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Use of Selegiline as Monotherapy and in Combination with Levodopa in the Management of Parkinson's Disease: Perspectives from the MONOCOMB Study

Published online by Cambridge University Press:  18 June 2007

Sven E. Pålhagen  and
Esa Heinonen
Sven E. Pålhagen
Affiliation:
Department of Neurology, Karolinska University Hospital, Huddinge, Stockholm, Sweden; Email: sven.palhagen@karolinska.se
Esa Heinonen
Affiliation:
University of Helsinki, Institute of Biotechnology, Helsinki, Finland; Email: esa.heinonen@helsinki.fi
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Extract

ABSTRACT

The MONOCOMB study was a double-blind, randomized, controlled trial initiated to examine the impact of selegiline monotherapy on time to the start of levodopa therapy and, subsequently, to compare the progression of PD in patients treated with individualized levodopa plus selegiline or placebo.

Previously untreated patients with idiopathic PD (N = 157) were randomized to receive selegiline 10 mg/day or placebo until levodopa was required; experimental medication was then withdrawn for 8 weeks. Patients were then randomized to levodopa (50 mg/day, titrated in 50 mg/day increments to 150 mg/day) plus either selegiline or placebo. Treatment was continued until patients required additional antiparkinsonian therapy or up to 7 years after initial randomization. The primary efficacy outcome for the monotherapy phase of the study was time to introduction of levodopa. Primary efficacy endpoints for the combined therapy phase were: time to development of fluctuations in disability; and time to the addition of supplementary antiparkinsonian treatment.

Selegiline significantly delayed the time when levodopa therapy became necessary during the monotherapy phase, although mean total UPDRS scores at time of initiation of levodopa were similar in both groups. Selegiline was also associated with improvements in PD' symptom status and disability as reflected in a broad range of well-established indices. After the 8 week wash out period the disability of the clinical condition of the patients in the selegiline group was still significantly better in the selegiline group than in the placebo group. During the combination phase of the study, the use of selegiline as an adjunct to levodopa enabled a given degree of therapeutic effect to be achieved with a demonstrably lower total consumption of levodopa. Patients treated with selegiline plus levodopa also exhibited a distinct (p = 0.005) slowing in the anticipated increase in the UPDRS scores over time, as for example in a mean UPDRS total score after 5 years 10 points lower than in patients on levodopa and placebo. The emergence of motor (wearing-off) fluctuations was delayed by selegiline, and the proportion of patients experiencing these events was lower than with placebo (20% versus 34%; p = 0.053).

Mild gastrointestinal events were significantly more common with selegiline monotherapy than with placebo (12 versus. 3; p = 0.028). The overall rates of AEs during the combination therapy phase were 69% in the selegiline group and 54% in the placebo group (p = 0.053). Significantly more patients in the selegiline group reported nausea. Of the five deaths that occurred during the combination therapy phase of the study (selegiline N = 4, placebo N = 1) none was expressly attributed to study medication.

The results of MONOCOMB, among the largest and longest-duration placebo-controlled studies to report experience with selegiline monotherapy in early-phase PD, confirm that selegiline is effective in retarding the progression of early PD, that it has levodopa-sparing qualities in more advanced disease, and that it is reasonably well-tolerated in long-term use.

Keywords

controlled triallevodopamonoamine oxidase-B inhibitorParkinson's diseaseselegiline.
Type
Research Article
Information
Progress in Neurotherapeutics and Neuropsychopharmacology , Volume 3 , Issue 1 , January 2008 , pp. 49 - 71
Copyright
© 2008 Cambridge University Press

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Footnotes

The MONOCOMB study was sponsored by Orion Corporation, Orion Pharma, Espoo, Finland.

