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Life Extension Magazine

LE Magazine January 2002

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Addendum One
Diet and Inflammation

In addition to toxic cytokines, there are other inflammatory pathways that can be mediated via diet modification. A common problem involves over-production of pro-inflammatory hormone-like "messengers" (such as prostaglandin E2) and under-production of anti-inflammatory "messengers" (such as prostaglandin E1 and E3).

The good news is that omega-3 fatty acids found in fish oil help
to suppress the formation of undesirable prostaglandin E2 and promote synthesis of beneficial prostaglandin E3.[1,2] Gamma linolenic acid (GLA) induces production of the anti-inflammatory prostaglandin E1.[3, 4] What you eat can significantly affect whether you have more of the beneficial prostaglandins (E1 and E3) as opposed to the pro-inflammatory prostaglandin E2.

Since prostaglandin E2 is a culprit in inflammation, reducing foods that are high in omega-6 fatty acids and increasing omega-3 rich foods, such as salmon and other fish can be beneficial. Limiting foods that convert to arachidonic acid can help reduce inflammation. [Arachidonic acid is a precursor to both prostaglandin E2 and the pro-inflammatory cytokine leuk-otriene B(4)].[5] Another dietary factor that can lead to high levels of arachidonic acid is the over-consumption of high-glycemic index carbohydrates that causes excess production of insulin.[6]

Foods that may contribute to chronic inflammation are foods with a high glycemic index (things that you digest quickly) like fruit juices or rice cakes, food heavy in polyunsaturated fats or saturated fats, and foods high in arachidonic acid

1. Watanabe S, Katagiri K, Onozaki K, et al. Dietary docosahexaenoic acid but not eicosapentaenoic acid suppresses lipopolysaccharide-induced interleukin-1 beta mRNA induction in mouse spleen leukocytes. Prostaglandins Leukot Essent Fatty Acids 2000 Mar;62(3):147-52.

2. Kelley VE, Ferretti A, Izui S, et al. A fish oil diet rich in eicosapentaenoic acid reduces cyclooxygenase metabolites, and suppresses lupus in MRL-lpr mice. J Immunol 1985 Mar;134(3):1914-9.

3. Fan YY, Ramos KS, Chapkin RS. Dietary gamma-linolenic acid enhances mouse macrophage-derived prostaglandin E1 which inhibits vascular smooth muscle cell proliferation. J Nutr 1997 Sep;127(9):1765-71.

4. Das UN, Ramadevi G, Rao KP, et al. Prostaglandins can modify gamma-radiation and chemical induced cytotoxicity and genetic damage in vitro and in vivo. Prostaglandins 1989 Dec;38(6):689-716.

5. Brock TG, McNish RW, Peters-Golden M. Arachidonic acid is preferentially metabolized by cyclooxygenase-2 to prostacyclin and prostaglandin E2. J Biol Chem 1999 Apr 23;274(17):11660-6.

6. Kreisberg JI, Patel PY. The effects of insulin, glucose and diabetes on prostaglandin production by rat kidney glomeruli and cultured glomerular mesangial cells. Prostaglandins Leukot Med 1983 Aug;11(4):431-42.


Addendum Two

Pentoxifylline Studies

Pentoxifylline (PTX) is a prescription drug approved by the FDA to treat peripheral vascular disease. The standard dose is 1200 mg a day to improve circulation. To suppress pro-inflammatory cytokines, a lower dose of 400 mg to 800 mg a day can be used. What follows is a brief description of studies showing benefits to PTX that extend beyond its FDA-approved use. Please note that it is illegal for the manufactures of PTX to distribute this off-label information to the public. Life Extension can provide this information because we do not sell PTX.

A controlled study on human diabetics with advanced renal failure showed that 400 mg a day of PTX reduced TNF-á levels by approximately 35%. In the pentoxiphylline group, a measurement of kidney impairment was reduced 59%. There were no changes in those given placebo. The researchers noted that inflammatory cytokines such as TNF-á have long been implicated in the development and progression of diabetic kidney failure.[1] Organ failure induced by TNF-á has been confirmed by other studies.[2]

Pentoxifylline Sources

You can obtain pentoxifylline from any pharmacy with a doctor's prescription. Here is the price for 100 tablets of the three available brands:

Trental 400 mg (name brand) $80.59
Pentoxil 400 mg (generic)
$53.09
Pentoxifylline 400 mg (extended release generic) $53.09

Prices obtained from a Walgreen's pharmacy located in Ft. Lauderdale, Florida.

Since you will only take one to two tablets a day of pentoxifylline, this is a relatively inexpensive drug.

Aging causes a progressive decline of blood delivery to the tissues. Those afflicted with diabetes suffer from accelerated circulatory deficit. In a study on diabetic rats, just two weeks of PTX administration resulted in a correction of nerve conduction deficit amounting to 56.5% in the sciatic motor nerve and 69.8% in saphenous sensory nerve. PTX restored the micro-vascular deficit by 50.4%. This study indicates that PTX may be of particular benefit to diabetics, especially those suffering from neuropathy, kidney disease and other vascular disorders.

It is not just age-related disease that has been linked to chronic inflammation. A growing body of evidence points to a chronic inflammatory state as an underlying cause of kidney failure, asthma, pancreatitis, lupus, certain skin diseases and other afflictions.

