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CONCLUSION:

Deprenyl has a unique selectivity to the nigrostriatal dopaminergic neurons, and for the time being is the only promising tool for this purpose in humans because of the following reasons:

a) Given concurrently with levodopa and a peripheral decarboxylase inhibitor (-)Deprenyl is now widely used in Parkinson's disease21, it is an effective antidepressant 22,23 and its beneficial effect on Alzheimer's disease was recently demonstrated24. The small dose administration of (-)Deprenyl even for several years was described to be free of significant side effects25.

b) The supplementation of (-)Deprenyl to Madopar significantly prolonged the survival of parkinsonian patients as compared to those on Madopar alone indicating that (-)Deprenyl protected somehow the nigrostriatal dopaminergic neurons in these patients6.

c) (-)Deprenyl exerts its specific pharmacological effect in animals with an excellent safety margin17.

d) (-)Deprenyl turned out to be an efficient inhibitor of the uptake of dopamine in the striatum and this effect was found to play an important role in the facilitation of the activity of the nigrostriatal dopaminergic neurons in animals treated continuously with (-)Deprenyl 12,26,28.

e) (-)Deprenyl in striking contrast with the MAO inhibitors used previously inhibits the noradrenaline releasing effect of indirectly-acting amine in vascular smooth muscle. This latter effect of (-)Deprenyl, which is not shared even with other known selective inhibitors of the B type MAO26, is the reason of its safety. It is at present, the only MAO inhibitor free of the "Cheese effect" 28.

f) The selectivity of (-)Deprenyl, in the small dose range, to the nigrostriatal dopaminergic neuron is also supported by our findings that whereas the turnover rate of dopamine was enhanced in the striatum, a significant decrease of the turnover rate of noradrenaline and unchanged level of this amine in the brain stem were found 29.

 

 

REFERENCES:

1)Physician's Desk Reference (1992) 2250-52 Suppl. for revision

2)Milgram N. W., Use of L-Deprenyl for Retention of Specific Physiological Functions. United States Patent No.5,151,449, Sep. 29, 1992

3)Dow A., Deprenyl The Anti-Aging Drug. Hallberg Publishing Corporation, 1993

4)J. Knoll, Role of B-type monoamine oxidase inhibition in the treatment of Parkinson's Disease. An update, In N.S. Shah and A.G. Donald (eds) Movement Disorders, Plenum Press, NY, (1986).

5) Knoll J. Medicamentous strategy for improving the quality of life in the senescence. Wiener Mediziniche Wochenschrift. suppl. 98:1-18, (1986)

6) Birkmayer, W., Knoll, J., Riederer, P., Youdim, M.B.H., Hars, Vera, and Marton J., "Increased Life Expectancy Resulting from Addition of L-Deprenyl to Madopar Treatment in Parkinson's Disease: A long term Study. Jouranl of Neural Transmission. Vol. 64-113-27.

7) Study run by the University College Hospital and Medical School Committe on the Ethics of Clinical Investigations.

8) Sunderland, T., Mueller, EA., Cohen, RH., Jimerson, DC., Pickar, D., Murphy, DL., Tyramine pressor Sensitivity Changes during deprenyl Treatment. Psychopharmacology J., 86(4):432-7, (1985).

9) Elsworth, J.D.,Glover, Vivette, Reynolds, G.P., Sandler, M., Lees,A.J.,Phuapradit, P., Shaw, K.M., Stern, G.M., and Kumar, Parveen, Deprenyl Administration in Man: A Selective Monoamine Oxidase B Inhibitor without the "Cheese Effect" (Psychopharmacology,1978)

10) Stern G., Lees, A., Parkinson's disease: The Facts. (1982)

11) Leber P.,"Deprenyl in the Treatment of Symptom Fluctuations in Advance Parkinsons Disease", Clinical Neuropharmacology, Vol II, No.1, 45-55 (1988).

12) Knoll, J., The Facilitation of Dopaminergic activity in the aged brain by (-)deprenyl a proposal for a strategy to improve the quality of life in senescence. Mechanism of Ageing and Development J., 30(2):109-22, (1985).

13) Heinonen, E., Myllilis, V., Sotaniemi K., Lamintausta R., Salonen, J.S., Antilla M., Savijiarvi M., Kotila M., Rinne UK. Pharmacokinetics and Metabolism of Deprenyl., Acta Neurologica Scandinavica, 126:98-9, (1989).

14) J. Knoll, The Theory of Active Reflexes: An Analysis of Some Fundamental Mechanisms of Higher Nervous Activity.

