It will be of little avail to the people that the laws are made by men of their own choice, if the laws be so voluminous that they cannot be read, or so incoherent that they cannot be understood; if they be repealed or revised before they are promulgated, or undergo such incessant changes that no man who knows what the law is today can guess what it will be tomorrow.
- Federalist No. 62, James Madison
February 27, 1788
Notwithstanding the above, we wish you all a very free and happy Fourth of July!
The FDA recommends that U.S. Customs Service agents at mail-inspection sites be required to send back all small foreign drug shipments they find, said William Hubbard, senior associate commissioner at the FDA, in a House commerce oversight subcommittee meeting. The only exemption would be for "compassionate use," where seriously ill patients order drugs from overseas that are not available in the U.S.
Although Congress authorized a rule allowing reimportation of prescription drugs by individuals in last year's final budget reconciliation package (as a way to help individuals buy drugs at the reduced prices often available in other, poorer, countries), it is "looking doubtful" that such a regulation will be issued, according to Department of Health and Human Services Secretary Tommy G. Thompson. The FDA claims that such freedom cannot be allowed while the agency is unable to certify that the drugs coming back into the country are safe and are the same drugs that were exported. This is a fine excuse to protect their pharmaceutical company clients from price competition and to ensure the continued availability of six-figure-salary jobs at pharmaceutical companies for former FDA officials.
- The Wall Street Journal, June 8, 2001, p. B2
- Pharmaceutical & Medical Device Law Bulletin, April 2001, p.9
On April 19, 2001, the FDA's Arthritis Advisory Committee considered data for a synthetic DHEA (dehydroepiandrosterone) product submitted by Genelabs Technologies (Redwood City, CA) as a treatment for systemic lupus erythematosus, a serious autoimmune condition for which there are few and limited treatments. The meeting largely pitted clinicians against an FDA statistical review that repeatedly characterized Genelabs' data as "not statistically significant," especially for adverse events when compared with placebo. The really odd (and fishy) thing about this meeting was that the FDA did not ask the Arthritis Advisory Committee to vote, thus avoiding a formal recommendation. This is considered highly unusual. We fear that this indicates the FDA will use any ploy to avoid approving DHEA for the treatment of any disease. The FDA well knows that DHEA is available as a dietary supplement and that the courts support First Amendment protection of the communication of truthful information about the effects of dietary supplements. Lost in the FDA's calculations is the suffering of lupus victims.
- Nature Biotechnology 19:500 (2001)
The FDA has sent warning letters to a number of manufacturers of popular soft drinks that contain herbs such as ginseng, gingko, and echinacea. Companies warned include US Mills, Inc., Hansen Beverage Co., and Fresh Samantha. The FDA demands that these companies prove that the herbs, which are "unapproved food additives" under current food (but not dietary supplement) law, are safe. New food-additive approvals usually cost $10 million to hundreds of millions of dollars and often take over a decade. Other companies selling herb-laced drinks, such as SoBe, will also face the same problem. These companies could avoid the "unapproved food additive" problem by relabeling their drinks as dietary supplements, but then they would have to list the amounts of the ingredients, including the herbs, that they contain. Customers would likely find out that the drinks contain very small and uncompetitive amounts of the herbal ingredients compared to other available dietary supplements.
- "New FDA Letters Warn Manufacturers of Tougher Stance on Herbal Additives,"
The Wall Street Journal, June 8, 2001
In pregnant women with low exposure to lead, high intakes of calcium (greater than 2000 mg/day) decreased the serum concentration of lead by inhibiting the breakdown of bone to release calcium for the fetus. Lead is accumulated over a lifetime and largely stored in bone. Hence, even a low exposure to lead can result in significant releases of lead during pregnancy unless inhibited by, for example, a high calcium intake. Moreover, calcium blocks the intestinal absorption of lead. The calcium supplement in this study1 was twice the amount of calcium recommended for women during pregnancy and approached the upper level for calcium of 2500 mg/day.
