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Observation |

Pleuropulmonary Fibrosis After Long-term Treatment With the Dopamine Agonist Pergolide for Parkinson Disease FREE

Ron Tintner, MD; Prasad Manian, MD; Polly Gauthier, MD; Joseph Jankovic, MD
[+] Author Affiliations

Author Affiliations: Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine (Drs Tintner and Jankovic), Medical Clinic of Houston, LLP (Dr Manian), and Department of Pathology, St Luke’s Episcopal Hospital (Dr Gauthier), Houston, Tex. Dr Tintner is now with the Department of Neurology, Methodist Neuroscience Institute, Houston.


Arch Neurol. 2005;62(8):1290-1295. doi:10.1001/archneur.62.8.1290.
Text Size: A A A
Published online

Dopamine agonists are increasingly used in the treatment of Parkinson disease, but they may cause serious adverse effects. In December 1983, symptoms of Parkinson disease developed in a 55-year-old man with no history of pulmonary disease, smoking, or asbestos exposure. He began treatment with dopamine agonists bromocriptine mesylate (in 1984) and pergolide mesylate (in 1989). In late 2000, pulmonary symptoms developed. Chest radiographs and computed tomographic findings showed a mass in the right upper lobe and effusion. A biopsy specimen showed pleural and parenchymal fibrosis. This syndrome resolved after cessation of pergolide therapy and a switch to pramipexole dihydrochloride. This case draws attention to the association of long-term ergot dopamine agonist therapy with pleuropulmonary fibrosis, which can develop as late as 11 years after the initiation of therapy. We also review evidence that the risk of this complication is substantially lower with the newer nonergot dopamine agonists.

Figures in this Article

Dopamine agonists are used in the treatment of Parkinson disease (PD), restless legs syndrome, and other neurological and endocrine disorders.1 Recent data on dopamine agonists in PD support earlier, and thus longer, use of these agents to prevent motor complications and possibly to slow neurodegeneration.2 Based on their structure, these agents can be classified as ergot (bromocriptine mesylate, pergolide mesylate, and cabergoline) (Figure 1A) or as nonergot derivatives (pramipexole dihydrochloride and ropinirole hydrochloride) (Figure 1B). In addition to a variety of gastrointestinal tract, psychiatric, and autonomic adverse effects common to all these agents, fibrotic syndromes involving the retroperitoneum, pleura, and pericardium are infrequent but potentially life-threatening complications of the ergot agents. These complications have hitherto been described within the first several years of use, but the case reported herein suggests that vigilance must be maintained throughout the treatment period.

Place holder to copy figure label and caption
Figure 1.

Structural formulas of dopamine agonists. A, Pergolide and ergot dopamine agonists. B, Pramipexole dihydrochloride and ropinirole hydrochloride (nonergot dopamine agonists).

Graphic Jump Location

In December 1983, a man aged 55 years complained of left arm stiffness, soreness, and paresthesias. On examination, he had decreased blink frequency, poverty of spontaneous movement in general and especially of the left upper extremity, stiff gait, and en bloc turning. His left arm was kept in slight flexion and had increased tone with cogwheel rigidity and decreased rapid alternating movements. A diagnosis of PD was made, but no treatment was started until September 1984, when bromocriptine mesylate therapy was started and the dosage was titrated to 22.5 mg/d with moderate improvement in left arm symptoms. In July 1985, the bromocriptine mesylate dosage was reduced to 15 mg/d and carbidopa and levodopa therapy were started and increased to 3 divided doses of 75 and 300 mg, respectively, with marked symptomatic improvement. Slight deterioration ensued over the next years, and in October 1987, amantadine hydrochloride therapy at a dosage of 200 mg/d was added with minimal symptomatic benefit. In June 1989, after stopping amantadine therapy because of ankle edema, his left-sided PD symptoms increased, and subsequently improved partially when amantadine therapy was restarted. In August 1989, bromocriptine therapy was discontinued and pergolide mesylate therapy at a dosage of 1.5 mg/d was initiated. His parkinsonism progressed, necessitating adjustment of the levodopa dosage. In August 2000, a cough and shortness of breath developed that led to the diagnosis of pleural effusion (Figure 2A). At that time, he also received daily treatment with tolterodine tartrate, 2 mg; lisinopril, 5 mg; spironolactone, 25 mg; furosemide, 40 mg; and aspirin, 81 mg.

