Life Enhancement News with Durk Pearson and Sandy Shaw

November 2004 Blog with Durk and Sandy

by Jamie Riedeman on Nov 25, 2004

November 2004 Blog with Durk and Sandy

A man has a property in his opinions and the free communication of them. He has an equal property in the free use of his faculties, and free choice of the objects on which to employ them. In a word, as a man is said to have a right to his property, he may be equally said to have a property in his rights. Where an excess of power prevails, property of no sort is duly respected. No man is safe in his opinions, his person, his faculties, or his possessions. … Government is instituted to protect property of every sort; as well that which lies in the various rights of individuals. This being the end of government, that alone is a just government which impartially secures to every man whatever is his own.— James Madison, National Gazette, March 26, 1792

In all criminal prosecutions, the accused shall enjoy the right to a speedy and public trial, by an impartial jury of the State and district wherein the crime shall have been committed; … and to be informed the nature and cause of the accusation; to be confronted with the witnesses against him; to have compulsory process for obtaining witnesses in his favor, and to have the assistance of counsel for his defense.— From the Sixth Amendment, U.S. Constitution

In Suits at common law, where the value in controversy shall exceed twenty dollars,* the right of trial by jury shall be preserved, and no fact tried by a jury shall be otherwise re-examined in any Court of the United States, than according to the rules of the common law.— From the Seventh Amendment, U.S. Constitution

*Converted to today’s dollar, this might be about $500.

The FDA and Your Right to a Jury Trial

All of the law governing crimes as defined by the rules and regulations of regulatory agencies, such as the FDA, has done a wild detour around the rights of Americans as specified in the U.S. Constitution, such as the major right to a jury trial as commanded by the Sixth and Seventh Amendments, above. When you are accused of crimes by a regulatory agency, you don’t get a jury trial at all.* You come under so-called administrative law, which is completely different from the common law. You get to appeal to an administrative court, in which the judge (actually a magistrate) is paid by the very agency that has accused you of a criminal act. There is no independent judiciary. If the judge allows you (and usually does, but he doesn’t have to), you can have an attorney represent you. You have no right to discovery for obtaining exculpatory evidence. The only right you have to information from the agency is that available through the Freedom of Information Act, and the agency can still stall in providing it, long enough to virtually prohibit its use by you during your administrative hearing. Any statements made by government agents are likely to be assumed true unless you can rebut them, whereas nothing presented by you will be assumed true unless you can document its truth (almost as bad as being considered guilty until you can prove yourself innocent). But, worst of all, you will be allowed no jury trial.

*You were supposed to have the right to a jury trial if accused of a crime that could result in imprisonment for 6 months or longer. However, a recent circuit court of appeals decision ruled that you can be charged with several counts, each of which could result in imprisonment for 6 months, and, without a jury trial, be required to serve the sentences consecutively; this effectively eliminates the requirement of a jury trial for those threatened with imprisonment for 6 months or longer.

If, after appearing before the first magistrate, you get a decision with which you are in disagreement, you can appeal to an internal appeal board (still under the authority and the pay of the agency that has accused you) that is often located on the other side of the country. You will probably have to hire a second set of attorneys to represent you at the new geographical location. All that the appeal board will review is what is already in the administrative record. You can present no new evidence. Moreover, the first magistrate has broad powers on what he/she will and will not allow into the administrative record. After you have appeared before the appeal board, you have “exhausted your administrative remedies,” and if you are still dissatisfied with the outcome and still have some money, you can appeal to a federal district court. But all the district court will review is what is in the administrative record, and you still do not get a jury trial!

It generally costs between $200,000 and $1,000,000 (if you have it) to “exhaust your administrative remedies” and the process may take 8 to 10 years (a far cry from a speedy public trial!). That is why most accused companies “settle” by paying the FDA’s fines without admitting any guilt, though failure to mount a defense probably makes most people assume guilt.

