January 2005 Blog with Durk and Sandy

January 25, 2005

January 2005 Blog with Durk and Sandy

Consensus is the business of politics. If it’s consensus, it isn’t science. If it’s science, it isn’t consensus. Period.— Michael Crichton, State of Fear

Omega-3 Fatty Acids and Coronary Heart Disease Health Claim

Bowing to the inevitable, the FDA has authorized a widened omega-3 fatty acids and CHD health claim and permits its use on food products: “Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease. Each serving of [name of food] provides [x] grams of EPA and DHA omega-3 fatty acids. [See nutrition information for total fat, saturated fat, and cholesterol content.]”

New X Prize: This One for Extending Lifespan!

Following up on the great success of the X Prize in stimulating private sector investment in space travel, the Methuselah Foundation now offers the Methuselah Mouse Prize, an award of $500,000 for the research team that develops the longest-living Mus musculus(house mouse). According to the January 2005 Life Extension, there are already six teams around the world competing for the new prize. For more information on the Methuselah Foundation, visit www.methuselahfoundation.org.

FDA Evaluation of Drugs Is Flawed, a Threat to the Public Health

“Another concern regarding the FDA’s evaluation of experimental cancer therapeutics is that there is no specific distinction within the FDA for therapeutics aimed at acutely lethal versus chronic diseases. Thus, immunotherapies for chronic arthritis are evaluated alongside those for pancreatic cancer, which has a two-year mortality rate of over 97%. This lack of division based on disease severity can lead to an imbalance in risk-benefit judgments in regulating the development of novel approaches to treat lethal cancers.”1

  1. Pardoll and Allison. Cancer immunotherapy: breaking the barriers to harvest the crop. Nature Med 10(9):890 (2004).

Comment: One outcome of the risk-benefit imbalance mentioned above is the recent “discovery” that Vioxx® and other (e.g., Celebrex®) selective COX-2 inhibitors increase the risk of heart attacks. While used for the treatment of arthritis, COX-2 inhibitors are effective in the treatment of the many kinds of cancer in which COX-2 is upregulated and where the additional risk of heart attack may be acceptable when the risk of death from the cancer is greater than that from a heart attack. There was early evidence1 that selective COX-2 inhibitors, because they inhibit the COX-2-dependent manufacture of prostacyclin (PGI2), an important anticlotting factor, while not inhibiting the COX-1-dependent manufacture of thromboxane A2, an important proclotting factor, could pose an increased heart attack risk. The FDA should have realized this and gone slowly on approving selective COX-2 inhibitor drugs for chronic diseases, such as arthritis, or requiring more label warnings; the fact that they didn’t is a frightening example of the agency’s incompetence. (Just watch, though. The failure of the agency in recognizing the potential risks of the COX-2 class of drugs will be used by the FDA and its Commsymps as the basis for new demands for new FDA powers and a bigger budget. Only in government does massively lethal failure result in massive funding increases.)

  1. For example, see Cheng et al. Role of prostacyclin in the cardiovascular response to thromboxane A2. Science 296:539-41 (2002)

More on the Failure of Antioxidant Trials in the Prevention of Heart Attacks

There has been much discussion of possible reasons that many long-term trials of antioxidant vitamins E and C did not provide protection against heart attacks. For example, as reported in Reference 1 below, Vitamin E supplementation in intervention trials to prevent cardiovascular disease was found to be efficacious in two trials (CHAOS and SPACE), whereas six other trials (ATBC, GISSI, PPP, SECURE, HOPE, and VEAPS) found no benefits.1 The authors1 note that there were widely varying doses of vitamin E used in these studies and that it is not known what doses of vitamin E are necessary to suppress oxidative stress in humans. They go on to point out that, importantly, “… none of these studies incorporated measures of oxidative stress, such as measurement of F2-isoprostanes, to determine the level of oxidative stress and the ability of vitamin E [at the doses studied] to effectively lower the level of oxidative stress in the study subjects.” [Emphasis added]

“In small single human studies involving subjects with conditions associated with elevated levels of F2-isoprostanes, some have found that vitamin E supplementation reduces the production of F2-isoprostanes, whereas others have not. In healthy subjects, vitamin E has no effects on urinary F2-isoprostane concentrations at doses of up to 2000 IU/day for up to 8 weeks. Moreover, a high dose of vitamin C (2500 mg/day) had no effect on lowering F2-isoprostane levels in normal subjects but was found to be effective in suppressing isoprostane formation in smokers … What such findings suggest is that oxidative stress is a complex phenomenon that may be influenced by covariates and that appropriate selection of antioxidant(s) and dose to effectively suppress oxidative stress in specific situations is less than predictable. On the other hand, it suggests that measurements of F2-isoprostanes may provide a uniquely valuable approach to elucidate these complexities and establish effective antioxidant dose regimens that can then be formally tested in individuals with a variety of disease states to determine whether amelioration of oxidative stress mitigates manifestations of disease.” [Emphasis added; reference citations deleted from quote]

