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| Trade names | Almirid, Cripar |
| Other names | Dihydroergocriptine; 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 |
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| Routes of administration | Oral |
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| Pharmacokinetic data | |
| Eliminationhalf-life | 12–16 hours |
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| ECHA InfoCard | 100.042.706 |
| Chemical and physical data | |
| Formula | C32H43N5O5 |
| Molar mass | 577.726 g·mol−1 |
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Dihydroergocryptine (DHEC), sold under the brand namesAlmirid andCripar among others, is adopamine agonist of theergoline group that is used as anantiparkinson agent in the treatment ofParkinson's disease.[1] It is takenby mouth.[citation needed]
Dihydroergocryptine has been shown to be particularly effective as monotherapy in the early stages ofParkinson's disease. Initial monotherapy with a dopamine agonist (other examples includepergolide,pramipexole, andropinirole) is associated with reduced risk for motor complications in Parkinson patients relative tolevodopa.[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]
Dihydroergocryptine can also be used inmigraine prophylaxis,[11] as well as for the treatment oflow blood pressure in elderly patients and peripheralvascular disorder.[12] More commonly, it is used in combination with two similar compounds,dihydroergocornine anddihydroergocristine. This mixture is calledergoloid or codergocrine.[13]
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]
Severalin vitro andin vivo studies have demonstrated that dihydroergocriptine is an effective anti-Parkinson drug, most likely exerting its effects as a potentagonist of D2 receptors. TheKd of DHEC is found to be around 5-8 nM at D2 receptors. Less certain is the contribution of its partialD1 receptor andD3 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 withserotonergic andadrenergic receptors.[5]
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]
Dihydroergocryptine is a mixture of two very similar compounds,alpha- andbeta-dihydroergocryptine (epicriptine) at a ratio of 2:1.[12] Thebeta differs from thealpha form only in the position of a singlemethyl group, which is a consequence of thebiosynthesis of the parent compoundergocryptine, in which theproteinogenic amino acidleucine is replaced byisoleucine.[17]
Dihydroergocryptine is a hydrogenatedergot derivative that is also structurally very similar tobromocriptine, 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 mainlyD2-likereceptor agonists.[5]
