligomeric procyanins of Crataegus has been shown to lead to an increase in coronary blood flow in both cats and dogs. Double-blind clinical trials have demonstrated simultaneous cardiotropic and vasodilatory actions of Crataegus. In essence, Crataegus increases coronary perfusion, has a mild hypotensive effect, antagonizes atherogenesis, and has positive inotropic and negative chronotropic actions. In a recent multicenter, placebo-controlled, double-blind study, an extract of Crataegus was shown to clearly improve the cardiac performance of patients with New York Heart Association class II heart failure. In this study, the primary parameter analyzed was the heart rate product (systolic blood pressure x heart rate). Recent studies have suggested that the mechanism of cardiac action for Crataegus species may be due to the inhibition of the 3‘, 5‘-cyclic adenosine monophosphate phosphodiesterase.
Hawthorn is relatively devoid of adverse effects. In fact, in comparison with other inotropic drugs such as epinephrine, amrinone, milrinone, and digoxin, Crataegus has a potentially reduced arrhythmogenic risk because of its ability to prolong the effective refractory period, while the other drugs mentioned previously all shorten this parameter. Also, it should be noted that concomitant use of hawthorn with digitalis can markedly enhance the activity of digitalis. Undoubtedly, more studies are needed to show that hawthorn can be used safely and effectively.
Because of its resemblance to Panax ginseng (Asian ginseng), Panax notoginseng has acquired the common name of pseudoginseng, especially since it is often an adulterant of P ginseng preparations. In traditional Chinese medicine, the root of P notoginseng is used for analgesia and hemostasis. It is also often used in the treatment of patients with angina and coronary artery disease. Panax notoginseng has been described as a calcium ion channel antagonist in vascular tissue. More specifically, its pharmacological action may be as a novel and selective calcium ion antagonist that does not interact with the L-type calcium ion channel but rather may interact with the receptor-operated calcium ion channel.
Although clinical trials are lacking, in vitro studies using P notoginseng suggest possible cardiovascular effects. One study that used purified notoginsenoside R1, extracted from P notoginseng, on human left umbilical vein endothelial cells showed a dose- and time-dependent synthesis of tissue-type plasminogen activating factor without affecting the synthesis of plasminogen activating inhibitor. Thus, fibrinolytic parameters were enhanced. Another study suggests that P notoginseng saponins may inhibit atherogenesis by interfering with the proliferation of smooth muscle cells. In vitro and in vivo studies using rats and rabbits demonstrate that P notoginseng may be useful as an antianginal drug, since it dilates coronary arteries in all concentrations. The role of P notoginseng in the treatment of hypertension is less certain, since P notoginseng causes vasodilation or vasoconstriction depending on the concentration and target vessel. The results of these in vitro and in vivo studies are encouraging; however, clinical trials will be necessary to make a more informed decision regarding the use of P notoginseng.
Salvia miltiorrhiza (dan-shen), a relative of the Western sage Salvia officinalis, is native to China. In traditional Chinese medicine, the root of S miltiorrhiza is used as a circulatory stimulant, sedative, and cooling drug. Salvia miltiorrhiza may be useful as an antianginal drug because it has been shown to dilate coronary arteries in all concentrations, similar to P notoginseng. Also, S miltiorrhiza has variable action on other vessels depending on its concentration, so it may not be as helpful in treating hypertension. In vitro, S miltiorrhiza, in a dose-dependent fashion, inhibits platelet aggregation and serotonin release induced by either adenosine diphosphate or epinephrine, which is thought to be mediated by an increase in platelet cyclic adenosine monophosphate caused by S miltiorrhiza's inhibition of cyclic adenosine monophosphate phosphodiesterase. Salvia miltiorrhiza appears to have a protective action on ischemic myocardium, enhancing the recovery of contractile force on reoxygenation. More recently, S miltiorrhiza has been shown to protect myocardial mitochondrial membranes from ischemia-reperfusion injury and lipid peroxidation because of its free radical–scavenging effects. Qualitatively and quantitatively, a decoction of S miltiorrhiza was as efficacious as the more expensive isolated tanshinones. Clinical trials will be necessary to evaluate the safety and efficacy of S miltiorrhiza. Of note, it has been observed clinically that when S miltiorrhiza and warfarin sodium are coadministered, there is an increased incidence in warfarin-related adverse effects; in rats S miltiorrhiza was shown to increase the plasma concentrations of warfarin as well as the prothrombin time.