References

Ahlskog, J.E. (2003). Slowing Parkinson's disease progression: recent dopamine agonist trials. Neurology, 60, 381–389.Google Scholar
Albin, R.L., & Frey, K.A. (2003). Initial agonist treatment of Parkinson disease: a critique. Neurology, 60, 390–394.Google Scholar
Albin, R.L., Nichols, T.E., & Frey, K.A. (2002). Brain imaging to assess the effects of dopamine agonists on progression of Parkinson disease. Journal of the American Medical Association, 288, 311–312; author reply, 312–313.Google Scholar
Allain, H., Pollak, P., & Neukirch, H.C. (1993). Symptomatic effect of selegiline in de novo Parkinsonian patients. The French Selegiline Multicenter Trial. Movement Disorders, 8 (Suppl. 1), S36–S40.Google Scholar
Anon (2006). Rasagiline. Parkinson's disease: a simple me-too. Prescrire International, 15, 220.Google Scholar
Ben-Shlomo, Y., Churchyard, A., Head, J., et al. (1998). Investigation by Parkinson's Disease Research Group of United Kingdom into excess mortality seen with combined levodopa and selegiline treatment in patients with early, mild Parkinson's disease: further results of randomised trial and confidential inquiry. British Medical Journal, 316, 1191–1196.Google Scholar
Brannan, T., & Yahr, M.D. (1995). Comparative study of selegiline plus l-dopa-carbidopa versus L-dopa-carbidopa alone in the treatment of Parkinson's disease. Annals of Neurology, 37, 95–98.Google Scholar
Caraceni, T., & Musicco, M. (2001). Levodopa or dopamine agonists, or deprenyl as initial treatment for Parkinson's disease. A randomized multicenter study. Parkinsonism & Related Disorders, 7, 107–114.Google Scholar
Chen, J.J., & Ly, A.V. (2006). Rasagiline: a second-generation monoamine oxidase type-B inhibitor for the treatment of Parkinson's disease. American Journal of Health-System Pharmacy, 63, 915–928.Google Scholar
Clark, C.E., & Moore, A.P. (2006). Parkinson's disease. . Last accessed 23 December 2006.Google Scholar
Ebadi, M., Sharma, S., Shavali, S., & El Refaey, H. (2002). Neuroprotective actions of selegiline. Journal of Neuroscience Research, 67, 285–289.Google Scholar
Folstein, M.F., Folstein, S.E., & McHugh, P.R. (1975). “Mini-mental state”. A practical method for grading the cognitive state of patients for the clinician. Journal of Psychiatric Research, 12, 189–198.Google Scholar
Ganz, P.A. (1990). Methods of assessing the effect of drug therapy on quality of life. Drug Safety, 5, 233–242.Google Scholar
Goetz, C.G., Poewe, W., Rascol, O., & Sampaio, C. (2005). Evidence-based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004. Movement Disorders, 20, 523–539.Google Scholar
Golbe, L.I., & Duvoisin, R.C. (1987). Double-blind trial of R-(–)-deprenyl for the “on-off” effect complicating Parkinson's disease. Journal of Neural Transmission Supplement, 25, 123–129.Google Scholar
Golbe, L.I., Lieberman, A.N., Muenter, M.D., et al. (1998). Deprenyl in the treatment of symptom fluctuations in advanced Parkinson's disease. Clinical Neuropharmacology, 11, 45–55.Google Scholar
Hamilton, M.A. (1960). Rating scale for depression. Journal of Neurology, Neurosurgery, and Psychiatry, 21, 56–62.Google Scholar
Hara, M.R., Thomas, B., Cascio, M.B., et al. (2006). Neuroprotection by pharmacologic blockade of the GAPDH death cascade. Proceedings of the National Academy of Science of the United States of America, 103, 3887–3889.Google Scholar
Heinonen, E. (1995). Selegiline in the Treatment of Parkinson's Disease. Pharmacokinetic and Clinical Studies, Research Report No. 13, Department of Neurology, University of Turku, Turku, Finland, pp. 30–33.Google Scholar
Hoehn, M.M., & Yahr, M.D. (1967). Parkinsonism: onset, progression and mortality. Neurology, 17, 427–442.Google Scholar
Ives, N.J., Stowe, R.L., Marro, J., et al. (2004). Monoamine oxidase type B inhibitors in early Parkinson's disease: meta-analysis of 17 randomised trials involving 3525 patients. British Medical Journal, 329, 593–599.Google Scholar
