関: dihydroergocryptine

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/03/29 17:02:49」(JST)

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Dihydroergocryptine (DHEC, trade names Almirid, Cripar) is a dopamine agonist of the ergoline chemical class that is used as an antiparkinson agent.^[1] Dihydroergocryptine has been shown to be particularly effective as monotherapy in the early stages of Parkinson's disease. Initial monotherapy with a dopamine agonist (other examples include pergolide, pramipexole, and ropinirole) is associated with reduced risk for motor complications in Parkinson patients relative to levodopa.^[2] DHEC, like other dopamine agonists, aims to mimic the endogenous neurotransmitter and exert an antiparkinsonian effect.^[3] Recent evidence also supports that dopamine receptor agonists, instead of L-DOPA may slow or prevent the progression of Parkinson's disease.^[4]

Dihydroergocryptine can also be used in migraine prophylaxis,^[5] as well as for the treatment of low blood pressure in elderly patients and peripheral vascular disorder.^[6] More commonly, it is used in combination with two similar compounds, dihydroergocornine and dihydroergocristine. This mixture is called ergoloid or codergocrine.^[7]

Chemistry

Dihydroergocryptine is a mixture of two very similar compounds, alpha- and beta-dihydroergocryptine (epicriptine) at a ratio of 2:1.^[6] The beta differs from the alpha form only in the position of a single methyl group, which is a consequence of the biosynthesis of the parent compound ergocryptine, in which the proteinogenic amino acid leucine is replaced by isoleucine.^[8]

Dihydroergocryptine is a hydrogenated ergot derivative that is also structurally very similar to bromocriptine, another drug that has anti-Parkinson effects. DHEC differs in that it is hydrogenated in C9–C10 and lacks bromine in C2. In fact, all ergot derivatives are uniquely or mainly D₂-like receptor agonists.^[9]

Pharmacodynamics

Several in vitro and in vivo studies have demonstrated that dihydroergocriptine is an effective anti-Parkinson drug, most likely exerting its effects as a potent agonist of D₂ receptors. The K_d of DHEC is found to be around 5-8 nM at D2 receptors. Less certain is the contribution of its partial D₁ receptor and D₃ receptor agonist activity. DHEC has a lower affinity for D₁ and D₃ receptors (K_d is around 30 nM for both) than for D₂ receptors.^[3] It is widely believed that dopamine receptor agonists demonstrate their antiparkinsonian effects by stimulating D2 receptors primarily, but other dopamine receptors, such as D1 and D3 may be involved.^[3]

Remarkably, DHEC does not significantly interact with serotonergic and adrenergic receptors.^[9]

Pharmacokinetics

Dihydroergocriptine has two main pharmacokinetic advantages over levodopa.

The first pharmacokinetic advantage is its half-life of 12 to 16 hours. This relatively long half-life is considered to contribute to the compound's effectiveness in Parkinson's disease, particularly since it allows for more continuous stimulation of brain dopaminergic receptors than short-acting drugs such as levodopa. Though the exact reason is not known, continuous stimulation is considered to reduce risk for motor complications.^[2]

The second pharamcokinetic advantage is the lack of dietary influence on drug absorption. This characteristic also allows for more sustained dopamine receptor stimulation.^[9]

DHEC can be taken with a single oral dose and is rapidly absorbed. Peak plasma concentrations occur between 30 and 120 minutes after administration. The strong first-pass hepatic metabolism results in poor bioavailability. Less than 5% of the original dosage reaches the circulation.^[9]

Treatment

The relatively long half-life and lack of dietary influence of dihydroergocriptine is considered to contribute to the compound's effectiveness in Parkinson's disease, particularly since it allows for more continuous stimulation of brain dopaminergic receptors than short-acting drugs such as levodopa.^[9] DHEC is also proven to be a safe and effective in improving symptoms in Parkinson's patients.^[10]

"Motor improvements"

Motor improvements in Parkinson's patients are usually observed in patients who take at least a mean daily dose of approximately 40 mg.^[11] Patients on DHEC demonstrate a better score than if they were on L-Dopa on the Webster scale, a standardized rating scale of Parkinson's Disease symptoms such as gait parameters and dyskinesia.^[9]^[12] Another clinical study has shown that DHEC had superior efficacy in reducing the clinical and motorcomplications associated with long-term L-Dopa use, as well as in reducing the incidence and severity of adverse effects.^[13]

"Neuroprotective effects"

Activation of presynaptic dopamine autoreceptors by dihydroergocriptine leads to reduced dopamine receptor turnover and indirect antioxident effects. In particular, further activation of intracellular kinase systems due to dopamine agonists are hypothesized to lead to antiapoptotic effects that also help in halting and slowing the disease progression.^[2] This may also contribute to prevention of development of motor fluctuations, though more research is needed.^[14]

Modern agonists like dihydroergocryptine typically cost two to three times more than levadopa therapy. More health economics assessments may be needed to determine whether the initial increased costs of the agonists are offset by less patients needing surgery in later stages of the disease.^[15]