Place holder to copy figure label and caption
Figure 2.

Radiological findings in the chest of our patient. A, Radiograph demonstrates right-sided infiltrate. B and C, Computed tomographic scans of different axial sections along the rostrocaudal axis after thoracentesis shows a mass in the right upper lobe of the lung abutting the pleura with fibrotic strands radiating from the mass into the lung parenchyma. Pleural plaques are seen. Each tick mark indicates 1 cm.

Graphic Jump Location

Computed tomography of the chest showed a mass in the right upper lobe of the lung and pleural plaques (Figure 2B and C). Because of coronary artery disease (with a previous inferior myocardial infarction) and evidence of congestive heart failure (an ejection fraction of 40%), a stent was placed in the left anterior descending coronary artery. He underwent multiple thoracenteses for recurrent bloody pleural effusions and multiple computed tomography–guided biopsies with a final diagnosis of fibrosis. He was readmitted to the hospital in October 2000 and underwent thoracotomy and biopsy of the right lung and pleura. The biopsy results showed fibrotic changes in the pleura with mild chronic inflammation (Figure 3).

Place holder to copy figure label and caption
Figure 3.

Hematoxylin-eosin–stained sections from pleura. These grossly demonstrated fibrosis. All the sections contained fibrinous and fibrous pleuritis. The cells within the areas of fibrosis are spindled, oriented parallel to the surface mesothelium, and without nuclear atypia. The morphologic and immunohistochemical findings were believed to be consistent with a reactive process (original magnification ×100 and ×40 for A and B, respectively).

Graphic Jump Location

Pramipexole dihydrochloride was substituted for pergolide, and the dosage was gradually increased to 3 mg/d in November 2000.

In July 2001 he had mild motor fluctuations related to long-term levodopa therapy, but his parkinsonism was relatively well controlled. In addition to 3 mg/d of pramipexole, he was receiving 50 mg of carbidopa and 200 mg of levodopa 5 times per day and half of a tablet of combined 50-mg carbidopa and 200-mg levodopa (controlled-release Sinemet) at bedtime. He has continued to do well without recurrence of pulmonary signs or symptoms through July 2002.

This case draws attention to a potentially life-threatening complication associated with the use of ergot drugs, particularly pergolide, in the treatment of PD. Pleural effusion and pleuropulmonary fibrosis, confirmed by biopsy findings, developed while the patient received pergolide. He had no prior exposures or risk factors for development of pleuropulmonary fibrosis except for an earlier 5-year exposure to bromocriptine. Because this ergot drug is also associated with fibrotic syndromes, it may have played a contributory role, but the fact that the pleuropulmonary fibrosis occurred 11 years after discontinuation of bromocriptine therapy and resolved immediately after discontinuation of pergolide therapy strongly suggests that pergolide was the causative agent.

Ten cases of fibrosis of serosal membranes associated with pergolide use have been reported in the literature (Table). In addition, 3 cases of restrictive pericarditis have been reported in an abstract form but without documentation of latency or dosage11 (Table). In all of the reported cases of pergolide-induced fibrotic reactions, the symptoms occurred within 3 years of initiation of treatment. Our case differs from the published reports in that the complication took 11 years to develop; however, since the initial report of this case in abstract form, development of pericardial fibrosis in another patient after 11 years has been reported in the Japanese literature.13 A recent newsletter has reported fibrosing alveolitis in a 48-year-old woman who had been taking pergolide for more than 6 years before development of shortness of breath and reduced exercise tolerance with computed tomographic evidence of hypersensitivity pneumonitis and fibrosing alveolitis. However, no dosage or response to discontinuation of therapy data were documented.12

Table Graphic Jump LocationTable. Literature Reports of Serosal Fibrosis Syndromes Associated With Pergolide

Serosal fibrosis syndromes have been associated not only with ergot dopamine agonists such as bromocriptine, pergolide, lisuride, cabergoline, mesulergine, and dihydroergocryptine used in the treatment of PD,8,1620 but also with other ergots not used in PD. In particular, methysergide maleate21 has been reported to have rates of fibrosis estimated at 1 for every 5000 treated patients. The 2 newest dopamine agonists used for PD, pramipexole and ropinirole, are not ergolines (Figure 1B). Because these drugs have not been associated with fibrotic reactions, it has been postulated that mechanisms other than dopamine activation play a role in the development of dopamine agonist–associated fibrosis. Apomorphine hydrochloride, a nonergot agonist at the D1 and D2 dopamine receptors, has also not been associated with fibrotic reactions.

