Friday, August 23, 2013

Gift of the Grape : Part 1 Free-Radical-Taming Resveratrol Can Help Your Health, Heart and Muscles by Jerry Brainum

In November 1991 French scientist Serge Renaud appeared on “60 Minutes.” The topic was the mystery of how French people followed diets high in saturated fat yet had a 40 percent lower incidence of cardiovascular disease than Americans. Renaud attributed the difference to the French custom of drinking red wine each day with meals.

The phenomenon came to be known as the French paradox. While alcohol itself was known to elevate a protective cholesterol carrier in the blood called high-density lipoprotein, something else in red wine clearly added to the effect, since no other alcohol-containing beverage could match the protective effects of red wine.

Within a short time the protective factor in wine was identified as an esoteric plant substance called resveratrol. It turned out that, although red wine was by far the richest source in the human diet, resveratrol is found in 72 plants as well.

Resveratrol was first identified in a plant called the white hellebore back in 1940. In 1963 a plant called Polygonum cuspidatum, or Japanese knotwood, which was commonly used in traditional Chinese and Japanese medicine, was found to be a rich source of resveratrol. Plants produce resveratrol when under stress, since it offers a number of protective effects, making resveratrol a phytoalexin.

Subsequent research showed that red wine also contains other natural substances, such as various polyphenols, that work in conjunction with resveratrol to provide beneficial effects. Resveratrol itself has been the subject of hundreds of studies, many still in progress. The studies have indicated that it affects a number of systems and processes at once,1 offering a plethora of health benefits, including cardiovascular protection, cancer prevention and, most intriguing of all, antiaging effects.

The sheer breadth of research purporting to show the health benefits associated with resveratrol has led to a boom in sales of resveratrol supplements derived from extracts of Japanese knotwood, particularly over the Internet. Without doubt, resveratrol has emerged as the most popular—and pricey—antiaging supplement on the market. Countless human guinea pigs are dosing themselves with amounts of resveratrol equivalent to drinking thousands of bottles of red wine daily. It’s costing them several hundred dollars per month. Yet all—I repeat, all—the research that “proves” the effectiveness of resveratrol involves either isolated-cell or animal studies. The only human studies involve dosage safety and pharmacokinetic issues, meaning how the body metabolizes resveratrol.

In fact, while resveratrol is easily absorbed orally, it rapidly—within 30 minutes after intake—undergoes two processes in which it is conjugated, or complexed, with sulfate and glucuronide by enzymes in the liver, converting it into at least five metabolites. Resveratrol itself lasts for an average of only eight to 14 minutes in the body, but the metabolites stay around for an average of 9.2 hours. The big controversy now among scientists is whether the metabolites offer any actual biological activity while they’re there. One theory is that they can be converted back into the active form of resveratrol, called trans-resveratrol, or TREV, in tissues, but that has not yet occurred in any human study.

The impressive animal and isolated-cell studies indicate that resveratrol surely must be doing something in the body. Internet resveratrol groupies think that taking huge doses will overcome the formidable barriers to its activity in the body. Beneficial effects in animals usually involve large doses, and the idea is to duplicate those effects by using megadoses.

That’s nothing short of biochemical gambling. No one yet knows the long-term safety of humans taking huge doses of resveratrol. Short-term studies have shown that people taking as much as 5,000 milligrams a day experience no side effects. Rats have gotten 300 milligrams per kilogram of bodyweight with no apparent detriment, but that’s hardly proof of human safety. There are some initial indications, as we’ll see, that taking huge doses of resveratrol for an extended time could cause some serious health problems.

Does Resveratrol Prevent Cancer?
Animal and test-tube studies show that resveratrol blocks all stages of cancer, from initiation to progression. It acts as a potent antioxidant and affects various enzymes in the body. Cell studies show that it induces the death of tumors found in leukemia, colon, breast, prostate and esophageal cancers. The initial study that found its cancer-preventive effect was published in 1997; applying a topical version of resveratrol inhibited 98 percent of skin tumors in mice exposed to carcinogens.2

Grapes, from which resveratrol comes, were among 600 plants tested for cancer-prevention properties in the study. The research consensus today is that only large doses of resveratrol are capable of initiating a cell signal that causes cancer cells to kill themselves—a process called apoptosis. Resveratrol inhibits enzymes, such as cyclooxygenase, that are involved in inflammatory processes, a cornerstone of cancer. Resveratrol also inhibits angiogenesis, a process whereby tumors develop new blood vessels. It’s a process essential to the maintenance and spread of cancer cells in the body, and blocking it leads to the rapid death of tumors.

