Hi all,
I think selegiline can be discussed from controversial points of view.
On the one hand there are articles which point to the neuroprotective & life prolonging site of selegiline - and the other hand you also find reports which indicate an excess mortality and the combination with Parkinson.
Cheers
Alex
"Deprenyl, excess mortality, and epidemiological traps.
Riggs JE.
Department of Neurology, West Virginia University School of Medicine, Morgantown 26506, USA.
Compared with the findings for an age-matched group not taking deprenyl, a higher risk of mortality in Parkinson's disease patients taking deprenyl has recently been reported. Since a biological basis for this observation was not apparent, an epidemiological explanation was sought. Expected mortality over a 6-year period in four hypothetical age-matched groups was determined. Although groups were age matched, ages of individuals within the groups varied. Variation of individual ages within each group, without affecting the age-match comparability, produced a marked variation in expected group mortality. Mortality comparisons between age-matched groups can be invalid. This epidemiological trap might account for the recent unexplained high mortality observed in a group of Parkinson's disease patients taking deprenyl.
PMID: 9197952 "
"
The necessity of having a proper dose of (-)deprenyl (D) to prolong the life spans of rats explains discrepancies among different studies in the past.
Kitani K, Kanai S, Miyasaka K, Carrillo MC, Ivy GO.
National Institute for Longevity Sciences, Morioka-cho, Obu-shi, Aichi, Japan. kitani@nils.go.jp
(-)Deprenyl (D) has been shown to be effective in prolonging life span in experimental animals, although, there are some discrepancies in its effect on the life span the even within the same species (rats). The present study aims to clarify the reason for these discrepancies. Male F344/DuCrj rats began receiving subcutaneous (s.c.) injections of D at the age of 18 months. Doses used were 0.25, 0.50, and 1.0 mg/kg/injection (inj.), three times a week. Average life spans of animals were significantly longer in male rats given 0.25 and 0.5 mg/kg/inj.; however, rats given a 1.0 mg/kg dose began dying earlier than control rats, leading to an inverse U-shaped dose-efficacy relationship, a hormesis. Old (27-month-old) rats given different doses of D for 1 month showed a typical hormetic response for antioxidant enzyme activities, indicating a significant increase in superoxide dismutase (SOD) and catalase (CAT) activities in brain dopaminergic regions with four lower doses (0.25 to 2 mg/kg/inj., 3 times a week), but a significantly negative response with the highest dose (4 mg/kg/inj.). Our results clearly indicate that a proper dose of D within a certain dose range can significantly increase the life span of rats, but that a greater dose becomes less effective and may actually adversely affect the life span of rats. A similar hormetic response for its effect on antioxidant enzyme activities and the parallel between the two different effects of D suggest a possible causal relationship between these two effects of D. The presence of this effective dose range of D may explain previously reported discrepancies in the effect of D on the life span of animals."
"Pharmacological aspects of (-)-deprenyl.
Magyar K, Pálfi M, Tábi T, Kalász H, Szende B, Szöko E.
Department of Pharmacodynamics, Semmelweis University, H-1445, Budapest, P.O.B.: 370 Hungary. magykal@net.sote.hu
Deprenyl, the selective irreversible inhibitor of monoamine oxidase-B (MAO-B), has been synthesised as a potential antidepressant, however, due to its dopamine potentiating capacity, became a registered drug in the treatment of Parkinson's disease. Deprenyl possesses a wide range of pharmacological activities; some of them are not related to its MAO-B inhibitory potency. Beside its dopamine potentiating effect, it renders protection against a number of dopaminergic, cholinergic and noradrenergic neurotoxins with a complex mechanism of action. By inducing antioxidant enzymes and decreasing the formation of reactive oxygen species, deprenyl is able to combat an oxidative challenge implicated as a common causative factor in neurodegenerative diseases. In a dose substantially lower than required for MAO-B inhibition (10(-9)-10(-13) M), deprenyl interferes with early apoptotic signalling events induced by various kinds of insults in cell cultures of neuroectodermal origin, thus protecting cells from apoptotic death. Deprenyl requires metabolic conversion to a hitherto unidentified metabolite to exert its antiapoptotic effect, which serves to protect the integrity of the mitochondrion by inducing transcriptional and translational changes. Pharmacokinetic and metabolism studies have revealed that deprenyl undergoes intensive first pass metabolism, and its major metabolites also possess pharmacological activities. The ratio of the parent compound and its metabolites reaching the systemic circulation and the brain are highly dependent on the routes of administration. Therefore, in the treatment of neurodegenerative diseases, reconsideration of the dosing schedule, by lowering the dose of deprenyl and choosing the most appropriate route of administration, would diminish undesired adverse effects, with unaltered neuroprotective potency. Copyright 2004 Bentham Science Publishers Ltd.