Herbal Medicine for the Treatment of Hypertension

The root of R serpentina (snakeroot), the natural source of the alkaloid reserpine, has been a Hindu Ayurvedic remedy since ancient times. In 1931, Indian literature first described the use of R serpentina root for the treatment of hypertension and psychoses; however, the use of Rauwolfia alkaloids in Western medicine did not begin until the mid1940s. Both standardized whole root preparations of R serpentina and its reserpine alkaloid are officially monographed in the United States Pharmacopeia. A powdered whole root of 200 to 300 mg orally is equivalent to 0.5 mg of reserpine.
Reserpine was one of the first drugs used on a large scale to treat systemic hypertension. It acts by irreversibly blocking the uptake of biogenic amines (norepinephrine, dopamine, and serotonin) in the storage vesicles of central and peripheral adrenergic neurons, thus leaving the catecholamines to be destroyed by the intraneuronal monoamine oxidase in the cytoplasm. The depletion of catecholamines accounts for reserpine's sympatholytic and antihypertensive actions. Reserpine's effects are long lasting, since recovery of sympathetic function requires synthesis of new storage vesicles, which takes days to weeks. Reserpine lowers blood pressure by decreasing cardiac output, peripheral vascular resistance, heart rate, and renin secretion. With the introduction of other antihypertensive drugs with fewer central nervous system adverse effects, the use of reserpine has diminished. The daily oral dose of reserpine should be 0.25 mg or less, and as little as 0.05 mg if given with a diuretic. Using the whole root, the usual adult dose is 50 to 200 mg/d administered once daily or in 2 divided doses.
Rauwolfia alkaloids are contraindicated for use in patients with previously demonstrated hypersensitivity to these substances, in patients with a history of mental depression (especially with suicidal tendencies), in patients with active peptic ulcer disease or ulcerative colitis, and in patients receiving electroconvulsive therapy. The most common adverse effects are sedation and inability to concentrate and perform complex tasks. Reserpine may cause mental depression, sometimes resulting in suicide, and its use must be discontinued at the first sign of depression. Reserpine's sympatholytic effect and its enhancement of parasympathetic actions account for its well-described adverse effects: nasal congestion, increased gastric secretion, and mild diarrhea.
Stephania tetrandra is an herb sometimes used in traditional Chinese medicine to treat hypertension. Tetrandrine, an alkaloid extract of S tetrandra, has been shown to be a calcium ion channel antagonist, paralleling the effects of verapamil. Tetrandrine blocks T and L calcium channels, interferes with the binding of diltiazem and methoxyverapamil at calcium-channel binding sites, and suppresses aldosterone production. A parenteral dose (15 mg/kg) of tetrandrine in conscious rats decreases mean, systolic, and diastolic blood pressures for more than 30 minutes; however, an intravenous 40-mg/kg dose killed the rats by myocardial depression. In stroke-prone hypertensive rats, an oral dose of 25 or 50 mg/kg produced a gradual and sustained hypotensive effect after 48 hours without affecting plasma renin activity. In addition to its cardiovascular actions, tetrandrine has reported antineoplastic, immunosuppressive, and mutagenic effects.
Tetrandrine is 90% protein-bound with an elimination half-life of 88 minutes, according to dog studies; however, rat studies have shown a sustained hypotensive effect for more than 48 hours after a 25- or 50-mg oral dose. Tetrandrine causes liver necrosis in dogs orally administered 40 mg/kg of tetrandrine 3 times weekly for 2 months, reversible swelling of liver cells with a 20-mg/kg dose, and no observable changes with a 10-mg/kg dose. Given the evidence of hepatotoxicity, many more studies are necessary to establish a safe dosage of tetrandrine in humans.
More recently, tetrandrine has been implicated in an outbreak of rapidly progressive renal failure, termed Chinese herb nephropathy. Numerous individuals developed the condition after using a combination of several Chinese herbs as part of a dieting regimen. It has been hypothesized that the cause may be attributed to misidentification of S tetrandra; nonetheless, questions still remain as to the role of tetrandra in the development of this serious toxic effect.
The root of Lingusticum wallichii is used in traditional Chinese medicine as a circulatory stimulant, hypotensive drug, and sedative. Tetramethylpyrazine, the active constituent extracted from L wallichii, inhibits platelet aggregation in vitro and lowers blood pressure by vasodilation in dogs. With its actions independent of the endothelium, tetramethylpyrazine's vasodilatory effect is mediated by calcium channel antagonism and nonselective antagonism of -adrenergic receptors. Some evidence suggests that tetramethylpyrazine acts on the pulmonary vasculature. Currently, there is insufficient information to evaluate the safety and efficacy of this herbal medicinal.
Uncaria rhynchophylla is sometimes used in traditional Chinese medicine to treat hypertension. Its indole alkaloids, rhynchophylline and hirsutine, are thought to be the active principles of U rhynchophylla's vasodilatory effect. The mechanism of U rhynchophylla's actions is unclear. Some studies point to an alteration in calcium ion flux in response to activation, whereas others point to hirsutine's inhibition of nicotine-induced dopamine release. One in vitro study has shown U rhynchophylla extract relaxes norepinephrine-precontracted rat aorta through endothelium-dependent and -independent mechanisms. For the endothelium-dependent component, U rhynchophylla extract appears to stimulate endothelium-derived relaxing factor and/or nitric oxide release without involving muscarinic receptors. Also, in vitro and in vivo studies have shown that rhynchophylline can inhibit platelet aggregation and reduce platelet thromboses induced with collagen or adenosine diphosphate plus epinephrine. Safety and efficacy cannot be evaluated at this time because of a lack of clinical data.
Veratrum (hellebore) is a perennial herb grown in many parts of the world. Varieties include Veratrum viride from Canada and the eastern United States, Veratrum californicum from the western United States, Veratrum album from Alaska and Europe, and Veratrum japonicum from Asia. All Veratrum plants contain poisonous alkaloids known to cause vomiting, bradycardia, and hypotension. Most cases of Veratrum poisonings are due to misidentification with other plants. Although once a treatment for hypertension, the use of Veratrum alkaloids has lost favor owing to a low therapeutic index and unacceptable toxicity, as well as the introduction of safer antihypertensive drug alternatives.
Veratrum alkaloids enhance nerve and muscle excitability by increasing sodium ion conductivity. They act on the posterior wall of the left ventricle and the coronary sinus baroreceptors, causing reflex hypotension and bradycardia via the vagus nerve (Bezold-Jarisch reflex). Nausea and vomiting are secondary to the alkaloids' actions on the nodose ganglion.
The diagnosis of Veratrum toxicity is established by history, identification of the plant, and strong clinical suspicion. Clinical symptoms usually occur quickly, often within 30 minutes. Treatment is mainly supportive and directed at controlling bradycardia and hypotension. Veratrum-induced bradycardia usually responds to treatment with atropine; however, the blood pressure response to atropine is more variable and requires the addition of pressors. Other electrocardiographic changes, such as atrioventricular dissociation, may also be reversible with atropine. Seizures are a rare complication and may be treated with conventional anticonvulsants. For patients with preexisting cardiac disease, the use of -agonists or pacing may be necessary. Nausea may be controlled with phenothiazine antiemetics. Recovery usually occurs within 24 to 48 hours.
Evodia rutaecarpa (wu-chu-yu) is a Chinese herbal drug that has been used as a treatment for hypertension. It contains an active vasorelaxant component called rutaecarpine that can cause endothelium-dependent vasodilation in experimental models.