This may sound almost funny, but the results aren’t funny at all. When the FDA puts its dietary supplement Good Manufacturing Practices (GMPs) in place (and they have promised the final rule for public comments in October), there won’t be a First Amendment that can protect us from accusations of violating GMPs, as we have been able to do to protect ourselves from FDA attack for providing FDA-forbidden truthful information on labels. The dietary supplement industry will come under the administrative law regime of the FDA. The FDA will, if they have their way, have broad discretion to define whether you are meeting the vaguely written rules and can send in inspectors to hound you into doing whatever they want you to do (such as to stop suing the FDA …). If you don’t think that this will have a dramatic impact on the availability, price, and innovation of dietary supplements, as well as the exercise of constitutional rights, you are living in a dream world.

In the clear language of the U.S. Constitution, there are no federal actions that are not covered by the Bill of Rights. There is nothing in the Constitution that provides exemptions. The FDA used to think that they weren’t subject to the First Amendment; they know better now. (We were able to take advantage of recent U.S. Supreme Court jurisprudence favorable for “commercial speech” under the First Amendment, such as 44 Liquormart and Coors.) We don’t think that the FDA and other regulatory agencies should be able to impose criminal penalties and fines on people while stripping those people of their Sixth and Seventh Amendment rights to a jury trial. It is certainly inconvenient and undoubtedly costly for the government to have to provide jury trials for the accused, but the purpose of the U.S. Constitution was to limit the authority of government so as to avoid tyranny, not to make putting people in jail and imposing fines easy and inexpensive for the government. As we see it, the relatively unimpeded imposition of criminal penalties and (usually) large fines by regulatory agencies under administrative (not common law) rules and regulations, with near blanket denial of the right of trial by jury, is not only unconstitutional but a grave threat to freedom and the rule of law in the U.S.

So please don’t think that we are through with the FDA by bringing the agency into line with the First Amendment. We next have to deal with the imminent threats to the availability and cost of supplements posed by the agency with its Good Manufacturing Practices. We will continue fighting for freedom of informed choice to the limit of our resources. Please help us by sending a donation for any amount to the Durk Pearson & Sandy Shaw FDA Litigation Fund, Emord & Associates, 1800 Alexander Bell Drive, Suite 200, Reston, VA 20191. You can read our joint comments with others on the FDA’s proposed GMPs at

Addendum to the above

FDA Announces Modernization of the Food GMPs

Oh no! With the dietary supplement industry reeling in anticipation of new costly and generally unreasonable Good Manufacturing Practices, the FDA has now announced that it will be “updating” the food GMPs.* One possible reason for this is that the dietary supplements are by statute supposed to be regulated as foods, and the GMPs for dietary supplements are by statute to be patterned after those of foods. The proposed new GMPs for supplements are, in fact, patterned after those of the drug GMPs, which is one of our strongest legal arguments against them. It may be that the FDA is about to “strengthen” its food GMPs in light of illnesses and deaths resulting from eating common foods (generally because of microbial contamination) and also to justify its unreasonably stringent dietary supplement GMPs.

*Food Safety Magazine.

Just what we all need—a significant increase in food prices from FDA regulations that, judging from past history, are unlikely to provide any additional safety. And, of course, the lovers of government controls (we call them left-wingers) will blame the greedy multinational companies for the price increases, and the uninformed and poorly educated public will mostly agree.

Tryptophan and the Response to Selective Serotonin Reuptake Inhibitors (SSRIs)

Recent reports have indicated that some people, particularly children and adolescents, may respond to at least some SSRIs by becoming more suicidal and more impulsively violent, rather than less so.1 There are a number of possible reasons for this. We report here the results of a rat study2 which indicates that the response to an SSRI depends upon the amount of tryptophan in the circulation and, hence, upon diet (or tryptophan or 5-hydroxytryptophan supplementation).

