Mais les résultats doivent être attendus longtemps et il n'y a généralement pas de temps amoxicilline prix L'autre cas, c'est que l'achat d'un ou d'un autre antibiotique dans une pharmacie classique nécessite des dépenses matérielles considérables et pas toutes les personnes ne peuvent acheter des produits pharmaceutiques aussi coûteux.
022-024_Hirose_JON_S_03_06 20.07.2006 8:52 Uhr Seite 22
J Neurol (2006) 253 [Suppl 3]: III/22–III/24DOI 10.1007/s00415-006-3004-8
G. Hirose, M.D., Ph.D. (౧)Department of Neurology
Tel.: +81-76/252-2101Fax: +81-76/252-2102
vation led to the most important discovery that identi-
fied markedly depleted DA, one of the catecholamines,as the pathogenesis of PD. This discovery automatically
Drugs that either block dopamine receptors or deplete
led to the development of L-dopa for treating patients
dopamine storage produce a functional dopaminergic
deficient state, and hence cause clinical symptoms that
Parkinsonian symptoms induced by neuroleptics or
mimic idiopathic Parkinson’s disease (PD). Historically,
dopamine depleting drugs cannot be distinguished clin-
the emergence of this typical drug-induced parkinson-
ically from those seen in PD. The main symptoms of DIP
ism (DIP) after the use of phenothiazines was reported
are akinesia/bradykinesia and rigidity, which appear in
shortly after introduction of the drug in the early 1950s.
limbs bilaterally rather than unilaterally in a rapidly
Soon the relationship between parkinsonian symptoms
progressive fashion. Masked face and reduced blinking
and dopamine (DA) deficiency became apparent among
are also noted. Rigidity is less frequent, with cogwheel
patients who were treated with neuroleptics. This obser-
rigidity usually observed symmetrically in both limbs.
022-024_Hirose_JON_S_03_06 20.07.2006 8:52 Uhr Seite 23
Tremor is the least common of the major clinical symp-
roleptics blocks the receptors in only between 38 and
toms, usually seen symmetrically in both hands during
63 % of cases . This D2 receptor occupancy clearly
posture and action. A pill-rolling tremor at rest, a char-
explains the appearance of DIP and more than 80 % oc-
acteristic symptom of PD, is very rare among patients
cupancy of D2 receptors always causes parkinsonism
with DIP. Postural instability due to decreased response
while less than 80 % occupancy does not usually cause
to body displacements results in loss of balance and
DIP. The occupancy of regular doses of clozapine and
falls. Flexed posture is another abnormality, which is
other atypical neuroleptics is less than 60–70 %. But
probably due to truncal rigidity. Arm swing is also re-
higher dosage of atypical neuroleptics, if used, produces
duced and shuffling is quite common while walking.
increased D2 blocking, resulting in parkinsonism. The
There is a tendency to run forward with small steps.
mechanism of action of atypical neuroleptics has been
DIP usually appears later than akathisia and dystonia
studied in more detail. The degree of receptor binding of
after taking neuroleptics with 50 % of cases within the
classical antipsychotics is much tighter than that of
first 30 days and 90 % within 72 days . But Freyhan re-
atypical neuroleptics . Radioactive haloperidol and
ported that the majority of patients developed parkin-
chlorpromazine dissociated very slowly over a 30 min-
sonian symptoms before the 20th day , and Medinar
utes time span, whereas radioactive clozapine and que-
found parkinsonism within the first week . Patients
tiapine dissociated rapidly in less than 60 seconds. This
treated with lower doses of neuroleptics or antiparkin-
phenomenon is called the “fast-off-D2” theory .
sonian drugs improve over a period of 7–8 weeks, but
Therefore, atypical neuroleptics will clinically help pa-
some of the parkinsonian symptoms continue in 50 % of
tients by transiently occupying D2 receptors and rapidly
the patients with DIP despite anticholinergic drug treat-
dissociating to result in normal dopamine neurotrans-
ment. Some of these patients later develop or transform
to PD, probably reflecting early subclinical dopaminer-
Another hypothesis of the atypicality of newer an-
gic deficiency prior to administration of neuroleptics.
tipsychotics is that these drugs block 5-HT2A receptorsas well as D2 receptors . The inhibitory action of 5-HT2A receptors on DA secretion can be blocked by atyp-
icals, hence higher endogenous dopamine concentra-tion is available at dopaminergic terminals which helps
The incidence of DIP in the general population is re-
dopamine transmission. However, this serotonin-
ported to be 20 % of patients with parkinsonism, less
dopamine balance theory has not yet been proved sci-
than half of PD cases . The incidence of DIP among
patients taking neuroleptics varies from 15 to 40 %, de-
The newer calcium-entry blockers, such as flunar-
pending upon the type and dose of neuroleptics .
izine and cinnarizine are structurally related to neu-
According to the epidemiological study by Ayd, three
roleptics such as piperazine derivatives. These drugs
risk factors for DIP were identified, namely old age, fe-
have been well documented as a cause of DIP. The
male gender, and the use of potent neuroleptics .
elderly are particularly vulnerable to these agents. The-
Many patients who develop DIP have had a predisposing
oretical explanations of this include the inhibition of
subclinical depletion of DA and recent reports support
calcium entry into striatal neurons and direct dopamin-
this explanation [6, 7]. DIP may remit spontaneously
ergic blocking effects. It was recently proved that D2 re-
without any change in the dose of neuroleptics, and the
ceptor-binding potential was blocked and reduced to
long-term effects of neuroleptics may be different from
14–63 % by 131I-benzamide SPECT study . Older age
the acute effect of DA receptor blocking.
and long-term use of the agents are predisposing factorsfor this illness and preexisting basal ganglia dysfunctiondue to old age, and vascular disease can explain why DIP
DIP is usually dose-dependent for each potent neu-roleptic drug, and all patients eventually would develop
DIP if high enough doses of the drugs were used. Thiswas studied extensively by the recent use of PET with se-
Treatment of DIP should be considered, if disabling
lective radioactive ligands, and now we know that DA re-
parkinsonian symptoms are observed. Those patients
ceptor occupancy is directly related to parkinsonism
usually need antipsychotic drugs for a primary psychi-
[8–10]. The mechanism of action of neuroleptics is hy-
atric illness, therefore the dose of neuroleptics should be
pothesized to be related to the degree of D2-dopamine
checked carefully and, if overdosed, the first approach is
receptor occupancy. This was confirmed by several re-
to reduce the responsible dopamine D2 blocking agents
ports that regular doses of classical neuroleptics block
or switch to less potent drugs. If it is impossible to stop
D2 receptors in 70–89 % of cases, while atypical neu-
or change the drugs because of the degree of psychiatric
022-024_Hirose_JON_S_03_06 20.07.2006 8:52 Uhr Seite 24
illness, then anticholinergic drugs or amantadine
fewer anticholinergic side effects . Promethazine
should be considered to ameliorate DIP. Elderly patients
may be tried for patients with akathisia as well as DIP
can gain more benefit from amantadine because of
because of its strong antihistaminic effect.
7. Burns DJ, Brooks DJ (1993) Nigral dys-
8. Farde L, Wiesel FA, Nordström AL et al.
13. Meltzer HY, Li Z, Kaneda Y, Ichikawa J
role in drugs to treat schizophrenia.
ventional and atypical neuroleptics.
9. Farde L, Nordström AL, Wiesel FX et al.
14. Brucke T, Wobler C, Podreka I et al.
10. Nyberg S, Dencker SJ, Malm U et al.
occupancy in high-dose neuroleptic-treated patients. Int J Neuropsycho-pharmacol 1:95–101
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