Update: Pergolide, Cabergoline and Heart Damage

[ZucchiniFlower]

Parkinson's drugs can cause heart damage-studies


By Gene Emery and Toni Clarke

BOSTON, Jan 3 (Reuters) - Two Parkinson's disease drugs cause the same kind of heart damage that led to the withdrawal of the diet drug combination "fen-phen," according to two studies published on Wednesday.

Patients taking the drugs pergolide, developed by Eli Lilly & Co. <LLY.N> and sold under the brand name Permax, and cabergoline, developed by Pfizer Inc. <PFE.N> and sold under the brand Dostinex, had a sharply higher risk of heart valve damage than those taking other therapies, the studies said.

The studies, one of which analyzed the records of 11,417 patients in Britain and one of which tested 245 patients in Italy, reinforce the results of earlier, smaller studies showing that drugs which activate a cellular receptor known as 5-HT2b can cause damage to the heart valve, a serious condition that can lead to heart failure and sudden death.

"We recommend that physicians not prescribe drugs that have this biochemical property," said Bryan Roth, a researcher at the University of North Carolina, Chapel Hill, who was not involved in the trials but viewed the data and commented on it in The New England Journal of Medicine, where both studies appeared.

Such drugs also include the migraine headache drug ergotamine and the amphetamine derivative known as "ecstasy."

Roth said his team, in a separate piece of research that has yet to be published or reviewed by the scientific community, has identified several other big-selling drugs that have until now not been known to activate the 5-HT2b receptor.

He declined to reveal the names of the drugs until the research has been published.

"We recommend that every drug be screened at this receptor before it goes into humans," Roth told Reuters in an interview. "It costs just pennies per drug for such a screen."

The British study showed that patients taking pergolide were 7.1 times more likely to develop heart valve damage than those who took other treatments. Patients taking the highest doses of the drug had a 37 times greater risk.

The study showed that patients taking cabergoline were 4.9 times more likely to develop heart valve damage. At higher doses patients were 50.3 times more likely to suffer damage.

Both drugs are available in generic form.

A second study, conducted in Italy, tested 245 people, of whom 155 had Parkinson's disease. Of the diseased population, one group received pergolide, one group received cabergoline, and one group received an alternative Parkinson's treatment. The non-diseased control group received nothing.

The results showed that 23.4 percent of patients taking pergolide and 28.6 percent of patients taking cabergoline suffered heart damage, compared to just 5.6 percent in the control group.

"These are huge risks," said Roth. He said they were similar to the kind of damage seen with fen-phen, whose main ingredients were withdrawn in 1997 and forced the drug-maker Wyeth <WYE.N> to take more than $21 billion in charges to cover liabilities.

Wyeth's recalled drugs were fenfluramine, or Pondimin, and dexfenfluramine, or Redux. To make fen-phen, one or the other was combined with another drug called phentermine that is still sold by other companies.

Wyeth, then called American Home Products, recalled Pondimin and Redux after some of the 6 million Americans who had taken fen-phen developed heart-valve problems.

Roth said pergolide is also used to treat restless leg syndrome, a condition in which patients feel a crawling sensation in their legs combined with a need to move them.

[toyL]

Thanks for the info, ZF.

[ZucchiniFlower]

From the study:
NEJM: Volume 356:29-38 January 4, 2007 Number 1


Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation
René Schade, M.D., Frank Andersohn, M.D.,

"In conclusion, our study showed that treatment with either pergolide or cabergoline, particularly at daily doses greater than 3 mg and for periods of 6 months or longer, was associated with a substantially increased risk of newly diagnosed cardiac-valve regurgitation. There was no evidence of such an increase in risk with the use of other dopamine agonists."

ABSTRACT

Background Case reports and echocardiographic studies suggest that the ergot-derived dopamine agonists pergolide and cabergoline, used in the treatment of Parkinson's disease and the restless legs syndrome, may increase the risk of cardiac-valve regurgitation.

Methods We used data from the United Kingdom General Practice Research Database to identify a population-based cohort comprising 11,417 subjects 40 to 80 years of age who were prescribed antiparkinsonian drugs between 1988 and 2005.