Resveratrol inhibits cancer by activating phase-two detoxifying enzymes in the liver. The phase-one system in the liver can activate carcinogens, such as tobacco smoke, but the phase-two system renders the incipient carcinogen harmless. The same phase-two enzymes in the liver convert active resveratrol into its metabolites.

Resveratrol and Cardiovascular Disease
Resveratrol was identified as the primary protective factor found in red wine when nonalcoholic extracts proved equally effective in preventing cardiovascular disease. Later research demonstrated that the more likely protective factors in red wine were polyphenol compounds called procyanidins. Still, resveratrol may offer cardiovascular protection through several mechanisms. By inhibiting the activity of COX enzymes, resveratrol prevents the platelet aggregation that leads to clotting; the immediate cause of most heart attacks and strokes is a clot formed in narrowed arteries. Something that prevents excessive internal clotting may offer protection against cardiovascular disease. Low-dose aspirin works the same way.

Resveratrol aids in vasodilation, the widening of blood vessels, by inhibiting the COX enzymes that produce the lipid thromboxane, which is synthesized from the fatty acid arachidonic acid. Resveratrol also increases the dilation activity of nitric oxide in blood vessels. Oxidation of low-density-lipoprotein cholesterol, or LDL, is known to cause cardiovascular disease, and resveratrol as an antioxidant prevents that by chelating the trace mineral copper, which when free in the blood is a potent oxidizing agent. That, by the way, is a problem with large doses of resveratrol. It’s so effective in chelating copper that it can cause copper deficiency, which in turn leads to problems with collagen production, as copper acts as a coenzyme in collagen synthesis in the body. A lack of copper can cause nerve transmission problems, as well as tendinitis, a common side effect experienced by those taking large doses of resveratrol.

The good news is that two recent studies show that you don’t need huge amounts of resveratrol to get cardiovascular protection. One study found that drinking a moderate amount—a five-ounce glass daily—of red wine was enough to stimulate nitric oxide production in human platelets.3 The other study found that giving middle-aged mice lower doses of resveratrol—4.9 milligrams per kilogram of bodyweight—increased beneficial gene activity in the heart the way a calorie-restricted diet does.4 Researchers said that high doses were not only not required but could prove detrimental.

One way that resveratrol is thought to work is by activating a protective enzyme called sirtuin-1, a.k.a. SIRT1. Overactivating the enzyme induces heart failure in animals, according to a 2007 study published in

Circulation Research.

Other recent studies show that resveratrol helps prevent excessive fat accumulation in the liver that occurs in obese people and those who drink too much. In a study involving rats with nonalcoholic fatty liver, giving them resveratrol decreased inflammation in the liver by inhibiting tissue necrosis factor-A, a potent inflammation inducer, and by upregulating the body’s natural antioxidant activity.5 A study found that resveratrol also blocked liver fat accumulation in mice that were given alcohol. Excess fat in the liver predisposes to the development of cirrhosis and liver cancer. The mechanism in the study involved increased production of SIRT1, which then stimulated the activity of AMPK, a compound that aids in fat breakdown.6

The body chemistry of resveratrol tells only half of its story. In Part 2 we’ll look more deeply into its impact on the body’s aging processes and why it’s relevant to bodybuilders.

1 Pirola, L., et al. (2008). Resveratrol: One molecule, many targets.IUNMB Life. 60:323-32.

2 Jang, M., et al. (1997). Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science. 275:218-220.

3 Gresele, P., et al. (2008). Resveratrol, at concentrations attainable with moderate wine consumption, stimulates human platelet nitric oxide production. J Nutr. 138:1602-1608.

4 Barger, J.L., et al. (2008). A low dose of dietary resveratrol partially minics caloric restriction and retards aging parameters in mice.PLOS One. 3:e2264.
5 Bujanda, L., et al. (2008). Resveratrol inhibits nonalcoholic fatty liver in rats. BMC Gastroenterol. 8:40.
6 Ajmo, T., et al. (2008). Resveratrol alleviates alcoholic fatty liver in mice. Am J Physiol Gastroint Liver Physiol. 295:4. In press.

©,2013 Jerry Brainum. Any reprinting in any type of media, including electronic and foreign is expressly prohibited.