15) Birkmayer, W. and Hornykiewicks,O., Wiener Klinische Wochenschrift, "The effect of L-3,4-Dihydroxyphenylalanine on Akinesia in Parkinsonism"

Vol.73,787-88

16) Timar, J., Knoll, B., Knoll, J., Long Term Administration of Deprenyl, a compound which facilitates dopaminergic tone in the brain, leaves the sensitivity of dopamine receptors to apomorphine unchanged.. Archives Internationales De Pharmacodynamie Et De Therapie. 284(2):255-66, (1986).

17) Knoll J. The Pharmacology of (-) deprenyl. Journal of Neural Transmission, 22:75-89, (1986).

18) Knoll J., R(-) Deprenyl facilitates the Activity of the Nigrostriatal dopaminergic neuron. J. Neural Transm., suppl. 25 (1987) 45-66.

19) Knoll, J., Magyar K, some puzzling effects of Monoamine oxidase inhibitors, Adv. Biochem. Psycopharmacol.., 5 (1972) 393-408.

20) Knoll, J., The possible Mechanism of Action of (-)deprenyl in Parkinson's Disease. J. Neural transmission., 43 (1978) 177-198.

21)Birkmayer W., Riederer, P., Parkinson's Disease. Biochemistry. Clinical Pathology and Treatment, Springer-Verlag, Wien-NY, (1983).

22)Mann, J.J., Gershon, S., L-deprenyl, a selective monoamine Oxidase type B inhibitor in endogenous depression. Life Sci., 26 (1980) 877-882.

23)Quitkin, F.M., McGrath, P., Leibowitz, M.R., Stewart, J., Howard, A., Monoamine oxidase inhibitors in bipolar endogenous depressives. J. Clin. Psychopharmacol., y (1981) 70-74.

24)Tariot P.N., Cohen, R.M., Sunderland, T., Newhouse, P.A., Yount, D., Mellow, A.M., Weingartner, H., Mueller, E.A. and Murphy, D.L., L-deprenyl in Alzheimer's Disease. Preliminary evidence for behavioral changes with monoamine oxidase B inhibition. Arch.Gen. Psychiatry, 44 (1987),427-433.

25)Riederer, P., Prunztec (eds) MAO-B inhibitor deprenyl. A new therapeutic concept in the treatment of Parkinson's Disease, J. Neural Trans. Suppl. 25 (1987), pp.197.

26)Knoll, J., Critical role of MAO inhibitors in Parkinson's Disease. Adv. in Neurol., 45 (1986) 107-110.

27)Knoll, J., On the dual nature of Monoamine Oxidase. Horizons Biochem. Biophys., 5 (1987)37-64.

28)Knoll, J., Deprenyl: the history of its development and pharmacological action. Acta Neurol.Scand., Suppl. 95 (1993) 57-80.

29) Zsilla, O., Knoll,J., The action of (-) deprenyl on monoamine turnover rate in the brain. Adv. Biochem., Psychopharmacol., 31 (1982) 211-217.

30) Dilman, V., Dean, W., The Neuroendochrine Theory of Aging and Degenerative Disease. Pensacola Fl., The Center for Bio-Gerontology, (1992).

31)Dallo, J., Knoll, J., Yen, TT., The Aphrodisiac effect of (-) deprenyl in male rats, Acta Physiol. Hung (Hungary)-75 Suppl; p 75-6, (1990).

32) Fowkes, S., Deprenyl: The anti-aging drug. Smart Drugs News. 2(5); Oct. 1993.

33)Sbessl AJ. Prevention and Management of late state complications in Parkinson's Disease. J. Neurol. Sci. (Canada). 19 (1 supply): p 113-6. (1992).

34)Therapeutic Drugs. Colin Dollery. Churchill Livingstone (1999).

 

 

 

 

 

 

GLOSSARY:LOSSARY:

Bradykinesia: gradual loss of spontaneous movement.

Chemical Scavenger: A chemical that consumes or renders inactive the impurities in a mixture.

"corpus striatum": a part of the brain that help regulate motor activities.

Dementia: loss of intellectual abilities.

Dopamine: a chemical messenger, deficient in the brains of Parkinson's disease patients, that transmits impulses from one nerve cell to another.

Parkinsonism: a term referring to a group of conditions that are characterized by four typical symptoms: Tremor, rigidity, postural instability, and bradykinesia.

"substantia nigra": movement-control center in the brain where loss of dopamine-producing nerve cells triggers the symptoms of Parkinson's disease; substancia nigra means "black substance", so called because the cells in this area are dark.

Wearing-off effect: the tendency, following long-term levodopa treatment, for each dose of the drug to be effective for shorter and shorter periods.

 

 

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