Durk Pearson and Sandy Shaw sue the FDA for qualified Health Claims 1999

At the behest of Durk Pearson and Sandy Shaw, Emord & Associates sued the FDA in the 1990s for refusing Pearson and Shaw’s request to authorize four specific health claims for dietary supplements.  Pearson and Shaw sought agency approval of claims associating antioxidant vitamins with cancer risk reduction; omega-3 fatty acids with vascular disease risk … Continue reading "Durk Pearson and Sandy Shaw sue the FDA for qualified Health Claims 1999"

At the behest of Durk Pearson and Sandy Shaw, Emord & Associates sued the FDA in the 1990s for refusing Pearson and Shaw’s request to authorize four specific health claims for dietary supplements.  Pearson and Shaw sought agency approval of claims associating antioxidant vitamins with cancer risk reduction; omega-3 fatty acids with vascular disease risk reduction; folic acid with neural tube defect risk reduction; and fiber with colorectal cancer risk reduction.  In particular, Pearson and Shaw argued that if FDA did not approve the claims under its “significant scientific agreement” standard, it nevertheless had to allow them to comply with the First Amendment, resorting to a succinct disclaimer to communicate its doubts about the science supporting the claims.  The FDA refused to allow any of the claims or rely on claim qualification as a less speech restrictive alternative to outright suppression, and our firm, as Pearson and Shaw’s counsel, sued the agency.  That suit resulted in a landmark victory over the FDA before the United States Court of Appeals for the D.C. Circuit in Pearson v. Shalala (1999).

In Pearson v. Shalala, the D.C. Circuit agreed with Pearson and Shaw that FDA was obligated by the First Amendment to favor disclosure with accurate, succinct and reasonable disclaimers over suppression and to rely on claim qualification rather than outright suppression.  That then ultimately led to the FDA’s qualified claim regime, but only after Emord & Associates defeated the FDA several more times in federal court for refusing to abide by the Pearson v. Shalala decision.

Here are the decisions in which the firm defeated the FDA:

Pearson v. Shalala
Pearson v. Shalala, en banc
Pearson v. Shalala II
Pearson v. Thompson
Whitaker v. Thompson I
Whitaker v. Thompson II
Whitaker v. Thompson III

Alliance for Natural Health US v. Sebelius, et al.

Emord & Associates has petitioned the FDA for approximately 100 qualified health claims.  The following claims have been allowed by FDA either directly or after the firm has defeated the agency in federal court:

Antioxidant Vitamins C and E and Reduction in the Risk of Site-Specific Cancers

  • Vitamin C

Gastric (Stomach) Cancer:  “One weak study and one study with inconsistent results suggest that vitamin C supplements may reduce the risk of gastric cancer. Based on these studies, FDA concludes that it is highly uncertain that vitamin C supplements reduce the risk of gastric cancer.”

  • Vitamin E

Bladder Cancer:  “One small study suggests that vitamin E supplements may reduce the risk of bladder cancer. However, two small studies showed no reduction of risk. Based on these studies, FDA concludes that it is highly unlikely that vitamin E supplements reduce the risk of bladder cancer.”

Colorectal Cancer:  “Two weak studies and one study with inconsistent results suggest that vitamin E supplements may reduce the risk of colorectal cancer. However, another limited study showed no reduction of risk. Based on these studies, FDA concludes that it is highly unlikely that vitamin E supplements reduce the risk of colorectal cancer.”

Renal Cell Cancer:  “One weak and limited study suggests that vitamin E supplements may reduce the risk of renal cell cancer. FDA concludes that it is highly uncertain that vitamin E supplements reduce the risk of renal cell cancer.”

Antioxidant Vitamins and Risk of Certain Cancers

  • “Some scientific evidence suggests that consumption of antioxidant vitamins may reduce the risk of certain forms of cancer. However, FDA has determined that this evidence is limited and not conclusive.”
  • “Some scientific evidence suggests that consumption of antioxidant vitamins may reduce the risk of certain forms of cancer. However, FDA does not endorse this claim because this evidence is limited and not conclusive.”
  • “FDA has determined that although some scientific evidence suggests that consumption of antioxidant vitamins may reduce the risk of certain forms of cancer, this evidence is limited and not conclusive.”

B Vitamins and Vascular Disease

  • “As part of a well-balanced diet that is low in saturated fat and cholesterol, Folic Acid, Vitamin B6 and Vitamin B12 may reduce the risk of vascular disease.  FDA evaluated the above claim and found that, while it is known that diets low in saturated fat and cholesterol reduce the risk of heart disease and other vascular diseases, the evidence in support of the above claim is inconclusive.”

Calcium and Colon/Rectal Cancers and Recurrent Colon Polyps

  • “Some evidence suggests that calcium supplements may reduce the risk of colon/rectal cancer, however, FDA has determined that this evidence is limited and not conclusive.”
  • “Very limited and preliminary evidence suggests that calcium supplements may reduce the risk of colon/rectal polyps. FDA concludes that there is little scientific evidence to support this claim.”

Calcium and Hypertension; Pregnancy Induced Hypertension; and Preeclampsia

  • “Some scientific evidence suggests that calcium supplements may reduce the risk of hypertension. However, FDA has determined that the evidence is inconsistent and not conclusive.”
  • “Four studies, including a large clinical trial, do not show that calcium supplements reduce the risk of pregnancy-induced hypertension during pregnancy. However, three other studies suggest that calcium supplements may reduce the risk. Based on these studies, FDA concludes that it is highly unlikely that calcium supplements reduce the risk of pregnancy-induced hypertension.”
  • “Three studies, including a large clinical trial, do not show that calcium supplements reduce the risk of preeclampsia during pregnancy. However, two other studies suggest that calcium supplements may reduce the risk. Based on these studies, FDA concludes that it is highly unlikely that calcium supplements reduce the risk of preeclampsia.”

Chromium Picolinate and Insulin Resistance

  • “One small study suggests that chromium picolinate may reduce the risk of insulin resistance, and therefore possibly may reduce the risk of type 2 diabetes. FDA concludes, however, that the existence of such a relationship between chromium picolinate and either insulin resistance or type 2 diabetes is highly uncertain.”

Folic Acid and Neural Tube Defects (and here)

  • “0.8 mg folic acid in a dietary supplement is more effective in reducing the risk of neural tube defects than a lower amount in foods in common form. FDA does not endorse this claim. Public health authorities recommend that women consume 0.4 mg folic acid daily from fortified foods or dietary supplements or both to reduce the risk of neural tube defects.”
  • “Healthful diets with adequate folate may reduce a woman’s risk of having a child with a brain or spinal cord birth defect. The Institute of Medicine of the National Academy of Sciences recommends that women capable of becoming pregnant consume 400 mcg folate daily from supplements, fortified foods, or both, in addition to consuming food folate from a varied diet.”
  • “Healthful diets with adequate folate may reduce a woman’s risk of having a child with a brain or spinal cord birth defect. The scientific evidence that 400 mcg folic acid daily reduces the risk of such defects is stronger than the evidence for the effectiveness of lower amounts. This is because most such tests have not looked at amounts less than 400 mcg folic acid daily.”
  • “Healthful diets with adequate folate may reduce a woman’s risk of having a child with a brain or spinal cord birth defect. Women capable of becoming pregnant should take 400 mcg folate/day from fortified foods and/or a supplement, in addition to food folate from a varied diet. It is not known whether the same level of protection can be achieved by using only food that is naturally rich in folate. Neither is it known whether lower intakes would be protective or whether there is a threshold below which no protection occurs.”
  • “Healthful diets with adequate folate may reduce a woman’s risk of having a child with a brain or spinal cord birth defect. Women capable of becoming pregnant should take 400 mcg of folate per day from a supplement or fortified foods and consume food folate from a varied diet. It is not known whether the same level of protection can be achieved by using lower amounts.”

Folic Acid, Vitamin B6, and Vitamin B12 and Vascular Disease

  • “It is known that diets low in saturated fat and cholesterol may reduce the risk of heart disease. The scientific evidence about whether folic acid, vitamin B6 and vitamin B12 may also reduce the risk of heart disease and other vascular diseases is suggestive, but not conclusive. Studies in the general population have generally found that these vitamins lower homocysteine, an amino acid found in the blood. It is not known whether elevated levels of homocysteine may cause vascular disease or whether high homocysteine levels are caused by other factors. Studies that will directly evaluate whether reducing homocysteine may also reduce the risk of vascular disease are not yet complete.”

Omega-3 Fatty Acids and Reduced Risk of Coronary Heart Disease

  • “Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease.  One serving of [Name of the food] provides [  ] gram of EPA and DHA omega-3 fatty acids.  [See nutrition information for total fat, saturated fat, and cholesterol content.]”

Phosphatidylserine and Cognitive Dysfunction and Dementia (and here and here)

  • Dementia:  “Consumption of phosphatidylserine may reduce the risk of dementia in the elderly.  Very limited and preliminary scientific research suggests that phosphatidylserine may reduce the risk of dementia in the elderly. FDA concludes that there is little scientific evidence supporting this claim.”
  • Cognitive dysfunction:  “Consumption of phosphatidylserine may reduce the risk of cognitive dysfunction in the elderly. Very limited and preliminary scientific research suggests that phosphatidylserine may reduce the risk of cognitive dysfunction in the elderly. FDA concludes that there is little scientific evidence supporting this claim.”

Selenium and Reduced Risk of Site-specific Cancers

  • Bladder Cancer:  “One study suggests that selenium intake may reduce the risk of bladder cancer in women.  However, one smaller study showed no reduction in risk.  Based on these studies, FDA concludes that it is highly uncertain that selenium supplements reduce the risk of bladder cancer in women.”  
  • Prostate Cancer:  “Two weak studies suggest that selenium intake may reduce the risk of prostate cancer. However, four stronger studies and three weak studies showed no reduction in risk.  Based on these studies, FDA concludes that it is highly unlikely that selenium supplements reduce the risk of prostate cancer.”
  • Thyroid Cancer:  “One weak, small study suggests that selenium intake may reduce the risk of thyroid cancer. Based on this study, FDA concludes that it is highly uncertain that selenium supplements reduce the risk of thyroid cancer.”

Tomatoes and Prostate, Ovarian, Gastric and Pancreatic Cancers

  • Prostate Cancer:  “Very limited and preliminary scientific research suggests that eating one-half to one cup of tomatoes and/or tomato sauce a week may reduce the risk of prostate cancer. FDA concludes that there is little scientific evidence supporting this claim.”
  • Gastric Cancer:  “Four studies did not show that tomato intake reduces the risk of gastric cancer, but three studies suggest that tomato intake may reduce this risk. Based on these studies, FDA concludes that it is unlikely that tomatoes reduce the risk of gastric cancer.”
  • Ovarian Cancer:  “One study suggests that consumption of tomato sauce two times per week may reduce the risk of ovarian cancer; while this same study shows that consumption of tomatoes or tomato juice had no effect on ovarian cancer risk. FDA concludes that it is highly uncertain that tomato sauce reduces the risk of ovarian cancer.”
  • Pancreatic Cancer:  “One study suggests that consuming tomatoes does not reduce the risk of pancreatic cancer, but one weaker, more limited study suggests that consuming tomatoes may reduce this risk.

Information sourced directly from Emord and Associates.

Emord & Associates has extensive experience in prosecuting health claim petitions before the FDA.  Indeed, the qualified health claim regime at FDA is a result of the landmark decision reached in Pearson v. Shalala (1999) in which the firm served as lead counsel for the victorious plaintiffs. http://emord.com/firm-profile/health-claims/

1998 Nobel Prize for Discovery of Arginine’s role in creating Nitric Oxide

The Nobel Prize in Physiology or Medicine in 1998 recognized the health benefits of nitric oxide. Arginine, an amino acid that helps the body create nitric oxide, is one of the key ingredients in Muscle Memory™, a Designer Food® created by Durk Pearson and Sandy Shaw, who were among the first scientists to recommend that taking arginine supplements could help achieve a variety of life-extending benefits. Muscle Memory™ has been a life enhancement classic for more than a decade which enhances the body’s ability to form nitric oxide and helps support muscle and heart health.

 

Subject: Nobel Prize for Arginine and Nitric oxide discovery–https://www.nobelprize.org/prizes/medicine/1998/press-release/

Nitric oxide protects the heart, stimulates the brain, kills bacteria, etc.

It was a sensation that this simple, common air pollutant, which is formed when nitrogen burns, for instance in automobile exhaust fumes, could exert important functions in the organism. It was particularly surprising since NO is totally different from any other known signal molecule and so unstable that it is converted to nitrate and nitrite within 10 seconds. NO was known to be produced in bacteria but this simple molecule was not expected to be important in higher animals such as mammals.

Further research results rapidly confirmed that NO is a signal molecule of key importance for the cardiovascular system and it was also found to exert a series of other functions. We know today that NO acts as a signal molecule in the nervous system, as a weapon against infections, as a regulator of blood pressure and as a gatekeeper of blood flow to different organs. NO is present in most living creatures and made by many different types of cells.

– When NO is produced by the innermost cell layer of the arteries, the endothelium, it rapidly spreads through the cell membranes to the underlying muscle cells. Their contraction is turned off by NO, resulting in a dilatation of the arteries. In this way, NO controls the blood pressure and its distribution. It also prevents the formation of thrombi.

– When NO is formed in nerve cells, it spreads rapidly in all directions, activating all cells in the vicinity. This can modulate many functions, from behaviour to gastrointestinal motility.

– When NO is produced in white blood cells (such as macrophages), huge quantities are achieved and become toxic to invading bacteria and parasites.

Importance in medicine today and tomorrow

Heart: In atherosclerosis, the endothelium has a reduced capacity to produce NO. However, NO can be furnished by treatment with nitroglycerin. Large efforts in drug discovery are currently aimed at generating more powerful and selective cardiac drugs based on the new knowledge of NO as a signal molecule.

Shock: Bacterial infections can lead to sepsis and circulatory shock. In this situation, NO plays a harmful role. White blood cells react to bacterial products by releasing enormous amounts of NO that dilate the blood vessels. The blood pressure drops and the patient may become unconscious. In this situation, inhibitors of NO synthesis may be useful in intensive care treatment.

Lungs: Intensive care patients can be treated by inhalation of NO gas. This has provided good results and even saved lives. For instance, NO gas has been used to reduce dangerously high blood pressure in the lungs of infants. But the dosage is critical since the gas can be toxic at high concentrations.

Cancer: White blood cells use NO not only to kill infectious agents such as bacteria, fungi and parasites, but also to defend the host against tumours. Scientists are currently testing whether NO can be used to stop the growth of tumours since this gas can induce programmed cell death, apoptosis.

Impotence: NO can initiate erection of the penis by dilating the blood vessels to the erectile bodies. This knowledge has already led to the development of new drugs against impotence.

Diagnostic analyses: Inflammatory diseases can be revealed by analysing the production of NO from e.g. lungs and intestines. This is used for diagnosing asthma, colitis, and other diseases.

NO is important for the olfactory sense and our capacity to recognise different scents. It may even be important for our memory.

Nitroglycerin

Alfred Nobel invented dynamite, a product in which the explosion-prone nitroglycerin is curbed by being absorbed in kieselguhr, a porous soil rich in shells of diatoms. When Nobel was taken ill with heart disease, his doctor prescribed nitroglycerin. Nobel refused to take it, knowing that it caused headache and ruling out that it could eliminate chest pain. In a letter, Nobel wrote: It is ironical that I am now ordered by my physician to eat nitroglycerin. It has been known since last century that the explosive, nitroglycerin, has beneficial effects against chest pain. However, it would take 100 years until it was clarified that nitroglycerin acts by releasing NO gas.

For more information about Muscle Memory™ and its benefits visit www.lifepriority.com or call 800-787-5438 — 8 am-11 pm, CST (M-F).

Life Priority, established in 1994, offers supplements that are scientifically-formulated, results-oriented, and GRAS (Generally Recognized As Safe) and are manufactured at USDA and FDA inspected facilities.

*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.

*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.

LE NEWS: The Power of Arginine

The Power of Arginine
DURK PEARSON & SANDY SHAW’S®
LIFE EXTENSION NEWSLETTERTM
©1988-1991

Life Extension Newsletter, written by Life Extension scientists Pearson & Shaw, was prescient with regard to many of the biomedical ideas it first brought to the attention of the public. Unfortunately, it is no longer available and thus, with the permission of the authors, we reproduce selected portions for your enlightenment. Please note the return of another Pearson & Shaw Newsletter, Life Extension News, the current issue of which is contained in this publication. The growth hormone story picks up where Sandy breaks her leg at a gerontological conference where she is initially attended to by no less than Dr. Denham Harman, M.D., Ph.D., father of the Free Radical Theory of Aging.

ISSUE #25
ARGININE RELEASES GROWTH HORMONE
Having a broken foot is extremely inconvenient and sometimes dangerous. Just try going up or down stairs on crutches! We had been about to start arginine supplementation experiments on ourselves for immunostimulation, when Sandy’s broken foot provided us with a golden opportunity. We had read scientific reports of arginine stimulating the healing of broken bones in experimental animals, and Sandy decided to take it.