The authors report previous animal studies in which the amount of plasma tryptophan resulted in differential responses to SSRIs. For example, in one study, acute tryptophan depletion led to a significant decrease in extracellular brain serotonin levels in rats pretreated with the SSRI fluvoxamine for 2 weeks, but not in animals that were not tryptophan-depleted.

The Sprague-Dawley rats in the new study2 were randomly assigned to one of three dietary conditions: one group received a control diet with 0.24 g of tryptophan/100 g of food; another group received the same diet but with 10% of the amount of tryptophan (low tryptophan) in the control diet; and the third group received the control diet plus 200% of the tryptophan in the control diet (high tryptophan). The animals were then treated with the SSRI fluvoxamine or with fenfluramine, which causes release of serotonin, and the results were compared.

Levels of serotonin (5-HT) and 5-HIAA (a metabolite of serotonin) were significantly reduced after the low-tryptophan diet, while serotonin, but not 5-HIAA, was increased after the high-tryptophan diet. There was a trend toward an increase of serotonin release in the high-tryptophan diet as compared to controls.

The animals were tested on a task requiring differential reinforcement of low-rate responding (DRL), where the animal has to learn to wait a certain period of time (typically 72 s) after a cue to push a lever for a reward. This is used as a behavioral screening test in rodents for antidepressant activity. Note that low levels of serotonin, present in many cases of human depression, result in impaired impulse regulation; we would expect, therefore, that (as it appears to work the same in rats) animals with low levels of serotonin would have trouble controlling, for such a long period of time, their impulse to push the lever.

The authors report, “The effect of the TRP [tryptophan] high diet on DRL performance in the present study is similar to the effect of oral fluvoxamine administration of 20 mg/kg, suggesting that TRP supplementation may have antidepressant potential. It is of note in this respect that the increase in extracellular 5-HT [serotonin] following a TRP high diet in this study is in the same order of magnitude as the 5-HT increase following oral administration of 30 mg/kg of fluvoxamine observed previously in our laboratory.”3(Emphasis added.) So, surprise, surprise, tryptophan supplementation alone has an antidepressant potential, something that was noted by hundreds of thousands, possibly millions, of people before the FDA effectively banned tryptophan dietary supplements by prohibiting tryptophan imports and (in our opinion, no coincidence) paved the way for the rise of the SSRIs.

The authors conclude: “… the findings of this study suggest that nutritional factors play an important role in the biosynthesis of 5-HT. Increasing 5-HT levels by increasing the availability of TRP might augment the therapeutic efficacy of SSRIs, whereas malnutrition may render patients refractory to SSRI treatment.” This is something that needs to be followed up in the case of depressed children and teenagers. It may be that those responding the “wrong” way to SSRIs are those with low plasma tryptophan levels and that, with adequate plasma tryptophan levels, some will do better on lower doses of the drugs or may not even need antidepressant drugs at all.

  1. For example, see Check, “Bitter pills.” Nature 431:122-4 (2004). In this article, some psychiatrists are said to blame a side effect called akathisia, an agitated state that can occur in a minority of patients on antidepressants. However, this is just placing a label on the problem rather than an explanation. In fact, low plasma serotonin levels can induce what is called agitated depression. It is interesting to note that Wyeth, the maker of the SSRI Effexor®, warned doctors in August 2003 about the link to suicidal thoughts in young patients, based on findings in clinical trials (and added the warning to its label), but was forced by the FDA to withdraw the warning because that was not the official FDA position at that time! Once again, FDA censorship puts lives at risk. See Mathews, “Congress to air controversies over drug trials,” The Wall Street Journal, Sept. 8, 2004, pp B1, B9.
  2. van der Stelt et al. Effects of dietary tryptophan variations on extracellular serotonin in the dorsal hippocampus of rats. Psychopharmacology 172:137-44 (2004).
  3. Bosker et al. Effects of single and repeated oral administration of fluvoxamine on extracellular serotonin in the median raphe nucleus and dorsal hippocampus of the rat. Neuropharmacology 34:501-8 (1995).