A total of 753 women were enrolled initially, with a final sample of 195 women selected for lead determinations. The final group was selected so as to maintain an equal number of African-American and white women and to oversample women with low (less than 1000 mg/day) and high (over 2000mg/day) intakes of calcium. Calcium intake was estimated by food frequency questionnaires, as well as evaluation of calcium from prenatal vitamins, calcium supplements, and calcium-containing antacids. The results showed that higher calcium intake was associated with lower blood lead concentrations from week 20 to the end of pregnancy. The findings also suggested that relatively high intakes of calcium (over 2000 mg/day) may be needed to obtain the maximum blunting of the rise in blood lead during pregnancy.
1. Johnson, "High Calcium Intake Blunts Pregnancy-Induced Increases in Maternal Blood Lead," Nutrition Reviews 59(5):152-156 (2001).
Dysplasia, a pretumor lesion, develops in the prostates of rats treated for 16 weeks with a combined regimen of testosterone and estradiol. (Some testosterone is naturally converted to estradiol by the enzyme aromatase.) This regimen also increases prolactin levels in the blood. However, bromocriptine (Parlodel®) effectively inhibited the evolution of tumors (six out of eight rats) and the often associated inflammation (five out of eight rats) in most of the animals. These data extend the many previous studies that have detailed marked influences of pituitary prolactin release on rat prostatic functions. However, the current study is the first to implicate pituitary prolactin release in prostatic pretumors.
Carcinogenesis 18(8):1505-1510 (1997), as reported in the July 1998 Life Extension magazine
The two of us have been taking bromocriptine (our current dose is 2.5 mg total per day, taken in two divided doses) for over 25 years for its antioxidant and dopaminergic neuron-protective effects, as well as its prolactin-suppressing effects (see p. 766 of our best-selling 1982 book, Life Extension, a Practical Scientific Approach, for Durk's use for a problem of long-time hyperprolactinemia). As we noted in the book (p. 339), bromocriptine has been shown in animal studies to suppress the development of breast cancer after exposure to DMBA, a polynuclear aromatic hydrocarbon combustion tar. Also, on p. 190, we note that excess prolactin can be a contributing cause of prostate enlargement.
It is known that prolactin levels increase in response to stress. A new study1 examined the effects of elevated (but still physiological) concentrations of prolactin (PRL) on the responses of cultured endothelial cells after mechanical injury to cell monolayers. The authors report that, when treated at the time of injury with PRL levels of 62.5-1000 ng/mL, cells at the wound front became abnormal in shape and reductions in f-actin staining in comparison to controls that were not PRL-treated. High PRL concentrations also inhibited the adhesion of cells to their growth surface in a dose-dependent manner. Thus, the authors propose that these novel effects of PRL may be mediated by activation of an endothelial-cell PRL receptor. The results also suggest that high prolactin levels, such as might occur during prolonged and/or frequent stress, use of high-dose anabolic steroids, or the higher prolactin levels seen in aging, might contribute to endothelial cell damage and hence increase the risk of cardiovascular disease.
1. Merkle et al., "Structural and Functional Effects of High Prolactin Levels on Injured Endothelial Cells," Endocrine 13(1):37-46 (2000).
Reduced heart-rate variability (HRV) is a predictor of arrhythmia and sudden cardiac death and is also known to be associated with age. A recent Danish study has found dietary intake of n-3 fatty acids and wine to be correlated with HRV. (However, after controlling for n-3 fatty acids, the correlation between wine and HRV was no longer significant. Apparently, at least in these Danish subjects, those who consumed high levels of fish were likely also to drink higher levels of wine.) Additional research1 on the patients in that study verified the patients' dietary intake of n-3 fatty acids (through consumption of fish) by measuring the n-3 fatty acid composition of the patients' blood granulocyte membranes and adipose (fat) tissue. The researchers found the level of docosahexaenoic acid (DHA) in granulocytes had the highest correlation with HRV.
