Inflammation: Chronic

Pentoxifylline Studies
This section discusses the positive results obtained in numerous studies when pentoxifylline was administered to reduce the damaging effects of chronic inflammation.

PTX is a prescription drug approved by the FDA to treat peripheral vascular disease. The standard dose is 1200 mg daily to improve circulation. To suppress pro-inflammatory cytokines, a lower dose of 400 mg twice a day can be used. A brief description of studies showing benefits of PTX extending beyond its FDA-approved use follows.

A controlled study on human diabetics with advanced renal failure showed that 400 mg daily of PTX reduced TNF-a levels by approximately 35%. In the PTX 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-a have long been implicated in the development and progression of diabetic kidney failure (Navarro et al. 1999a). Organ failure induced by TNF-a has also been confirmed by other studies (Boldt et al. 2001).

Aging causes a progressive decline of blood delivery to the tissues. Those who have diabetes experience accelerated circulatory deficit. In a study on diabetic rats, just 2 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 the saphenous sensory nerve. PTX restored the microvascular deficit by 50.4% (Flint et al. 2000). 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 conditions.

In a study on human asthmatics (Entzian et al. 1998), PTX was shown to be almost 6 times more effective in suppressing TNF-a than the popular anti-asthma drug theophylline. The doctors concluded that PTX may be an especially promising candidate as an asthma therapy.

Lupus is an autoimmune disease. About 90% of its victims develop kidney problems. In a group of pediatric lupus patients, PTX helped to stop the deterioration of kidney function (Vazquez Garcia et al. 2000). The clinical manifestations of experimental systemic lupus erythematosus (SLE) correlate with an increased secretion of TNF-a and IL-1(b). In a mouse study, PTX significantly reduced the production of IL-1b and TNF-a. The result was significantly lower anti-DNA antibodies (a blood marker of lupus activity) and a substantially 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) (Segal et al. 2001).

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 seven anemic patients with advanced renal failure, PTX suppressed TNF-a and reversed the anemic state (Navarro et al. 1999b).

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 TNF-a 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 (Gomez-Cambronero et al. 2000).

Psoriasis is characterized by abnormal cell proliferation, inflammation, and increased levels of inflammatory cytokines. In an experiment on nude mice, PTX was shown to reduce cell proliferation and thickening of skin. Improvement was seen in the classical signs of psoriasis (Gilhar et al. 1996). A study on dogs showed that PTX was one of several drugs helpful in treating atopic dermatitis (Marsella et al. 2001). In mice, a study showed PTX to be effective in treating contact- and irritant-induced dermatitis by suppressing excess production of TNF-a (Schwarz et al. 1993).

An increase in TNF-a has been implicated in leprosy skin reactions. PTX has also been shown to work with other drugs in producing a quick response to this inflammatory cytokine-induced condition (Sampaio et al. 1998; Welsh et al. 1999).

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 in inflammatory cytokines (Fischer et al. 2001). Other studies show that PTX helps to prevent the fibrosis (Moser et al. 2000).

Inflammation plays a pivotal role in the pathogenesis of organ injury after cardiopulmonary bypass. Elderly patients appear to be especially prone to developing 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 (Boldt et al. 2001). The researchers 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 microcirculation 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 (Schwarz et al. 1993). 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 might 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 (Schwarz et al. 1993). The real value to PTX may be its long-term use after surgery to protect against the chronic inflammatory syndrome, to which so many of the elderly are vulnerable. The maintenance dose of PTX needed may be as low as 400 mg daily. (Remember: High-dose fish oil and other nutrients have shown similar benefits to PTX.)

When to Avoid PTX and Other Anti-Inflammatories
PTX should not be used by individuals with bleeding disorders such as a recent cerebral or retinal hemorrhage (PDR 2001). Patients taking Coumadin should have more frequent monitoring (once a week) of prothrombin times (White et al. 1989; Stigendal et al. 1999). Those with other types of bleeding should receive frequent physician examinations. According to two studies, PTX should be avoided by Parkinson's disease patients (Godwin-Austen et al. 1980; Serrano-Duenas et al. 2001).

It is important to note that the body uses TNF-a to acutely fight infections. If patients show any sign of infectious disease, drugs such as Enbrel (that inhibit the effects of TNF-a), are temporarily discontinued. A new FDA advisory states that patients should be tested and treated for inactive tuberculosis prior to therapy with another TNF-a inhibiting therapy (infliximab). Because PTX, fish oil, and nettle directly suppress TNF-a, these agents should be temporarily discontinued during the time when one has an active infection.

Sources of Pentoxifylline
Pentoxifylline can be obtained from any pharmacy with a physician's prescription. Here are sample prices for 100 tablets of the three available brands (prices obtained from a Walgreen's pharmacy located in Ft. Lauderdale, FL in January 2002):

Trental 400 mg
(name brand) $80.59

Pentoxil 400 mg
(generic) $53.09

Pentoxifylline 400 mg
(extended-release generic) $53.09

Because only 1-2 tablets daily are taken, pentoxifylline is a relatively inexpensive drug.

