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PubMed2005

Pergolide is an inhibitor of voltage-gated potassium channels, including Kv1.5, and causes pulmonary vasoconstriction.

BACKGROUND: Pergolide produces clinical benefit in Parkinson disease by stimulating dopamine D1 and D2 receptors. An increased incidence of carcinoid-like heart valve disease (CLHVD) has been noted in pergolide users, reminiscent of that induced by certain anorexigens used for weight reduction. Anorexigens that modulate serotonin release and reuptake, such as dexfenfluramine, were withdrawn from sale because of CLHVD. Interestingly, the anorexigens also caused pulmonary arterial hypertension (PAH). Anorexigens were shown to enhance hypoxic pulmonary vasoconstriction, in part by inhibiting voltage-gated K+ channels (Kv) in pulmonary artery smooth muscle cells (PASMCs). Although PAH has not been associated with pergolide use, we hypothesized that pergolide might have similar effects on hypoxic pulmonary vasoconstriction and Kv channels. METHODS AND RESULTS: Pergolide enhanced hypoxic pulmonary vasoconstriction in the isolated perfused rat lung compared with control lungs (mean pulmonary artery pressure 32+/-3 versus 21+/-2 mm Hg; P<0.01). Pergolide also caused vasoconstriction in rat pulmonary artery rings. Pergolide inhibited PASMC potassium current density, resulting in membrane depolarization (from -51+/-2 to -44+/-1 mV) and increased cytosolic calcium in both rat and human PASMCs. Pergolide directly inhibited heterologously expressed Kv1.5 and KCa channels. CONCLUSIONS: Pergolide causes Kv channel inhibition and, despite being from a different class of drugs, has pulmonary vascular effects reminiscent of dexfenfluramine. Coupled with their shared proclivity to induce CLHVD, these findings suggest that clinical monitoring for pergolide-induced PAH should be considered.

Animals↗
PubMed1995

A crossover, controlled study comparing pergolide with bromocriptine as an adjunct to levodopa for the treatment of Parkinson's disease.

A single-blind, crossover study was carried out to compare the efficacy and safety of pergolide against that of bromocriptine in 57 patients with Parkinson's disease who showed a declining response to levodopa therapy. Patients were randomly assigned to receive either bromocriptine followed by pergolide, or pergolide followed by bromocriptine. Both drugs were administered for 12 weeks. Patients were assessed by a clinician blinded to treatment assignment using the New York University Parkinson's Disease Scale. The average daily dose of pergolide was 2.3 +/- 0.8 mg and of bromocriptine 24.2 +/- 8.4 mg. Addition of pergolide or bromocriptine resulted in a significant improvement in total scores when compared with the previous treatment of levodopa alone (pergolide, p = 0.0001; bromocriptine, p = 0.0005). Pergolide was more effective than bromocriptine in daily living scores (p = 0.02) and motor scores (p = 0.038). No differences in the incidence of dyskinesias, dystonias, or psychosis were observed between groups. Fewer adverse events were recorded in the pergolide group, and most patients and physicians preferred pergolide to bromocriptine. Pergolide as adjunctive therapy to levodopa was more effective than bromocriptine in this short-term trial.

Aged↗
PubMed2005

Valvular heart disease in patients taking pergolide.

OBJECTIVE: To Investigate the frequency of valvular heart disease in patients taking pergolide. PATIENTS AND METHODS: The medical records of patients seen at the Mayo Clinic in Jacksonville, Fla, between 1998 and 2003 were searched electronically for the word pergolide and the presence of a 2-dimensional echocardiogram. Patients who had not taken pergolide before undergoing echocardlography served as the control group. Echocardiograms were reviewed for the presence of valvular regurgitation. The frequency of valvular disease in patients taking pergolide was calculated and compared with controls. Associations with dosage and years of treatment also were examined. RESULTS: Fifty-five patients made up the pergolide group, and 63 served as controls. When looking at aortic regurgitation (AR) of any degree, 45% of patients in the pergolide group had AR, compared with 21% of controls (P = .006). The frequency of moderate to severe valvular regurgitation in the pergolide group was 11% (95% confidence interval [CI], 4%-22%), 13% (95% CI, 5%-24%), and 13% (95% CI, 5%-24%) for the tricuspid, mitral, and aortic valves, respectively. No statistical difference was identified in the frequency of moderate to severe valvular regurgitation (mitral, tricuspid, or aortic) when compared with controls. There was marginal evidence of an association between a higher daily dosage of pergolide and moderate to severe AR (P = .05). CONCLUSION: The frequency of AR appears to be Increased in patients taking pergolide. Our study suggests that if a cause-effect relationship exists between pergolide and valvular heart disease, it likely occurs at a low but clinically important Incidence and may be associated with dosage.

