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Cabergoline A long-acting dopamine agonist in Parkinson's disease.

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in the synthesis of dopamine, possibly at the level of biopterin stimulation of tyrosine hydroxylase [ 5 , 61. In contrast to
the suggestion of Wolters and colleagues [I], we would propose that the normal PET scans in patients with manganeseinduced parkinsonism do not necessarily indicate postsynaptic striatal or globus pallidus dysfunction. Particularly in the
face of levodopa responsiveness, one can still invoke a disturbance of nigral dopaminergic neurons at a metabolic level
before the formation of dopa itself.
‘Movement Disordws Clinic
Toronto Western Hospital
Toronto, Ontario, Canada
Khedoke-McMaster Medical Centre
Hamilton, Onlario, Canada
Rej&enceJ
1. Wolters ECh, Huang C-C, Clarke C, et al. Positron emission
tomography in manganese intoxication. Ann Neurol 1989;26:
647-65 I
2. Huang C-C, Chu N-S, Lu C-S, et al. Chronic manganese inroxication. Arch Neurol 1989;46:1104-1 106
3. Lang AE, Garnett ES, Riley DE, et al. Lcvodopa responsive parkinsonism: variable 6[18F)fluoro-L-dopa PET findings. Neurology 1988;38(Suppl 1):260
4. Martin WRW, Stoessl AJ, Palmer M, et d. PET scanning in
dystonia. Adv Neurol 1988;50:223-229
5. LeWitr PA, Miller LP, Levine K A , et al. Pterin abnormalities in
dystonia: A metabolic marker with therapeuric implications. Adv
Neurol 1988;jO:193-201
6. Fink JK, Barton N, Cohen W, et al. Dystonia with marked diurnal variation associated with biopterin deficiency. Neurology
1988;38:707-7 11
Reply
E.Ch. Wolters, MD,“ C . X . Huang, MD,‘ C. Clark, PhD,t
R. F. Peppard, MD,” J. Okada, MD,* N.-S. Chu, MD,7
M. J. Adam, PhD,# T. J. Ruth, PhD,Q D. L,MD,$
and D. B. Calne. MD”
We agree with Lang and Garnett that the defect in manganese-induced parkinsonism may arise at a stage prior to Laromatic aminoacid decarboxylase. However, we consider
that a lesion postsynaptic to the dopaminergic nerve ending
is equally possible. The notion that a therapeutic response to
raising a neurotransmitter level implies integrity of the postsynaptic receptors is difficult to sustain. Evidence against this
concept is provided by the well-established therapeutic response seen in myasthenia gravis, in which anticholincsterase
drugs increase the level of acetylcholine at the neuromuscular junction, yet the primary pathology of the disease affects
the receptors of the neuroinuscular junction.
‘Belzherg Laboratow of Clinical Neuroscience,
Dioision of Neurology
Departments of f Psychiatv and $Radiology
DTRI UMFIPET
Univwsity Ho.@itul, UBC Site
Vancouvw, BC, Canada
‘Department of Neurology
Chang Gung Medical ColLege Hospital
Taipei, Taiwan, Republic of China
Cabergoline: A Long-acting
Dopamine Agonist in
Parkinson’s Disease
G. Lera, MD, J. Vaamonde, MD, J. Muruzabal, LM,
and J. A. Obeso, M D
Chronic levodopa therapy is associated with complications
such as motor fluctuations, dyskinesias, nocturnal immobility, and early morning dystonia. Intravenous or duodenal
levodopa infusion and subcutaneous administration of dopamine agonists like lisuride or apomorphine allow an adequate
therapeutic control to be regained in many cases [l, 2). Such
approaches, however, are not very practical and it will be
difficult to use them widely. Cabergoline (Cb) is a new ergot
derivative with high affinity for dopamine type 2 (D-2) receptors, with an active half-life of about 65 hours [ 3 ] . Cabergoline could be a suitable drug to provide continuous dopaminergic stimulation by the oral route. W e have treated 18
