J Neurochem. 2004 Dec;91(5):1075-81.
Pramipexole protects against apoptotic
cell death by non-dopaminergic mechanisms.
Gu M, Iravani MM, Cooper JM, King D, Jenner P, Schapira AH.
Royal Free and University College Medical School, University College
London, London, UK.
We have investigated the ability of pramipexole, a dopamine agonist
used in the symptomatic treatment of Parkinson's disease (PD), to
protect against cell death induced by 1-methyl-4-phenylpyridinium
(MPP+) and rotenone in dopaminergic and non-dopaminergic cells.
Pre-incubation with either the active (-)- or inactive (+)-enantiomer
forms of pramipexole (10 microm) decreased cell death in response
to MPP+ and rotenone in dopaminergic SHSY-5Y cells and in non-dopaminergic
JK cells. The protective effect was not prevented by dopamine receptor
blockade using sulpiride or clozapine. Protection occurred at concentrations
at which pramipexole did not demonstrate antioxidant activity, as
shown by the failure to maintain aconitase activity. However, pramipexole
reduced caspase-3 activation, decreased the release of cytochrome
c and prevented the fall in the mitochondrial membrane potential
induced by MPP+ and rotenone. This suggests that pramipexole has
anti-apoptotic actions. The results extend the evidence for the
neuroprotective effects of pramipexole and indicate that this is
not dependent on dopamine receptor occupation or antioxidant activity.
Further evaluation is required to determine whether the neuroprotective
action of pramipexole is translated to a disease-modifying effect
in PD patients.
Depress Anxiety. 2004;20(3):131-8. Pramipexole in treatment-resistant depression:
an extended follow-up.
Cassano P, Lattanzi L, Soldani F, Navari S, Battistini G, Gemignani
A, Cassano GB.
Department of Psychiatry, Neurobiology, Pharmacology and Biotechnology,
University of Pisa, Pisa, Italy.
We evaluated the long-term antidepressant safety and response
of adjunctive pramipexole, a D2-D3 dopamine agonist, in the course
of drug-resistant depression. Twenty-three patients with treatment-resistant
major depressive episode (MDE) were followed up after a 16-week
pramipexole add-on trial. Pramipexole was added to current treatment
with TCA or SSRI, at increasing doses from 0.375-1.500 mg/day.
The LIFE scale was administered at baseline of the acute trial,
at Weeks 16, 32, and 48. Patients were analyzed for sustained
remission (score= <2 at LIFE for at least 8 weeks) and recurrence
(after remission score > =3 at LIFE for at least 2 weeks) of
depression. Of 23 patients, 12 had major depression and 11 had
bipolar depression (16 women; mean age=52.8 years). Mean age of
onset and median duration of current MDE were 35.1 years and 6
months, respectively; all subjects had at least two prior MDEs.
Mean pramipexole dose was 0.990 mg/day. Median duration of follow-up
was 28 weeks. Mean baseline MADRS and CGI-S scores were 33.7+/-8.4
(sd) and 4.6+/-0.8, respectively. Median time to sustained remission
from baseline was 10 weeks and overall 60.9% (14/23) of subjects
recovered within Week 22. Recurrence of depression occurred in
35.7% (5/14) of remitters after Week 24 and within Week 28 from
remission. Although there were no sleep attacks, two cases of
hypomania and one case of psychotic mania occurred at Weeks 22,
24, and 30, respectively. Pramipexole augmentation of antidepressant
treatment was relatively safe and presumably effective in the
long-term course of treatment resistant depression. (c) 2004 Wiley-Liss,
Inc.
Neuropsychobiology. 2004;50(1):65-70. Low-dose pramipexole in the management
of restless legs syndrome. An open label trial.
Stiasny-Kolster K, Oertel WH.
Department of Neurology, Center of Nervous Diseases, Philipps University,
Marburg, Germany.