Adult↗
PubMed1993

Dopamine receptor affinities in vitro and neurochemical effects in vivo of pergolide and its metabolites.

Pergolide (LY127809, CAS 66104-23-2), pergolide sulfone and pergolide sulfoxide inhibited 3H-dopamine binding to dopamine receptors in bovine striatal membranes with Ki values of 2.5, 4.6 and 15.5 nmol/l, respectively. Despropyl pergolide and despropyl pergolide sulfoxide are not as potent, with Ki values of 58.6 and 158.8 nmol/l, respectively. The derivatives of pergolide inhibit the binding of antagonist ligands 3H-Sch23390 and 3H-Spiperone to D1 and D2 dopamine receptors, respectively, in bovine striatal membranes with higher Ki concentrations. Upon administration to rats, pergolide sulfoxide and sulfone were as effective as pergolide in increasing acetylcholine levels and decreasing the metabolites of dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) levels in striatum, while the despropyl derivatives of pergolide and pergolide sulfoxide were only marginally effective in increasing acetylcholine levels in striatum.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

Trial of subtherapeutic pergolide in de novo Parkinson's disease.

The effect of pergolide 25 mug twice daily on levodopa initiation was assessed in a randomized, placebo-controlled, parallel group, double-blind multicenter trial in 106 untreated early Parkinson's disease patients. The primary endpoint of mean time until levodopa was 520 days (95% confidence interval [CI], 422-618 days) for pergolide versus 434 days (95% CI, 358-609 days) for placebo. However, this increase of 86 days for pergolide was not statistically significant. The wash-in effect of pergolide was significant at 6 weeks (change in mean Unified Parkinson's Disease Rating Scale [UPDRS] 2 and 3 was -0.1 [95% CI, -1.4 to 1.3] for pergolide vs. 2.2 [95% CI, 1.1-3.3] for placebo). At termination, the change from baseline in mean UPDRS 2 and 3 score was 11.4 (95% CI, 8.8-14) for pergolide and 14.6 (95% CI, 12-17.2) for placebo (P=0.08). There was no significant change in UPDRS 2 and 3 for the 83 patients achieving the planned 4-week washout at termination (pergolide 1.2 [95% CI, -0.8 to 3.2] vs. placebo 0.0 [95% CI, -1.6 to 1.6]. Adverse events were infrequent and occurred equally for pergolide and placebo. The study shows no evidence of a neuroprotective effect but indicates a mild symptomatic benefit from pergolide at a dose normally considered subtherapeutic.

Adult↗
PubMedDate not supplied

Chronic dietary pergolide preserves nigrostriatal neuronal integrity in aged-Fischer-344 rats.

Pergolide, a potent D2 presynaptic agonist with postsynaptic D2 agonist activity and some D1 agonist activity was administered in the diet (0.5 mg/kg/day) of male Fischer 344 rats from age 3 to age 26 months. We hypothesized that the potent D2 presynaptic activity would reduce the baseline release of dopamine (DA) and thereby slow the formation of toxic oxidative metabolites that lead to age-related deterioration of nigrostriatal DA neurons. Pair-fed rats served as controls. We observed age-related losses of fluorescent DA cell bodies in the substantia nigra pars compacta and of fluorescent DA terminals in the striatum; chronic pergolide administration prevented these losses. Pergolide administration also prevented the age-related diminution of DA fluorescence intensity in substantia nigra cell bodies. A large decline in 3H-DA uptake with age was partially prevented by pergolide administration. We found no age-related alteration in the concentration of DA in the striatum and pergolide did not alter this concentration. Pergolide treatment resulted in only minor alterations in striatal 3H-spiperone binding and no change in dendritic arborizations of either DA substantia nigra neurons or medium spiny striatal neurons. Pergolide administration also prevented an age-related decline in circulating FSH levels. The uptake data and quantitative morphological findings suggest that pergolide administration in the diet for 2 years exerts a protective effect on age-related deterioration of DA nigrostriatal neurons. This finding was consistent with clinical reports of a subset of patients with Parkinson's disease in whom long-term efficacy of pergolide therapy is observed.