Furthermore, cases have now been reported of restrictive valvular heart disease associated with pergolide.14,15 Three of these cases report histologically confirmed changes consisting of endocardial plaque formation overlying normal valvular architecture, ie, serosal fibrosis.14 This resembles the valvular pathology of carcinoid valve disease,22 as well as that seen with ergots such as methysergide23 and ergotamine tartrate24 and the anorexic agents fenfluramine hydrochloride and dexfenfluramine hydrochloride.25 A case of bromocriptine-associated valvular disease has now also been reported but without the pathological evidence.26 A subsequent report15 documented the clinical and echocardiographic findings in 2 patients and the pathological findings in one of them, who had been treated with more than 5 mg/d of pergolide mesylate and who developed symptomatic severe heart failure due to restrictive valvular disease. The report also described the echocardiographic data of another 8 patients taking similar doses of pergolide and presenting no clinical signs of heart failure. The authors suggest a possible role of high doses of pergolide in inducing restrictive valvular disease, but as other cases demonstrate here, that is not necessarily true. However, in that previous report, valvular disease developed extremely rapidly (3 and 18 months). Since initial submission of this report, several other cases have been reported and received comment.2729

The mechanism of fibrotic reaction by ergot alkaloids is unknown. Proposed mechanisms include an idiosyncratic immune reaction and modulation at peripheral neurotransmitter or humoral receptor sites. These compounds all share the ergoline nucleus, similar to that of lysergic acid, with structurally different peptides attached to the C8 region of the ergoline ring (Figure 1A). The ergots are all antagonists at serotonin 2 receptors, although pergolide and even bromocriptine are less potent in this action than methysergide; in addition, this drug-receptor interaction may not constitute pure antagonism. Pergolide and other ergots may also modulate other serotonergic receptors. The ergots have cytostatic, endocrine, and immunosuppressant actions besides neurotransmitter modulation.30 It has been suggested that the fibrotic complications are dose related or seen with recent increases in dosage,8 although that does not seem to be the case in our patient.

Fibrosis probably results from fibroblast stimulation by various factors.31 Connective tissue growth factor has recently been described as a fibrogenic factor that induces collagen type I and fibronectin, and the deposition of such molecules leads to fibrotic disease in many tissues. Connective tissue growth factor is believed to play a crucial role in fibrotic disease formation in many tissues. Connective tissue growth factor in turn is regulated by many factors, including transforming growth factor β, dexamethasone, and serotonin. Furthermore, transforming growth factor β stimulates pleural fibrosis and pleural effusions32 via pathways in series and parallel with connective tissue growth factor.

Another possibility is that pergolide- and ergot-induced fibrotic syndromes involve serotonin. Fibrotic complications have been reported with carcinoid syndrome in which there is overproduction of serotonin.33,34 Serotonin has also been shown to trigger the transforming growth factor β–mediated cascade35 via serotonin 2A receptors. Fibroblast stimulation has also been demonstrated through serotonin 1B receptors. Most ergots also have actions at serotonin receptors.30 Methysergide, the ergot most frequently linked to fibrotic complications, is an antagonist at serotonin 2A receptors, which one would predict would interfere with the fibrotic cascade. The pharmacology of the ergot drugs at the serotonin receptors of the immune system has not been fully elucidated, and thus an action of the ergots at serotonin receptors remains at least a possible explanation for these fibrotic complications. In addition, atypical antipsychotics such as olanzapine and clozapine are fairly potent serotonin 2A antagonists and have not been associated with fibrosis.

Another related hypothesis is that this occurs because of interference with pineal function, which is profoundly affected by serotonergic function. Pinealectomy leads to increased formation of fibrous tissue in the abdominal cavity. It also leads to reduced formation and/or action of prostaglandin E1 and thromboxane A2. Prostaglandin E1 plays an important role in enhancing function of T-suppressor lymphocytes that control overactive antibody-producing B lymphocytes in situations such as collagen diseases, lithium-induced fibrosis, and cardiomyopathies.36

