June 2005 Blog with Durk and Sandy

There is no worse tyranny than to force a man to pay for what he does not want merely because you think it would be good for him.— Robert Heinlein

All laws which are repugnant to the Constitution are null and void.— Marbury v. Madison, 5 US (2 Cranch) 137, 174, 176 (1803)

Right. But you cannot enforce this without the help of the courts. The right of the states to nullify unconstitutional federal laws (nothing in the Constitution prohibited it, and both Madison and Jefferson wrote in support of state nullification of the federal Alien and Sedition Acts) is impossible in the face of overwhelming federal military might. Ah, the dangers of standing armies that the Founders warned us of.

A General Accounting Office (GAO) study of FDA in 1975 revealed that 150 FDA officials owned stock in the companies they were supposed to regulate.— Barry Lynes, The Healing of Cancer Marcus Books, Queensville, Ontario, 1989. . . the task force considered many issues in its deliberations, including: to insure [that] the existence of dietary supplements on the market does not act as a disincentive for drug development.— FDA “Dietary Supplements Task Force Final Report” June 1992 (released June 1993), pp 2 and 71


The FDA’s desperate battle to censor (in violation of the First Amendment) the communication by dietary supplement manufacturers and vendors of truthful and nonmisleading information on the effects of supplements on disease is part and parcel of the agency’s commitment to protecting the pharmaceutical industry from competition by dietary supplements. The big problem that we have now is that the courts cannot be relied upon to uphold and defend the Constitution and to strike down the agency’s self-interested distortions in the construction of statutes. Judges too often focus upon their fears of the consequences of the exercise of freedom of speech rather than that the federal government shall “make no law … abridging the freedom of speech” (First Amendment). How otherwise would we have gotten McCain-Feingold, a blatant federal abridgment of political free speech?

FLASH! Court Strikes Ephedra Ban

Wow! We have just received news (4/14/05) of an exciting and positive new development: the U.S. District Court, District of Utah, Central Division (Judge Tena Campbell presiding) has overturned the FDA’s Final Rule in which the agency banned all ephedra alkaloid-containing dietary supplements. This is a well-reasoned court decision (copy available from Cynthia Lewis or DuWayne Hamilton at Emord & Associates, 202-466-6937), in which the most important points go far beyond ephedra to an examination of the FDA’s interpretation of the powers granted to it by Congressional statute, which provide the only authority FDA has in dealing with dietary supplements. The court has found that the FDA has gone beyond its authority under the DSHEA (Dietary Supplement Health and Education Act) in its attempt to ban ephedra.

Although we were not parties to this suit, our brilliant constitutional law attorney, Jonathan Emord, represented the plaintiffs (Nutraceutical Corporation).

The FDA banned all ephedra-containing products on the basis of a risk-benefit analysis in which the agency declared that “in the absence of a sufficient benefit, the presence of even a relatively small risk of an important adverse health effect to a user may be unreasonable,” justifying (according to the agency) the agency’s conclusion that ephedra alkaloid-containing dietary supplements (EDS) “present a significant or unreasonable risk of injury,” thus meeting (supposedly) the adulteration provision in DSHEA, which permits the agency to ban a supplement’s sale.

However, nowhere in the DSHEA is there a provision authorizing FDA to conduct a risk-benefit analysis. The court notes that “The imposition of a risk-benefit analysis requires the producer of an EDS to establish a benefit and alleviates the burden Congress placed squarely on the government to demonstrate the existence of a significant or unreasonable risk.” In a footnote, the court agrees with the plaintiffs that if food producers had to “show a benefit as a precondition to sale, the sale of foods such as potato chips might be prohibited.” In fact, DSHEA provides that dietary supplements are to be regulated as foods, and foods are not required to provide evidence of a benefit for legal sale.

We realized at the time of the Final Rule that this usurpation of authority by the FDA to require the establishment of a benefit for a dietary supplement was not authorized by statute and constituted a serious risk to the future availability of any dietary supplement. It invoked drug requirements (establishing safety and efficacy) for dietary supplements. This court decision has clearly thrown out the FDA’s claim of authority to do risk-benefit analyses to regulate dietary supplements. In the FDA’s risk-benefit analysis for EDS, the FDA didn’t even allow for a weight-loss benefit because, although FDA admitted there was evidence to support a modest, short-term weight loss, the FDA couldn’t determine whether such weight loss was associated with improved health outcomes, such as improved cardiovascular risk factors. Of course, to determine the latter would have required at least one very large, extremely expensive intervention trial, as must be done for drugs. To require this of dietary supplements would mean that most dietary supplements could no longer be sold. The purpose of DSHEA, after all, was to prevent the FDA from regulating dietary supplements as drugs.