  1. Montuschi et al. Isoprostanes: markers and mediators of oxidative stress. FASEB J 18:1791-1800 (2004).

Possible Induction of Terminal Differentiation of Breast Cancer and Prostate Cancer through PPARgamma

Drugs (thiazolidinediones) that activate the peroxisome-proliferator-activated receptor gamma (PPARgamma) are widely used in the treatment of diabetes, where they improve insulin sensitivity, largely via the stimulation of adipogenesis, whereby preadipocytes differentiate into small adipocytes. (Small adipocytes are much more sensitive to insulin than are large adipocytes stuffed with fat.) Natural agonists (ligands) of PPARgamma include some fatty acids, such as docosahexaenoic acid and oleic acid.

Recent reports suggest that activation of PPARgamma may lead to terminal differentiation of human breast1 and prostate2 cancers. The paper on human breast cancer reports that PPARgamma is consistently expressed in metastatic disease and that activation of this nuclear receptor by ligands causes human breast cancer to undergo “dramatic morphological and molecular changes that are characteristic of a more differentiated, less malignant state.”

Keratin 19 and mucin-1 are two proteins whose expression is interpreted as a marker of breast cancer malignancy; they were suppressed by the thiazolidinedione pioglitazone.1The authors also report that “… once activation of PPARgamma occurs for several days, the drug can be removed and the cells retain a substantially reduced capacity for clonogenic growth.”

The prostate cancer paper reported that human prostate cancer cells also expressed PPARgamma at “prominent” levels, while normal prostate cells had very low expression. PC-3 human prostate cancer cells cultured with the thiazolidinedione troglitazone* showed “dramatic morphological changes … suggesting that the cells became less malignant.” Moreover, troglitazone decreased by 50% the amount of PSA (prostate-specific antigen) produced by these cells. The authors also studied the culture of human prostate cancer tumors obtained surgically with the same drug and found marked and selective (about 60%) necrosis of the cancer cells, but not the adjacent normal cells.

 


*Removed from the market due to liver toxicity. Rosiglitazone has replaced it as a PPARgamma agonist, but requires liver tests.

 


Another paper3 reports that PPARgamma ligands are potent inhibitors of angiogenesis, one possible factor in the anticancer effects of PPARgamma induction. In this paper, the authors report that human umbilical vein endothelial cells (HUVEC) express PPARgamma mRNA and protein and that activation of PPARgamma by certain ligands, including ciglitazone (a thiazolidinedione) dose-dependently suppresses HUVEC differentiation into tubelike structures that form early in blood vessel development. Moreover, the PPARgamma ligands also inhibited the proliferation of HUVEC in response to various growth factors. They even found that administration of the PPARgamma natural receptor ligand 15d-PGJ2 in rat cornea prevented vascular endothelial cell growth factor-induced angiogenesis.

It is not clear how activation of PPARgamma could cause all these effects, but even without this knowledge, it still may be useful in treatment. There is much less risk of cytotoxicity with the thiazolidinediones than with many conventional chemotherapeutic agents. However, they are by no means risk-free. Troglitazone itself was removed from the market due to liver toxicity (resulting from fatty accumulation in the liver), where a few patients even required liver transplants as a result. As PPARgamma activators increase adipogenesis (creation of fat cells), it improves insulin sensitivity but may also increase weight. In fact, there is a PPARgamma “paradox” in that both PPARgamma hyperactivity as a result of thiazolidinedione treatment and PPARgamma underactivity due to genetically induced insufficiency protect against obesity-induced insulin insensitivity, leading to the “somewhat perverse, but provocative inference that ‘normal’ amounts of PPARgamma activity, under certain circumstances, promote disease, and that both agonists and antagonists of PPARgamma could be clinically useful. In this regard PPARgamma could be viewed as a ‘thrifty gene,’ promoting fat storage to survive starvation … leading to disease when food is plentiful.”4 All of the potential consequences of fatty accumulation resulting from long-term use of potent activators of PPARgamma have yet to be discovered, but in the context of serious breast or prostate cancer, these considerations may be of less importance.

