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Novaldex: Ideal Fat-burning Drug

Human trials of beta-3 selective drugs have thus far proved disappointing; the drugs seem to work much better in animals than humans.

Tamoxifen citrate, better known by its trade name Nolvadex, is usually prescribed to treat or prevent breast cancer in women. It functions as an estrogen-receptor blocker, since it's structurally similar to estrogen and can displace the hormone at estrogen-cell-receptor sites. If estrogen cannot interact with cellular receptors, it becomes inactive. Nolvadex has proven safe and effective in treating breast cancer, particularly in older women who have an abundance of estrogen cell receptors in their breasts.

Nolvadex's ability to block the effects of estrogen is also popular with bodybuilders, especially those who use anabolic steroids. Many steroids convert into estrogen through the action of the enzyme aromatase, and in men that can create an imbalance in the ratio of androgens to estrogen, leading to such side effects as excess water retention, since estrogen promotes the release of aldosterone, a water-retaining hormone, from the adrenal glands. It can also cause gynecomastia, or male breasts, and an increase in subcutaneous fat, which is fat stored just under the skin that obscures muscular definition.

To combat those effects, many bodybuilders take Nolvadex in doses of 10 to 50 milligrams daily. Lately, however, it's lately been superseded by another breast cancer drug, Arimidex. Unlike Nolvadex, which just blocks cellular estrogen receptors, Arimidex inhibits the ubiquitous aromatase, thus preventing estrogen synthesis.

Nolvadex is far cheaper and easier to obtain than Arimidex, which costs about $10 per pill. Bodybuilders often use Nolvadex during a steroid cycle, hoping that it will prevent the side effects associated with higher estrogen levels. They also frequently use it at the end of a cycle to help regain normal testosterone levels and prevent the testosterone-estrogen imbalance.

Some bodybuilders inject themselves with human chorionic gonadotropin (HCG) at the end of a steroid cycle. HCG, commonly sold as Pregnyl, has a structure similar to that of luteinizing hormone (LH), a pituitary gland hormone that controls testosterone synthesis in the Leydig cells of the testes. The problem is, HCG stimulates estrogen synthesis as well as testosterone, so bodybuilders often combine it with Nolvadex to prevent estrogen side effects.

Misconceptions surround Nolvadex, which is generally thought of as a benign drug that doesn't have to be cycled. For example, while it usually acts as an estrogen antagonist by blocking estrogen cell receptors, it may also act as an estrogen agonist, meaning that it exerts estrogenlike effects. That makes sense, since Nolvadex is similar in structure to estrogen. Isoflavones found in soy work in a similar manner for the same reason'they look like estrogen. So, when taken in large doses or for an extended time, Nolvadex can yield some of the same undesirable effects as estrogen.

A little-known problem with Nolvadex, at least according to research on animals, is that it blocks at least two enzymes in the testes that the body needs for testosterone synthesis. That's a paradoxical effect: By blocking estrogen'and so toning down the negative-feedback mechanism whereby the brain detects high blood levels of estrogen, leading to a lowering of LH and other testosterone-stimulating hormones'Nolvadex should increase testosterone production. That enzyme-blocking effect hasn't yet been observed in humans, but it would help explain why long-term Nolvadex users may experience the effects usually seen with higher estrogen levels.

While Nolvadex may have saved the lives of many breast cancer patients, it can cause serious problems when used by healthy young women. A recent case study disclosed the effects of long-term use in a 26-year-old female bodybuilder.1 The woman denied using any other type of drug, including anabolic steroids, but she did take 20 to 40 milligrams of Nolvadex a day for six months. She used it because she'd heard that it would help lower bodyfat.

Nolvadex did indeed speed fat loss from her buttocks and upper thighs'both of which have a preponderance of estrogen receptors in women. Paradoxically, however, it also limited her ability to lose fat from her abdominal area. Then there were the side effects: loss of breast mass, night sweats and hot flashes, the latter effects due to the chemical menopause induced by Nolvadex. Because it effectively blocks estrogen action in women, it also increases testosterone activity.

Nolvadex is linked to serious side effects in women:

'Endometrial cancer, or cancer of the uterus
'Excessive blood clotting, which can lead to a stroke
'Birth defects if used during pregnancy
'Ovarian cysts
'Loss of bone density due to lack of estrogen activity
'Cataracts and other eye damage affecting the cornea and retina
'Hot flashes
'Vaginal discharge
'Loss of sex drive

Women who stay on Nolvadex for extended periods are potentially subject to bone-wasting diseases, such as osteoporosis. While Nolvadex is not the most dangerous drug in the bodybuilding drug culture, it can hardly be considered benign, especially for women.

The Ideal Fat-burning Drug Most drugs prescribed to treat obesity leave much to be desired. The current crop of so-called diet pills are mainly updated versions of the original diet drug introduced about 50 years ago'amphetamine'which dropped out of favor because it caused overstimulation and in many cases outright brain pathology that looked like schizophrenia. The drugs used today share one thing with amphetamines: They decrease appetite. On the other hand, they don't actually provide efficient fat loss simply because they don't specifically target the inherent metabolic problems that are at the root of most obesity.

