Posted September 19, 2019
Jon Kaiser, Ph.D., K-PAX Pharmaceuticals
Gulf War Illness (GWI) is a complex, chronic and highly variable disease producing numerous symptoms spanning multiple physiological domains. There are currently no established treatments for GWI. It is estimated that up to one third of the nearly 700,000 Veterans from the 1990-91 Persian Gulf War are afflicted with this debilitating condition. Despite decades of research there is no unanimously accepted GWI definition or etiology, though many symptoms clearly relate to nervous system dysfunction and much of the research has focused on pathobiology of the nervous system. Emerging evidence also supports the possibility that GWI may represent mitochondrial disease resulting from long-term effects of exposure to multiple toxicants in theater.
Dr. Jon Kaiser at K-PAX Pharmaceuticals (Mill Valley, CA) was awarded an FY13 GWIRP Innovative Treatment Evaluation Award (ITEA) to conduct a Phase 2 open-label trial of their GWI Nutrient Formula (mitochondrial modulators) paired with low dose methylphenidate hydrochloride (Ritalin®) to evaluate the potential for improved mitochondrial metabolism and an improvement of symptoms in ill Gulf War Veterans. Mitochondria are known as the “powerhouse” of the cell as they are responsible for producing energy and regulating cellular metabolism. Mitochondrial dysfunction can simultaneously affect the cells of multiple organ systems and is frequently associated with a waxing and waning pattern of symptoms, as is the case in GWI. Thus it is reasoned that combining methylphenidate, a well-known stimulant of central nervous system neuronal activity, with mitochondrial support and enhancement may result in sustained improvement in cognitive dysfunction and fatigue symptoms in GWI patients.
The trial, conducted at the Palo Alto VA Health Care System from 2015-2017, examined 15 veterans, aged 46 – 62, that met the Kansas definition for GWI. Subjects took the mitochondrial modulating GWI Nutrient Formula and methylphenidate in tablet form, twice daily for 12 weeks. The primary outcome was based on the GWI Symptoms Assessment Tool (SAT), which represents the cumulative score of each GWI symptom present, including its severity rating. Mitochondrial function assessments were also conducted at baseline and throughout the study.
The mean change in SAT total score from baseline to Week 12 decreased 8.8 points (p < 0.001, 95% confidence interval) representing a mean 25% reduction in GWI symptoms. This treatment effect was shown to be statistically significant when compared to baseline using multiple analysis methods. There were also statistically significant reductions in individual symptom measurements for fatigue, alertness, pain and sleep problems. Of four indirect assays for mitochondrial health, a reduction in the level of lipid peroxides, a marker of systemic oxidative stress, showed a statistically significant reduction.
Results from this innovative combination therapy were recently published in the Journal of Psychiatric Research and demonstrate an overall benefit to symptomatic Gulf War Veterans, possibly linked to improved mitochondrial redox status. A larger randomized, double-blinded, placebo-controlled trial is necessary to determine if the observed benefit can be replicated and to validate use of respirometric measurement of mitochondrial function to directly assess the treatment effect and potentially identify GWI subgroups most responsive to KPAX002 administration.
Public and Technical Abstracts: A Prospective Open-Label Clinical Trial of Methylphenidate plus a GWI-Specific Nutrient Formula in Patients with Gulf War Illness and Concentration Disturbances
Last updated Thursday, May 26, 2022