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11-22-2006, 03:31 PM
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In Remembrance
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Yet it isn't mentioned...trial participants ignored again....I just want to mention in passing that this DBS neurosurgeon says no conflicts of interest. Refl ection and Reaction http://neurology.thelancet.com Vol 5 December 2006 991 rationale and evidence of benefi t in animal models. 14,15 Unfortunately, mounting experience from these trials suggests that our current hypotheses of the mechanism of neurodegeneration in Parkinson’s disease might still be inadequate to predict which treatment approaches should be pursued. In light of these uncertainties and the huge costs of undertaking trials, such as the TCH346 study, futility analyses will be increasingly used in the initial evaluation of putative neuroprotective drugs.16 Although available animal models, which largely produce a non-progressive presynaptic nigrostriatal dopamine defi ciency, have been especially useful in predicting symptomatic treatment eff ects, so far they have been disappointing in predicting outcomes of trials studying neuroprotection as well as neurorestoration. Two of the highest priorities in this area of research must be the development of animal models that more closely mimic the progressive multisystems nature of the neurodegenerative process of PD and the establishment of biomarkers that accurately refl ect the state of neuronal dysfunction and death in the many brain regions aff ected. Until these are available, further eff orts—eg, use of a large simple study design with multiple functional outcomes analysed by global statistical tests as proposed by the NIH NET-PD programme15—might provide some clinical evidence to suggest disease modifi cation, but will never convincingly prove that the underlying progressive degenerative process has been truly altered. Perhaps it is now time “for something completely diff erent” in our approach to neuroprotection for PD. Although the scientifi c underpinnings that supported a move to large-scale trials seemed sound, we now need to step back and critically assess our current concepts of disease patho genesis and possibly reconsider ongoing eff orts that are continuing to build on a potentially faulty foundation. Advances in our understanding of genetic causes of PD, the infl uence of other genes and environmental factors on the penetrance and manifestations of these disorders, and the generation of better animal models may provide new insights that can redirect our eff orts. Perhaps only when neuroprotective trials are grounded in further basic-science discovery will we see the development of treatments that are not subsequently classifi ed as another “dead parrot”. Anthony E Lang University of Toronto, Toronto, Canada lang@uhnres.utoronto.ca I have no conflicts of interest. 1 Olanow CW, Schapira AHV, LeWitt PA, et al. TCH346 as a neuroprotective drug in Parkinson’s disease: a double-blind, randomised, controlled trial. Lancet Neurol 2006; 5: 1013–20. 2 Waldmeier P, Bozyczko-Coyne D, Williams M, Vaught JL. Recent clinical failures in Parkinson’s disease with apoptosis inhibitors underline the need for a paradigm shift in drug discovery for neurodegenerative diseases. Biochem Pharmacol 2006; 72: 1197–206. 3 Parkinson Study Group. Eff ect of deprenyl on the progression of disability in early Parkinson’s disease. N Engl J Med 1989; 321: 1364–71. 4 Shoulson I, Parkinson Study Group PRECEPT Investigators. CEP-1347 treatment fails to favorably modify the progression of Parkinson’s disease (PRECEPT) study. Neurology 2006; 67: 185. 5 Rascol O, Olanow W, Brooks D, Koch G, Truffi net P, Bejuit R. A 2-year, multicenter, placebo-controlled, double-blind, parallel-group study of the eff ect of riluzole on Parkinson’s disease progression. Mov Disord 2002; 17 (suppl 5): S39. 6 Olanow CW, Hauser RA, Gauger L, et al. The eff ect of deprenyl and levodopa on the progression of Parkinson’s disease. Ann Neurol 1995; 38: 771–77. 7 Palhagen S, Heinonen E, Haegglund J, et al. Selegiline slows the progression of the symptoms of Parkinson disease. Neurology 2006; 66: 1200–06. 8 Siderowf A, Parkinson Study Group. A controlled, randomized, delayed-start study of rasagiline in early Parkinson disease. Arch Neurol 2004; 61: 561–66. 9 Shults CW, Oakes D, Kieburtz K, et al. Eff ects of coenzyme Q10 in early Parkinson disease: evidence of slowing of the functional decline. Arch Neurol 2002; 59: 1541–50. 10 Holloway R, Shoulson I, Kieburtz K, et al. Pramipexole vs levodopa as initial treatment for Parkinson disease: a randomized controlled trial. JAMA 2000; 284: 1931–38. 11 Whone AL, Watts RL, Stoessl AJ, et al. Slower progression of Parkinson’s disease with ropinirole versus levodopa: the REAL-PET study. Ann Neurol 2003; 54: 93–101. 12 Fahn S, Shoulson I, Kieburtz K, et al. Levodopa and the progression of Parkinson’s disease. N Engl J Med 2004; 351: 2498–508. 13 Schapira AH, Obeso J. Timing of treatment initiation in Parkinson’s disease: a need for reappraisal? Ann Neurol 2006; 59: 559–62. 14 Ravina BM, Fagan SC, Hart RG, et al. Neuroprotective agents for clinical trials in Parkinson’s disease: a systematic assessment. Neurology 2003; 60: 1234–40. 15 Kieburtz K. Issues in neuroprotection clinical trials in Parkinson’s disease. Neurology 2006; 66 (10 suppl 4): S50–57.
16 NINDS NET-PD Investigators. A randomized, double-blind, futility clinical trial of creatine and minocycline in early Parkinson disease. Neurology |
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