Dihydroergocryptine

Last updated
Dihydroergocryptine
Dihydroergocryptine.svg
Clinical data
Trade names Almirid, Cripar
Other namesDihydroergocriptine; DHEC; 12'-Hydroxy-2'-(1-methylethyl)-5'α-(2-methylpropyl)-9,10α-dihydroergotaman-3',6',18-trione; (5'α,10α)-9,10-Dihydro-12'-hydroxy-2'-(1-methylethyl)-5'-(2-methylpropyl)-ergotaman-3',6',18-trione
Pregnancy
category
  • Contraindicated
Routes of
administration 		Oral
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Elimination half-life 12–16 hours
Identifiers
  • (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
CAS Number
PubChem CID
ChemSpider
UNII
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.042.706 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C32H43N5O5
Molar mass 577.726 g·mol−1
3D model (JSmol)
  • 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(c[nH]5)C[C@H]7N(C)C6)C(C)C
  • 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 Yes check.svgY
  • Key:PBUNVLRHZGSROC-VTIMJTGVSA-N Yes check.svgY
   (verify)

Dihydroergocryptine (DHEC), sold under the brand names Almirid and Cripar among others, is a dopamine agonist of the ergoline group that is used as an antiparkinson agent in the treatment of Parkinson's disease. [1] It is taken by mouth.[ citation needed ]

Contents

Medical uses

Parkinson's disease

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 levodopa may slow or prevent the progression of Parkinson's disease. [4]

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. [5] DHEC is also proven to be a safe and effective in improving symptoms in Parkinson's patients. [6]

Motor improvements in Parkinson's patients are usually observed in patients who take at least a mean daily dose of approximately 40 mg. [7] Patients on DHEC demonstrate a better score than if they were on levodopa on the Webster scale, a standardized rating scale of Parkinson's Disease symptoms such as gait parameters and dyskinesia. [5] [8] Another clinical study has shown that DHEC had superior efficacy in reducing the clinical and motorcomplications associated with long-term levodopa use, as well as in reducing the incidence and severity of adverse effects. [1]

Activation of presynaptic dopamine autoreceptors by dihydroergocriptine leads to reduced dopamine receptor turnover and indirect antioxidant 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. [9]

Modern agonists like dihydroergocryptine typically cost two to three times more than levodopa 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. [10]

Other uses

Dihydroergocryptine can also be used in migraine prophylaxis, [11] as well as for the treatment of low blood pressure in elderly patients and peripheral vascular disorder. [12] More commonly, it is used in combination with two similar compounds, dihydroergocornine and dihydroergocristine. This mixture is called ergoloid or codergocrine. [13]

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. [5] There is also no interference with levodopa metabolism. [10] 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. [7]

Acute side-effects usually accompany the beginning of treatment but tend to decrease as the patient develops increased tolerance to the drug. [14] In randomized, double-blinded trials, individuals on different dopamine agonists, including dihydroergocryptine, did not differ in discontinuation rate associated with adverse events. [15] [16] 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. [6]

Pharmacology

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 Kd 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 (Kd 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 is said to not significantly interact with serotonergic and adrenergic receptors. [5]

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 pharmacokinetic advantage is the lack of dietary influence on drug absorption. This characteristic also allows for more sustained dopamine receptor stimulation. [5]

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. [5]

Chemistry

Dihydroergocryptine is a mixture of two very similar compounds, alpha- and beta-dihydroergocryptine (epicriptine) at a ratio of 2:1. [12] 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. [17]

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. [5]

Related Research Articles

<span class="mw-page-title-main">Dopamine receptor</span> Class of G protein-coupled receptors

Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein interactions. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.

<span class="mw-page-title-main">Amantadine</span> Medication used to treat dyskinesia

Amantadine, sold under the brand name Gocovri among others, is a medication used to treat dyskinesia associated with parkinsonism and influenza caused by type A influenzavirus, though its use for the latter is no longer recommended because of widespread drug resistance. It is also used for a variety of other uses. The drug is taken by mouth.

<span class="mw-page-title-main">Dopamine antagonist</span> Drug which blocks dopamine receptors

A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have found use in treating schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetics used in the treatment of nausea and vomiting.

<span class="mw-page-title-main">Cabergoline</span> Chemical compound

Cabergoline, sold under the brand name Dostinex among others, is a dopaminergic medication used in the treatment of high prolactin levels, prolactinomas, Parkinson's disease, and for other indications. It is taken by mouth.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Pramipexole</span> Dopamine agonist medication

Pramipexole, sold under the brand Mirapex among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipexole is a dopamine agonist of the non-ergoline class.

