Johannes Tack

Pharmacological properties of a wide array of ergolines at functional alpha1-adrenoceptor subtypes

Ergot alkaloids act as (partial) agonists or antagonists at serotonergic, dopaminergic and α-adrenergic receptors. In contrast to their affinity at serotonergic (5-HT) and dopaminergic receptor subtypes, only limited information is available concerning their interaction with α-adrenoceptor subtypes. This especially holds true for native α-adrenoceptors. Therefore, we studied the pharmacological profile of 25 ergolines at α1A-, α1B- and α1D-adrenoceptors in vascular rings or strips of rat and guinea pig endowed with these receptors. Contractile responses were studied by measurement of isometric tension changes in rat tail artery (α1A, α1B), guinea pig spleen (α1B) and rat thoracic aorta (α1D). The anti-migraine drugs ergotamine and dihydroergotamine, the anti-parkinsonian drug lisuride and the anti-hyperprolactinemic drug terguride behaved as antagonists or low-efficacy partial agonists at all three α1-adrenoceptor subtypes with nanomolar receptor affinity. Derivatives of these drugs showed lower affinity at α1-adrenoceptors than the parent compounds. Each individual ergoline derivative tested showed low discriminatory capability at the subtypes, α1A, α1B, α1D. A low discriminatory power between the subtypes (α1A, α1B, α1D) seems to be a class effect of the ergolines. The nanomolar affinities of ergotamine, dihydroergotamine and lisuride for α1-adrenoceptors may affect their effectiveness as anti-migraine and anti-parkinsonian drugs, respectively.

Plasma Levels of lormetazepam after Sublingual and Oral Administration of 1 MG to Humans

AbstractA new galenical formulation containing 1 mg lormeta-zepam (LMZ) for sublingual administration (“sleeping wafer”, see Figure 1) has been developed. In an open-cross over design the plasma lormetazepam levels were monitored radioimmunologically in 16 volunteers. Subjects received the sublingual formulation and an oral tablet (NoctamidR-1) in a randomized sequence at weekly intervals. After sublingual administration the mean plasma lormetazepam levels were significantly higher between 7.5 and 25 minutes than after administration of the tablet. The earlier rise in plasma LMZ levels is also reflected in partial areas under the plasma level curve up to 45 minutes. LMZ was completely absorbed from both formulations as shown in total AUCs.It is anticipated that sublingual administration of the new formulation will lead to a 40 - 50 % reduction of sleep latency. Possibilities for therapeutic application of the new formulation are discussed.

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

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 Gelva®7883 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°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.