The court additionally found that “The plain language of the statute requires a dose-specific analysis. Legislative history also confirms Congress’ intent to require that a finding of adulteration be dose-specific: ‘a safety finding cannot be entered against a supplement based upon a dosage not recommended to consumers in the labeling.’” [Court quotes from Sen. Rep. No. 103-410 at 36] Hence, the FDA cannot simply ban all ephedra alkaloid-containing dietary supplements and has failed “to prove by a preponderance of the evidence that a dosage of 10 mg or less of ephedrine alkaloids presents a significant or unreasonable risk of illness or injury,” as required by the DSHEA in order to find a supplement to be “adulterated.”

Congratulations and many thanks to Jonathan Emord and his associates and Nutraceutical Corp. for this magnificent victory!


Elevated levels of C-reactive protein (CRP), a molecule associated with inflammation, are found in, inter alia, heart disease, rheumatoid arthritis, diabetes, gastrointestinal cancer, chronic kidney failure,1 and possibly sudden cardiac death.2

A recent paper3 reports that, using data on 3920 subjects aged 20 years or older in the National Health and Nutrition Examination Survey (1999–2000), “the odds ratio (OR) for increased CRP concentration (>3.0 mg/L) was 0.49 (95% CI 0.37–0.65; P for trend <0.001) for the highest quintile of fiber intake compared with the lowest. There was a slight weakening of the relationship after adjustment for age, gender, race, education, smoking, physical activity, body mass index, total energy, and fat intake.

Decreased dietary fiber intake has been reported to be an important risk factor for cardiovascular disease, but the mechanism (or even whether dietary fiber is just a marker for something else) is unknown.3 Hence, the establishment of an anti-inflammatory property for dietary fiber would be very important. Note: This study didn’t report data on the separate effects of soluble and insoluble fiber.

One possible mechanism for an inflammatory modulating effect of dietary fiber is through its influence on the composition of the resident intestinal microflora, which are known to help maintain gut homeostasis by balancing proinflammatory and anti-inflammatory responses in the gut.4 The maintenance of a healthy gut microflora may provide protection against GI disorders, such as infection-induced diarrhea, inflammatory bowel disease, and even cancer.5


  1. Menon et al. Relationship between C-reactive protein, albumin, and cardiovascular disease in patients with chronic kidney disease. Am J Kidney Dis42:44-52 (2003).
  2. Albert et al. Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death. Circulation 105:2595-9 (2002).
  3. Ajani et al. Dietary fiber and C-reactive protein: findings from National Health and Nutrition Examination Survey data. J Nutr 134:1181-5 (2004).
  4. Mohamadzadeh et al. Lactobacilli activate human dendritic cells that skew T cells toward T helper 1 polarization. Proc Natl Acad Sci USA 102(8):2880-5 (2005).
  5. Puupponen-Pimia et al. Development of functional ingredients for gut health. Trends Food Sci Technol 13:3-11 (2002).


A pilot study1 examined the effects of vitamin D (cholecalciferol) as a potential treatment for rising PSA levels in the absence of any other signs or symptoms of advancing disease after early treatment for prostate cancer. The need to find ways to treat what is called PSA relapse before the consideration of androgen abatement is important because the latter treatment has a limited period of efficacy, since the cancer cells ultimately become androgen-insensitive and the treatment itself has potentially severe side effects (e.g., impotence and loss of fertility).

The 15 patients in this study had a mean length of time of 65 months from surgery or radiation before they were started on 2000 IU/day of vitamin D. The patients were followed up for a median period of 8 months (4–21 months).

Vitamin D is converted in the body to the hormone calcitriol. Prostate cancer cells slow their rate of replication when exposed to calcitriol. However, the concentrations of calcitriol required for this response are well in excess of the normal physiological levels of the hormone, while physiological concentrations of 25-hydroxycholecalciferol, a metabolite of vitamin D, can also produce this effect.1 Past studies are reported to have shown that 2000 IU/day of vitamin D improved bone-pain scores and muscle strength in patients with metastatic prostate cancer.1

Of the 15 patients, eight had a decrease in absolute serum PSA level that lasted for 5–17 months after starting vitamin D treatment, while another patient had a PSA value that fluctuated around the baseline value, with no clear trend for increase or decrease. In the absence of vitamin D supplementation, there was no significant change in the rate of rise of PSA. In the vitamin D-treated patients, the PSA doubling time increased (that is, it took significantly longer for PSA levels to increase to twice their initial value) in 14 out of 15 patients.