PMID: 15279565 "
"Effect of selegiline against selective neurotoxins]
[Article in Russian]
Magyar K.
Department of Pharmacodynamics, Semmelweis University of Medicine, Budapest, Hungary.
The complexity of the pharmacological activity of selegiline cannot be considered only as a result of a simple MAO-B inhibition. The mechanism of its neuroprotective action against the noradrenergic neurotoxin DSP-4 was widely studied (-)-p-fluoro-deprenyl (PFD), the chemical derivative of selegiline, with its possible metabolites were also involved into these studies. The results suggested that the uptake inhibitory effect of selegiline, and mainly that of its metabolite (-)-methylamphetamine (MA), played an essential role in the protection. MA was more potent to inhibit the uptake of noradrenaline and dopamine, than the parent compound. Neither selegiline nor its metabolite inhibited the reuptake of serotonin. In respect of the protection against DSP-4 induced toxicity PFD and its metabolites behaved similarly to selegiline, but their effects were more lasting than that of selegiline. After oral treatment selegiline undergoes an intensive "first pass" metabolism, which leads to an enhanced formation of MA. The better understanding of the fate of selegiline in the body, including its pharmacokinetic behaviour and metabolism, may contribute to a better knowledge of the complex pharmacological activity of the drug. The results could be summarised as follows. a) MAO-B inhibition-which is due to the parent compound-is an irreversible "hit and run" effect, the level of which after an initial phase is independent of the presence of the substance which caused it. b) The uptake inhibition is a reversible process and strictly proportional to the concentration of the substance responsible for the effect. In this respect the uptake inhibitory action of the metabolites exceeds that of the parent compounds. The role of the reversible uptake inhibition in neuroprotection may partly explain the need of the daily administration of selegiline to parkinsonian patients in spite of the irreversible MAO-B inhibitory action of the drug.
PMID: 9503567"
Luv2increase, please don't over-react.
According to this paper, http://dmd.aspetjour...t/full/25/6/657, "the metabolites excreted 2 days after administration of 2.5-10 mg of selegiline hydrochloride amounted to 44-58% of the dose." The paper also says that 37% of the metabolites end up as ®-Methamphetamine, and 3% end up as ®-Amphetamine.
Luv2increase, I don't understand where you get the figure of 00000222222333 micrograms of amphetamine-like metabolites from ingesting 1 mg of selegiline from? The actual value is magnitudes higher! Even if you were making an estimate, try to be in the ballpark okay? From my point of view, selegiline should be avoided, and please respect my opinion. Don't start accusing people of being unscientific and giving bad advice when you cannot find scientific evidence to debunk my case.
Everyone, I would be extremely wary of selegiline. Just because people here on imminst have made a lot of posts, doesn't make them right. Some, as I've said before, have financial reasons for sticking around, hence the many posts to establish credibility. Always keep an open mind.
Here is an analogy for you: 1/2 ounce of quality Grey Goose vodka in a sitting is not bad for an individual's health yet 12 ounces are.
Can you catch my drift here?
It is extremely erroneous to assume that such an extremely low amount of amphetamine and/or methamphetamine (notably R isomer ---> although makes no difference here) is bad for an individual's health. You also cannot exclude the fact that selegiline itself is the main beneficial constituent in which should be focused on here. Ever heard the term of the pros outweighing the cons? I hope so. Although, in this instance, there is no cons; therefore, one can safely conclude that selegiline is most definitely beneficial for one's health. This isn't only my words, but the findings of numerous studies have concluded so.
I'm off to bed.
Edited by brotherx, 15 August 2008 - 08:31 AM.