<span class="mw-page-title-main">Dopamine agonist</span> Compound that activates dopamine receptors

A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used in the treatment of the motor symptoms of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. Impulse control disorders are associated with the use of dopamine agonists for whatever condition.

<span class="mw-page-title-main">Lisuride</span> Chemical compound

Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth.

<span class="mw-page-title-main">Rotigotine</span> Dopamine agonist medication

Rotigotine, sold under the brand name Neupro among others, is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson's disease and restless legs syndrome. It is formulated as a once-daily transdermal patch which provides a slow and constant supply of the drug over the course of 24 hours.

In the management of Parkinson's disease, due to the chronic nature of Parkinson's disease (PD), a broad-based program is needed that includes patient and family education, support-group services, general wellness maintenance, exercise, and nutrition. At present, no cure for the disease is known, but medications or surgery can provide relief from the symptoms.

<span class="mw-page-title-main">Piribedil</span> Drug used in the management of Parkinsons disease

Piribedil (trade names Pronoran, Trivastal Retard, Trastal, Trivastan, Clarium and others) is an antiparkinsonian agent and piperazine derivative which acts as a D2 and D3 receptor agonist. It also has α2-adrenergic antagonist properties.

<span class="mw-page-title-main">Istradefylline</span> Chemical compound

Istradefylline, sold under the brand name Nourianz, is a medication used as an add-on treatment to levodopa/carbidopa in adults with Parkinson's disease (PD) experiencing "off" episodes. Istradefylline reduces "off" periods resulting from long-term treatment with the antiparkinson drug levodopa. An "off" episode is a time when a patient's medications are not working well, causing an increase in PD symptoms, such as tremor and difficulty walking.

<span class="mw-page-title-main">Levodopa</span> Dopaminergic medication

Levodopa, also known as L-DOPA and sold under many brand names, is a dopaminergic medication which is used in the treatment of Parkinson's disease and certain other conditions like dopamine-responsive dystonia and restless legs syndrome. The drug is usually used and formulated in combination with a peripherally selective aromatic L-amino acid decarboxylase (AAAD) inhibitor like carbidopa or benserazide. Levodopa is taken by mouth, by inhalation, through an intestinal tube, or by administration into fat.

<span class="mw-page-title-main">Dopamine dysregulation syndrome</span> Neuralogical disorder caused by long-term use of dopaminergic drugs

Dopamine dysregulation syndrome (DDS) is a dysfunction of the reward system observed in some individuals taking dopaminergic medications for an extended length of time. It is characterized by severely disinhibited patterns of behavior, leading to problems such as addiction to the offending medication, gambling addiction, or compulsive sexual behavior, along with a general orientation towards immediate gratification. It typically occurs in people with Parkinson's disease or restless legs syndrome (RLS) who have taken dopamine agonist medications for an extended period of time.

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<span class="mw-page-title-main">Roxindole</span> Dopaminergic & serotonergic drug developed for schizophrenia treatment

Roxindole (EMD-49,980) is a dopaminergic and serotonergic drug which was originally developed by Merck KGaA for the treatment of schizophrenia. In clinical trials its antipsychotic efficacy was only modest but it was unexpectedly found to produce potent and rapid antidepressant and anxiolytic effects. As a result, roxindole was further researched for the treatment of depression instead. It has also been investigated as a therapy for Parkinson's disease and prolactinoma.

<span class="mw-page-title-main">OSU-6162</span> Chemical compound

OSU-6162 (PNU-96391) is a compound which acts as a partial agonist at both dopamine D2 receptors and 5-HT2A receptors. It acts as a dopamine stabilizer in a similar manner to the closely related drug pridopidine, and has antipsychotic, anti-addictive and anti-Parkinsonian effects in animal studies. Both enantiomers show similar activity but with different ratios of effects, with the (S) enantiomer (–)-OSU-6162 that is more commonly used in research, having higher binding affinity to D2 but is a weaker partial agonist at 5-HT2A, while the (R) enantiomer (+)-OSU-6162 has higher efficacy at 5-HT2A but lower D2 affinity.

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<span class="mw-page-title-main">Mesdopetam</span> Chemical compound

Mesdopetam (INNTooltip International Nonproprietary Name; developmental code names IRL-790, IPN60170) is a dopamine D2 and D3 receptor antagonist with preference for the D3 receptor which is under development for the treatment of Parkinson's disease, drug-induced dyskinesia, and psychotic disorders. It has been described by its developers as having "psychomotor stabilizing" properties.