Other nutrients have been shown to cause growth hormone release, including niacin (200 mg is a mild GH releaser) (Irie, 1967,1970), tyrosine (nutrient amino acid – releases a small amount of GH in a small percentage of subjects with 40 gram intravenous doses), and methionine (nutrient amino acid – releases GH but can cause atherosclerosis under certain conditions). The nutrient amino acid arginine and ornithine (another amino acid) are both relatively strong GH releasers. Arginine and ornithine can release enough GH to equal that found in a heavily exercising teenager.At this time, Sandy was 35 years old, and far over the hill in terms of exercise-induced GH release. She took 10 grams of arginine a day in a single dose on an empty stomach. (One might be able to ingest that amount daily in a very high protein diet heavy in chicken or turkey. Sandy was also taking about 2 grams of choline and 2 grams of vitamin B5 per day.) About 45 minutes to one hour after taking the arginine, Sandy did bench presses for about 3 minutes, once daily, on her back, so there was no stress on the broken foot. After six weeks on this regimen, she had lost about 25 pounds of fat and had put on about 5 pounds of muscle! We were amazed. We thought that amount of arginine might be enough to stimulate the release of growth hormone. We knew that growth hormone increased the ratio of muscle to fat. (Christy, 1979; Murad, 1980) But we didn’t realize how dramatic the effect could be in an essentially sedentary middle-aged research scientist. Arnold Schwarzenegger in his Bodybuilding for Men said that putting on 5 pounds of muscle would be difficult for an adult man working out every day for a year!

Arginine and ornithine cause growth hormone release via your brain’s cholinergic nervous system. (Casanueva, 1984) This is the system that uses acetylcholine – made in the brain from the nutrient choline with the help of the cofactor vitamin B5 – to transmit information between the nerve cells. Without adequate amounts of acetylcholine, neither arginine nor ornithine can cause growth hormone release, though we know of no evidence that choline or vitamin B5 alone can cause GH release. This is why we recommend the use of a choline + B5 supplement in conjunction with arginine or ornithine GH releasers. Note that many antihistamines, cold pills, and the non prescription sedative diphenhydramine are anticholinergics. These drugs will block the GH releasing effects of arginine and ornithine.

Contrary to what some people believe (and some fraudulent products claim), you can’t develop winning muscle mass without exercise, even if you take a growth hormone releaser like arginine. But arginine is very effective at helping you maintain muscle mass you already have, even if you are not exercising. We are two 47 year-old research scientists and almost completely sedentary, but we regularly take arginine supplements, as described below, and maintain the well muscled bodies we had twenty years ago. You may have seen 5’3″ Sandy bend steel horseshoes on television.

In 1982, after we reported our ideas and experiences regarding the use of growth hormone releasers such as arginine in our first book, Life Extension, A Practical Scientific Approach, there was a world-wide shortage of arginine for several months, and a world-wide shortage of ornithine for about a year! Their main prior use had been as ingredients in culture media.

ARGININE SUPPLEMENTATION
We personally use arginine in either one of two different ways: we take 12-24 grams 45 minutes to one hour before exercise (to enhance the effects of the exercise) or just before bedtime (to enhance both sex and the natural pulse of growth hormone release shortly after one falls asleep). We generally recommend the following total daily quantities of arginine (free base) for healthy male adults: Weight 100 to 140 pounds, 12 grams; 140 to 200 pounds, 18 grams; over 200 pounds, 24 grams. For healthy female non-pregnant, non-lactating adults: under 120 pounds, 6 grams; 120 to 180 pounds, 12 grams; over 180 pounds, 18 grams. Women are usually more sensitive to the GH releasing effects of arginine and ornithine than men. (Merimee, 1969) Start with about 25% of your target quantity, and increase it gradually over a period of a few days to minimize the occurrence of minor side effects such as nausea. If you prefer ornithine, use half of these amounts. The dose figures given in the literature usually refer to the amount of amino acid free base used, such as arginine. Many commercial products contain an acid addition salt such as arginine hydrochloride rather than the free base arginine. Some of the product labels give the amount of the contents as the free base, other as the hydrochloride. Unless the amount of the amino acid is given as the free base (eg, 6 grams arginine), you will need to take about 20% more since the hydrochloride adds about 20% to the weight without contributing to the GH releasing activity.

Don’t assume that more is always better. It is unlikely that a 60 gram dose would cause significantly more GH release that a 24 gram dose. A 30 gram injection of arginine is used to test pituitary function: this dose has been chosen to be high enough to completely saturate this GH release mechanism. (See the Cautions at the end of this article for side effects and precautions.)

It is important not to ingest certain other amino acids, either as a supplement or in foods, at the same time or shortly before taking the arginine. Some of these other amino acids, including lysine, compete with arginine to enter the brain (where the action takes place). You can take your protein supplement or high protein low glycemic index carbohydrate meal after your workout.

Casanueva, Villanueva, Cabranes, Cabezas-Cerrato, Fernandez-Cruz, “Cholinergic Mediation of Growth Hormone Secretion Elicited by Arginine, Clonidine, and Physical Exercise In Man,” J. Clin. Endocr. Metab.59(3):526-530 (1984)
Christy, “Anterior Pituitary Function in Normal Subjects and in Patients with Systemic Diseases,” in Obese, et al, editors Cecil Textbook of Medicine, 15th ed, pp.2085-2091, Philadelphia:Saunders (1979)
Irie, et al, “Effect of Nicotinic Acid Administration on Plasma Growth Hormone Concentrations,” Proc Soc Exptl Biol Med 126:708 (1967)
Merimee, et al, “Arginine Initiated Release of Growth Hormone: Factors Modifying the Response in Normal Men,” New Eng J Med. 280(26) :1434-1435 (1969)
Murad and Haynes, “Adenohypophyseal Hormones and Related Substances,” in Gilman, Goodman, Gilman editors Goodman and Gilman’s Pharmacological Basis of Therapeutics 6th ed, pp.1369-1396, New York:MacMillan (1980)

ISSUE #25 PAGE 7
CAUTION
Arginine Side Effects: Most men and some women report increased libido with arginine supplements. There may also be increased irritability. A large release of GH can also cause nausea. Remember how Arnold Schwarzenegger used to keep a barf bucket next to his workout station when he was a teen-ager? He said that if he wasn’t working out hard enough to throw up, he wasn’t working out hard enough to win. In his twenties, this no longer happened because the exercise no longer caused such a big GH release. You are less likely to have annoying side effects if you start out with a small amount, and gradually increase your dose over a period of couple of weeks.

Ornitine Side Effects: Arginine, but not ornithine is found in ordinary food protein. Arginine has been given to medically monitored subjects at up to 60 grams per day without reports of serious problems. Much less is known about the safety of the regular use of large amounts of ornithine. Since about half of the arginine that you ingest is normally converted to ornithine in your body, it isn’t surprising that the reported side effects of ornithine are similar to those of arginine. It takes about half as much ornithine as arginine to release a given amount of GH, but ornithine costs twice as much. We generally use arginine, considering it to be more medically conservative. The immunostimulant and wound healing stimulant effects of arginine are far better established, too. Moreover, arginine but not ornithine, increases sperm count.

Choline Side Effects: Too much choline and/or vitamin B5 can cause the production of too much acetylcholine. Since acetylcholine is what makes your muscles contract, this can cause excessive muscle tone. The most common symptoms or cholinergic excess is a stiff neck, a tension headache, or gut cramps, diarrhea, or constipation. You are less likely to have annoying side effects if you start out with a small amount, and gradually increase your dose over a period of a couple of weeks. Do not use choline bitartrate; in effective doses, there is so much bitartrate in this form of choline that diarrhea is almost inevitable. Chronic diarrhea isn’t just annoying; potassium loss can be so large that it may cause heart failure by ventricular fibrillation.

Niacin Side Effects: 200 milligrams of niacin will most certainly cause transitory skin flushing and a sensation or heat, burning, or itching, though this is not dangerous. Do not take more than 800 milligrams of niacin per day without medical supervision, since the livers of some individuals cannot tolerate higher doses.

Although the growth hormone releasing effects or arginine and ornithine have been stressed in this article, we do not wish to imply that all of the anabolic, wound healing, and immunostimulant effects of arginine and ornithine are due to their GH releasing activity. Arginine and ornithine also act as precursors to polyamines such as spermine and spermidine, which are growth stimulating substances, and these two amino acids have many other uses within the body, too. Nevertheless, the anabolic, wound healing, and immunostimulant effects of growth hormone itself are so similar to those of arginine and ornithine that we did not think that an exploration of this distinction would be of much interest to body builders and athletes.

ISSUE #13 PAGE 3
STIMULATION OF THE IMMUNE SYSTEM AND OF HEALING BY ARGININE
We have previously written about immune system stimulation and increased healing rate in experimental animals and humans with oral arginine supplements. Now a new clinical study reports the benefits of large (25 g) supplements of arginine in a liquid diet for postoperative recovery of major abdominal surgery for cancer.

The purpose of the study was to try to reduce the immunosuppression and catabolic response (loss of lean body tissue) that normally occurs after such a trauma. Glycine (43 g/day) was administered to other patients (who did not receive arginine) as a test of its possible utility. Although many animal studies have demonstrated the efficacy of arginine, relatively few human studies had been done. Barbul, in his excellent review, reports some of these. (For example, Dr. Barbul administered oral arginine hydrochloride (30 g/day) for one week and noted a significant increase in peripheral blood mean lymphocyte blastogenic response to con A and PHA, measures of immune system activity.)

The mean total daily caloric intake in this experiment was not significantly different between the arginine and glycine supplemented groups. However, daily nitrogen balance became positive after day 5 in the arginine group (indicating that lean body tissue was being built up faster than it was being broken down), whereas it remained negative in the glycine group throughout the seven day study period. There were increases in immune system T-lymphocyte activation in the arginine group and a slight increase in the glycine group, the difference between the two groups being significant. Only the arginine group had an increase in the CD4 (T helper cell) activity. (T helper cells are needed to help your immune system recognize and react to infections and cancer cells. AIDS patients fall prey to many infections because the AIDS virus kills the T helper cells.) Growth hormone increased in both groups, but somatomedin C (which mediates the effects of growth hormone) was significantly increased only in the arginine group on day 7.

Daly, et al, “Immune and Metabolic Effects of Arginine in the Surgical Patient,” Ann. Surg. Vol. 208(4), pp. 512 523 (1988)

ISSUE #23 PAGE 93
ARGININE-DERIVED NITRIC OXIDE AND ITS EFFECTS
An entirely new and important effect of the amino acid arginine has recently been discovered.

In 1987, scientists suggested that endothelium-derived relaxing factor (EDRF), a substance with important functions in the vascular (circulatory) system, such as blood pressure regulation, was nitric oxide, a gas. Now, a mere two years later, a lot more is known about nitric oxide, with evidence indicating that it is about nitric oxide, with evidence indicating that it is EDRF and that it is derived from the amino acid L-arginine. A two-day symposium was just held at the Royal Society in London entitled “Nitric Oxide from L-Arginine.”

Nitric oxide (NO) has now been found to also participate in regulation of the nervous and immune systems and is produced from arginine by the liver, adrenal, and kidney. The biological roles include control of vascular resistance and of platelet function. NO can mediate a profound vasorelaxation (reducing blood pressure) and inhibit both platelet adhesion (stickiness) and aggregation (clumping) which can lead to coronary thrombosis heart attacks and occlusive strokes. It has been hypothesized that some cardiovascular disease patients do not manufacture adequate amounts of NO. A lack of NO may play a role in vasospasm, which can lead to hypoxic tissue damage, just as occurs in a coronary or an occlusive stoke. Basal NO release is central to control of blood pressure and flow. High doses of an analog-antagonist of arginine called L-NMMA causes acute hypertension which is rapidly reversed by intravenous L-arginine. Endothelium derived relaxation is impaired by atherosclerosis and inhibited by LDL. LDL, when oxidized, is an even more effective inhibitor, which depresses NO production by endothelial cells. We would like to see a double-blind placebo controlled trial of arginine and antioxidant nutrient supplements for the control of hypertension and to inhibit abnormal clot formation.

Macrophage mediated killing of tumor cells and of some bacteria seems to involve NO. Some of the effects of L-arginine on immune functions, including increased thymic lymphopoiesis (increased T-cell production), stimulation of lymphocyte proliferation, interleukin production, promotion of tumor and graft refection and of wound healing, may involve NO derived from the arginine. Both animal experiments and double-blind placebo controlled trials in humans have shown that arginine supplements are immunostimulants and wound healing accelerators.

Griffith, Randall, “Nitric Oxide Comes of Age,” The Lancet pp. 875-876, Oct. 7, 1989
Palmer, Ashton, Moncada, Nature 333: 664-666 (1988)
Feigl, “EDRF – A Protective Factor?” letter to Nature 331: 11 Feb. 1988
Jacobs, “L-Arginine is Endogenous Source Of NO,” Trends in Pharmacological Sciences, Sept. 1988
Collier and Vallance, “Second Messenger Role for NO Widens to Nervous and Immune Systems,” Trends in Pharmacological Sciences, Nov. 1989

ISSUE, #26 PAGE 13
L-ARGININE REDUCES BLOOD PRESSURE IN HUMANS
In issue #23 [above] we wrote about a newly-discovered natural function of arginine: it serves as the precursor to NO, nitric oxide, a gas which is now believed to be endothelium-derived relaxing factor (EDRF) that powerfully relaxes blood vessels. Doctors at the Keio University School of Medicine in Tokyo recently tested the effects on human blood pressure of an infusion of L-arginine. They administered a dose of 500 mg/kg over 30 minutes (that is quite a lot, for example, the dose would be 35 grams for a 154 pound man) to five healthy men aged 24 to 37 and to five patients (four male) with essential hypertension aged 30 to 65. The antihypertensive drugs the latter patients were taking were withdrawn 4-7 days before the experiment.

The infusion caused rapid onset of hypotension in both groups, reducing both systolic and diastolic blood pressure. Blood pressure returned to baseline levels by 20 minutes following the infusion. The researchers thought the effects were probably caused by EDRF induced vasodilation.

In animal studies, L-arginine alone has not caused hypotension, although it has reversed the pressure (blood pressure increasing) effects of NG-monomethyl-L-arginine, a competitive inhibitor of EDRF synthetase (the enzyme that converts L-arginine to NO).

We would like to see a double-blind placebo controlled study of 12-18 grams of oral L-arginine (a common growth hormone releaser dose) on blood pressure. A lower dose taken orally would deliver less L-arginine than would be delivered over a longer period of time.

Nakaki, et al, “L-Arginine-Induced Hypotension,” The Lancet pg. 696, Sep. 15, 1990

ISSUE #26 PAGE 12
ARGININE AND SEX
We have found some very interesting information on arginine that suggests a mechanism for sexual enhancement (our own observations and those of others) reported anecdotally by both men and women using an arginine formulation.

On pp. 93-94 of issue #23, we discussed endothelium-derived relaxing factor (EDRF), a substance that relaxes blood vessels, and, thus, is important in the regulation of blood pressure (it has other functions, too, such as inhibiting platelet adhesion and aggregation which can lead to blood clots, occlusive strokes, and coronary thrombosis). It was recently discovered that EDRF is NO, nitric oxide, a gas, and that NO is produced from arginine by the liver, adrenal, and kidney.

Penile erection results when smooth muscle of the corpus cavernosum relaxes, which is followed by venous occlusion and engorgement of the corporal sinusoids (cavities) with blood. Four scientists now report that stimulation-induced relaxation of corporal smooth muscle is markedly inhibited by an inhibitor (NG-nitro-L-arginine) of the biosynthesis of NO from arginine, as well as by other agents that interfere with the biological actions of NO. Thus, penile erection may be mediated by NO. The chart included with their report shows that addition of L-arginine to rabbit corpus cavernosum preparations containing NG-nitro-L-arginine alone.

We have also had reports of increases in libido in women who take arginine. Although women do not have penile erection during sex, there is blood engorgement of homologous tissues: perhaps this is mediated by NO.

Ignarro, Bush, Buga, Rajfer, Nature (scientific correspondence), pp. 131-132 (13 Sept. 1990)

ISSUE #22 PAGE 84
POSSIBLE IMPROVED FERTILITY WITH ARGININE
Arginine Supplements Increase Sperm Count and Sperm Motility in Men With Low Sperm Counts/Motility

L-arginine enhanced sperm motility in vitro, with response to arginine following a dose-response curve (more L-arginine causing greater motility). Other substances tested that did not enhance sperm motility included L-ornithine, d-arginine, L-lysine, and the arginine analogs L-homoarginine and L-nitroarginine.

A daily dose of 4 grams of L-arginine was used to treat 178 men with sterility because of oligospermia (low sperm count). Sperm count increased by 100% in 42 cases (23.6%) and 15 pregnancies occurred soon after in this group. In 69 patients (38.7%), there was a marked increase in the number and motility of sperm and 13 pregnancies resulted. In 21 cases (12.3%) a moderate increase occurred in sperm count (but it was still classified as oligospermic) and in half sperm motility improved. In 46 patients (25.4%), there was no improvement in either sperm count or motility: these patients had severe oligospermia. The authors note that in some studies arginine treatment of oligospermic patients was unsuccessful probably, they propose, because of insufficient doses (1 to 2 grams daily). Other studies they cite reported significant improvement in more than 30% of patients given larger doses (10 to 20 grams daily).

Schachter, Goldman, Zukerman, “Treatment of Oligospermia with the Amino Acid Arginine,” The Journal of Urology 110:311 (1973)

Re-post permission Durk Pearson and Sandy Shaw to Life Priority Inc.

Live Long and Prosper – Durk Pearson and Sandy Shaw

 

Life Priority, established in 1994, offers supplements that are scientifically-formulated, results-oriented, and GRAS (Generally Recognized As Safe) and are manufactured at USDA and FDA inspected facilities.
*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.
*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.

