Cabergoline: Wikis

  
  

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Cabergoline
Systematic (IUPAC) name
N-[3-(Dimethylamino)propyl]-N-[(ethylamino)carbonyl]- 6-(2-propenyl)-8g-ergoline-8-carboxamide
or
1-[(6-allylergolin8β-yl)- carbonyl]-1- [3-(dimethylamino)propyl]-3-ethylurea
Identifiers
CAS number 81409-90-7
ATC code G02CB03 N04BC06
PubChem 54746
DrugBank APRD00836
ChemSpider 49452
Chemical data
Formula C26H37N5O2 
Mol. mass 451.604 g/mol
SMILES eMolecules & PubChem
Pharmacokinetic data
Bioavailability First-pass effect seen; absolute bioavailability unknown
Protein binding Moderately bound (40% to 42%); concentration- independent
Metabolism Hepatic, predominately via hydrolysis of the acylurea bond or the urea moiety
Half life 63-69 hours (estimated)
Excretion Urine (22%), feces (60%)
Therapeutic considerations
Pregnancy cat. B(US)
Legal status -only (US)
Routes Oral
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Cabergoline (brand names Dostinex and Cabaser), an ergot derivative, is a potent dopamine receptor agonist on D2 receptors. In vitro, rat studies show cabergoline has a direct inhibitory effect on pituitary lactotroph (prolactin) cells. [1] It is frequently used as a second-line agent in the management of prolactinomas when bromocriptine is ineffective.

Contents

History

Cabergoline was invented by scientists working for the Italian drug company Farmitalia-Carlo Erba SpA in Milan in 1981/82, who were experimenting with semisynthetic derivatives of the ergot alkaloids. Farmitalia-Carlo Erba was acquired by Pharmacia in 1992, which in turn was acquired by Pfizer in 2002. The drug was not FDA approved until 2002. It went generic in late 2005 following US patent expiration.

Intellectual property

Farmitalia filed for patent protection of Cabergoline in 1982, and U.S. Patent 4,526,892 was granted in July 1985.

Pharmacokinetics

Following a single oral dose, resorption of cabergoline from the gastrointestinal (GI) tract is highly variable, typically occurring within 0.5 to 4 hours. Ingestion with food does not alter its absorption rate. Human bioavailability has not been determined since the drug is intended for oral use only. In mice and rats the absolute bioavailability has been determined to be 30 and 63 percent, respectively. Cabergoline is rapidly and extensively metabolized in the liver and excreted in bile and to a lesser extent in urine. All metabolites are less active than the parental drug or inactive altogether. The human elimination half-life is estimated to be 63 to 68 hours in patients with Parkinson's disease and 79 to 115 hours in patients with pituitary tumors. Average elimination half-life is 80h.

Mechanism of Action

Cabergoline is a long-acting dopamine D2-receptor agonist and in vitro rat studies show a direct inhibitory effect on the prolactin secretion in the pituitary's lactotroph cells. Cabergoline decreased serum prolactin levels in reserpinized rats.

Receptor-binding studies indicate low affinity for: dopamine D1-receptors, α1-adrenergic-receptors, α2-adrenergic-receptors, 5-HT1-serotonin receptors and 5-HT2-serotonin receptors. [2]

Carcinogenity

In rodents a dose-dependent increase in malignant tumors has been found. The correlation is thought to be species specific. No clinical data exists on carcinogenity in humans.[citation needed]

Uses

Off-label/recreational uses

It has at times been used as an adjunct to SSRI antidepressants as there is some evidence that it counteracts certain side effects of those drugs, such as reduced libido and anorgasmia. It also has been suggested online that it has a possible recreational use in reducing or eliminating the male refractory period. It is also used by bodybuilders to control gynecomastia caused by elevated prolactin levels through the use of anabolic steroids such as Nandrolone and Trenbolone. Additionally, a study that recently concluded Phase III trials, is showing it to decrease the risk of ovarian hyperstimulation syndrome (OHSS) in females undergoing stimulated cycles of in vitro fertilization (IVF). A study on rats found that cabergoline reduces voluntary alcohol consumption.