An immunologic or hypersensitivity reaction has also been proposed as a mechanism for ergot-induced fibrosis. It is possible that the ergoline ring structure acts as a hapten to induce an immune response. Fibrotic reactions have been hypothesized to occur as a result of a hypersensitivity reaction to antigens, eg, leaking into the retroperitoneum from atheromatous plaques in the aorta or the common iliac arteries.37 Mast cells are hypothesized to participate in processes leading to tissue fibrosis in human lung and skin. There is evidence that asbestos-mediated pulmonary fibrosis may be mediated through mast cell–released serotonin and histamine.38 Human mast cell tryptase is a potent inducer of DNA synthesis in fibroblasts from multiple sources, including human lung but with target cell specificity.39

Delayed drug reactions can be immune or nonimmune mediated. Both types are generally not due to the parent compounds but to their metabolites,40 and it is possible that the fibrotic process is not caused by the parent compound but by a metabolite. Altered pathways of xenobiotic metabolism can have profound effects on metabolic activation of pulmonary drug toxicity.41 At least 10 metabolites of pergolide have been detected, including N-despropylpergolide, pergolide sulfoxide, and pergolide sulfone. Pergolide sulfoxide and pergolide sulfone are dopamine agonists in animals. The other detected metabolites have not been identified, and it is not known whether any other metabolites are active pharmacologically.42 The late onset of serosal fibrosis could be triggered by the appearance or increased concentration of a pergolide (or other ergot) metabolite due to induction or inhibition of an alternate metabolic pathway, as has been shown in the case of phenobarbital-potentiating carbon tetrachloride toxicity.41

Our report provides evidence that ergot dopamine agonists such as pergolide can induce pulmonary fibrosis and possibly other serosal fibrotic syndromes, even after more than a decade of treatment. Therefore, patients presenting with symptoms of pleural, pericardial, or retroperitoneal fibrosis while taking ergot dopamine agonists should switch to a nonergot dopamine agonist. On the other hand, the risk of fibrosis even with long-term ergot exposure is so minimal and usually reversible that it should not outweigh the potential benefits. However, because there is no evidence that the ergot dopamine agonists currently licensed in the United States are clinically superior to the nonergot dopamine agonists, any increased risk should be balanced by increased benefit. A high level of vigilance of this potential complication, however, is prudent.

Correspondence: Ron Tintner, MD, Department of Neurology, Methodist Neuroscience Institute, 6560 Fannin, Suite 904, Houston, TX 77030 (rtintner@tmh.tmc.edu).

Accepted for Publication: August 2, 2004.

Author Contributions:Study concept and design: Tintner, Manian, and Jankovic. Acquisition of data: Tintner and Manian. Analysis and interpretation of data: Tintner, Manian, Gauthier, and Jankovic. Drafting of the manuscript: Tintner and Jankovic. Critical revision of the manuscript for important intellectual content: Tintner, Manian, and Gauthier. Administrative, technical, and material support: Tintner, Manian, and Jankovic. Study supervision: Gauthier and Jankovic.

