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CURRENT SCIENCE REVIEWS by Joe Bruman February 1997 p. 1 of 3 Olanow C, Riederer P, (eds):Neur 1996;47:Supp 3:137-218: Nine reviews covering everything ever done, tried, or said about Eldepryl (selegiline) for PD, by leading authorities. Subjects: -Pharmacology of selegiline -Natural history of Parkinson's Disease -Etiology of Parkinson's Disease, with emphasis on the MPTP story -Oxidative stress and pathogenesis of Parkinson's Disease -Modulation of gene expression vs. monoamine oxidase inhibition -Levodopa toxicity -Selegiline monotherapy in treatment of Parkinson's Disease -Selegiline in combination therapy of Parkinson's Disease -Neuroprotection and mortality issues related to selegiline Gerlach M et al;(ibid): Deprenyl (Eldepryl) was first developed as a novel antidepressant; later applied and promoted by W. Birkmayer as the well-known treatment for Parkinson's. Precise effects still not fully understood. Poewe W, Wenning G;(ibid): PD seems to progress faster in the preclinical and early stages than in the advanced stage. Levodopa relieves symptoms but its influence on progression remains controversial. Langston J;(ibid): Discovery of MPTP as a relatively straightforward cause of most PD symptoms caused a wave of searching for environmental factors, but none has been identified for sure as yet. Jenner P et al;(ibid): Oxidative stress is still considered (by some) as a major factor in PD, so the antioxidant properties (direct or indirect) of selegiline may make it useful in long-term treatment. Tatton W et al;(ibid): Reduction of oxidative damage to mitochondria may inhibit the apoptosis associated with the neurodegeneration of PD, but the protective role of (-)-Deprenyl in this is unlikely. Fahn S;(ibid): Levodopa may be toxic, maybe not. The answer bears on whether levodopa therapy should be started early or delayed as long as possible. Koller W;(ibid): Selegiline may be useful in conjunction with levodopa but is of little value by itself. Myllyla V et al;(ibid): Selegiline enhances the action of levodopa and reduces fluctuations of disability in advanced stages of PD. Olanow C;(ibid): Selegiline may have a neuroprotective effect to delay progression of PD. It also has been claimed to shorten survival duration. Probably "yes" on the first, "no" on the second point. CURRENT SCIENCE REVIEWS by Joe Bruman February 1997 p. 2 of 3 Rappert E et al;Neur 1996;47:1493-1495; In a double-blind test of liquid levodopa/carbidopa (Sinemet), 23 patients were able to take higher doses than with conventional tablet form, without penalty in dyskinesia. The liquid form permits a more constant level of the drug in plasma, and of dopamine in the brain. Ondo W, Jankovic J;Neur 1996;47:1435-1441: Authors studied 54 patients with "restless legs syndrome" (including some with PD and some with ET) to learn more about the etiology of RLS. 92% of those with idiopathic RLS had family history indicating autosomal dominance. Idiopathic and sporadic/ neuropathic RLS seem to be distinct etiologic groups, although both respond to levodopa/dopamine agonist therapy. Ramig L et al;Neur 1996;47:1496-1504: Authors compared the Lee Silverman Voice Treatment with placebo (respiration only) treatment in 35 PD patients, finding that LSVT yielded better and long-lasting speech improvement. Maraganore D et al;Neur 1996;47:1512-1517: Anticipation (earlier onset in successive generations) in familial PD of 33 related pairs may have resulted from referral or other bias, rather than a postulated gene defect. Eichhorn T et al;Neur 1996;47:1608-1609: Contrary to an earlier report, Ondansetron for L-dopa-induced psychosis was effective in only 2 of 7 PD patients, and not for long. Suggest formal comparison trial with clozapine, and meanwhile to try only if clozapine fails to work. Steiger M et al;J Neur N'surg Psych 1996;61:645-648: The motor pathways controlling axial movements differ from those controlling distal limb movements, and the two types of movement also are differently affected by the progression of PD. Many PD patients find trouble turning over in bed, and use limbs to assist the maneuver. Authors studied 32 PD patients (29 on H-Y scale of 3 or higher) by withholding levodopa to evoke the "off" state, then restoring it to regain the "on" state. They conclude that in late stages of PD at least some aspects of axial motor control remain levodopa-responsive. Toth M et al;Neur 1997;48:88-91: About half of PD patients lose weight, supposedly by expending more energy at rest than controls. But careful test of 16 patients (and 46 controls) showed that total expenditure is less, because of reduced physical activity. Kurth M et al;Neur 1996;48:81-87: Tolcapone prolongs the plasma half-life of levodopa, by inhibiting COMT, which destroys it. In a 6-week trial for efficacy and safety, 151 patients received 50, 200, or 400mg three times daily, or placebo. The drug reduced "off" time, prolonged "on" time, delayed end-of-dose effect, permitted lower overall levodopa dosage, and was well tolerated. CURRENT SCIENCE REVIEWS by Joe Bruman February 1997 P. 3 of 3 Blake C et al;Movem't Dis 1997;12:3-8: Little bodies within cells called mitochondria perform a series of reactions that enable the cell to carry out its intended function. Deficiency of the intermediate enzyme Complex I in substantia nigra cells of autopsied PD patients supports the oxidative stress hypothesis of PD etiology. Authors studied blood platelets from live patients and controls to look for other variables in the respiratory chain that might correlate with PD. Kyoko I et al;Movem't Dis 1997;12:9-16: Authors studied Complex IV in substantia nigra cells of autopsied PD patients and controls (see above) but conclude that defects are due to aging rather than PD. Ziv I et al;Movem't Dis 1997;12:17-23: >From study of levodopa in cultured chick neurons, authors found that levodopa is a potent inducer of apoptosis in those cells, and the effect is inhibited by antioxidants. Prochazka A et al;Movem't Dis 1997;12:24-32: Rigidity, one of the "classic triad" of PD symptoms, is usually assessed by qualitative and subjective judgement. Authors found that a simple physical measurement device is much more accurate. Antonini A et al;Movem't Dis 1997;12:33-38: Authors studied long-term changes in striatal D2 receptors of 9 PD patients and 10 controls by means of PET scans using the radioactive marker Raclopride. Lobbezoo F et al;Movem't Dis 1997;12:73-78: Bruxism (grinding or clenching teeth) during sleep is common in the general population. In trials on 10 PD patients, authors found that l-dopa inhibits sleep bruxism. Zappia M et al;Movem't Dis 1997;12:103-106: Measurement of movement time (in a standard motor test) after a large dose (250mg) of levodopa, in 74 PD patients who had been under treatment and 21 de novo patients, accurately predicted the long- term responsiveness to levodopa. Negrotti A, Calzetti S;Movem't Dis 1997;12:107-110: Parkinsonism induced by the calcium antagonists Cinnarizine or Flunarizine in 13 elderly patients persisted for 7 years or more after withdrawal of the offending drug. Gwynn K, Caviness J;Movem't Dis 1997;12:119-121: A 69-yr-old paychiatric patient developed tardive (delayed) dyskinesia and other parkinsonian symptoms 3 weeks after withdrawal of the neuroleptic Risperidone. Symptoms persisted until interruption of follow-up 4 weeks later. Creange A et al;Movem't Dis 1997;121-123: A case of parkinsonism associated with Sjogren's syndrome (exocrine gland impairment). Krauss J et al;Movem't Dis 1997;12:124-126: Rather severe symptoms of a long-term PD patient improved after an ischemic stroke in the subthalamic area and internal capsule. J. R. Bruman (818) 789-3694 3527 Cody Road Sherman Oaks CA 91403