 

“Free Radical Theory on Aging”scientist Denham Harman

Scientist and researcher Denham Harmon is best known for his “Free Radical Theory on Aging” Dr. Harman developed the free-radical theory of aging in 1954. The theory holds that one of the byproducts of oxygen use is adverse chemical reactions in cells, which results in aging and, ultimately, death. Initially the theory was scoffed at, but by the 1980s, free radicals had increasingly become part of research into cancer, cardiovascular disease and strokes. Free radicals have since been linked to Alzheimer’s disease.

Durk Pearson & Sandy Shaw–Life Extension Book Dedication: This book is dedicated to Dr. Denham Harmon, originator of the free radical theory
on aging, whose papers first interested in this field.

“We heard about Dr. Denham Harmon’s free radical series of aging.  Free radicals are damaging molecules with an up-paired electron.  You’ve probable heard of antioxidants like vitamins C and E and beta carotene.  Well one of the main functions of these antioxidant nutrients is to protect you from free radicals.  Free radicals play a significant role in cardiovascular disease, certain types of cancer, quite likely aging itself.” Sandy Shaw

Obituary Published in the Washington Post Nov.29 2014:

Denham Harman, was a scientific researcher who developed a prominent theory on aging that is still  used to study cancer, Alzheimer’s disease and other illnesses, died Nov. 25 2014, at a hospital in Omaha. He was 98.

The death was announced by Tom O’Connor, a spokesman for the University of Nebraska Medical Center, where Dr. Harman worked as a researcher since 1958. The cause was not disclosed.

 

Harvard Medical School professor David Sinclair said that Dr. Harman’s research inspired thousands of young scientists, including himself, to work on aging research.Dr. Denham Harman, shown here in 2006, has died at 98. (Nati Harnik/Associated Press)

“Dr. Harman is one of the most influential scientists of the past 50 years, bringing world-class science to what was once a backwater of biology,” Sinclair said in an interview, adding that Dr. Harman’s theory “is a cornerstone of the aging field.”

Dr. Harman thought that with a healthy diet, regular exercise and certain vitamins, particularly vitamins C and E, aging could be slowed by reducing the production of free radicals. He also recommended limiting alcohol consumption and not smoking.

Richard Hodes, the director of the National Institute on Aging, called Dr. Harman a pioneer of aging research.

“The free-radical hypothesis has been a central element of the field ever since Dr. Harman’s landmark paper,” Hodes said. “Beyond his own work and continued exploration of the free-radical hypothesis, Dr. Harman’s contribution to science has helped lay the foundation for important, related areas of inquiry such as the mitochondrial and DNA-damage hypotheses.”

Sourced from www.washingtonpost.com/national/health-science/denham-harman-who-developed-the-free-radical-theory-of-aging-dies-at-98/2014/11/29/4b92963e-7583-11e4-9d9b-86d397daad27_story.html

Self-Defense Against Infection

Avoid infections, and enhancing immune surveillance to prevent them in the first place is what we consider the best strategy.

Self-Defense Against Infection  By Durk Pearson and Sandy Shaw

First appeared in the July 2008 issue of Life Extension News

Helping Your Immune System Help You

Largely because of FDA regulatory hurdles, life-extension-bookthere are only two new antibiotics in the pipeline and no end in sight for the drought in new antibiotic developments. As a result, antibiotic-resistant infections are becoming a very serious problem, especially so if you have to go to a hospital, where these resistant “bugs” are prevalent. A very close friend of ours died recently from an infection (sepsis) that he got as a result of a catheter implanted in a hospital while being treated for cancer. He never got the chance to benefit (or not) from the cancer treatments. In our opinion, the hospital’s oversight for potential catheter-related infections, a very common occurrence, was very poor, but that is another story. The point we are making here is that you need to avoid infections, and enhancing immune surveillance to prevent them in the first place is what we consider the best strategy.

Rather than just taking supplements that are alleged to “enhance immune activity,” we strive to identify particular types of immune activity that deliver the sort of protection we’re interested in, and we then search the literature for natural substances that can safely provide that type of protection. In the case of infections, we are particularly excited by the protection provided by theanine, isoleucine, and vitamin D. We explain below.

Theanine in Tea Enhances Adaptive Immune Function in Response to Bacteria, Viruses, and Tumors

A new paper in Nutrition Reviews1 reports on the impressive, adaptive immune-enhancing activity of theanine, a unique amino acid found only (as far as is known) in tea (Camellia sinensis). Brewed tea contains millimolar concentrations of theanine.1

Theanine has been found to prime gammadelta T cells, which comprise about 2–5% of total peripheral blood T cells and which mobilize (expanding by up to 50-fold) in response to alkylamines produced by bacteria. Theanine is catabolized in the kidney, resulting in the production of ethylamine, an alkylamine* that primes the gammadelta T cells known as Vgamma2Vdelta2 T cells. Priming does not cause these cells to expand in the absence of antigen but does cause them to more efficiently expand and to produce the potent antimicrobial IFNgamma (interferon gamma) in response to microbial antigens. It is like cocking a gun: the cocking itself doesn’t result in discharge but is a necessary prerequisite for discharge. Consumption of 5–6 cups a day of tea (containing 190 mg of theanine) by human volunteers increased the capacity of Vgamma2Vdelta2 T cells to secrete IFNgamma by up to 15-fold in response to ethylamine or dead bacteria.1 As noted above, the theanine or tea containing it does not increase IFNgamma secretion (which is associated with fever and other flu like symptoms) but primes the T cells to enable them to more efficiently secrete IFNgamma in response to infection.1

*Interestingly, alkylamines are also found in apples and wine and are found in up to millimolar concentrations in urine, breast milk, and amniotic fluid. See Reference 1.

The article reported that severe combined immunodeficient mice reconstituted with human peripheral blood mononuclear cells containing Vgamma2Vdelta2 T cells were protected against death from gram-negative and gram-positive bacteria. Moreover, in the same type of mice, “adoptive transfer of Vgamma2Vdelta2 T cells enhances survival against challenge with a variety of myelomas, carcinomas, and lymphomas. Such enhancement was improved when Vgamma2Vdelta2 cells were first primed.” There are clinical trials in progress testing whether the priming of these cells (by risedronate, a bisphosphonate used to treat osteoporosis, or adoptive transfer of Vgamma2Vdelta2 cells) can effectively treat lymphomas, kidney carcinoma, and solid tumors.

Moreover, a recently published, double-blind, placebo-controlled trial of a proprietary blend of theanine and catechins reported that in healthy human subjects aged 19–70 taking the formulation for three months, the incidence of cold and flu symptoms was decreased by 30%. The authors of Reference 1 found that the protective effect was due to a 30% increase, compared to placebo, in the ability of Vgamma2Vdelta2 T cells to secrete IFNgamma ex vivo (tested outside of the body). (A disclosure, under “conflict of interest” given at the end of this review article, reports that one of the authors owns stock in the company selling the proprietary blend.)

Adaptive Immunity Prevents Growth of Occult Cancer

Another paper2 reports on explicit examinations of the adaptive immune process whereby occult cancers (small, undetectable masses of cancerous cells) are maintained in a small size. In this paper, the authors show that cancer can be prevented from growing beyond a tiny, undetectable size by T cells of the adaptive immune system. Under such conditions of “equilibrium,” loss of immune competence or of the antigenicity (ability of the immune system to recognize the tumor cells) disrupts the process and results in tumor expansion. This is thought to be the reason that some occult cancers emerge when patients have received an organ transplant and immunosuppressive therapy. The authors also propose that suppression by the adaptive immune system may account for why most older men have occult prostate cancers but only in a fraction of them does development of symptomatic prostate cancer occur.

Briefly, the experiments involved exposing mice to a cancer-causing chemical, 3’-methylcholanthrene (MCA), that resulted in the development of sarcomas in some of the mice. They found that “of 187 mice treated with low-dose MCA, 86 (46%) developed progressively growing sarcomas following depletion of CD4/CD8 cells, IFNgamma, and/or IL-12—components that participate in adaptive immunity. . . . We therefore considered the possibility that at least some of the MCA-treated wild-type mice that remained free of progressively growing tumors harboured fully transformed sarcoma cells, the outgrowth of which was immunologically restrained.” In the MCA model, transformed cells emerge exclusively at the site of injection. “Examination of the injection site in 129/SvEv mice treated with 25 µg MCA revealed the presence of small 2–8-mm masses that became palpable within 150 days of MCA injection but did not change in size during an additional 150 days.”

The authors concluded that net tumor cell expansion was being immunologically restrained. They concluded that “maintaining cancer in an equilibrium state may represent a relevant goal of cancer immunotherapy in which augmentation of adaptive tumour immunity could result in improved tumour control” of some kinds of cancers.

The Essential Amino Acid Isoleucine Induces Antimicrobial Peptides in Epithelial Tissues

An exciting paper3 from 2000 that has seemingly been forgotten reported that the essential amino acid isoleucine induces beta-defensins (antimicrobial peptides) in skin, airway, gut, and urogenital tract epithelial tissues, thus providing important protection against microbes by drilling holes in their membranes. “In addition to their direct antimicrobial activities, beta-defensins are chemotactic [attractive] for memory T cells, suggesting that they play an important role in the integration of the innate and acquired [adaptive] immune responses. . . . Isoleucine induced the expression of the beta-defensin 10- to 12-fold with peak activity between 3.12 µg/ml and 12.5 µg/ml.”1

Moreover, the authors found that isoleucine was highly specific in its induction of beta-defensin, as other amino acids did not do so. Isoleucine acts as a signal for the presence of potentially harmful microbes.1 It is an alkylamine1 (as is theanine, see above) and, though they didn’t test for it here, isoleucine probably primes the gammadelta T cells in the same way as theanine. The researchers note that “alkylamines are produced in vitro by a number of pathogenic bacteria includingSalmonella typhimurium, Listeria monocytogenes, and Yersinia enterocolitica.

Vitamin D Against Infections

A recent paper4 reports that bacterial invasion is recognized in injury and stimulates the production of antimicrobial peptides through a vitamin D-dependent mechanism. The authors discovered this via an investigation of the expression of genes influenced by vitamin D3 (1,25D3, the active form) in the setting of wound repair.

They found that “injury triggers a local increase in 1,25D3 signaling in skin.” Then they found that 1,25D3 stimulated an increase in the expression of TLR2 [toll-like receptor 2] and CD14, microbial pattern recognition receptors, and cathelicidin, an antimicrobial peptide.

A somewhat earlier paper5 found that toll-like receptor activation in human macrophages caused an upregulation of the expression of the vitamin D receptor and the vitamin D1-hydroxylase genes that resulted in the induction of the antimicrobial peptide cathelicidin. The cathelicidin killed intracellular Mycobacterium tuberculosis.(The action of the vitamin D receptor in the killing of the tuberculosis microbe links the long-standing knowledge that tuberculosis patients do better when exposed to sunlight.) The authors suggest that innate differences in the ability of human populations to produce vitamin D “may contribute to susceptibility of microbial infections.”

We strive to identify particular types of immune activity that deliver the sort of protection we want, and we then search for natural substances that can safely provide that type of protection.

As part of their study,5 the authors found that “Addition of 1,25D3 to primary human macrophages infected with virulent M. tuberculosis reduced the number of viablebacilli . . . By demonstrating that TLR stimulation of human macrophages induces: (i) the enzyme that catalyzes conversion of 25D3 to active 1,25D3; (ii) the expression of the vitamin D receptor (VDR); and (iii) relevant downstream targets of VDR (including cathelicidin), the present results provide an explanation for the action of vitamin D as a key link between TLR activation and [certain] antibacterial responses in innate immunity.”

Finally, in another report,6 the vitamin D receptor was found to be required for the development of natural killer T cells, which are important cells in immune regulation, tumor surveillance, and host defense against pathogens.

Why Vitamin K Should Be Taken with Vitamin D

We add this section because, while vitamin D and calcium supplements increase the absorption of calcium, adequate vitamin K is essential to ensure that the calcium ends up in bone rather than as calcium deposits in blood vessels. The proper regulation of calcium is carried out by osteocalcin, a hormone like peptide produced by osteoblasts (bone cells that manufacture bone).7 Vitamin K is required for the conversion of the preosteocalcin molecule to osteocalcin, its active form. (In fact, mice with the osteocalcin gene knocked out have abnormally high amounts of visceral fat, and early clinical observations revealed “significantly lower serum OC [osteocalcin] values in patients suffering from type 2 diabetes compared to healthy persons, and restoration of glycemic control resulted in increased OC levels.”7

While the recommended daily allowance of vitamin K is 1 µg/kg of body weight per day, that is based only upon adequate levels for proper blood clotting and not on the amount required for optimal bone formation or to prevent calcium deposition in blood vessels by carboxylating osteocalcin. “There is some evidence that the current RDA may not be sufficient to maximally carboxylate [activate] this protein [osteocalcin].”7 Most dietary vitamin K comes from a few leafy green vegetables and four vegetable oils (soybean, cottonseed, canola, and olive); however, the bioavailability from vegetables is relatively poor. “The 2005 Dietary Guidelines for Americans recommends 3 cups/week of dark green vegetables, which contain about 100 to 570 µg/serving of vitamin K.”8 However, what is actually absorbed is unclear and likely to be much less.

Studies such as that of Sokoll et al.9 found that increasing vitamin K intake from 100 to 420 µg/day resulted in a significant decline in the percentage of uncarboxylated osteocalcin within five days, suggesting that the “normal” intake of vitamin K in the North American population is not sufficient to maximally carboxylate osteocalcin.

References

  1. Bukowski and Percival. L-Theanine intervention enhances human gammadelta T lymphocyte function. Nutr Rev 66(2):96-102 (2007).
  2. Koebel et al. Adaptive immunity maintains occult cancer in an equilibrium state.Nature 450:903-6 (2007); also see commentary on this paper in same issue.
  3. Fehibaum et al. An essential amino acid induces epithelial beta-defensin expression. Proc Natl Acad Sci USA 97(23):12723-8 (2000).
  4. Schauber et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest 117(3):803-11 (2007).
  5. Liu et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 311(5768):1770-3 (2006).
  6. Yu and Cantorna. The vitamin D receptor is required for iNKT cell development.Proc Natl Acad Sci USA 105(13):5207-12 (2008).
  7. Booth and Suttle. Dietary intake and adequacy of vitamin K. J Nutr 128: 785-8 (1998).
  8. Johnson. Influence of vitamin K on anticoagulant therapy depends on vitamin K status and the source and chemical forms of vitamin K. Nutr Rev 63(3):91-7 (2005).
  9. Sokoll et al. Changes in serum osteocalcin, plasma phylloquinone, and urinary gamma-carboxyglutamic acid in response to altered intakes of dietary phylloquinone in human subjects. Am J Clin Nutr 65:779-84 (1997).

©2008 by Durk Pearson & Sandy Shaw

Life Priority is proud to have a working relationship with Durk Pearson and Sandy Shaw since 1994. We offer many of the Pearson & Shaw Designer Food formulas.

Life Priority Inc. 11184 Antioch # 417  Overland Park, Ks. 66210

 800-787-5438      www.lifepriority.com

 

Life Priority, established in 1994, offers supplements that are scientifically-formulated, results-oriented, and GRAS (Generally Recognized As Safe) and are manufactured at USDA and FDA inspected facilities.
*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.
*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.

Arginine and Muscle Memory- The “Fountain of Youth?” (Interview with Life Extension Scientists: Durk Pearson & Sandy Shaw)

Life Priority Presents— Durk Pearson and Sandy Shaw’s   MUSCLE MEMORY

Dear Customer:

One of the most valuable products offered by Life   Priority, Muscle Memory, has been described as “Youth in a Bottle”   by the formulators, Durk Pearson and Sandy Shaw. When you use it consistently   before workouts or at bedtime (on an empty stomach), you will experience why   this could be your personal fountain of youth.

The enclosed interview will describe the value of using   Muscle Memory. In 1991, I began using this formula to increase my strength   and endurance, speed up my recovery time, and have less soreness after   exercise. The use of Muscle Memory allows you to get the most from your   exercise.

For optimum results, use 1-3 servings of Muscle Memory 1   hour before exercise on an empty stomach (avoid eating protein 2-3 hours   before work outs) or 1 hour before bedtime. Read label instructions before   using Muscle Memory.

Here’s to the Retention of the Youth that is still in   you!

Greg Pryor, President Life Priority

____________________________________________________________________

Interview on Muscle Memory with scientists   Durk Pearson and Sandy Shaw–

Greg: Durk and Sandy, our customers   want to know about the Muscle Memory. Would you explain the formula to our customers   and the reasons why you created it? What is growth hormone and how important   is it to keep our bodies supplied with nutrients that increase the release of   gro

wth hormone?

Durk: Sure Greg, our interest in growth   hormone and it’s history goes back a long, long way, to the early ’70s, when   we realized that not everything associated with aging was necessarily caused   by free radicals and that corrective treatments could go beyond controlling   free radicals. Sandy and I became concerned about changes in the neuroendocrine   system that occurred with aging. For example, as a woman gets older, one of   the obvious changes is menopause. In males, there is a reduction in   testosterone. Some of these changes are in response to internal   “clocks”; others may be due to random damage, possibly related to   free radicals, possibly related to something else, such as receptor loss or   down-regulation. One of the most striking changes we noticed was the loss of   immune system function with age. A person at age 70 is lucky to have 20% of   their T-cell function left compared with when they were a young adult. That’s   why pneumonia used to be called “the old man’s friend.” That is,   pneumonia would kill you over a period of a few days; whereas something like   cancer would kill you over a period of a year, much more miserably.