We conducted a nested case–control analysis within this cohort in which each patient with newly diagnosed cardiac-valve regurgitation was matched with up to 25 control subjects from the cohort, according to age, sex, and year of entry into the cohort. Incidence-rate ratios for cardiac-valve regurgitation with the use of different dopamine agonists were estimated by conditional logistic-regression analysis.

Results Of 31 case patients with newly diagnosed cardiac-valve regurgitation, 6 were currently exposed to pergolide, 6 were currently exposed to cabergoline, and 19 had not been exposed to any dopamine agonist within the previous year. The rate of cardiac-valve regurgitation was increased with current use of pergolide (incidence-rate ratio, 7.1; 95% confidence interval [CI], 2.3 to 22.3) and cabergoline (incidence-rate ratio, 4.9; 95% CI, 1.5 to 15.6), but not with current use of other dopamine agonists.

Conclusions In this study, use of the dopamine agonists pergolide and cabergoline was associated with an increased risk of newly diagnosed cardiac-valve regurgitation.

[paula_w]

"Roth said his team, in a separate piece of research that has yet to be published or reviewed by the scientific community, has identified several other big-selling drugs that have until now not been known to activate the 5-HT2b receptor.

He declined to reveal the names of the drugs until the research has been published."

Now that's a real case of lack of transparency. "Aw come on give us a hint, please tell us which medicines are killing people. Pretty please."

paula:(

[ZucchiniFlower]

Paula, they may be other ergot derived drugs. I used to take ergotamine for migraines that I used to get. Thank god those days are over. It may be other migraine medicines too:

5-Hydroxytryptamine (5-HT) and the initiation of migraine: new perspectives

1994

Abstract

The hypothesis that 5-hydroxytryptamine (5-HT) acting through 5-HT2c receptors is a key factor in the initiation of migraine has been re-evaluated in the light of recent basic and clinical scientific developments. The key findings are that nitric oxide is an important trigger for migraine, that 5-HT2B/5-HT2C receptors are present on endothelial cells and trigger nitric oxide release when activated and that supersensitivity of the 5-HT2B/5-HT2C receptor is a neurochemical feature predisposing to headache. Taken together the data bring new perspectives to the role of 5-HT acting through 5-HT2C (or closely similar) receptors in the initiation of migraine.

****************

"Pathological assessment of the surgically removed valves showed noninflammatory fibrotic degeneration, hypothesized to involve the 5-HT2B serotonin receptors."

from:

Research Article
Role of COMT inhibitors and dopamine agonists in the treatment of motor fluctuations

http://www3.interscience.wiley.com/cgi-bin/fulltext/110444918/HTMLSTART

From this reference:

Severe multivalvular heart disease: A new complication of the ergot derivative dopamine agonists:

21 May 2004

Abstract
Abstract CASE REPORTS DISCUSSION References
We report on 4 new cases of valvular heart disease in Parkinson's disease patients treated with the ergot derivative dopamine agonists pergolide and cabergoline. Noninflammatory fibrotic degeneration of cardiac valves has been reported to occur in patients with carcinoid syndrome and to occasionally complicate therapies with the anti-migraine ergot alkaloid ergotamine and methysergide and with the appetite suppressants fenfluramine and dexfenfluramine. In these cases, the pathogenesis is suspected to involve serotonin-mediated abnormal fibrogenesis by means of the 5-HT2B receptors, which are expressed in the fibroblasts of heart valves. Based on strikingly similar echocardiographic and histopathological features, we strongly suspect that ergot-derived dopamine agonists may cause a valvular heart disease nearly identical to that seen in those conditions. These cases add to a rapidly growing and worrying list of similar published reports, suggesting that we may well be facing a novel, yet unrecognized, complication of this class of agents, which are widely used not only in Parkinson's disease but also in restless legs syndrome and various common endocrine dysfunctions. Therefore, until more is known about the true prevalence of this side effect, we propose that an assessment of cardiac function be performed before and in the course of a long-term therapy with ergot derivative dopamine agonists. © 2004 Movement Disorder Society

http://www3.interscience.wiley.com/cgi-bin/fulltext/108567064/HTMLSTARTW

[ZucchiniFlower]

I read that the 5-HT2b receptor is expressed in very low levels in the human brain, and is mainly expressed in the peripheral organs. Only low expressionis found in the blood or brain. Most other serotonin receptors are found mainly in the brain (like 5-HT2c).