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Sunday, August 4, 2013

DNP: Still Dangerous After All These Years By Jerry Brainum

En route to a call that came in from a local gym, paramedic Mack Jackson ponders what the emergency could be. As an amateur bodybuilder himself, Mack knows what can happen in a gym. A weight falling on someone’s foot. A newbie exerciser overexerting him- or herself on the treadmill. Perhaps it’s someone who unknowingly became dehydrated on this warm summer day by not drinking enough water during the workout.
    Arriving at the gym, Mack and the other paramedics are directed to a muscular 22-year-old bodybuilder, who’s prostrate in a corner of the gym floor. As the medical crew begins to examine him, someone says, “He was training intensely, but then he stood up and hit the ground like someone hit him on his head.”
The patient is clearly lethargic, weak and has vomited a few times. When questioned, he seems confused but does manage to reply to questions about prior medical history, use of medications, allergies and other things that might explain his present condition. Nothing seems obvious; however, some clues emerge from his appearance. His skin is flushed and hot, and he is sweating profusely. While sweating is hardly unusual in a warm gym, it’s the color of his sweat that catches the medics’ collective attention: It’s a pale yellow that’s also apparent on his white T-shirt. Initial examination reveals a rapid heart rate and elevated blood glucose level.
    Another member of the gym gathers the bodybuilder’s belongings and checks his locker. As the paramedics move the bodybuilder into the waiting ambulance, the gym member hands Mack the patient’s clothes, along with a bottle of capsules filled with a yellow powder and a page printed off the Internet titled “DNP for Fat Loss.”
     On the way to the hospital the bodybuilder’s temperature rises to 104 degrees. Noting that, the paramedics increase body-cooling measures, such as removing his clothes and putting ice packs on his groin and under his arms. The air-conditioning in the ambulance is also set to maximum. The EMT crew radios the hospital that they may have a toxicological emergency coming in. They are told by a hospital physician to keep the patient still and calm and continue giving him intravenous fluids.
     Even with the supportive measures the bodybuilder’s temperature continues to rise. At the hospital he develops pulmonary edema—fluid in the lungs—suffers damage to his liver and heart, along with kidney failure,then slips into cardiac arrest and dies.
     The healthy young bodybuilder had succumbed to the effects of 2,4 dinitrophenol, or DNP, a popular and extremely dangerous substance touted for producing dramatic and rapid fat loss. Rumors abound that DNP is the secret weapon that many pro bodybuilders use to get ripped in a relatively short time. In fact, a few years ago an elite pro bodybuilder contacted me about using it in preparation for the Mr. Olympia contest.
I advised against it, informing him of the dangers, but he’d found out that another top pro was a regular user of DNP and insisted on trying it himself. He referred me to a man who later became notorious for distributing designer steroids to world-class athletes. That man was going to supply and encapsulate the DNP for him. Within a few days, however, the bodybuilder called me back and told me that he had abandoned the notion of using DNP in his preparation for the Olympia because it made him feel very ill and weak. He was one of the lucky ones; he survived.
     DNP first attracted attention in 1919 after French munitions workers began experiencing unexplained massive fat losses. They were exposed to DNP while making explosives consisting of 40 percent DNP and 60 percent TNT. DNP is chemically similar to TNT and is a precursor of the latter compound. The workers also showed other symptoms, such as malaise, headaches, dizziness and night sweats.
     During the 1930s doctors who were aware of the effects of DNP on the French munitions workers wondered whether it could prove useful as a weight-loss drug under controlled conditions. Sure enough, initial studies showed that a daily dose of 300 to 400 milligrams of DNP for only two weeks resulted in metabolism increases that ranged from 36 to 95 percent over baseline levels. That contrasted with thyroid hormones, which increased metabolism an average of only 10 percent above normal.
     The initial studies reporting on the fat-loss potential of DNP were all short-term, with none lasting more than three months. Those early researchers noted that they couldn’t predict toxic effects with extended use. Sure enough, other studies began appearing that showed that DNP was hardly innocuous. A 1933 issue of the Journal of the American Medical Association told of a severe skin reaction in a woman who took DNP for two weeks. A 50-year-old Viennese doctor in San Francisco took an overdose of it for weight-loss purposes and cooked himself from the inside. After using a prior, lower dose of DNP without incident, he had opted for a dose that was beyond the suggested safe range. When told by another physician that he should avoid being so reckless again, the Viennese doctor said that he would take a higher dose, and if it killed him, he would just be “another martyr to science.” While he didn’t exactly become a medical martyr, he did die an agonizing death.