Herbal Medicine for the Treatment of Congestive Heart Failure

A number of herbs contain potent cardioactive glycosides, which have positive inotropic actions on the heart. The drugs digitoxin, derived from either D purpurea (foxglove) or Digitalis lanata, and digoxin, derived from D lanata alone, have been used in the treatment of congestive heart failure for many decades. Cardiac glycosides have a low therapeutic index, and the dose must be adjusted to the needs of each patient. The only way to control dosage is to use standardized powdered digitalis, digitoxin, or digoxin. When 12 different strains of D lanata plants were cultured and examined, their total cardenolide yield ranged from 30 to almost 1000 nmol/1 g. As is evident, treating congestive heart failure with nonstandardized herbal drugs would be dangerous and foolhardy.
Some common plant sources of cardiac glycosides include D purpurea (foxglove, already mentioned), Adonis microcarpa and Adonis vernalis (adonis), Apocynum cannabinum (black Indian hemp), Asclepiascurassavica (redheaded cotton bush), Asclepias friticosa (balloon cotton), Calotropis precera (king's crown), Carissa spectabilis (wintersweet), Cerebra manghas (sea mango), Cheiranthus cheiri (wallflower), Convallaria majalis (lily of the valley, convallaria), Cryptostegia grandiflora (rubber vine), Helleborus niger (black hellebore), Helleborus viridus, Nerium oleander (oleander), Plumeria rubra (frangipani), Selenicerus grandiflorus (cactus grandiflorus), Strophanthus hispidus and Strophanthus kombe (strophanus), Thevetia peruviana (yellow oleander), and Urginea maritima (squill). Even the venom glands of the animal Bufo marinus (cane toad) contain cardiac glycosides. Recently, the digitalislike steroid in the venom of the B marinus toad was identified as a previously described steroid, marinobufagenin. Marinobufagenin demonstrated high digoxinlike immunoreactivity and was antagonized with an antidigoxin antibody.
Accidental poisonings and even suicide attempts with ingestion of cardiac glycosides are abundant in the medical literature. Some herbal remedies (eg, Siberian ginseng) can elevate synthetic digoxin drug levels and cause toxic effects. In the United States, there are about 15,000 intoxications due to accidental or intentional ingestion of poisonous plants annually. In 1993, 2388 toxic exposures in the United States were reported to be due to plant glycosides. Of these, the largest percentage were attributed to oleander (ie, 25%). In the case of oleander, all plant tissues, including the seeds, roots, stems, leaves, berries, and blossoms, are considered extremely toxic. In fact, death in humans has been reported following ingestion of as little as 1 oleander leaf. The clinical manifestations of oleander intoxication, as well as other natural glycosides, is virtually identical to digoxin overdose. Morbidity and mortality are mainly related to cardiotoxic adverse effects that usually include life-threatening ventricular tachyarrhythmias, bradycardia, and heart block. The diagnosis should rely on the clinical presentation of unexplained hyperkalemia, and cardiac, neurologic, and gastrointestinal symptoms. The diagnosis can be further supported by the detection of the substance digoxin in a radioimmunoassay for digoxin. However, the extent of cross-reactivity between the cardiac glycosides from herbal sources and antibodies used in the radioimmunoassays has not been clearly defined. For this reason, digoxin assays may serve to confirm the suspected diagnosis but not to quantify the severity. Once the diagnosis has been established, the use of digoxin-specific Fab antibody fragments may be helpful in the treatment of severe intoxication. Other modalities, such as dialysis, cannot be easily facilitated because, like digoxin, natural glycosides are distributed extensively into peripheral tissues.

Rejuvenate Your Immune System with Antioxidant Nutrients

No doubt you've heard that antioxidants are essential to good health. But did you know that many doctors and nutritionists consider them the most important supplements you can take? In light of that, it's worth finding out a bit more about what they do and which ones you should be taking. To get the lowdown, as well as a recommendation for a simple supplement program, we turned to Richard Firshein, D.O., a New York City-based osteopath, author of The Nutraceutical Revolution (Riverhead Books, 1998).
Taking supplements in your 20s and 30s is a good idea, but by your 40s and 50s it becomes vital. By then, you've already sustained some free radical damage from the cumulative effects of poor diet, excess stress, sun damage and hormonal shifts.
Q: What exactly are antioxidants and why are they so important?
A: Basically, antioxidants are nutrients that prevent or reduce the production of free radicals, those unstable molecules that can attack healthy cells and lead to cancer, cardiovascular disease, aging processes and complications with diabetes. The fundamental antioxidants I recommend patients supplement with are A, C, E, Selenium, and Zinc. Vitamin C is found in many fruits and vegetables; vitamin E in grains; and vitamin A in yellow vegetables like squash. Many nuts and seeds contain the minerals selenium and zinc.
Q: Is it true that antioxidants tend to work with one another? If so, which should be taken together?
A: Yes, antioxidants do work synergistically with one another, meaning one supports the action of another. For instance, when vitamin E has mopped up as many free radicals as it can hold, vitamin C removes them from vitamin E, freeing E up to continue its work. Because of these relationships, you should take C, E, and selenium (which boosts E's effectiveness) together. Zinc and vitamins C and E also help increase the absorption of vitamin A.
Getting adequate amounts of each nutrient is also important because different antioxidants help support different areas of the body. For example, vitamin E is fat-soluble, meaning it's stored in the lipid, or fat-containing, membranes around cells. E helps prevent cardiovascular disease by insulating cells and protecting them from free radicals. Vitamin C, on the other hand, is water-soluble (meaning it is not stored in the body but rather flushed from the system), so it works best in the liquid portion of cells or in the bloodstream. It aids in respiration, serving as the first line of defense against pollution and helping to ease colds as well as chronic respiratory conditions like asthma. Also water-soluble, vitamin A (in the form of beta-carotene) provides your skin with protection from the sun's damaging rays. The mineral selenium supports liver function while zinc protects the immune system and, in men, the prostate.