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T36-44KP5R9-4R&_coverDate=03%2F28%2F1994&_alid=518792746&_rdoc=1&_fmt=&_orig=search&_qd=1&_cdi=4938&_sort=d&view=c&_acct=C000022659&_version=1&_urlVersion=0&_userid=501045&md5=3da0d2d0f2d9b3da084c5d72be404498

[ZucchiniFlower]

(Circulation. 2000;102:2836.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports
Evidence for Possible Involvement of 5-HT2B Receptors in the Cardiac Valvulopathy Associated With Fenfluramine and Other Serotonergic Medications
Richard B. Rothman, MD, PhD; Michael H. Baumann, PhD; Jason E. Savage, BS; Laura Rauser, BS; Ace McBride, BS; Sandra J. Hufeisen, BS; Bryan L. Roth, MD, PhD
Background—Serotonergic medications with various mechanisms of action are used to treat psychiatric disorders and are being investigated as treatments for drug dependence. The occurrence of fenfluramine-associated valvular heart disease (VHD) has raised concerns that other serotonergic medications might also increase the risk of developing VHD. We hypothesized that fenfluramine or its metabolite norfenfluramine and other medications known to produce VHD have preferentially high affinities for a particular serotonin receptor subtype capable of stimulating mitogenesis.

Methods and Results—Medications known or suspected to cause VHD (positive controls) and medications not associated with VHD (negative controls) were screened for activity at 11 cloned serotonin receptor subtypes by use of ligand-binding methods and functional assays. The positive control drugs were (±)-fenfluramine; (+)-fenfluramine; (-)-fenfluramine; its metabolites (±)-norfenfluramine, (+)-norfenfluramine, and (-)-norfenfluramine; ergotamine; and methysergide and its metabolite methylergonovine. The negative control drugs were phentermine, fluoxetine, its metabolite norfluoxetine, and trazodone and its active metabolite m-chlorophenylpiperazine. (±)-, (+)-, and (-)-Norfenfluramine, ergotamine, and methylergonovine all had preferentially high affinities for the cloned human serotonin 5-HT2B receptor and were partial to full agonists at the 5-HT2B receptor.

Conclusions—Our data imply that activation of 5-HT2B receptors is necessary to produce VHD and that serotonergic medications that do not activate 5-HT2B receptors are unlikely to produce VHD.

We suggest that all clinically available medications with serotonergic activity and their active metabolites be screened for agonist activity at 5-HT2B receptors and that clinicians should consider suspending their use of medications with significant activity at 5-HT2B receptors.

[ZucchiniFlower]

From the discussion in the above article:


The study reported here examined the interaction of 9 medications that are associated with VHD (positive controls) and 5 medications that are not associated with VHD (negative controls) at 11 cloned 5-HT receptors. We sought to identify a mitogenic 5-HT receptor that would be activated by the positive but not the negative controls. We hypothesized that this CASR mediates fenfluramine-associated VHD. Among the receptors assayed, the 5-HT2B receptor has 5 characteristics consistent with its being the CASR: (1) it is located on both mitral and aortic valves10 ; (2) it mediates mitogenisis27 ; (3) the norfenfluramines have high affinity and efficacy at the 5-HT2B receptor; (4) ergotamine and methylergonovine, the active metabolite of methysergide, are high-affinity partial agonists for the 5-HT2B receptor; and (5) with the exception of mCPP (see below), the negative control drugs (fluoxetine, norfluoxetine, phentermine) have very low affinity for this site and lack agonist effects at this receptor. The 5-HT2C receptor is ruled out as the CASR, primarily because few of these receptors are expressed in heart valves.10

