Dopamine agonists in Parkinson's disease

See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/15482980 Dopamine agonists in Parkinson's disease Article in Neurology · April 1995 DOI: 10.1212/WNL.45.3_Suppl_3.S28 · Source: PubMed CITATIONS READS 38 106 4 authors, including: Erik Ch. Wolters Paul Bergmans 309 PUBLICATIONS 10,032 CITATIONS 76 PUBLICATIONS 1,821 CITATIONS Maastricht University SEE PROFILE Johnson & Johnson SEE PROFILE Michael A Kuiper Medisch Centrum Leeuwarden 207 PUBLICATIONS 4,570 CITATIONS SEE PROFILE All content following this page was uploaded by Michael A Kuiper on 17 December 2016. The user has requested enhancement of the downloaded file. All in-text references underlined in blue are added to the original document and are linked to publications on ResearchGate, letting you access and read them immediately. zy Dopamine agonists in Parkinson’s disease Erik Ch. Wolters, MD, PhD; Gerrit Tissingh, MD; Paul L.M. Bergmans, MD; and Michael A. Kuiper, MD Article abstract-The main pathologic hallmark of Parkinson’s disease is a degeneration of the dopaminergic cells in the substantia nigra, pars compacta and-to a lesser extent-in the ventral tegmental area. Striatal dopamine concentrations are significantly reduced before clinical symptoms become apparent. Recent neuroanatomic and function studies have revealed that the nigrostriatal dopaminergic projection is only one of the neuronal elements integrated into extensive basal ganglia-thalamocortical circuits that are intimately involved in the regulation of motor activity. The possibilities for therapeutic intervention a t the level of the different dopamine receptor subtypes and their effect on the regulation of motor behavior will be briefly reviewed. Dopamine precursors are considered to provide the best symptomatic treatment, whereas dopamine agonists, although less effective, might be important in slowing the progression of the disease. Our results with pergolide as monotherapy and in combination therapy in patients with Parkinson’s disease also are discussed. NEUROLOGY 1995;45(~~ppl3):S28-S34 zyxwvutsrq The predominant neuropathologic feature in Parkinson’s disease (PD) is a degeneration of the dopaminergic cells i n the substantia nigra pars compacta (SNC). This results in a marked loss of cerebral, especially striatal, dopamine. Striatal dopamine concentrations are said to be reduced to about 20% before clinical symptoms become apparent.l.2 These symptoms include bradykinesia, rigidity, tremor, and postural instability. Although it is generally accepted that PD primarily results from a loss of dopaminergic neurons in the SNC, the resulting alterations in activity in the basal ganglia, which a r e responsible for parkinsonian motor deficits, remain poorly understood. The dopaminergic nigrostriatal projection is only one of the neuronal elements integrated in extensive basal ganglia-thalamocortical circuits that are intimately involved in the regulation of motor act i ~ i t y .Some ~ , ~ have suggested that multiple basal ganglia-thalamocortical circuits exist. These circuits are arranged in a parallel fashion and subserve different aspects of motor, cognitive, and complex behavioral processes, depending on the cortical areas involved in the particular circuit^.^,^ The connections between the main input structure of the basal ganglia (the striaturn) and the output structures of the basal ganglia (the internal segment of the globus pallidus [GPil and the reticular part of the substantia nigra [SNRI) are modulated by “direct” and “indirect” routes, both originating from different populations of striatal neurons (figure 1A). The “direct” and “indirect” striatal output path- ways have opposite effects on the output neurons of the basal ganglia to the thalamus. A balance in these pathways is essential for the regulation of normal movement. The output cells of the “direct” r o u t e a r e thought to be y-aminobutyric acid (GABAIergic. Substance P is present as a cotransmitter in these cells, and they predominantly express D1 receptors. Striatal output cells of the “indirect” route, projecting to the external segment of the globus pallidus (GPe), also are thought to be GABAergic, but they contain met-enkephalin as a cotransmitter and express predominantly D, recept o m 8 It is assumed that an increase in the output from the basal ganglia