Dopaminergic agents are considered the treatment of choice for restless
legs syndrome (RLS); levodopa is the only substance licensed for
this disorder in some European countries. However, in a substantial
proportion of patients symptoms are not adequately controlled for
a whole night due to the short half-life of levodopa or because
symptom augmentation may develop. To further investigate the impact
of pramipexole on the management of RLS we performed a short-term
open label trial with pramipexole in 17 patients who were being
insufficiently treated with levodopa or for whom pramipexole was
primarily being considered because of the severity of the RLS symptoms.
A single dose of 0.125-0.75 mg pramipexole (mean 0.3 +/- 0.2 mg)
in the evening resulted in a significant improvement of subjective
RLS symptoms as rated by the International RLS Study Group Severity
Scale (IRLS scores: 29.8 +/- 4.7 baseline vs. 7.3 +/- 5.9 endpoint;
p = 0.0001). Polysomnographic recordings showed a significant improvement
of the periodic leg movements (PLM) index, PLM sleep arousal index,
sleep-onset latency, total sleep time and sleep efficiency. All
patients who had developed a worsening of RLS symptoms under levodopa
recovered from daytime symptoms after their medication was switched
to pramipexole. Since pramipexole was well tolerated, an ideal dosage
to control RLS symptoms could be reached rapidly. Pramipexole has
proven a suitable alternative in patients with moderate to severe
RLS, particularly when their therapy has to be switched to a dopamine
agonist.
Zh Nevrol Psikhiatr Im S S Korsakova. 2004;104(1):24-30.
A comparative study of efficacy of dopamine
receptors agonists and catechol-O-methyltransferase in the treatment
of late stages of Parkinsons disease.
Krivonos OV, Fedorova NV, Chigir IP.
Dopamine receptors agonists and catechol-O-methyltransferase (COMT)
inhibitors are the novel classes of the drugs for Parkinson's
disease (PD) treatment in both early and late stages. In the latter
one, there is an increase of substantia nigra neurons degeneration,
striatum denervation, changes of dopamine receptors state, dysregulation
of Levadopa uptake, dopamine synthesis and storage, decrease of
dopamine receptors density in striatum that results in clinical
picture alteration and development of pharmaco-therapeutic side-effects,
as well as motor fluctuations and drug diskinesias. The use of
dopamine receptors agonists and COMT inhibitors at the late PD
stages in combination with other antiparkinsonian medications
allows improving pharmaco-therapeutic efficacy, along with patient's
daily activity and quality of life.
Neurology. 2003 Nov 25;61(10):1418-20. The effects of pramipexole in REM sleep
behavior disorder.
Fantini ML, Gagnon JF, Filipini D, Montplaisir J.
Centre detude du sommeil et des rythmes biologiques, Hopital du
Sacre-Coeur, Montreal, Canada.
The authors evaluated the effects of pramipexole, a dopaminergic
D2-D3 receptor agonist, on eight patients with idiopathic REM
sleep behavior disorder. Five patients reported a sustained reduction
in the frequency or intensity of sleep motor behaviors, which
was confirmed by video recording, although no change was observed
for the percentage of phasic EMG activity during REM sleep. Surprisingly,
a decrease in the percentage of time spent with REM sleep muscle
atonia was observed with treatment. The treatment did not modify
the indexes of periodic leg movements.
J Neurol Sci. 2003 Dec 15;216(1):81-7. Efficacy, safety, and tolerability of pramipexole
in untreated and levodopa-treated patients with Parkinson's disease.
Wong KS, Lu CS, Shan DE, Yang CC, Tsoi TH, Mok V.
Department of Medicine and Therapeutics, The Chinese University
of Hong Kong, Hong Kong.
OBJECTIVE: To evaluate the efficacy and safety of the non-ergot
dopamine agonist pramipexole in untreated and levodopa-treated
Chinese patients with early or advanced Parkinson's disease. METHODS:
This randomized, double-blind, placebo-controlled, parallel-group
study, which was conducted in Hong Kong and Taiwan, comprised
a screening period of at least 1 week, a dose-escalation period
of 7 weeks, and a maintenance period of 8 weeks (total duration
of treatment: 15 weeks). During the dose-escalation period, the
dose of pramipexole (or number of placebo tablets) was escalated
in a blinded fashion according to a predetermined schedule to
the optimum tolerated dose of pramipexole, administered three
times a day (minimum dose=0.375 mg/day; maximum dose=4.5 mg/day).