The authors note that, even without any treatment, prostate cancer patients may remain symptom-free for a long time. From the onset of PSA relapse in the absence of treatment, it took a median of about 7.5 years for postsurgical patients to develop distant metastases, and then a further median 6.5 years to death. The authors suggest that, in the face of such a long development time, a cheap and relatively safe substance such as vitamin D could be very useful, assuming that larger studies replicate these findings of a reduced rise in PSA.

As vitamin D is cheap, beneficial, and has few potential side effects at 2000 IU/day, we already take that much. In fact, earlier studies had already shown vitamin D to be protective against cancer, type 1 diabetes, heart disease, and osteoporosis.2 Another study3 found that 1,25-dihydroxyvitamin D3 (D3), an active metabolite of vitamin D, is neuroprotective, inducing neurotrophic factors such as GDNF (glial-derived neurotrophic factor), NGF (nerve-growth factor), and NT3/NT4 (neurotrophin 3/4) in vivo and in vitroin rodents. The authors of the latter paper, in fact, suggest that “… this vitamin [D3] may be potentially useful in treatment of Parkinson’s disease and other neurodegenerative disorders.”


  1. Woo et al. Pilot study: potential role of vitamin D (cholecalciferol) in patients with PSA relapse after definitive therapy. Nutr Cancer 51(1):32-6 (2005).
  2. See, e.g., Holick. Vitamin D: importance in the prevention of cancers, type 1 diabetes, heart disease, and osteoporosis. Am J Clin Nutr 79:362-71 (2004).
  3. Wang et al. Vitamin D3 attenuates 6-hydroxydopamine-inducing neurotoxicity in rats. Brain Res 904:67-75 (2001).


One problem with comparing healthcare systems in the U.S. versus other countries by, for example, considering life expectancy or infant mortality rates is that the U.S. population is made up of many disparate ethnic and racial groups that have strikingly different lifespans, while infant mortality rates differ widely depending upon such factors as race, geographic location, income, and education.1

A better measure of a country’s healthcare system may be mortality rates for diseases that modern medicine can treat effectively. A comparison of breast cancer mortality ratio (the percentage of those diagnosed with the disease who die of it is shown in parentheses) shows: New Zealand (46%), United Kingdom (46%), France (35%), Germany (31%), Canada (28%), Australia (28%), and the United States (25%).1Prostate cancer mortality ratio (the percentage of those diagnosed with the disease who die of it is shown in parentheses) shows: United Kingdom (57%), France (49%), Germany (44%), Australia (35%), New Zealand (30%), Canada (25%), and the United States (19%).1 As these figures clearly show, patients diagnosed with prostate or breast cancer in the U.S. have a better chance of survival than those in other countries. The figures were obtained from Gerard F. Anderson and Peter S. Hussey, “Multinational Comparisons of Health Systems Data,” Commonwealth Fund, October 2000.


  1. Goodman JC. Health care in a free society: rebutting the myths of national health insurance. Cato Institute Policy Analysis No. 532, Jan 27, 2005.


An interesting paper1 reports that greater linoleic acid (an n-6 fatty acid) consumption is associated across time and countries with a greater risk of homicide. The linoleic acid consumption was calculated from World Health Organization disappearance data for 12 major seed oils in the food supply over the years 1961 to 2000 in Argentina, Australia, Canada, the United Kingdom, and the United States. The apparent consumption of linoleic acid ranged from 0.29 en% (percentage of daily food energy) for Australia (1962) to 8.3 en% for the U.S. (1990s). Correlations between greater linoleic acid consumption (disappearance) and homicide mortality in each country were significant in linear regression models.

The data for greater homicide risk with increased linoleic acid consumption are consistent with other studies reporting that reduced consumption (as measured by lower tissue levels) of the n-3 fatty acids EPA and/or DHA is correlated with increased hostility measures in 4000 subjects in the CARDIA epidemiological study, in aggressive cocaine addicts, and in violent prisoners.1 The authors note that one mechanism that may link reduced n-3 fatty acids or increased linoleic acid consumption with increased homicide is a deficit in serotonergic neurotransmission in the frontal cortex, which is associated with increased impulsive violent behavior.