parkinsonian patients with complex “on-off” fluctuations and
disabling dyskinesias with C b for a mean period of 12.5
months (range 10-18 mo). Cabergoline given once a day was
added to levodopa-carbidopa in an open, increasing dose,
piiot study. The mean C b daily dose was 12.2 2 3.4 mg
(range 3-18 mg). The levndopa-carbidopa daily dose was
reduced from 1,102.9 mg (baseline) to 691.1 mg after Cb
treatment (p < 0.05, Student’s t test). The number of “off”
hours a day was reduced by 79.2% with respect to the baseline assessment (6.7 hr vs 1.7 hr) ( p < 0.01). The score
obtained by the Unified Rating Scale for Parkinson’s Disease
when “off” was also reduced by a mean of 5 3 2 , (baseline
63.5, after Cb 29.6). “On” dyskinesias were enhanced in
duration and severity by at least 50% in 8 patients, and “off”
period dystonia was abolished in 2, reduced by 50% in 5 ,
and unaltered in 2. Five patients abandoned the study after a
mean treatment period of 9.2 months (range 7-1 1 mo) because of inefficacy (2 patients), increased diphasic dyskinesias
(I), severe nausea and vomiting (11, and heart failure (1).
These results suggest that Cb, associated with levodopa, has a
clear antiparkinsonian effect when given once a day. If the
hypothesis that intermittent oral levodopa therapy exerts a
deleterious effect on the dopaminergic response Cdh be validated [I, 4,5], C b could help to minimize and possibly avoid
the therapeutic problems associated with chronic levodopa
therapy.
Movement Disorders Unit
Department of Neurolog$j
Clinica Universitaria, Unizm idad de Navavra
Pamplona. Spuin
References
1. Obeso JA, Luquin MR, Vaamonde J, et al. Continuous dopaminergic stimulation for Parkinson’s disease. Can J Neurol Sci
1987;14:488-492
2. Stibe CMH, Lees AJ, Kempsrer PA, Stern GM. Subcutaneous
apomorphine in parkinsunian On-Offoscillations. Lancet 1988;
1:403-406
3. Ferrari C, Barbueri C, Caldara R, et al. Long-lasting prolactinlowering effect of Cabergoline, a new dopamine agonist, in hyAnnals of Neurology Vol 28
No 4 October 1090 593
perprolactinemic patients. J Clin Endocrinol Metab 1986;63:
94 1-945
4. Vaamonde J, Luquin MR, Obeso JA. Levodopa consumption
reduces dopaminergic responsiveness in Parkinson’s disease. Clin
Neurophxmacol 1989;12:271-284
5. Mouradian MM, Henser IJE, Baronti F, Chase TN. Modification
of centrd dopaminergic mechanisms by continuous levodopa
therapy for ac,vanced Parkinsonvsdisease, Ann Neural 1900;27:
18-23
Extracellular Amino
Acids in Traumatic Spinal
Cord Injury
Anders Lehmann, PhD
Panter and colleagues {l)recently reported on changes in
the levels of extracellular amino acids after impact trauma in
the spinal cord. My opinion is that the results may be artifactual because of the experimental protocol. In brief, microdialysis probes were implanted into the rabbit spinal cord,
and as the authors wished to measure both cations and amino
acids in the dialysates, the probes were perfused with distilled water instead of physiological saline. The authors claim
that “pilot studies have shown that there are no differences
between basal amino acid levels from microdialysis experiments using a distilled water perfusate and those obtained
using physiological saline (n = 4).”
The possible importance of amino acids in cerebral osmoregulation has been the subject of at least three independent microdialysis studies E2-41. These have unambiguoudy
demonstrated that the concentration of certain amino acids
depelnds strictly on the osmolality of the perfusion medium.
