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Explaining Unexplained Illnesses by Martin Pall, PhD
Explaining "Unexplained Illnesses":
Disease Paradigm for Chronic Fatigue Syndrome, Multiple Chemical Sensitivity, Fibromyalgia, Posttraumatic Stress Disorder, Gulf War Syndrome and Others
We are excited to present information from the forthcoming book by Martin L. Pall, PhD, who shows that all these conditions - and probably many others - involve the same key biochemical response: elevated levels of nitric oxide (NO) and its oxidant product peroxynitrite (ONOO-), which initiate a biochemical vicious cycle. Although the mechanisms underlying this ongoing NO/ONOO- cycle are well-documented, Dr. Pall presents new information about how this cycle interacts to produce patterns of symptoms. The theory elegantly answers many questions, including:
- If CFS, MCS, FM, PTSD and GWS have a common biochemical link, why is there such a variety of symptoms?
- Why do symptoms vary among sufferers of the same condition?
- What roles do infection, chemical exposure, physical trauma, and severe psychological stress play?
- How do short-term stressors initiate chronic illness?
- What are the common symptoms and signs?
- What is an approach that corrects the cause, rather than treating the symptoms?
- How does the biochemistry of the NO/ONOO- cycle produce chronic illness?
- What are the principles underlying the NO/ONOO- cycle mechanism?
- Can the NO/ONOO- cycle explain other previously unexplained properties of these illnesses?
- How might 14 additional illnesses/diseases also be caused by the NO/ONOO- cycle etiology?
- And many more...
All this is backed up with more than 1,500 references to scientific literature.
Symptoms are generated by elevated levels of nitric oxide, peroxynitrite and several other consequences of the NO/ONOO- cycle, such as elevated activity of NF-kappa B, superoxide, inflammatory cytokines and activity of two transmitter systems, the vanilloid receptor and the NMDA receptor. Therapy should focus on down-regulating the NO/ONOO- cycle biochemistry. Peroxynitrite is a potent oxidant, and it or its products initiate oxidative chain reactions, causing damage to both proteins and DNA. When its levels are sufficiently elevated, it can cause programmed cell death (apoptosis), an important mechanism in neurodegenerative diseases. Peroxynitrite attacks several of the important proteins in mitochondria, acting along with superoxide and nitric oxide in lower energy metabolism. Such energy metabolism dysfunction lowers the availability of ATP, the energy currency in cells, and is an important part of NO/ONOO- cycle biochemistry.
Much of the mechanism of the NO/ONOO- cycle is local, impacting one tissue but not necessarily impacting an adjacent tissue. Different people suffering from these illnesses may have distinct tissues impacted by NO/ONOO- cycle biochemistry, and this variation in tissue distribution leads to an almost infinite variation of symptoms and signs. This is proposed to be responsible for the extraordinary variation in symptoms and signs reported in comparisons of one patient with another.
Conditions caused by the NO/ONOO- cycle are best treated by using agents that are expected to down-regulate NO/ONOO- cycle biochemistry. At least 30 therapeutic agents or classes of agents are available today that are expected to down-regulate cycle biochemistry. Of these 30, clinical trial studies have been performed on 12, and all 12 show evidence of efficacy in treatment of these multisystem diseases or closely related illnesses. Clinical observations and/or anecdotal reports suggest that six additional agents or classes of agents are also effective in treatment.
None of these reach the effectiveness of a "magic bullet," providing in most cases, modest improvements. Given the complexity of the NO/ONOO- cycle, this is not surprising. The question that must be raised is whether combinations of several types of these agents will be more effective than individual agents alone. Five physicians have independently developed therapy protocols using from 14 to 18 agents or classes of agents predicted to lower the cycle biochemistry. All five report substantial improvements in their patients. The patients involved in these therapies suffer from CFS, FM, chemical injury or unexplained chronic fatigue, and each of these types of patients show apparent substantial improvement. Two of these protocols have been tested and reported to be effective in clinical trials. It appears, therefore, that complex combinations of these agents are more effective than single agents in the treatment of these diseases. It also appears that the NO/ONOO- cycle mechanism makes useful predictions on what combinations of agents are likely to be effective in the therapy of multisystem diseases.
- Short term stressors that initiate cases of multisystem illnesses act by raising nitric oxide synthesis and consequent levels of nitric oxide and its oxidant product peroxynitrite.
- Initiation is converted into a chronic illness through the action of vicious cycle mechanisms, through which chronic elevation of nitric oxide and peroxynitrite and other cycle elements is produced and maintained.
- Symptoms and signs of these illnesses are generated by elevated levels of nitric oxide and/or other important consequences of the proposed mechanism, i.e. elevated levels of peroxynitrite or inflammatory cytokines, oxidative stress and elevated NMDA and vanilloid receptor activity.
- Because the compounds involved, nitric oxide, superoxide and peroxynitrite have quite limited diffusion distances in biological tissues and because the mechanisms involved in the cycle act at the level of individual cells, the fundamental mechanisms are local.
- Therapy should focus on down-regulating NO/ONOO- cycle biochemistry.
An Elegant Explanation
- It is integrative: It integrates into a common scheme a wide variety of previously unexplained diseases/illnesses.
- It is comprehensive: It encompasses a wide variety of observations about these diseases including their patterns of case initiation, their chronic nature, and many of the shared and unique chronic symptoms and signs. It also explains the reported efficacy of over a dozen distinct agents. Each of these aspects has previously challenged explanation, and explaining their combination has been a much larger challenge.
- It is parsimonious: It explains by a relatively simple conceptual framework, many previously unexplained observations.
- It is fundamental: Because it is based primarily at the biochemical level, it explains much of the complexity of these diseases through the impact of a common biochemistry on a variety of organismal functions.
Martin L. Pall, PhD, is Professor of Biochemistry and Basic Medical Sciences at Washington State University in Pullman, where he teaches portions of the medical biochemistry course for first-year medical students. His long term interests in biological regulatory mechanisms and in free radicals and reactive oxygen/nitrogen species have been key influences in leading him to his conceptual breakthrough in viewing chronic fatigue syndrome (CFS), multiple chemical sensitivity (MCS), fibromyalgia, and related multi-system illnesses. Dr. Pall is a member of the American Society for Biochemistry and Molecular Biology and is on the editorial board of the Journal of Chronic Fatigue Syndrome (Haworth). He is on the Scientific Advisory Board of Ariston Pharmaceuticals and the advisory board of the Environmental Law Centre in London, and has advised the South Australian government on multiple chemical sensitivity.