Joseph Knoll’s response to Hector Warnes'  response

Joseph Knoll: The Discovery of the Enhancer Regulation in the Mammalian Brain and the Development of the Synthetic Enhancer Substances

            In response to your question whether we compared the antiaging effect of deprenyl with antiaging effect of other antiaging drugs in the same strain rats, we compared the pharmacological profile of anti-aging compounds with deprenyl (DEP) and also measured  their  CAE effect.

An example:

            From therapeutic perspective, the value of treating PD with DEP was a significant finding in the USA, first published by Tetrud and Langston in 1989. They concluded that DEP-treatment delayed the need for levodopa therapy. In their study the average time until levodopa was needed was 312.1 days in the placebo group and 548.9 days for patients in the DEP group. This finding was already confirmed in the 1989 DATATOP multicenter study by the Parkinson Study Group. Important multicenter studies, such as the French Selegiline Multicenter Trial (FSMT), the Finnish Study the Swedish Parkinson Study Group and the Norwegian-Danish Study Group, confirmed the usefulness of the drug in de novo PD.

            When the DATATOP study was planned, DEP’s enhancer effect was unknown, so the organizers' hypothesis was that the activity of MAO and the formation of free radicals predispose patients to nigral degeneration and contribute to the emergence and progression of PD. In accord with their working hypothesis, they expected that DEP, the MAO inhibitor, α-tocopherol, the antioxidant, and the combination of the two compounds would slow the disease’s clinical progression.

            They selected patients with early, untreated PD and measured the delay in the onset of disability necessitating levodopa therapy. In the first phase of the trial, 401 subjects were assigned to -tocopherol or placebo and 399 subjects were assigned to DEP, alone or with -tocopherol. Only 97 subjects who received DEP reached the "end" of the trial (i.e., the onset of disability necessitating levodopa therapy) during an average 12 months of follow-up compared with 176 subjects who did not receive DEP. The risk of reaching the end of the trial was reduced by 57% for the subjects who received DEP, and these patients also had a significant reduction in their risk of having to give up full-time employment. Following the course of changes, the authors concluded in their next paper that DEP, but not -tocopherol, delayed the onset of disability associated with early, otherwise untreated PD.

            The unexpected outcome of the DATATOP study, the finding that DEP delayed the need for levodopa therapy, but -tocopherol fell short of expectation, clearly proved that DEP exerts an unknown pharmacological effect of basic importance and -tocopherol is devoid of this effect. Now we know that DEP as a CAE substance is an enhancer of the impulse propagation mediated release of catecholamines. A comparative pharmacological analysis of DEP and -tocopherol proved that -tocopherol is devoid of the enhancer effect (Miklya, Knoll B, Knoll J  2003).

            This conclusion was also supported by the clinical trial with rasagiline, the selective MAO-B inhibitor, performed by the Parkinson Study Group. The trial revealed that unlike the early selegiline trials, rasagiline failed to demonstrate a decreased need for levodopa. Similar to -tocopherol, rasagiline is also devoid of the CAE effect of DEP (Miklya 2014).

References

Miklya I. Essential difference between the pharmacological spectrum of (-)-deprenyl and rasagiline. Pharmacol Rev.2014; 66: 453-8.

Miklya I, Knoll B, Knoll J. A pharmacological analysis elucidating why, in contrast to (-)-deprenyl (selegiline) a-tocopherol was ineffective in the DATATOP study. Life Sci. 2003; 72: 2641-8.

October 19, 2017