Paul Cheney, MD, PhD was the opening speaker at the 15th International Symposium of Functional Medicine in Carlsbad, CA on Thursday, May 22. He spoke for almost three hours.
His presentation, "Chronic Fatigue Syndrome, Oxidative Stress, and Pain: A Physician's Personal and Professional Journey Through the Functional Medicine Model" received a five-minute standing ovation from the over 600 physicians and researchers in attendance from 14 countries.
The Institute of Functional Medicine will be offering a DVD within 30 to 60 days through www.functionalmedicine.org
Cell Associated Therapy for Chronic Fatigue Syndrome: Is this the Next Frontier?
BACKGROUND: Chronic Fatigue Syndrome (CFS) is a disorder of unknown cause characterized by significant functional disability associated with fatigue, pain and neuropsychological complaints. For over twenty years since the first clear clinical presentation of CFS in the United States by Straus(1) and Jones(2) and the first epidemic of CFS was reported in Lake Tahoe(3), the therapeutic domain for CFS has been dominated by pharmaceutical, nutriceutical, herbaceutical, or alternative medical interventions. After these twenty-plus years, there is no consensus on what optimal therapy looks like and many reasons to believe that this situation will continue as it has for years to come. With the advent of stem cell therapy in chronic illness, we are entering a new era in medicine where the old therapeutic ideas are being challenged if not rejected, in favor of newer ideas about therapies that are more appropriate for the treatment of complex chronic illness.
Low molecular weight, cell signaling peptides or factors (CSF's) from human bone cell cultures have been used as implants to successfully heal non-union bone fractures at UCLA as far back as 1982(4). More recently, implanted human fetal brain tissue(5) as well as cultured human stem cell transplants(6) have been used to successfully (at least initially) treat younger (though interestingly not older) patients with Parkinson's disease. Other studies have shown that donor embryonic cells need not be human to work(7). It has additionally been shown that injected low molecular weight cell signaling factors alone can induce functional recovery from Parkinson's-like syndromes induced by drugs in monkeys(8). Finally, human bone marrow derived CSF therapy via intra-coronary IV infusion for acute myocardial infarction was shown to produce a significant improvement (67%) in myocardial left ventricular performance as compared to untreated patients who only had a marginal improvement (7%) over a six month time period(9).
In Europe, cell associated therapies known as "live cell" products have been used as injections for over seventy years in health spas as rejuvenation therapy and by physicians for the treatment of chronic disease(10). Pope Pius XII received live cell injections on his deathbed by the leading Swiss proponent at that time, Dr. Paul Niehans, and lived another four years(11). There is over a half century long history of their safe use in humans. In the U.S., this type of therapy was first legitimized in 1981 with the publication of a 59% remission rate of an immunosuppressive disease of childhood in the New England Journal of Medicine using intramuscular injections of thymus extract from 5-day-old calves(12). In the case of CFS, the first successful use of CSF's was reported by Steinbach in 1994 with the use of an injected low molecular weight extract of porcine Liver (Kutapressin)(13). We completed a six month pilot study of nine patients in 2000 using oral, frozen extracts from porcine sourced, multiple organ extracts with mixed though promising results. This present study explores further the potential for cell associated therapy using low molecular weight peptides derived from mammalian tissue extracts in CFS. METHODS: Eighteen patients from a national referral practice, meeting the 1994 case definition for CFS, were enrolled in a prospective, one year therapeutic protocol using porcine cell signaling factors derived from heart and liver tissue homogenates. In the 18 patient study cohort, the average age was 42.6 (range 15-63) with 10 females (55.5%) and 8 males (44.4%). The average length of illness was 15 years (3-21 range). At the start of the study, the average Karnofsky Performance Scale (KPS) score was 60 (40-70) and only two patients were employed (part-time) out of 18. The rest were disabled.
The study length was one year consisting of two parts, each six months long. The primary endpoint was KPS as determined by physician interview at study conclusion. Primary studies with pre- and post-interrogations included echocardiography, both with and without oxygen, impedance cardiography, urine organic acid analysis and 24-hour hormone analysis. Secondary testing included a set of routine blood test panels.
