Pharmacokinetics and first clinical experiences with an antihypertensive dopamine (DA2) agonist

Abstract

The pharmacokinetic properties and first clinical experiences with the antihypertensive dopamine (DA2) agonist, carmoxirole, are summarized. In man carmoxirole was rapidly absorbed. On oral administration the maximum plasma concentration was reached after 2-3 h. The drug was metabolized, mainly to an ester-type glucuronide, and was excreted (unchanged carmoxirole plus glucuronide) largely by the kidneys. The plasma half-life of the parent compound was 5.5 h. For the dose range tested (0.5 to 1.5 mg) the pharmacokinetics were linear. The drug was rapidly distributed in animals but only very small amounts penetrated the blood-brain barrier. Carmoxirole did not affect supine blood pressure in healthy subjects, but under the conditions of the Schellong's test some orthostatic reactions occurred with high doses. In patients the blood pressure was reduced for at least 8 h after single oral doses. On repeated administration for several weeks a relevant antihypertensive effect was still measurable 12 and 24 h after dose. The most frequently reported adverse events have been headache, dizziness, tiredness, nausea, and gastric disorders. These symptoms are considered to be mainly due to blood pressure reduction, as is frequently observed at the beginning of antihypertensive therapy. In patients the incidence of orthostatic reactions is appreciably lower than in healthy subjects, and in both change of position was sufficient to relieve the symptoms.

Multivariate, Multi-omic Analysis in 799,429 Individuals Identifies 134 Loci Associated with Somatoform Traits

“…Notably, four of these compounds were dopamine receptor antagonists, including atypical antipsychotics (nemonapride, melperone, and benperidol) and a peripherally active D2 receptor antagonist with antihypertensive properties (carmoxirole). 87 Two compounds (PD-0325901 and selumetinib) were found to reverse the brain transcriptomic expression signature of the somatoform factor by targeting the MAP2K1 gene. One of these, PD-0325901, has potent anti-inflammatory activity.…”

Suppression of Noradrenaline Spillover by the Dopamine Prodrug γ-L-Glutamyl-L-Dopa: A Central Effect?

“…Of particular interest is the inhibitory presynaptic receptors, expecially a-2 adrenoceptors, but also adenosine, muscarine, opiate, prostaglandin and dopamine-2 (DA-2) receptors, which, upon stimulation, diminish neuronal noradrenaline (NA) release from varicosities and inhibit adrenergic neurotransmission (2). Previous studies have shown that dopamine (DA) agonists, such as bromocriptine, co-dergocrine, ibopamine and carmoxirole, exert their therapeutic effects in hypertension and/or congestive heart failure at least partly through inhibition of sympathetic nerve activity mediated via DA-2 receptors (3,4).…”