Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0012833 (dizziness)
 9,689 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies in animal models show a selective D1 receptor agonist with full functional efficacy compared with dopamine to have antiparkinsonian efficacy of similar magnitude to levodopa, without the same propensity for inducing dyskinesia. To date, no such agent has been tested in humans. ABT-431 is the prodrug of A-86929, a full, selective D1 receptor agonist. Subjects (n = 14) with levodopa-responsive Parkinson's disease received five doses of ABT-431 (5, 10, 20, 30, and 40 mg) and one of placebo after a 12-hour levodopa holiday. Response was assessed by using the Unified Parkinson's Disease Rating Scale motor subsection. Dyskinesia was separately graded. ABT-431 showed efficacy significantly superior to placebo at doses of 10 mg and more, and of similar magnitude to that seen with levodopa. Dyskinesia was reduced in several patients after receiving ABT-431. There were no serious adverse events, the most common minor events being nausea and emesis, dizziness, and hypotension. Assuming that ABT-431 is not transformed in humans into an unknown active D2 metabolite, and remains selective for D1 receptors, it is the first dopamine D1 receptor agonist to demonstrate a full antiparkinsonian effect in patients with Parkinson's disease. These preliminary findings also suggest that it may exhibit a reduced tendency to provoke dyskinesia. The emergence of a well-tolerated D1 agonist should allow for the development of a better understanding of the relation between motor efficacy and dyskinesia in Parkinson's disease.
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PMID:ABT-431, a D1 receptor agonist prodrug, has efficacy in Parkinson's disease. 1036 Jul 65

Adrogolide (ABT-431; DAS-431) is a chemically stable prodrug that is converted rapidly (<1 min) in plasma to A-86929, a full agonist at dopamine D1 receptors. In in vitro functional assays, A-86929 is over 400 times more selective for dopamine D1 than D2 receptors. In rats with a unilateral loss of striatal dopamine, A-86929 produces contralateral rotations that are inhibited by dopamine D1 but not by dopamine D2 receptor antagonists. Adrogolide improves behavioral disability and locomotor activity scores in MPTP-lesioned marmosets, a model of Parkinson's disease (PD), and shows no tolerance upon repeated dosing for 28 days. In PD patients, intravenous (i.v.) adrogolide has antiparkinson efficacy equivalent to that of L-DOPA with a tendency towards a reduced liability to induce dyskinesia. The adverse events associated with its use were of mild-to-moderate severity and included injection site reaction, asthenia, headache, nausea, vomiting, postural hypotension, vasodilitation, and dizziness. Adrogolide can also attenuate the ability of cocaine to induce cocaine-seeking behavior and does not itself induce cocaine-seeking behavior in a rodent model of cocaine craving and relapse. In human cocaine abusers, i.v. adrogolide reduces cocaine craving and other cocaine-induced subjective effects. The results of animal abuse liability studies indicate that adrogolide is unlikely to have abuse potential in man. Adrogolide has also been reported to reverse haloperidol-induced cognitive deficits in monkeys, suggesting that it may be an effective treatment for the cognitive dysfunction associated with aging and disease. Adrogolide undergoes a high hepatic "first-pass" metabolism in man after oral dosing and, as a result, has a low oral bioavailability (approximately 4%). This limitation may potentially be circumvented by oral inhalation formulations for intrapulmonary delivery that greatly increase the bioavailability of adrogolide. As the first full dopamine D1 receptor agonist to show efficacy in PD patients and to reduce the craving and subjective effects of cocaine in cocaine abusers, adrogolide represents an important tool in understanding the pharmacotherapeutic potential of dopamine D1 receptor agonists.
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PMID:Adrogolide HCl (ABT-431; DAS-431), a prodrug of the dopamine D1 receptor agonist, A-86929: preclinical pharmacology and clinical data. 1160 45