The accompanying editorial by J. Thomas Bigger, Jr., and Terek El-Sherif stated that "The details of the antiarrhythmic action for n-3 PUFA [polyunsaturated fatty acids] remain to be elucidated . . . but the overall body of evidence from epidemiological studies and two clinical trials suggests that n-3 PUFA have an important antiarrhythmic effect in patients with coronary heart disease. Unfortunately, coronary heart disease is often announced by sudden cardiac death. Given the safety and low cost of implementing a recommendation for a modest amount of fish in the diet, adequate dietary fish intake has a significant role to play in the primary and secondary prevention of out-of-hospital sudden cardiac death."
The American Heart Association, publisher of Circulation, now recommends increased fish consumption to at least two fish servings per week. Their latest recommendation notes that "Because of the beneficial effects of n-3 fatty acids on risk of coronary artery disease as well as other diseases such as inflammatory and autoimmune diseases, the current intake, which is generally low, should be increased."
- Inform, June 2001, p. 619*
*Inform is published by the American Oil Chemists Society as a source of international news on research and development of fats, oils, and related materials.
1. Circulation 103:651-657 (2001), as reported in Inform, June 2001, p. 618.
Dariush Mozaffarian of the University of Washington Veterans Affairs Medical Center in Seattle, Washington, reported at the 41st Annual Conference on Cardiovascular Disease Epidemiology and Prevention in San Antonio, Texas, that, in a study group of average age 72 years, eating fatty fish (such as tuna, salmon, and mackerel, but not fried lean fish, such as cod and snapper) at least once a week was found to lead to a 44% lower risk of dying from a heart attack.
- Inform, May 2001, p. 500
A new paper published in The Lancet1 reports an epidemiological study of 6272 Swedish men followed for 30 years. They found that the men who ate no fish had a two-fold to three-fold higher frequency of prostate cancer than did those who ate moderate or high amounts. The authors propose that ". . . fish consumption could be associated with decreased risk of prostate cancer." One of the n-3 fatty acids, eicosapentaenoic acid (EPA), competes with arachidonic acid as a substrate for cyclooxygenases and can therefore have an important effect on the formation of tumor-growth-enhancing prostaglandins.
1. Terry et al., "Fatty Fish Consumption and Risk of Prostate Cancer," The Lancet 357:1764-1766 (2001).
n-3 PUFAs (polyunsaturated fatty acids) are offered by Hoffmann-LaRoche in a highly purified powdered form that has no fishy taste or smell, even in pancakes - not even if you burp after eating the pancakes. We have added to each serving of our pancakes (about three pancakes) a similar amount of n-3 fatty acids to what you would get in one meal of fatty fish. So if you hate fish, you don't have to eat it; you can get your n-3 fatty acids in delicious and healthful pancakes instead. Each serving contains not only the n-3 fatty acids, but 17 grams of protein (from 90% whey protein), 3 grams of fiber, and whole-grain rye flour, which contains lignans (phytoestrogens) converted by intestinal bacteria to enterolactone and other mammalian lignans that may protect against chronic disease.1
1. See, e.g., Venharanta et al., "Risk of Acute Coronary Events According to Serum Concentrations of Enterolactone," The Lancet 354:2112-2115 (1999); Rickard and Thompson, "Phytoestrogens and Lignans: Effects on Reproduction and Chronic Disease," Chapter 16 of Antinutrients and Phytochemicals in Food, ed. by Fereidoon Shahidi, ACS Symposium Series 662, 1997; [Rye and soy vs. prostate cancer], Prostate 42(4):304-314 (2000); Grasten et al.,"Rye Bread Improves Bowel Function and Decreases the Concentrations of Some Compounds that Are Putative Colon Cancer Risk Markers in Middle-Aged Women and Men," J Nutr 130:2215-2221 (2000).
A Canadian company, International Medical Innovations, Inc., of Toronto, has released information on a new product for measuring cholesterol level that does away with the need for a blood sample and painful lancets. The procedure takes three minutes and reads a color change in a drop of liquid on the palm of the hand using a hand-held spectrophotometer. Skin cholesterol, the firm said, correlates strongly with angiographically proven coronary artery disease and thus may be a superior assessment measurement than blood cholesterol. The test has received a medical device license from Health Canada for sale in Canada, and a submission to the FDA is anticipated. A home version of the test is being developed (see www.imin.ca).