References

  1. 1 2 Battistin L, Bardin PG, Ferro-Milone F, Ravenna C, Toso V, Reboldi G (January 1999). "Alpha-dihydroergocryptine in Parkinson's disease: a multicentre randomized double blind parallel group study". Acta Neurologica Scandinavica. 99 (1): 36–42. doi:10.1111/j.1600-0404.1999.tb00655.x. PMID   9925236. S2CID   45192184.
  2. 1 2 3 Antonini A, Tolosa E, Mizuno Y, Yamamoto M, Poewe WH (October 2009). "A reassessment of risks and benefits of dopamine agonists in Parkinson's disease". The Lancet. Neurology. 8 (10): 929–37. doi:10.1016/S1474-4422(09)70225-X. PMID   19709931. S2CID   33649811.
  3. 1 2 3 Gerlach M, Double K, Arzberger T, Leblhuber F, Tatschner T, Riederer P (October 2003). "Dopamine receptor agonists in current clinical use: comparative dopamine receptor binding profiles defined in the human striatum". Journal of Neural Transmission. 110 (10): 1119–27. doi:10.1007/s00702-003-0027-5. PMID   14523624. S2CID   10073899.
  4. ↑ Parkinson Study Group (April 2002). "Dopamine transporter brain imaging to assess the effects of pramipexole vs levodopa on Parkinson disease progression". JAMA. 287 (13): 1653–61. doi: 10.1001/jama.287.13.1653 . PMID   11926889.
  5. 1 2 3 4 5 6 7 Albanese A, Colosimo C (May 2003). "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. S2CID   18094044.
  6. 1 2 Bergamasco B, Frattola L, Muratorio A, Piccoli F, Mailland F, Parnetti L (June 2000). "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. doi:10.1034/j.1600-0404.2000.90295a.x. PMID   10877152. S2CID   9859381.
  7. 1 2 Martignoni E, Pacchetti C, Sibilla L, Bruggi P, Pedevilla M, Nappi G (February 1991). "Dihydroergocryptine in the treatment of Parkinson's disease: a six months' double-blind clinical trial". Clinical Neuropharmacology. 14 (1): 78–83. doi:10.1097/00002826-199102000-00006. PMID   1903079.
  8. ↑ Ramaker C, Marinus J, Stiggelbout AM, Van Hilten BJ (September 2002). "Systematic evaluation of rating scales for impairment and disability in Parkinson's disease". Movement Disorders. 17 (5): 867–76. doi:10.1002/mds.10248. PMID   12360535. S2CID   2562332.
  9. ↑ Olanow CW (February 1992). "A rationale for dopamine agonists as primary therapy for Parkinson's disease". The Canadian Journal of Neurological Sciences. 19 (1 Suppl): 108–12. doi: 10.1017/S0317167100041469 . PMID   1349262.
  10. 1 2 Clarke CE, Guttman M (November 2002). "Dopamine agonist monotherapy in Parkinson's disease". Lancet. 360 (9347): 1767–9. doi:10.1016/S0140-6736(02)11668-0. PMID   12480442. S2CID   25118777.
  11. ↑ Micieli G, Cavallini A, Marcheselli S, Mailland F, Ambrosoli L, Nappi G (April 2001). "Alpha-dihydroergocryptine and predictive factors in migraine prophylaxis". International Journal of Clinical Pharmacology and Therapeutics. 39 (4): 144–51. doi:10.5414/cpp39144. PMID   11332869.
  12. 1 2 Haberfeld, H, ed. (2007). Austria-Codex (in German) (2007/2008 ed.). Vienna: Österreichischer Apothekerverlag. ISBN   978-3-85200-183-8.
  13. ↑ Drugs.com: Ergoloid Mesylates
  14. ↑ Yamamoto M, Schapira AH (April 2008). "Dopamine agonists in Parkinson's disease". Expert Review of Neurotherapeutics. 8 (4): 671–7. doi:10.1586/14737175.8.4.671. PMID   18416667. S2CID   207194957.
  15. ↑ Rascol O, Goetz C, Koller W, Poewe W, Sampaio C (May 2002). "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. S2CID   24426198.
  16. ↑ Goetz CG, Poewe W, Rascol O, Sampaio C (May 2005). "Evidence-based medical review update: pharmacological and surgical treatments of Parkinson's disease: 2001 to 2004". Movement Disorders. 20 (5): 523–39. doi:10.1002/mds.20464. PMID   15818599. S2CID   16260982.
  17. ↑ Steinhilber D, Schubert-Zsilavecz M, Roth HJ (2005). Medizinische Chemie (in German). Stuttgart: Deutscher Apotheker Verlag. p. 142. ISBN   978-3-7692-3483-1.


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