In the initial six month trial period, the primary therapy was a transdermal, porcine liver extract applied to the skin along with low dose hGH at 0.2 mg SQ per week. This therapy had previously been used in our pilot study of 2000 except that a different porcine liver extract was given as an oral frozen extract. For the final six months, the patients received an oral, frozen porcine extract consisting of 50% porcine adolescent heart extract and 50% porcine mesenchymal or fetal extract. Patients were evaluated at six months for KPS and echocardiography and impedance cardiography as well as at study endpoint.
As support therapy, a standard group of therapies, mostly anti-oxidant nutriceuticals and pharmaceuticals for sleep, used by this clinic for ten years or more was also part of the study protocol but was not a significant shift from the patients' normal therapeutic routine, pre-study. All the patients had been on most of these therapies for a year or more pre-therapy and therefore represented a baseline therapy. Additional therapies were allowed on a case-by-case basis for symptom management but patients were asked to limit the addition of any new therapies during the study period.
RESULTS: Sixteen of eighteen patients completed the study. Two patients failed to complete the study due to intolerances and are not part of the final analysis but remain on parts of the protocol due to some favorable aspects of the therapy for them. Both these patients had a strong history of environmental illness and previous intolerances to many other agents. There were no severe reactions reported.
Through the first six months of therapy, there was no significant improvement in functional measures (KPS) but some notable changes were seen in both echocardiography (drop in IVRT, p < 0.00006) and in impedance cardiography (rise in stroke volume, p < 0.00004). However, during the next six months, notable improvement was reported by some patients attributable, by most participants, to the heart/mesenchyme porcine extract. Final endpoint KPS scores, compared to pre-study KPS scores, showed a significant improvement of an average of 10 KPS points (p < 0.006). Furthermore, almost all the improvement was reported in the oxygen tolerant subgroup compared to the non-responders who were mostly oxygen toxic. Because the discovery of near universal oxygen toxicity in CFS came after the start of the study, we were only able to establish in two patients, who were late getting started, that they converted from oxygen toxic to oxygen responsive while on therapy and both were responders.
CONCLUSION: Therapy with low molecular weight peptides from cell associated, mammalian tissue homogenates appear to offer a significant benefit in CFS, especially where it counts the most, namely function. A 10-point rise in KPS score will change lives and the response over baseline function was shown to be highly significant (p < 0.0005). The use of several tissue extracts as opposed to only one appears to be more effective though this cannot be known with certainty from this study. Both tissue extracts (liver and heart/mesenchyme) appeared to be bioactive but especially the heart. Intolerance was observed in 2 of 18 or 11% and was observed in the most environmentally challenged (EI) of the 18 who were treated. Both patients had a history of intolerance to other therapies and the subsequent finding of porcine liver toxicity in a subsequent study, especially in EI patients, may help explain their failure to respond well and their intolerance to this protocol. It is likely, therefore, that future, mixed CSF protocols based on this and other studies will have even better outcomes, including EI patients.
1. Straus,SE., Tosato,G., Armstrong,G., Lawley,T., Preble,OT., Henle,W., Davey,R., Pearson,G., Epstein,J., Brus,I. and Blaese,RM., "Persisting Illness and Fatigue in Adults with Evidence of Epstein-Barr Virus Infection", Ann. Intern. Med.,102:7-16,1985.
2. Jones,JF., Ray,CG., Minnich,LL., Hicks,MJ., Kibler,R. and Lucas,DO., "Evidence for Active Epstein-Barr Virus Infection in Patients with Persistent, Unexplained Illnesses; Elevated Anti-Early Antigen Antibodies",Ann. Intern. Med.,102:1-7,1985
3. Buchwald,D., Cheney, PR., Peterson,DL., Henry,B., Wormsley,SB., Geiger,A., Ablashi,DV., Salahuddin,Z., Saxinger,C., Biddle,R., Kikinis,R., Jolesz,FA., Folks,T., Balachandran,N., Peter,JB., Gallo,RC.,and Komaroff,AL., "A Chronic Illness Characterized by Fatigue, Neurologic and Immunologic Disorders, and Active Human Herpesvirus-6 Infection", Annals of Internal Medicine, Jan.15,1992:116(2),pp.103-113.