  1. Hibbeln et al. Increasing homicide rates and linoleic acid consumption among five western countries, 1961–2000. Lipids 39(12):1207-13 (2004).


The p53 protein, being intensively studied for its cancer-suppressive function (p53 is mutated in about half of all human cancers1), is also linked to longevity. A recent mouse model in which the animals were engineered to have an increased function of p53 showed the expected decrease in cancer incidence, but the mice also aged prematurely.2,3 However, in a different mouse model in which genetically engineered (in a different way) mice had extra p53 activity, the mice had an enhanced DNA damage response, were tumor-resistant, and aged normally.4

It is now believed that p53 is a key regulatory protein that balances the need for cell proliferation against the need for cancer suppression (by reducing cellular proliferation).5 Cellular senescence, an important part of the aging process at the cellular level, is an irreversible arrest of proliferation, though cells can continue to survive for a lengthy period of time. The accumulation of senescent cells (including stem cells) contributes to aging. Hence, it would appear that a certain amount of p53 activity is essential to prevent cancer, but too much activity leads to reduced tissue renewal and repair, stem cell deletion, and organismal aging.

We now have human data on this balancing act of p53.1,6 In a study of polymorphic variation in the human p53 gene,6 scientists discovered that replacing the arginine at position 72 with a proline results in a human p53 with less apoptosis-inducing potential (reduced suppression of cancer). In a formal meta-analysis of the published literature, the scientists found that carriers of the TP53 codon 72 Pro/Pro (two alleles with the arginine replaced by proline) have an increased cancer risk compared to Arg/Arg carriers (no replacement of arginine by proline). Finally, they found that in a prospective study of 1226 people aged 85 years and over, carriers of the Pro/Pro genotype (that is, p53 with a reduced suppression of cancer) had a 41% increased survival despite a 2.54-fold increased proportional mortality from cancer.6 The result is a significant decrease in mortality from all causes but cancer and a nonsignificant increase in mortality from cancer. Hence, the authors suggest, “… human p53 protect[s] against cancer but at a cost of longevity.” This is an example of antagonistic pleiotropy, where adaptations that increase fitness in early life lead to reduced survival in old age.

Not much is known about manipulable factors that affect p53 expression. One paper7reports that statins (HMG-CoA reductase inhibitors) attenuated the p53 response to DNA damage in HepG2 cell culture. Some research has been published on possible anticancer effects of statins. How a possible decreased p53 response to DNA damage might fit in with that is unclear. In a different paper,8 it was reported that glucocorticoid receptor activation resulted in enhancement of p53 activity and inhibition of neural cell proliferation. As the authors note, “… it merits mention that glucocorticoids are used to reduce inflammation and edema in neuro-oncology; a hitherto unrecognized benefit of such treatment may be proliferation arrest.” On the other hand, chronic exposure to high levels of glucocorticoids might be expected to damage the brain by suppressing neurogenesis, such as occurs in depression.


  1. Donehower. p53: guardian and suppressor of longevity? Exp Gerontol 40:7-9 (2005).
  2. Ferbeyre and Lowe. The price of tumour suppression? Nature 415:26-7 (2002).
  3. Tyner et al. p53 mutant mice that display early ageing-associated phenotypes. Nature 415:45-53 (2002).
  4. Garcia-Cao et al. “Super p53” mice exhibit enhanced DNA damage response, are tumor-resistant, and age normally. EMBO J 21(22):6225-35 (2002).
  5. Campisi. Fragile fugue: p53 in aging, cancer, and IGF signaling. Nature Med 10(3):231-2 (2004).
  6. Heemst et al. Variation in the human TP53 gene affects old age survival and cancer mortality. Exp Gerontol 40:11-15 (2005).
  7. Paajarvi et al. HMG-CoA reductase inhibitors, statins, induce phosphorylation of Mdm2 and attenuate the p53 response to DNA damage. FASEB J 19:476-8 (2005).
  8. Crochemore et al. Enhancement of p53 activity and inhibition of neural cell proliferation by glucocorticoid receptor activation. FASEB J 16:761-70 (2002).