  1. Mueller et al. Terminal differentiation of human breast cancer through PPARgamma. Molec Cell 1:465-70 (1998).
  2. Kubota et al. Ligand for peroxisome proliferator-activated receptor gamma (troglitazone) has potent antitumor effect against human prostate cancer both in vitro and in vivo. Cancer Res 58:3344-52 (1998).
  3. Xin et al. Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem 274(13):9116-21 (1999).
  4. Lowell. PPARgamma: an essential regulator of adipogenesis and modulator of fat cell function. Cell 99:239-42 (1999).

Estrogen Upregulates Production of Prostacyclin through COX-2

A new paper1 reports that estrogens that activate the estrogen alpha receptor (ERalpha) cause the upregulation of COX-2 in female mice, with a resulting increased production of prostacyclin (PGI2). Prostacyclin is known to provide atheroprotection by inhibiting platelet activation and vascular contraction and proliferation, inhibiting leukocyte-endothelial cell interactions, and inhibiting cholesteryl ester hydrolase.1 Atherosclerotic plaques have a decreased capacity to manufacture prostacyclin. The authors propose that these mechanisms are responsible for the protection against atherogenesis in female mice. The protective effect of estrogen was eliminated in ovariectomized female mice lacking the prostacyclin receptor.

Ovariectomized animals are used as models of oxidative stress. Hence, menopause and the decline of circulating estrogens contribute to aging and to the loss of protection against atherosclerosis by increasing oxidative stress and by the loss of ERalpha activation that increases prostacyclin. The paper warns that selective COX-2 inhibitors may be particularly problematic for women. (This suggests that a reanalysis of the results of the trials of estrogen effects on cardiovascular disease in women might be a good idea, since the concurrent use of COX-2 inhibitors was not corrected for.) They are especially concerned about the use of these drugs in juvenile arthritis, a disease that predominantly affects females.

  1. Egan et al. COX-2-derived prostacyclin confers atheroprotection on female mice. Science 306:1954-7 (2004); see also comments on this paper in Couzin. Estrogen’s ties to COX-2 may explain heart disease gender gap. Science306:1277 (2004).

Arginine Protects Against NSAID-Induced Gastrointestinal Toxicity

One of the reasons that selective COX-2 inhibitors were developed is that nonsteroidal anti-inflammatory drugs such as ibuprofen or aspirin can cause gastric mucosal injury, including bleeding, because they inhibit COX-1. About 16,000 Americans die each year from NSAID-induced gut hemorrhage. The COX-2 inhibitors celecoxib, rofecoxib, and valdecoxib were approved by the FDA on the basis of trials lasting typically three to six months that had as their end point endoscopically visualized gastric ulcerations.1Hence, the focus was on gastric injury, even though early trials (e.g., Vigor® with Vioxx) noted a significant increase by a factor of five in the incidence of heart attack, while serious gastrointestinal events among those receiving rofecoxib were half that of those receiving the traditional NSAID naproxen (Aleve®).1

Two recent papers report on the protective effects of arginine against the gastric lesions induced by NSAIDs. In the first,2 the authors note that nitric oxide (NO) is a potent inhibitor of white cell adhesion to the microvasculature, an early event in the initiation of many types of gut injury, including that of NSAIDs. They note that many NO-releasing drugs used as vasodilators (such as glyceryl trinitrate, isoamyl nitrate, and nitroprusside) are protective against acute hemorrhagic mucosal injury caused by topical irritants. Transdermal application of nitroglycerin prevented mucosal damage that would otherwise have been caused by the NSAID indomethacin via effects on blood flow and leukocyte adhesion.

The second paper3 found that arginine, the amino acid precursor of nitric oxide, was protective against gastric injury induced by the NSAID ibuprofen. Male Wistar rats were the unfortunate subjects. Rats receiving oral administration of 100 mg/kg of ibuprofen suffered severe damage to the gastric mucosa, accompanied by a significant increase in myeloperoxidase activity, indicating increased neutrophil activation. Treatment with equimolar doses of arginine* along with the ibuprofen resulted in considerably reduced number and intensity of lesions. Arginine also significantly decreased the hemorrhagic score. The activity of xanthine oxidase, a major source of oxidative stress that the authors believe may be involved in NSAID-induced gastric lesions, was significantly inhibited by arginine.

 


*This is a very small amount; the amount of arginine in a dietary supplement is far larger than the usual human dose of ibuprofen.

 


The authors2 note that a conservative estimate for those using NSAIDs suffering digestive complications at some time is 20–50% and that 1–2% of those using NSAIDs continuously are hospitalized each year. Hence, these results suggest that use of arginine concurrently with ibuprofen or other COX-1 inhibiting NSAIDs might prevent many of these complications and even hospitalizations.