4. Demers C, Hamdy R "Bone morphogenic proteins" Science & Medicine Nov/Dec 1999; Vol 6, No 6: 8- 17.
5. Lindvall O, Brundin P, Widner H "Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease" Science 1990; 247: 574-577
6. Cowley, G. "The new war on Parkinson's disease" Newsweek 2000; 22 May issue: 52-58
7. Isacson O, Deacon T, Pakzaban P, Galpern WR, Dinsmore J and Burns LH. "Transplanted exogenic neural cells in neurodegenerative disease models exhibit remarkable axonal target specificity and distinct growth paterns of glial and axonal fibers" Nature Medicine 1995;1: 1189-1194.
8. Gash DM and eleven others "Functional recovery in Parkinsonian monkeys treated with GDNF" Nature 1996; 380: 252-255
9. Dexler et al "Intracoronary autologous bone-marrow transfer after myocardial infarction: the BOOST controlled clinical trial Lancet (2004 Jul 10); 364 (9429); 141-8
10. Niehans, Paul., Introduction to Cellular Therapy NY: Coopers Square Publ., 1960
11. Culbert, ML in Live Cell Therapy for the 21st Century Chula Vista, CA: The Robert W. Bradford Foundation - Publ., 1993
12. Osmond ME, et al, "Demonstration of abnormal immunity, T-cell histamine H-2 receptor deficiency, and successful therapy with thymic extract", N. Eng. J. Med., Jan 15, 1981
13. Steinbach,T., Hermann,W., Lawyer,C., Montefiore,D., Wagle,S., Gawish,A., and Ferguson,D., "Subjective Reduction in Symptoms Following Long Term Treatment with a Porcine Liver Extract: A Phase I Trial", Clin. Inf. Dis., Volume 18, Suppl. I, pgs. S114, January, 1994.
Oxygen Toxicity as a Locus of Control for Chronic Fatigue Syndrome
BACKGROUND Chronic Fatigue Syndrome is a disorder of unknown cause characterized by significant functional disability associated with fatigue, pain and neuropsychological complaints. The subject of oxygen utilization, and especially the lack of it in CFS, has been the focus of many investigations(1,2). Indeed, the response of oxygen utilization in CFS to maximum exercise (VO2 max) was used as an FDA approved end-point marker in the multi-center trial of Ampligen, a biological response modifier(3). These studies demonstrate that CFS patients use oxygen at a reduced rate for a normalized peak exercise activity.
The oxygen response deficit with exercise in CFS is very appealing as an avenue of explanation for fatigue. Whether it is cause or effect, however, is unknown. We began our studies on oxygen itself by noting with echocardiography that patients with CFS had a much higher incidence of diastolic dysfunction than control groups(4). Diastolic dysfunction, especially in a younger cohort such as CFS, is most likely related to an underlying energy deficit(5). In addition,diastolic dysfunction, which is known to lower cardiac output, was shown to be associated with low cardiac output (CI < 3.0) in 80% of our CFS patients. Other studies have correlated (p<0.002) low cardiac output with CFS dysfunction and especially post-exertional fatigue(6). Low cardiac output can certainly cause lowered oxygen consumption but whether low cardiac output alone is responsible for low oxygen utilization is uncertain.
Further echocardiography investigations of CFS in this clinic revealed, using saline contrast bubble studies, evidence of patent foramen ovale (PFO) in a shocking 90%(7), 4-5 times the expected result by chance alone and much higher than any other known PFO association. Such a finding raised the possibility of oxygen toxicity physiology in CFS. This study extends the relationship of oxygen utilization disorders common in CFS and examines the concept of oxygen toxicity as it might apply to CFS.
METHODS: During a ten-month period, 67 consecutive patients presenting for either initial or follow-up evaluation for CFS were evaluated using echocardiography coupled to a series of varied interrogations on the echo table in real time. After routine, though expanded echocardiography, each patient was evaluated for IVRT response before, during and after oxygen administration for 5 minutes each, initially at 4 lpm NC and then typically at progressively higher doses up to 40% FIO2 mask oxygen at 10 lpm flow rate if they were non-toxic to 4 lpm NC. IVRT or isovolumetric relaxation time is an internal timing measurement in milliseconds (msec) on echocardiography, which is inversely related to cellular free energy in myocardial cells. IVRT was measured in triplicate using continuous wave (cw) doppler and averaged for each result.