A recent American Cancer Society report1 claims that since 1999, cancer has surpassed heart disease as the primary cause of death in Americans younger than age 85. A graph shows that between 1975 and 2001, heart disease mortality rates, starting at a much higher level than the overall cancer mortality rates, have fallen steeply in a near-linear fashion, while cancer mortality rates have stayed nearly the same. The heart disease mortality and cancer mortality lines crossed in about 1999. However, because heart disease is such an important cause of death in those over 85, the absolute number of deaths from heart disease (696,947 in 2002) is still greater than that from cancer (557,271 in 2002). Lynn Ries, a health statistician at the National Cancer Institute, says, “We have gone from six heart deaths per each cancer death in 1970 to three heart deaths per cancer death.”


  1. Twombly. News: cancer surpasses heart disease as leading cause of death for all but the very elderly. J Natl Cancer Inst 97(5):330-1 (2005).


As you know, cholinesterase inhibitors are a new class of drugs used in the treatment of Alzheimer’s disease. Cerebral-selective cholinesterase inhibitors (these work primarily in the brain, rather than equally affecting cholinesterase throughout the body) include donepezil and galantamine. Clinical trials using donepezil (presumably as a monotherapy) show Alzheimer’s patients deriving long-lasting beneficial effects, for at least two years.1

Two new studies1,2 by two independent groups using donepezil reveal exciting new effects in humans. Donepezil was chosen for the first study1 because it is the most widely used selective cerebral cholinesterase inhibitor for Alzheimer’s, with a low rate of side effects. The first study1 was a randomized, controlled study of donepezil in 24 healthy elderly males 61–70 years of age. The effects of donepezil at 5 mg/day for 4 weeks and then 10 mg/day for another 4 weeks were determined for GH release and IGF-1 levels.

The authors cite an earlier study in which the cerebral-selective cholinesterase inhibitor rivastigmine powerfully enhanced GH release in response to repeated GHRH (growth hormone-releasing hormone) pulses in healthy elderly male and female subjects. The mechanism for this potentiation is probably via the inhibition of somatostatin, a hormone that inhibits growth hormone release from the pituitary.1 One benefit of using a selective cholinesterase inhibitor to increase GH release as compared to using GH itself is (aside from the cost and inconvenience of injections) that the GH release in response to the cholinesterase inhibitor is still subject to natural regulatory mechanisms, so that the GH is released when it normally would be, only more so, whereas GH treatments cause GH effects without control mechanisms in place to limit it to physiological functionality. As a consequence, human treatment with actual GH has been fraught with side effects, such as edema, arthralgia, myalgia, and nerve-compression syndromes,1 as well as increased blood sugar levels (reduced glucose tolerance).

The authors report that “The main finding of this study was that full-dose treatment with the cerebral-selective ChEI donepezil elevated basal GH and IGF-1 to a remarkably increased level in the elderly male.” In fact, they found an increase of total serum IGF-1 of 31%, resulting in levels that are seen in males 20 years younger. The authors note the correlation of IGF-1 with lean body mass, bone mineral density, and cognitive function.1 IGF-1 is an important neuroprotective growth factor. They also note that lower IGF-1 levels are correlated with an increased risk of cardiovascular disease. On the potential downside, higher levels of IGF-1 are correlated with increased risks of certain cancers, such as prostate, breast, colorectal, and lung, but (the authors state) the associations are “modest and vary between sites.”

The second study2 examined, in 21 Alzheimer’s patients, the effects of 10 mg/day of donepezil for a month on release of inflammatory cytokines by peripheral blood mononuclear cells (PBMC), immune cells in the periphery. The important negative effects of excess inflammatory cytokines (largely released by the brain’s resident immune cells, microglia) on brain function are well established. The authors note that PBMC from Alzheimer’s patients release more amyloid precursor protein (APP) as compared to normal individuals; hence, they suggest that PBMC could be a circulating factory of APP that can deliver abnormal amyloid for deposition in the brain and peripheral tissues. In fact, inflammatory cytokines have been shown to increase APP expression in Alzheimer’s.

One of the interesting effects of acetylcholine is that, acting through the vagus nerve, it acts as an anti-inflammatory.3 Hence we have long thought that it would help to reduce inflammatory processes by increasing cholinergic activity through a choline and vitamin B5 (required to convert choline to acetylcholine) supplement. Now we also take our galantamine supplement to increase acetylcholine further.