Possible Antiatherosclerotic Effects of Hot Tubs

The lucky (or unlucky, depending upon your point of view) rats chosen for this study1were given 15 minutes of hot water baths daily for 4 weeks to study the effects of heat shock on the development of atherosclerosis.

Previous studies have reported beneficial effects of saunas, including improved vascular endothelial function and cardiac function in chronic heart failure patients in Japan; enhanced endothelial nitric oxide production; suppression of proliferation of vascular smooth muscle cells (VSMCs), as occurs in atherosclerotic lesions; and inhibition of necrotic cell death in VSMCs.1 Thermal treatment has preconditioning effects against myocardial ischemia/reperfusion injury and is reported to suppress macrophage activation and attenuate inflammatory cytokine production, as well as to release heat-shock proteins that help prevent damage to DNA and other macromolecules.1

In this recent study, hollow polyethylene tubes were placed around femoral arteries (“cuffs”) to induce intimal thickening, possibly as a result of the hypoxia resulting from the process. The intima is prone to thickening in atherosclerosis. The experimental animals then received their daily hot baths at temperatures between 40.5ºC (104.9ºF) and 41.5ºC (106.7ºF). Four weeks after the placement of the cuffs, neointima was formed in the subendothelial layers of the arteries in the control animals, while thermal treatment produced a marked reduction in intimal thickening. There was no thickening in control animals that did not receive the cuffs or baths.

The authors found that the thermal treatments resulted in a marked enhancement of expression of heat-shock protein 72 (HSP72) in the adventitia and media of the arteries, regardless of whether they had been cuffed with the hollow polyethylene tubes. The HSP72 had increased expression even after only one bath, and it lasted for at least 72 hours afterward. They also reported an increase in p22-phox, a major component of the oxidative enzyme NADPH oxidase in the cuffed animals, whereas there was little or no p22-phox expression in the thermal-treated arteries of cuffed or noncuffed animals.

Happy soaking!

  1. Okada et al. Thermal treatment attenuates neointimal thickening with enhanced expression of heat-shock protein 72 and suppression of oxidative stress. Circulation 109:1763-8 (2004).

High-Dose Alpha-Lipoic Acid Has Antiobesity Effects in Rats

A new study1 reports that high-dose (supraphysiological) alpha-lipoic acid suppresses hypothalamic AMP-kinase, a nutrient sensor and food-intake regulator, resulting in antiobesity effects.

AMP-activated protein kinase (AMPK) has recently been identified as a nutrient sensor, the activity of which is inhibited by exposure to anorexigenic (feeding-inhibitory) signals, such as leptin, insulin, high glucose, and refeeding (after fasting).2 The inhibition of AMPK is, in fact, necessary for leptin’s effects on food intake and body weight, and failure of leptin to suppress AMPK is a cause of leptin resistance.2 AMPK is also reported to be increased by stress. The enzyme regulates energy metabolism by inhibiting energy-consuming pathways and inducing pathways that generate ATP. It enhances feeding (orexigenic) signals in the fasting state, while low AMPK signaling results in suppression of feeding under ad libitum conditions.2 Hence, suppression of AMPK in the hypothalamus is a potential way to inhibit feeding by mimicking a fully fed condition.5

The new study1 reports that, in Sprague-Dawley rats treated with intraperitoneal or intracerebroventricular injections or high doses of oral alpha-lipoic acid (what would amount to about 2.5 g per day in an adult human), hypothalamic AMPK is suppressed, with decreases in food intake and weight loss. Results showed that the treated rats had increased energy expenditure compared to controls and that there was an increase in the uncoupling protein-1 (Ucp-1), which is associated with increased energy expenditure and reduced oxidative stress. One interpretation of these results is that the increased levels of Ucp-1 increase overall energy expenditure by oxidizing fat stores.3The oral doses of alpha-lipoic acid received by the Sprague-Dawley rats in the study were 0.25%, 0.5%, and 1% by weight in rat chow. The rats receiving 0.25% alpha-lipoic acid showed a trend toward reduced body weight that was, however, not significant at P<0.05. Reduced weight in rats getting 0.5% and 1% alpha-lipoic acid was significant at this level. Hence, rats receiving 0.5% wt/wt of alpha-lipoic acid would amount to about 2.5 g of the substance per day in a human consuming 500 g (dry weight) of food. The authors suggest that, since alpha-lipoic acid is known to stimulate glucose transport and ATP synthesis in peripheral tissues, it may decrease hypothalamic AMPK activity by increasing glucose uptake, glucose metabolism, or both in the hypothalamus.5