Aging↗
PubMed1988

Pergolide: long-term use in Parkinson's disease.

Previous short-term studies have shown that the dopamine agonist pergolide improves control of Parkinson's disease when used in conjunction with carbidopa-levodopa (Sinemet). We assessed the long-term outcome (2 1/2- to 3-year follow-up) in patients with Parkinson's disease who participated in our previous pergolide double-blind trial and were subsequently switched to open-label pergolide therapy. Of 41 evaluable patients who began pergolide therapy, 10 (24%) experienced sustained substantial benefit that persisted to the end of this investigation. A total of 23 patients (56%) remained on pergolide therapy and, as a group, had considerable improvement over baseline at 2 1/2 to 3 years on the basis of several measurements of efficacy. A tendency toward deterioration could be reversed in many patients by larger or more frequent doses of carbidopa-levodopa; nevertheless, all but four patients were still taking the same dose or less of carbidopa-levodopa at the end of this study as at the onset. Patients with the best initial response to pergolide seemed most likely to experience long-term benefit. Confusion and hallucinations were the side effects most likely to necessitate discontinuation of pergolide. Symptoms suggestive of dose-related angina pectoris occurred in four patients in the open-label phase and two patients in the earlier double-blind phase (13% of patients who started pergolide therapy); these symptoms were easily controlled by dose reduction or discontinuation of pergolide, without sequelae. Dose-related leukopenia developed in one patient.

Aged↗
PubMed2004

Treatment of Parkinson's disease with pergolide and relation to restrictive valvular heart disease.

BACKGROUND: Restrictive valvular heart disease has been reported in patients with Parkinson's disease treated with pergolide. However, few data are available on frequency, severity, dose dependency, and reversibility of pergolide-induced disease, nor on the pulmonary pressures of these patients. We aimed to clarify these characteristics in a large group of patients. METHODS: 78 patients with Parkinson's disease treated with pergolide and 18 never treated with an ergot-derived dopamine agonist (controls) were evaluated by echocardiography. A valvular scoring system was used, ranging from 1 (proven ergot-like restrictive valvular heart disease) to 4 (no disease). For the mitral valve, tenting areas and tenting distances were measured. Systolic pulmonary artery pressures were derived from the tricuspid regurgitant jet. FINDINGS: Restrictive valvular heart disease of any type was present in 26 (33%) patients in the pergolide group and none in controls (p=0.0025). Important disease (score 1 or 2) was present in 15 (19%) patients in the pergolide group and none in controls (p=0.066). Mean tenting distances and tenting areas of the mitral valve were 1.08 cm (range 0.55-2.66) and 2.39 cm2 (0.88-4.59) in the restrictive mitral valve group versus 0.63 cm (0.22-1.20) and 1.39 cm2 (0.39-3.23) in the non-restrictive group (p=0.003 and p<0.0001, respectively). Significant correlation was noted between cumulative doses of pergolide and tenting areas of the mitral valves (r=0.412, p=0.017). Mean systolic pulmonary artery pressures were 39.3 mm Hg (range 25-71) in the high-dose group versus 38.5 mm Hg (20-65) in the low-dose group (p=0.76) and 31 mm Hg (25-40) in controls (p=0.02 vs all patients given pergolide). In six patients, pergolide treatment was stopped because of restrictive valvular heart disease, in two of whom regression of disease was shown. INTERPRETATION: Restrictive valvular heart disease is not a rare finding in patients treated with pergolide. Clinicians should consider changing to a non-ergot drug if this disease is diagnosed.

Aged↗
PubMed1983

Elevation of serum corticosterone in rats by dopamine agonists related in structure to pergolide.