In a study on human asthmatics, PTX was shown to be almost six times more effective in suppressing TNF-á than the popular anti-asthma drug theophylline. The doctors concluded that PTX may be an especially promising candidate as an asthma therapy.[3]

Lupus is an autoimmune disease and about 90% of its victims develop kidney problems. In a group of pediatric lupus patients, PTX helped to stop the deterioration of kidney function.19 The clinical manifestations of experimental systemic lupus erythematosus(SLE) correlate with an increased secretion of TNF-á and IL-1. In a mouse study, PTX significantly reduced the production of TNF-á and IL-1. The result was significantly lower anti-DNA antibodies (a blood marker of lupus activity) and substantial lower rate of protein in the urine (indicating reduced kidney damage). The scientists concluded that the early administration of PTX improves the clinical status of mice with this autoimmune disease (lupus).[4]

In advanced kidney failure, anemia can be induced by an inflammatory cytokine attack on erythropoietin, the major natural hormone responsible for red blood cell (RBC) production. In a group of 7 anemic patients with advanced renal failure, PTX suppressed TNF-á and reversed the anemic state.[5]

Free radicals and inflammatory cytokines have been implicated in pancreatitis. Inflammation of the pancreas is associated with a greater risk of pancreatic cancer. Many of the antioxidants used by Foundation members reduce the incidence of pancreatitis. In one study on acute pancreatitis, PTX was shown to reduce pancreatic inflammation and attenuate the depletion of pancreatic glutathione. PTX also inhibited the expected increase in tumor necrosis factor-alpha levels and prevented mitochondrial damage. Mitochondria are the power plants within all of our cells. The scientists suggested that PTX be considered as an adjuvant treatment of acute pancreatitis.[6]

Psoriasis is characterized by abnormal cell proliferation, inflammation and increased levels of inflammatory cytokines. In an experimental on nude mice, PTX was shown to reduce cell proliferation and thickening of skin. Improvement was seen in the classical signs of psoriasis.[7] A study on dogs showed that PTX was one of several drugs helpful in treating atopic dermatitis.[8] A mouse study showed PTX to be effective in treating contact- and irritant-induced dermatitis by suppressing excess production of TNF-á.[9]

An increase in TNF-a has been implicated in leprosy skin reactions and PTX has been shown to work with other drugs in producing a quick response to this inflammatory cytokine-induced condition.[10,11]

Fibrosis is a common problem for cancer patients undergoing radiation therapy. PTX in combination with vitamin E has been shown to help heal these lesions. Scientists have speculated that the efficacy of this treatment is probably due to a combination of blood flow stimulation and reduction inflammatory cytokines.[12] Other studies show that PTX helps to prevent the fibrosis.[13]

Inflammation plays a pivotal role in the pathogenesis of organ injury after cardiopulmonary bypass. Elderly patients appear to be especially prone to develop systemic inflammation. In a controlled study, patients undergoing cardiopulmonary bypass were given PTX before and right after surgery. Compared to the group receiving PTX, the control group showed a greater increase in C-reactive protein, IL-6 and other inflammatory cytokines. The PTX treated patients recovered faster than the controls.[7] The doctors conducting the study stated the PTX group showed less inflammatory response than the controls and urged that more studies be done.

When it comes to healing after surgery, several factors are involved including restoration of micro-circulation and strength of the inflammatory response. In a study on rats, PTX significantly shortened the time needed for healing in colonic anastomoses (reconnecting the large intestine after removing a section of it as occurs for colon cancer patients). In the rats receiving PTX, inflammatory response was markedly reduced and restoration of circulation improved. The scientists concluded by stating that PTX administration could prevent failures of colonic anastomoses.[9] This study provides further evidence that PTX can be of significant benefit to the surgical patient by speeding the healing process. High DHA fish oil may also provide these benefits.

Some surgeons may be concerned that PTX could cause excess bleeding, yet one study showed that by modulating the dose of various anti-clotting agents (including PTX), the risk of surgical bleeding and abnormal blood clots could be reduced.9 We believe that the real value to PTX may be its long-term use after surgery to protect against the chronic inflammatory syndrome that so many of the elderly are vulnerable to. The maintenance dose of PTX needed may be as low as 400 mg a day. Please note that high-dose fish oil and other nutrients have shown similar benefits to PTX.

Caution: PTX should not be used in those with bleeding disorders such as those with recent cerebral or retinal hemorrhage. Patients taking Coumadin should have more frequent monitored of pro-thrombin time. Those suffering from other types of bleeding should receive frequent physician examinations. Furthermore, we would consider evaluating the individual patient's coagulation status to see what effect PTX has on the template bleeding time. This is an inexpensive test that relates the biological effect of PTX (or other agents like aspirin, non-steroidal anti-inflammatory agents) on the function of platelets. All of these agents affect platelet aggregation and this effect can be manifested in a prolonged template bleeding time. According to two studies, PTX should be avoided by Parkinson's patients. It is important to note that the body does use tumor necrosis factor-alpha (TNF-á) to acutely fight infections. If patients are showing any sign of infectious disease, drugs like Enbrel (that inhibit the effects of TNF-á) are temporarily discontinued. A new FDA advisory states that patients should be tested and treated for inactive, or latent, tuberculosis prior to therapy with another TNF-á inhibiting therapy (infliximab). Since PTX, fish oil and nettle directly suppress TNF-á, perhaps these agents should be temporarily discontinued during the time when one has an active infection.


References on Page 4 of 4


 


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