Seven promising research approaches to studying CFS, FM or MCS:

1. Testing drugs that lower nitric oxide levels to see if they block the development of objectively measurable responses in CFS, such as those producing orthostatic intolerance. Drugs to be used might include nitric oxide scavengers, such as hydroxocobalamin or nitric oxide synthase inhibitors. Because orthostatic intolerance is a short term, objectively measurable parameter that may be predicted to decrease in response to decreases in nitric oxide in CFS patients, it is particularly attractive symptom of CFS to measure here.
2. Measuring biochemical responses in MCS patients to chemical exposure, to determine whether the predicted responses are seen. For example, we have already reported that both citrulline levels (a measure of nitric oxide synthesis activity) and protein carbonyl levels (a measure of oxidative damage, such as expected due to the action of peroxynitrite) are both elevated in sera of CFS patients. Our theory predicts that these will also rise in MCS patients on exposure to chemicals. This is a simple, testable prediction of the theory which may be useful not only as a direct test of the theory but also as important, objectively measurable criteria for diagnosis.
3. Similarly, we predict that the serum citrulline levels and protein carbonyl levels will be elevated in fibromyalgia patients vs controls. This should also be studied.
4. I have three prominent physicians and a Ph.D. nutritionist who are interested in working with me on a clinical trial of certain nutritional supplements to determine if they are effective in the treatment of CFS patients. The supplements chosen are ones that are predicted to act synergistically to produce improvement in what is proposed to be the central biochemistry of CFS. The goal here is not only to determine whether these produce subjective improvement in these patients but also whether such objectively measurable changes, such as the citrulline and protein carbonyl levels discussed above, also show improvement. It is these objectively measurable changes that may be needed to convince others that an approach really may have some effect. Given the frustration that CFS patients have with the lack of any accepted, effective treatment, such a trial may be of great potential benefit to such patients. There may be a convergence of interest here, between the science and the needs of patients - any theory worthy of the name should pay off in terms of therapy.
5. My theory proposes that chemical exposure in MCS acts via both increased nitric oxide and increased activity of the NMDA receptors in the brain. It follows that the symptoms induced on chemical exposure should be blocked by drugs that either lower NMDA activity or drugs that lower nitric oxide synthesis. These predictions suggest that these drugs should be tested in placebo-controlled trials in MCS patients to determine whether they produce a significant decrease in chemical sensitivity. Such placebo-controlled trials are the "gold standard" for drug tests and these may be very important because they are a direct test of the proposed mechanism and also because they may suggest useful therapeutic approaches to treatment.
6. I have proposed three possible receptor mechanism by which MCS patients might detect and respond to hydrophobic chemicals and produce their chemical sensitivity. Which, if any of these is involved is unclear. However, the most promising of these three is a protein called PIN which regulates the synthesis of nitric oxide. The site on the protein that regulates nitric oxide synthesis also has sites for binding of hydrophobic chemicals, thus possibly explaining the action of these chemicals in MCS. We don't know if this explanation is correct and consequently, it is important to study the properties of this protein to determine if they are consistent with the properties reported for MCS. These studies may help determine the viability of this mechanism and, if the proposed mechanism is correct, will lead to simple assays for chemical activity in MCS. In this way, it may be possible to test chemicals and chemical mixtures to determine their predicted activity in triggering chemical sensitivity in MCS.
7. Finally, the central role of the nitric oxide product, peroxynitrite, in this theory predicts that scavengers of peroxynitrite should be useful in therapy. However, although some scavengers have been described, their activity in the human body appears to be distinctly limited. Consequently, it is desirable to study the activity of other compounds as possible peroxynitrite scavengers. We have done some work in this area, but it is still in its infancy.

It should be emphasized that procedures for all research involving human subjects must first be approved the Washington State University Institutional Review Board (IRB).

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