  1. FitzGerald. Coxibs and cardiovascular disease. New Engl J Med 351(17):1709-11 (2004).
  2. Whittle. Nitric oxide and the gut injury induced by non-steroidal anti-inflammatory drugs. Inflammopharmacol 11(4-6):415-22 (2003).
  3. Jimenez et al. Role of L-arginine in ibuprofen-induced oxidative stress and neutrophil infiltration in gastric mucosa. Free Rad Res 38(9):903-11 (2004)

Inactivation of COX-1 by Red Wine

Inhibition of COX-1 causes an important antiplatelet (anticlotting) effect by inhibiting the production of the proclotting thromboxane A2 while not affecting the ability of COX-2 to continue to produce prostacyclin, a major anticlotting substance. (See article above for potential side effects from excessive inhibition of COX-1.) A new paper1 now reports that resveratrol and chemically related compounds (m-hydroquinones, such as catechins, epicatechins, and quercetin) found in red wines are potent inactivators of COX-1, with no similar effect on COX-2. Inhibition of COX-1 (though not selective) is, of course, a mechanism for aspirin’s antiplatelet atheroprotective effects.

The inhibition of COX-1 by resveratrol was reported to occur at low micromolar concentrations. The poor absorption of resveratrol may limit the inhibition of COX-1, but there is evidence of antiplatelet effects by red wine. It may be that the poor absorption of resveratrol is why we have never heard of hemorrhagic or ulcerative mucosal damage as a result of drinking moderate amounts of red wine. The polyphenols found in many vegetables and fruits have this COX-1-inhibiting-type structure; perhaps this is one of the mechanisms by which diets rich in fruits and vegetables help protect against cardiovascular disease. Since fruits and vegetables have been major constituents of animal diets for hundreds of millions of years, it is not surprising that the polyphenols in them do not cause gut hemorrhage at normal intakes.

  1. Szewczuk and Penning. Mechanism-based inactivation of COX-1 by red wine m-hydroquinones: a structure-activity study. J Nat Prod 67i(11):1777-82 (2004).

Risk of Heart Attack and Stroke after Acute Infection or Vaccination

Chronic inflammation is thought to be a major factor in atherosclerosis, cancer, and aging. Acute inflammation (activation of the immune system and the release of inflammatory cytokines) occurs in the presence of infection and vaccination. Hence, the authors of a newly published paper1 undertook a study of the association between heart attack and stroke and the occurrence of acute infection and vaccination through the United Kingdom General Practice Research Database of computerized medical records for over 5 million people.

Among 20,486 people who had a first heart attack and 19,063 people who had a first stroke who had received influenza vaccine, there was no increase in the risk of heart attack or stroke in the period after influenza, tetanus, or pneumococcal vaccines. However, the risks were substantially greater after a diagnosis of systemic respiratory tract infection, with the risk particularly high during the first three days. The risks of heart attack or stroke were raised significantly, but to a lesser extent than systemic respiratory tract infection by urinary tract infection. A separate paper reports that periodontitis, a source of chronic inflammation, reduces the antiatherogenic effects of high-density lipoprotein (HDL),2 thereby potentially increasing the risk of heart attack or stroke.

These results are not surprising in the face of earlier findings that inflammatory markers such as C-reactive protein are good indicators of cardiovascular risk. The authors of this paper1 also note that an increased leukocyte count “may herald a short period of increased risk of stroke.”

  1. Smeeth et al. Risk of myocardial infarction and stroke after acute infection or vaccination. New Engl J Med 351:2611-8 (2004).
  2. Pussinen et al. Periodontitis decreases the antiatherogenic potency of high density lipoprotein. J Lipid Res 45:139-47 (2004).

Anti-Inflammatory, Antisepsis Effects of Glycine

In the context of the article just above, we would like to mention the anti-inflammatory and antisepsis effects of the amino acid glycine. An interesting paper1 notes that glycine has been shown to protect against endotoxin shock in the rat by inhibiting TNF-alpha (tumor necrosis factor-alpha, a major inflammatory cytokine released in response to bacterial infection). In their paper, the authors studied the effects of glycine on lipopolysaccharide (LPS, a bacterial cell-wall constituent that activates the immune system, causing the release of inflammatory cytokines)-induced cell-surface-marker expression, phagocytosis, and cytokine production in purified monocytes from healthy human donors. Glycine decreased LPS-induced TNF-alpha production and increased IL-10 expression (IL-10 is an important anti-inflammatory cytokine) in a dose-dependent manner. In a whole blood assay, glycine also reduced TNF-alpha and, in addition, reduced IL-1beta (another major inflammatory cytokine) as well as increasing IL-10.

