Cabergoline

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Cabergoline
Cabergoline.svg
Systematic (IUPAC) name
(6aR,9R,10aR)-N-[3-(dimethylamino)propyl]-N-(ethylcarbamoyl)-7-prop-2-enyl-6,6a,8,9,10,10a-hexahydro-4H-indolo[4,3-fg]quinoline-9-carboxamide
Clinical data
Trade names Cabaser, Dostinex
AHFS/Drugs.com monograph
Licence data US FDA:link
Pregnancy
category
  • US: B (No risk in non-human studies)
Legal status
Routes of
administration		 Oral
Pharmacokinetic data
Bioavailability First-pass effect seen; absolute bioavailability unknown
Protein binding Moderately bound (40–42%); concentration-independent
Metabolism Hepatic, predominately via hydrolysis of the acylurea bond or the urea moiety
Biological half-life 63–69 hours (estimated)
Excretion Urine (22%), feces (60%)
Identifiers
CAS Number 81409-90-7 YesY
ATC code G02CB03 (WHO) N04BC06
PubChem CID: 54746
IUPHAR/BPS 37
DrugBank DB00248 YesY
ChemSpider 49452 YesY
UNII LL60K9J05T YesY
KEGG D00987 YesY
ChEBI CHEBI:3286 YesY
ChEMBL CHEMBL1201087 N
Chemical data
Formula C26H37N5O2
Molecular mass 451.604 g/mol
  • O=C(NCC)N(C(=O)[C@@H]2C[C@@H]3c4cccc1c4c(cn1)C[C@H]3N(C2)C\C=C)CCCN(C)C
  • InChI=1S/C26H37N5O2/c1-5-11-30-17-19(25(32)31(26(33)27-6-2)13-8-12-29(3)4)14-21-20-9-7-10-22-24(20)18(16-28-22)15-23(21)30/h5,7,9-10,16,19,21,23,28H,1,6,8,11-15,17H2,2-4H3,(H,27,33)/t19-,21-,23-/m1/s1 YesY
  • Key:KORNTPPJEAJQIU-KJXAQDMKSA-N YesY
 NYesY (what is this?)  (verify)

Cabergoline (brand names Caberlin, Dostinex and Cabaser), an ergot derivative, is a potent dopamine receptor agonist on D2 receptors. Rat studies show cabergoline has a direct inhibitory effect on pituitary lactotroph (prolactin) cells.[1] It is frequently used as a first-line agent in the management of prolactinomas due to higher affinity for D2 receptor sites, less severe side effects, and more convenient dosing schedule than the older bromocriptine.

History

Cabergoline was first synthesized by scientists working for the Italian drug company Farmitalia-Carlo Erba SpA in Milan in 1981/82,[2] 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 approved by the FDA on December 23, 1996. It went generic in late 2005 following US patent expiration.

Intellectual property

Farmitalia filed a patent application for Cabergoline in 1982, and U.S. Patent 4,526,892 issued in July 1985.

Pharmacology

Although cabergoline is commonly described principally as a dopamine D2 receptor agonist, it also possesses significant affinity for the D3, D4, 5-HT1A, 5-HT2A, 5-HT2B, 5-HT2C, α2B- receptors, and moderate/low affinity for the D1 and 5-HT7 receptors. Cabergoline functions as an agonist at all of these receptors except for 5-HT7 and α2B-, where it acts as an antagonist.[3]

Binding profile[4]

Receptor Binding Affinity (Ki [nM]) Action
5-HT1A 20.0 Agonist
5-HT1B 479 Unknown
5-HT1D 8.71 Unknown
5-HT2A 6.17 Agonist
5-HT2B 1.17 Agonist
5-HT2C 692 Agonist
α1A adrenergic 288 Unknown
α1B adrenergic 60.3 Unknown
α1D adrenergic 166 Unknown
α2A adrenergic 12 Unknown
α2B adrenergic 72.4 Antagonist
α2C adrenergic 22.4 Unknown
β1 adrenergic >10,000 Unknown
β2 adrenergic >10,000 Unknown
D1 214 Agonist
D2S 0.62 Agonist
D2L 0.95 Agonist
D3 0.79 Agonist
D4 56.2 Agonist
D5 22.4 Unknown

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 80 hours.

The therapeutic effect in treatment of hyperprolactinemia will typically persist for at least 4 weeks after cessation of treatment.