Taurine is particularly sensitive in this respect and increases
when perfusion buffer (NaC1) is decreased by as little as 25
mM {33. Glutamate, aspartate, and gamma-aminobutyric acid
(GABA) are less sensitive but the magnitude of the elevation of the transmitter amino acids is remarkable 12, 31. For
instance, omission of NaCl from the perfusion buffer (which
corresponds to a decrease in calculated osmolality from
316.8 to 72.8 mmolikg) enhances the concentration of glutamate by 15 to 20 times in rat hippocampal microdialysates
[2] and by 30 times in microdialysates from the rat dentate
gyrus {3}. This response may be submaximal and it could be
anticipated that perfusion with distilled water produces even
greater effects on glutamate, GABA, and certain other
amino acids. There is no reason to believe that the spinal
cord differs fundamentally from the hippocampus 121, dentate gyrus 133,or pyriform cortex {4]in response to perfusion with hyposmotic fluid. Likewise, species differences
seem very unlikely. Taking into account the perfusion rate
and length of the microdialysis probe used by Panter and
associates 111, the “basd’ concentrations reported are in the
range that could be expected during hyposmotic challenge. It
is puzzling, though, that the amino acid levels were relatively
stable for at least 80 minutes. The statement that steady-state
concentrations were reached after onIy 20 minutes is in sharp
contrast to a unanimous literature (for references, see IS]).
594 Annals of Neurology Vol 28 No 4 October 1990
The comparison is, however, difficult to make because of the
effect of distilled water.
If Panter and associates [l’Jare able to support their contelltion in a controlled study, it would be ofgreat interest for
those investigating the role of amino acids as osmoeffectors
in the central nervous system. If not, it means that changes in
extracellular amino acids after impact trauma were studied
against a grossly abnormal background and consequently
need to be reinvestigated.
K4ereeceJ
1. Panter SS, Y m SW, Faden AI. Alteration in extracellular amino
acids after traumatic spinal cord injury. Ann Neurol 1990;27:9699
2. Lehmann A. Effects of microdialysis-perfusion with anisosmotic
media on extracelluh amino acids in the rat hippocampus and
skeletal muscle. J Neurochem 1989;53:525-515
1. Solis JM, Herranz AS, Herreras 0,
et al. Does taurine act as an
osmoregulatory substance in the rat brain? Neurosci Lett 1988;
91~53-58
4. Wade JV, Olson JP, Samson FE, Pazdernik TL. A possible rolc
for taurine in osmoregulation within the brain. J Neurochem
1988;511740-745
5. Benveniste H. Brain microdialysis.J Neurochem 1989;52:1667-
1679
Reply
S. Scott Panter, PhD, and Alan I. Faden, MD
Dr Lehmann raises the issue of whether osmolality of the
perfusate affects the extracellular levels of amino acids, as
determined using microdialysis in uninjured or injured tissue. Recent work by Lehmann and others [l-31 shows that
changing the osmolality of the perfusate during ongoing microdialysis in uninjured tissue can alter the concentrations of
certain amino acids, particularly taurine and glutamate.
We have directly compared isotonic (physiological saline)
and hypotonic (distilled water) perfusates with regard to
basal levels of amino acids in uninjured rat brain. The extracellular levels of only two amino acids were significantly
altered by perfusate osmolality; levels of taurine were increased and glutamine decreased by the use of hypotonic
perfusate. All other amino acids (glutamate, aspartate, glycine, serine, threonine, alanine, and gamma-aminobutyric
acid) were not statistically different.
We have also compared the use of either isotonic (artificial
cerebral spinal fluid) or hypotonic (distilled waterj perfusates
in experiments examining trauma-related increases in extracellular amino acids in rat brain. Fluid percussion injury to
rat brain caused significant increases in the extracellular
levels of all excitatory (aspartate and glutamate), inhibitory,
and nonneurotransmitter amino acids measured, with no differences in the degree or duration of increase related to
osmolality of the perfusate.
In our original studies. trauma was administered 20 to 30
minutes folIowing insertion of the probe, but we now
routinely use a 90-minute waiting period between probe in-
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dopamine, long, acting, agonists, disease, parkinson, cabergoline
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