    In the early 1930s DNP was a popular weight-loss drug, with an estimated 100,000 people using it over a period of 15 months. More than 1,200,000 capsules were dispensed from one clinic in San Francisco, and more than 20 companies sold it under such trade names as Nox-Ben-ol, Nitroment, Nitraphen, Redusols, Formula 17, Slim, Dinitrenal ,and Dinitrole. Those proprietary formulas were sold in drugstores without a prescription, warnings or usage directions. Only New Jersey, Louisiana and California required prescriptions to obtain DNP.
    While initial problems related to this substance were at first thought to be related to careless use, more serious toxic reactions began appearing, including skin rashes, a severe depression of white blood cell count, jaundice and disturbances in the senses of smell and taste. Several people, such as the previously mentioned doctor, died after using DNP. That led to a 1934 warning issued by the Food and Drug Administration. Although the FDA could do little more than warn about possible toxic effects, its experts were also analyzing various products, finding that DNP was often an unlisted ingredient.
    In 1935 an epidemic of cataracts occurred, mostly in young women who had used DNP for fat loss. Some cases occurred months or years after the last dose. One ophthalmologist estimated that more than 164 people were affected in that manner. Newspapers featured such headlines as, “Blinded by Weight-Loss Drug,” and “Anti-fat Drug May Cause Blindness.” In 1938, with the passage of the Federal Food, Drug and Cosmetic Act, the FDA was granted enforcing powers and promptly removed DNP from the market. Prior to passage of that law, the FDA had prepared a special exhibit for Senate committee hearings. Called the chamber of horrors, the exhibit included several deadly substances sold on the market, including DNP.
While DNP lost its legal status as a weight-loss drug by the FDA action, it remained in use in industrial settings, as a wood preservative, in photo developing, and as a weed killer. In the 1970s Russian workers manufacturing a pesticide that included it as an ingredient became ill. A 1982 medical journal reported that DNP as an ingredient in herbicides led to “undiagnosed fevers.”
     Around the same time, DNP reemerged in the bodybuilding world under the name Hexalon. The distribution was limited to professional bodybuilders, who were warned not to exceed the suggested dosage or death could ensue. That dire warning didn’t dissuade any of the athletes who used it, since they were also told that when used properly, Hexalon would burn off fat at an unprecedented rate, making them appear cut to the bone. Those who used Hexalon often reported feeling as if they had the flu, with weakness and fatigue.
In Texas a Russian-born doctor named Nicholas Bachynsky was dispensing DNP, which he called Mitcal, at his chain of medical clinics. He claimed to have first learned about DNP in 1963 while translating Russian medical journals for the United States government. The Russians had given their soldiers DNP to help keep them warm in winter. The main side effect noted was weight loss.
     Bachynsky’s ads touted an average weight-loss of 15 pounds a week. The only side effect, the ads noted, was increased body heat. The ads also said no deaths had occurred with the use of Mitcal, though one weightlifter had committed suicide by overdosing on it in 1984. According to Bachynsky, DNP “decreased useful energy production, thus making an overefficient metabolism very inefficient.” The treatments cost an average of $1,300 each—though DNP is a relatively inexpensive chemical.
Although Bachynsky asserted that no one had died from his treatment, he hedged his bets by having prospective clients sign a waver that warned of blood clots,, cataract formation, hemorrhage, allergic reactions and, yes, even death. Clearly the small print was ignored by those who envisioned a 15-pound-a-week weight loss, since more than 15,000 people signed up for the treatment.
   In 1982 the FDA began receiving complaints from many of Bachynsky’s customers about such adverse reactions as fever, shortness of breath, dizziness and extreme sweating. FDA investigators who arrived at Bachynsky’s clinics in Houston noted that the pharmacy next door to the clinic—also owned by Bachynsky—stored bulk containers of dinitrophenol from Eastman Kodak Company that were labeled “For chemical purposes only, not for drug use.”
    In 1985 the Texas attorney general sued Bachynsky and his clinics, charging that the doctor had failed to advise his patients that Mitcal was not recognized as safe for weight loss, was highly toxic and not approved by the FDA. On March 21, 1986, Bachynsky was found guilty of drug violations and ordered to pay $86,000 in fines and fees. He was also issued an injunction against further use of DNP. In July he was charged with violating the injunction after it was learned that he was still dispensing DNP at his Dallas clinic. In 1990 Bachynsky’s medical license was revoked, and he was sentenced to 10 years in prison for insurance fraud.