The authors conclude that “Our data indicate that GLY [glycine] has a potential to be used as an additional immunomodulatory tool in the early phase of sepsis and in different pathophysiological situations related to hypoxia and reperfusion.” This could be a significant medical advance, since sepsis is the fourth largest cause of death among Americans.

Another paper2 on glycine notes that “Glycine also inhibits the proliferation and migration of endothelial cells and smooth muscle cells, suggesting that glycine may be beneficial in inhibiting graft rejection, cardiovascular disease, and angiogenesis.” These effects occur via glycine’s reduction of the inflammatory immune response. This paper2also reports that “In rats injected with PG-PS [a primary structural component of gram-positive bacterial cell walls that causes a rheumatoid arthritis condition in rats] intra-articularly, dietary glycine attentuates ankle swelling and decreases infiltration of inflammatory cells, edema, and synovial hyperplasia in the joint.” Hence, by modulating immune activation, glycine may be a useful therapeutic for some autoimmune diseases.

A third paper3 reports that administration of glycine one hour after cecal (part of the large intestine) ligation and puncture (a procedure producing highly deadly sepsis in the absence of treatment) decreased the mortality rate in male adult rats from 50% to 0% at 10 days after the procedure. These authors conclude that “… this amino acid appears to be a useful adjunct for maintaining cellular functions and preventing lethality from polymicrobial sepsis.”

The use of glycine for these purposes is, of course, experimental. It is not clear what the proper dose should be or what possible problems might be caused by excessive doses. There has been little study of glycine’s use as a therapeutic in humans, except as an antirejection agent in transplantation, and data on potential toxicity of chronic high-dose intake are limited.

  1. Spittler et al. Immunomodulatory effects of glycine on LPS-treated monocytes: reduced TNFalpha production and accelerated IL-10 expression. FASEB J13:563-71 (1999).
  2. Zhong et al. L-Glycine: a novel anti-inflammatory, immunomodulatory, and cytoprotective agent. Curr Opin Clin Nutr Metabol Care 6:229-40 (2003).
  3. Yang et al. Glycine attenuates hepatocellular depression during early sepsis and reduces sepsis-induced mortality,” Crit Care Med 29:1201-6 (2001).

Risk of Heart Attack and Exposure to Traffic

A new paper1 reports that exposure to traffic increases the risk of a heart attack within one hour afterward by 2.92 times compared to nonexposed individuals. The authors found that “The time the subjects spent in cars, on public transportation, or on motorcycles or bicycles was consistently linked with an increase in the risk of myocardial infarction.” The study was based on 691 subjects from the Cooperative Health Research in the Region of Augsburg Myocardial Infarction Registry in Augsburg (southern Germany) for the period from February 1999 to July 2001. Data on subjects’ activities during the period preceding the heart attack were obtained with the use of patient diaries. The authors also note that “… the estimated risks were larger for morning and afternoon hours than for night hours, when the density of the traffic is low. … Particulate matter is considered to be of primary concern.”

Antioxidants may be protective against the inflammatory effects of roadway particulate pollution. One paper2 reports that lung inflammation is a key response to increased levels of particulate air pollution. They tested the ability of N-acetylcysteine(50 mg/kg ip) to protect against lung inflammation in a rat model of short-term exposure to concentrated ambient particles (CAP). They found that rats breathing the CAPs suffered severe oxidative stress associated with increased numbers of polymorphonuclear leukocytes (an inflammatory response) in bronchoalveolar lavage and slight lung edema. CAPs-exposed animals showed slight bronchiolar inflammation and thickened blood vessels in the bronchioles, which effects were prevented by N-acetylcysteine (NAC). NAC prevented accumulation of oxidants but only partially prevented accumulation of oxidized proteins (carbonyls).

The authors concluded that “The observed preventive effect of NAC suggests that treatment with low doses of this antioxidant could be used to ameliorate the toxic effects of particulate air pollution.”

Watch out for indoor particulate pollution too.

  1. Peters et al. Exposure to traffic and the onset of myocardial infarction. New Engl J Med 351:1721-30 (2004).
  2. Rhoden et al. N-Acetylcysteine prevents lung inflammation after short-term inhalation exposure to concentrated ambient particles. Toxicol Sci 79:296-303 (2004).

