Pulmonary delivery of a dopamine D-1 agonist, ABT-431, in dogs and humans

Zheng, Yuqun; Marsh, Kennan C.; Bertz, Richard; El-Shourbagy, Tawakol A.; Adjei, Akwete

doi:10.1016/s0378-5173(99)00296-3

Cited by 12 publications

(3 citation statements)

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“…In man ABT has a low oral bioavailability (±4%) due to a high hepatic “first-pass” metabolism [ 47 ]. This limitation has been circumvented by oral inhalation formulations for intrapulmonary delivery that greatly increase its bioavailability [ 48 ]. Because ABT-431 showed no advantage in decreased dyskinesia compared to L-DOPA and because of the challenge of finding an oral dose formulation, it was not further developed.…”

Section: The Search For Selective D1 Agonistsmentioning

confidence: 99%

The Discovery of Novel Selective D1 Dopaminergic Agonists: A-68930, A-77636, A-86929, and ABT-413

Martin¹

2011

International Journal of Medicinal Chemistry

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The novel selective D1 dopaminergic full agonists A-68930, A-77636 were discovered by the synthesis of molecules to probe the bioactive conformation of the partial agonist SKF-38393, by the use of this information to add D1 affinity and selectivity to a screening hit, and by traditional medicinal chemistry exploration of structure-activity relationships. The subsequent design of A-86929 and ABT-413 capitalized on these results, recently disclosed agonists, and traditional medicinal chemistry.

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Section: The Search For Selective D1 Agonistsmentioning

confidence: 99%

The Discovery of Novel Selective D1 Dopaminergic Agonists: A-68930, A-77636, A-86929, and ABT-413

Martin¹

2011

International Journal of Medicinal Chemistry

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“…Over 40 years have elapsed since pressurized metered-dose inhalers (pMDIs) were first introduced as a convenient delivery system for targeting bronchodilator drugs, and later corticosteroids, directly into the lungs of patients with asthma . The lungs have also been recognized as an efficient pathway for drugs to the bloodstream due to their large adsorptive surface area , and the lower activity of bound enzymes compared to those present in the liver and kidneys . pMDIs are the least expensive devices for inhalation therapy, accounting for more than 80% of the total prescribed aerosols.…”

Section: Introductionmentioning

confidence: 99%

Surfactant Design for the 1,1,1,2-Tetrafluoroethane−Water Interface: ab initioCalculations andin situHigh-Pressure Tensiometry

et al. 2006

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In situ high-pressure tensiometry and ab initio calculations were used to rationally design surfactants for the 1,1,1,2-tetrafluoroethane-water (HFA134a|W) interface. Nonbonded pair interaction (binding) energies (E(b)) of the complexes between HFA134a and candidate surfactant tails were used to quantify the HFA-philicity of selected moieties. The interaction between HFA134a and an ether-based tail was shown to be predominantly electrostatic in nature and much more favorable than that between HFA134a and a methyl-based fragment. The interfacial activity of (i) amphiphiles typically found in FDA-approved pressurized metered-dose inhaler (pMDI) formulations, (ii) a series of nonionic surfactants with methylene-based tails, and (iii) a series of nonionic surfactants with ether-based tails was investigated at the HFA134a|W interface using in situ tensiometry. This is the first time that the tension of the surfactant-modified HFA134a|W interface has been reported in the literature. The ether-based surfactants were shown to be very interfacially active, with tension decreasing by as much as 27 mN.m(-)(1). However, the methyl-based surfactants, including those from FDA-approved formulations, did not exhibit high activity at the HFA134a|W interface. These results are in direct agreement with the E(b) calculations. Significant differences in interfacial activity are noted for surfactants at the 2H,3H-perfluoropentane (HPFP)|water and HFA134a|W interfaces. Care should be taken, therefore, when results from the mimicking solvent (HPFP) are extrapolated to HFA134a-based systems. The results shown here are of relevance in the selection of surfactants capable of forming and stabilizing reverse aqueous aggregates in HFA-based pMDIs, which are promising formulations for the systemic delivery of biomolecules to and through the lungs.

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“…dose in dogs and up to 25% of a 5 mg A-86929 equivalent i.v. dose of A-86929 in man (37). These studies indicate that the pulmonary delivery systems may be a suitable alternative to oral delivery of adrogolide.…”

Section: Formulation Studiesmentioning

confidence: 75%

Adrogolide HCl (ABT‐431; DAS‐431), a Prodrug of the Dopamine D₁ Receptor Agonist, A‐86929: Preclinical Pharmacology and Clinical Data

Giardina

Williams

2001

CNS Drug Reviews

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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 D 1 receptors. In in vitro functional assays, A-86929 is over 400 times more selective for dopamine D 1 than D 2 receptors. In rats with a unilateral loss of striatal dopamine, A-86929 produces contralateral rotations that are inhibited by dopamine D 1 but not by dopamine D 2 receptor antagonists. Adrogolide improves behavioral disability and locomotor activity scores in MPTPlesioned 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 re- 305CNS Drug Reviews Vol. 7, No. 3, pp. 305-316 © 2001 Neva Press, Branford, Connecticut Address correspondence and reprint requests to: William J. Giardina, PhD, CNS Diseases Research D-4N5, AP9A, Abbott Laboratories, 100 Abbott Park Road Abbott Park, IL 60064-6125, USA. Fax: +1 (847) 937-9195; E-mail: william.j.giardina@abbott.com ported 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 (@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 D 1 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 D 1 receptor agonists.

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Pulmonary delivery of a dopamine D-1 agonist, ABT-431, in dogs and humans

Cited by 12 publications

References 3 publications

The Discovery of Novel Selective D1 Dopaminergic Agonists: A-68930, A-77636, A-86929, and ABT-413

The Discovery of Novel Selective D1 Dopaminergic Agonists: A-68930, A-77636, A-86929, and ABT-413

Surfactant Design for the 1,1,1,2-Tetrafluoroethane−Water Interface: ab initioCalculations andin situHigh-Pressure Tensiometry

Adrogolide HCl (ABT‐431; DAS‐431), a Prodrug of the Dopamine D₁ Receptor Agonist, A‐86929: Preclinical Pharmacology and Clinical Data

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Pulmonary delivery of a dopamine D-1 agonist, ABT-431, in dogs and humans

Cited by 12 publications

References 3 publications

The Discovery of Novel Selective D1 Dopaminergic Agonists: A-68930, A-77636, A-86929, and ABT-413

The Discovery of Novel Selective D1 Dopaminergic Agonists: A-68930, A-77636, A-86929, and ABT-413

Surfactant Design for the 1,1,1,2-Tetrafluoroethane−Water Interface: ab initioCalculations andin situHigh-Pressure Tensiometry

Adrogolide HCl (ABT‐431; DAS‐431), a Prodrug of the Dopamine D1 Receptor Agonist, A‐86929: Preclinical Pharmacology and Clinical Data

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Adrogolide HCl (ABT‐431; DAS‐431), a Prodrug of the Dopamine D₁ Receptor Agonist, A‐86929: Preclinical Pharmacology and Clinical Data