In the 67 patient cohort, the average patient age was 49.3 (range 17-67). There were 48 females (71.6%) and 19 males (28.4%). Almost all the patients were fully or partially disabled and all had been ill for at least 5 years with the average length of illness being 14 years. Three patients did not meet severity criteria for CFS at the time they were evaluated and three were deemed atypical for CFS on clinical grounds. These six outliers were evaluated separately from the group. All 67 patients were categorized as either new patients or patients on various treatment algorithms if they were follow-up patients. The various treatment algorithms are complex as well as novel and cannot be fully discussed here but serve to illustrate the power of the proposed oxygen toxicity model to discriminate among various treatments.
Controls (N=17) were selected to approximately match the CFS patients' age and sex distribution and were largely selected from the community. The average age was 45.0 (range 19-75). There were 10 females (59%) and 7 males (41%). All were either working or in school full time though 2 were non-medically retired and all were deemed functionally normal for age with no prior history of CFS though only a minority had unblemished medical histories. RESULTS: Because results depended on treatment status, the 67 patient cohort, as well as an additional 24 patients from a more limited evaluation cohort for a total of 91 patients, were segregated into a) new patients, b) patients treated in this clinic with standard therapies, c) patients treated in this clinic with standard therapies plus one novel, low molecular weight (LMW), cell signaling factor (CSF) peptide in a transdermal gel and d) patients treated in this clinic with standard therapies plus an expanded set of LMW, cell signaling factor gels. Of the 67 consecutive patients, less those who did not meet criteria for CFS and/or were deemed atypical (6 were so categorized), 26 were new patients and 25 of 26 or 96.1% were toxic to oxygen as evidenced by a rise in IVRT on exposure to oxygen and indicating a reduction in myocardial cellular energetics. It took three minutes or less to see this IVRT response take effect and 3-5 minutes to return to baseline once off oxygen. 26 of 26 new patients or 100% were toxic to 40% mask oxygen. This contrasts to 6 of 17 or 35% of the controls that were toxic to oxygen at 4 lpm and 11 of 17 or 65% of controls that were toxic to 40% mask oxygen. When patients from the group of 67 consecutive cases, excluding the 6 outliers as well as treatment responders, were statistically compared (N = 53) in their IVRT response on oxygen to the controls (N = 17) on oxygen at 4 lpm NC, there was almost no chance they could have been the same group (p < 0.0004). With respect to treated groups b), c) and d), there were 9 of 12 patients or 75% on standard therapy for at least three months who were toxic at 4 lpm and 12 of 12 or 100% toxic at 40% mask oxygen. There were 15 of 23 or 65% toxic on a single CSF gel therapy for at least three months and 23 of 23 or 100% toxic at 40% mask oxygen. Finally, there were 9 of 30 or 30% toxic on an expanded set of CSF gel therapies for at least three months and 8 of 14 or 57% toxic at 40% mask oxygen. Of special note in those patients receiving the expanded set of CSF's, was the fact that in a separate prospective study lasting one year of 16 patients on an expanded CSF therapy protocol, there was a 75% (12 of 16) clinical response rate with a mean Karnofsy Performance Scale (KPS) improvement of 10 points (p<0.006) in which the responders had an oxygen tolerance rate on 4 lpm of 92% (11 of 12) whereas the non-responders (25%) had a 75% rate of oxygen toxicity (3 of 4).
There were a total of six patients out of the consecutive group of 67 fully evaluated patients who either did not fully meet the severity criteria for CFS (three were working full time but were otherwise typical for CFS) or were clinically atypical (three). From these two groups of outliers, all were tolerant to 4 lpm though 4 of 6 (2 from each group) or 67% were toxic to 40% mask oxygen, a result similar to controls. The interesting thing about the atypical group was that they all three had significant environmental illness and could be distinguished from controls by their real-time IVRT response to porcine liver derived CSF's suggesting that a defect in detoxification underlies their illness apart from oxygen toxicity.