Antioxidants Diabetes

What are the best antioxidants to treat diabetes?

Due to the many therapeutic benefits of antioxidants diabetes and various other conditions can be treated. The disorder is characterized by two types, Type 1 and Type 2, which we discuss in detail below.What is Diabetes and How is it Treated?Diabetes is a disorder of blood sugar (glucose) metabolism, whereby your body is not properly breaking down glucose in the blood stream, a necessary function for cell nutrition and function.The less common Type 1 Diabetes symptoms are brought on by the body's inability to produce insulin. Insulin breaks down blood glucose so it can be used by your body.But 90% of all diabetes is Type 2, wherein the body can produce the insulin needed, but cells do not respond to it, making it ineffectual. Obesity is a major cause of Type 2 Diabetes.Diabetes is a very serious condition, as it can lead to severe illness and even death. Variations in blood sugar level, too low and too high (hypoglycemia and hyperglycemia), can lead to atherosclerosis (fatty deposit buildup), neuropathy (loss of nerve function), retinopathy (eye disease and leading cause of blindness) and nephropathy (kidney damage).We discuss the antioxidants to help prevent and treat these diabetes symptoms below.It is very important to have your blood sugar levels checked to see if you might have diabetes. You should also learn about how with antioxidants diabetes can be controlled, in conjunction with a healthy diet and exercise regimen.
Diabetes Antioxidants - How can you treat diabetes?

Treatment of diabetes starts with a healthy diet and regular exercise. Your diet should be low in refined sugars, fats (especially trans fats found in deep-fried and fast food), and animal products. Your diet should be high in fiber, grains and legumes (beans, peas). Nuts are good, as are onions and garlic for maintaining blood glucose levels.Exercise, especially aerobic like running or swimming is great for everyone, but can also help your body metabolize glucose, as well as reduce cholesterol levels and improve circulation. Exercise also helps in weight control - as we mention above obesity is a major cause of Type 2 Diabetes.In addtion to a healthy diet and exercise, we recommend adding antioxidants as well as other important nutrients to your health program. Although you can get antioxidants from food, it may not be enough as many foods are depleted of beneficial antioxidants and your ability to use these antioxidants might be compromised if you have diabetes or are elderly.

Antioxidants Diabetes -

The best antioxidantsAntioxidants are natural substances that can neutralize free radicals. Free radicals are toxic chemicals that can do serious damage to cells and tissues which can eventually lead to cancer and other diseases. So antioxidants remove these dangerous free radicals from the body.It is widely believed that elevated blood glucose levels might lead to an increase in free radicals. It has also been shown that many people with diabetes have depleted levels of antioxidants in their bodies.This is why supplementing antioxidants can be beneficial for diabetes sufferers, not only to maintain antioxidant levels in the body but also to treat the long-term complications that can arise.Following are some of the many important antioxidants diabetes sufferers might benefit from:

Antioxidants Diabetes - Treating Specific Conditions

Atherosclerosis (Fatty Deposit Buildup)Green Tea - contains the antioxidant OPC which lowers cholesterol and helps prevent blood vessel constriction.Turmeric Extract - contains the antioxidant curcumin which that can lower LDL (bad) cholesterol and improve blood flow.Vitamin E & Vitamin C - work together to strengthen the heart and stop the progression of artherosclerosis.

Neuropathy (Nerve Damage) Alpha Lipoic Acid (ALA) is one of the most powerful antioxidants. It works in conjunction with Vitamin C and Vitamin E to decrease pain associated with neuropathy.

Retinopathy (Eye Damage)Bilberry extract contains powerful antioxidants that can protect veins and arteries of the eye and prevent conditions such as macular degeneration, or damage of the retina.Vitamin C and Vitamin E can protect the retina and maintain eye health.

Nephropathy (Kidney Damage)Alpha Lipoic Acid (ALA) - by helping prevent atherosclerosis and improve fatty acid metabolism, ALA promotes proper kidney function.In addition to the specific antioxidants to treat the various conditions that can arise from diabetes, it is important to maintain antioxidant levels for general health and well-being. Antioxidants are an essential part of any health regimen, for the young and old, healthy and sick alike.Antioxidants help prevent and treat a wide range of illnesses, so you have to be sure to include antioxidants as part of a healthy nutritional program.

Antioxidants Diabetes - How can you get all of these important antioxidants?

