Pergolide, sold under the brand namePermax andPrascend (veterinary) among others, is anergoline-baseddopamine receptoragonist used in some countries for thetreatment ofParkinson's disease. Parkinson's disease is associated with reduceddopamine synthesis in thesubstantia nigra of thebrain. Pergolide acts on many of the same receptors as dopamine to increase receptor activity.
It was patented in 1978[2] and approved for medical use in 1989.[3] In 2007, pergolide was withdrawn from the U.S. market for human use after several published studies revealed a link between the drug and increased rates ofvalvular heart disease.[4] However, a veterinary form of pergolide, marketed under the trade name Prascend, is permitted for the treatment ofpituitary pars intermedia dysfunction (PPID) also known as equine Cushing's syndrome (ECS) in horses.[5]
Pergolide is no longer available for use by humans in the United States, however, it is still used in various other countries, where it is used to treat various conditions including Parkinson's disease, hyperprolactinemia, and restless leg syndrome.[citation needed]
Pergolide acts as an agonist ofdopamineD2 andD1 andserotonin5-HT1A,5-HT1B,5-HT2A,5-HT2B, and5-HT2Creceptors. It may possess agonist activity at other dopamine receptor subtypes as well, similar to cabergoline. Although pergolide is more potent as an agonist of the D2 receptor, it has high D1 receptoraffinity and is one of the most potent D1 receptor agonists of thedopamine receptor agonists that are clinically available.[7] The agonist activity of pergolide at the D1 receptor somewhat alters its clinical and side effect profile in the treatment of Parkinson's disease. Pergolide has been said to behallucinogenic due to activation of 5-HT2A receptors.[8][9] However, other sources have stated that the drug is non-hallucinogenic.[10] It has been associated withcardiac valvulopathy due to activation of 5-HT2B receptors.[11]
Notes: All receptors are human except α2D-adrenergic, which is rat (no human counterpart), and 5-HT6, 5-HT7, σ1, and σ2, which are all rodent (rat or guinea pig).[12][15]
The drug is in decreasing use, as it was reported in 2003 to be associated with a form of heart disease calledcardiac fibrosis.[17] In 2007, the United StatesFood and Drug Administration announced a voluntary withdrawal of the drug by manufacturers due to the possibility of heart valve damage.[18] Pergolide is not currently available in the United States for human use. This problem is thought to be due to pergolide's action at the 5-HT2B serotonin receptors of cardiac myocytes, causing proliferative valve disease by the same mechanism asergotamine,methysergide,fenfluramine, and other serotonin 5-HT2B agonists, including serotonin itself when elevated in the blood incarcinoid syndrome. Pergolide can rarely causeRaynaud's phenomenon. Among similar antiparkinsonian drugs,cabergoline, but notlisuride, exhibit this same type of serotonin receptor binding.[19] In January 2007,cabergoline (Dostinex) was also reported to be associated with valvular proliferation heart damage.[20] In March 2007, pergolide was withdrawn from the U.S. market for human use due to serious valvular damage that was shown in two independent studies.[21]
Pergolide has also been shown to impair associative learning.[22]
At least one British pergolide user has attracted some media attention with claims that it has caused him to develop agambling addiction.[23][24] In June 2010, it was reported that more than 100 Australian users of the drug are suing the manufacturer over both gambling andsex addiction[25] problems they claim are the result of the drug's side effects.
^US patent 4166182A, Kornfeld EC, Bach NJ, "6-n-propyl-8-methoxymethyl or methylmercaptomethylergolines and related compounds", published 1979-08-28, issued 1979-08-28, assigned to Eli Lilly and Co
^"Pergolide (marketed as Permax)".FDA Public Health Advisory. Archived from the original on 2007-04-08. Retrieved2019-12-16.{{cite web}}: CS1 maint: bot: original URL status unknown (link)
^Cussac D, Boutet-Robinet E, Ailhaud MC, Newman-Tancredi A, Martel JC, Danty N, et al. (October 2008). "Agonist-directed trafficking of signalling at serotonin 5-HT2A, 5-HT2B and 5-HT2C-VSV receptors mediated Gq/11 activation and calcium mobilisation in CHO cells".European Journal of Pharmacology.594 (1–3):32–38.doi:10.1016/j.ejphar.2008.07.040.PMID18703043.
^Cavero I, Guillon JM (2014). "Safety Pharmacology assessment of drugs with biased 5-HT(2B) receptor agonism mediating cardiac valvulopathy".Journal of Pharmacological and Toxicological Methods.69 (2):150–161.doi:10.1016/j.vascn.2013.12.004.PMID24361689.
^abMillan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes".The Journal of Pharmacology and Experimental Therapeutics.303 (2):791–804.doi:10.1124/jpet.102.039867.PMID12388666.S2CID6200455.
^Newman-Tancredi A, Cussac D, Audinot V, Nicolas JP, De Ceuninck F, Boutin JA, et al. (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor".The Journal of Pharmacology and Experimental Therapeutics.303 (2):805–814.doi:10.1124/jpet.102.039875.PMID12388667.S2CID35238120.
^Newman-Tancredi A, Cussac D, Quentric Y, Touzard M, Verrièle L, Carpentier N, et al. (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. III. Agonist and antagonist properties at serotonin, 5-HT(1) and 5-HT(2), receptor subtypes".The Journal of Pharmacology and Experimental Therapeutics.303 (2):815–822.doi:10.1124/jpet.102.039883.PMID12388668.S2CID19260572.
^van Ameringen M, Mancini C, Farvolden P, Oakman J (October 2000). "Drugs in development for social anxiety disorder: more to social anxiety than meets the SSRI".Expert Opinion on Investigational Drugs.9 (10):2215–2231.doi:10.1517/13543784.9.10.2215.PMID11060802.
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