Tan  EKJankovic  J Choosing dopamine agonists in Parkinson’s disease. Clin Neuropharmacol 2001;24247- 253
PubMed
Tintner  RJankovic  J Treatment options for Parkinson’s disease. Curr Opin Neurol 2002;15467- 476
PubMed
Lund  BCNeiman  RFPerry  PJ Treatment of Parkinson’s disease with ropinirole after pergolide-induced retroperitoneal fibrosis. Pharmacotherapy 1999;191437- 1438
PubMed
Jimenez-Jimenez  FJLopez-Alvarez  JSanchez-Chapado  M  et al.  Retroperitoneal fibrosis in a patient with Parkinson’s disease treated with pergolide. Clin Neuropharmacol 1995;18277- 279
PubMed
Danoff  SKGrasso  METerry  PBFlynn  JA Pleuropulmonary disease due to pergolide use for restless legs syndrome. Chest 2001;120313- 316
PubMed
Mondal  BKSuri  S Pergolide-induced retroperitoneal fibrosis [case report]. Int J Clin Pract 2000;54403
PubMed
Shaunak  SWilkins  APilling  JBDick  DJ Pericardial, retroperitoneal, and pleural fibrosis induced by pergolide. J Neurol Neurosurg Psychiatry 1999;6679- 81
PubMed
Varsano  SGershman  MHamaoui  E Pergolide-induced dyspnea, bilateral pleural effusion and peripheral edema [case report]. Respiration 2000;67580- 582
Kunkler  RBOsborn  DEAbbott  RJ Retroperitoneal fibrosis caused by treatment with pergolide in a patient with Parkinson’s disease [case report]. Br J Urol 1998;82147
PubMed
Balachandran  KPStewart  DBerg  GAOldroyd  KG Chronic pericardial constriction linked to the antiparkinsonian dopamine agonist pergolide. Postgrad Med J 2002;7849- 50
PubMed
Tolar  MGorelick  RFeldman  R Constrictive pericarditis in Parkinson’s disease patients treated with pergolide [abstract]. Ann Neurol 2001;50S32
 Pergolide: serosal fibrotic complications. Mersey ADR Newsletter2000/2001:2
Kuwabara  T Pergolide-induced pleural effusion in a patient with juvenile parkinsonism [in Japanese]. Rinsho Shinkeigaku 2002;42757- 760
PubMed
Pritchett  AMMorrison  JFEdwards  WDSchaff  HVConnolly  HMEspinosa  RE Valvular heart disease in patients taking pergolide. Mayo Clin Proc 2002;771280- 1286
PubMed
Van Camp  GFlamez  ACosyns  BGoldstein  JPerdaens  CSchoors  D Heart valvular disease in patients with Parkinson’s disease treated with high-dose pergolide. Neurology 2003;61859- 861
PubMed
Bhatt  MHKeenan  SPFleetham  JACalne  DB Pleuropulmonary disease associated with dopamine agonist therapy. Ann Neurol 1991;30613- 616
PubMed
 Pleuropulmonary changes during long-term bromocriptine treatment for Parkinson’s disease [letter]. Lancet 1981;144- 45
PubMed
Ling  LHAhlskog  JEMunger  TMLimper  AHOh  JK Constrictive pericarditis and pleuropulmonary disease linked to ergot dopamine agonist therapy (cabergoline) for Parkinson’s disease. Mayo Clin Proc 1999;74371- 375
PubMed
Geminiani  GFetoni  VGenitrini  SGiovannini  PTamma  FCaraceni  T Cabergoline in Parkinson’s disease complicated by motor fluctuations. Mov Disord 1996;11495- 500
PubMed
Oechsner  MGroenke  LMueller  D Pleural fibrosis associated with dihydroergocryptine treatment. Acta Neurol Scand 2000;101283- 285
PubMed
Silberstein  SD Methysergide. Cephalalgia 1998;18421- 435
PubMed
Robiolio  PRigolin  VWilson  J Carcinoid heart disease: correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation 1995;92790- 795