Should you take all of these antioxidant herbs, vitamins, amino acids and minerals separately or together in one comprehensive formula?We recommend that you take these antioxidant nutrients together if possible for many reasons:1. Taking each herb, vitamin and mineral separately could prove very costly as you would have to buy many different supplements.2. Mixing and matching antioxidant nutrients on your own could be dangerous to your health.3. Many herbs and nutrients working together can offer more therapeutic benefits, often better than a single nutrient on its own.4. All of these nutrients have to be balanced perfectly in order to be optimally effective.We have found a nutritional product that contains all of these antioxidants for diabetes in a synergized comprehensive formula. The product is called Optimum Diabetics, and it is a safe, natural nutritional supplement.It is made up of all natural therapeutic ingredients that can boost your body's antioxidants as well as treat the diabetes symptoms and conditions that can arise.We thoroughly researched the company that makes this natural formula and have found that they adhere to strict GMP compliance, which are the highest manufacturing standards in the world. This ensures the quality and effectiveness of the ingredients.Also, they only use standardized herbal extracts, the purest herbal extracts with the highest quality and therapeutic benefits.Lastly, all of the nutritional products are formulated by a highly trained, highly credentialed scientific team that can blend these ingredients perfectly to ensure that they do not interact adversely and offer the maximum benefits to your body.Many of our editors and visitors have experienced success with Optimum Diabetics. Although they do not have diabetes, they have used Optimum Diabetics for its full range of antioxidants and other vitamins, minerals and nutrients for general health and well-being.As with all health supplements, be sure to consult your physician or qualified medical professional before taking any macular degeneration treatment or other herbal supplements.As we are learning the importance of antioxidants diabetes sufferers should be aware of their many therapeutic benefits. By incorporating antioxidants diabetes patients can replenish their bodies supplies, and treat any conditions that may arise. Learn about antioxidants diabetes symptoms above and how natural antioxidant supplements can improve your health today.

Tocotrienols-A Potent Antioxidant

DEFINITION OF TOCOTRIENOL

Vitamin E is one of the most important phytonutrients in edible oils. It consists of eight naturally occuring isomers, a family of four tocopherols (alpha, beta, gamma and delta) and four tocotrienols (alpha, beta, gamma and delta) homologues.
All the eight isomers share some important traits:
The head, or chroman ring in technical term
The tail, which is called the phytyl tail for tocopherols
The active group on the head of the molecule, which is called the hydroxy group


The chroman ring has chemical groups which are called methyl groups attached to it. Alpha has all three available sites filled while beta and gamma have two methyl groups but in different positions. Whereas delta has only one.
The tocotrienol tail has three double bonds while the tocopherol tail has none. In the chemical parlance, bonds are the forces that keep atoms together. A single bond means the atoms share two electrons, a double bond means they share four electrons.
The structural name for alpha-tocopherol is 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-chromanol.
The structural name for alpha-tocotrienol is 2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltrideca-3',7',11'-trienyl)-6- chromanol.

SOURCES OF TOCOTRIENOLS
Edible oil originating from plants are rich source for tocotrienols. Crude palm oil extracted from the fruits of oil palm (Elaeis guineensis) particularly contains a high amount of tocotrienols (up to 800 mg/kg), mainly consisting of gamma-tocotrienol and alpha-tocotrienol. It also contain the most potent form of all commercially available tocotrienols - delta-tocotrienol.
Tocotrienols are also found in oil derived from rice bran, barley, wheat germ and rye.Common sources of tocotrienols are:
Palm
Rice
Wheat

Barley
Rye
Oat

Tocotrienols From Normal Diet Alone
Since tocotrienols only occur at very low levels in nature, with the highest concentration found in palm oil, so it is virtually impossible to attain the amount of tocotrienols that show beneficial effects from the normal diet alone. For example, one would need to consume a cup of palm olein (cooking oil) a day to get the level required for effectiveness as described in most studies.

Sources
Amount Taken To Achieve the Required Levels of Tocotrienols
RBD Palm Olein (Cooking Oil)
1 tea cup (~ 80 g)
Rice Bran Oil
2 tea cup (~ 160 g)
Barley
3.0 kg
Wheatgerm
1.5 kg
Oats
4.0 kg

HEALTH BENEFITS

Cholesterol Reduction

Inhibit cholesterol production in the liver, thereby lowering total blood cholesterol.
Alpha tocotrienol suppresses hepatic HMG-CoA reductase activity that results in the lowering of LDL cholesterol levels.
Tocotrienols which are naturally occurring in palm oil have been shown to suppress lower plasma cholesterol in human.
Combination of gamma-tocotrienol and alpha-tocopherol is found as a potential hypolipemic agent in hyperlipemic humans at atherogenic risk.
Tocotrienols inhibit cholesterogenesis by suppressing HMG-CoA reductase.

Reversing Arteriosclerosis

Reverses arterial blockage (carotid arteriosclerosis), hence reducing the risk factors for cardio-vascular diseases such as arteriosclerosis and stroke. Palm based tocotrienols is the first and natural compound to be shown by human study, to have the ability to reverse arteriosclerosis.
Medical human research showed that patients with confirmed carotid arteriosclerosis, who consumed 240mg of palm based tocotrienols/ day for 18-36 months had a decrease in the amount of cholesterol plaque in their carotid artery while those receiving placebo did not show such an effect.
Palm based tocotrienol protects the ApoE knockout mice against cholesterol build-up and hence prevent arteriosclerosis.


Protection Against Ischemia/Reperfusion Heart Injury

Medical study suggests that palm based tocotrienols were more efficient than alpha-tocopherol alone in the protection of the heart against oxidative stress induced by ischemic reperfusion.

Inhibit of Platelet Aggregation

Delta-tocotrienol was significantly more potent than the alpha and gamma-tocotrienols, in the inhibition of platelet aggregation.
Palm based tocotrienols may serve as an antithrombotic agent by decreasing platelet aggregation significantly.