Tests on the treated mice showed no toxicity or illness in relation to food intake or organ pathology, and animals had unchanged blood-cell counts and blood chemistry.

2.5 g per day of alpha-lipoic acid for a human is a very high dose and is definitely supraphysiologic (far beyond any conceivable dietary intake). Though the mice had no obvious toxicity, humans may metabolize such large amounts of alpha-lipoic acid differently. Originally, the nutrient was investigated as an antidote to certain mushroom poisonings in humans. It was very effective, but at doses of 6–8 g per day, decreased survival resulted, with liver mitochondrial damage. Hence, any experimentation with high-dose alpha-lipoic acid is just that, an experiment, and is therefore best done under the close supervision of a nutritionally expert physician. Durk is currently experimenting with 2 g of alpha-lipoic acid per day and has found it helpful in reducing his weight. Sandy is taking 1.25 g of alpha-lipoic acid daily.

  1. Min-Seon Kim et al. Anti-obesity effects of alpha-lipoic acid mediated by suppression of hypothalamic AMP-activated protein kinase. Nature Med10(7):727-33 (2004).
  2. Minokoshi Y, Alquier T, Furukawa N, Kim YB, Lee A, Xue B, Mu J, Foufelle F, Ferre P, Birnbaum MJ, Stuck BJ, Kahn BB. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 2004 Apr 1;428(6982):569-74.
  3. Small et al. Cellular energy sensor balances the scales. Nature Med 10(7):681-2 (2004).
  4. Watt MJ, Steinberg GR, Chan S, Garnham A, Kemp BE, Febbraio MA.Beta-adrenergic stimulation of skeletal muscle HSL can be overridden by AMPK signaling. FASEB J 2004;18(12):1445-6. Epub 2004 Jul 01.
  5. This study didn’t report the effects of alpha-lipoic acid on AMPK in skeletal muscle. However, experimental evidence indicates that AMPK has opposite effects in peripheral tissues; for example, leptin activates AMPK in skeletal muscle, whereas it inactivates AMPK in the hypothalamus. In muscle, AMPK exerts an antilipolytic effect that may override the lipolytic effect of adrenaline.4Authors of another recent study note that AMPK is activated in skeletal muscle by an increase in energy expenditure, as in exercise, and by lack of fuel, leading to (among other things) an increase in fatty acid oxidation.6 The same paper also reported that AICAR, an inducer of AMPK, inhibited oxidative stress and NFkappaB activation resulting from hyperglycemia in incubated HUVECs (human umbilical-vein endothelial cells). The authors describe a recent study in which the diabetes drug metformin was shown to activate AMPK in skeletal muscle of patients treated with the drug. Moreover, they mention a recent finding that adiponectin, a hormone released by fat cells that increases insulin sensitivity in experimental animals, also activates AMPK in skeletal muscle. See Yamauchi et al, “Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase,” Nature Med 8(11):1288-95 (2002). This was a mouse study.
  6. Ruderman et al. Malonyl-CoA and AMP-activated protein kinase (AMPK): possible links between insulin resistance in muscle and early endothelial cell damage in diabetes. Biochem Soc Trans 31(Pt 1):201-6 (2003).