PubMed
Misch  K Development of heart valve lesions during methysergide therapy. BMJ 1974;2365- 366
PubMed
Redfield  MNicholson  WEdwards  WTajik  A Valve disease associated with ergot alkaloid use: echocardiographic and pathological relations. Ann Intern Med 1992;11750- 52
PubMed
Connolly  HCrary  JMcGoon  M Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337581- 588
PubMed
Serratrice  JDisdier  PHabib  GViallet  FWeiller  P Fibrotic valvular heart disease subsequent to bromocriptine treatment. Cardiol Rev 2002;10334- 336
PubMed
Rascol  OPathak  ABagheri  HMontastruc  JL New concerns about old drugs: valvular heart disease on ergot derivative dopamine agonists as an exemplary situation of pharmacovigilance. Mov Disord 2004;19611- 613
PubMed
Agarwal  PFahn  SFrucht  SJ Diagnosis and management of pergolide-induced fibrosis. Mov Disord 2004;19699- 704
PubMed
Horvath  JFross  RDKleiner-Fisman  G  et al.  Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists. Mov Disord 2004;19656- 662
PubMed
Rehacek  ZSajdl  P Ergot Alkaloids: Chemistry, Biological Effects, Biotechnology.  Amsterdam, the Netherlands: Elsevier Science Inc; 1990
Park  SKKim  JSeomun  Y  et al.  Hydrogen peroxide is a novel inducer of connective tissue growth factor. Biochem Biophys Res Commun 2001;284966- 971
PubMed
Lee  YCLane  KB The many faces of transforming growth factor-β in pleural diseases. Curr Opin Pulm Med 2001;7173- 179
PubMed
Kucuk  ONoskin  GPetersen  K  et al.  Lower extremity vasospasm associated with ischemic neuropathy, dermal fibrosis, and digital gangrene in a patient with carcinoid syndrome. Cancer 1988;621026- 1029
PubMed
Morand  JJLagrassa  SAbitan  R  et al.  Edema caused by retroperitoneal and tricuspid fibrosis with sclerodermatous cutaneous involvement disclosing carcinoid tumor: apropos of a case and review of the literature [in French]. Rev Med Interne 1997;18388- 395
PubMed
Grewal  JSMukhin  YVGarnovskaya  MNRaymond  JRGreene  EL Serotonin 5-HT2A receptor induces TGF-β1 expression in mesangial cells via ERK: proliferative and fibrotic signals. Am J Physiol 1999;276F922- F930
PubMed
Cunnane  SCManku  MSHorrobin  DF The pineal and regulation of fibrosis: pinealectomy as a model of primary biliary cirrhosis: roles of melatonin and prostaglandins in fibrosis and regulation of T lymphocytes. Med Hypotheses 1979;5403- 414
PubMed
Erton  MLIlker  YNCeyhan  NAkdas  A Retroperitoneal fibrosis due to malignancy: a case report. Int Urol Nephrol 1995;27147- 150
PubMed
Keith  IDay  RLemaire  SLemaire  I Asbestos-induced fibrosis in rats: increase in lung mast cells and autacoid contents. Exp Lung Res 1987;13311- 327
PubMed
Hartmann  TRuoss  SJRaymond  WWSeuwen  KCaughey  GH Human tryptase as a potent, cell-specific mitogen: role of signaling pathways in synergistic responses. Am J Physiol 1992;262L528- L534
PubMed
Anderson  JA Allergic reactions to drugs and biological agents. JAMA 1992;2682844- 2857
PubMed
Gram  TE Chemically reactive intermediates and pulmonary xenobiotic toxicity. Pharmacol Rev 1997;49297- 341
PubMed
 Pergolide manufacturers [package insert].  Indianapolis, Ind: Eli Lilly & Co; 2001