Two chemical analogs of pergolide were examined to test further the idea that pergolide elevates serum corticosterone concentration in rats by activation of brain dopaminergic receptors. LY116467, which contains an N-methyl substituent in place of the N-n-propyl substituent in pergolide, was less potent than pergolide in lowering brain levels of 3,4-dihydroxyphenylacetic acid (Dopac), the metabolite of dopamine. LY116467 increased serum corticosterone concentration in rats at a dose of 3 mg/kg (a higher dose than is required for pergolide), and the effect was prevented by spiperone pretreatment. LY141865, which has been reported to differ from pergolide in not activating dopamine-sensitive adenylate cyclase and which was found in this study to have much less affinity for serotonin receptors than does pergolide, increased serum corticosterone in much the same manner as pergolide, only slightly higher doses being required. The effect of LY141865 was prevented by pretreatment with haloperidol but not domperidone. Both haloperidol and domperidone increased serum prolactin concentration when given alone or in combination with LY141865, indicating they were both capable of blocking peripheral (pituitary) dopamine receptors. In contrast, haloperidol but not domperidone caused a marked elevation in brain levels of Dopac and of homovanillic acid and prevented the lowering of these brain dopamine metabolites by LY141865. The ability of LY141865 to increase serum corticosterone concentration was attenuated in rats that had received four daily injections of pergolide mesylate, indicating corss-tolerance had occurred. These results strengthen the hypothesis that activation of brain dopaminergic receptors leads to increased serum corticosterone concentration in rats.

3,4-Dihydroxyphenylacetic Acid↗
PubMed2005

[Effects of low-dose pergolide therapy on cardiac valves in patients with Parkinson's disease].

BACKGROUND: Pergolide mesilate is widely used to treat Parkinson's disease in both the USA and Japan, but the maintenance dose is distinctly different between the USA (usually more than 1.5 mg/day) and Japan (usually less than 1.5 mg/day). Although several reports from the USA have suggested that mitral, aortic, and tricuspid valvular lesions were caused by pergolide, it is unclear whether low-dose pergolide therapy causes such valvular lesions. OBJECTIVES: The effects of low-dose pergolide therapy on cardiac valves were studied in Japanese patients with Parkinson's disease. METHODS: One hundred and five consecutive patients with Parkinson's disease approved for our protocol were enrolled in this study. Forty patients were treated with low-dose pergolide (0.05-1.5 mg/day for 2-115 months), and were included in the pergolide group (mean age 71 +/- 6 years). The other 44 patients received no ergot-derived dopamine receptor agonists, and 32 patients acted as age-matched controls (mean age 71 +/- 7 years). Both groups of patients underwent echocardiographic examination to detect organic lesions in cardiac valves such as thickening of the leaflet, annular calcification, restriction of valve motion and valvular tenting, and valvular regurgitation greater than 2 + on the 4-point scale. RESULTS: No significant difference was observed in the incidence of aortic, mitral and pulmonic valve lesions between the pergolide group and the control group. Although no organic lesions were detected in the tricuspid valve, the incidence of tricuspid regurgitation was significantly higher in the pergolide group than in the control group (p < 0.05). CONCLUSIONS: Although low-dose pergolide of less than 1.5 mg/day does not cause serious damage in the left-sided valves, it may induce tricuspid regurgitation.

Aged↗
PubMed1983

The effects of pergolide on the cardiovascular system of 40 patients with Parkinson's disease.

The effect of pergolide, a semisynthetic ergot alkaloid, on the cardiovascular system of 40 patients with Parkinson's disease (PD) was evaluated. The mean daily dose of pergolide was 2.4 mg (range, 0.1 to 10 mg). The mean duration of follow-up was 6 months (range, 2 weeks to 20 months). The 40 patients were selected only on the basis of severe PD. All 13 patients in the first part of the study underwent 1 to 5 days of Holter monitoring before starting pergolide. Monitoring was then carried out for an additional period of between 2 and 10 weeks while the patients were on pergolide. Seven of the 13 patients manifested repetitive ventricular rhythms. These were isolated and unassociated with increases in premature ventricular contractions. The dose at which the RVRs occurred was a function of the presence or absence of heart disease. The changes occurred below 3 mg/day in patients with heart disease and above 3 mg/day in patients without heart disease. Pergolide was discontinued in three of the patients with heart disease. It was concluded that pergolide may, in the diseased heart, predispose to RVRs. In the second part of the study, Holter monitoring was carried out only at the discretion of the cardiologist, and five patients were so monitored. None of these patients was rejected from the study. Only one patient (with heart disease) of the 27 patients in the second part of the study experienced an arrhythmia. This consisted of an increase in PVCs on 4 mg/day of pergolide. Pergolide was discontinued. Eight of the 40 patients in these early dose-ranging studies experienced orthostasis, two with syncope, immediately on addition of pergolide (0.1 to 0.4 mg) to levodopa. The orthostasis could be eliminated in all but two patients by reducing or discontinuing levodopa.

