As stated earlier in this chapter,
an inexpensive C-reactive protein (high-sensitivity) blood test
(CRP-hs) can help reveal if you have systemic inflammation. If
your C-reactive protein level is over 1.3 (mg/L), this is an
indication that you have an inflammatory event occurring in your
body. Those with elevated CRP-hs levels (and who have a disease
associated with chronic inflammation) should consider using a
supplement protocol and/or prescription drugs known to suppress
elevated pro-inflammatory cytokines.
The Importance of Cytokine Testing for Those Suffering From
Chronic Illness
There are many chronic disease states that can now be
managed by the proper utilization of the Inflammatory Cytokine
Blood Panel. If you are elderly, or suffer from any serious
disorder, these cytokine tests can enable your doctor to
prescribe therapies that specifically target the inflammatory
cytokine responsible for your poor state of health.
From a practical standpoint, if
you suffer from congestive heart failure, and your levels of
TNF-a remain persistently high, you may ask your doctor to
prescribe the drug Enbrel®, which specifically counteracts the
destructive effects of TNF-a.
If you suffer from cancer and your
levels of IL-6 remain persistently high, you may consider high
dose DHEA or asking your doctor to prescribe a bisphosphonate
drug (such as Zometa® that protects against bone destruction
that releases excess IL-6 into the body. Those with prostate,
certain types of breast cancer, and other hormonally driven
cancer should consider other IL-6 lowering therapies (such as
high dose DHA fish oil extract) in lieu of DHEA.
Some cancer and patients display
elevated levels of IL-8, which induces cancer cells to express
growth factors that fuel their propagation. In hepatitis C,
elevated IL-8 signals interferon drug resistance. An IL-8
suppressing therapy will soon be available to Americans (it is
already used in Japan).
Those with systemic inflammatory
disease often manifest high levels of IL-1b. If diet, the
anti-inflammatory supplements (fish oil, borage oil, DHEA, etc.)
and cytokine-suppressing drugs (pentoxifylline, 400 mg twice a
day) fail to suppress this destructive cytokine, then ask your
doctor to prescribe the drug Arava (leflunomide),
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:
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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. |
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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. |
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Nettle leaf has been shown to
suppress the proinflammatory cytokine TNF-a. Take 1000 mg
daily. |
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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 and Tocotrienols. NAC is an amino acid
with antiviral and liver protectant properties. One 600 mg
capsule daily is recommended. |
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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.
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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. Life Extension can provide this information because
it does not sell PTX.