Anti-Inflammatory, Antisepsis Effects of Glycine

In the context of the article just above, we would like to mention the anti-inflammatory and antisepsis effects of the amino acid glycine. An interesting paper1 notes that glycine has been shown to protect against endotoxin shock in the rat by inhibiting TNF-alpha (tumor necrosis factor-alpha, a major inflammatory cytokine released in response to bacterial infection). In their paper, the authors studied the effects of glycine on lipopolysaccharide (LPS, a bacterial cell-wall constituent that activates the immune system, causing the release of inflammatory cytokines)-induced cell-surface-marker expression, phagocytosis, and cytokine production in purified monocytes from healthy human donors. Glycine decreased LPS-induced TNF-alpha production and increased IL-10 expression (IL-10 is an important anti-inflammatory cytokine) in a dose-dependent manner. In a whole blood assay, glycine also reduced TNF-alpha and, in addition, reduced IL-1beta (another major inflammatory cytokine) as well as increasing IL-10.

The authors conclude that “Our data indicate that GLY [glycine] has a potential to be used as an additional immunomodulatory tool in the early phase of sepsis and in different pathophysiological situations related to hypoxia and reperfusion.” This could be a significant medical advance, since sepsis is the fourth largest cause of death among Americans.

Another paper2 on glycine notes that “Glycine also inhibits the proliferation and migration of endothelial cells and smooth muscle cells, suggesting that glycine may be beneficial in inhibiting graft rejection, cardiovascular disease, and angiogenesis.” These effects occur via glycine’s reduction of the inflammatory immune response. This paper2also reports that “In rats injected with PG-PS [a primary structural component of gram-positive bacterial cell walls that causes a rheumatoid arthritis condition in rats] intra-articularly, dietary glycine attentuates ankle swelling and decreases infiltration of inflammatory cells, edema, and synovial hyperplasia in the joint.” Hence, by modulating immune activation, glycine may be a useful therapeutic for some autoimmune diseases.

A third paper3 reports that administration of glycine one hour after cecal (part of the large intestine) ligation and puncture (a procedure producing highly deadly sepsis in the absence of treatment) decreased the mortality rate in male adult rats from 50% to 0% at 10 days after the procedure. These authors conclude that “… this amino acid appears to be a useful adjunct for maintaining cellular functions and preventing lethality from polymicrobial sepsis.”

The use of glycine for these purposes is, of course, experimental. It is not clear what the proper dose should be or what possible problems might be caused by excessive doses. There has been little study of glycine’s use as a therapeutic in humans, except as an antirejection agent in transplantation, and data on potential toxicity of chronic high-dose intake are limited.

  1. Spittler et al. Immunomodulatory effects of glycine on LPS-treated monocytes: reduced TNFalpha production and accelerated IL-10 expression. FASEB J13:563-71 (1999).
  2. Zhong et al. L-Glycine: a novel anti-inflammatory, immunomodulatory, and cytoprotective agent. Curr Opin Clin Nutr Metabol Care 6:229-40 (2003).
  3. Yang et al. Glycine attenuates hepatocellular depression during early sepsis and reduces sepsis-induced mortality,” Crit Care Med 29:1201-6 (2001).

Risk of Heart Attack and Exposure to Traffic

A new paper1 reports that exposure to traffic increases the risk of a heart attack within one hour afterward by 2.92 times compared to nonexposed individuals. The authors found that “The time the subjects spent in cars, on public transportation, or on motorcycles or bicycles was consistently linked with an increase in the risk of myocardial infarction.” The study was based on 691 subjects from the Cooperative Health Research in the Region of Augsburg Myocardial Infarction Registry in Augsburg (southern Germany) for the period from February 1999 to July 2001. Data on subjects’ activities during the period preceding the heart attack were obtained with the use of patient diaries. The authors also note that “… the estimated risks were larger for morning and afternoon hours than for night hours, when the density of the traffic is low. … Particulate matter is considered to be of primary concern.”

Antioxidants may be protective against the inflammatory effects of roadway particulate pollution. One paper2 reports that lung inflammation is a key response to increased levels of particulate air pollution. They tested the ability of N-acetylcysteine(50 mg/kg ip) to protect against lung inflammation in a rat model of short-term exposure to concentrated ambient particles (CAP). They found that rats breathing the CAPs suffered severe oxidative stress associated with increased numbers of polymorphonuclear leukocytes (an inflammatory response) in bronchoalveolar lavage and slight lung edema. CAPs-exposed animals showed slight bronchiolar inflammation and thickened blood vessels in the bronchioles, which effects were prevented by N-acetylcysteine (NAC). NAC prevented accumulation of oxidants but only partially prevented accumulation of oxidized proteins (carbonyls).