Diet and Inflammation
In addition to toxic cytokines, there are other inflammatory pathways that can be mediated via diet modification. A common problem involves overproduction of pro - inflammatory hormone-like "messengers" (such as prostaglandin E2) and underproduction 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 (Kelley et al. 1985; Watanabe et al. 2000). Gamma - linolenic acid (GLA) induces production of the anti-inflammatory prostaglandin E1 (Das et al. 1989; Fan et al. 1997). 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.

Because prostaglandin E2 is a culprit in inflammation, reducing the consumption of foods that are high in omega-6 fatty acids and increasing the consumption of 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 leukotriene B(4) (Brock et al. 1999). Another dietary factor that can lead to high levels of arachidonic acid is the overconsumption of high-glycemic index carbohydrates that cause excess production of insulin (Kreisberg et al. 1983). These quickly digestible foods include fruit juices or rice cakes. Food heavy in polyunsaturated fats or saturated fats can also increase prostaglandin E2.

Additionally, a study of elderly patients with heart disease requiring elective surgery (Tepaske et al. 2001) found that nutritional supplements containing omega-3 polyunsaturated fatty acids (as well as yeast and L-arginine) improved the outlook for high-risk patients when given a minimum of 5 days prior to surgery.

The number of inflammatory-related diseases that could be successfully treated with cytokine-lowering therapy is staggering. PTX and supplements such as fish oil, nettle leaf, DHEA, and vitamin K possess mechanisms of suppressing inflammatory cytokines. Unfortunately, there are no side-by-side comparisons to enable us to categorically state whether PTX or natural agents (such as DHA fish oil) work better.

Foods cooked at high temperatures can produce a browning effect in which glycotoxins are formed from the reaction of sugars and oxidized fats with protein. Glycotoxins may contribute to low-grade chronic inflammation. High glycemic foods may also contribute to the inflammatory process. Dietary modifications to reduce inflammation should include elimination of foods and cooking processes that contribute to a chronic state.

For those who have multiple degenerative diseases, the cytokine profile blood test and the C-reactive protein blood test are highly recommended. This may be done through your own physician or the Life Extension Foundation. If your cytokine test reveals excess levels of cytokines such as TNF-a, IL-1(b), or both, nutritional supplementation, dietary modifications, and low-cost prescription medications such as PTX are advised.

The following supplements are suggested:

• The docosahexaenoic acid (DHA) fraction of fish oil may be the most effective nonprescription supplement to suppress pro-inflammatory cytokines. Gamma-linolenic acid (GLA) is a precursor of PGE1, a potent anti-inflammatory agent. A product called Super EPA/DHA provides 1400 mg of EPA and 1000 mg of DHA in 4 capsules.
• DHEA is a hormone that decreases with age. DHEA has been shown to suppress IL-6, an inflammatory cytokine that often increases as people age. Typical doses of DHEA are 25-50 mg daily, although some people take 100 mg daily. Refer to the DHEA Replacement protocol for suggested blood tests to safely and optimally use DHEA.
• Nettle leaf has been shown to suppress the proinflammatory cytokine TNF-a. Take 1000 mg daily.
• Vitamin E and N-acetyl-cysteine (NAC) are protective antioxidants with anti-inflammatory properties. Vitamin E that contains gamma-tocopherol and tocotrienols provides the most broad-spectrum protection. Take 1 capsule daily of Gamma E Tocopherols with Sesame Lignans and Tocotrienols with Sesame Lignans. NAC is an amino acid with antiviral and liver protectant properties. One 600 mg capsule daily is recommended.
• Vitamin K helps reduce levels of IL-6, a pro-inflammatory messenger. Vitamin K also helps in the treatment of osteoporosis by regulating calcium and promoting bone calcification. One 10 mg capsule daily is recommended for prevention purposes. Do not take vitamin K if you are taking Coumadin or some other type of anticoagulant medicine.
• Consuming at least 1000 mg  per day of carnosine and/or 300 mg of the European drug aminoguanidine can inhibit pathological glycation reactions in the body.

Note: It is illegal for the manufacturers of PTX to distribute this off-label information to the public. Vitamin Depot Online.com can provide this information because it does not sell PTX.

Product availability

Super EPA/DHA with Sesame Lignans, DHEA, nettle leaf, Gamma E Tocopherol with Sesame Lignans,  NAC, Super Carnosine, and Super K with K2 are available by telephoning (800) 544-4440 or by ordering online. Call (800) 208-3444 for more information on blood testing. Pentoxifylline (PTX) and Enbrel are prescription medications.