Anti-cancer and Tumour Suppresive

Palm based tocotrienols had shown to inhibit human breast cancer cells irrespective of estrogen receptor status. Tocopherol has no effect at all on human breast cancer cells.
Delta - tocotrienol was found to be the most effective tocotrienols in inducing apoptosis (cell death) in estrogen-responsive and estrogen-nonresponsive human breast cancer cells.
Confer anti-cancer properties.
Inhibit tumor growth of certain cancers.
Alpha-tocotrienol and gamma-tocotrienol have shown to prolong the life span of cancer-infected mice.
Gamma-tocotrienol is 3 times more potent in inhibiting growth of human breast cancer cultured cells than Tamoxifen.

Potent Natural Super - Antioxidant

Alpha-tocotrienol has been shown to be 40 - 60 times more potent than alpha-tocopherol as an antioxidant in the prevention of lipid peroxidation.
Delta-tocotrienol is the most potent antioxidant (highest antioxidant potency) of all commercially available tocotrienols and has been shown to be the most effective tocotrienol in inhibiting human breast cancer and liver cancer cells.
Effective antioxidant in the prevention of protein oxidation and lipid peroxidation after strenous exercise for athletes, joggers and body builders.

Anti - Aging / Cosmetics and Personal Care

Preferentially accumulates at the strata corneum of the skin. First line of defense against free radicals generated in the skin by UV/ozone rays. Prevention of skin aging and damage by oxidative rays. Being a more potent antioxidant, the tocotrienols neutralizes free radicals at a faster rate and hence protect tocopherols.
Protection against UV-induced skin damage and skin aging.
Tocotrienols topically applied onto the skin was found to penetrate rapidly through the skin and the highest concentrations are found in the uppermost 5 microns.
Tocotrienol-treated skin contained Vitamin E at concentration 7-30 fold higher than control values.
Tocotrienol augments the efficacy of sunscreens containing compounds that reduce penetration of or absorb ultraviolet radiation.

Lower Blood Pressure
Palm gamma-tocotrienol has ability to prevent development of increased blood pressure in Spontaneously Hypertensive Rats (SHR) after 3 months supplementation.


Scientific References for Tocotrienols· Antioxidant Activity · Cholesterol Reduction · Cardiovascular Health & Protection · Cancer Prevention - Breast Cancer · Cancer Prevention - Liver Cancer · Anti-Cancer - General· Anti-Aging· Neuroprotective Property · Distribution & Bioavailability· Analytical & Isolation Methods· Sources, Chemistry & Metabolism· Toxicology & Other Health Benefits

Antioxidants

Antioxidants are a group of compounds that help to protect the body from the formation and elimination of free-radicals. Free-radicals are formed from exposure to sunlight and pollution and also as a byproduct of cell metabolism. Alcohol, cigarette smoke, stress and even diet also affect the level of free-radical development in the body. Excellent antioxidants include Vitamin A, Vitamin E, Vitamin C, zinc, selenium, ginkgo biloba, grape seed extract, and green tea extract.
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Vitamin C FormulaVitamin C Formula is a Life Plus formulation of one of nature's most important nutrients. Vitamin C is also referred to as ascorbic acid. It is essential, and our bodies do not manufacture it. Because Vitamin C is water soluble, it is easily "dumped" into the urine and eliminated when super large amounts are taken at one time. In order to preserve the highest levels in the body, Life Plus Vitamin C Formula is uniquely formulated to be a slow release tablet.
Vitamin E ComplexVita-E-Complex contains the entire family of compounds called tocopherols, which are composed of d-alpha, d-gamma, d-delta, and d-beta-tocophero. Vitamin E is one of the most important single antioxidants and is considered to be the master vitamin that provides nutritional support to the lipid portions of our cells, such as the cell membranes. Vitamin E helps nutritionally support red blood cells that carry oxygen to the tissues and organs throughout the body. It is an antioxidant that helps support the nervous, cardiovascular, and circulatory systems.

Antioxidant Vitamins

What are antioxidant vitamins?
Much research has recently focused on how antioxidant vitamins may reduce cardiovascular disease risk. Antioxidant vitamins — E, C and beta carotene (a form of vitamin A) — have potential health-promoting properties. Though the data are incomplete, up to 30 percent of Americans are taking some form of antioxidant supplement.
AHA Scientific Position
The American Heart Association doesn't recommend using antioxidant vitamin supplements until more complete data are available. We continue to recommend that people eat a variety of nutrient-rich foods daily from all the basic food groups.
Eating a variety of foods low in saturated fat, trans fat and cholesterol will provide a natural source of these vitamins, minerals and fiber.
Background
Oxidation of low-density lipoprotein (LDL or "bad") cholesterol is important in the development of fatty buildups in the arteries. This process, called atherosclerosis, can lead to heart attacks and strokes. Until recently, it was thought that LDL cholesterol lipoprotein oxidation and its biological effects could be prevented by using antioxidant supplements. However, more recent clinical trials have failed to demonstrate a beneficial effect of antioxidant supplements. Some studies even suggest that antioxidant supplement use could have harmful effects.
Using dietary supplements of antioxidants to prevent cardiovascular disease should not be recommended until their effect is proved in clinical trials that directly test their impact on CVD end points. Beneficial effects must be demonstrated in well designed (randomized, placebo-controlled) clinical trials before recommending widespread use to prevent cardiovascular disease.
At this time, the scientific evidence supports a diet high in food sources of antioxidants and other heart-protecting nutrients, such as fruits, vegetables, whole grains and nuts instead of antioxidant supplements to reduce risk of CVD.
Related AHA publications:
Easy Food Tips for Heart-Healthy Eating (also in Spanish}