to the thalamus (figure 1B) is the consequence of a loss of dopamine, ultimately resulting in a reduction of cortical activation, which accounts for most of the parkinsonian signs.4 Dopamine precursors. Following the discovery that patients with PD were suffering from a deficiency of dopamine in the basal ganglia, levodopa was successfully administered to supplement the depleted dopamine stores. To date, this treatment is still considered to be the most effective method of controlling the symptoms of PD. Long-term treatment with levodopa, however, frequently results in a fading of the therapeutic effect (“wearing off‘) and the development of serious motor side effects, such as “on-off’ motor oscillations and dyskinesias (“narrowing of the therapeutic wind0w”).~-1~ Under such conditions, increasing the levodopa dosage further only gives rise to more side effects without adding any beneficial effect. Recently, it has been zy zyxwvutsrq zyxwvutsrqpon ~ ~ ~~~~ From the Postgraduate School of Neuroscience, Department of Neurology, Academic Hospital, Vrije Universiteit, Amsterdam, The Netherlands. Address correspondence and reprint requests to Dr. E. Ch. Wolters, Postgraduate School of Neuroscience, Department of Neurology, Academic Hospital, Vrije Universiteit, Amsterdam, The Netherlands. 528 NEUROLOGY 45 (Suppl3) March 1995 zyxwvut ‘P-zyxwvut Frontal cortex output i‘ln I n patients with early PD who require dopamine agonist therapy, the selective monoamine oxidase type B (MAO-B) inhibitor selegiline (which inhibits dopamine breakdown) was found to delay the onset of disability by about 9 months. This may be explained both by t h e actual rise in striatal dopamine levels and by a protectivelpreventive effect induced by the decreased oxidative stress following the decreased formation of hydrogen peroxide.l9 zy zyxwvutsr zyxwvutsrq zyxwvuts Dopamine agonists. During the last decade, treatment with D, receptor agonists has expanded the therapeutic Figure 1. Schematic representation of the main connections in a basal gangliapotential for the treatthalamocortical circuit. (A) Normal status: The two output routes (‘‘indirect” and “direct”) ment of PD. Although are in balance at the level of the output structures. (B) Presumed disturbances in various compounds, Parkinson’s disease: Depletion of dopamine in the striatum leads to an imbalance in the such as lisuride, bromotwo output routes and a suppression of thalamocortical activity. ENK, enkephalin; GP, criptine, 4-propyl-9-hyglobus pallidus; GPE, external segment of GP; GPI, internal segment of GP; MD, droxynaphthoxazine mediodorsal thalamic nucleus; SNR, pars reticulata of the substantia nigra; SNC, pars (PHNO), cabergoline compacta of the substantia nigra; SP, substance P; STN, subthalamic nucleus; VAI VL, ventral anterial lventral lateral thalamic nuclei. (Reprinted with permission.7) a n d pergolide, have been clinically tested,,O bromocriptine and pergolide are the most frequently suggested that long-term treatment with levodopa prescribed. Pergolide and bromocriptine both have a might actually accelerate the degeneration of high agonistic affinity for the D, receptor. It has dopaminergic neurons.13-16 been reported that bromocriptine is a partial antagoGlutathione metabolism is a prerequisite for the nist for the D, receptor, whereas pergolide is a weak normal processing of hydrogen peroxide. Consistent agonist for the same receptor.21,22 impairment of glutathione metabolism in the striaA dopamine-agonist-induced protective effect on tum is found not only in patients with PD, but also the normal age-related degeneration of dopaminerin normal subjects with pathologic signs of subclingic cells was originally established in rats fed with ical PD (incidental Lewy body d i ~ e a s e 1 . lIn ~ papergolide from the age of 3 months.23This protectients with PD, a mitochondria1 complex I defitive effect might result from a decreased oxidative ciency and an increased superoxide dismutase stress, in turn resulting from the decreased striatal (SOD) activity are also established, resulting in indopamine content, induced by an autoreceptor-mecreased hydrogen peroxide formation. Moreover, diated reduction in presynaptic dopamine synthethe free iron concentration seems to be increased, favoring abnormal processing of hydrogen peroxide sis. The consequence of a decreased