Proterguride, a highly potent dopamine receptor agonist promising for transdermal administration in Parkinson's disease: Interactions with α1-, 5-HT2- and H1-receptors

Q3 · MEDICINE

Article

Author: S. Jähnichen ; J. Tack ; H.H. Pertz ; T. Görnemann ; B. Schurad ; R. Horowski

Dopamine receptor agonists play an important role in the treatment of Parkinson's disease and hyperprolactinemic conditions. Proterguride (n-propyldihydrolisuride) was already reported to be a highly potent dopamine receptor agonist, thus its action at different non-dopaminergic monoamine receptors, alpha(1A/1B/1D), 5-HT(2A/2B)- and histamine H(1), was investigated using different functional in vitro assays. The drug behaved as an antagonist at alpha(1)-adrenoceptors without the ability to discriminate between the subtypes (pA(2) values: alpha(1A) 7.31; alpha(1B) 7.37; alpha(1D) 7.35) and showed antagonistic properties at the histamine H(1) receptor. In contrast, at serotonergic receptors (5-HT(2A), 5-HT(2B)) proterguride acted as a partial agonist. The drug stimulated 5-HT(2A) receptors of rat tail artery in lower concentrations than 5-HT itself but failed to evoke comparable efficacy (proterguride: pEC(50) 8.34, E(max) 53% related to the maximum response to 5-HT; 5-HT: pEC(50) 7.03). Agonism at 5-HT(2B) receptors is presently considered to be involved in drug-induced valvular heart disease. Activation of 5-HT(2B) receptors in porcine pulmonary arteries by proterguride (pEC(50) 7.13, E(max) 49%; E(max) (5-HT) 69%), however, occurred at concentrations much higher than plasma concentrations achieving dopaminergic efficacy in humans. The results are discussed focussing on the relevance of action at 5-HT(2B) receptors as well as their significance for a transdermal administration of proterguride. Since it is well accepted that pulsatile dopaminergic stimulation is associated with treatment-related motor complications in the dopaminergic therapy of Parkinson's disease, the transdermal route of administration is of great clinical interest due to the possibility to achieve constant plasma concentrations.

01 Jan 2005·Drug Development and Industrial PharmacyQ4 · MEDICINE

Evaluation of the Transdermal Permeation Behavior of Proterguride from Drug in Adhesive Matrix Patches Through Hairless Mouse Skin

Q4 · MEDICINE

Article

Author: Johannes Tack ; Ralph Lipp ; Björn Schurad

The transdermal in vitro permeation behavior of the highly potent dopamine agonist Proterguride was investigated using hairless mouse skin as a model membrane. Drug in adhesive matrix formulations based on different types of pressure-sensitive adhesives (Eudragit E 100 and Gelva7883 as acrylates, Oppanol B 15 SFN as polyisobutylene, and BioPSA 7-4202 as silicone) with a drug load of 3% by weight were manufactured. All patches were examined for drug crystallization by polarized microscopy immediately after the manufacturing process and after storage for 30 days in sealed aluminium laminate bags at ambient temperature and at 40 degrees C, respectively. Furthermore, the influence of the drug load in acrylate-based formulations onto the steady-state flux of Proterguride was examined. The Eudragit E 100 system delivered a significantly higher steady-state flux than the systems based on Oppanol B 15 SFN and also a somewhat higher steady-state flux than the Gelva-based patch. An addition of 10% by weight of the crystallization inhibitor povidone 25 did not significantly influence the steady-state flux of Proterguride from acrylate matrices. The lipophilic silicone and polyisobutylene adhesives facilitated drug crystallization within the short storage periods at both conditions, probably due to the absence of povidone 25, which was incompatible with these polymers. Varying the drug load in acrylate-based formulations led to a linear increase of the steady-state flux until the steady-state flux of Proterguride leveled off and the patches tended to drug crystallization. It was found that Gelva-based patches show good physical stability, good skin adhesion, and moderate flux values and, thus, can be evaluated as a basis for a suitable formulation for the transdermal administration of Proterguride.

01 Jan 1988·XenobioticaQ4 · MEDICINE

Pharmacokinetics of proterguride in rat and cynomolgus monkey

Q4 · MEDICINE

Article

Author: M Hümpel ; W Krause

1. The pharmacokinetics of proterguride were studied in rat and cynomolgus monkey using 3H- and 14C-labelled drug and a radioimmunoassay for concentration measurements of unchanged drug. 2. Proterguride was rapidly and completely absorbed at low doses but not completely at higher dose levels, especially in rat. 3. Bioavailability was 18% in the monkey (low and high doses) and 79% (low doses) and 38% (high dose), respectively, in the rat. 4. Proterguride was able to pass the blood-brain barrier achieving concentrations in brain similar to those in plasma. 5. Excretion of labelled compounds was mainly in the faeces in rat, but in monkey elimination was equal in faeces and urine.

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Indication	Highest Phase	Country/Location	Organization	Date
Parkinson Disease	Phase 1	-	Spofa As	-
Parkinson Disease	Phase 1	-	Bayer AG	-

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