The authors concluded that “The observed preventive effect of NAC suggests that treatment with low doses of this antioxidant could be used to ameliorate the toxic effects of particulate air pollution.”

Watch out for indoor particulate pollution too.

  1. Peters et al. Exposure to traffic and the onset of myocardial infarction. New Engl J Med 351:1721-30 (2004).
  2. Rhoden et al. N-Acetylcysteine prevents lung inflammation after short-term inhalation exposure to concentrated ambient particles. Toxicol Sci 79:296-303 (2004).

Green Tea Polyphenols as Acetylcholinesterase Inhibitors for Memory Improvement

A recent paper1 reports that in 4–5-week-old male ICR rats fed a regular chow diet supplemented with 0.2% by weight of green tea polyphenols for 7 days, the animals had improved memory in the step-through latency test after pretreatment with scopolamine. Scopolamine is a muscarinic cholinergic receptor blocker that causes memory deficits as a result of reduced cholinergic neurotransmission. Memory is assessed via a test (step-through latency) in which the animals are placed in a box with two compartments, one light and one dark. During training, the animals are placed in the lighted compartment, and when they enter the dark compartment (which they normally prefer), they receive a shock. Their ability to remember this later is the basis for memory assessment. Increased latency in the treated animals, i.e., delayed entry into the dark compartment (as compared to nontreated animals) after previous shock, is a measure of the memory-enhancing effects of acetylcholinesterase inhibitors. The authors found that “Chronic administration of TP [green tea polyphenols] significantly increased latency time.” They found that “TP administration dramatically inhibited AChE [acetylcholinesterase] activity (71% inhibition) as compared to the control. … The concentration required for 50% enzyme inhibition (IC50) was 248 µg/ml.”

This may be yet another mechanism for beneficial effects from green tea polyphenols.

  1. Kim et al. Effects of green tea polyphenol on cognitive and acetylcholinesterase activities. Biosci Biotechnol Biochem 68(9):1977-9 (2004).

The Cholinergic Anti-Inflammatory Pathway

The cholinergic nervous system, acting via the vagus nerve, serves as one of the human body’s natural anti-inflammatory mechanisms to prevent excessive release of inflammatory cytokines in (for example) infection/sepsis or autoimmune diseases, such as rheumatoid arthritis.1

The nicotinic acetylcholine receptor alpha7 subunit has recently been identified as essential to the cholinergic anti-inflammatory effects.1 Nicotine directly activates this nicotinic acetylcholine receptor alpha7 subunit. However, due to nicotine’s addictive and other adverse effects (e.g., it promotes angiogenesis), nobody is very enthusiastic about using it as an anti-inflammatory. The authors suggest that “… it is now reasonable to consider the therapeutic potential for targeting the nicotinic acetylcholine receptor alpha7 subunit to inhibit TNF [tumor necrosis factor, a potent inflammatory cytokine], either by direct pharmacological approaches or through increasing activity in the vagus nerve.”1

We would like to point out that acetylcholine acts as an agonist at the nicotinic and muscarinic acetylcholine receptors. Though it is not selective for the nicotinic receptors, a choline and vitamin B5 supplement does increase acetylcholine synthesis and release2,3 and, hence, can be expected to activate nicotinic acetylcholine receptors. One nice thing about choline and vitamin B5 supplements is that both are very safe to take and will not result in nasty side effects, hitherto unknown, emerging years later, as may occur with highly selective xenobiotic drugs (for example, selective COX-2 inhibitors), especially when used chronically.

Galantamine (extracted from the snowdrop flower bulb) acts as an agonist to nicotinic acetylcholine receptors4 and, hence, should enhance the cholinergic anti-inflammatory pathway. Anti-inflammatories such as curcumin have been shown to protect against Alzheimer’s disease, as does galantamine. See our interview “Maintain Your Brain the Durk Pearson & Sandy Shaw Way” in the May 2004 issue of Life Enhancement (free from Life Enhancement Products at 1-800-543-3873).

  1. Wang et al. Nicotinic acetylcholine receptor alpha7 subunit is an essential regulatory of inflammation. Nature 421:384-8 (2003).
  2. Wurtman. Choline metabolism as a basis for the selective vulnerability of cholinergic neurons. Trends Neurol Sci 15(4):117-22 (1992).
  3. Ulus and Wurtman. Choline increases acetylcholine release. [Letter] LancetMarch 14, 1987.
  4. Lloyd and Williams. Neuronal nicotinic acetylcholine receptors as novel drug targets. J Pharmacol Exp Therapeut 292(2):461-7 (2000).