- Inform, May 2001, pp. 500-501
At a scientific meeting organized by the New York Academy of Sciences (Alcohol and Wine in Health and Disease, April 26-29, 2001, in Palo Alto, CA), a consensus statement is now cautiously recommending moderate consumption of alcohol. "If you drink, do so with moderation. But if you do not drink, ask your doctor. Moderate alcohol consumption at meals may be advisable." Prior to this, the recommendation on alcohol was "If you don't drink, don't start." Participants at this meeting agreed that efforts to prevent alcohol abuse should continue but that there should be no effort to induce moderate drinkers to quit. Curtis Ellison (Boston University, MA) noted that even if 5% of current abstainers became abusers, there would still be a net public health benefit from alcohol consumption.
- Gaetano, Simini, "Drink in Moderation, Says Consensus Panel," The Lancet 357:1511 (2001)
The National Cholesterol Education Program (NCEP), a federal government health panel, recently issued new clinical guidelines establishing "healthy" levels of cholesterol (LDL and HDL) and for reducing excessively high LDL levels. Because of the reduction in the acceptable levels of total and LDL cholesterol, the sales of the popular cholesterol-lowering statin drugs may grow by up to $10 billion a year in the U.S. over the next four years. The number of Americans taking prescription drugs to lower their cholesterol could triple from the current 13,000,000.
In 2000, sales of cholesterol reducers in the U.S. were over $9 billion, including $4.1 billion for Pfizer's Lipitor (atorvastatin) and $2.8 billion for Merck's Zocor (simvastatin). The statins represent about 90% of the cholesterol-lowering drug market.1 The upcoming production of generic versions of older statins, such as Merck's Mevacor (lovastatin), now a minor drug in the statin market due to the advent of more effective statins, could result in a large usage of statins among those who cannot now afford them.
Strangely, there appears to have been no mention of niacin, which only a few years ago was called by the FDA the "drug of choice" for cholesterol reduction. Niacin is very effective at lowering LDL, VLDL, and triglycerides and also greatly increases HDL. Long-term studies have shown reductions in disease progression and mortality in subjects with cardiovascular disease. Nicotinic acid (but not nicotinamide) in gram doses is reported in the PDR Generics (first edition, p. 2035) to produce an average 10-20%reduction in total and LDL-cholesterol, a 30-70% reduction in triglycerides, and an average 20-35% increase in HDL-cholesterol. In a 1999 review,2 niacin was said to have greater ability to increase HDL than any other drug. Perhaps the fact that there is not a lot of money to be made selling niacin, especially as it is a dietary supplement offered in a highly competitive market, has something to do with this focus on statins. Nobody is spending large sums of money promoting niacin or conducting large double-blind studies with it. Then, of course, there is the harmless flushing caused by niacin that some people apparently do not like. (Perhaps those people would change their minds about the flush if they were to try taking niacin during sex; histamine release is required for orgasm, and the niacin flush is caused by histamine release.)
It is true that some people's livers cannot handle doses above about 800 mg a day, and it can be a problem for those with peptic ulcer. Liver tests should be done before niacin use and after to ensure that any possible liver problem is detected early. The PDR Generics notes (first edition, p. 2036), "Great caution must be exercised when Niacin is used in patients with coronary disease or gallbladder disease. Patients with a past history of jaundice, hepatobiliary disease, or peptic ulcer should be observed closely during Nicotinic Acid therapy. Frequent monitoring of liver function tests and blood glucose should be performed to ascertain that the drug is producing no adverse effects on these organ systems. Diabetic patients may experience a dose-related rise in glucose intolerance, the clinical significance of which is unclear." A recent study3reported that while niacin use increased blood glucose levels modestly by 8.7 and 6.3 mg/dL for participants with and without diabetes, respectively, it also increased HDL by 29% and 29% and decreased triglycerides by 23% and 28% and LDL by 8% and 9%, respectively. Two of 125 diabetic patients and three of 363 nondiabetic patients, all of whom were on niacin, had elevated plasma alanine aminotransferase, a liver enzyme.