Adult↗
PubMedDate not supplied

Protective effects of pergolide on dopamine levels in the 6-hydroxydopamine-lesioned mouse brain.

Pergolide, along with bromocriptine and lisuride, is one of the most active dopamine receptor agonists. To determine whether or not pergolide protects against dopaminergic neuronal damage, via its activity on monoamine metabolism, we studied the effects of pergolide pretreatment on changes in monomaines and their metabolites in the mouse striatum after intracerebroventricular injection of 6-hydroxydopamine with pretreatment of desipramine. After intracerebroventricular administration of 6-hydroxydopamine (40 micrograms) in mice, the levels of dopamine and its metabolites (DOPAC, HVA) in the striatum rapidly decreased to 49%, 29% and 68%, respectively, of the naive controls at week 1 but then gradually recovered to control levels at weeks 2 and 4. Repeated pretreatment with pergolide (0.5 mg/kg, i.p.) for 7 days before administration of 6-hydroxydopamine, almost completely protected against reduction in striatal dopamine and its metabolites 1 week after injection of 6-hydroxydopamine. Therefore, pergolide could normalize the decreased dopamine synthesis or storage, and has a neuroprotective effect against dopaminergic dysfunction induced by the neurotoxin, 6-hydroxydopamine. Although we found that pergolide did not show radical scavenging activity in an in vitro system that generated hydroxyl radicals, it has been reported in vivo that pergolide treatment may induce Cu/Zn superoxide dismutase in the rat striatum. Considering these findings, pergolide may well be protective to dopaminergic neurons, largely because of its effects on presynaptic autoreceptors and on its induction of Cu/Zn superoxide dismutase. Further research on the neuroprotective effects of pergolide in Parkinson disease models, by injection of 6-hydroxydopamine, is needed to clarify its mechanism of action on dopaminergic indices.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1983

Involvement of central dopamine receptors in the hypotensive action of pergolide.

The involvement of central dopamine receptors in the hypotensive action of the dopaminergic ergoline, pergolide was determined in anesthetized rats. Intravenous (i.v.) or intracerebroventricular (i.v.t.) administration of pergolide (12.5, 25 and 50 micrograms/kg) produced dose-dependent decreases in blood pressure. The magnitude of hypotension seen following either i.v. or i.v.t. administration of pergolide was similar. However, while both sulpiride (1 mg/kg, i.v.) as well as phentolamine (1 mg/kg, i.v.) antagonized the hypotensive action of i.v. pergolide, only sulpiride (1 mg/kg, i.v.t.) was able to antagonize the hypotension seen following i.v.t. administration of pergolide. Phentolamine (1 mg/kg, i.v.t.) did not alter the central hypotensive action of pergolide. In a separate group of rats, clonidine (25 micrograms/kg, i.v.t.) also produced a decrease in blood pressure. While phentolamine (i.v.t.) antagonized the central hypotensive action of clonidine, sulpiride (i.v.t.) did not have any effect on the action of clonidine. These results show that selective activation of central dopamine receptors was responsible for the hypotensive action of centrally-administered pergolide. In a separate group of rats greater splanchnic sympathetic nerve activity was measured. Intravenous pergolide produced similar hypotensive response as seen in previous groups, and this was accompanied by a concomitant decrease in the sympathetic nerve activity. The maximum fall in blood pressure (26 +/- 6 mm Hg) was correlated with a 40% reduction in sympathetic nerve activity. The return of blood pressure to control levels occurred after 60-70 min and was also associated with the return of sympathetic nerve activity to control levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Effects of pergolide on sensorimotor gating of the startle reflex in rats.