There are several observations that, at first glance, are difficult to reconcile with the hypothesis that the 5-HT2B receptor mediates the valvulopathy associated with administration of fenfluramine, ergotamine, and methysergide. First, whereas (+)-fenfluramine produces primarily aortic regurgitation,4 7 ergotamine and methysergide produce primarily mitral regurgitation.16 Given that 5-HT2B receptors are found on both valves,10 the mechanism underlying the anatomic specificity of the valvulopathy associated with these 2 classes of drugs is enigmatic. Second, methysergide appears to produce a more severe form of VHD than fenfluramine. Patients with fenfluramine-associated VHD are clinically asymptomatic and typically do not have audible heart murmurs.2 The best estimate of the incidence of clinically significant fenfluramine-associated VHD is 0.07% per year.7 In contrast, patients treated with methysergide developed clinically significant VHD, including new heart murmurs,16 with an incidence of 3%.16 Thus, although methylergonovine is a less effective agonist at the 5-HT2B receptor than norfenfluramine, it produces a more severe form of VHD in a greater number of patients. Third, methysergide administration is associated with fibrosis of other anatomic sites in addition to heart valves.28 In contrast, fenfluramine-associated fibrosis appears to be localized to heart valves.

Fourth, the finding that mCPP has activity at 5-HT2B receptors must be reconciled with observations that trazodone, from which it is metabolically derived, is not associated with VHD. Therapeutic doses of trazodone generate plasma levels of mCPP from 150 to 550 nmol/L,29 which are in the range needed to activate 5-HT2B receptors. However, trazodone is a potent 5-HT2B receptor antagonist, and its plasma levels are {approx}5-fold higher than that of mCPP.29 Thus, trazodone would act to block activation of 5-HT2B receptors by mCPP.

Thus, a possible explanation for the differing degrees of VHD prevalence seen among the 5-HT2B agonists is the degree of 5-HT2B antagonism produced by either parent drug or metabolites. Methysergide, as a very-low-efficacy 5-HT2B agonist, would act to antagonize the agonist effects of methylergonovine (Table 2Up). However, methysergide is rapidly metabolized to methylergonovine, is more rapidly eliminated, and achieves blood levels 10-fold lower than methyergonovine.15 Because the agonist actions of methylergonovine are most likely not significantly blocked by its parent drug, methysergide administration would probably cause a higher prevalence of VHD. In the case of fenfluramine, (+)-fenfluramine and (-)-fenfluramine have lower efficacy ({approx}40%) at the 5-HT2B receptor than (+)-norfenfluramine (75%) and achieve blood levels twice that of norfenfluramine.8 This indicates that the parent drugs would partially antagonize activation of 5-HT2B receptors by (+)-norfenfluramine. This may explain why the fenfluramines appear to produce a less severe form of VHD than methysergide (see above).

Taken at face value, the 5-HT2B hypothesis predicts that elevations of plasma 5-HT should produce valvulopathy in both the aortic and mitral valves. Indeed, 5-HT is the most potent and efficacious agonist at the 5-HT2B receptor. Medications such as lithium and monoamine oxidase inhibitors produce sustained 2-fold increases in plasma 5-HT and are not associated with VHD.30 31 This suggests that modest elevations of plasma 5-HT are unlikely to produce this adverse effect. Patients with carcinoid syndrome develop extremely high levels of plasma 5-HT (>500 nmol/L32 ), and fibrotic valve lesions occur exclusively on the right side of the heart. Although some attribute the lack of left-sided VHD in carcinoid syndrome to the almost complete removal of plasma 5-HT by the lung before the blood empties into the left atrium,12 this hypothesis fails to take into account the fact that the blood samples taken for analysis of 5-HT are withdrawn from the antecubital vein in the arm, the blood of which is derived most directly from the left side of the heart. Although the right side of the heart is undoubtedly bathed in higher concentrations of 5-HT than the left side, the left side is clearly exposed to 5-HT concentrations well in excess of that necessary to completely activate the 5-HT2B receptor. Thus, it is not clear why carcinoid syndrome produces fibrotic lesions on the valves of the right side of the heart, whereas fenfluramine, methysergide and ergotamine affect primarily the valves of the left side.