CONCLUSION: These results demonstrate that within certain well defined limits of the case definition for CFS, the relative cardiac cellular energetic response to oxygen in CFS (strongly negative) compared to controls (strongly positive to weakly negative) is significantly different (p < 0.0004). Furthermore, that the absolute response to oxygen (toxic vs. tolerant) yields 96% sensitivity (CFS being essentially a strongly oxygen toxic state) and 65% specificity compared to controls (35% are weakly toxic) at 4 lpm NC. At 40% mask oxygen, 100% of CFS cases are toxic, but so were 65% of controls. When patients were sub-categorized according to increasingly powerful treatment algorithms, they were increasingly transformed to an oxygen tolerant state, which in the case of the most powerful algorithm, was associated with a significantly (p<0.006) improved clinical status. We conclude that CFS is an oxygen toxic state and that oxygen toxicity status appears to determine outcome in therapeutic trials and is therefore, a locus of control in chronic fatigue syndrome.
DISCUSSION: While it could be argued that this study simply reveals different levels of aerobic conditioning, there are several arguments against this including 1) the most oxygen responsive control had had a cardiac transplant five years ago and hasn't been able to do significant aerobic activity for five years and 2) this doesn't explain the oxygen tolerance found in the 6 atypical cases, all of whom were moderately to severely deconditioned, nor an oxygen toxic control who is a college athlete. Finally, the ability to transform the oxygen toxic state with ever more effective therapies, without an exercise program in place, suggests that the oxygen toxic state is related to some fundamental problem inherent to CFS. These findings appear to force a narrowing of potential causes of CFS because whatever pathophysiology one puts forth must explain universal oxygen toxicity in chronic fatigue syndrome and must explain a 90% incidence of PFO. In fact, it is the relative oxygen toxic state of fetal physiology, which is indirectly responsible for PFO, that is a key argument for the study interpretation. The missing piece to this puzzle may be that we see a super-select group of CFS patients at our clinic. While it is possible that we are masked off from other possibly non-oxygen toxic and less severe cases of CFS, this is not likely if they are disabled since we do see a wide spectrum of disabled patients from all parts of the US and abroad.
It is also important to view oxygen toxicity as less a cause of CFS but rather a final common pathway whose presence is downstream from the issue of etiology or etiologies, though it appears to determine outcome. I strongly suspect that the emerging model of CFS as an oxygen toxic state will not be an etiologic based model but rather a model much like the cancer model. For example, there are many etiologies for cancer and many downstream complications and presentations, but only the cancer cell matters and ultimately determines outcome. Oxygen toxicity is analogous to the cancer cell in CFS and once established, may be independent of etiology but nevertheless, determines outcome.
1. De Becker et al. "Exercise capacity in Chronic Fatigue Syndrome", Arch. Intern. Med. 2000 : 160 ; 3270
2. Stevens,SR, "Using Exercise Testing to Document Functional Disability in CFS", Journal of Chronic Fatigue Syndrome", 1995:Vol 1, Numbers ¾; 127-129
3. Strayer,DR., Carter,WA., Brodsky,I., Cheney,PR., Peterson,DL., Salvato,P., Thompson,C., Loveless,MO., Shapiro,D., Elsasser,W., and Gillespie,D., "A Controlled Clinical Trial with a Specifically Configured RNA Drug, Poly (I): Poly (C12U) in Chronic Fatigue Syndrome", Clin. Inf. Dis., Volume 18, Suppl. I, S88-95, January, 1994.
4. Cheney,PR and Lucki,NC "Evidence for Diastolic Dysfunction in the Chronic Fatigue Syndrome enhanced by Tilt-Echocardiography: A study of ninety consecutive cases." IACFS Meetings, Jan 2007, Ft Lauderdale, FL
5. Morgan,JP, "Abnormal modulation of calcium as a major cause of cardiac contractile dysfunction" NEJM 1991;325:625-632
6. Peckerman,A et.al.,"Abnormal Impedance Cardiography Predicts Syndrome Severity in Chronic Fatigue Syndrome",The American Journal Of The Medical Sciences, 2003:Vol326,No2;
7. Cheney,PR and Lucki,NC, "Evidence of Increased Frequency of Patent Foramen Ovale (PFO) in the Chronic Fatigue Syndrome with Enriched Oxygen Modulation of the PFO" IACFS Meetings, Jan 2007, Ft Lauderdale, FL
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