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C. D. Jurgensmeier, P. Bhosale, P. S. Bernstein; A Phase 1 Clinical Study of 4-Methylpyrazole (4-MP) as a Potential Dark Adaptation Inhibitor for the Long-Term Treatment of Stargardt Disease and Geographic Atrophy. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3677.
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A number of research groups are currently developing novel pharmaceutical agents for Stargardt disease and geographic atrophy that decrease lipofuscin accumulation by inhibiting enzymes of the vertebrate visual cycle, but these drugs are either not yet approved for human use, or they have significant long-term side effects. 4-Methylpyrazole (4-MP) is another appealing possible pharmacological therapy for these disorders due to its known inhibition of the visual cycle in rodents, its lack of toxicity in long-term administration, and its FDA approval as an alcohol dehydrogenase inhibitor for the treatment of ethylene glycol and methanol poisoning in humans. It is unknown whether inhibition of dark adaptation comparable to that seen in rodents also occurs in humans receiving 4-MP.
In a randomized, double-blind, phase 1 clinical trial, adults ≥18 years old who had no significant ocular pathologies were given intravenous infusions of either 4-MP (15 mg/kg) or placebo for a total of three infusions of each during six weekly visits. A blood sample was drawn from the opposite arm and tested by HPLC to assure therapeutic levels were attained. Dark adaptation was assessed by Goldmann-Weekers adaptometry, and results were quantified and transferred to statistical software.
Nine participants served as their own controls. Each participant demonstrated a linear, rod and cone mediated, log-based response during the initial phase of dark adaptation (roughly 7-10 mins) during both placebo and 4-MP sessions. Comparison of these results showed that at the α = 0.05 level, there were no statistically significant differences between the linear slopes of the 4-MP and placebo testing sessions.
4-MP does not appear to be a sufficient inhibitor of the human visual cycle to be considered further as a treatment for Stargardt disease or similar ocular disorders.
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