This dose was then maintained for the duration of the maintenance
period. Efficacy was primarily assessed by the Unified Parkinson's
Disease Rating Scale (UPDRS). Safety and tolerability were evaluated
by treatment-emergent adverse event reports, clinical laboratory
test results (blood chemistry, hematology, and urinalysis), vital
signs, and electrocardiograms. RESULTS: Pramipexole was significantly
more effective than placebo in reducing the total scores of the
UPDRS Part II, Part III, and Parts II and III combined. Approximately
70% of both the placebo- and pramipexole-treated patients evaluated
in this analysis were on levodopa. Regardless of levodopa use,
the mean UPDRS total scores showed a consistently greater improvement
in pramipexole patients than in placebo patients. Mean scores
for pramipexole patients not on levodopa showed a greater improvement
than did pramipexole patients on levodopa. The mean improvement
for the pramipexole/no levodopa group relative to the placebo/no
levodopa group at week 15 was 10.93 points (i.e., -14.43 points
minus -3.50 points). The mean improvement for the pramipexole/levodopa
group relative to the placebo/levodopa group at week 15 was 9.04
points (i.e., -10.26 points minus -1.22 points). Pramipexole was
also superior to placebo as measured by improvement in the modified
Hoehn and Yahr Scale and a reduction in the number of "off"
hours for patients on concomitant levodopa therapy. CONCLUSIONS:
Pramipexole is an effective and well-tolerated therapy, with or
without concomitant levodopa, for Chinese patients with Parkinson's
disease.
CNS Drugs. 2003;17(13):965-73. Pramipexole in routine clinical practice:
a prospective observational trial in Parkinson's disease.
Reichmann H, Brecht MH, Koster J, Kraus PH, Lemke MR.
Department of Neurology, Technical University of Dresden, Dresden,
Germany.
OBJECTIVE: The mixed dopamine D2/D3 receptor agonist pramipexole
is effective as monotherapy in early Parkinson's disease and as
adjunctive therapy in advanced disease. Clinical trials suggest
that the benefits of pramipexole may extend beyond the relief
of motor symptoms (akinesia, rigidity and tremor at rest) to amelioration
of depressive symptoms in Parkinson's disease. The aim of this
study was to confirm the beneficial effects of pramipexole on
the core symptoms of Parkinson's disease (with a focus on tremor),
as well as to assess its antidepressant activity, during routine
clinical practice. The study also aimed to demonstrate the practicability
of the Snaith-Hamilton Pleasure Scale (SHAPS-D), the Tremor Impact
Scale (TIS) and the Short Parkinson's Evaluation Scale (SPES)
under conditions of routine clinical practice. STUDY DESIGN: This
was a prospective observational study. PATIENTS: Data for 657
outpatients with Parkinson's disease were collected from German
hospitals and specialist practices. The majority of patients were
in Hoehn & Yahr stage II or III and were receiving levodopa.
METHODS: Pramipexole (Sifrol) was initiated at a dosage of 0.375
mg/day (using a three-times-daily schedule) and titrated upwards,
as required, at weekly intervals over a 4-week period to a maximum
dosage of 4.5 mg/day (three times daily). Clinical evaluation
was performed at baseline, at the end of the titration phase and
at the end of maintenance therapy. Patients were assessed via
the German questionnaire versions of the physician-assessed SPES,
the self-evaluated TIS and the SHAPS-D. Changes in scale scores
were evaluated nonparametrically, using the Wilcoxon-matched pairs
test. Cronbach's alpha was used as a measure for item consistency.
