Rainer Palluk

Neuroendocrine and side effect profile of pramipexole, a new dopamine receptor agonist, in humans

The effects and tolerability of pramipexole, a new dopamine D2‐receptor agonist, on prolactin, human growth hormone, thyrotropin, Cortisol, and corticotropin levels were investigated in a randomized, double‐blind, crossover study in 12 healthy volunteers. Single oral doses of 0.1, 0.2, and 0.3 mg pramipexole and placebo were studied over a period of 24 hours. Pramipexole decreased serum prolactin levels in a dose‐dependent manner, with a maximum effect after 2 to 4 hours. Serum levels of human growth hormone were dose‐dependently increased; however, this effect was only significant 2 hours after drug administration. Furthermore, a slight increase in serum Cortisol levels and a slight decrease in serum thyrotropin levels was observed. Our findings show for the first time pharmacodynamic effects of pramipexole after single oral doses in healthy volunteers. The compound was well tolerated and showed an endocrine profile similar to other dopamine D2‐agonists.

Compensation of muscarinic bronchial effects of talsaclidine by concomitant sympathetic activation in guinea pigs.

The aim of the present investigation was to determine the reasons why the muscarinic receptor agonist talsaclidine (WAL 2014 FU, 1-azabicyclo[2.2.2] octane,3-(2-propynyloxy)-, (R)-,(E)-2-butenedioate) is devoid of bronchospastic effects in anaesthetized guinea pigs but causes contracture in isolated tracheal muscle from this species. Effects on airway resistance were assessed with a modified Konzett-Rossler method in guinea pigs anaesthetized with urethane. Intravenous injection of 1-64 mg/kg talsaclidine did not cause substantial bronchospasm in control animals. After blockade of beta-adrenoceptors, the muscarinic receptor agonist induced dose-dependent bronchospasm which could be blocked by atropine. In despinalized animals and in animals with spinal transection, talsaclidine was bronchospastic but ED50 values were higher and maximal effects were smaller than in intact animals after beta-adrenoceptor blockade. In adrenalectomized guinea pigs, talsaclidine was nearly as bronchospastic as after blockade of beta-adrenoceptors. In contrast, the muscarinic ganglion stimulant McN-A-343, 4-(m-chlorophenylcarbamoyloxy)-2-butyn-trimethyl-ammonium chloride, (2-32 mg/kg i.v.), which has a muscarinic receptor profile similar to that of talsaclidine, i.e., full muscarinic agonism and highest affinity at muscarinic M1 receptors, partial agonism at muscarinic M3 receptors, but in contrast to talsaclidine does not penetrate the blood-brain barrier, caused dose-dependent bronchospasm in control animals. These results indicate that talsaclidine has bronchospastic potential which, however, does not become evident in vivo because of functional antagonism via beta-adrenoceptors resulting from concomitant activation of the sympathetic nervous system in general and the adrenals in particular. It can be concluded that the unique profile of action of talsaclidine is due to partial agonism at bronchial muscarinic M3 receptors, a prerequisite for susceptibility to functional antagonism, and to its ability to penetrate the blood-brain barrier readily and to induce sympathetic activation as a result of full agonism at peripheral ganglionic and adrenal as well as central muscarinic M1 receptors.

In vivo pharmacology of BIIR 561 CL, a novel combined antagonist of AMPA receptors and voltage‐dependent Na+ channels

Glutamate receptors of the α‐amino‐3‐hydroxy‐5‐methyl‐4‐isoxazolepropionic acid (AMPA) subtype and voltage‐gated Na+ channels are associated with diseases of the central nervous system characterized by neuronal over‐excitation as in epilepsy or cerebral ischaemia. In animal models, AMPA receptor antagonists and Na+ channel blockers provide protection in these conditions. Dimethyl‐{2‐[2‐(3‐phenyl‐[1,2,4]oxadiazol‐5‐yl)‐phenoxyl]‐ethyl}‐amine hydrochloride (BIIR 561 CL) combines both, AMPA receptor – and Na+ channel blocking properties in one molecule. Here, BIIR 561 CL was investigated in vivo. BIIR 561 CL protected mice against AMPA‐induced toxicity with an ED50 value of 4.5 mg kg−1 following subcutaneous (s.c.) administration. A 0.1% solution of BIIR 561 CL provided local anaesthesia in the corneal reflex test in rabbits. In mice, the compound prevented tonic seizures in the maximal electroshock (MES) model with an ED50 value of 3.0 mg kg−1 s.c. In amygdala‐kindled rats, BIIR 561 CL inhibited seizures at doses of 3 and 11 mg kg−1 following intraperitoneal (i.p.) injection. The data show that the combination of blocking AMPA receptor‐ and voltage‐gated Na+ channels in one molecule induces effective protection in animal models of neuronal over‐excitation.