amount of striatal dopamine is a reduction in the formation of hywith the formation of cytotoxic free OH-radicals. drogen peroxide and fewer free radicals. During levodopa therapy, the basal ganglia are In general, the therapeutic effects of dopamine bathed in nonphysiologic amounts of dopamine, agonists on parkinsonian disability are less drathus further increasing oxidative stress by enmatic than the clinical effects seen with levodopa, hanced generation of hydrogen peroxide through but dopamine agonists induce fewer dyskinesias. A dopamine auto-oxidation and leading to a progresgenerally accepted therapeutic protocol for PD is a sive lipid peroxidation of the cell membranes of combination of low-dose levodopa with one of the neighboring neurons, with consequent nigral cell D, receptor agonists. This treatment usually redeath.18Thus theoretically, the fading of the therasults in optimal control of the symptoms with fewer peutic response and the development of serious side effects. It is well-known, however, that both D, motor side effects of levodopa therapy might be reand D, receptors are targets for the action of dopalated to the rate of progression of the disease. -GABA =Glutamate zyxw March 1995 NEUROLOGY 45 (Suppl3) 529 zyxwvut zyxwvuts Table 1. Characteristics of the patients entered into the three pergolide trials (as monotherapy,as an adjunct to levodopa, and replacing bromocriptine as an adjunct to levodopa, respectively) N Sex (M/F) Age (yrs) Age a t onset (yrs) Disease duration (yrs) Hoehn & Yahr stage Columbia Rating Scale Levodopa daily dose (mg) Bromocriptine daily dose (mg) De novo Early combination Late combination 20 1317 59.2 55.2 4 64 36/28 67.4 59.9 7.5 44 26/18 71.3 62.7 8.6 11-111 11-IV 111-IV 19.6 29.6 37.1 - 540 547 - - 15 2 11 5 2 - 9 2 - - 2 Discontinuations Complications Lost to follow-up Deaths 1 2 with bromocriptine and CY 208-243improved the motor response (measured by locomotion, hand dexterity, and disability scores) when compared with treatment with bromocriptine alone in MPTPlesioned monkeys,26but not in patients with PD.27 We recently showed that the benzazepine derivative, SKF 81297,induced rotational behavior away from the lesion and stimulated the use of the dominant right hand in unilaterally (left-sided) MPTPlesioned monkeys in a D,-selective manner.28The compound appeared to be inactive in the D, receptor-mediated inhibition of striatal acetylcholine release, a functional in vitro model system for the D, receptor,29and displayed full agonistic activity as a D, agonist in human cell lines.29We also demonstrated an interesting synergistic action of the selective D, agonist, SKF' 81297, and the D, agonist, LY 171555, on the motor behavior of unilaterally MPTP-lesioned monkeys. Coadministration of behaviorally active doses resulted in a prolongation of motor stimulation when compared with either of the drugs alone, whereas the combination of these drugs in nonbehaviorally active doses induced a significant stimulation of motor behavior.30 In summary, dopamine agonists seem to protect the basal ganglia from further oxidative stress, and their symptomatic effect-although less complete t h a n t h a t of levodopa-might depend on both dopamine D, and D, receptor activity. zyxwv zyxwvutsrqpo zyxwvu mine in the striatum. This concept provides a rationale for the requirement of both D, and D, receptor stimulation to restore as completely as possible the motor activity in animal models for PD.24 The only clinically available D, agonist, CY 208243,stimulated the motor behavior of patients with idiopathic PD.25Unfortunately, due to toxic side effects, no optimal dosage could be established. It is interesting to note that the combined treatment Pergolide monotherapy in de novo PD patients. Patients and methods. We investigated the clinical efficacy of pergolide monotherapy in an open-label study. Patients were included if their functional disability required dopamine agonist therapy and if treatment with selegiline, anticholinergics, or 1.0 amantadine had been withdrawn at least 3 months before entry into the study. Diagnosis of idiopathic PD was 0.8 h based on clinical signs and Y ." symptoms of bradykinesia, hypokinesia, rigidity, r e s t Q 0.6 ............................ tremor, or postural instability, with normal lZ3I(1,2,3.. iodo-2-hydroxy-6-methoxy-Nbenzamide) single photon emission tomography (lZ3IIBZM SPET) scans. Patients with clinically significant pulmonary, hepatic, renal, cardiac, psychiatric, or demento'2 ing disease a n d infections I - 1 I I I I were excluded. 1 2 3 Pergolide therapy was initiYears since entry into trial ated at a dose of 0.05 mg and increased every other day by 0.05-mg increments until the first clinical effects were Figure 2. Kaplan-Meier curve of the cumulative probability of effective pergolide noted, mainly at dosages of monotherapy in 18 patients with de novo Parkinson's disease. 95% Confidence limits are shown. 0.15 to 0.25 mg two or three CI 3 ii ..........................a 1 zyxwvutsrqpo I I ~ 530 NEUROLOGY 45 (Suppl3) March 1995 Table 2. Mean improvement of PD symptomatologyin PD patients 6 months after initiating pergolide therapy (as monotherapy, as adjunct to levodopa, and replacing bromocriptine as adjunct to levodopa, respectively). Results are expressed as percentage improvements in Columbia University Rating Scale and percentages of levodopa and bromocriptine daily dose reduction No. of patients Total daily pergolide dose (mg) I zy zyxwvuts De novo Early combination Late combination 18 53 1.5 39 1.6 0.85 Improvement (%) Columbia rating score >50%improvement (% patients) <lo% improvement (% patients) Axial subscore Nonaxial subscore Dexterity subscore Rigidity subscore Tremor subscore Levodopa dose reduction (%) Bromocriptine dose reduction (%) 36 28 6 25 44 36 58 43 - times daily (total daily dosages of between 0.3 and 0.75 mg). After a stable dosage period of 2 weeks, the dosage was gradually increased until a satisfactory response (functional ability, meeting the patients expectations) was reached. Cotreatment with domperidone, 10 mg two or three times daily, was permitted to treat side effects, such as orthostatic hypotension and GI complaints. Patients were evaluated every 2 weeks during the first 2 months, then every 4 weeks during the first year, and every 10 t o 12 weeks thereafter. Recording of side effects, motor complications (“wearing off,” dyskinesias and dystonias, and “onoff” fluctuations), Columbia University Rating Scale (CRS) (assessment of Parkinsonian disability on a 25-item, 100-point scale31), and Hoehn and Yahr score assessments was standard procedure at each visit. Safety assessments included regular blood pressure monitoring (lying and standing), chest x-rays, electrocardiograms, hemograms, and blood chemistry analysis. The end point of the study was reached when patients’ functional disability required combination of pergolide with levodopa, or when side effects required discontinuation of pergolide monotherapy. Results. Patient characteristics are shown in table 1.A total of 20 de novo patients, including six with early onset PD (<40 years of age), were enrolled. Two patients discontinued pergolide treatment because of the development of adverse events: One developed severe orthostatic hypotension that did not respond to cotreatment with domperidone and discontinued after 4 weeks of treatment; another had vivid nightmares, paranoia, and acoustic hallucinations and discontinued after 1 week. Clinical efficacy was determined by recording the CRS 6 months after commencement of pergolide therapy in the 18 evaluable patients (table 2). The combined total scores of all patients improved by a mean of 36% when compared with the score before 37 29 9 31 41 32 49 47 27 - 32 20 31 29 31 33 37 22 23 100 initiation of pergolide. The greatest improvements were seen in the nonaxial items, such as rigidity (58%improvement) and tremor (43%improvement). The mean daily pergolide dose in the 18 patients after 6 months of treatment was 0.85 mg, given in two to three dosages of 0.35 mg (range, 0.25 to 0.5). To date, during a mean of 30 (range, 24 to 39) months of study, six of the 18 patients have reached the end point and require levodopa combination therapy. The end point in these patients occurred after 6 (where pergolide failed to induce any satisfjmg effect at all), 12, 15, 15,27, and 39 months of monotherapy, respectively (figure 2). After 1year, the mean dose of pergolide was 1.13 mg (n = 16); after 2 years the mean dose was 1.45 mg (n = 14); and after 3 years the mean dose was 2.15 mg (n = 10). Including the two patients who were withdrawn because of side effects, 80% of the patients judged their functional disability