Sandy: A case of viral pneumonia might   not even stop an otherwise healthy young person from going to work- just make   them miserable for a while- and certainly would never put them in the   hospital. The same virus could easily kill somebody in their 70’s.

Durk: We also noted that as you get   older you start putting on more and more body fat and it becomes harder and   harder to put on lean body mass. A potentially disastrous occurrence is the   fact that it takes longer and longer for wounds to heal. A wound that would   have healed in 5 weeks when you were in your teens or early 20’s might not   heal for 5 months when you’re in your 70’s.

Sandy: What we figured out is that all of   these changes were consistent with a reduction in the release of human growth   hormone.

Durk: Growth hormone (GH) doesn’t make   a person grow any taller after they’ve gone through puberty. You just don’t   grow any taller after that. However, during our mid-20’s to 30 or so, there’s   a big drop in GH output. And that’s when a person begins to find it much more   difficult to put on lean body mass by exercising. For example, if a person in   their teens or early 20’s does heavy exercise, they will release a relatively   large amount of GH from their pituitary. Or if they’re injured, they’ll also   release GH. By the time they’re in their 40’s, it takes a heck of an injury   to get a good GH release, and exercise will rarely do it anymore.

Sandy: It is possible to improve the   response of the GH-releasing system through the use of nutrients, and that’s   something that we became interested in during the 1970’s.

Durk: About 1976 we came to the   conclusion that it was quite possible that a reduction in GH was responsible   for many of the problems of aging, and we got a private grant to do   literature research on this. In fact, the private granting foundation asked   the person who won the Nobel Prize for sequencing human growth hormone   whether he thought our idea had any merit. He said, “Yes, this sounds   interesting. Let’s hope they follow up on it.”

So, as we proceeded to read more about   it, the more interesting it looked. Our thoughts turned to how you get GH   released, because actual human GH was very difficult to come by. Since then,   recombinant human GH has made the hormone much more available, although it’s   still very expensive.

Sandy: So what we did then was to look for   various substances that would cause release of endogenous GH, and we found   out that there were quite a few. For example, some of the opiates will do it,   but for obvious reasons that wasn’t really a suitable source.

Durk: We found out that there were   certain drugs that would do it, for example, L-dopa. But it’s highly   experimental for those who don’t have Parkinson’s disease to take L-dopa   every day for the rest of their lives. What we finally found is that amino   acids release GH, and some do it much better than others. In particular,   different amino acids had different ratios of insulin release to GH release.   Our goal was to find one that would maximize GH release and minimize insulin   release. Arginine and ornithine both fit that criterion.

We decided to use arginine for two   reasons. (Although ornithine was twice as powerful as arginine on a   gram-for-gram basis, it costs twice as much.) The first reason was that you   have a minute amount of ornithine in your diet, whereas you have substantial   amounts of arginine.

Sandy: Ornithine isn’t used to make   proteins.

Durk: You make proteins that contain   arginine. And as a result, we thought the choice of arginine would be more   conservative with respect to what human metabolism is adapted to. Also, we   found out that 20 grams of arginine is normally used intravenously as a   provocative test for GH release to see if a person’s pituitary is responding   normally. We wanted to find out whether oral doses were also capable of doing   that.

It turned out that oral arginine was   particularly effective at releasing GH when you add a couple of additional   factors to it, choline and vitamin B5 (pantothenate). That’s because GH   release involves the cholinergic nervous system.

Arginine along with choline and B5   works just fine when taken orally as long as you don’t have a lot of other   proteins in your stomach breaking down into amino acids that compete with   arginine’s entry into the brain. It worked even better than we had expected.

Sandy was the first experimental subject   matter for this treatment. We were at a Gordon research conference on the   biology of aging back in 1979. And Sandy   jumped up to try to get something off a shelf in our room, and when she came   back down she didn’t come down on her foot straight and there was this   horrible cracking sound.

Sandy: I noticed that my foot was swelling   up, and it was very tender and I couldn’t walk on it very well. I had to   hobble around.

Durk: In fact, it was Dr. Denham   Harman, the father of the free-radical theory of aging, who diagnosed her as   having a probable broken foot and suggested she get it X-rayed.

Sandy: Which I did, and it was broken. We   were aware of studies on animals with broken bones that healed faster with an   arginine supplement. And so we thought, “Well, we’ve done enough   literature search on this; time to start taking it.” The arginine growth   hormone release should help to speed up the healing.

Durk: Because she wasn’t moving around   nearly as much, she thought she ought to do some exercise, so she did some   bench presses lying on her back, which didn’t put any load on her foot. I   knew how much weight she was lifting, and I measured how far she lifted it   and counted the number of times she did it- she spent about 3 minutes a day   on it- and, by golly, in 5 weeks she lost about 20 pounds of fat and put on   about 5 pounds of lean body mass. Arnold Schwarzenegger in “The   Education of a Bodybuilder” said it would be difficult for a dedicated   male bodybuilder to accomplish that much gain in a year.

Also, the foot seemed to be completely   healed up a lot sooner than we expected. The doctor said it would be 2 or 3   months before she was really able to walk around on it. Yet in 5 weeks she   felt fine, had it X-rayed, and it was okay. I mean, it wasn’t broken anymore;   not only that, in the X-ray it didn’t look like it had ever been broken.

Another very interesting story involves   a friend of ours, a plump, sedentary, gourmet, 72 years old, who fell down on   an icy sidewalk several years ago and broke his arm. This guy is very   sedentary. His idea of exercise is taking the elevator from his condominium   down to the underground parking garage, underneath his law office and taking   the elevator up to his office.

His doctor told him that in about 5   months he would probably have to do bone grafts because he didn’t think it   would heal, given our friend’s age and condition. Well, our friend called us   up and said “Didn’t you once tell me something about accelerated wound   healing?” He asked the doctor about that and the doctor was very   dogmatic. “No, it’s not possible to speed up wound healing, there’s   nothing that can be done about it.” So he called us back and we told him   about Muscle Memory our formulation of arginine, choline, and B5, and sent   him some samples. He started taking three servings when he went to bed at   night. Five weeks later he felt so good, he went back to the doctor and said,   “I want you to take the cast off.” The doctor got a real snicker out   of that.

Sandy: He thought it was simply ridiculous.   But the patient asked for it, so he took another X-ray.

Durk: The doctor was absolutely   dumbfounded when he looked at the X-ray. It looked as though the bone had   never been broken, there was not shadow on it indicating a fracture and the   bone was a full density.

If a 12 year-old breaks an arm, you can   take the cast off at 5 weeks. But if you X-ray it, the bone is not going to   be at full density. Here, you have a guy who’s 72 years old with full density   at 5 weeks! In fact, the doctor said that if he hadn’t personally taken the   original X-ray, personally taken the second X-ray, and personally set that   arm and put it in a cast, he’d call it some type of insurance scam, because   what he saw was “completely impossible.”

We’ve heard of this sort of thing   happening to a lot of people using our arginine, choline and B5 combination,   like bodybuilders and Olympic athletes and so forth, who have also found out   how useful this is. It really helps a lot in maintaining the ability to gain   strength from peak output exercise. It also seems to help improve skin   elasticity. A lot of people who’ve been taking it for a year or so notice   that their skin, particularly on their face and neck, stays nice and tight.   And that’s because GH causes the liver to release IGF-1, which in turn   up-regulates production of elastin in the skin and also, I might add, in the   arteries. Elastin’s the molecule that makes tissue all nice and springy and   elastic. Anybody who has seen the skin pinch test done on the back of my own   hands can see that it’s really much more elastic than you would expect for   someone who’s 54 years old. We’ve been taking this formulation since 1979 now   -18 years – which is a pretty significant fraction of our adult lifetimes.

Durk: Remember, there are various   things that can limit your life span and also your quality of life. One thing   is simply muscular strength. A lot of elderly people end up falling down,   breaking their hips and then dying within the next year, because they never   really recover. Such falls have been traced in some cases to the loss of   equilibrium due to damage to the inner ear. But in most cases it’s thought to   be due to lack of muscular strength. A person who stumbles can usually right   himself but if you don’t have enough muscular strength, down you go. This   seems to be a major problem. The average woman over 65, I believe, cannot   lift 10 pounds.

Sandy: That’s right. It’s pretty shocking.

Durk: When you consider that a gallon   just of milk weighs about 9 pounds, you realize what a big limitation that   is. Another thing GH does is help maintain the function of T-cells in the   immune system. The heart of that is the thymus, where T-cells are produced,   selected, and educated or programmed. Maintaining GH levels can help retain   thymus function and thymus mass.

Maintaining elasticity goes beyond the   production of elastin. One very important thing about arginine is that it is   a very powerful sacrificial target for cross-linkers. If nothing else gets   you, you’re going to end up having to go on kidney dialysis at the age of 90   or 100 or 120, because, throughout your lifetime, cross-linking reactions are   taking place in the collagen in the basement membrane of your kidneys.

Sandy: As a result of glycosylation, this   causes the kidney’s basement membranes to thicken throughout life, and   eventually it becomes thick enough that it is not filtering the serum well at   all. In people who have diabetes, the process is accelerated. Diabetics   usually die of kidney failure. There was a very exciting study in diabetic   mice that were given arginine to what would be – scaled up to a human dose –   about 3 gm of arginine a day. They found that the mice that received the   arginine had normal kidneys when they became old as compared with controls.   The diabetic mice that did not receive arginine were dying of kidney failure.   They had thickened basement membranes in their kidneys.

Durk: In fact, what they found was that   there was no increase in thickness after about 6 months in the basement   membranes of those mice that got the arginine. It entirely abolished that   age-related increase in basement membrane thickness and cross-linkage.

Sandy: It’s interesting to note, too, that   the tests also have a basement membrane that thickens throughout life.

Durk: In some cases GH can block the   effects of insulin. And a person who has type II diabetes is already insulin   resistant. You don’t want to make them anymore insulin resistant. In fact, we   have found that in a small percentage of type II diabetics, the blood sugar   will go sky high if they take Muscle Memory. With most others, that doesn’t   happen. In fact, gradually increasing the doses of Muscle Memory may result   in an increased insulin sensitivity and a decrease in blood sugar levels.   However, this is something that has to be done under a doctor’s supervision,   where they’re actually measuring your blood sugar response as you go from   perhaps half of one serving of the nutrients to start and gradually work your   way up.

Sandy: That’s why we recommend on the label   that diabetics not use the product.

Durk: Let me also mention another   precaution: Arginine can increase the rate of growth of all tissues and that   includes, potentially, cancerous tissues. If cancer already exists, it might   accelerate its growth.

Sandy: I was reading in one paper about   breast cancer and GH. The authors found an improvement in the immune response   to the tumor in those patients taking GH, but, at the same time, the tumor   was getting assistance in growing, because growth factors – any growth   factors – do exactly that: improve growth.

Durk: Right. If a person has cancer,   they do not want to take this. If they’ve had cancer, and their doctor says,   “We got it all, there’s none left,” then there’s no reason that   they shouldn’t be able to take it.

Sandy: But caution is always the byword. I   think that by now your customers know that the two of us are extremely   conservative. We try to take as few risks as we possibly can and hope that   will contribute to our being able to live a very long time.

Durk: Another interesting thing I’ve   discovered: I’m pretty doggone sedentary; I spend most of my time lying on my   waterbed or a lounge chair reading scientific journals. But sometimes I go   out and do some very vigorous things like digging post holes or carting   concrete sacks around or branding cattle or digging out a hot spring. Believe   me, shoveling mud is a very, very backbreaking task. I find that if I don’t   take Muscle Memory before I do that, I will have aches and pains starting the   next day that’ll be really bad and will last several days.

Sandy: How achy were you after the cattle   branding?

Durk: Not at all because I was sopping   up Muscle Memory all day; over the day I took about three servings of Muscle   Memory spread out over the day. I just mixed it up in a drink and put it in   the cooler.

Durk: For GH release, you need to take   it all at once: two servings for a woman or three for a man, preferably at   bedtime, because about an hour and a half after you go to sleep is your   biggest GH release if you’re past, say, your mid 20’s. Or, alternatively,   about 3/4 of an hour before you engage in heavy peak-output exercise. But in   the cases of branding or digging out a hot spring, I’m usually at it all day   long. So I take about three servings, put it in some ice water, and stick it   in the cooler. I usually mix it with a couple of servings of Lift as well. I   just drink that throughout the day. No aches and pains that day. No aches and   pains the next day or the day after.

Durk: Basically what you want is to   mimic, as far as possible, the natural pulsatile release. What you don’t want   to do is to have elevated levels of GH all the time.

Sandy: Which is what you get with GH   infusions or even subcutaneous injections of GH that they’re giving elderly   people. These are not like the physiological releases of growth hormone.

Durk: GH is supposed to be released in   pulses, like insulin, and a continuous high level results in a resistance to   GH and all sorts of problems downstream from that. Now when you’re sipping   three servings over a period of maybe 6 hours of heavy work throughout the   day, you’re not going to get any GH release effect, but you will get the   beneficial effects of the arginine-derived nitric oxide.

Sandy: There have been a number of studies   of arginine with respect to atherosclerosis, particularly in animal models   like rabbits. The first sign you see before you see any fatty streaks or any   other visible evidence of atherosclerosis is that the arteries fail to dilate   in response to acetylcholine. That can be reversed by infusing arginine.

Durk: Instantly reversed! Twenty   seconds after you bathe the rabbits artery with the arginine, you’ve reversed   that resistance and normalized the response of the arteries so they dilate.

We know of one case where that happened   in a human. Our 72-year-old friend, after his arm healed up so fast, called   up and said, “Would it hurt me to continue taking this stuff? It really   makes me feel good, and it sure healed me up. I think this is doing a lot of good   for me.” He wasn’t a diabetic, so we said, “Well, we’ve been taking   it for 10 years now, go right ahead and do it.”

Sandy: So he started doing that. About a   year and a half later, he had a fast-synchronized MRI scan of his brain,   which gives very fine pictures of the cerebral arteries. He said that the   doctor that did this, a different doctor from the one who fixed his arm, was   absolutely astounded because, of his three major cerebral arteries, two of   them were completely clear, and one of them had about a 20% obstruction,   which is about the bottom end of the ability of this technique to measure at   that time. The doctor asked him what sort of diet he was on – was he a   vegetarian? Was he on a Pritikin diet, or what? And he said, “Well, my   diet was bacon and eggs every breakfast.” And that’s just about true;   those are the sort of things he eats. He’d be better off if he ate a lot more   veggies, but that isn’t what he eats.

Sandy: We don’t know what his arteries   looked like before he started using the arginine supplement, but the end   result is certainly consistent with what the experimental studies have shown   with arginine.

Arginine has also been studied for its   effects on blood pressure. Part of the blood pressure regulation process is   the arteries being able to dilate under the control of the cholinergic   nervous system.

Durk: And this is mediated by nitric   oxide. The scientist who figured that out won the Nobel Prize for it.

Sandy: A lot of people who have high blood   pressure, especially associated with atherosclerosis, have a failure of their   nitric oxide artery dilation system, and arginine often can help reverse   that.

Durk: We’ve been told that, under a   physician’s supervision, some people have been able to reduce their doses of   anti-hypertensive medication by taking Muscle Memory throughout the day. Some   people have even been able to discontinue the drugs entirely, particularly if   they add potassium and magnesium along with an arginine, choline and B5   supplement throughout the day. But this should be done only under a   physician’s supervision.

Sandy: One other thing to keep in mind is   that using nutrients to get GH release is a very different thing from using   the hormone itself, from the point of view of the feedback controls that   regulate the release of hormones in the pituitary and elsewhere. When you   take growth hormone itself, you bypass the normal regulatory features that   control when the hormone is released and how much is released. You put GH in   there, and you just override those controls. When you take arginine and   choline and B5, you still have all of those regulatory mechanisms in place to   control how much is released and when its released.

Durk: Another thing that we definitely   don’t want to forget is that the mechanism that causes erections in male   mammals is, in fact, nitric oxide. That’s what causes the vasodilation that   results in the corpus cavernosa engorgement with blood producing an erection.   If you take Muscle Memory 30-45 minutes before sex, you’re likely to notice   the difference. There’s similar erectile tissue in women inside the lining of   the vagina.

Sandy: Just like the arteries that we talked   about earlier in the development of artherosclerosis, the cholinergic   mechanisms are also involved in the dilation of the blood vessels to the penis.

Durk: I’m not at all surprised that   occurs.

Durk: I think that Muscle Memory does a   lot to make your neuroendocrine system look younger. In fact, the mixture was   used in a double-blind, placebo-controlled study at a private fertility   clinic. They took women who were not ovulating and put them on pergodile,   which is a dopaminergic agonist, FDA-approved for fertility purposes (as well   as for treating Parkinson’s patients). Most of them ovulated after they’d   been on Pergodile for a while. The ones that had failed to ovulate after 6   months were put on two servings of the arginine-choline-B5 mixture at bedtime   every night in addition to Pergodile.

The doctor said that the results were   absolutely amazing: 80% of the women ovulated within days of going on the   mixture. He said it was like turning on a light switch. I might add that one   woman was about 1 and a half years postmenopausal; another one was about 2   and a half years postmenopausal. So, in a lot of ways, Muscle Memory makes   your endocrine system look like that of a younger person.

Durk: Yes, in fact, it can. We reported   that over a decade ago in one of our Life Extension books. A few hundred   milligrams of buffered niacin can indeed do that; that’s what I take at   bedtime along with my Muscle Memory. About 200 mg of niacin will give you   double or triple the GH level compared with backgrounds. This is significant,   but it’s nowhere near as big a pulse as you would likely get with the   arginine-choline-B5 in Muscle Memory.

