用户名： 密   码：
注册 | 忘记密码？
药品详细

Pergolide(培高利特)

化学结构式图
中文名
培高利特
英文名
Pergolide
分子式
C19H26N2S
化学名
(2R,4R,7R)-4-[(methylsulfanyl)methyl]-6-propyl-6,11-diazatetracyclo[7.6.1.0^{2,7}.0^{12,16}]hexadeca-1(16),9,12,14-tetraene
分子量
Average: 314.488
Monoisotopic: 314.181669532
CAS号
66104-22-1
ATC分类
N04B 未知
药物类型
small molecule
阶段
approved, withdrawn
商品名
Permax (Eli Lilly);
同义名
Pergolida [INN-Spanish];Pergolide Mesylate;Pergolide Methanesulfonate;Pergolidum [INN-Latin];
基本介绍

Pergolide is a long-acting dopamine agonist approved in 1982 for the treatment of Parkinson’s Disease. It is an ergot derivative that acts on the dopamine D2 and D3, alpha2- and alpha1-adrenergic, and 5-hydroxytryptamine (5-HT) receptors. It was indicated as adjunct therapy with levodopa/carbidopa in the symptomatic treatment of parkinsonian syndrome. It was later found that pergolide increased the risk of cardiac valvulopathy. The drug was withdrawn from the US market in March 2007 and from the Canadian market in August 2007.