to be adequately treated after 1 year of pergolide treatment, as did 70% of patients after 2 years. A cumulative probability predicts that over 60% of patients will judge their functional disability to be adequately treated after 3 years. Adverse events were experienced by 6 of the 20 patients. Five patients, mainly the older ones, experienced orthostatic hypotension (one dropout); four experienced nausea, vomiting, and abdominal discomfort. The GI side effects could be adequately suppressed with domperidone. Psychiatric side effects were seen in two patients. One was withdrawn due to overt psychosis; the other had anxiety and slight paranoia. Peripheral edema was seen in one patient, while another showed a skin rash resembling erythromelalgia. Neither hyperkinesias nor “on-off‘ fluctuations occurred. It is particularly noteworthy that these complications did not occur in the six early-onset PD patients. Quinn et a P found the incidence of hyperkinesias, “on-off) fluctuations, or both to in- zyxwvutsr zyxw March 1995 NEUROLOGY 45 (Suppl3) 531 zyxwvu crease steeply with time in early-onset PD patients treated with levodopa, reaching a n incidence of 75% after treatment lasting 3 years. Earlier studies with dopamine agonist monotherapy showed much lower figures than those for levodopa for cumulative percentages of motor complications, irrespective of whether the patients were treated with ~ - a~ lrule, pergolide, lisuride, or b r ~ m o c r i p t i n e . ~As surprisingly fewer motor complications were seen in these patients, compared with patients on levodopa m ~ n o t h e r a p y . ~ ~ Few reports on pergolide monotherapy in de novo PD patients exist, and results are modest. Reduction of disability (20 to 30%) was reached in 16 of the 20 patients reported by Rinne,33mostly at daily dosages of approximately 3 mg or higher. Adverse events occurred frequently, involving mainly GI and psychiatric disturbances (18%). Seven of 10 patients reported by Wright et a141discontinued pergolide because of intolerable side effects, some within a few days of starting treatment. In these earlier studies only one third to one half of the patients could be maintained on pergolide monotherapy for more than a year,33whereas in our study, 14 of 20 patients continued treatment for more than 2 years. In addition, we showed a similar efficacy to that reported in these early studies at a considerably lower daily dose (0.85 mg vs 3.0 mg). It must be pointed out, however, that our study was biased; patients were aware of the goals of the study, while Rinne33arrived at his results in a retrospective study and did not administer domperidone to manage peripheral side effects. Pergolide in early combination with levodopa. Patients and methods. With the exception of the results reported by Diamond et al,42studies in patients with advanced PD have shown that pergolide, given in combination with levodopa, provides good clinical results and permits a reduction in the levodopa dosage.43We assessed the safety and efficacy of pergolide as an adjunct to levodopa monotherapy in an open-label, prospective study of 64 patients with moderate PD over a 6-month period. To be eligible for the trial, patients had to have been receiving levodopa for less than 3 years and to have demonstrated a “wearing-off” effect o r required more than 600 mg levodopa daily. Amantadine, anticholinergics, or both were continued unchanged throughout the study. Diagnosis was based on clinical signs and symptoms, the patients showing bradykinesia, rigidity, rest tremor, or postural instability, and an excellent response to levodopa therapy. Patients with levodopa-induced motor complications, such as hyperkinesias and “on-off” fluctuations, or with clinically significant pulmonary, hepatic, renal, cardiac, psychiatric, or dementing disease or infections, were excluded. Pergolide was initiated at a dose of 0.05 mg and increased every other day by 0.05 mg up to a dose of 0.25 mg three times daily. The daily dose thereafter could be increased or decreased by 0.25 mg per week until an optimal response or a maximum dose of 3.0 mg was reached. While the optimal dose of pergolide was being sought, attempts also were made t o decrease the levodopa dosage. Cotreatment with domperidone was permitted to treat side effects. Patients were assessed every 2 weeks during the first 2 