Durk: You would typically get one   several times as big as with the niacin alone.

Durk: I use it myself whenever I have   to learn some sort of new motor type-task. Also, we have had some interesting   comments from various people. We know a retired professional golfer in his   sixties who, over a period of about 5 weeks, took five strokes off his game.   Normally at his age – he’d been playing at least a few times a week for 20   years – you’re not going to get better; you’re just going to get worse with   the passage of time. And that’s what he said; his game had gradually been   getting worse over the years. Taking five strokes off in 5 weeks is not   something that normally happens. But it’s been found that nitric oxide   release is absolutely essential for motor learning in the cerebellum, and it   also appears to be necessary for long-term potentiation in the brain, which   is the mechanism that’s involved in long-term memory. And I think that   explains his success.

Durk: When you go over it all, it   really sounds like too much of a panacea to be real. As the years have gone   on we’ve found more and more delightful things about arginine.

Durk: I’ll tell you this; if you’re   full of anabolic steroids to the point where you’ve down-regulated your   anabolic steroid receptors, the dietary supplement might conceivably not   work. Another possibility is that people who abuse GH by injecting it,   subcutaneously or intramuscularly, are definitely going to develop resistance   to it because it’s not being given in the pulsatile manner. Moreover the   doses of many GH releasers are inadequate, and most formulations lack   adequate choline and B5.

Sandy: Another thing is that, people who are   restricting their calorie intake significantly are going to be less likely to   release growth hormone because, under the conditions of fasting or caloric   restriction, animals go into a state where they do not grow. They reserve the   energy that they’re getting for more important things, like maintenance.   Growth is not a priority when you’re getting a restricted amount of energy   intake. So, for people who are on a diet that’s low enough, they may not get   a growth hormone release.

Durk: Also, if a person takes a big   slug of protein supplement, like 50 gm of protein, along with their Muscle   Memory, not much of that arginine is going to get to the brain compared with   taking it on an empty stomach. I’m afraid that a lot of body-builders may be   taking a protein supplement along with Muscle Memory before exercising. What   they should do is take the Muscle Memory before the exercise and take the   protein afterwards.

Muscle MemoryTM was designed by Life Extension scientists Durk Pearson   & Sandy Shaw for their own use.

Durk Pearson and Sandy Shaw were among the first scientists, beginning more   that 15 years ago, to recommend that people take arginine supplements
(along with choline and B-5) to boost their natural GH release and thereby   achieve a variety of life-extending benefits, including building lean muscle   mass
(in preference to fat), accelerating wound healing, strengthening bones,   improving immunity, and enhancing skin flexibility.

Muscle MemoryTM has been a Life Priority classic since 1994, for more   than a decade for:

  • People who recognize that the ingredients in        Muscle MemoryTM help accelerate physical fitness.
  • Those interested in the role of nutrition in        biological aging.       Muscle MemoryTM helps trigger your own internal biochemical        resources of mental and physical power for enhanced vitality and        youthfulness.
  • Store in a cool, dry, dark place.

SUGGESTED USE: Read the directions on the bottle   before consuming.
Use 1-3 tablespoons 45 minutes before work-outs (on an empty   stomach) or take 1-3 tablespoons of 1 hour before bedtime.

Order Muscle MemoryTM now!

 

www.lifepriority.com.

© Copyright LIFE PRIORITY

Life Priority, established in 1994, offers supplements that are scientifically-formulated, results-oriented, and GRAS (Generally Recognized As Safe) and are manufactured at USDA and FDA inspected facilities.
*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.
*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.

In the News: Women’s Dementia Worsens Faster Than Men’s

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 18 No. 4 • August 2015

In the News: Women’s Dementia Worsens Faster Than Men’s

So says a headline in the July 22, 2015 The Wall Street Journal. According to the study (398 subjects who participated in the Alzheimer’s Disease Neuroimaging Initiative), women’s cognitive decline took place about twice as fast as men’s. The good news is that it is very likely, based on scientific studies showing that women need more choline than men do (Fischer, 2007), and that, as choline has been identified as a nutrient important to cognition (Poly, 2011) a deficiency of choline is one cause of this vulnerability to dementia in women. Not only does estrogen play an important role in the cholinergic nervous system (Fischer, 2007, Craig, 2010)—estrogen that declines rapidly following menopause—but it is known that in older people, choline is taken up less effectively into the brain (Cohen, 1995). In addition, women are much more susceptible to autoimmune diseases than men are and the cholinergic nervous system is a major antiinflammatory system (Tracey, 2007).

Add it all up and the evidence points to a need for additional choline in older women. The amount of choline recommended by the Institute of Medicine (IOM) for non-pregnant women, 425 mg a day, is (in our judgment) too low to supply adequate amounts of choline to older women when you consider the reduced ability to transport choline into the brain, the loss of estrogen, and also the variation (dietary composition (van Wijk, 2012), choline consumption, genetic and epigenetic differences in the ability to absorb choline from the diet, get it into the brain, and then convert it to phospatidylcholine via biochemical pathways) between individuals suggests that the amount that may be adequate for much of the population per the IOM recommendation may not be adequate for YOU.

In short, choline is a major nutrient for keeping your cognitive function in good condition as you get older. We ourselves take 2 grams a day of choline in the form of choline dihydrogen citrate.

References

  • Fischer, daCosta, Kwock, et al. Sex and menopausal status influence human dietary requirements for the nutrient choline. Am J Clin Nutr.85(5):1275-85 (2007).
  • Poly, Massaro, Seshadri, et al. The relation of dietary choline to cognitive performance and white-matter hyperintensity in the Framingham Offspring Cohort. Am J Clin Nutr. 94:1584-91 (2011).
  • Craig, Brammer, Maki, et al. The interactive effect of acute ovarian suppression and the cholinergic system on visuospatial working memory in young women.35:987-1000 (2010).
  • Cohen, Renshaw, Stoll, et al. Decreased brain choline uptake in older adults. An in vivo proton magnetic resonance spectroscopy study. 274(11):902-7 (1995).
  • Physiology and immunology of the cholinergic antiinflammatory pathway.J Clin Invest.117(2):289-96 (2007).
  • van Wijk, Watkins, Bohlke, et al. Plasma choline concentration varies with different dietary levels of vitamins B6, B12and folic acid in rats maintained on choline-adequate diets. Br J Nutr. 107:1408-12 (2012).

 

Life Priority, established in 1994, offers supplements that are scientifically-formulated, results-oriented, and GRAS (Generally Recognized As Safe) and are manufactured at USDA and FDA inspected facilities.
*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.
*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.

Ring the Bell for Magnesium Priority

Magnesium is important to cardiovascular health

*Interview with Durk Pearson and Sandy Shaw Regarding the Importance of Magnesium Priority

Epidemiological studies conducted in countries such as Germany, Sweden, South Africa, and Italy strongly suggest that low levels of magnesium in the water supply are associated with coronary heart disease.1-4  Indeed, it is now becoming clear that inadequate levels of magnesium is a ring the bell magnesiumproblem throughout the Western World, and that a lower than normal dietary intake increases the risk of hypertension, cardiac arrhythmias, ischemic heart disease, arherogenesis and sudden cardiac death.5  Moreover, shortages of serum magnesium often appear to be associated with other cardiovascular problems including coronary vasospasm.  The above data has been evident for quite some time.

 However, as Durk Pearson & Sandy Shaw point out, there are other reasons for increasing dietary supplementary intake of magnesium beyond the RDA.  If you miss the ringing of the magnesium bell and what they have to say in the following exchange, you miss at your own risk.

DURK: For many years it’s been realized that magnesium is important to cardiovascular health and inadequate quantities of magnesium lead to an increased incidence of cardiovascular disease.  Unfortunately, many of the most common sources of magnesium, such as milk of magnesia have a low bioavailability (not being fully absorbed in the body).  A few years ago the FDA proposed reducing the magnesium RDA from 400 to 200 mg.  There was such an outcry about it that they backed off. Four hundred (400) milligrams is about the lowest amount an adult ought to consider taking, and most people aren’t getting even half of that in their diet.  Most forms of magnesium are not well absorbed.  To the best of my knowledge magnesium aspartate is the best.

GREG: How much magnesium are you and Sandy taking a day?

 DURK: I was taking 4 capsules per day of  Magnesium Priority™ for a total of 400 mg per magnesiumday.  However, I’ve recently doubled that to 800 mg (8 capsules) and so has Sandy because of an interesting paper we read about loud noises (from shooting firearms) caused damage to the cochlea hair cells in the ear and even to the auditory nerve.  The scientists found that this excitotoxic damage can be partially prevented and recovery from temporary hearing loss (due to the loud noise) hastened with 700 mg a day of magnesium in the form of magnesium aspartate.

 SANDY:  This is not an adequate substitute for ear protectors when one is shooting a gun or operating noisy machinery, however.

_________________________________

For many years it’s been realized that

magnesium is important to cardiovascular

health and that inadequate quantities

of magnesium lead to an increased

incidence of cardiovascular disease.

__________________________________

GREG: Or while subjecting oneself to loud music or attending concerts, I’ll bet.

DURK: Perhaps. But the study shows that at least some excitotoxic damage can be prevented.

GREG: Is this the way that taurine operates?

DURK: Both taurine and magnesium help prevent excitotoxic damage, among other things.  And the taurine is certainly concentrated in the nervous system.  However, magnesium and taurine don’t necessarily work in exactly the same place in the excitotoxin cascade.

GREG: Can the benefit of one add to the benefit of the other?

DURK: Possibly…plausibly.

__________________________________

The scientists found that this excitotoxic

damage can be partially prevented and

recovery from temporary hearing loss

(due to the loud noise) hastened with

700 mg a day of magnesium in the

form of magnesium aspartate.

____________________________________

 GREG: Can they at least be supplementary?

DURK: They might be, but we don’t know of any data from taurine plus magnesium.  In any case we’ve increased our magnesium dose.  In addition, this probably gives us more cardiovascular protection.  There have been a lot of suggestions that 800 mg of magnesium is a good idea for cardiovascular protection; but the way we figure it, some excitotoxin damage is going on all the time.  Taking magnesium “sounds” like a good way of reducing possible damage due to inadvertent exposure.  Even though we’re not exposed to loud noises without ear protection, there’s going to be natural excitotoxin damage occurring as part of the wear and tear of everyday life and aging.

Many common sources of magnesium such as dolomite-which contains a mixture of Magnesium imagesCA22T0OKcalcium and magnesium carbonate-and milk of magnesia (magnesium hydroxide), as we’ve said, have relatively low bioavailability.

GREG: Magnesium Priority™ contains 400 mg of magnesium aspartate, as well as 80 mg of ascorbyl palmitate in 4 capsules.  If a person chooses to take 800 mg, how fast should one increase from 4 to 8 capsules per day?

DURK: Start out the first few days with just 1 capsule and then 2 and 3 and then 4; slowly build it up to 8.  If you start out right away taking 8 caps per day, you’re pretty sure to get diarrhea.

GREG: I hear you and, therefore, I intend to make Magnesium Priority™ a daily part of my dietary supplement regimen.

References:

  • Teitge JE. Incidence in myocardial infarct and mineral content of the drinking water.  Z Gesemine Inn Med. 1990; 45:478-485
  •  Marier JR, Neri LC. Quantifying the role of magnesium in the interrelationship  between human mortality/morbidity and water hardness.  Magnesium 1985; 4:53-59
  • Rubenowitz E, Axelsson G, Rylander R. Magnesium in drinking water and death from acute myocardial infarction.  Am J Epidemiol 1996; 143:456-462
  • Bernardi D, dini FL, Azzarelli A, Giaconi A, Volterrani C, Lunardi M. Sudden cardiac death rate in an area characterized by high incidence of coronary artery disease and low hardness of drinking water.  Angiology 1995; 46:145-149
  • Altura BM, Altura BT.  Cardiovascular risk factors and magnesium: relationships to atherosclerosis, ischemic heart disease and hypertension.  Magnes Trace Elem  1991; 10: 182-192
  * Life Priority Inc. products are not intended to diagnose, treat or cure any medical condition. *These Statements have not been evaluated by the FDA. These products are not intended to diagnose, treat, cure or prevent any disease. The information provided is for educational purposes only. Information provided is not intended to replace the advice of your doctor or competent health care professional. Rev 2/09
Life Priority Inc. 11184 Antioch Rd. #417 Overland Park, KS. 66210   www.lifepriority.com  
800-787-5438 or 913-438-5433 Fax 913-438-5444

 

 Life Priority, established in 1994, offers supplements that are scientifically-formulated, results-oriented, and GRAS (Generally Recognized As Safe) and are manufactured at USDA and FDA inspected facilities.
*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.
*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.

 

Why the Niacin Flush May Be Surprisingly Beneficial to Your Health – Sandy Shaw

Why the Niacin Flush May
Be Surprisingly
Beneficial to Your Health

Why the Niacin Flush May
Be Surprisingly
Beneficial to Your Health 

Why We Think It May Reduce the Risk of ALZHEIMER’S
DISEASE and Other Inflammatory Diseases,
Including Atherosclerosis, Type 2 Diabetes,
Ulcerative Colitis, Even Male Pattern Baldness

Sandy Shaw

WITHOUT PRIOR REVIEW BY DURK

It has not been read or reviewed by Durk Pearson, due to considerations that include, importantly, that time has run out and Shaw insisted on getting the paper into print without waiting. Shaw and Pearson have extensively discussed the elements of the paper so that the word “we” can be understood as the result of these discussions, but not based upon a reading of the Shaw paper by Pearson. Other than this disclaimer, everything remains as it is in the paper, with an expectation that more will be written on this subject to appear in future Durk & Sandy newsletters.

Here we explain why we think that the niacin flush (see description of flush just below this paragraph) may be a key part of the cardioprotective effect of high dose immediate-release (flushing) niacin’s highly protective effects on lipid metabolism, such as potent reductions of LDL and VLDL and triglycerides, while increasing HDL and, moreover, why the niacin flush may play an important role in reducing the risk of Alzheimer’s disease, atherosclerosis, type 2 diabetes, and other inflammatory diseases.

NOTE TO OUR READERS: This paper has become both much longer and included much more complex data and mechanistic detail to evaluate than the author (Sandy Shaw) originally anticipated. As a result, we have included in this first section of the paper the basic elements of how we believe the protective mechanism works and data on some diseases that we believe supports that interpretation. The next issue of our newsletter and subsequent issues will include the remaining parts of our analysis, with data from other diseases that we believe also appear to have significant risk reduction by the same mechanism, including detailed analysis of atherosclerosis, type 2 diabetes, and other diseases that show up in our literature searches. Sandy conceived the idea of examining the literature on the subject, read the papers discussed, and analyzed the data presented in the papers. Durk has read the analysis in detail and is in agreement with it.

WHAT IS THE FLUSH? Though we have heard it described as a transient skin reddening (from increased blood flow) accompanied by a sensation of heat associated with itching, we have come to realize that not everybody is feeling the same thing when they say “niacin flush.” The reason is that while both of us find the niacin flush AS WE EXPERIENCE IT to be pleasant, many people find it intolerable. Thus we think that what people who hate the flush mean when they say “niacin flush” is not a pleasant hot with mild itch but a hot with very unpleasant biting and burning sensations (as if being bitten by an insect or stabbed with tiny knives). In studying the mechanisms involved in the niacin flush to the extent they are now understood, we have an idea why many people are having this unpleasant flush. After we have discussed how we understand some of what causes the niacin flush, we will explain what we think may be making it intolerable for many. See below in section on “What Is Intolerable About the Niacin Flush?”

We understand, then, that some people can’t tolerate the niacin flush (caused by acute release of the prostaglandin PGD2) and, as a result, won’t use high dose plain niacin. It may be possible to reduce the flush to a tolerable level and, if so, it might be a much more sensible strategy (so you would end up with a flush like what we experience) than eliminating the flush if you want to get niacin’s lipid-lowering benefits. What has happened to niacin research, however, as a result of this crash program by certain drug companies to get rid of the flush, is that data on plain niacin and the effects of the acute release of prostaglandin D2 (which induces the flush) have to a considerable extent disappeared as more and more research focuses on the “extended release” or other non-flushing versions of niacin, which are not the same as plain niacin. “Extended release” niacin is not the same as plain niacin, for which extensive literature exists showing its potent lipid benefits. You do not see very much in the literature on head to head comparisons of “non-flushing niacin” (ersatz niacin) to plain (flushing) niacin in humans to identify what it is that the flush is doing.

THE KEY TO UNDERSTANDING THE EFFECTS OF THE PGD2-CAUSED NIACIN FLUSH IS TO REALIZE THAT IN ITS ACUTE RELEASE, PGD2 ACTS IN MANY MODEL SYSTEMS AS AN ANTI-INFLAMMATORY. IN ITS CHRONIC RELEASE, PGD2 APPEARS TO BE USUALLY PRO-INFLAMMATORY, but depending on the rate at which PGD2 is released, the amount released, and the state of inflammation in the tissue where it is released, you can get a pro-inflammatory or an anti-inflammatory effect. As the old saying goes, the devil is in the details and it is the rush to avoid considering the details so as to rapidly develop a non-flushing niacin that is leading to the rash abandonment by some drug companies and health practitioners of flushing (immediate-release or plain) niacin.