Disaggregating Toxic Protein Clumps in Neurodegenerative and other Chronic Diseases: Dopamine, L-Dopa, and Adrenaline

Last issue, we discussed (see “Connecting Alzheimer’s, Cardiovascular Disease, Parkinson’s Disease, and Type 2 Diabetes”) some of the aggregated proteins involved in the title diseases and possible ways to get rid of some of them. A great deal of further work on how to prevent abnormal protein clumps from forming and how to get rid of clumps once they have formed has been published. Here are some of the latest.

One recent paper1 shows that catecholamines [dopamine, L-dopa, adrenaline (also called epinephrine)] inhibit fibrillation of amyloid-beta (as found in Alzheimer’s) and alpha-synuclein (Parkinson’s disease). More interestingly, the researchers found that oxidized metabolites (such as quinones and aminochromes) of these catecholamines were actually more effective in inhibiting fibrillation than the parent catecholamines themselves. Dopamineochrome and adrenochrome were specifically shown to inhibit alpha-synuclein fibrillation. The researchers found that coincubation of ascorbic acid or soluble vitamin E with these compounds had no effect on dopamine or L-dopa inhibition of fibrillation, though they reported that ascorbic acid itself caused weak inhibition of fibrillation.

Not only did the catecholamines inhibit fibrillation, but they also caused disaggregation of existing fibrils. These results suggest that increasing the supplies of catecholamine precursors, such as tyrosine and phenylalanine (along with their cofactors vitamins C and B6, folic acid, and copper) may be a useful strategy in helping to reduce the formation of, as well as disaggregating, amyloid-beta and alpha-synuclein fibrils.

The authors note, “Our data indicate that the presence of micromolar concentrations of dopamine or L-dopa is sufficient to significantly inhibit fibril formation or disaggregate existing fibrils of amyloid-beta or alpha-synuclein in vitro. Because estimates of dopamine concentrations in striatal-nerve terminals and L-dopa concentrations in the striatum after administration are >>50 and 50 µM, respectively, the concentrations used in our experiments are physiologically relevant.”

Red Wine Polyphenols

A study2 of the effects of several red wine-related polyphenols on the formation of amyloid-beta fibrils in vitro reports that several of them dose-dependently inhibited the formation of fibrillated amyloid-beta, with the activity decreasing in order of myricetin = morin = quercetin > kaempferol > (+)-catechin = (-)-epicatechin. The polyphenols were also reported to destabilize preformed fibrillated amyloid-beta protein. For example, they found that when fresh amyloid-beta(1–40) was incubated with fibrillated amyloid beta(1–40), there was clear fibril extension, as observed under electron microscopy. However 50-µM myricetin completely abolished the extension. Myricetin also abolished the extension of fibrillated amyloid-beta(1–42), while morin, quercetin, and kaempferol inhibited the extension of both these fibrillated amyloid-beta forms.

The authors propose that their results may help explain the negative correlation between moderate red wine drinking and the occurrence of Alzheimer’s disease.

  1. Li et al. Dopamine and L-dopa disaggregate amyloid fibrils: implications for Parkinson’s and Alzheimer’s disease. FASEB J 2004 Jun;18(9):962-4. See also Epub 2004 Apr 1.
  2. Ono et al. Potent anti-amyloidogenic and fibril-destabilizing effects of polyphenols in vitro: implications for the prevention and therapeutics of Alzheimer’s disease. J Neurochem 87:172-81 (2003).

HDL: Not Always “Good” Cholesterol

Recent reports explain how HDL can, under certain conditions, be converted from a protective anti-inflammatory type of cholesterol to a pro-inflammatory type, which may help explain why some people with normal HDL levels still have heart attacks.