RESULTS: Pramipexole significantly improved SPES subscores for
motor symptoms, complications of therapy, psychological status
and activities of daily living. Pramipexole also reduced the detrimental
effect of tremor on activities of daily living and social interactions,
as assessed by patients via the TIS. As indicated by the results
of the SHAPS-D questionnaire, pramipexole significantly reduced
anhedonia in patients who had associated depression. Internal
consistency of SPES subscales was found to be unaltered between
the initial evaluation and follow-up. Likewise, internal consistency
for TIS and SHAPS-D was demonstrated. Pramipexole was well tolerated
and accepted by the vast majority of physicians and patients.
CONCLUSION: In addition to ameliorating the core symptoms of akinesia
and rigidity in Parkinson's disease, pramipexole improves tremor
and depressive symptoms in routine clinical practice. The SPES,
TIS and SHAPS-D were found to be useful instruments with validity
in this study.
Eur J Neurol. 2003 Jul;10(4):399-406. Pramipexole and pergolide in the treatment
of depression in Parkinsons disease: a national multicentre prospective
randomized study.
Rektorova I, Rektor I, Bares M, Dostal V, Ehler E, Fanfrdlova
Z, Fiedler J, Klajblova H, Kulist'ak P, Ressner P, Svatova J,
Urbanek K, Veliskova J.
First Department of Neurology, Masaryk University, St Annes Teaching
Hospital, Brno, Czech Republic.
An 8-month multicentre prospective randomized study aimed at comparing
the effects of dopamine receptor agonists pramipexole (PPX; Mirapexin)
and pergolide (PRG; Permax) as add-on to L-dopa therapy on depression
[Montgomery and Asberg Depression Rating Scale (MADRS)] in 41
non-demented patients (25 men, 16 women) suffering from both mild
or moderate depression and advanced Parkinson's disease (PD).
The assessment was performed by a blinded independent observer.
Motor symptoms (UPDRS III), motor complications (UPDRS IV), activities
of daily living (UPDRS II and VI) and depressive symptoms as measured
by Self - Rating Depression Scale by Zung were evaluated in an
open-label design. The average value of Zung scores decreased
significantly in both groups with no statistical difference between
both groups. A significant decrease in the average value of MADRS
scores was present only in the PPX group. The average UPDRS scores
decreased significantly with no statistical difference between
both groups at the comparable average total daily dose of both
preparations. In both cases, the total daily dose of L-dopa decreased
significantly but the decrease was statistically more pronounced
in the PRG group. Our results demonstrate the antidepressant effect
of PPX in patients with PD while we can't make any conclusions
with regard to antidepressant effect of PRG.
Funct Neurol. 2002 Oct-Dec;17(4):199-201. Pramipexole in Parkinsons disease. A short-term
study using the combined levodopa-dopamine agonist test.
Fabbrini G, Barbanti P, Aurilia C, Pauletti C, Meco G.
Department of Neurosciences, University of Rome La Sapienza, Italy.
The aim of our study was to investigate the efficacy of pramipexole
in advanced parkinsonian patients by means of an acute stimulation
test. We studied the motor effects of pramipexole in fluctuating
parkinsonian patients by comparing the response to acute levodopa
with the response to levodopa + pramipexole. The adjunct of pramipexole
to levodopa increased the time spent on from 136 +/- 22.3 to 186
+/- 20.6 minutes (p<0.01), while it did not change the latency
to on, the magnitude of the motor improvement, or the duration
and severity of dyskinesias. The main effect of pramipexole in
fluctuating parkinsonian patients is an increased duration of
the on phase.
Nervenarzt. 2002 Aug;73(8):745-50. Pramipexole in Parkinson disease. Results
of a treatment observation.
Reichmann H, Brecht HM, Kraus PH, Lemke MR.
Klinik und Poliklinik fur Neurologie, Universitatsklinikum Carl
Gustav Carus, Technische Universitat Dresden, Fetscherstrasse
74, 01307 Dresden.