It has long been known that the prostaglandins PGD2 and PGE2 are responsible for inflammation induction (Haworth, 2007). Later in the biosynthetic pathways of these prostaglandins, anti-inflammatory circuits are induced (Haworth, 2007). Here is where we believe is the source of a major misunderstanding concerning the pro-inflammatory or anti-inflammatory effects of PGD2, the prostaglandin that causes the niacin flush: A CHRONICALLY HIGH LEVEL OF A SIGNALING MOLECULE, SUCH AS PGD2 (generally pro-inflammatory when at a chronically high level) CAN INTERFERE WITH SIGNALS BY ACUTELY RELEASED (PULSATILE) AMOUNTS OF THAT SIGNALING MOLECULE (generally anti-inflammatory) BY THE ACUTE SIGNAL SIMPLY BEING “LOST” IN THE NOISE OF THE CHRONICALLY HIGH LEVEL OF THAT MOLECULE. Hence, we think that chronically high levels of PGD2 are likely to prevent or reduce the effect of acute signals of PGD2 that would otherwise be anti-inflammatory. See sections on Alzheimer’s disease (AD) below, where chronically high PGD2 signaling is thought to be a major cause of the neurodegenerative features characteristic of AD (Maesaka, 2013).

  • Haworth and Buckley. Resolving the problem of persistence in the switch from acute to chronic inflammation. Proc Natl Acad Sci U S A. 104(52):20647-8 (2007).
  • Maesaka, Sodam, Palaia, et al. Prostaglandin D2 synthase: apoptotic factor in Alzheimer plasma, inducer of reactive oxygen species, inflammatory cytokines, and dialysis dementia. J Nephropathol. 2(3):166-80 (2013).

In this section, we look at PGD2 release in model systems:

DATA ON ACUTE AND CHRONIC RELEASE OF PGD2

Prostaglandin D2 in the Resolution of Inflammation
Ulcerative Colitis

There is considerable difficulty in interpreting the huge amount of scientific literature on prostaglandins when you read that a certain tissue level is associated with a certain stage of an inflammatory disease. Most of the literature that we’ve seen is bogged down with difficulties in interpreting the role of the prostaglandin in the inflammatory process because of not knowing whether the tissue level measured is part of a pulsatile release or a chronic release.

A very interesting recent paper (Vong, 2010) was published by scientists who believe that the increased expression of prostaglandin D2 synthesis and its EP1 receptor that they detected in individuals in long-term remission from ulcerative colitis suggest that the release of PGD2 in response to acute releases of inflammatory stimuli could be important antiinflammatory protection to maintain colonic mucosal homeostasis.

To study this phenomenon in human patients, the scientists took rectal biopsies from patients with active ulcerative colitis, which have elevated levels of PGE2, PGI2, and PGF2alpha. “Several studies of experimental colitis suggest important roles for PGD2 in promoting the resolution of inflammation and long-term alterations in colonocyte and barrier function …” They examined PGD2 levels in biopsies for ulcerative colitis patients, comparing them with those of healthy individuals who had no prior history of UC or those from healthy individuals who had experienced a prior bout of UC but had been in remission without medication for >4 years. “We observed a pronounced elevation of PGD2 synthesis and DPI receptor expression only in healthy individuals with a prior history of UC. In these individuals, as has been observed in animal studies, the elevated mucosal PGD2 may contribute to the maintenance of colonic tissue homeostasis and possibly, also to an increased risk of colorectal cancer.”

One difficulty here is that the biopsy represents a snapshot of PGD2 levels at one point. Was the PGD2 being released as an acute pulse at that point or was it being measured at a chronic level? The authors are hot to track down the cause of this association (the apparent anti-inflammatory effect of PGD2 in maintaining remission in UC) and say, “we believe that PGD2 plays an important role in the initial maintenance of mucosal homeostasis.” We might as well add our own hypothesis to the mix. On the basis of other data on anti-inflammatory effects of pulsatile release of PGD2, we would expect the most protective effects of PGD2 release in this model to occur at an optimal level of a pulse of PGD2 released over a limited time period in response to pro-inflammatory stimuli, but not too little to prevent inflammation so as to maintain remission, or too much to increase PGD2 to levels that would potentiate inflammation and, perhaps, be part of an increased risk of colorectal cancer the scientists here mention as a possibility.

For example, the scientists note that their results are “consistent with studies of rodents in which prolonged elevations of PGD2 synthesis were observed after resolution of colitis.” This prolonged elevation contributed not only to resolution of inflammation but also to “long term alterations in epithelial function, some of which may have contributed to an increased susceptibility to colon cancer.” This suggests that the protective response of the immune system in some animals and humans of increasing PGD2 release in response to inflammation to modulate that inflammation may go too far and result in long-term adverse effects such as increased risk of colon cancer. It appears to us that pulsatile PGD2 release a few times a day with immediate release niacin supplementation may offer better protection against a variety of inflammatory diseases.

  • Vong, Ferraz, Panaccione, et al. A pro-resolution mediator, prostaglandin D(2), is specifically up-regulated in individuals in long-term remission from ulcerative colitis. Proc Natl Acad Sci U S A.107(26):12023-7 (2010).

MALE PATTERN BALDNESS (Nieves, 2014)

The hair follicle in male pattern baldness balding areas (but not in normal hair of balding men) have chronically high levels of prostaglandin D2 accompanied by lower levels of prostaglandin E2. One way that minoxidil has been found to work is by increasing prostaglandin E2, which in this model “normalizes” the PGD2/PGE2 ratio. However, PGE2 is an inflammatory molecule, so you wouldn’t want to increase it very much, and that is undoubtedly the “secret” of minoxidil, to NORMALIZE the ratio of PGD2/PGE2 so as to eliminate a chronically high PGD2 level.

One of the signals of the catagen phase of hair growth, where hair growth ceases for a time and some hair follicles die, is the release of very large amounts (7 fold higher than baseline) of PGD2 (Nieves, 2014). For that reason, there is interest in blocking PGD2 as a “treatment” for balding. But once again, there is a risk that blocking PGD2’s unwanted effects will also block important beneficial effects of PGD2. This, not surprisingly, is a major problem in medicine, that the change you want in a certain tissue at a certain time and by a certain amount may cause harm elsewhere where you do not want that change.

  • Nieves and Garza. Does prostaglandin D2 hold the cure to male pattern baldness? Exp Dermatol. 23(4):224-7 (2014).

ANTI-INFLAMMATORY ROLE OF PGD2 IN ACUTE
LUNG INFLAMMATION (Murata, 2012)

The authors of this paper (Murata, 2012) studied the role of PGD2 signaling in acute lung injury (ALI). Administering endotoxin (lipopolysaccharide (LPS), a potent bacterial inflammatory factor) increased edema and neutrophil infiltration into the wild type mouse lung, typical effects seen in inflammation. “Treatment with either an agonist to the PGD2 receptor, DP, or a degradation product of PGD2, 15-deoxy-delta12,14-PGJ2, exerted a therapeutic action against ALI.” The effect of LPS inhalation by the wild type mice peaked on day 1, hence this was an acute effect. The authors found, however, that whether PGD2 had an anti-inflammatory effect or a pro-inflammatory effect depended upon the stage at which the PGD2 was administered, with PGD2 at later stages of ALI being anti-inflammatory (reducing the invasiveness of neutrophils).

  • Murata, Aritake, Tsubosaka, et al. Anti-inflammatory role of PGD2 in acute lung inflammation and therapeutic application of its signal enhancement. Proc Natl Acad Sci. 110(13):5205-10 (2013).

ALZHEIMER’S DISEASE: MICROGLIAL PGE2
(PROSTAGLANDIN E2) SIGNALING VIA EP4
RECEPTOR SUPPRESSES ALZHEIMER
ASSOCIATED INFLAMMATION

A signaling system is reported here (Woodling, 2014) that the authors found to regulate an important protective anti-inflammatory mechanism in the early stages of Alzheimer pathology that decreases significantly (along with its protective effect) as the disease progresses. This is a signal from the prostaglandin PGE2 to its EP4 receptor. See section below on the PGE2 receptor system (EP1, 2, 3, and 4) and new findings suggesting that it is a key to some of the antiinflammatory properties of DHA (docosahexaenoic acid, an omega 3 fatty acid found in fish oils) and possibly that of curcumin.

As reported in a 2012 paper (Ruan, 2012), the EP1 receptor for PGE2 appears to be the key target for DHA and fish oils. There they showed that, in cultured stromal cells, the IC50 for fish oil (that is, the amount that inhibited 50% of the PGE2 activity) was 18 mg/L or 54 μM. The authors calculated that, for a 150 pound human containing 4-5 liters of blood, “consuming 100 mg. fish oil should yield IC50 results.” (This depends, of course, on how the DHA partitions in the blood and tissues, but the calculation provides a crude estimate.) The authors then indicate that they would recommend taking 500-1000 mg fish oil daily on the basis of their findings.

It is interesting to note the opposing effects of PGD2 (the prostaglandin that induces the niacin flush) and PGE2 in the balding model (above), where chronically high PGD2 resulted in suppression of PGE2. A pulsatile release of PGD2 (an ACUTE release) as in the niacin flush would be anti-inflammatory, not pro-inflammatory as with chronically high PGD2. Hence, you could see an INCREASE in PGE2 by suppressing chronically high PGD2. The balding model, in fact, shows hair growth and the cessation of hair follicle death resulting from slight modulation in the ratio of PGD2/PGE2, in which PGE2 is increased, while chronically high PGD2 levels are reduced to “normalize” the ratio. The niacin flush causes pulsatile, not chronic, release of PGD2. It is relevant to note that another paper (see just below) describes CHRONICALLY high PGD2 signalling in full-blown Alzheimer’s. We predict, in fact, that high dose niacin in the immediate-release flushable form will REDUCE the risk of Alzheimer’s, and that getting rid of the flush would probably eliminate this protective effect. If you could get rid of the flush and still retain all the protective benefits of the flush, then fine, go ahead and get rid of it. But so far, the focus seems to be on suppressing the flush without adequately understanding what the flush has to do with the protective effects of immediate release niacin.

Also, note in the urate crystal inflammation model (below) that a 5.2 fold pulsatile (acute) increase in PGD2 was anti-inflammatory, decreasing inflammatory signaling by PGE2. The opposing effects of certain dose and time-dependent releases of PGD2 and PGE2 would appear to be a system to examine closely in relation to Alzheimer’s.

  • Woodling, Wang, Priyam, et al. Suppression of Alzheimer-associated inflammation by microglial prostaglandin-E2 EP4 receptor signaling. J Neurosci.34(17):5882-94 (2014).
  • Ruan and So. Screening and identification of dietary oils and unsaturated fatty acids in inhibiting inflammatory prostaglandin E. BMC Complement Altern Med.12:143 (2012).

ALZHEIMER’S DISEASE:
INCREASED LEVELS OF A FORM OF
PGD2 SYNTHASE

In a very complex analysis (Maesaka, 2013), researchers found that a form of PGD2 synthase, L-PGDS, can in a chain of biochemical reactions, convert arachidonic acid to 15deoxyPGdelta12,14 J2(15dPGJ2), the primary ligand for peroxisome proliferator activator receptor gamma (PPARgamma), and that 15dPGJ2 has been reported to induce apoptosis in human astrocytes and cortical neurons, which could be prevented by inhibitors of L-PGDS, such as IGF, insulin, and erythropoeiten as well as PGE1, PGE2, and COX2 and caspase inhibitors. The authors identified L-PGDS “as a dominant inducer of apoptosis in AD plasma,” presumably by increasing PGD2 signalling to a chronically high level.

  • Maesaka, Sodam, Palaia, et al. Prostaglandin D2 synthase: apoptotic factor in Alzheimer plasma, inducer of reactive oxygen species, inflammatory cytokines, and dialysis dementia. J Nephropathol. 2(3):166-180 (2013).

Interestingly, another paper (Ryan, 2008) reports that 15dPGJ2 (that as noted just above induces apoptosis in brain astrocytes and cortical neurons) impairs phosphatidylcholine synthesis by promoting cysteine cross-linking in the enzyme cytidyltransferase alpha. This cross-linking could be reduced by N-acetylcysteine (Ryan, 2008).

The sleep impairments observed in Alzheimer patients may be, at least to some extent, linked to chronically high PGD2 signaling, as PGD2 is an important sleep-inducing molecule (Urade 1999). The signal of a transient pulse of a substance is lost in the noise of a continuously high background level of that substance.

  • Ryan, Chen, Vennalaganti, et al. 15-deoxy-delta12,14-prostaglandin J2 impairs phosphatidylcholine synthesis and induces nuclear accumulation of thiol-modified cytidyltransferase. J Biol Chem.283(36):24628-40 (2008).
  • Urade and Hayaishi. Prostaglandin D2 and sleep regulation. Biochim Biophys Acta. 1436:606-15 (1999).

REDUCTION OF URATE CRYSTAL INFLAMMATION
BY ACUTELY ELEVATED PGD2

After struggling through the analysis of prostaglandin D2 synthase’s link to apoptosis in Alzheimer’s disease (just above this paragraph), if you did, you may be hoping for something a little simpler. This one is.

Here, researchers found (Jung, 2007) that in mice fed root extracts of traditional oriental medicinal plants,* inflammation elicited by injecting 2 mg of monosodium urate crystals into the pouch resulted in a rapid and dramatic decrease in the measured inflammatory parameters, including neutrophil density, IL-6 and TNFalpha mRNA. Leukocyte count, IL-6, prostaglandin E2, along with prostaglandin D2 were examined in the pouch exudate. Remarkably, the concentration of the potentially anti-inflammatory Prostaglandin D2 rose 5.2 fold. The authors of this 2007 paper were very excited about these results and thought this could point to a novel way to treat inflammation, the cause of the intense pain of uric acid crystals in gout. They seem to have been right, but nothing appears to have come of this.

* Dried roots of Acanthopanax senticosus, Angelica sinensis, and Scuttelaria baicalensis.

  • Jung, Schumacher, Kim, et al. Reduction of urate crystal-induced inflammation by root extracts from traditional oriental medicinal plants: elevation of prostaglandin D2 levels. Arthritis Res Ther.9:R64 (2007).

PGD2 IN THE SKIN

A recent paper (Shimura, 2010) reports on the role of PDG2 in allergic responses in the skin, focusing on mast cells expressing the hematopoeitic PGD synthase found in dendritic cells. They discussed rapid excretion of PDG2 in response to various allergens, including an irritant compound. “A possible anti-pruritic [anti-itch] potential of PGD2 in the scratching behavior of mice was recently proposed.” [It was AFTER Sandy performed the experiment on her itchy skin described just below that she read about this finding. Serendipity!] When released rapidly in response to allergens, PGD2 can act as an anti-inflammatory, while when released in excess quantities it exacerbates the allergic response (Shimura, 2010).

  • Shimura, Satoh, Igawa, et al. Dendritic cells express hematopoietic prostaglandin D synthase and function as a source of prostaglandin D2 in the skin. Am J Pathol.176:227-37 (2010).

SANDY’S ITCHY SKIN—DISCOVERING THE EFFECT OF
ELIMINATING THE NIACIN FLUSH THE HARD WAY

Sandy had developed an itchy skin condition (probably a result of severe hypothyroidism) and had, as a result, discontinued high dose niacin about a month ago because of increased itchiness and of stabbing sensations (see description of the niacin flush above) during the flush. The itchiness got worse until it became such a serious problem that she had to take two prescription drugs to keep the itchiness under control. Hydrocortisone cream didn’t help at all, which is consistent with the reported effect of chronically elevated PGD2 in blunting the antiinflammatory effect of corticosteroids (Barnes, 2009). This doesn’t PROVE that it was chronically high PGD2 in her skin that made the hydrocortisone salve ineffective, but is consistent with data showing that effect. As a matter of fact, Sandy has a mild case of COPD, which is reported to exhibit resistance to the antiinflammatory effects of corticosteroids, suggesting the possibility that she has chronically elevated PGD2 in her lungs. The fact that it hasn’t gotten progressively worse over the years, as COPD typically does, MAY be due to her ingestion of high dose immediate-release niacin which could be reducing the inflammatory activity by discharging the release of PGD2 via pulses, thereby preventing chronic PGD2 release as a sort of constant dribble rather than as pulses. This is our hypothesis. There might be another way to explain all this, and we certainly can’t prove there isn’t (given that it is impossible to disprove a negative), but we think our explanation is quite plausible and consistent with all the data we’ve seen.

It is interesting to note that curcumin restores corticosteroid sensitivity in monocytes exposed to oxidants by maintaining HDAC-2 (histone deacetylase 2) levels (Gonzalez, 2012); HDAC-2 levels are known to be reduced in COPD. Could this be another example of a natural substance that reduces chronically high levels of PGD2? It is certainly consistent with a large amount of the literature on COPD, PGD2, and HDAC-2.

  • Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol.71:451-64 (2009).
  • Gonzalez, Ballester, Lopez-Posadas, et al. Effects of flavonoids and other polyphenols on inflammation. Crit Rev Food Sci Nutr. 51(4):331-62 (2011).

EXPERIMENT: When I (Sandy) realized that it might be the loss of the flush that was causing my monster skin itch, I took 400 mg of niacin on an empty stomach to induce the flush. After that, the flush ensued and went on for the normal period of time it usually does after I take niacin, during which the itching was intensified, the itching then subsiding to a very low level. Plus, a little bonus, my painful knee osteoarthritis had become much less painful when I went out to the supermarket a few minutes later. It had become worse during the month I was off high-dose niacin. NOTE: I still took Personal Radical Shield during this period and so was getting between 250 and 500 mg/day of niacin, but my regular dose of niacin was around 2 grams a day in addition to that.