Viewed collectively, these considerations suggest that activation of 5-HT2B receptors may be necessary to produce VHD. Clearly, other factors also determine the susceptibility of an individual to develop the lesion, its anatomic location, and its severity. Despite our lack of knowledge of what these factors might be, these data suggest that serotonergic medications, which do not activate 5-HT2B receptors, are unlikely to produce VHD. These findings further suggest that the simplest pathogenic mechanism to explain anorexigen-associated VHD is a direct activation of 5-HT2B receptors by norfenfluramine. This mechanism does not necessitate the formulation of unlikely synergistic mechanisms between phentermine and fenfluramine33 or a role for plasma 5-HT to explain the occurrence of VHD. Finally, on the basis of these results and those recently reported by Fitzgerald et al,10 we suggest that all clinically available medications with serotonergic activity and their metabolites should be screened for agonist activity at 5-HT2B receptors.

Note Added in Proof
Dr Roth’s laboratory has begun to measure the efficacies of clinically used serotonergic compounds at the h5-HT2B receptor and have not yet found any that are agonists.

[paula_w]

The study reported here examined the interaction of 9 medications that are associated with VHD (positive controls) and 5 medications that are not associated with VHD (negative controls) at 11 cloned 5-HT receptors. We sought to identify a mitogenic 5-HT receptor that would be activated by the positive but not the negative controls. We hypothesized that this CASR mediates fenfluramine-associated VHD. Among the receptors assayed, the 5-HT2B receptor has 5 characteristics consistent with its being the CASR: (1) it is located on both mitral and aortic valves10 ; (2) it mediates mitogenisis27 ; (3) the norfenfluramines have high affinity and efficacy at the 5-HT2B receptor; (4) ergotamine and methylergonovine, the active metabolite of methysergide, are high-affinity partial agonists for the 5-HT2B receptor; and (5) with the exception of mCPP (see below), the negative control drugs (fluoxetine, norfluoxetine, phentermine) have very low affinity for this site and lack agonist effects at this receptor. The 5-HT2C receptor is ruled out as the CASR, primarily because few of these receptors are expressed in heart valves.10


Does this mean that fluoxetine, which is generic Prozac is relatively safe? I've been taking one 20mg capsule a day for the last several years.

paula

[olsen]

ZF and paula--you 2 never cease to amaze me with your knowledge, info, and interpretations--thanks!. with my skepticism, I note that the studies published (yes in the New england Journal) were conducted in Britian and Italy--although the drug cos involved--eli lilly hdqtrs in indianapolis and Pfizer in NYC-- are both in the united states. I do wonder if possible career suicide might be a one of the considerations for any US researchers looking into this realm of clinical studies...
madelyn

[paula_w]

:mad: And that's where I get angry at people who are so quick to sue. We ask for faster treatments and relief for our symptoms, and then when they discover a side effect after the fact, greed takes over on the patients' side, fueled by greedy attorneys. Innocent people should not lose their careers - ok just a little vent.

paula

[Stitcher]

To Quote Paula_W...in "Update: Pergolide, Cabergoline and Heart Damage"
Quote:
And that's where I get angry at people who are so quick to sue. We ask for faster treatments and relief for our symptoms, and then when they discover a side effect after the fact, greed takes over on the patients' side, fueled by greedy attorneys. Innocent people should not lose their careers - ok just a little vent.

See new post today: "Fast-Multiplying Lawsuits Can Stymie Medical Science, Authors Warn"

[ZucchiniFlower]

Paula, Prozac is safe in that regard. It deals with the other kind of receptor that's not linked to heart damage.

I used to take alot of ergotamine, so I'm glad my valves have been checked (actually checked for mitral valve prolapse because my mom has it and I had symptoms).