Kim, S.G., Lee, C.H., & Park, J.W. (2004). Deprenyl, a therapeutic agent for Parkinson's disease, inhibits arsenic toxicity potentiated by GSH depletion via inhibition of JNK activation. Journal of Toxicology and Environmental Health: Part A, 67, 2013–2024.Google Scholar
Kirollos, C., Charlett, A., Bowes, S.G., et al. (1996). Time course of physical and psychological responses to selegiline monotherapy in newly diagnosed, idiopathic parkinsonism. European Journal of Clinical Pharmacology, 50, 7–18.Google Scholar
Lang, A.E., & Fahn, S. (1989). Assessment of Parkinson's disease. In: Munsat, T.L. (ed.), Quantification of Neurologic Deficit. Boston: Butterworths, pp. 285–309.
Larsen, J.P., Boas, J., & Erdal, J.E. (1999). Does selegiline modify the progression of early Parkinson's disease? Results from a five-year study. The Norwegian-Danish Study Group. European Journal of Neurology, 6, 539–547.Google Scholar
Lees, A.J., on behalf of the Parkinson's Disease Research Group of the United Kingdom (1995). Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson's disease. British Medical Journal, 311, 1602–1607.Google Scholar
Macleod, A.D., Counsell, C.E., Ives, N., & Stowe, R. (2005). Monoamine oxidase B inhibitors for early Parkinson's disease. Cochrane Database of Systemic Reviews, July 20, (3), CD004898.Google Scholar
Magyar, K., & Szende, B. (2004). (−)-Deprenyl, a selective MAO-B inhibitor, with apoptotic and anti-apoptotic properties. Neurotoxicology, 25, 233–242.Google Scholar
Matsubara, K., Senda, T., Uezono, T., et al. (2001). l-Deprenyl prevents the cell hypoxia induced by dopaminergic neurotoxins, MPP(+) and beta-carbolinium: a microdialysis study in rats. Neuroscience Letters, 302, 65–68.Google Scholar
Muralikrishnan, D., Samantaray, S., & Mohanakumar, K.P. (2003). d-deprenyl protects nigrostriatal neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced dopaminergic neurotoxicity. Synapse, 5, 7–13.Google Scholar
Myllylä, V.V., Sotaniemi, K.A., Vuorinen, J.A., & Heinonen, E.H. (1992). Selegiline as initial treatment in de novo parkinsonian patients. Neurology, 42, 339–343.Google Scholar
Myllylä, V.V., Heinonen, E.H., Vuorinen, J.A., Kilkku, O.I., & Sotaniemi, K.A. (1995). Early selegiline therapy reduces levodopa dose requirement in Parkinson's disease. Acta Neurological Scandinavica, 91, 177–182.Google Scholar
Myllylä, V.V., Sotaniemi, K.A., Hakulinen, P., Maki-Ikola, O., & Heinonen, E.H. (1997). Selegiline as the primary treatment of Parkinson's disease – a long-term double-blind study. Acta Neurological Scandinavica, 95, 211–218.Google Scholar
Naoi, M., Maruyama, W., Takahashi, T., Akao, Y., & Nakagawa, Y. (2000a). Involvement of endogenous N-methyl(R)salsolinol in Parkinson's disease: induction of apoptosis and protection by (−)deprenyl. Journal of Neural Transmission Supplement, 58, 111–121.Google Scholar
Naoi, M., Maruyama, W., Yagi, K., & Youdim, M. (2000b). Anti-apoptotic function of l-(−)deprenyl (selegiline) and related compounds. Neurobiology (Bp), 8, 69–80.Google Scholar
Olanow, C.W., Hauser, R.A., Gauger, L., et al. (1995). The effect of deprenyl and levodopa on the progression of Parkinson's disease. Annals of Neurology, 38, 771–777.Google Scholar
Olanow, C.W., Myllylä, V.V., Sotaniemi, K.A., et al. (1998). Effect of selegiline on mortality in patients with Parkinson's disease: a meta-analysis. Neurology, 51, 825–830.Google Scholar
Pålhagen, S., Heinonen, E.H., Hägglund, J., et al. (1998). Selegiline delays the onset of disability in de novo Parkinsonian patients. Swedish Parkinson Study Group. Neurology, 51, 520–525.Google Scholar
Parkinson Study Group (1993). Effects of tocopherol and deprenyl on the progression of disability in early Parkinson's disease. New England Journal of Medicine, 328, 176–183.Google Scholar
Parkinson Study Group (2000). Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. Journal of the American Medical Association, 284, 1931–1938.Google Scholar
Parkinson Study Group (2002). A controlled trial of rasagiline in early Parkinson disease: the TEMPO Study. Archives of Neurology, 59, 1937–1943.Google Scholar