Pramipexole is a novel, internationally available selective nonergot
D2 dopamine agonist. The effectiveness, tolerability, and safety
of pramipexole have been extensively proven in controlled trials
in patients in the early and advanced stage of Parkinson's disease
as monotherapy and in combination with L dopa. These trials indicated
specific activity against tremor, anhedonia, and depression. Therefore,
the present prospective, multicenter postmarketing surveillance
study evaluated for the first time to what extent the results
from the controlled pramipexole trials could be replicated under
routine conditions in neurological practice and clinics. Modern
scales were applied for the assessment of tremor and mood, i.e.,
the Short Parkinson's Evaluation Scale (SPES), the Tremor Impact
Scale (TIS), and the German version of the Snaith-Hamilton Pleasure
Scale (SHAPS-D). In 298 German Centers, 657 Parkinson's patients
(365 men, 292 women) in advanced disease stages were treated with
pramipexole in combination with levodopa. The average ages (+/-
SD) were 67 (+/- 8.9) years for men and 69 (+/- 9.4) years for
females. Motor functioning, especially tremor, motor complications,
depression, and activities of daily living improved highly significantly
(P < 0.0005), including self-rating by the patients. The dosage
of levodopa could be reduced on average by 8% (P < 0.0001).
This might contribute to a slowing of the disease progression
in the long run. Dropouts due to side effects were observed only
in 3.5% of the patients. Using new assessment scales suitable
for routine application allowed confirmation of the results from
controlled clinical trials with regard to tremor, anhedonia, and
depression. The average daily dosage of pramipexole prescribed
was 1.05 mg and thus was definitely lower than the average daily
dosages of 2.35-2.66 mg used in controlled trials. This signifies
that the option to adjust dosage according to effectiveness and
tolerability under routine conditions yields a considerably lower
incidence of adverse effects.
J Neurol Neurosurg Psychiatry. 2002 Jun;72(6):713-20.
Pramipexole in patients with Parkinson's
disease and marked drug resistant tremor: a randomised, double
blind, placebo controlled multicentre study.
Pogarell O, Gasser T, van Hilten JJ, Spieker S, Pollentier S,
Meier D, Oertel WH.
Department of Neurology, Philipps-University of Marburg, Marburg,
Germany.
OBJECTIVE: To compare the tremorlytic properties of pramipexole,
a non-ergoline dopamine agonist to those of placebo as add on
medication in patients with Parkinson's disease. METHODS: Eighty
four patients with early or advanced Parkinson's disease and marked,
drug resistant tremor under a stable and optimised antiparkinsonian
medication were included in a double blind, randomised, placebo
controlled, multicentre study and assigned to add on treatment
(7 week dose titration interval, 4 week maintenance period) with
either pramipexole (n=44) or placebo (n=40) as adjunct. The primary
end point was the absolute change in tremor score, defined as
the sum of tremor related items (16, 20, 21) of the unified Parkinson's
disease rating scale (UPDRS) in "on" periods. Secondary
end points included the percentage change in tremor score, the
absolute and percentage changes in long term EMG tremor registration,
and the change in tremor self rating scales. Safety and tolerability
were assessed on the basis of adverse events, laboratory tests,
ECG, and vital signs. RESULTS: Pramipexole was significantly superior
to placebo with a difference between treatment groups in the mean
absolute change in tremor score of -4.4 (95% confidence interval
(95% CI) -6.2 to -2.5) (p<0.0001), corresponding to a difference
in the mean percentage change of -34.7% in favour of pramipexole.
The secondary end points were consistent with the significant
change in tremor score and provided further evidence for the benefit
of pramipexole compared with placebo. Long term EMG registration
as an objective measure showed a difference in mean absolute change
in tremor occurrence of -15.2% (95%CI -21.4 to -9.0) (p<0.0001),
and a difference in the mean percentage change of -45.7% in favour
of pramipexole. The treatment effects increased during dose titration
and remained stable during the 4 week maintenance dose period
until the end of the study. The average daily pramipexole dose
during maintenance was 4.1 (SD 0.9) mg. Safety analysis showed
an increased rate of fatigue, insomnia, nausea, abdominal pain,
and headache under pramipexole, comparable with previous studies.
