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.
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J. R. Bruman   (818) 789-3694
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