months and every 4 weeks thereafter. Side effects, motor complications (“wearing off,” dyskinesias and dystonias, “on-off” fluctuations), CRS, and Hoehn and Yahr score assessments were evaluated at each visit. Safety assessments included regular blood pressure monitoring (lyinghtanding), hemograms, and blood chemistry analysis. If clinically indicated, chest x-rays and electrocardiograms were obtained. Results. Sixty-four patients were enrolled in this trial. Patient characteristics are shown in table 1. Side effects necessitated discontinuation of pergolide treatment in nine patients (14%) because of psychiatric complications in five, GI complaints in three, and orthostatic hypotension in one. None of these responded to domperidone cotreatment. Two patients were lost to follow-up. Clinical improvement for the 53 evaluable patients, expressed as percentage improvement in the CRS, is shown in table 2. All patients responded to pergolide treatment; the mean improvement in the CRS score was 37%. The greatest improvement was observed in the nonaxial performances (41%). The mean daily pergolide dose was 1.5 mg. Pergolide permitted the dose of levodopa to be decreased from 565 to 410 mg. Adverse events were seen in 26 of the 62 patients with PD (excluding two lost to follow-up). Seventeen patients, mainly the elderly, experienced orthostatic hypotension (one withdrawal); 16 experienced nausea, vomiting, and abdominal discomfort (three withdrawals), mainly suppressed adequately with domperidone. Psychiatric side effects were seen in eight patients (five withdrawals), and peripheral skin rash (erythromelalgia), edema, and/or dyspnea occurred in seven. Hyperkinesias, such as chorea and dystonia, occurred in 15 patients, but these completely disappeared after reducing the levodopa dosage. No pleural effusions or abnormal findings were observed during any chest x-ray, and no pathology or changes t o earlier recordings were observed during any cardiograms. In this study, we have shown that pergolide has efficacy as an adjunct to levodopa treatment in PD patients who demonstrate “wearing-off” effects to levodopa. Pergolide allowed the levodopa dosage to be reduced. These results, of early combination of pergolide with levodopa (that is, initiation of pergolide within 3 years of the initiation of levodopa), are comparable with those from other zyxwvu zyxwv zyxwvutsrqpon 532 NEUROLOGY 45 (Suppl3) March 1995 Pergolide in late combination with levodopa. Patients and methods. We have also assessed the safety a n d efficacy of pergolide i n replacing bromocriptine in patients with moderate to severe PD in whom bromocriptine and levodopa therapy was complicated by loss of efficacy, hyperkinesias, “on-off” oscillations, or all of these. Amantadine, anticholinergics, or both were continued unaltered throughout the study. The protocol was similar to that for pergolide in early combination therapy. Bromocriptine was gradually withdrawn over a period of 5 days, and pergolide was started 2 days after bromocriptine therapy was completely terminated. Patients were assessed at 2 days, then every 2 weeks during the first 2 months and every 4 weeks thereafter. CRS scores were determined 6 months after substitution of pergolide for bromocriptine and compared with the scores for bromocriptineflevodopa treatment. Results. Forty-four patients were enrolled in this open-label study. Patient characteristics are shown in table 1. In total, five patients discontinued: One stopped because of adverse events (psychiatric complications); two died from unknown, probably unrelated causes (autopsies were not performed); and two were lost to follow-up. Clinical results after 6 months of treatment for the 39 evaluable patients are shown in table 2. Mean CRS scores of these patients improved by 32%. Improvements greater than 50% were observed in 20% of patients, and improvements of less than 10% were observed in 31% of patients. Patients who did not deteriorate after discontinuation of bromocriptine appeared to be the most likely to benefit from substitution with pergolide, while those who did deteriorate benefited least. The mean daily dose of pergolide after 6 months was 1.6 mg. Pergolide administration allowed the levodopa dosage to be decreased from 533 to 408 mg (a reduction of 23%), mainly because the number of levodopa doses could be reduced from