In an early study,1 researchers found that HDL becomes inflammatory during the acute phase response (APR), which is a systemic reaction to infectious and noninfectious tissue-destructive processes. In rabbits, the protective effects of HDL rapidly declined during the APR, until by the third day these effects were completely lost. The level of Apo A-1, the primary protein constituent of HDL, was reduced by 73%, while the levels of paraoxonase (which destroys organic peroxides) and platelet activating factor acetylhydrolase (two enzyme systems associated with HDL) declined by 71% and 90%, respectively. Infecting mice with influenza reduced the ability of HDL to inhibit LDL oxidation and LDL-induced monocyte chemotactic activity in human artery cell-wall cocultures, resulting in the loss of HDL’s anti-inflammatory properties.2

A new study3-5 now shows that an inflammatory enzyme, myeloperoxidase, selectively targets apolipoprotein A-1 (Apo A-1), which in turn eliminates the anti-inflammatory effects of HDL. The authors of this study report that in cardiovascular disease patients or in those with diabetes, HDL is actually proinflammatory as compared to HDL in normal individuals. The myeloperoxidase-catalyzed oxidation, chlorination, and nitration of HDL and Apo A-1 result in the loss of the ability of HDL to remove cholesterol from macrophages.

Short-term (acute-phase) changes in HDL are probably normal parts of the immune response. However, these results suggest that chronic inflammatory states such as occur in cardiovascular disease and diabetes have a negative impact on the protective effects of HDL. Under these circumstances, HDL is no longer “good” cholesterol.

  1. Van Lenten et al. Anti-inflammatory HDL becomes pro-inflammatory during the acute phase response. J Clin Investig 96:2758-67 (1995).
  2. Van Lenten et al. High-density lipoprotein loses its anti-inflammatory properties during acute influenza A infection. Circulation 103:2283-8 (2001).
  3. Fogelman. When good cholesterol goes bad. Nature Med 10(9):902-3 (2004).
  4. Service. Enzyme deactivates heart-friendly HDL. Science 305:1558-9 (2004).
  5. Zheng et al. Apolipoprotein A-1 is a selective target for myeloperoxidase-catalyzed oxidation and functional impairment in subjects with cardiovascular disease. J Clin Investig 114(4):529-41 (2004).

Proinflammatory Cytokine Tumor Necrosis Factor-Alpha Increases with Hostility and Aggression

Tumor necrosis factor-alpha (TNF-alpha) is an important inflammatory cytokine that has been implicated in the pathogenesis of cardiovascular disease.1 TNF-alpha is released at all stages of inflammation associated with atherogenesis, promoting the expression of adhesion molecules on endothelial cells that contribute to cells such as macrophages accumulating at the site of atherogenic lesions, and it also triggers the release of the pro-inflammatory cytokine IL-6, which has been reported to be associated with the risk of future heart attacks in healthy men.2 TNF-alpha also increases the concentrations of C-reactive protein, another inflammatory risk factor for cardiovascular disease.1

The authors1 report that increased TNF-alpha has also been linked to depression. The study examined 62 healthy, nonsmoking men aged 18–45 years. They were assessed for aggression, hostility, and anger, using the 29-item Buss and Perry aggression questionnaire (BPAQ), which is said to be widely used. The subjects also had blood samples evaluated for TNF-alpha expression. Results showed that higher total scores on the BPAQ were significantly associated with greater LPS-stimulated TNF-alpha expression (LPS is lipopolysaccharide, a bacterial cell-membrane component). Higher scores on the BPAQ were associated with higher TNF-alpha levels.

Hence, men who exhibited higher levels of hostility and aggression, as measured by the test, had higher levels of TNF-alpha expression in response to LPS. The authors note that the triad of aggression, hostility, and anger is inversely associated with serotonergic activity and that serotonin inhibits monocyte-associated TNF-alpha production induced by exposure to LPS. This suggests that supplementation with tryptophan or 5-hydroxytryptophan may reduce aggression, hostility, and anger and the increased TNF-alpha response to LPS. In severe cases, however, fluoxetine, the most selective SSRI, may be helpful.