Figures

Place holder to copy figure label and caption
Figure 1.

Structural formulas of dopamine agonists. A, Pergolide and ergot dopamine agonists. B, Pramipexole dihydrochloride and ropinirole hydrochloride (nonergot dopamine agonists).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Radiological findings in the chest of our patient. A, Radiograph demonstrates right-sided infiltrate. B and C, Computed tomographic scans of different axial sections along the rostrocaudal axis after thoracentesis shows a mass in the right upper lobe of the lung abutting the pleura with fibrotic strands radiating from the mass into the lung parenchyma. Pleural plaques are seen. Each tick mark indicates 1 cm.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

Hematoxylin-eosin–stained sections from pleura. These grossly demonstrated fibrosis. All the sections contained fibrinous and fibrous pleuritis. The cells within the areas of fibrosis are spindled, oriented parallel to the surface mesothelium, and without nuclear atypia. The morphologic and immunohistochemical findings were believed to be consistent with a reactive process (original magnification ×100 and ×40 for A and B, respectively).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable. Literature Reports of Serosal Fibrosis Syndromes Associated With Pergolide

References

Tan  EKJankovic  J Choosing dopamine agonists in Parkinson’s disease. Clin Neuropharmacol 2001;24247- 253
PubMed
Tintner  RJankovic  J Treatment options for Parkinson’s disease. Curr Opin Neurol 2002;15467- 476
PubMed
Lund  BCNeiman  RFPerry  PJ Treatment of Parkinson’s disease with ropinirole after pergolide-induced retroperitoneal fibrosis. Pharmacotherapy 1999;191437- 1438
PubMed
Jimenez-Jimenez  FJLopez-Alvarez  JSanchez-Chapado  M  et al.  Retroperitoneal fibrosis in a patient with Parkinson’s disease treated with pergolide. Clin Neuropharmacol 1995;18277- 279
PubMed
Danoff  SKGrasso  METerry  PBFlynn  JA Pleuropulmonary disease due to pergolide use for restless legs syndrome. Chest 2001;120313- 316
PubMed
Mondal  BKSuri  S Pergolide-induced retroperitoneal fibrosis [case report]. Int J Clin Pract 2000;54403
PubMed
Shaunak  SWilkins  APilling  JBDick  DJ Pericardial, retroperitoneal, and pleural fibrosis induced by pergolide. J Neurol Neurosurg Psychiatry 1999;6679- 81
PubMed
Varsano  SGershman  MHamaoui  E Pergolide-induced dyspnea, bilateral pleural effusion and peripheral edema [case report]. Respiration 2000;67580- 582
Kunkler  RBOsborn  DEAbbott  RJ Retroperitoneal fibrosis caused by treatment with pergolide in a patient with Parkinson’s disease [case report]. Br J Urol 1998;82147
PubMed
Balachandran  KPStewart  DBerg  GAOldroyd  KG Chronic pericardial constriction linked to the antiparkinsonian dopamine agonist pergolide. Postgrad Med J 2002;7849- 50
PubMed
Tolar  MGorelick  RFeldman  R Constrictive pericarditis in Parkinson’s disease patients treated with pergolide [abstract]. Ann Neurol 2001;50S32
 Pergolide: serosal fibrotic complications. Mersey ADR Newsletter2000/2001:2
Kuwabara  T Pergolide-induced pleural effusion in a patient with juvenile parkinsonism [in Japanese]. Rinsho Shinkeigaku 2002;42757- 760
PubMed
Pritchett  AMMorrison  JFEdwards  WDSchaff  HVConnolly  HMEspinosa  RE Valvular heart disease in patients taking pergolide. Mayo Clin Proc 2002;771280- 1286
PubMed
Van Camp  GFlamez  ACosyns  BGoldstein  JPerdaens  CSchoors  D Heart valvular disease in patients with Parkinson’s disease treated with high-dose pergolide. Neurology 2003;61859- 861
PubMed
Bhatt  MHKeenan  SPFleetham  JACalne  DB Pleuropulmonary disease associated with dopamine agonist therapy. Ann Neurol 1991;30613- 616
PubMed
 Pleuropulmonary changes during long-term bromocriptine treatment for Parkinson’s disease [letter]. Lancet 1981;144- 45
PubMed
Ling  LHAhlskog  JEMunger  TMLimper  AHOh  JK Constrictive pericarditis and pleuropulmonary disease linked to ergot dopamine agonist therapy (cabergoline) for Parkinson’s disease. Mayo Clin Proc 1999;74371- 375
PubMed
Geminiani  GFetoni  VGenitrini  SGiovannini  PTamma  FCaraceni  T Cabergoline in Parkinson’s disease complicated by motor fluctuations. Mov Disord 1996;11495- 500
PubMed
Oechsner  MGroenke  LMueller  D Pleural fibrosis associated with dihydroergocryptine treatment. Acta Neurol Scand 2000;101283- 285
PubMed
Silberstein  SD Methysergide. Cephalalgia 1998;18421- 435
PubMed
Robiolio  PRigolin  VWilson  J Carcinoid heart disease: correlation of high serotonin levels with valvular abnormalities detected by cardiac catheterization and echocardiography. Circulation 1995;92790- 795
PubMed
Misch  K Development of heart valve lesions during methysergide therapy. BMJ 1974;2365- 366
PubMed
Redfield  MNicholson  WEdwards  WTajik  A Valve disease associated with ergot alkaloid use: echocardiographic and pathological relations. Ann Intern Med 1992;11750- 52
PubMed
Connolly  HCrary  JMcGoon  M Valvular heart disease associated with fenfluramine-phentermine. N Engl J Med 1997;337581- 588
PubMed
Serratrice  JDisdier  PHabib  GViallet  FWeiller  P Fibrotic valvular heart disease subsequent to bromocriptine treatment. Cardiol Rev 2002;10334- 336
PubMed
Rascol  OPathak  ABagheri  HMontastruc  JL New concerns about old drugs: valvular heart disease on ergot derivative dopamine agonists as an exemplary situation of pharmacovigilance. Mov Disord 2004;19611- 613
PubMed
Agarwal  PFahn  SFrucht  SJ Diagnosis and management of pergolide-induced fibrosis. Mov Disord 2004;19699- 704
PubMed
Horvath  JFross  RDKleiner-Fisman  G  et al.  Severe multivalvular heart disease: a new complication of the ergot derivative dopamine agonists. Mov Disord 2004;19656- 662
PubMed
Rehacek  ZSajdl  P Ergot Alkaloids: Chemistry, Biological Effects, Biotechnology.  Amsterdam, the Netherlands: Elsevier Science Inc; 1990
Park  SKKim  JSeomun  Y  et al.  Hydrogen peroxide is a novel inducer of connective tissue growth factor. Biochem Biophys Res Commun 2001;284966- 971
PubMed
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