Parkinson Study Group (2004a). Levodopa and the progression of Parkinson's disease. New England Journal of Medicine, 351, 2498–2508.Google Scholar
Parkinson Study Group (2004b). A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Archives of Neurology, 61, 561–566.Google Scholar
Parkinson Study Group (2005). A randomized placebo-controlled trial of rasagiline in levodopa-treated patients with Parkinson disease and motor fluctuations: the PRESTO study. Archives of Neurology, 62, 241–248.Google Scholar
Presthus, J., & Hajba, A. (1983). Deprenyl (selegiline) combined with levodopa and a decarboxylase inhibitor in the treatment of Parkinson's disease. Acta Neurological Scandinavica Supplement, 95, 127–133.Google Scholar
Presthus, J., Berstad, J., & Lien, K. (1987). Selegiline (l-deprenyl) and low-dose levodopa treatment of Parkinson's disease. A double-blind crossover trial. Acta Neurological Scandinavica, 76, 200–203.Google Scholar
Przuntek, H., Conrad, B., Dichgans, J., et al. (1999). SELEDO: a 5-year long-term trial on the effect of selegiline in early Parkinsonian patients treated with levodopa. European Journal of Neurology, 6, 141–150.Google Scholar
Rascol, O., Brooks, D.J., Korczyn, A.D., De Deyn, P.P., Clarke, C.E., & Lang, A.E. (2000). A five-year study of the incidence of dyskinesia in patients with early Parkinson's disease who were treated with ropinirole or levodopa. 056 Study Group. New England Journal of Medicine, 342, 1484–1491.Google Scholar
Rascol, O., Goetz, C., Koller, W., Poewe, W., & Sampaio, C. (2002). Treatment interventions for Parkinson's disease: an evidence based assessment. The Lancet, 359, 1589–1598.Google Scholar
Rinne, U.K., Siirtola, T., & Sonninen, V. (1978). l-deprenyl treatment of on–off phenomena in Parkinson's disease. Journal of Neural Transmission, 43, 253–262.Google Scholar
Rinne, U.K., Bracco, F., Chouza, C., et al. (1998). Early treatment of Parkinson's disease with cabergoline delays the onset of motor complications. Results of a double-blind levodopa controlled trial. The PKDS009 Study Group. Drugs, 55 (Suppl. 1), 23–30.Google Scholar
Saravanan, K.S., Sindhu, K.M., Senthilkumar, K.S., & Mohanakumar, K.P. (2006). l-deprenyl protects against rotenone-induced, oxidative stress-mediated dopaminergic neurodegeneration in rats. Neurochemistry International, 49, 28–40.Google Scholar
Schachter, M., Marsden, C.D., Parkes, J.D., Jenner, P., & Testa, B. (1980). Deprenyl in the management of response fluctuations in patients with Parkinson's disease on levodopa. Journal of Neurology, Neurosurgery, and Psychiatry, 43, 1016–1021.Google Scholar
Shan, D.E., & Yeh, S.I. (1996). An add-on study of selegiline to Madopar in the treatment of parkinsonian patients with dose-related fluctuations: comparison between Jumexal and Parkryl. Zhonghua Yi Xue Za Zhi (Taipei), 58, 264–268.Google Scholar
Shoulson, I., Oakes, D., Fahn, S., et al. (2002). Impact of sustained deprenyl (selegiline) in levodopa-treated Parkinson's disease: a randomized placebo-controlled extension of the deprenyl and tocopherol antioxidative therapy of parkinsonism trial. Annals of Neurology, 51, 604–612.Google Scholar
Stern, G.M., Lees, A.J., & Sandler, M. (1978). Recent observations on the clinical pharmacology of (−)deprenyl. Journal of Neural Transmission, 43, 245–251.Google Scholar
Szende, B., Bokonyi, G., Bocsi, J., Keri, G., Timar, F., & Magyar, K. (2001). Anti-apoptotic and apoptotic action of (−)-deprenyl and its metabolites. Journal of Neural Transmission, 108, 25–33.Google Scholar
Tatton, W., Chalmers-Redman, R., & Tatton, N. (2003). Neuroprotection by deprenyl and other propargylamines: glyceraldehyde-3-phosphate dehydrogenase rather than monoamine oxidase B. Journal of Neural Transmission, 110, 509–515.Google Scholar
Tetrud, J.W., & Langston, J.W. (1989). The effect of deprenyl (selegiline) on the natural history of Parkinson's disease. Science, 245, 519–522.Google Scholar
Whone, A.L., Watts, R.L., Stoessl, A.J., et al. (2003). Slower progression of Parkinson's disease with ropinirole versus levodopa: the REAL-PET study. Annals of Neurology, 54, 93–101.Google Scholar