Antioxidants and Cardiovascular Diseases
How does oxidation work in cardiovascular disease?
Atherosclerosis is a condition where the walls of the arteries are damaged and narrowed by deposits of plaque (cholesterol and other fatty substances, calcium, fibrin, and cellular wastes) , eventually blocking off the flow of blood. Plaque deposits can result in bleeding (hemorrhage) or formation of a blood clot (thrombus). When hemorrhage or thrombus blocks the flow of blood through the entire artery, a heart attack or a stroke occurs. High blood levels of cholesterol - particularly the cholesterol carried by low-density lipoprotein ("LDL", a protein found in blood) - are associated with an increased risk of atherosclerosis.
Normal LDL in plasma is not oxidized. Oxidation of LDL is believed to contribute to the development of atherosclerosis (Frei 1995). Macrophage cells preferentially take up oxidized LDL, become loaded with lipids, and convert into "foam cells" (Aviram 1996). Foam cells accumulate in fatty streaks, early signs of atherosclerosis. Humans produce auto-antibodies against oxidized LDL, and the levels of such auto-antibodies are higher in patients with atherosclerosis (Frei 1995).
The identification of LDL oxidation as a key event in atherosclerosis suggests that it may be possible to reduce the risk of atherosclerosis by antioxidant supplementation (Ylä-Herttuala 1991). Vitamin E is the major naturally-occurring antioxidant in human lipoproteins (Bowry et al. 1992). Most circulating carotenoids are associated with lipoproteins in plasma (Clevidence and Bieri 1993). The largest fraction of total carotenoids is found in LDL, as evidenced by the typically yellow color of this lipoprotein fraction (Clevidence and Bieri 1993). The largest fraction of hydrocarbon carotenoids (e.g., beta-carotene and lycopene), as well as most vitamin E and other tocopherols, is transported by LDL (Clevidence and Bieri 1993; Goulinet and Chapman 1997; Oshima et al. 1997), suggesting that these compounds in particular may play an important role in preventing oxidative modification of this lipoprotein fraction. The more polar xanthophylls (oxygenated carotenoids such as lutein, zeaxanthin, canthaxanthin, beta-cryptoxanthin, and capsanthin) are distributed more evenly between HDL and LDL (Clevidence and Bieri 1993; Goulinet and Chapman 1997; Oshima et al. 1997). For example, a Japanese study found that ~70% of hydrocarbon carotenoids (lycopene, alpha-carotene, and beta-carotene) were found in LDL, whereas the polar xanthophylls (capsanthin, lutein, and zeaxanthin) were distributed about equally between HDL and LDL (Oshima et al. 1997). The authors speculated that these polar xanthophylls might be localized at the polar surface of lipoproteins high in phospholipids (as is HDL) (Oshima et al. 1997). Upon subfractionation of LDL particles, it was found that lycopene, beta-carotene and beta-cryptoxanthin are found mostly in larger, less-dense LDL particles whereas lutein and zeaxanthin are mostly in the smaller, more dense LDL particles (Lowe et al. 1999). Interestingly, the more dense LDL subfractions, which had lower overall carotenoid and vitamin E concentrations, were also more easily oxidized (Lowe et al. 1999).
Epidemiological and clinical data indicate that dietary antioxidants may protect against cardiovascular disease (Frei 1995). Several epidemiological studies have shown an inverse association between serum levels of beta-carotene and other carotenoids and coronary heart disease (reviewed by Kritchevsky 1999). One study found that serum levels of alpha- and beta-carotene and lycopene were 1.9-, 1.7-, and 2.7-fold higher, respectively, in Israeli men than in Czech men; mortality rates, blood pressure, and coronary heart disease rates in the subjects were highest in Czech and lowest in Israeli men (Bobak et al. 1999). However, clinical studies with carotenoid supplementation have been equivocal, and in fact some major clinical trials with beta-carotene supplementation have shown either no or negative effects on chronic diseases such as cardiovascular disease and cancer (reviewed by Mayne 1996 and Kritchevsky 1999). Carotenoids are regarded as good biomarkers for fruit and vegetable dietary intake, but other plant-derived compounds may well play a significant role in health. Still, studies have shown that supplementation with vitamin E (Reaven and Witztum 1993) and other small compounds (including vitamin C, beta-carotene and other carotenoids, and drugs such as probucol) can decrease the susceptibility of LDL to oxidation (Jialal and Fuller 1995); these compounds have in common their antioxidant activity.
Carotid intima-media thickness ("carotid IMT", essentially the thickness of one of the main arteries in the neck) is a measure of asymptomatic early atherosclerosis; in one atherosclerosis risk study, carotid IMT was found to be inversely correlated to the levels of lutein and zeaxanthin, which are xanthophylls (oxygenated carotenoids) regarded as biomarkers of fruit and vegetable intake (Iribarren et al. 1997). Another study found that lutein and cryptoxanthin were twice as high in a population (Toulouse) that had a much lower incidence of coronary heart disease than another group (Belfast), suggesting that such xanthophylls (hydroxycarotenoids) may be useful as antioxidant supplements (Howard et al. 1996).