USDA Ban on Ranchers Testing Their Cattle for BSE Is a Violation of the First Amendment

As you are probably aware, the USDA has prohibited private testing of cattle by meatpackers or ranchers for bovine spongiform encephalopathy (BSE, or “mad cow” disease).1 The supposed reason is that misinformation as a result of badly done tests or even fraud could thereby be passed on to the public. However, the USDA rule doesn’t simply prohibit false or misleading information, it prohibits the communication by any entity other than itself of all BSE test information, including entirely truthful and nonmisleading information. This is a violation of the First Amendment (cases cited below).

It is clear that the USDA is regulating speech (information) in this case. The USDA is not prohibiting anybody from buying lab equipment for making any tests or even from performing any tests; the prohibition is on the communication of BSE test information to the public and is, hence, a pure First Amendment issue.

The prohibition of the communication of truthful, nonmisleading information in several recent commercial speech cases is right on point. We ourselves have been coplaintiffs in a number of suits against the FDA in which the agency prohibited the communication of truthful, nonmisleading information concerning the effects of dietary supplements and in which the courts ruled this to be a violation of the First Amendment. In fact, owing to our and our coplaintiffs’ victories in these cases, we have forced the FDA to make a dramatic change in its speech regulation policies by allowing health claims (called “qualified health claims,” which include an FDA disclaimer) that do not meet its as yet undefined “significant scientific agreement” standard if there is scientific evidence supporting the claim.

We have been able to force the agency to permit claims (long overdue and only after 9 years of litigation) that, for example, “antioxidant vitamins may reduce the risk of cancer” and “fish oils (omega-3 fatty acids) may reduce the risk of cardiovascular disease.” (In the case of the latter claim, fish oils eaten as two fatty fish meals a week or fish oil supplements reduce the risk of a sudden-death heart attack by 50–80%, information the FDA banned on fish oil products and fish at a cost of some 1,000,000 unnecessary deaths of Americans during the course of the litigation. Osama bin Laden killed only 3000 Americans in the 9/11 attack. So much for protecting the public health …) The point is that, now that these court decisions are in place, it will be much easier to win a case arguing that USDA prohibition of BSE-free claims by banning private tests is a violation of the First Amendment.

The real reason for the ban on private BSE testing, we believe, is that the companies who did such testing would have an advantage in the market by being able to advertise BSE-free beef (if that is what they found). It would put pressure on other companies also to do such testing, and a lot of them probably would rather not bear the expense. Much easier to lobby the USDA to “level the playing field” by making private BSE testing illegal. In addition, the USDA doesn’t want to be “scooped” by private BSE testers and made to look incompetent, if not unnecessary. Hence, the USDA does all the testing itself, and we all know how reliable and trustworthy the government is …

We realize that most attorneys representing ranchers or meatpackers may know little (if anything) about First Amendment jurisprudence. We suggest, therefore, that if you want a brilliant and honest First Amendment attorney to represent you in such a case, you contact Jonathan Emord, who represented us in all our winning FDA cases and who is continuing to battle on for us and our coplaintiffs in other FDA cases where we hope to break new ground. (We do not get anything for this plug; we just want to see the First Amendment case against the USDA argued correctly.) You can reach him at Emord & Associates, P.C., 1800 Alexander Bell Drive, Suite 200, Reston, VA 20191, tel (202) 466-6937, fax (202) 466-6938, jemord@emord.com.

Court decisions: FDA in violation of First Amendment. Pearson v. Shalala, 164 F3d 650 (DC Cir 1999, en banc rehearing denied); Pearson v. Shalala, 130 F Supp 2d 105 (DDC 2001) (“Pearson II”); Pearson v. Thompson, 141 F Supp 2d 105 (DDC 2001) (“Pearson III”).

Supreme Court commercial speech decisions: 44Liquormart v. Rhode Island, 517 US 484 (1996); Rubin v. Coors Brewing Co., 514 US 476 (1995); Thompson v. Western States Med. Ctr., 535 US 357 (2002). (The two of us, Julian Whitaker, M.D., and others filed an amicus curiae brief in this case, which we believe substantially helped the court to come to the 5–4 decision in favor of First Amendment protection for commercial speech of compounding pharmacists.)

Also, see Smith v. Goguen, 415 US 566, 572 (1974). (The due process doctrine of vagueness demands a greater degree of specificity when a statute’s literal scope is capable of reaching expression sheltered by the First Amendment.)

  1. Adamy. U.S. rejects meatpacker’s bid to conduct mad-cow testing. The Wall Street Journal, April 12, 2004, p. B6.



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