Side effects

Dihydroergocryptine has been suggested to produce fewer side-effects and have similar efficacy to a classical dopamine agonist due to its biochemical profile.^[9] There is also no interference with levodopa metabolism.^[15] Although DHEC may come with some acute side-effects described further below, DHEC has overall good tolerability with little to no withdrawal or changes in its scheduling.^[16]

Acute side-effects usually accompany the beginning of treatment but tend to decrease as the patient develops increased tolerance to the drug.^[17] In randomized, double-blinded trials, individuals on different dopamine agonists, including dihydroergocryptine, did not differ in discontinuation rate associated with adverse events.^[18]^[19] However there do seem to be a higher incidence of dopaminergic related side-effects such as hallucinations and gastrointestinal complaints tend to be more frequent.^[10]

Nausea
Vomiting
Anxiety
Cardiac arrhythmias
Postural hypotension
Somnolence
Hallucinations
Impulse control disorders
Peripheral oedema

References

^ Battistin, L.; Bardin, P. G.; Ferro-Milone, F.; Ravenna, C.; Toso, V.; Reboldi, G. (1999). "Alpha-dihydroergocryptine in Parkinson's disease: A multicentre randomized double blind parallel group study". Acta neurologica Scandinavica 99 (1): 36–42. PMID 9925236. edit
^ ^a ^b ^c Antonini, A; Tolosa, E, Mizuno, Y, Yamamoto, M, Poewe, WH (2009 Oct). "A reassessment of risks and benefits of dopamine agonists in Parkinson's disease". Lancet neurology 8 (10): 929–37. doi:10.1016/S1474-4422(09)70225-X. PMID 19709931.
^ ^a ^b ^c Gerlach, M; Double, K; Arzberger, T; Leblhuber, F; Tatschner, T; Riederer, P (2003 Oct). "Dopamine receptor agonists in current clinical use: comparative dopamine receptor binding profiles defined in the human striatum.". Journal of neural transmission (Vienna, Austria : 1996) 110 (10): 1119–27. doi:10.1007/s00702-003-0027-5. PMID 14523624.
^ Parkinson Study, Group (2002 Apr 3). "Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression.". JAMA: the Journal of the American Medical Association 287 (13): 1653–61. PMID 11926889.
^ Micieli, G.; Cavallini, A.; Marcheselli, S.; Mailland, F.; Ambrosoli, L.; Nappi, G. (2001). "Alpha-dihydroergocryptine and predictive factors in migraine prophylaxis". International journal of clinical pharmacology and therapeutics 39 (4): 144–151. PMID 11332869. edit
^ ^a ^b Haberfeld, H, ed. (2007). Austria-Codex (in German) (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 3-85200-183-8.
^ Drugs.com: Ergoloid Mesylates
^ Steinhilber, D; Schubert-Zsilavecz, M; Roth, HJ (2005). Medizinische Chemie (in German). Stuttgart: Deutscher Apotheker Verlag. p. 142. ISBN 3-7692-3483-9.
^ ^a ^b ^c ^d ^e ^f ^g Albanese, A; Colosimo, C (2003 May). "Dihydroergocriptine in Parkinson's disease: clinical efficacy and comparison with other dopamine agonists". Acta neurologica Scandinavica 107 (5): 349–55. doi:10.1034/j.1600-0404.2003.02049.x. PMID 12713527.
^ ^a ^b Bergamasco, B; Frattola, L; Muratorio, A; Piccoli, F; Mailland, F; Parnetti, L (2000 Jun). "Alpha-dihydroergocryptine in the treatment of de novo parkinsonian patients: results of a multicentre, randomized, double-blind, placebo-controlled study.". Acta neurologica Scandinavica 101 (6): 372–80. PMID 10877152.
^ "Dihydroergocryptine in the treatment of Parkinson's disease: a six months' double-blind clinical trial". Clin Neuropharmacol 14 (1): 78–83. February 1991. PMID 1903079.
^ Ramaker, C; Marinus, J; Stiggelbout, AM; Van Hilten, BJ (2002 Sep). "Systematic evaluation of rating scales for impairment and disability in Parkinson's disease.". Movement disorders : official journal of the Movement Disorder Society 17 (5): 867–76. doi:10.1002/mds.10248. PMID 12360535.
^ Battistin, L; Bardin, PG; Ferro-Milone, F; Ravenna, C; Toso, V; Reboldi, G (1999 Jan). "Alpha-dihydroergocryptine in Parkinson's disease: a multicentre randomized double blind parallel group study.". Acta neurologica Scandinavica 99 (1): 36–42. PMID 9925236.
^ Olanow, CW (1992 Feb). "A rationale for dopamine agonists as primary therapy for Parkinson's disease". The Canadian journal of neurological sciences. Le journal canadien des sciences neurologiques 19 (1 Suppl): 108–12. PMID 1349262.
^ ^a ^b Clarke, C.E.; Gutman, M. (30). "Dopamine agonist monotherapy in Parkinson's Disease". Lancet 360 (9347): 1767–1769. doi:10.1016/S0140-6736(02)11668-0. PMID 12480442.
^ Martignoni, E; Pacchetti, C; Sibilla, L; Bruggi, P; Pedevilla, M; Nappi, G (1991 Feb). "Dihydroergocryptine in the treatment of Parkinson's disease: a six months' double-blind clinical trial.". Clinical neuropharmacology 14 (1): 78–83. PMID 1903079.
^ Yamamoto, M; Schapira, AH (2008 Apr). "Dopamine agonists in Parkinson's disease". Expert Review of Neurotherapeutics 8 (4): 671–7. doi:10.1586/14737175.8.4.671. PMID 18416667.
^ Rascol, O; Goetz, C, Koller, W, Poewe, W, Sampaio, C (2002 May 4). "Treatment interventions for Parkinson's disease: an evidence based assessment". Lancet 359 (9317): 1589–98. doi:10.1016/S0140-6736(02)08520-3. PMID 12047983.
^ Goetz, CG; Poewe, W, Rascol, O, Sampaio, C (2005 May). "Evidence-based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004". Movement disorders : official journal of the Movement Disorder Society 20 (5): 523–39. doi:10.1002/mds.20464. PMID 15818599.