For a relationship between osteoarthritis and prostaglandin D2, see:

  • Zayed, Li, Chabane, et al. Increased expression of lipocalin-type prostaglandin D2 synthase in osteoarthritic cartilage. Arthritis Res Ther. 2008, 10(6):R146 doi:10.1186/ar2581 (2008).

Mitigation of Inflammation with Foods

A 2012 paper (Wu, 2012) reported that polyphenols and other compounds found in foods such as fruits, berries, vegetables, nuts, whole grains, and foods of marine origin contain components can “play an important role in attenuating and mitigating chronic pro-inflammatory processes associated with chronic diseases,” such as atherosclerosis, ischemic heart disease, cancer, obesity, inflammatory bowel disease, Crohn’s disease, diabetes and autoimmnune diseases. Surprisingly few papers on the mitigation of inflammation discuss prostaglandins explicitly, revealing that there is an immense area here where increased knowledge could promote improvements in controlling the chronic inflammatory diseases associated with aging.

When you control a biochemical pathway to regulate processes taking place far downstream, it is usually best to think of ways to regulate closer to the downstream site that is a problem because regulation at the upper end of the chemical pathway will affect many processes that have nothing to do with your problem and may produce unwanted off-target effects. THAT, in fact, is one of the major problems with statins … that their effects are taking place far upstream in the process of synthesizing cholesterol (Cederberg, 2015) and there are frequent undesired effects such as myopathy and an alarmingly high increased risk of developing type 2 diabetes.

  • Wu and Schauss. Mitigation of inflammation with foods.J Agric Food Chem.60:6703-17 (2012). Cederberg, Stancakova, Yaluri, et al. Increased risk of diabetes with statin treatment is associated with impaired insulin sensitivity and insulin secretion: a 6 year follow-up study of the METSIM cohort. 58:1109-17 (2015).

STATINS IN COMBINATION WITH NIACIN

As we note in the paragraph above, statins have been found to reduce insulin sensitivity, and this is associated with a large increase in the risk of developing type 2 diabetes. The combination of statins with niacin also have a significant effect in reducing the beneficial effects of increased HDL cholesterol that is seen with immediate release niacin (Keene, 2014). The mechanism that causes statins to increase the risk of type 2 diabetes are, we think, a likely place to look for what causes this adverse effect of statins on the protective effect of niacin on reduced risk of non-fatal heart attacks, the most common kind of heart attack.

Most Heart Attacks Are Non-Fatal, So the Reported
Highly Protective Effect of Niacin Against the
Incidence of Non-Fatal Heart Attacks Is Important

In a paper (Keene, 2014) providing a meta-analysis of 117,411 patients, very interesting differences between the effects of niacin taken by patients NOT RECEIVING STATINS (BEFORE THE STATIN ERA) and those who, later, were taking niacin and statins emerged. Very statistically significant results showed that in those patients NOT taking statins, niacin was associated with a significant reduction in non-fatal heart attacks (myocardial infarction) (odds ratio was 0.69, 0.56 to 0.85, p=0.0004). However, in studies where statins were already being taken, niacin showed no significant effect on the incidence of non-fatal heart attacks. The researchers say, “In the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents [niacin, fibrates, or CETP inhibitors, all of which increase HDL levels] do not support this concept [that increasing HDL would generally reduce cardiovascular events].” Statins interfere with an important protective effect of niacin. It is important to note that NON-FATAL MYOCARDIAL INFARCTIONS are the most COMMON type of heart attack, so reduction of these heart attacks is not at all unimportant, though the word FATAL may be somewhat distracting from the significance of these results.

Studies with statins HAVE repeatedly shown that reductions in LDL cholesterol with statins “has repeatedly been found to reduce cardiac events and all cause mortality in the setting of both secondary and primary prevention.” However, the increased protection against cardiovascular events expected by increased HDL has not been seen. See paragraph above. Hence, something in the interaction of statins with niacin and fibrates, where niacin and fibrates increase HDL cholesterol and which (when taken WITHOUT CONCURRENT INGESTION OF STATINS), reduces the risk of non-fatal myocardial infarctions, results in a loss of that protective effect of niacin or fibrates.

The studies with niacin were confounded by the fact that some of the patients were given aspirin or laropriprant to inhibit flushing. Laroopriprant is thought to interfere with prostaglandin pathways which, as you will see below in our discussion of prostaglandins, could be very important, and the authors of this paper (Keene, 2014) suggest that this effect “could confound the effect of niacin.”

  • Keene, Price, Shun-Shin, and Francis. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. 349:g4379 (2014) doi: 10.1136/bmj.g4379 (18 July 2014).

2012 REVIEW PAPER ON PGD SYNTHASE AND PGD2
IN IMMUNE RESPONSE (Joo, 2012)

A good recent review of PGD synthase and PGD2 described a variety of model systems in which PGD2 exhibited a proinflammatory or antiinflammatory effect. For example, a paper is cited in which a human model of an acute inflammatory response induced by the administration of LPS provides data “strongly” supporting anti-inflammatory effects of PGD2. PGD2 and its cyclopentenone prostaglandin derivatives are reported by the review’s authors to have antiinflammatory properties with functions in the resolution of inflammation, and “there is considerable interest in the importance of PGD2 and its distal products in the mediation and resolution of inflammation.” (Joo, 2012). Other models show pro-inflammatory effects. The devil is in the details of the amounts released, the time course over which the release takes place, and the inflammatory milieu of the tissue involved (as we have noted above, an acute signal of a molecule released into an environment with a high chronic level of that molecule may not convey the acute signal very well or at all).

  • Joo and Sadikot. PGD synthase and PGD2 in immune response. Mediators Inflamm. 2012:503128. doi: 10.1155/2012/503128 (2012).

Interestingly, in sleeping sickness, PGD2 is increased and the microorganism responsible for the disease has been shown to induce the production of PGD2 in culture. PGD2 is a well-known sleep promoting prostaglandin. The review authors (Joo, 2012) published a paper earlier in which they showed that PGD2 inhibits a “key proinflammatory immunoglobulin cell surface receptor TREM-1 in vitro in macrophages.” In another of the authors’ papers, they showed that the administration of PGD2 in a mouse model of P. aeruginosa lung infection resulted in enhanced clearance of P. aeruginosa from the lungs. Moreover, their study showed that mice that had COX-2 inhibited (via knockout) had enhanced clearance of the bacterium and that this effect was related to a decrease in PGE2. There we see the interaction and apparent opposing effects between PGD2 and PGE2 that has appeared in other studies.

This paper is useful for presenting an analysis of several models of inflammation and the effects of various forms of PGD2-synthase and PGD2.

PGE2 RECEPTOR SYSTEM

The inducible and inflammatory COX-2 pathway synthesizes the release of inflammatory amounts of PGE2 (Ruan, 2012). There are three different PGE2 synthases, enzymes that manufacture PGE2 from arachidonic acid. The PGE2 produced is then received by one of four PGE2 receptors, EP1, 2, 3, and 4), which is associated with pain, vascular diseases, and cancer cell growth (Ruan, 2012). DHA’s anti-inflammatory effects are mediated, at least in part, by its action at the EP1 receptor of PGE2 (Ruan, 2012) while the antiinflammatory action of curcumin is reported to be via the reduction of IL-1 beta-stimulated microsomal PGES. PGES enzymes convert the prostaglandin PGH2 to PGE2 (Kats, 2013).

  • Ruan and So. Screening and identification of dietary oils and unsaturated fatty acids in inhibiting inflammatory prostaglandin E. BMC Complement Altern Med.12:143 (2012).
  • Kats, Bage, Georgsson, et al. Inhibition of microsomal prostaglandin E synthase-1 by aminothiazoles decreases prostaglandin E2 synthesis in vitro and ameliorates experimental periodontitis in vivo. FASEB J.27:2328-41 (2013).

YIN-YANG BALANCE BETWEEN
PROINFLAMMATORY AND ANTI-INFLAMMATORY
PROSTAGLANDINS

This is what some researchers refer to as a “yin yang” system, where you have (for example) prostaglandins PGE2 and PGD2 working a balance of pro-inflammatory and anti-inflammatory effects depending on how much is released, the time course of the release, and the inflammatory milieu of the tissue where they are released. Acute inflammation onset and resolution have also been identified in a paper (Rajakariar, 2007) as being regulated by the balance of PGD2 and 15d-PGJ2.

  • Rajakariar, Hilliar, Lawrence, et al. Hematopoietic prostaglandin D2 synthase controls the onset and resolution of acute inflammation through PGD2 and 15-deoxy-delta12,14 PGJ2. Proc Natl Acad Sci U S A. 104(52):20979-84 (2007).

“The devil may be in the details,
But so are the angels.”

—Sandy Shaw

It would appear that all of the most important chronic diseases of man, including cardiovascular disease, cancer, and Alzheimer’s disease are critically regulated by this sort of balancing act. The devil may be in the details, but so are the angels. Another way of putting it is that you shouldn’t be in too great a rush to throw out the devils until you understand whether, by doing so, you are throwing out some or all of the angels.

What Is Intolerable About the Niacin Flush?

The niacin flush appears to be the devil in the details that most disturbs people who would use niacin but can’t stand the flush. There are many interacting biochemical pathways regulating pro-inflammatory and anti-inflammatory effects in the skin, but it would be helpful to isolate some particularly important players in the niacin flush. First, of course, is PGD2, the acute release of which is closely associated with the strength and timing of the flush in relation to when you took the niacin. Preventing the acute release of PGD2 comes close to getting rid of the flush, but doesn’t eliminate it entirely, pointing to other regulatory factors being involved (Kamanna, 2009).

But there are a number of different prostaglandins that have interactions with each other and can counter-regulate each other, and so on. Importantly, as we describe above, PGE2 seems to be in a balancing act with PGD2 in some models of inflammation, so that the nastiness of the niacin flush MAY be linked to the release of PGE2 (our supposition). A prediction of this hypothesis would be that inhibitors of the release of PGE2 would reduce how much of the nasty burning and sensations of insects biting would occur during the flush. A recent paper (Gonzalez, 2012) reported that a study of the inhibitory effects of flavonoids on the release of PGE2 in peritoneal macrophages found that some flavonoids were as effective as aspirin in this inhibitory activity, including quercetin, resveratrol, apigenin, genistein, or kaempferol, but the authors were surprised that luteolin, fisetin, or morin did NOT inhibit the PGE2 release in the peritoneal macrophages.

Here, again, we have another remarkable little clue on the psychodynamics of the niacin flush: a paper (Papaliodis, 2008) that reports that luteolin suppresses the niacin flush!! Another piece for the puzzle of what the niacin flush is all about. Moreover, to add a little additional spice to this, it has been reported (Ren, 2009) that some flavonoids produce a little skin flush of their own. The paper (Gonzalez, 2012) also mentioned that flavonols appear to exert the highest activity (in papers on anti-inflammatory effects via inhibition of lipoxygenases). Cocoa is an excellent source for flavonols. We are currently taking a flavonol-enriched supplement (expensive, however) called Cocoa-Via® as a source of these flavonols.

  • Kamanna, Ganji, Kashyap. The mechanism and mitigation of niacin-induced flushing. Int J Clin Pract.63(9):1369-77 (2009).
  • González, Ballester, López-Posadas, et al. Effects of flavonoids and other polyphenols on inflammation. Crit Rev Food Sci Nutr. 51(4):331-62 (2011).
  • Papaliodis, Boucher, Kempuraj, and Theoharides. The flavonoid luteolin inhibits niacin-induced flush. Br J Pharmacol. 153:1382-7 (2008).
  • Ren, Kaplan, Hernandez, et al. Phenolic acids suppress adipocyte lipolysis via activation of the nicotinic acid receptor GPR109A (HM74a/PUMA-G). J Lipid Res. 50:908-14 (2009).

REDUCING THE NIACIN FLUSH

A recent paper (Jacobson, 2010) that discussed in amazing detail how to reduce the niacin flush begins by noting that “[n]iacin is the most effective lipid modifying agent for raising high density lipoprotein [HDL] cholesterol …” The author explains that in clinical trials, over 60% of niacin users experienced mild or moderate flushing, with 5% to 20% of patients discontinuing niacin therapy because of the flush.

The author (Jacobson, 2010) goes on to explain various ways to reduce the flush, including taking niacin with meals or at bedtime with a low-fat snack and avoiding exacerbating factors such as alcohol or hot beverages. He also indicates that taking 325 mg of aspirin along with niacin suppresses the flush. However, aspirin has many effects on prostaglandin chemistry and as prostaglandins appear to play an important role in the beneficial cardioprotective effects of niacin, we do not recommend taking aspirin along with niacin to reduce the flush.

  • A “hot” topic in dyslipidemia management—“How to Beat a Flush:” optimizing niacin tolerability to promote long-term treatment adherence and coronary disease prevention. Mayo Clinic Proc. 85(4):365-79 (2010).

IN THE BEGINNING,
THERE WAS IMMEDIATE RELEASE NIACIN

To get some feel for the data on clinical effects of immediate release niacin over its first fifty years of use, a paper published in 2005 in the Journal of Internal Medicine (Carlson, 2005) provides an informative review. At this point, the switchover to the non- flushing niacin had not occurred to a great extent, as Niaspan had just become available. Hence, the review focused largely on immediate release niacin that caused a strong flush. Indeed, the author of this review (Carlson, 2005) had been doing pioneering work on niacin for over 40 years.

It was discovered early (some of the early data were published by the author of this review with a coauthor (see Carlson, 1962) that nicotinic acid (niacin) lowers free fatty acids by inhibiting the mobilization of free fatty acids from adipose tissue, a process called lipolysis; the antilipolytic effect of niacin is now considered a major source of the benefits of niacin. The early researchers found that the inhibition of mobilization of free fatty acids by niacin did not change the overall energy metabolism in the heart but “switched its oxidative metabolism from lipids to carbohydrates.” This is a major effect of niacin in its protective cardiovascular role. The inhibitory effect of niacin on the rise of free fatty acids and triglycerides that occurs during emotional stress was reported in a 1962 paper (Carlson, 1962) on experiments in humans.

As of the date of this review, the author stated, “[i]t is now generally accepted that nicotinic acid is the most powerful drug for raising the concentration of HDL, in particular the subspecies HDL2.” He cites data from a study that found HDL cholesterol to rise by 50% in hyperlipidemic patients, but the subfraction of HDL2, the large HDL particles, increased by almost 100%.

Interestingly, the author referred to data showing that at that time researchers had already identified the niacin flush as being due to the release of prostaglandins (by experiments using the prostaglandin synthesis [cyclooxygenase] inhibitor indomethacin) and found that indomethacin markedly reduced the flush. Other studies published before the Carlson 1962 review suggested that PGD2 might be the prostaglandin responsible for the flush.

Carlson in that review also mentioned the discovery that niacin had fibrinolytic (clot busting) effects, having been shown to decrease the plasma levels of fibrinogen by 15% by inhibiting its synthesis by plasminogen activator inhibitor 1. The increased expression of PAI-1 was discussed by Carlson as being closely associated with hypertriglyceridemia (Carlson, 1962). A recent paper (Song, 2012) proposed that PGD2, which the authors found to be synthesized by COX-1 in platelets in both mice and humans, may “function as a homeostatic response to thrombogenic and hypertensive stimuli and may have particular relevance as a constraint on platelets during [flushing] niacin therapy.”

  • Nicotinic acid: the broad-spectrum lipid drug: a 50th anniversary review.J Intern Med. 258:94-114 (2005).
  • Carlson and Oro. The effect of nicotinic acid on the plasma free fatty acids; emonstration of a metabolic type of sympathicolysis. Acta Med Scand. 172:641-5 (1962).
  • Song, Stubbe, Ricciotti, et al. Niacin and biosynthesis of PGD2 by platelet COX-1 in mice and humans. J Clin Invest. 122(4):1459-68 (2012).

CONCLUSION:

In conclusion, there is a rush to develop a way to evade the niacin flush that causes an acute release of PGD2 in the use of niacin therapy to treat hyperlipidemia. This incredible rush, that has resulted in nearly a discontinuation of research on immediate release niacin is being done almost entirely for the purpose of making a non-flushing niacin available for commerce because it could make somebody a lot of money. Because of the entwined interests of government regulatory authorities at the FDA (users’ fees are a very important part of the FDA’s budget) and certain pharmaceutical companies which could benefit by the availability of such a non-flushing niacin product, this work is not (in our opinion) properly scientifically evaluating what it means to eliminate the niacin flush and what it might cost patients using the new forms of niacin (taking into account that many such patients would never take the flushing niacin in the first place) by actually comparing the two different forms of niacin. No such evaluation seems to be taking place. Just thought we ought to mention it …

The correct question that should be asked is not whether extended-release niacin has equivalent benefits to regular niacin—it doesn’t —but what benefits does it provide to which patients and what are its risks, questions that should be asked of any medicine. The almost desperate pursuit of “equivalence” between the two resembles a morbid fear of admitting that somebody might be giving up something of value by taking extended release niacin rather than immediate release niacin and—horror of horrors—finding out exactly what that something of value really is.