The results showed that the unstimulated PBMC of Alzheimer’s subjects in the study spontaneously produced higher amounts of the inflammatory cytokines IL-6 and IL-1beta, as well as more OSM (oncostatin-M), which has both pro-inflammatory and anti-inflammatory effects. The authors note that this means the patients’ PBMC were already partially activated, although unstimulated. The effects of the 1-month treatment with 10 mg/day of donepezil showed that both unstimulated (spontaneous) and PHA-stimulated PBMC in all subjects released lower levels of OSM, IL-1beta (57% reduction in spontaneous, 54% in stimulated conditions), and IL-6. The results indicate that, although Alzheimer’s is considered a brain disorder, it also has peripheral effects, in this case an increase in pro-inflammatory immune activity. Since increased inflammation promotes a variety of age-associated diseases, such as cancer, cardiovascular disease, and neurodegenerative diseases, a decrease in inflammation through increased acetylcholine could be a major health benefit of selective cerebral cholinesterase inhibitors.


  1. Obermayr et al. The age-related down-regulation of the growth hormone/insulin-like growth factor-1 axis in the elderly male is reversed considerably by donepezil, a drug for Alzheimer’s disease. Exp Gerontol 40:157-63 (2005).
  2. Reale et al. Acetylcholinesterase inhibitors effects on oncostatin-M, interleukin-1beta, and interleukin-6 release from lymphocytes of Alzheimer’s disease patients. Exp Gerontol 40:165-71 (2005).
  3. Borovikova et al. Vagus nerve stimulation attenuates the systemic inflammatory response to endotoxin. Nature 405:458-62 (2000).


There are practical methods to slow the digestion of carbohydrates and the release of glucose. One way is to eat high-amylose carbohydrates, such as high-amylose starches, which are digested slowly. However, most carbohydrates, including those from whole grains, are composed largely of amylopectin carbohydrates, which are quickly broken down into glucose. Adequate amounts of vinegar eaten with food also slow down gastric emptying, thus slowing digestion. Another way to slow the digestion of carbohydrates is to eat foods that contain components that inhibit the enzyme alpha-glucosidase, which carries out the final step in the digestive process of carbohydrates.1Drugs used for inhibiting this enzyme as a treatment for postprandial (after eating) hyperglycemia include acarbose, miglitol, and voglibose.1

Two papers in a recent issue of The Journal of Agricultural and Food Chemistry identify some food-derived alpha-glucosidase inhibitors in in vitro tests. The first paper1identifies a component of cumin seeds, cuminaldehyde, that potently inhibits alpha-glucosidase. The IC50 (quantity that reduces enzyme activity by 50%) is 0.00085 mg/ml for aldose reductase (enzyme that converts glucose to sorbitol—the polyol pathway—a source of serious hyperosmotic stress in diabetics) and 0.5 mg/ml for alpha-glucosidase.

A second paper2 reports testing a number of polyphenol-rich extracts of soft fruits for their ability to inhibit alpha-amylase (the first enzyme involved in carbohydrate metabolism, found in the mouth as well as in the gut) and alpha-glucosidase. The authors note that, in earlier studies by other scientists, “Polyphenolic extracts from a number of plants were found to be effective inhibitors of intestinal alpha-glucosidase activity with Ki values in the same range as synthetic inhibitors (acarbose and voglibose) already being used therapeutically to control non-insulin-dependent diabetes mellitus (NIDDM).”2 In their new study, the authors report that strawberry and raspberry extracts were more effective alpha-amylase inhibitors than blueberry and blackcurrant extracts. Alpha-glucosidase was more readily inhibited by blueberry and blackcurrant extracts. The extent of effectiveness in inhibiting alpha-glucosidase was related to the content of anthocyanins (anthocyanins are highly colored substances, usually blue or purple). The extracts most effective in inhibiting alpha-amylase contained larger amounts of tannins; other plant extracts with high tannin content, such as red grape, red wine, and green tea, were also effective inhibitors.2 In rats, intestinal alpha-glucosidase was also inhibited by the fruit extracts in the order of blueberry and blackcurrant, strawberry, raspberry, and red cabbage.2

In the first paper,1 the authors note that “It has been reported that alpha-glucosidase inhibitors usually do not alter the total amount of carbohydrate absorbed and, therefore, do not cause any net nutritional caloric loss, although they slow carbohydrate digestion.” However, it has been clear for many years that in order to slow aging, it is important to reduce blood glucose and insulin levels, as well as insulin signaling (as occurs in calorically restricted rodents). For this purpose, these plants and their extracts may be of great value.