RATIONALE: Prepulse inhibition (PPI), a cross-species measure of sensorimotor gating, is impaired in certain neuropsychiatric disorders, including schizophrenia. This study was designed to assess the effects of the D2-family agonist pergolide in rats, in anticipation of human studies of the dopaminergic regulation of PPI. METHODS: The effects of pergolide (0.0001-0.5 mg/kg) on PPI of the acoustic startle reflex were studied in rats using a wide range of prepulse intensities [1-15 dB(A) over background] and prepulse intervals (5-100 ms, onset to onset). Studies also examined the effects of the D2 antagonist haloperidol on pergolide-induced changes in PPI. RESULTS: Pergolide exhibited dose- and stimulus-dependent effects on PPI. Pergolide increased PPI when startle stimuli were preceded by weak prepulses [1-5 dB(A) over background] at the longest prepulse interval (100 ms), or intense prepulses [15 dB(A) over background] at short prepulse intervals (5-20 ms). Pergolide (0.5 mg/kg) also decreased PPI elicited by intense prepulses at long intervals (60-100 ms). Both PPI-enhancing and PPI-disruptive effects of pergolide were reversed by the D2 antagonist haloperidol. CONCLUSIONS: These effects of pergolide suggest that D2 substrates mediate opposing influences on PPI under different stimulus conditions. The dopaminergic regulation of sensorimotor gating appears to interact with stimulus characteristics such as relative intensity and temporal separation, allowing for dynamic shifts in both the quantity and quality of "gated" information.

Animals↗
PubMed2001

Switching from pergolide to pramipexole in patients with Parkinson's disease.

OBJECTIVE/BACKGROUND: To compare the safety and efficacy of pramipexole and pergolide in the treatment of mild to moderate Parkinson's disease (PD). In contrast to pergolide, a D1 and D2 dopamine agonist, pramipexole is a nonergoline dopamine agonist with D2 and preferential D3 dopamine receptor activity. This selective activity may result in clinically different effects. No prospective head-to-head comparison studies of pergolide and pramipexole have been reported. METHODS: Patients with PD who were maintained on an optimal dose of pergolide were converted to pramipexole, typically over a one-month period. Clinical assessments were performed just prior to conversion and after an optimal dose of pramipexole was achieved. RESULTS: Twenty-five patients were converted from pergolide to pramipexole during the period of July, 1997 to January, 1999. Three patients were lost to follow-up, and one patient died. Of the remaining 21 patients there were 11 men and 10 women, mean age was 67.3 years +/- 10.0 (range 51-84). Mean duration of symptoms prior to conversion was 12.5 years +/- 3.4 (range 5-19). All patients (except one) were on concomitant carbidopa/ levodopa and experienced motor fluctuations. After a mean follow-up of 5.9 +/- 2.9 months on pramipexole, the mean levodopa daily dose was reduced from 618.7mg to 581.2mg (16.5% reduction, p = 0.61). The mean daily doses of pergolide and pramipexole (in milligrams per day) were 2.1 +/- 1.5 (0.15-6) and 3.2 +/- 1.1 (0.75-6) respectively. Thirteen patients (62%) reported overall improvement (subjective global response) on pramipexole as compared to pergolide, 5 (24%) were unchanged and 3 (14%) reported worsening. Eighteen of the 21 patients (86%) remained on pramipexole after the study period. Although there was a slight trend toward improved scores on pramipexole, the difference was not statistically significant. CONCLUSION: This open label study failed to provide evidence of superior efficacy of either dopamine agonist. It is possible, however, that while somepatients may benefit more from either pergolide or pramipexole, other patients may obtain additional benefit from other DA agonists or combination therapy. Future randomized, controlled, double-blinded therapeutic trials are needed to determine which, if any, dopamine agonist is superior in the treatment of PD.

Accidental Falls↗
PubMed1985

Effect of the dopamine D-1 antagonist SCH 23390 on rotational behaviour induced by apomorphine and pergolide in 6-hydroxy-dopamine denervated rats.

The experiments concerned the effects of the D-1 dopamine antagonist SCH 23390 on the rotational behaviour induced by apomorphine and pergolide in 6-hydroxy-dopamine denervated rats. SCH 23390 dose dependently inhibited the rotational behaviour induced by apomorphine. A significant inhibitory effect was obtained after 0.05 mg/kg s.c. of SCH 23390, which involved a change of the typical two-peak pattern of rotation induced by apomorphine. While the first peak of rotation was not significantly modified, the last peak of rotation induced by apomorphine was inhibited in a dose-dependent manner. No significant inhibition of the total rotation induced by pergolide was observed after SCH 23390 pretreatment. SCH 23390 seemed to enhance the duration of the rotation induced by pergolide, resulting in an increase in the total number of turns. However, the intensity of the maximal peak of rotation induced by pergolide was significantly inhibited after 5.0 mg/kg s.c. of SCH 23390. Comparison of the potency with which SCH 23390 inhibited the apomorphine- and pergolide-induced maximal peaks of rotation reveals that SCH 23390 was approximately 100 times more potent in inhibiting the apomorphine than the pergolide response. The results, compared with those in our previous report, show that the D-2 dopamine antagonist sulpiride was 1000 times more potent in inhibiting the pergolide than the apomorphine rotation. The present results support the hypothesis that apomorphine and pergolide induce rotation in 6-hydroxy-dopamine denervated rats by differential actions on D-1 and D-2 receptor sites.