Contraindications and precautions

Pregnancy and lactation

  • Pregnancy: Approximately 100 female patients became pregnant under therapy with cabergoline for hyperprolactinemic conditions. The incidence of spontaneous abortions and congenital abnormalities was comparable to nontreated patients.[citation needed] Nevertheless, women wishing to become pregnant should wait a period of four weeks after discontinuation of cabergoline. Patients becoming pregnant under therapy should terminate cabergoline immediately, if possible.
  • Lactation: In rats cabergoline was found in the maternal milk. Since it is not known if this effect also occurs in humans, breastfeeding women should not be treated.

Side effects

Approximately 200 patients with newly diagnosed Parkinson's disease participated in a clinical study of cabergoline monotherapy. Seventy-nine (79) percent reported at least one side effect. These side effects were chiefly mild or moderate:

In a combination study with 2,000 patients also treated with levodopa, the incidence and severity of side effects was comparable to monotherapy. Encountered side effects required a termination of cabergoline treatment in 15% of patients. Additional side effects were infrequent cases of hematological side effects, and an occasional increase in liver enzymes or serum creatinine without signs or symptoms.

As with other ergot derivatives, pleuritis, exudative pleura disease, pleura fibrosis, lung fibrosis, and pericarditis are seen. These side effects are noted in less than 2% of patients. They require immediate termination of treatment. Clinical improvement and normalization of X-ray findings are normally seen soon after cabergoline withdrawal.

The reported incidence and severity of side effects in hyperprolactinemic patients was comparable.

Valvular heart disease

In two studies published in the New England Journal of Medicine on January 4, 2007, cabergoline was implicated along with pergolide in causing valvular heart disease.[3][4] Both drugs are ergot-derived dopamine agonists, although their molecular skeletons are different. As a result of this, the FDA removed pergolide from the U.S. market on March 29, 2007.[5] Since cabergoline is not approved in the U.S. for Parkinson's Disease, but for hyperprolactinemia, the drug remains on the market. The lower doses required for treatment of hyperprolactinemia have been found to be not associated with clinically significant valvular heart disease or cardiac valve regurgitation.[6][7]

Interactions

No interactions were noted with levodopa or selegiline. The drug should not be combined with other ergot derivatives. Dopamine antagonists such as antipsychotics and metoclopramide inhibit the clinical action of cabergoline and should therefore not be used concomitantly. The use of antihypertensive drugs should be intensively monitored because excessive hypotension may result from the combination.

Dosage

  • Parkinson's disease: Monotherapy: Initial dose should be 0.5 mg daily. The usual maintenance dose is 2 to 4 mg daily. Combination therapy: Usually 2 to 6 mg daily.
  • Tumors of the pituitary gland and other hyperprolactinemic conditions: Initially 0.5 mg per week, slowly titrated to 4.5 mg per week, if necessary.
  • Ablactation: According to specific treatment scheme.

External links

References

  1. ^ "Dostinex at www.rxlist.com". http://www.rxlist.com/cgi/generic/cabergoline.htm. Retrieved 2007-04-27. 
  2. ^ "Dostinex at www.rxlist.com". http://www.rxlist.com/cgi/generic/cabergoline.htm. Retrieved 2007-04-27. 
  3. ^ Schade, Rene; Andersohn, Frank; Suissa, Samy; Haverkamp, Wilhelm; Garbe, Edeltraut (2007-01-04), "Dopamine Agonists and the Risk of Cardiac-Valve Regurgitation", New England Journal of Medicine 356 (1): 29–38, doi:10.1056/NEJMoa062222, http://content.nejm.org/cgi/content/full/356/1/29 
  4. ^ Zanettini, Renzo; Antonini, Angelo; Gatto, Gemma; Gentile, Rosa; Tesei, Silvana; Pezzoli, Gianna (2007-01-04), "Valvular Heart Disease and the Use of Dopamine Agonists for Parkinson's Disease", New England Journal of Medicine 356 (1): 39–46, doi:10.1056/NEJMoa054830, http://content.nejm.org/cgi/content/full/356/1/39 
  5. ^ "Food and Drug Administration Public Health Advisory". 2007-03-29. http://www.fda.gov/cder/drug/advisory/pergolide.htm. Retrieved 2007-04-27. 
  6. ^ [1] Low dose cabergoline for hyperprolactinaemia is not associated with clinically significant valvular heart disease
  7. ^ [2] Treatment with low doses of cabergoline is not associated with increased prevalence of cardiac valve regurgitation in patients with hyperprolactinaemia







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