HUMAN STUDIES WITH “EXTENDED RELEASE” OR
“PROLONGED RELEASE” NIACIN LEAVE LITTLE
ROOM FOR DOUBT ABOUT THE LACK OF
EQUIVALENCE WITH THE BENEFITS OF
IMMEDIATE RELEASE NIACIN

  1. A human study of extended-release niacin on lipoprotein particle size, distribution and inflammatory markers in patients with coronary artery disease (Kuvin, 2006) found that compared with subjects who received placebo, 3 months of ER niacin resulted in significantly increased though “relatively small” increases in HDL and no significant change in total LDL levels. Regular niacin provides a very significant and clinically meaningful reduction in LDL. The patients participating in this study already had well-controlled LDL (that is, by prior treatment not including any form of niacin), so this study really did not explore the differences between ER niacin and immediate release niacin on the regulation of lipids.
  • Kuvin, Dave, Sliney, et al. Effects of extended-release niacin on lipoprotein particle size, distribution, and inflammatory markers in patients with coronary artery disease. Am J Cardiol. 98:743-5 (2006).
  1. In another human study (Plaisance, 2008), the effects of aerobic exercise and ER niacin were examined in 15 men with the metabolic syndrome. ER niacin lowered fasting but had no effect on the postprandial triglyceride AUC (amount under the curve), while it did decrease the insulin AUC. Immediate release niacin, however, reduces fasting triglycerides by 20-50%.
  • Plaisance, Mestek, Mahurin, et al. Postprandial triglyceride responses to aerobic exercise and extended-release niacin. Am J Clin Nutr. 88:30-7 (2008).
  1. In a third human trial (Jafri, 2009), ER niacin reduced LDL particle number and increased the number of HDL particles without changing total LDL cholesterol in patients with stable coronary artery disease. But the very significant lowering of LDL is considered a major protective feature of immediate release niacin.
  • Jafri, Alsheikh-Ali, Mooney, et al. Extended-release niacin reduces LDL particle number without changing total LDL cholesterol in patients with stable CAD [coronary artery disease]. J Clin Lipidol. 3:45-50 (2009).
  1. In another human trial (Westphal, 2006) (randomized, placebo-controlled double blind, 30 men with metabolic syndrome), a short term (6 week) treatment with ER niacin increased adiponectin by 56% and leptin by 26.8% but there was no change in the levels of the proinflammatory factors TNFalpha, IL-6 and C-reactive protein, no improvement in endothelial function (as measured by FMD), and an actual deterioration in glucose and insulin parameters. Despite increased levels of adiponectin, the authors note that this “fails to improve atheroprotective functions attributed to adiponectin, such as insulin sensitivity, anti-inflammation, and endothelial function.”
  • Westphal, Borucki, Taneva, et al. Extended-release niacin raises adiponectin and leptin. 193:361-5 (2007).

A review paper (Vosper, 2009) looking at niacin’s effects on prostaglandin chemistry, came to the conclusion that “recent advances in understanding of the contribution of prostaglandin metabolism to vascular wall health suggest that some of the beneficial effects of niacin may well result from activation of the same pathways responsible for the adverse [the flush] reactions. The purpose of this review is to emphasize that the search for agonists that show higher tolerability must take into account all aspects of signaling [by prostaglandin D2] through this [the DP1] receptor.”

  • Niacin: a re-emerging pharmaceutical for the treatment of dyslipidaemia.Br J Pharmacol. 158:429-41 (2009).

In another review paper (Song, 2013), the authors conclude that while the pursuit of a more tolerable form of niacin with some benefits that might add to statins might be attractive to a commercial sponsor, “Such pragmatic reasoning may drive the progressive abandonment of niacin, a drug that has long been a mainstay of cardiovascular therapy, while we still poorly understand its many potentially relevant mechanisms of action and have an incomplete picture of its clinical utility.” (Hear, hear!)

  • Song and FitzGerald. Niacin, an old drug with a new twist. J Lipid Res.54(10):2586-94 (2013).

A further review of niacin in its various forms (McCay, 2012) notes that “[w]hether other compounds that are converted to NA [nicotinic acid] or that contains NA, nicotinamide (NM) or their releasable moieties should be referred to as ‘niacin’ depends on the biological effects that are attributed to the compound, the interpretation of the evidence for the rates of uptake and metabolism, and/or the release of the chemical components (apparent bioavailability) that produce biological effects similar to the primary forms of niacin.”

  • MacKay, Hathcock, Guarneri. Niacin: chemical forms, bioavailability, and health effects. Nutr Rev.70(6):357-66 (2012).

LIVER TOXICITY

This review (McCay, Hathcock, Guarneri, 2012) noted that in the matter of LIVER TOXICITY, “[m]any severe reactions to NA, especially liver toxicity, have involved ill-advised or uninformed switching from NA preparations to ER-NA formulations without adjusting the dose.” That is, the same dose of niacin exhibits a greater risk of liver toxicity in the ER form. We suspect that this is caused by the loss of the PGD2 acutely released by plain niacin which in the ER form is more of a chronic release of PGD2, hence reducing the flushing effect but with the differences we have described in the body of this article above from an anti-inflammatory effect of acutely released PGD2 to a pro-inflammatory effect of chronically elevated levels of PGD2. John Hathcock, a co-author of this review, was formerly a prominent extensively-published scientist at the FDA who is an expert on matters of toxicity, writing frequently on toxicity issues involving nutrients. Dr. Hathcock left the FDA to become a scientist and analyst at the Council for Responsible Nutrition.

  • (McCay, Hathcock, Guarneri 2012 reference in paragraph above)

MORE ON STUDIES OF “EXTENDED RELEASE”
AND “PROLONGED RELEASE” VS. IMMEDIATE
RELEASE NIACIN

It was a surprise to us that in their review discussed just above (McCay, Hathcock, Guarneri, 2012), the authors stated their belief that “the beneficial lipid lowering effects of both NA [nicotinic acid] and ER-NA [extended-release nicotinic acid] are well established with data showing reduction of total triglyceride levels by 20-50%, reduction of LDL-C levels by 10-25%, increases of HDL-C by 10-30% and reduction of lipoprotein a levels by 10-30% which includes preferential reduction of the more atherogenic, small dense LDL-C” as the data we have seen do not tend to support an equivalent effect on lipid levels between NA and ER-NA. As to the declaration of interest for this review, the authors simply note that McCay and Hathcock are “employed by The Council for Responsible Nutrition, a trade association representing dietary supplement manufacturers and ingredient suppliers.” Hence, we do not know why they came to this conclusion, telling us only that they did an extensive search of the literature.

In our own search, we found a number of papers reporting discrepancies between immediate or extended-release niacin with that of immediate-release niacin on lipid lowering that we found to be convincing that there was no such equivalence. For example, a study (Usman, 2014) showed that extended-release niacin could suppress post-meal triglyceride levels but unlike immediate release niacin, it had to be administered just before the fat-containing meal. NON-FATAL MYOCARDIAL INFARCTIONS, as the authors of that study (Usman, 2014) explained “[t]his disparity is relevant because extended-release niacin dominates clinical use, even though only immediate-release niacin prevented hard cardiovascular outcomes.” The authors went on to describe another study (Plaisance, 2008) in which the researchers found that bedtime dosing of <1500 mg extended-release niacin for six weeks failed to suppress postprandial (after meal) triglycerides the next day, unlike immediate-release niacin. The Plaisance et al study, however, involved repeated (that is, chronic) use of niacin over six weeks, whereas the Usman et al study was just for a single dose and the pattern of suppression of triglycerides, the Usman group suggested, depended on post-dose pharmacodynamics, referring to “disappointing cardiovascular effects of bedtime extended-release niacin …”

The paper by other authors (Vogt, 2007) showed that prolonged-release niacin (in this paper they used Niaspan) did increase HDL but not as effectively as immediate-release niacin and that only immediate-release niacin had been shown to reduce cardiovascular event rates.

  • Usman, Qamar, Gadi, et al. Extended-release niacin acutely suppresses postprandial triglyceridemia. Am J Med.125(10):1026-35 (2012).
  • Plaisance, Mestek, Mahurin, et al. Postprandial triglyceride responses to aerobic exercise and extended-release niacin. Am J Clin Nutr.88(1):30-7 (2008).
  • Vogt, Kassner, Hostalek, et al. Prolonged-release nicotinic acid for the management of dyslipidemia: an update including results from the NAUTILUS study. Vasc Health Risk Manag.3(4):467-79 (2007).

SCHIZOPHRENIA AND THE NIACIN FLUSH

It is curious to note that a blunted flushing response to niacin has been observed in most schizophrenics, and even in a significant portion of first-degree relatives of schizophrenics (Shah, 1999), “suggest[ing] that niacin subsensitivity is a genetic trait …” (Messamore, 2003). A later paper by the same lead author (Messamore 2010) on niacin sensitivity and the arachidonic acid pathway in schizophrenia reported that, in a study of 20 schizophrenic adults compared to 20 controls, “[t]he schizophrenia-associated niacin response abnormality involves both diminished sensitivity and reduced efficacy.” This supports the possibility that the niacin flush plays a significant role in the clinical effects of niacin.

  • Shah, Ramchand, Peet. The niacin skin flush test: first-degree relatives show responses intermediate between patients and controls. Schizophr Res.38:314 (1999).
  • Relationship between the niacin skin flush and essential fatty acids in schizophrenia. Prostaglandins Leukot Essent Fatty Acids. 69:413-9 (2003).
  • Messamore, Hoffman, and Yao. Niacin sensitivity and the arachidonic acid pathway in schizophrenia. Schizophr Res.122(1-3):248-56 (2010).

A HUMAN STUDY OF DIETARY NIACIN AND THE
RISK OF INCIDENT ALZHEIMER’S (Morris, 2003)

Here, it was reported that, in a group of 3718 participants of 65 years and older residents of a Chicago community, evaluated through the use of dietary data and at least two cognitive assessments to detect cognitive changes over a median 5.5 years, higher food intake of niacin was associated with a slower annual rate of cognitive decline. The authors of this study reported in two case control studies conducted by others that there were lower blood levels of a nicotinic acid metabolite among demented patients than among age and sex matched controls. The detection of such a difference in cognitive changes in individuals ingesting such small amounts of dietary niacin is really surprising, as the participants in the highest fifth of intake (with a median of 22.4 mg/day) had an 80% statistically significant reduction in risk compared with the lowest quintile (12.6 mg/day). These authors attempted to determine whether there was a difference in participants with an apoE4 allele, but could not detect any. At these levels of niacin, it is hard to imagine it would be possible to measure such a small difference.

  • Morris, Evans, Bienias, et al. Dietary niacin and the risk of incident Alzheimer’s disease and of cognitive decline. J Neurol Neurosurg Psychiatry. 75:1093-9 (2004).

Sandy Shaw Copyright 2015

Life Priority, established in 1994, offers supplements that are scientifically-formulated, results-oriented, and GRAS (Generally Recognized As Safe) and are manufactured at USDA and FDA inspected facilities.
*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.
*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.

Restless Legs A Personal Observation by Sandy Shaw

Restless Legs— A Personal Observation by Sandy Shaw

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 18 No. 7 • November 2015


RESTLESS LEGS

PERSONAL OBSERVATIONS

by Sandy Shaw

My experience with restless legs finds that, at least in my case, it can be brought on or made worse by:

1. Drinking carbonated beverages—Carbon dioxide inhalation can induce arousal by activating serotonin receptors (Richerson, 2004). Certain serotonin receptors surprisingly, induce arousal. “It is now clear that 5-HT [serotonin] actually causes arousal.” (Richerson, 2004, pg. 451) “Serotonergic neurons in the midbrain are also chemosensitive, and might mediate non-respiratory responses to increased carbon dioxide, such as arousal.” (Richerson, 2004) This arousal may be what drinkers of carbonated beverages are looking for. I find that drinking carbonated beverages increases my symptoms of restless legs. How serotonergic activation would do that I do not know. It is known that serotonin receptors can be involved in motor control (Richerson, 2004). The absorption of carbon dioxide from drinking carbonated drinks may be modulated by taking GAS-X or similar remedy to cause the carbon dioxide gas to be “burped” out, reducing the amount that is absorbed in the gastrointestinal tract. (There has to be a reason why humans go to the trouble and expense of getting carbon dioxide into so many drinks. Yes, it is pleasurable, but why? It may have a stimulating effect to increase awareness and arousal via serotonergic receptors. There may be, however, other chemoreceptors involved in the arousal response to carbon dioxide. See (Buchanan, 2010).

2. Eating foods on an empty stomach when the food contains more than about 20 grams of sugar (sucrose). This may be due to the release of insulin and subsequent release of noradrenaline (Watson, 2006). “Thus, changes in insulin levels may modulate synaptic NE [norepinephrine/noradrenaline] levels and behaviors normally associated with noradrenergic activity.” (Watson, 2006). Although noradrenaline levels decrease with aging, there is the possibility of compensatory hypersensitivity (increased reactiveness to NE). (Ah, yes, it is a delicate balancing act to get the dose of noradrenaline just right.)

Eating sugar with a meal should reduce the likelihood of stimulating restless legs because of the dilution of the sugar and the consequent slower absorption of it. Good sweeteners that avoid insulin release include erythritol (unlike other sugar alcohols, doesn’t cause diarrhea), xylitol, other sugar alcohols, palatinose (a natural sugar, found in honey and sugar cane). These slowly releases sugar for a very low glycemic index effect and little increase in insulin). Synthetic sweeteners such as saccharin, aspartame, sucralose, and others have been shown to have a detrimental effect on the gut microbiota. Stevia may also have similar detrimental effects. See below for article on the potential adverse effects of various non-sucrose sweeteners, both natural and synthetic.

3. I speculate (this is purely a speculation) that restless legs may be a symptom of temporal lobe epilepsy (Ottoson, 2015), which I have, and the symptoms of which increase in my own case concurrently in response to the same inducing factors, such as #1 and #2 above. Moreover, the drugs and nutrients I use to control temporal lobe epilepsy, such as gabapentin (with GABA receptor inducing effects), glycine, and taurine, also are effective in controlling restless legs in my case. The latter are personal observations only. I make no claim of cause and effect or generalizability.

4. Drinking very cold drinks can bring it on in my case, perhaps due to adrenergic stimulation. (Rossato, 2014) “In vivo cold sensation is detected by specific sensors for cold temperature expressed on peripheral cutaneous nerve endings leading to adrenergic stimulation.” (Rossato, 2014) (There has to be a reason why humans prefer very cold drinks and throughout history have gone to great lengths and expense to get what is necessary (refrigeration, ice, deep storage in the earth, etc.) to get their drinks cold. One has to presume that there is a preferred psychopharmacological state. I think it may be, in this case, adrenergic activation (Rossato, 2014) —and/or possibly cholinergic activation—by very cold-detecting sensors in the mouth or gastrointestinal tract. People like the effects of being stimulated.)

“The effect of adrenoceptors agonists on the production of other important mediators involved in inflammation have also been investigated. Prostaglandins are produced via the metabolism of AA [arachidonic acid] by a cyclooxygenase (COX) and subsequently by prostaglandin synthases.” “Our laboratory has also demonstrated that NE [norepinephrine, noradrenaline] is able to increase COX-2 expression in LPS-stimulated microglia.” (Schlachetzki, 2010). LPS is lipopolysaccharide, a bacterial cell wall component that activates the immune system and its inflammatory effects. However, noradrenaline levels decline with aging, a detrimental effect on cognition (Schlachetzki, 2010). Clinical trials treating patients with dementia or cognitive impairments with beta adrenergic receptor blockers has resulted in both beneficial results and detrimental results. In other studies, increasing noradrenaline by treatment with insulin resulted in improvement cognition in demented patients but in another study increased the level of inflammatory markers in the CSF (cerebral spinal fluid). The data are conflicting at this point (or as of 2010).

References

  • Buchanan, Richerson. Central serotonin neurons are required for arousal to CO2. Proc Natl Acad Sci U S A. 107(37):16354-9 (2010).
  • Ottosson, Wu, Nolting, et al. Resin-acid derivatives as potent electrostatic openers of voltage gated K channels and suppressors of neuronal excitability.Sci Rep. 5:13278 (2015). “Many diseases that affect a large number of people, such as epilepsy, cardiac arrhythmia, and chronic pain, depend on increased electrical excitability.” Restless legs is a disorder that clearly involves increased electrical excitability.
  • Richerson. Serotonergic neurons as carbon dioxide sensors that maintain pH homeostasis. Nat Rev Neurosci. Jun;5(6):449-61 (2004).
  • Rossato, Granzotto, Macchi, et al. Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Mol Cell Endocrinol. 183:137-46 (2014).
  • Schlachetzki et al. Function of norepinephrine in neuroinflammation and chronic neurodegenerative diseases. In Biochemistry and Histocytochemistry … Ch. 1. Edited by Fuchs and Auer. Hauppauge NY: Nova Science Publishers, Inc. 2010.
  • Watson, Bernhardt, Reger, et al. Insulin effects on CSF norepinephrine and cognition in Alzheimer’s disease. Neurobiol Aging. 27:38-41 (2006).

 

Life Priority, established in 1994, offers supplements that are scientifically-formulated, results-oriented, and GRAS (Generally Recognized As Safe) and are manufactured at USDA and FDA inspected facilities.
*The products and statements made about specific products on this web site have not been evaluated by the United States Food and Drug Administration (FDA) and are not intended to diagnose, treat, cure or prevent disease. All information provided on this web site or any information contained on or in any product label or packaging is for informational purposes only and is not intended as a substitute for advice from your physician or other health care professional. You should not use the information on this web site for diagnosis or treatment of any health problem. Always consult with a healthcare professional before starting any new vitamins, supplements, diet, or exercise program, before taking any medication, or if you have or suspect you might have a health problem.
*Any testimonials on this web site are based on individual results and do not constitute a guarantee that you will achieve the same results.