[ashleyk]

Since Mirapex is a non-ergot dopamine receptor agonist, I hope that it is not causing heart valve damage as is being seen with Permax which is also an agonist. I assume the key is whether these agonist drugs are ergot derived or not.
Ashley

http://www.cc.nih.gov/phar/updates/01jan-feb.html
Pramipexole (Mirapex®): A Brief Review

Introduction
Pramipexole, a non-ergot dopamine receptor agonist, is effective in the treatment of both early and advanced Parkinson's disease (PD). Pramipexole and ropinirole, another dopamine receptor agonist, were the first non-ergot derivatives available for the treatment of PD. Ergot-derived dopamine agonists, such as bromocriptine, have been effective in the treatment of this disorder but are associated with many side effects, some potentially irreversible (e.g., pulmonary fibrosis). Use of dopamine agonists in the treatment of Parkinson's disease may delay the introduction of levodopa in the early stages of the disease and perhaps delay the development of levodopa-associated motor fluctuations ("on/off" phenomenon) and dyskinesias related to chronic use of levodopa. In advanced PD, dopamine agonists increase "on time" in patients with levodopa-associated motor fluctuations, thereby allowing for levodopa dose reduction in some patients. The long-term effectiveness of pramipexole in PD has not been evaluated, and it is unknown whether patients will develop tolerance to the dopamine-agonist effects of pramipexole.

Description
Mirapex® (pramipexole dihydrochloride) is marketed by Pharmacia & Upjohn and is available as 0.125-, 0.25-, 0.5-, 1-, and 1.5-mg tablets.

Indication
Pramipexole is indicated for the treatment of the signs and symptoms of idiopathic Parkinson's disease.

Pharmacology
Pramipexole dihydrochloride, a benzothiazolamine derivative, is a non-ergot dopamine receptor agonist. In vitro studies suggests that pramipexole has intrinsic activity and a high degree of binding specificity at the D2 subfamily of dopamine receptors. Known dopamine receptor subtypes include D2, D3, and D4. The D2 specificity and intrinsic activity of pramipexole is greater than that for the other available ergot-derived dopamine agonists, bromocriptine and pergolide. Pramipexole binds with higher affinity to D3 compared to D2 or D4 receptor subtypes, but the relevance of this specificity is not known. Pramipexole is believed to also stimulate presynaptic dopamine autoreceptors, with resultant inhibition of synthesis and release of dopamine in intact dopaminergic synapses. However, when presynaptic fibers are degenerated and postsynaptic receptors are hypersensitive, pramipexole exerts postsynaptic dopamine agonist activity. Although the precise mechanism of action of pramipexole for the treatment of PD is not known, it is believed to be related to stimulation of postsynaptic dopamine receptors in the striatum. Pramipexole binds with moderate affinity to a2-adrenergic receptors but has little or no affinity for a1, b-adrenergic, acetylcholine, D1, or serotonin receptors.

Pharmacokinetics
Pramipexole is rapidly absorbed, with maximal plasma concentrations achieved in 2 hours. The absolute bioavailability is > 90%, and food does not affect extent of absorption but may increase the time to maximal plasma concentrations by nearly 1 hour. Pramipexole is extensively distributed in body tissues and has a volume of distribution of about 500 L. Approximatly 15% of the drug is bound to plasma proteins. Pramipexole displays linear pharmacokinetics over the entire clinical dose range. Its terminal half-life is 8 hours in young, healthy volunteers and about 12 hours in elderly volunteers.

[wendy s]

I was on Permax for a year and a half from Aug. 2002 to Jan. 2004. My final dose was about 0.6 mg. (I think) three times a day, the nausea was so bad that I couldn't tolerate any more. Has anyone read if it says anywhere in the research whether that amount would cause problems with the valves?

[made it up]

Hi Wendy,
Regardless of the amount or length of time you took it or the dosage an echocardiogram is recommended to rule out valvulopathy which has an increased chance of occurring in people who have previously taken Permax.
Your G.P. or neurologist will probably be aware of the reports regarding the increased chance of it in pts who took Permax.
If they're not you can teach them something they don't know and in return they can find you a cardiologist who will order an echocardiogram and hopefully report you have no evidence of valvulopathy.
Cheers,
Lee