The AMPA receptor/Na(+) channel blocker BIIR 561 CL is protective in a model of global cerebral ischaemia.

In this study, we investigated whether the novel neuroprotective compound dimethyl-[2-[2-(3-phenyl-[1,2,4]oxadiazol-5-yl)-phenoxy]-ethyl]-amine hydrochloride, BIIR 561 CL, a combined non-competitive antagonist of AMPA receptors and blocker of voltage-gated Na+ channels, is protective in a rat model of severe global ischaemia. BIIR 561 CL administered immediately after 10 min of ischaemia (occlusion of both carotid arteries plus reduction of arterial blood pressure to 38-40 mm Hg) significantly reduced hippocampal damage at 4 x 26.8 mg/kg (subcutaneous injections). The competitive AMPA receptor antagonist 2,3-dihydro-6-nitro-7-sulfamoyl-benz(F)quinoxaline, NBQX, was used as a reference compound and was protective at 3x30 mg/kg (intraperitoneal and/or subcutaneous administration). BIIR 561 CL significantly reduced the ischaemia-induced premature mortality from 33.6% in the controls to 14.3%, whereas NBQX treatment had no statistically significant effect.Thus, BIIR 561 CL could be shown to reduce hippocampal damage and premature mortality in a model of severe global ischaemia. A compound with these properties might be an interesting candidate for the treatment of disorders related to global cerebral ischaemia in man.

Renal response to blood volume expansion in Brattleboro rats after acute treatment with vasopressin.

SummaryThe renal response to iso-oncotic blood volume expansion with bovine serum albumin was studied in anaesthetized homozygous Brattleboro (DI) rats after acute (1 day) pretreatment with 1 U arginine-vasopressin (AVP) compared to heterozygous controls. In AVP-treated DI (DI+AVP) rats, basal urine flow as well as urinary sodium, chloride, and potassium excretion, were not different from controls.Diuresis and kaliuresis induced by volume expansion were blunted in DI+AVP rats. However, natriuresis and chloruresis were exaggerated in DI+AVP rats. They increased faster, reached a higher maximum, but declined earlier, compared to controls. The blunted diuresis resulted in a positive volume balance by the end of the experiment in DI+AVP rats, whereas the controls showed restoration of normal balance. Significant retention of sodium and chloride was observed in controls, but not in DI+AVP rats, over the time of the experiment.DI+AVP rats lost significantly less potassium than controls during the experiment. As judged from the lithium clearance method, the exaggerated saluresis in DI+AVP rats was mainly due to a reduced proximal sodium reabsorption. Plasma immunoreactivity of atrial natriuretic peptide (ANP) rose during blood volume expansion and fell in the recovery period. It was not different between AVP-treated DI rats and controls at any time of the experiment. Inulin clearance was slightly, but not significantly, lower in DI+AVP rats and increased after blood volume expansion in DI+AVP rats only.The results indicate that acute AVP substitution may abolish the exaggerated volume loss, but not the increased saluresis known to occur in DI rats after blood volume expansion.

Hypotensive and bradycardic effects of talipexole (B-HT 920) in anaesthetized rabbits are antagonized by metoclopramide but not by yohimbine

SummaryThe interactions of talipexole (B-HT 920) and clonidine with selective α-adrenoceptor antagonists, yohimbine (a2) and prazosin (a1), as well as with dopamine receptor antagonists, metoclopramide (D2), domperidone (D2) and SCH23 390 (D1) were investigated in anaesthetized rabbits after i. v. administration.Both talipexole (0.03–0.1 mg/kg) and clonidine (0.01–0.03 mg/kg) dose-dependently induced hypotension and bradycardia. Talipexole had a shorter duration of action.The hypotensive effect of the α2-adrenoceptor and D2 agonist talipexole (0.03 mg/kg) was antagonized by pretreatment with metoclopramide (3 mg/kg) or domperidone (0.3–3 mg/kg),but not with yohimbine (3 mg/kg),prazosin (0.1 mg/kg) orSCH 23 390 (1 mg/kg). Its bradycardic effect was antagonized only by metoclopramide (3 mg/kg). The hypotensive and bradycardic effects of clonidine (0.03 mg/kg) were most effectively antagonized by yohimbine (0.3–3 mg/kg).These findings indicate that in anaesthetized rabbits after i. v. administration, talipexole may lower blood pressure by peripheral, and heart rate by central, dopamine D2 agonism.

Renal hyper-responsiveness to blood volume expansion in Brattleboro rats is not related to plasma ANF immunoreactivity

1. Anaesthetized homozygous Brattleboro (DI) rats were used to study the renal response to iso‐oncotic blood volume expansion.