  1. Lee. Cuminaldehyde: aldose reductase and alpha-glucosidase inhibitor derived from Cuminum cyminum L. seeds. J Agric Food Chem 53:2446-50 (2005).
  2. McDougall et al. Different polyphenol components of soft fruits inhibit alpha-amylase and alpha-glucosidase. J Agric Food Chem 53:2760-6 (2005).


Mechanisms tell you a lot about how a drug or natural substance works. It is perfectly legal to provide label information on mechanisms (structure-function claim) so long as you do not also point out on the label when that mechanism might be involved in the treatment of disease. The battle for First Amendment freedom of speech concerning the communication by manufacturers or vendors of dietary supplements (or foods) of truthful and nonmisleading information concerning when they may be useful in treating current disease (not just reducing the risk of getting the disease in the future) continues unabated since we initiated litigation against the FDA in 1994. In the meantime, we hope to see more information on mechanisms as structure-function claims on labels. When information is important enough, the public will eventually make the connection.

A new paper1 reports that a mixture of anthocyanins (colored—usually blue or purple—flavonoids widely distributed in fruits, vegetables, and red wines) inhibits phosphodiesterase-5, an enzyme that is inhibited by Viagra with well-known results. The authors note that “In vivo red wine-derived polyphenolic compounds were able to reduce blood pressure in normo- and hypertensive rats, and the amplitude of vasorelaxation changed as a function of the variability of wine constituents according to grape varieties, cultivar, and methods for obtaining wine.” They also mention that several studies have reported that the red wine- and grape-enhanced endothelial relaxation occurred via increased generation or biological activity of NO (nitric oxide). Knowing that the cyclic GMP in vascular smooth muscle cells is regulated by phosphodiesterase-5, which determines the duration and extent of vasorelaxation, they looked into the possibility that the enzyme was also involved in the vasorelaxing effects of the red wine and grape polyphenols.

The authors tested the effects on phosphodiesterase-5 activity of six anthocyanins isolated from cabernet sauvignon. The results showed that the mixture inhibited PDE5 (this test used a recombinant form of human PDE5A1 isoenzyme). The statistically significant inhibition began at 1 µM, and at 100 µM the inhibition was almost complete. The IC50 (concentration required to inhibit enzyme activity by 50%) was 11.6 µM, which the authors explain is very close to that of the PDE5 inhibitor drug zaprinast (9.8 µM). Malvidin-3-O-beta-glucoside (a blue anthocyanin also found in blueberries) was the most active compound in the mixture, with an IC50 of 35.4 µM. The degree of inhibition of the glucosides and aglycones followed malvidin > peonidin = delphinidin > petunidin > pelargonidin = cyanidin.

The authors conclude that “Pharmacological dosing, as might occur when dietary polyphenols are consumed as supplements, might lead to AC [anthocyanin] levels compatible with the range at which anthocyanins exert vasorelaxation through PDE inhibition.”

So the next time you see an advertisement for a dietary supplement product that claims to be “the natural alternative” to Viagra, just ask yourself whether it inhibits phosphodiesterase-5. If it doesn’t, it is not “the natural alternative” to Viagra, but just a mimic (assuming that it works at all).


  1. Dell’Agli et al. In vitro inhibition of human cGMP-specific phosphodiesterase-5 by polyphenols from red grapes. J Agric Food Chem 53:1960-5 (2005).


“‘Official: Killing Ants is Punishable by Law’ by Allan Hall, The Scotsman, July 30, 2003, reports that German gardeners face heavy fines if they destroy an ant hill. They must instead apply for a permit to have the ants carefully moved to local woods. Germany has appointed 85 ant-protection officers to enforce this law.” It doesn’t seem so unlikely that about 70 years ago, Germany developed National Socialism, the killer Nazi state, when you consider what sort of willingness to do what you’re told you’d have to have to actually propose such a law, let alone obey it. (Then there is the German law that requires names for new babies to conform to a government-approved list of names …) Gene pools make a difference. Lots of people who didn’t like being pushed around came here to America and then later moved west. They and their like-minded progeny are all that stand between us and a society where you can be commandeered to perform community service for ants. [Quote from Access to Energy (by Dr. Arthur B. Robinson, President and Research Professor, Oregon Institute of Science and Medicine), Box 1250, Cave Junction, OR 97523.]

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