Moderate alcohol consumption may also help.3 A paper reports that moderate alcohol consumption (2 alcoholic drinks a day) in 8 healthy men resulted in 39% reduction (gin) or 96% reduction (red wine) in monocyte adhesion after TNF-alpha stimulation of endothelial cells.

  1. Suarez et al. The relation of aggression, hostility, and anger to lipopolysaccharide-stimulated tumor necrosis factor (TNF)-alpha by blood monocytes from normal men. Brain, Behavior, Immunity 16:675-84 (2002).
  2. Ridker et al. Plasma concentration of interleukin-6 and the risk of future myocardial infarction among apparently healthy men. Circulation 101:1767-72 (2000).
  3. Badia et al. Decreased tumor necrosis factor-induced adhesion of human monocytes to endothelial cells after moderate alcohol consumption. Am J Clin Nutr 80:225-30 (2004).

Reforming the Food, Drug, and Cosmetic Act to Reflect Our Constitutional Rights and Modern Medicine

One major reform that would greatly ameliorate the FDA regulatory barriers that prevent the translation of modern research into practical products and that greatly slow the development of life extension technology would be to eliminate the Kefauver Amendments of 1962. Before 1962, the FDA was responsible for certifying safety, but once a drug was determined to be safe to use in a certain dose range, physicians and patients, along with scientists and clinicians doing research on the drug, determined over time what the drug was efficacious in treating. As noted in a recent issue of Regulation,1 Daniel B. Klein and Alexander Tabarrok argue, “In a sense, off-label uses are regulated according to the pre-1962 rules, under which the FDA held new drugs only to safety requirements, whereas on-label uses are regulated according to the post-1962 rules.” Thus, they say, “Off-label prescribing tells us something about how the world might look if the FDA were restricted to safety-testing alone.” Yet this is an understatement. The amount of innovation if the FDA certified only safety would increase dramatically, since the costs of getting FDA approval would decrease from about $800,000,000 per drug to roughly $50,000,000 per drug. It would allow many small and medium-sized companies rather than just a few very large companies to develop and market new drugs, and drug prices could be expected to be much lower than they are under the current FDA regulatory regime.

In fact, the inherent roadblock imposed by the FDA’s post-1962 efficacy rules has been noted in the scientific literature. In the July 2004 Neurodegeneration,2 for example, an article notes in a discussion of FDA regulatory reform that “Before 1962, the only requirement for drug approval was to show that a drug was safe in humans. Since that time, demonstration of drug efficacy in phase 2 and phase 3 clinical trials has been required. A relaxation of the current emphasis on ‘proof’ of efficacy, stopping short of eliminating all efficacy trials, would stimulate drug-discovery efforts. It is important to remember that the great majority of drugs approved before 1962 were concluded to be effective after careful retrospective analysis of clinical data. In fact, many drugs that were retroactively denied approval in the aftermath of the 1962 change might actually have been effective.”

Amazingly, there has been a bold bill introduced into the House of Representatives (HR2544) by Congressman Dana Rohrabacher (R-CA) that includes a provision to strike the effectiveness requirement (post-1962 Kefauver Amendments) of the Food, Drug, and Cosmetic Act. This bill also allows imports of drugs from anywhere so long as they do not violate valid U.S. patents and provided that they meet FDA composition and purity standards for the same drug when made in the United States. Note that this bypasses the FDA’s expensive and unreasonable drug GMPs; how the foreign manufacturer makes the drug is irrelevant so long as it meets composition and purity standards. We enthusiastically support this pioneering legislation and hope that others will contact their Congresscritter to ask them to be cosponsors (at present, the bill has none). It is likely that after the upcoming election, Congressmen may be more willing to stick their necks out for an FDA reform effort that increases, rather than decreases, freedom of informed choice.

  1. Klein and Tabarrok. Who certifies off-label? Regulation, Summer 2004, pp 60-63.
  2. Lansbury. Back to the future: the “old fashioned” way to new medications for neurodegeneration. Neurodegeneration (supplement to Nature), July 2004.

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