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 a low affinity for dopamine D1 receptors, α1-adrenergic receptors, and α2-adrenergic receptors.[1]

Uses

Off-label

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, thereby allowing men to experience multiple ejaculatory orgasms in rapid succession, and at least one scientific study supports those speculations.[8] It is also used by bodybuilders to control gynecomastia caused by elevated prolactin levels through the use of anabolic steroids such as nandrolone. Additionally, a systematic review and meta-analysis concluded that prophylactic treatment with cabergoline reduces the incidence, but not the severity, of ovarian hyperstimulation syndrome (OHSS), without compromising pregnancy outcomes, in females undergoing stimulated cycles of in vitro fertilization (IVF).[9] Also, a study on rats found that cabergoline reduces voluntary alcohol consumption, possibly by increasing GDNF expression in the ventral tegmental area.[10]

Contraindications and precautions

Pregnancy and lactation

Relatively little is known about the effects of this medication during pregnancy and lactation. In some cases the related bromocriptine may be an alternative when pregnancy is expected.[citation needed]

  • Pregnancy: available preliminary data indicates a somewhat increased rate of congenital abnormalities in patients who became pregnant while treated with cabergoline.[citation needed]. However, one study concluded that "foetal exposure to cabergoline through early pregnancy does not induce any increase in the risk of miscarriage or foetal malformation." [11]
  • Lactation: In rats cabergoline was found in the maternal milk. Since it is not known if this effect also occurs in humans, breastfeeding is usually not recommended if/when treatment with cabergoline is necessary.
  • Lactation suppression: In some countries cabergoline (Dostinex) is sometimes used as a lactation suppressant. It is also used in veterinary medicine to treat false pregnancy in dogs.

Side effects

Side effects are mostly dose dependent. Much more severe side effects are reported for treatment of Parkinson's disease and (off-label treatment) for restless leg syndrome which both typically require very high doses. The side effects are considered mild when used for treatment of hyperprolactinemia and other endocrine disorders or gynecologic indications where the typical dose is 10-100 times smaller than for Parkinson's disease.[citation needed]

Cabergoline requires slow dose titration (2–4 weeks for hyperprolactinemia, often much longer for other conditions) to minimise side effects. The extremely long bioavailability of the medication may complicate dosing regimens during titration and require particular precautions.

Cabergoline is considered the best tolerable option for hyperprolactinemia treatment although the newer and less tested quinagolide may offer similarly favourable side effect profile with quicker titration times.

Approximately 200 patients with newly diagnosed Parkinson's disease participated in a clinical study of cabergoline monotherapy.[citation needed] 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. It appears that the dose typically used for treatment of hyperprolactinemia is too low to cause this type of side effects.

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.[12][13] As a result of this, the FDA removed pergolide from the U.S. market on March 29, 2007.[14] 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.[15][16]

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 counteract some effects of cabergoline. 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.

Synthesis

Cabergoline synthesis:[17]
  • PROCESS FOR THE PREPARATION OF CABERGOLINE EA 200601628  (2007).
  • PROCESS AND INTERMEDIATES FOR PRODUCTION OF CABERGOLINE AND RELATED COMPOUNDS WO 02085902  (2002).
  • Serradell, M.N.; Azccheo, T.; Castaner, J.; Castaner, R.M.; Giudici, D.; Cabergoline. Drugs Fut 1987, 12, 9, 842.

See also

References

  1. ↑ 1.0 1.1 Lua error in package.lua at line 80: module 'strict' not found.
  2. ↑ US Patent 4526892 - Dimethylaminoalkyl-3-(ergoline-8'.beta.carbonyl)-ureas
  3. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  4. ↑ National Institute of Mental Health. PDSD Ki Database (Internet) [cited 2013 Jul 24]. ChapelHill (NC): University of North Carolina. 1998-2013. Available from: http://pdsp.med.unc.edu/pdsp.php
  5. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  6. ↑ Lua error in package.lua at line 80: module 'strict' not found. http://www.britishfibroidtrust.org.uk/journals/bft_Sankaran.pdf
  7. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  8. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  9. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  10. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  11. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  12. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  13. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  14. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  15. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  16. ↑ Lua error in package.lua at line 80: module 'strict' not found.
  17. ↑ Lua error in package.lua at line 80: module 'strict' not found.

External links

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