There are additional warnings for interactions between niacin and certain drugs. It should also be noted that sustained-release versions of niacin have been found to be associated with more adverse side effects than ordinary-release niacin. We recommend not using sustained-release niacin.
But statins also have adverse reactions and side effects. In the warnings for Lipitor and Zocor, for example, it is noted that the drug may cause liver-function abnormalities or myopathy (muscle aches or weakness) in conjunction with elevated levels of creatine phosphokinase (CPK) values. About 1% of patients are reported in the 1999 PDR to have persistently elevated liver enzymes with Zocor. Read the long discussions of possible side effects for statins in the PDR.
Another possible treatment could be small doses of a statin plus another cholesterol-reducing drug, food, or nutrient. (When using a statin with another drug, be sure to check the PDR for potential adverse interactions.) In one recent study, treatment with simvastatin at 12 mg/day and niacin at 3.2 g/day given to 80 of 160 subjects resulted in nearly a 70% reduction in the incidence of death, nonfatal myocardial infarction, stroke, and hospitalization for cardiovascular disease during a three-year followup.4 In that study, only one of 80 subjects withdrew from niacin because of flushing, while a few patients had their niacin dosage reduced due to increased liver transaminase levels. The usual starting dose for simvastatin is 20 mg, with pills available at doses of 5, 10, 20, and 40 mg.
n-3 (Omega-3) Fatty Acids are Very Effective at Reducing High Triglycerides
A surprisingly effective way to increase low HDL is moderate alcohol consumption. Recent results of the effects of moderate alcohol consumption on cardiovascular risk for diabetics, who are at unusually high risk for heart attack and other vascular problems, reported exceptional protection. For example, in a study5 involving 5103 type 2 diabetic women from the Nurses' Health Study, the age-adjusted risk ratio for coronary heart disease for those who reported a usual alcohol intake of 0.1 to 4.9 g of alcohol per day was 0.74, and the risk ratio for women reporting a usual daily alcohol intake greater than or equal to 5 g per day was 0.48. This inverse relationship remained significant even after multivariate analysis adjusting for multiple other cardiovascular risk factors. (Though there was apparently no adjustment for n-3 fatty acids, we do not know whether these American women, like the Danish subjects in the study mentioned above, also tended to eat more fish if they drank more alcohol. It seems unlikely to us, but that is just a guess.) A recent paper6 also reports that, in a study sample of 2006 men and women aged 18-88 participating in a national health survey carried out in former West Germany in 1987-1988, nondrinkers and heavy drinkers had higher C-reactive protein than moderate drinkers. C-reactive protein is a marker of inflammation and also of coronary heart disease risk.
We are not against the use of statins, which appear to be effective in reducing cholesterol and may have other useful effects. However, it appears to us that the conclusion of the NECP that people who cannot reduce cholesterol with diet and exercise should then take expensive statins is not an adequate analysis of the available options, and yet this advice stands to be of immense profit to a very small number of companies.
1. Jarvis, "New Cholesterol Study Could Boost Statin Sales," Chemical Marketing Reporter, June 11, 2001, p. 7.
2. Knopp, "Drug Treatment of Lipid Disorders," New England Journal of Medicine, Aug. 12, 1999, p. 504.
3. Elam et al., "Effect of Niacin on Lipid and Lipoprotein Levels and Glycemic Control in Patients with Diabetes and Peripheral Arterial Disease," Journal of the American Medical Association 284(10):1263-1270 (2000).
4. Zoler, "Niacin Plus Statin Cuts Coronary Events by 70%," Family Practice News, January 1, 2001, as reported in Clinical Pearls News, June 2001, p. 101.
5. Solomon et al., "Moderate Alcohol Consumption and Risk of Coronary Heart Disease Among Women with Type 2 Diabetes Mellitus," Circulation 102:494-499(2000).
6. Imhof et al., "Effect of Alcohol Consumption on Systemic Markers of Inflammation," The Lancet 357:763-767 (2001).