four or five to three daily. Hyperkinesias improved significantly in most patients and disappeared in 30% of patients, probably because of this reduction. The number of “on-off”oscillations was reduced in 10 of the 13 patients with these complications; the total “off” time was reduced by 45%. Side effects occurred in seven patients: GI complaints in five, orthostatic hypotension in four, psychiatric complications in four (one withdrawal), and peripheral edema in two. Peripheral side effects, with the exception of edema, were manageable with domperidone. No pleural effusions, changes in cardiograms, or abnormal findings were observed during three consecutive chest xrays and four cardiograms. cally stimulates both D, and D, receptors, possibly explaining the greater therapeutic effect of levodopa compared with that of D2 agonists. Recently, newly developed selective D, agonists were shown to stimulate motor behavior in nonhuman primate models of PD,28which suggests that the D, receptor is a possible target for the treatment of PD. It is interesting to note that the D, agonist pergolide is a weak agonist for t h e D, receptor, whereas bromocriptine is a partial D, antagonist; this might explain the differences in clinical efficacy between the two drugs. The recent developments of selective D, and D, agonists will open new perspectives for the treatment of PD. Several approaches for the treatment of PD can be considered, such as postponing levodopa therapy, keeping levodopa dosages as low as possible, or combining levodopa with dopamine agonists at an early stage. In younger patients, who are at high risk of suffering early levodopa-induced motor complication^,^^ treatment with dopamine agonists offers a possible approach for delaying levodopa therapy. More clinical research is warranted on this point, ‘however. The question still needs to be answered as to whether levodopa accelerates the rate of progression of the disease. Neuroimaging tools need to be designed to calibrate the progressive deterioration of dopaminergic cells and t o determine whether MAO-B inhibitors, dopamine agonists, or both will slow this process. In conclusion, the results of the studies described suggest t h a t low-dose pergolide i n monotherapy is effective in improving symptoms of early PD. By carefully optimizing the maintenance dosage of pergolide, the incidence of adverse events can be minimized, and they are usually manageable with domperidone. Pergolide, as an adjunct to levodopa therapy, leads to an improvement in the disability and allows the dosage of levodopa to be reduced, lowering the incidence and severity of levodopa-induced motor complications. In addition, an improvement in baseline disabilities has been demonstrated for pergolide in several patients who have a less than optimal response to levodopa plus bromocriptine and have been transferred to levodopa plus pergolide. zyxwvutsrqpo zyxwv zyxwvuts zyxwvutsrq Conclusion. The therapeutic approach for PD is still dominated by levodopa therapy, in spite of the major disadvantages of this compound. In the studies reported here, however, we have shown that the dopamine agonist pergolide has efficacy, not only as an early or late addition to levodopa therapy, but also in monotherapy. Dopamine agonists, such as bromocriptine and pergolide, do not seem to be as effective as levodopa in PD. Levodopa is converted to dopamine in the brain and, therefore, theoreti- References 1. Agid Y, Cervera P, Hirsch E, et al. Biochemistry of Parkinson’s disease 28 gears later: a critical review. Mov Disord 1989;4(suppl 1):126-144. 2. Hornvkiewicz 0. Kish SJ. Biochemical pathophgsiolom -. of Park;nson’s disease. Adv Neurol 1986;45:i9-34: 3. Alexander GE, Crutcher MD. Functional architecture of basal ganglia circuits: neural substrates of parallel processing. Trends Neurosci 1990;13:266-271. 4. Bergman H, Wichmann T, DeLong MR. Reversal of experimental parkinsonism by lesions of the subthalamic nucleus. Science 1990;249:1436-1438. 5 . Alexander GE, DeLong MR, Strick PL. Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Ann Rev Neurosci 1986;9:357-381. ~~ zy zyxw March 1995 NEUROLOGY 45 (Suppl3) 533 6. 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Drugs 1990;39:491-506. zyxw zyxwvutsrqpo zyxwv zyxwvutsrq zyxw zyxwvutsrqpon 534 NEUROLOGY 45 (Suppl3) March 1995 View publication stats