生产厂家
  • Ivax pharmaceuticals inc sub teva pharmaceuticals usa
  • Par pharmaceutical
  • Valeant pharmaceuticals international
封装厂家
参考
Synthesis Reference Not Available
General Reference
  1. Schade R, Andersohn F, Suissa S, Haverkamp W, Garbe E: Dopamine agonists and the risk of cardiac-valve regurgitation. N Engl J Med. 2007 Jan 4;356(1):29-38. Pubmed
  2. Breitenstein C, Korsukewitz C, Floel A, Kretzschmar T, Diederich K, Knecht S: Tonic dopaminergic stimulation impairs associative learning in healthy subjects. Neuropsychopharmacology. 2006 Nov;31(11):2552-64. Epub 2006 Jul 26. Pubmed
剂型
规格
化合物类型
Type small molecule
Classes
  • Ergolines
  • Indoloquinolines
Substructures
  • Ergolines
  • Ethers
  • Indoles and Indole Derivatives
  • Pyrroles
  • Benzene and Derivatives
  • Phenylpiperidines
  • Aliphatic and Aryl Amines
  • Phenethylamines
  • Heterocyclic compounds
  • Aromatic compounds
  • Tryptamines and Derivatives
  • Amphetamines
  • Piperidines
  • Indoloquinolines
适应症
PARKINSON 帕金森氏症;
药理
Indication Indicated as adjunctive treatment to levodopa/carbidopa in the management of the signs and symptoms of Parkinson's disease. It was withdrawn from the US and Canadian markets in 2007 due to an increased risk of cardiac valvulopathy.
Pharmacodynamics Pergolide stimulates centrally-located dopaminergic receptors resulting in a number of pharmacologic effects. Five dopamine receptor types from two dopaminergic subfamilies have been identified. The dopaminergic D1 receptor subfamily consists of D1 and D5 subreceptors and are associated with dyskinesias. The dopaminergic D2 receptor subfamily consists of D2, D3 and D4 subreceptors and has been associated with improvement of symptoms of movement disorders. Thus, agonist activity specific for D2 subfamily receptors, primarily D2 and D3 receptor subtypes, are the primary targets of dopaminergic antiparkinsonian agents. It is thought that postsynaptic D2 stimulation is primarily responsible for the antiparkinsonian effect of dopamine agonists, while presynaptic D2 stimulation confers neuroprotective effects. This semisynthetic ergot derivative exhibits potent agonist activity on dopamine D2- and D3-receptors. It also exhibits agonist activity on dopamine D4, D1, and D5, 5-hydroxytryptamine (5-HT)1A, 5-HT1B, 5-HT1D, 5-HT2A, 5-HT2B, 5-HT2C, α2A-, α2B-, α2C-, α1A-, α1B-, and α1D-adrenergic receptors. Parkinsonian Syndrome manifests when approximately 80% of dopaminergic activity in the nigrostriatal pathway of the brain is lost. As this striatum is involved in modulating the intensity of coordinated muscle activity (e.g. movement, balance, walking), loss of activity may result in dystonia (acute muscle contraction), Parkinsonism (including symptoms of bradykinesia, tremor, rigidity, and flattened affect), akathesia (inner restlessness), tardive dyskinesia (involuntary muscle movements usually associated with long-term loss of dopaminergic activity), and neuroleptic malignant syndrome, which manifests when complete blockage of nigrostriatal dopamine occurs. High dopaminergic activity in the mesolimbic pathway of the brain causes hallucinations and delusions; these side effects of dopamine agonists are manifestations seen in patients with schizophrenia who have overractivity in this area of the brain. The hallucinogenic side effects of dopamine agonists may also be due to 5-HT2A agonism. The tuberoinfundibular pathway of the brain originates in the hypothalamus and terminates in the pituitary gland. In this pathway, dopamine inhibits lactotrophs in anterior pituitary from secreting prolactin. Increased dopaminergic activity in the tuberoinfundibular pathway inhibits prolactin secretion. Pergolide also causes transient increases in somatotropin (growth hormone) secretion and decreases in luteinizing hormone (LH) concentrations.
Mechanism of action The dopamine D2 receptor is a 7-transmembrane G-protein coupled receptor associated with Gi proteins. In lactotrophs, stimulation of dopamine D2 receptor causes inhibition of adenylyl cyclase, which decreases intracellular cAMP concentrations and blocks IP3-dependent release of Ca2+ from intracellular stores. Decreases in intracellular calcium levels may also be brought about via inhibition of calcium influx through voltage-gated calcium channels, rather than via inhibition of adenylyl cyclase. Additionally, receptor activation blocks phosphorylation of p42/p44 MAPK and decreases MAPK/ERK kinase phosphorylation. Inhibition of MAPK appears to be mediated by c-Raf and B-Raf-dependent inhibition of MAPK/ERK kinase. Dopamine-stimulated growth hormone release from the pituitary gland is mediated by a decrease in intracellular calcium influx through voltage-gated calcium channels rather than via adenylyl cyclase inhibition. Stimulation of dopamine D2 receptors in the nigrostriatal pathway leads to improvements in coordinated muscle activity in those with movement disorders.
Absorption Significant amount may be absorbed (evidence on bioavailability still lacking).
Volume of distribution Not Available
Protein binding 90%
Metabolism
Extensively hepatic.
Route of elimination The major route of excretion is the kidney.
Half life 27 hours
Clearance Not Available
Toxicity Oral, rat LD50: 15 mg/kg. Symptoms of overdose include nausea, vomiting, convulsions, decreased blood pressure, and CNS stimulation.
Affected organisms
  • Humans and other mammals
Pathways Not Available
理化性质
Properties
State solid
Experimental Properties
Property Value Source
melting point 207.5 °C PhysProp
logP 4 Not Available
Predicted Properties
Property Value Source
water solubility 5.84e-04 g/l ALOGPS
logP 4.17 ALOGPS
logP 4.23 ChemAxon
logS -5.7 ALOGPS
pKa (strongest acidic) 17.35 ChemAxon
pKa (strongest basic) 9.49 ChemAxon
physiological charge 1 ChemAxon
hydrogen acceptor count 1 ChemAxon
hydrogen donor count 1 ChemAxon
polar surface area 19.03 ChemAxon
rotatable bond count 4 ChemAxon
refractivity 97.02 ChemAxon
polarizability 38.4 ChemAxon
药物相互作用
Drug Interaction
Tamoxifen Pergolide may decrease the therapeutic effect of Tamoxifen by decreasing the production of active metabolites. Concomitant therapy should be avoided.
Tamsulosin Pergolide, a CYP2D6 inhibitor, may decrease the metabolism and clearance of Tamsulosin, a CYP2D6 substrate. Monitor for changes in therapeutic/adverse effects of Tamsulosin if Pergolide is initiated, discontinued, or dose changed.
Telithromycin Telithromycin may reduce clearance of Pergolide. Consider alternate therapy or monitor for changes in the therapeutic/adverse effects of Pergolide if Telithromycin is initiated, discontinued or dose changed.
Thiothixene Thiothixene may antaonize the effects of the anti-Parkinsonian agent, Pergolide. Consider alternate therapy or monitor for decreased effects of both agents.
Tipranavir Tipranavir may increase the plasma concentration of Pergolide. Concomitant therapy should be avoided.
Tolterodine Peroglide may decrease the metabolism and clearance of Tolterodine. Monitor for adverse/toxic effects of Tolterodine.
Tramadol Pergolide may decrease the effect of Tramadol by decreasing active metabolite production. Increased risk of serotonin syndrome. Monitor for Tramadol efficacy and symptoms of serotonin syndrome.
Tranylcypromine Increased risk of serotonin syndrome. Use caution during concomitant therapy and monitor for symptoms of serotonin syndrome.
Trazodone Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Trimipramine Increased risk of serotonin syndrome. Pergolide, a strong CYP2D6 inhibitor, may also decrease the metabolism and clearance of Trimipramine, a CYP2D6 substrate. Monitor for symptoms of serotonin syndrome and changes in Trimipramine therapeutic and adverse effects if Pergolide is initiated, discontinued or dose changed.
Venlafaxine Increased risk of serotonin syndrome. Monitor for symptoms of serotonin syndrome.
Voriconazole Voriconazole may increase the serum concentration of pergolide likely by decreasing its metabolism. Concomitant therapy is contraindicated.
Ziprasidone The atypical antipsychotic, ziprasidone, may antagonize the effect of the dopamine agonist, pergolide. Consider alternate therapy or monitor for worsening of movement disorder.
Zolmitriptan Concomitant use of the serotonin 5-HT1D receptor agonist, zolmitriptan, and the ergot derivative, pergolide, may result in additive vasoconstrictive effects. Concomitant use within 24 hours is contraindicated.
Zuclopenthixol Antagonism may occur between zuclopenthixol, a dopamine D2 receptor antagonist, and pergolide, a dopamine agonist. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of both agents if concurrent therapy is initiated, discontinued or dose(s) changed. Pergolide, a strong CYP2D6 inhibitor, may increase the serum concentration of zuclopenthixol by decreasing its metabolism. Consider alternate therapy or monitor for changes in the therapeutic and adverse effects of zuclopenthixol if pergolide is initiated, discontinued or dose changed.
食物相互作用
  • Take with food to reduce gastric irritation and nausea

返回 | 收藏