CONCLUSION: Pramipexole proved to be an effective agent for patients
with Parkinson's disease and drug resistant tremor.
Expert Opin Pharmacother. 2002 Feb;3(2):197-210.
A review of pramipexole and its clinical
utility in Parkinsons disease.
Biglan KM, Holloway RG.
University of Rochester, Department of Neurology, 1351 Mt. Hope
Avenue, Suite 220, Rochester, NY 14620, USA.
Parkinson's disease (PD) is a common neurodegenerative disorder
characterised by selective loss of dopaminergic neurones in the
substantia nigra and resulting in progressive disability. Therapy
has focused on replacing depleted dopamine (DA) via supplementation
with levodopa or DA agonists. Pramipexole (Mirapex), Pharmacia
Corp.) has recently been approved for the treatment of PD. Evidence
from preclinical studies and clinical trials have proven the effectiveness
of this agent in ameliorating the symptoms of PD. There is also
non-human evidence that pramipexole may be neuroprotective and
could therefore possibly slow disease progression; however, this
has yet to be proven in humans. The use of pramipexole may be
limited by its side effect profile compared to standard therapies
and its relatively higher cost compared to levodopa. Despite these
concerns, pramipexole does have a role in the treatment of PD
in all stages of the illness and may arguably be the treatment
of choice in early disease. In addition to its use in PD, pramipexole
has shown some utility in the treatment of restless legs syndrome
(RLS), depression and schizophrenia.
Eur J Neurol. 2000 May;7 Suppl 1:21-5. Pramipexole in the treatment of advanced
Parkinsons disease.
Moller JC, Oertel WH.
Klinik fur Neurologie, Philipps-Universitat Marburg, Germany.
Pramipexole is a novel nonergoline dopamine agonist with a preference
for the dopamine D3 receptor subtype. Its efficacy and safety
in the treatment of advanced Parkinson's disease has been investigated
in several clinical studies. This review provides a summary of
the data currently available, particularly in reference to the
recent results of the European clinical phase III study and the
potential tremorlytic activity of pramipexole. Interim analysis
of the open-label European clinical phase III study has provided
evidence of long-term efficacy and safety of pramipexole. In another
study pramipexole has been shown to be significantly superior
to placebo with an improvement in tremor score by 48% (vs. 13%
in the placebo group). In addition to its likely usefulness in
the treatment of rest tremor in Parkinson's disease, data suggest
that pramipexole is of interest due to its reported low frequency
of cardiovascular and gastrointestinal side-effects. However,
studies comparing pramipexole with other antiparkinsonian agents
would be useful to further define its benefits in the treatment
of tremor-dominant Parkinson's disease and to further document
its favourable adverse event profile.
J Neural Transm. 2000;107(12):1369-79. The effect of repeated treatment with pramipexole
on the central dopamine D3 system.
Maj J, Rogoi Z, Margas W, Kata M, Dziedzicka-Wasylewska M.
Institute of Pharmacology, Polish Academy of Sciences, Krakow.
The study examined the effect of pramipexole (2-amino-4,5,6,7-tetrahydro-6-propyl-aminobenzthiazole
dihydrochloride; PRA), a new potent dopamine receptor agonist
with the high preference for D3 receptors, as compared to D2 or
D4, on the central dopamine D3 system. Experiments were conducted
on male Wistar rats. PRA was injected subcutaneously. PRA given
repeatedly (14 days, twice a day, in doses of 0.3 and 1 mg/kg),
but not acutely, potentiated the locomotor hyperactivity induced
by (+/-)-7-OH-DPAT (3mg/kg s.c.), when given 24h after the single
or the last dose of PRA. Administration of PRA, 1 mg/kg, for 3
or 7 days produced an effect similar to that described above,
whereas a dose of 0.3 mg/kg produced such an effect only after
7, but not 3, days. Repeated treatment with PRA (0.3 and 1 mg/kg,
14 days, twice daily) also enhanced the D3 receptor binding in
the islands of Calleja and nucleus accumbens (shell)--the brain
region known to be rich in D3 receptors--when [3H]7-OH-DPAT was
used as a ligand. Repeated PRA administration did not change the
concentration of mRNA coding for D3 receptors in the islands of
Calleja. The obtained results indicate that-- like the previously
studied typical antidepressants given repeatedly--PRA increases
the functional responsiveness and the binding to the brain dopamine
D3 receptors. Hence PRA may be considered as a potential antidepressant
drug.