Animals↗
PubMed1984

Biochemical and behavioral evaluation of pergolide as a dopamine agonist in the rat brain.

The ergot derivative pergolide was evaluated as a dopamine agonist using various behavioral and biochemical analyses. Spontaneous motor activity was decreased by small doses (0.1 mg/kg) of pergolide and increased with larger doses (above 0.5 mg/kg). Hypermotility after larger doses persisted for as long as 24 hr and was succeeded by a period of hypomotility. The doses of drug, sufficient to produce hypermotility, also produced stereotypy. With repeated daily injections (2 weeks), the period of hypermotility decreased and the ensuing period of hypomotility increased. Stereotyped behavior was similarly affected. Chronic administration of pergolide did not alter the magnitude of the behavioral responses. Levels of the dopamine (DA) metabolites, dihydroxyphenylacetate (DOPAC) and homovanillic acid (HVA), in the striatum and mesolimbic regions were decreased during the periods of hypermotility but returned to control levels during subsequent hypomotility. Activation of putative inhibitory presynaptic dopamine receptors by pergolide was studied by following accumulation of DOPA in rats treated with the dopamine neuron inhibiting agent, gamma-butyrolactone (GBL) and a DOPA-decarboxylase inhibitor. Pergolide significantly inhibited both striatal and mesolimbic accumulation of DOPA. In contrast, with changes in behavioral and metabolic indices, pergolide-induced inhibition of tyrosine hydroxylase was not affected by chronic treatment with pergolide. On the basis of both behavioral and biochemical data it is proposed that pergolide acts as a dopamine agonist with particularly long-lasting effects.

3,4-Dihydroxyphenylacetic Acid↗
PubMedDate not supplied

Cost-effectiveness of pergolide compared to bromocriptine in the treatment of Parkinson's disease: a decision-analytic model.

OBJECTIVE: To develop a decision-analytic model to assess the cost-effectiveness of pergolide versus bromocriptine in the treatment of Parkinson's disease (PD). METHODS: A Markov decision-analytic model is used to examine cost-effectiveness. The model ran for 20 cycles of 6 months' duration, and the patients progress through six stages: Hoehn-Yahr stages 1-5 and death. The transitional probabilities for each stage are derived from a 12-year longitudinal study of patients with PD. The costs in the model are derived from an expert panel containing six Australian neurologists. A review of the randomized controlled trials comparing the efficacy and safety of pergolide versus bromocriptine was undertaken. Five studies were identified, with four showing that pergolide offers superior efficacy when compared to bromocriptine. The Mizuno et al. (1995) study was the largest of the controlled trials and also measured patient Hoehn-Yahr status before and after treatment. This was identified as the most appropriate source of relative efficacy data for the model. The model examined various scenarios based on alternate durations of superior clinical benefit with pergolide compared to bromocriptine. The main analysis assumed that patients in each arm of the model would have identical Hoehn-Yahr status by the fifth year. Sensitivity analysis was used to determine cost-effectiveness in the case where the therapeutic benefit was of a shorter duration. RESULTS: The Mizuno study indicates that an additional 19.09% of patients improved by at least one stage on pergolide over bromocriptine, with an odds ratio of 2.26 (p < .01). The total health care cost per patient over the 10-year period was $46,323 in the pergolide treatment arm and $47,351 in the bromocriptine treatment arm, an incremental saving of $1028. Patients also spent extra time in Hoehn-Yahr stages 1, 2, and 3. In sensitivity analyses, when the benefit from pergolide expired between 6 months and 5 years after treatment cessation, cost savings ranged from $68 to $2535. CONCLUSION: Pergolide is cost saving and more efficacious than bromocriptine, and is therefore cost-effective.

Antiparkinson Agents↗