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Castillo-Huerta E, Garibay-Valencia M, Mirabent-González F.SourceHospital General Dr. Miguel Silva, Morelia, Michoacán.
Ginecología y obstetricia de México.Ginecol Obstet Mex.2013 Jul;81(7):370-6.
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[Prescription of ergot derivatives for lactation inhibition in France: Current practices].

Mirkou A, Suchovsky D, Gouraud A, Gillet A, Bernard N, Descotes J, Vial T.SourceCentre antipoison - centre de pharmacovigilance, hospices civils de Lyon, 162, avenue Lacassagne, 69003 Lyon, France.
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OBJECTIVES: To provide an overview of ergot derivatives prescription for lactation inhibition in France, either label (bromocriptine 2.5mg and lisuride 0.2mg) or off-label prescription (dihydroergocryptine and cabergoline).PATIENTS AND METHODS: Analysis based on a questionnaire sent to all 618 Fren
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The history of ergot of rye (Claviceps purpurea) III: 1940-80.

Lee MR.SourceUniversity of Edinburgh, Edinburgh, UK.
The journal of the Royal College of Physicians of Edinburgh.J R Coll Physicians Edinb.2010 Mar;40(1):77-80.
The period 1940-80 in the history of ergot was dominated by two investigators, Arthur Stoll and Albert Hofmann. There was great excitement when their group isolated from ergot preparations the powerful psychotropic agent lysergic acid diethylamide (LSD). It was thought that this substance would help
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★リンクテーブル★

リンク元	「メシル酸ジヒドロエルゴクリプチン」
関連記事	「mesylate」「dihydroergocryptine」

「メシル酸ジヒドロエルゴクリプチン」

alpha-Dihydroergocryptine
Systematic (IUPAC) name
	(2R,4R,7R)-N- [(1S,2S,4R,7S)- 2-hydroxy- 7-(2-methylpropyl)- 5,8-dioxo- 4-(propan-2-yl)- 3-oxa- 6,9-diazatricyclo [7.3.0.02,6]dodecan-4-yl]- 6-methyl- 6,11-diazatetracyclo [7.6.1.02,7.012,16] hexadeca- 1(16),9,12,14-tetraene- 4-carboxamide
Clinical data
Trade names	Almirid, Cripar
Pregnancy cat.	Contraindicated
Legal status	℞ Prescription only
Routes	Oral
Pharmacokinetic data
Half-life	12–16 hours
Identifiers
CAS number	25447-66-9
ATC code	N04BC03 (alpha/beta)
PubChem	CID 114948
ChemSpider	102887
UNII	67V3FSL2GL
ChEBI	CHEBI:59919
Synonyms	12'-Hydroxy- 2'-(1-methylethyl)- 5'α-(2-methylpropyl)- 9,10α-dihydroergotaman- 3',6',18-trione;; OR; (5'α,10α)-9,10-dihydro- 12'-hydroxy-2'- (1-methylethyl)- 5'-(2-methylpropyl)- ergotaman- 3',6',18-trione
Chemical data
Formula	C32H43N5O5
Mol. mass	577.715 g/mol
	SMILES O=C3N1CCC[C@H]1[C@]2(O)O[C@](C(=O)N2[C@H]3CC(C)C)(NC(=O)[C@@H]6C[C@@H]7c4cccc5c4c(cn5)C[C@H]7N(C)C6)C(C)C;
	InChI InChI=1S/C32H43N5O5/c1-17(2)12-25-29(39)36-11-7-10-26(36)32(41)37(25)30(40)31(42-32,18(3)4)34-28(38)20-13-22-21-8-6-9-23-27(21)19(15-33-23)14-24(22)35(5)16-20/h6,8-9,15,17-18,20,22,24-26,33,41H,7,10-14,16H2,1-5H3,(H,34,38)/t20-,22-,24-,25+,26+,31-,32+/m1/s1 ; Key:PBUNVLRHZGSROC-VTIMJTGVSA-N ;
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