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CURRENT SCIENCE REVIEWS By Joe Bruman Aug 1998 P. 1 of 4 Fahn S et al; Neur 1998;50S5:1-38: This supplement documents a special session on Tolcapone during the 4th International Congress on Movement Disorders, Vienna, 16-21 June 1996. Contributing authors are: Fahn S; Introduction and summary Kurth M, Adler C; Strategy of COMT inhibition Goetz C; Highlights of study results " Pharmacology of COMT inhibiton Chase T; Nonphysiologic dopamine replacement Jorga K; Pharmacology of Tolcapone Waters C et al; Tolcapone efficacy and safety Baas H et al; Reduction of wearing-off fluctuation Rajput A et al; Improvement of motor function Some of the articles are reprints, creating a catalog nightmare. Fahn S; Neur 1998;50S5:1-2: Since catechol-O-methyl transferase (COMT) is present both peripherally and in the brain, it metabolizes levodopa in the systemic (peripheral) circulation, and both levodopa and dopamine in the central nervous system (CNS). Kurth M, Adler C; Neur 1998;50S5:S3-S14: COMT inhibitors as adjuncts to levodopa therapy increase its availability to enter the brain and prolong "on" time by extending its half-life. Goetz C; Neur 1998;50S5:S15-S16: Tabular results and summary of a large controlled Tolcapone trial in North America and another in Europe, demonstrating its efficacy and safety. Chase T; Neur 1998;50S5:S17-S25: Effect of dopamine replenished by levodopa therapy may differ from that of endogenous supply. Chronic intermittent stimulation of DA receptors on striatal GABA-ergic neurons may sensitize adjacent NMDA receptors, leading to complications of long-term levodopa therapy. DA mimics (agonists) might be better. Goetz C; Neur 1998;50S5:S26-S30: Some COMT inhibitors cross the blood-brain barrier (Tolcapone) and some don't (Entacapone). Implications for therapy. Jorga K; Neur 1998;50S5:S31-S38: Pharmacokinetics, pharmacodynamics, and tolerability of Tolcapone as learned from early studies in healthy volunteers. Waters C et al; Neur 1997;49:665-671 (also in 50S5:S39ff): A 20-center controlled trial demonstrated Tolcapone long-term efficacy and safety, as well as benefit in early-stage PD. Baas H et al; J Neur N'surg Psych 1997;63:421-428 (also Neur): In a multicenter controlled trial, COMT inhibition with Tolcapone reduced the "wearing-off" phenomenon and levodopa requirement in fluctuating PD patients. Rajput A et al; Neur 1997;49:1066-1071: In a multi-center controlled trial, Tolcapone improved motor function in PD patients having the "wearing-off" phenomenon. CURRENT SCIENCE REVIEWS By Joe Bruman August 1998 p. 2 of 4 Koller W et al; Neur 1998;50S6:1-48: This supplement documents a 20-22 March 1997 conference in England of 11 U.S. and European research leaders on "Current and Emerging Drug Therapies in Management of Parkinson's Disease". Papers contributed are: Koller W, Tolosa E; Introduction and summary Tolosa E et al; History of levodopa and DA agonists Koller W, Rueda M; Mechanism of dopaminergic action Capildeo R; Sinemet CR vs. regular Sinemet Silver D, Ruggieri S; Initial therapy strategy Poewe W; Dopamine agonists as adjunct therapy Martinez-Martin, O'Brien C; COMT inhibition Lieberman A; Neuropsychiatric management Jenner P, Brin M; Levodopa neurotoxicity (all); Round-table discussion Tolosa E et al; Neur 1998;50S6:S2-S10: Discovery in 1960 of dopamine deficit in PD led to Birkmayer's successful trial, but value of oral levodopa wasn't confirmed until 1967 (by Cotzias). Apomorphine was tried in 1970 but didn’t become popular because of side effects. First successful agonist was bromocriptine in 1974; carbidopa/levodopa arrived in 1975. Koller W, Rueda M; Neur 1998;50S6:S11-S14: Levodopa is now given routinely with a decarboxylase inhibitor, and COMT inhibitors are newly introduced. To avoid complications of levodopa conversion, storage, and release, dopamine agonists can act directly on postsynaptic receptors with similar effect. Capildeo R; Neur 1998;50S6:S15-S17: Long-term adverse effects of levodopa are not fully confirmed, but sustained-release (CR) formulation was developed to simulate nature better by reducing fluctuation of plasma level. In a 5- yr multicenter trial it also reduced fluctuation of PD symptoms. Silver D, Ruggieri S; Neur 1998;50S6:S18-S22: Aims of therapy, and therefore initial drug strategy, depend on the age of the patient, but opinion varies widely as well. For under 50 they prefer selegiline, amantadine, anticholinergics. For those in their 50s, perhaps a dopamine agonist. For those over 60, avoid the first three because of cognition risks, and start with carbidopa/levodopa. Includes a decision tree. Poewe W;Neur 1998;50S6:S23-S26: Discussion of agonists in conjunction with levodopa therapy. Martinez-Martin P, O'Brien C; Neur 1998;50S6:S27-S32: The new drugs entacapone, nitacapone, and tolcapone inhibit catechol-o-methyl transferase (COMT), an enzyme that degrades levodopa peripherally. Tolcapone also can somewhat cross the blood-brain barrier to inhibit COMT centrally. COMT inhibitors