Other approaches to treating obesity typically involve drugs that interfere with fat uptake and digestion, such as Xenical, or Orlistat, which inhibits the lipase enzyme needed to digest fat. As a result, Orlistat suppresses digestion or absorption of about 30 percent of the fat content of any meal, leading to a lower calorie intake. People using it are advised to follow a lowfat diet, however, as eating too much fat while on the drug often leads to potentially embarrassing fat-malabsorption problems.

The most promising pharmacological approach to dealing with excessive bodyfat is thermogenic. It involves changing the way the body handles excess calories so that you oxidize, or burn, rather than store them. Since the first law of thermodynamics states that energy cannot be created or destroyed, it has to go somewhere. In thermogenesis, calories (energy) derived from fat are converted into heat. Since the heat produced doesn't result from activity'i.e., work or exercise'the effect is called a 'futile energy system.'

If you've ever used an over-the-counter fat-loss supplement containing ephedrine or ephedra, you've already experienced a thermogenic effect. Ephedrine's structure is similar to amphetamine's, and much of its fat-loss effect does come from appetite suppression. But ephedrine also interacts with beta-adrenergic cell receptors, leading to an increase in catecholamines, such as epinephrine and norepinephrine, which in turn initiate reactions that result in a thermogenic effect in fat cells.

The problem with ephedrine and many other over-the-counter fat-loss supplements is their lack of specificity. Beta-adrenergic cell receptors come in several different flavors, such as beta-1, beta-2, beta-3 and possibly others. For best results you want to target only beta-2 and, preferably, beta-3 receptors. Stimulating beta-1 receptors leads to side effects, such as excessive heart stimulation. While ephedrine does interact with beta-2 and beta-3 receptors, it also affects beta-1s, sometimes leading to the heart effects that have given ephedrine an unsavory reputation and made it a primary target for removal from the market by government watchdog agencies. The truth is that ephedrine significantly affects beta-1 receptors only in some people'or when taken in excessive doses'but that's another story.

In recent years drug researchers have determined that the primary beta-adrenergic receptor for thermogenesis is the beta-3, and drug companies rushed to produce a drug that specifically targeted that receptor. Among the advantages of such a drug would be a potent thermogenic effect but without the usual side effects. Some scientists have speculated that a low-level thermogenesis is the primary defect associated with obesity. Others have said that the reason some people can eat whatever they want with seeming impunity is their higher level of inherent thermogenesis.

In animals the most thermogenic tissue by far is brown adipose tissue, or BAT. Research shows that, in animals, beta-3 receptors interact primarily with BAT. In humans only infants show significant amounts of BAT, which is thought to regulate infant temperature. There's recent evidence that even common white adipose tissue also contains beta-3 receptors, though fewer than BAT does.

If a specific drug could target beta-3 receptors, wouldn't that result in effective fat loss? Drug companies have much to gain by producing such a drug (we're talking billions here, folks). Numerous studies have tested selective beta-3 drugs in species ranging from rats to dogs to monkeys, and the experimental drugs appeared to work as advertised, although some minor side effects, such as gastrointestinal distress, did occur. The drugs didn't seem to stimulate the heart or increase blood pressure, though, thus indicating that the effect wasn't spilling over into the beta-1 receptors, as it does with ephedrine.

Even so, human trials of beta-3 selective drugs have thus far proved disappointing; the drugs seem to work much better in animals than humans. Case in point: a study on the latest beta-3 drug, which carries the code name L-796568, indicating that it's experimental.2 Healthy obese men took either the drug or a placebo for 28 days. The drug induced no major fat oxidation or thermogenesis, but the subjects using it did show a minor change in fat mass. They also had lower levels of fat in the blood, so the drug did do something.

The obvious question is, Why didn't the drug work? According to the scientists involved in the study, either or both of two conditions may explain that. The first involves the exquisite sensitivity of beta-adrenergic cell receptors. They shut down rapidly when stimulated, and in this study they appeared to downregulate, or shut off, after only nine days. That also happens with other drugs that target beta-adrenergic receptors, such as clenbuterol and ephedrine, though ephedrine continues to work through other mechanisms, such as appetite suppression and the conversion of the relatively inactive T4 thyroid hormone into the far more active T3 form.

The other reason L-796568 proved a bust is simply the lack of brown adipose tissue in humans. On the other hand, beta-3 receptors also exist in plain old white fat too. So why the drug didn't work is something pharmacological researchers will have to figure out. When they do, a new era in effective fat loss will likely arrive.

1 Seehusen, D.A., et al. (2002). Tamoxifen as an ergogenic agent in women bodybuilders. Clin J Sports Med. 12:313-314.
2 Larsen, T.M., et al. (2002). Effect of a 28-day treatment with L-796568, a novel B-3 adrenergic receptor agonist, on energy expenditure and body composition in obese men. Am J Clin Nutr. 76:780-788. IM

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