Eur J Pharmacol. 1999 Nov 26;385(1):39-46. Efficacy of pramipexole, a new dopamine
receptor agonist, to relieve the parkinsonian-like muscle rigidity
in rats.
Lorenc-Koci E, Wolfarth S.
Department of Neuropsychopharmacology, Institute of Pharmacology,
Polish Academy of Sciences, 12 Sm&ecedil;tna Street, PL 31-343,
Krakow, Poland.
The aim of the present study was to assess the efficacy of pramipexole
(2-amino-4,5,6, 7-tetrahydro-6-propyl-amino-benzthiazole-dihydrochloride),
a new dopamine D(2)/D(3) receptor agonist, to attenuate parkinsonian-like
muscle rigidity in rats. Muscle tone was examined using a combined
mechano- and electromyographic (EMG) method, which simultaneously
measured the muscle resistance of a rat's hindlimb to passive
extension and flexion at the ankle joint, and the EMG acitivity
of the antagonistic muscles of that joint: gastrocnemius and tibialis
anterior. Muscle rigidity was produced by reserpine (5 mg/kg)
injected in combination with alpha-methyl-p-tyrosine (250 mg/kg)
or by haloperidol (0.5 mg/kg). Pramipexole in doses of 0.5-5 mg/kg
antagonized both reserpine+alpha-methyl-p-tyrosine- and haloperidol-induced
muscle rigidity. Pramipexole also reduced reserpine-enhanced tonic
and reflex EMG activities in the gastrocnemius muscle. The present
results suggest that stimulation of the postsynaptic dopamine
receptor may be chiefly responsible for the antiparkinsonian action
of pramipexole. The ability of pramipexole to diminish the parkinsonian-like
muscle rigidity seems to indicate a therapeutic value of this
compound in the treatment of Parkinson's disease.
Eur J Pharmacol. 1996 Sep 19;312(1):35-44. Inhibition of dopamine neuron firing by
pramipexole, a dopamine D3 receptor-preferring agonist: comparison
to other dopamine receptor agonists.
Piercey MF, Hoffmann WE, Smith MW, Hyslop DK.
CNS Research Pharmacia & Upjohn, Inc., Kalamazoo, MI 49001,
USA.
Pramipexole, an amino-benzathiazole [(S)-4,5,6,7-tetrahydro-N-6-propyl-2,
6-benzothiazolediamine dihydrochloride monohydrate] direct-acting
dopamine receptor agonist effective in treating Parkinson's disease,
bound selectively and with high affinity to dopamine D2-like receptors,
with highest affinity at dopamine D3 receptors. Ergot dopamine
receptor agonists (bromocriptine, lisuride, pergolide) bound to
both dopamine and non-dopamine receptors. Although all agonists
depressed dopamine neuron firing, only pramipexole and quinpirole
completely silenced firing when administered in slowly-accumulating
doses. High-dose pergolide, but not other ergots, completely suppressed
firing when given by a prompt bolus i.v. injection, suggesting
efficacy limitations may have involved receptor desensitization
for pergolide, but not for bromocriptine and lisuride. We conclude
that pramipexole differs from ergot dopamine receptor agonists
currently used in the treatment of Parkinson's disease by virtue
of its selectivity for dopamine receptors, its preferential affinity
for the dopamine D3 receptor subtype, and its greater efficacy
for stimulating dopamine receptors, as indicated in these electrophysiology
assays.