prolong response to levodopa and reduce motor fluctuations. Lieberman A; Neur 1998;50S6:S33-S38: About 27% of PD patients are demented, another 19% suffer cognitive impairment without dementia. About 40% of all PD patients are depressed, and 40% have anxiety or panic attacks. Discusses diagnosis and management of those symptoms. CURRENT SCIENCE REVIEWS By Joe Bruman August 1998 p. 3 of 4 Jenner P, Brin M; Neur 1998;50S6:S39-S45: Lab studies of levodopa neurotoxicity don't agree with clinical experience. Levodopa doesn't seem to harm dopamine cells either in healthy subjects or PD patients, but might add to oxidative stress in the latter. It doesn't appear toxic either to fetal neurons or to transplanted neurons, but definitive clinical trials are only currently beginning. Schneider J et al; Neur 1998;50:1630-1636: Encouraged by a prior open-label trial of ganglioside GM1, they did a controlled trial on 45 patients with mild to moderate PD. Results were again positive and they want to continue. Hocherman S, Giladi N; Neur 1998;50:1648-1654: They tested visuomotor control of hand movement in PD patients, finding that both direction and velocity impairment appeared before onset of the usual PD motor symptoms. Kuhn W et al; Neur 1998;50:1885-1886: Seven of nine postal workers exposed long-term to lead-sulfate batteries developed PD symptoms. Authors don't know whether the culprit was lead, the sulfur compounds, or something else. Maricle R et al; Neur 1998;50:1890-1892: In study of 18 PD patients in the first year of levodopa therapy they found mood elevation following infusion. The effect was greatest after a 2-day levodopa holiday, at the 6-month and 12-month assessments. Vatassery G et al; Neur 1998;50:1900-1902: Contrary to conventional wisdom, alpha-tocopherol (vitamin E) levels in the cerebrospinal fluid (CSF) of PD patients given large doses in the DATATOP study did rise, showing that it can pass the blood-brain barrier after all. [Since vitamin E is a potent antioxidant, this suggests it might be useful in PD.] Thulin P et al; Neur 1998;50:1920-1921: Concentration of levodopa in breast milk of a 25-yr-old PD patient on moderate dosage of Sinemet, and nursing a healthy 4.5-mo infant, was measurable but far below cause for concern. Matthews M et al; Neur 1998;50:1933-1934: Ginkgo Biloba in a few anecdotal reports has antiplatelet property which has led to brain and other hemorrhage. Should be avoided expecially by those on warfarin, aspirin, or other anticoagulants. Verhagen Metman L et al; Neur 1998;51:203-206: The widely used antitussive dextromethorphan (DM) is also an antagonist of the glutamate N-methyl-D-aspartate (NMDA), which is thought to be related to PD. In a controlled double-blind trial on 6 PD patients at the motor fluctuation stage, DM improved levodopa-induced dyskinesia without compromising the efficacy of levodopa. Trepanier L et al; Neur 1998;51:207-215: Neuropsychologic follow-up of 42 posteroventral pallidotomy recipients showed changes, generally negative, in cognitive and emotional function. CURRENT SCIENCE REVIEWS By Joe Bruman August 1998 p. 4 of 4 Trepanier L et al; Arch Neur 1998;55:881-883: Exchange of letters debating whether persistent cognitive effects follow unilateral posteroventral pallidotomy. A variety of neuropsychological test studies was inconclusive. Vale S; Lancet; 4 Jul 1998:36: Ginkgo Biloba extract, an OTC herbal product said to improve mental alertness, apparently caused mild brain hemorrhage in a man of 61, who recovered only upon stopping its use. Clarke P; Lancet; 11 Jul 1998:84-85: The mesolimbic dopamine system of the brain [associated with pleasure sensation] plays an important part in nicotine addiction, and a genetic anomaly in that system may account for individual variations in susceptibility. Chio A et al; Mov Disord 1998;13:400-405: "Tracer" surveys based on registered levodopa prescriptions have some limited use in surveys to determine the incidence of PD, but don't substitute for clinical examinations. Przedborski S, Jackson-Lewis V; Mov Disord 1998;13S1:35-58: Detailed analysis of MPTP toxicity as a possible clue to understanding the neurodegeneration of PD. Louis E et al; Arch Neur 1998;55:823-828: Although Essential Tremor (ET) is much more common than PD, its prevalence is poorly known. To test criteria for use in population surveys, they studied a cohort within a limited area. Information on tremor type and severity proved to be more pertinent than family history. van der Geest R et al; Clin Neuropharm 1998;21:159-168: Careful assay of pharmacokinetics, enantiomer* conversion, and metabolism of R-apomorphine in 10 PD patients showed, among other things: average plasma half-life 41 min, no expected interaction with COMT inhibiitors. *(mirror-image) Sawada H et al; Ann Neur 1998;44:110-119: Preincubation with D2-type agonists (e.g., bromocryptine) protects mesencephalic neurons against the oxidative stress of glutamate-induced neurotoxicity. -- J. R. Bruman (818) 789-3694 3527 Cody Road Sherman Oaks, CA 91403-5013