    While you would think that after a few years in prison Bachynsky would steer clear of DNP, apparently that wasn’t the case. In 2004 he and three other men were charged by the Securities and Exchange Commission with eliciting fraudulent securities related to a company they were involved in called Helvetia Pharmacueticals. The Florida-based company purported to treat cancer using a “patented therapy involving heat to destroy cancer cells.” The treatment was called “intracellular hyperthermia therapy.” The key ingredient was none other than DNP.
    While in prison in the 1990s, Bachynsky became acquainted with Dan Duchaine, notorious as the "steroid guru." Dan was also serving a prison term and listened intently to Bachynsky’s accounts of his experience with DNP. The fat-loss attributes particularly intrigued Duchaine, and when he was released from prison, he publicly announced that DNP was the king of fat-loss drugs. Another era of DNP had begun, one that hasn’t abated since.
    DNP interferes with a process called oxidative phosphorylation that results in the production of the immediate energy substance of the body, ATP. DNP uncouples oxidative phosphorylation in the mitochondria, or energy-producing portion, of cells, and that leads to a frantic use of other available energy sources by the body, particularly bodyfat. The process doesn’t produce any useful energy, however, creating heat, or futile energy, cycles. The heat can quickly exceed the body’s capacity, thus explaining the inherent danger of DNP use. In addition, the body shifts to anaerobic glycolysis as the primary cellular energy source, producing enough acid by-products to lead to lactic acidosis.
    DNP can be absorbed through the skin, explaining how the original French munitions workers got it into their bodies, as well as the farmers who used it to kill weeds. The suggested use for fat loss often involves taking it one week on and one week off. The daily dose range is two to 10 milligrams per kilogram (2.2 pounds) of bodyweight. The lethal dose is estimated to be between one and three grams when taken orally, but the three-gram-dose effect is cumulative over a five-day period; that is, three grams taken over five days could easily prove fatal. For example, if a 100-kilogram person takes 600 milligrams, he can get to three grams by the fifth day. Many have followed the suggested “safe dosage guidelines” and found otherwise.
    In a case widely reported on the Internet, a 22-year-old man died after using the suggested dose of DNP (600 milligrams a day). He had taken the dose for four days prior to his death. The signs and symptoms of DNP poisoning look similar to those of heat stroke and heat exhaustion. Various supportive measures are used in a hospital setting, such as body cooling, providing drugs to prevent seizures and calm the patient, and providing a drug called dantrolene, which prevents the release of calcium in muscle. That prevents muscle contraction, which lowers body heat. Keeping the body cool is a key to preventing death by DNP. Although headache may be present in a person who took DNP, aspirin is contraindicated in this case, since aspirin is also a weak uncoupler of oxidative phosphorylation and would only worsen the patient’s condition or kill him or her.
    Shortly before his death from congenital kidney disease, Dan Duchaine touted a “natural” form of DNP called usnic acid that was derived from a lichen. A few companies sold usnic acid as part of a commercial fat-loss supplement; however, the stuff was hardly safe or harmless. Several cases of liver failure deaths resulted from people having used a supplement containing the "safe" usnic acid. Small wonder, since one study showed that usnic acid was 50 times more potent than DNP in interfering with ATP production. The FDA subsequently removed usnic acid from the market. At least one company defied the FDA removal order, and kept usnic acid in their fat-loss formula. A female fitness competitor used the supplement and developed liver failure, which led to her suing the company that sold the product.
   Scientists regularly use DNP as an effective cell killer, and some recent studies show that it can block the formation of beta-amyloid, a protein that causes Alzheimer’s disease. One recent study even showed new neuron growth from DNP. But those are all highly controlled studies done in a lab setting. For all other uses, such as inducing fat loss, DNP is truly a roll of the dice: If you win, you lose a lot of fat fast. If you lose, you lose your life. Even Las Vegas offers better odds than that.


1 Leftwich, R.B., et al. (1982). Dinitrophenol poisoning: a diagnosis to consider in undiagnosed fever. Southern Med J. 75;182-184.
2 McFee, R.B., et al. (2004). Dying to be thin: a dinitrophenol-related fatality. Vet Human Toxicol. 46:251-54.

 ©,2013 Jerry Brainum. Any reprinting in any type of media, including electronic and foreign is expressly prohibited.



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