Few studies have used carotenoids (other than beta-carotene) as anti-atherogenic dietary supplements. One in vitro study showed that cell-mediated oxidation of LDL was inhibited by beta-carotene, but enhanced by lutein or lycopene (Dugas et al. 1998). The same researchers later reported that dietary (i. e., in vivo) supplementation of 15 mg per day of beta-carotene over four weeks resulted in a 3- to 6-fold increase in the beta-carotene content of LDL; the in vitro-tested increase in oxidation resistance of LDL isolated from the subjects was greater than the increase in oxidation resistance seen in LDL enriched in vitro 11- to 12-fold with beta-carotene (Dugas 1999). Again, no effect on LDL resistance to oxidation was seen for lycopene supplied as a dietary supplement (Dugas 1999). These results are in contradiction to studies that reported a significant decrease in serum lipid peroxidation and LDL oxidation after three weeks of lycopene dietary supplementation (Agarwal and Rao 1998), and that in vitro supplementation of beta-carotene, canthaxanthin, or zeaxanthin inhibited cell-mediated LDL oxidation (Carpenter et al.1997) A recent large study of the relationship between dietary antioxidant intake and risk for ischemic stroke (as a consequence of atherosclerosis) followed 43,738 men aged 40 -75 years over 8 years (Ascherio et al. 1999). This study found a significant inverse relation between lutein intake and risk for ischemic stroke but this was not independent of other dietary factors. The authors concluded that vitamin E and vitamin C supplements and specific carotenoids did not substantially reduce risk for stroke in the population studied.
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References:
Agarwal, S. and Rao, A. V. (1998) Tomato lycopene and low density lipoprotein oxidation: a human dietary intervention study. Lipids, 33: 981-984.
Ascherio, A., Rimm, E. B., Hernán, M. A., Giovannucci, E., Kawachi, I., Stampfer, M. J., and Willett, W. C. (1999) Relation of consumption of vitamin E, vitamin C, and carotenoids to risk for stroke among men in the United States. Ann. Intern. Med., 130:963-970.
Aviram, M. (1996) Interaction of oxidized low density lipoprotein with macrophages in atherosclerosis, and the antiatherogenicity of antioxidants. Eur. J. Clin. Chem. Clin. Biochem., 34(8):599-608.
Bobak, M., Hense, H. W., Kark, J., Kuch, B., Vojtisek, P., Sinnreich, R., Gostomzyk, J., Bui, M., von Eckardstein, A., Junker, R., Fobker, M., Schulte, H., Assmann, G., Marmot, M. (1999) An ecological study of determinants of coronary heart disease rates: a comparison of Czech, Bavarian and Israeli men. Int. J. Epidemiol., 28: 437-444.
Bowry, V. W., Ingold, K. U., and Stocker, R. (1992) Vitamin E in human low-density lipoprotein: when and how this antioxidant becomes a pro-oxidant. Biochem. J., 288(Part 2):341-344.
Carpenter, K. L. H., Van Der Veen, C., Hird, R., Dennis, I. F., Ding, T., Mitchinson, M. J. (1997) The carotenoids beta-carotene, canthaxanthin and zeaxanthin inhibit macrophage-mediated LDL oxidation. FEBS Letters, 401: 262-266.
Clevidence, B. A. and Bieri, J. G. (1993) Association of carotenoids with human plasma lipoproteins. Methods Enzymol., 214:33-46.
Dugas, T. R., Morel, D. W., and Harrison, E. H. (1998) Impact of LDL carotenoid and alpha-tocopherol content on LDL oxidation by endothelial cells in culture. J. Lipid Res., 39(5):999-1007.
Dugas, T. R,, Morel, D. W., and Harrison, E. H. (1999) Dietary supplementation with beta-carotene, but not with lycopene, inhibits endothelial cell-mediated oxidation of low-density lipoprotein. Free Radic. Biol. Med., 26: 1238-1244.
Frei, B. (1995) Cardiovascular disease and nutrient antioxidants: role of low-density lipoprotein oxidation. Crit. Rev. Food Sci. Nutr., 35(1-2):83-98.
Goulinet, S. and Chapman, M. J. (1997) Plasma LDL and HDL subspecies are heterogeneous in particle content of tocopherols and oxygenated and hydrocarbon carotenoids: relevance to oxidative resistance and atherogenesis. Arterioscler. Thromb. Vasc. Biol., 17:786-796.
Howard, A. N., Williams, N. R., Palmer, C. R., Cambou, J. P. Evans, A. E. Foote, J. W., Marques-Vidal, P. McCrum, E. E., Ruidavets, J. B., Nigdikar, S. V., Rajput-Williams, J., and Thurnham, D. I. (1996) Do hydroxy-carotenoids prevent coronary heart disease? A comparison between Belfast and Toulouse. Int. J. Vitam. Nutr. Res., 66(2):113-118.
Irribaren, C., Folsom, A. R., Jacobs, D. R., Jr., Gross, M. D., Belcher, J. D., and Eckfeldt, J. H. (1997) Association of serum vitamin levels, LDL susceptibility to oxidation, and autoantibodies agains MDA-LDL with carotid atherosclerosis: a case control study. Arterioscler. Thromb. Vasc. Biol., 17(6):1171-1177.
Jialal, I. and Fuller, C. J. (1995) Effect of vitamin E, vitamin C, and beta-carotene on LDL oxidation and atherosclerosis. Can. J. Cardiol., 11(Suppl. G):97G-103G.
Kritchevsky, S. B. (1999) ß-Carotene, carotenoids and the prevention of coronary heart disease. J. Nutr., 129: 5-8.
Lowe, G. M., Bilton, R. F., Davies, I. G., Ford, T. C., Billington, D., and Young, A. J. (1999) Carotenoid composition and antioxidant potential in subfractions of human low-density lipoprotein. Ann. Clin. Biochem., 36:323-332.
Mayne, S. T. (1996) Beta-carotene, carotenoids, and disease prevention in humans. FASEB J., 10:690-701.
Oshima, S., Sakamoto, H., Ishiguro, Y., and Terao, J. (1997) Accumulation and clearance of capsanthin in blood plasma after the ingestion of paprika juice in men. J. Nutr., 127:1475-1479.
Reaven, P. D. and Witztum, J. L. (1993) Comparison of supplementation of RRR-alpha-tocopherol and racemic alpha-tocopherol in humans: effects on lipid levels and lipoprotein susceptibitily to oxidation. Arterioscler. Thromb., 13(4):601-608.
Ylä-Herttuala, S. (1991) Macrophages and oxidized low density lipoproteins in the pathogenesis of atherosclerosis. Ann. Med., 23(5):561-567.