Erik Ch.M.J. Wolters

Clozapine: an antipsychotic agent in Parkinson's disease?

Article de synthese portant sur la pharmacocinetique, la chimiotherapie et la toxicite de la clozapine

The effect of corticosteroids and hemicholinium-3 on choline uptake and incorporation into acetylcholine in rat diaphragm

The glucocorticoids prednisolone and dexamethasone antagonize the inhibition by hemicholinium-3 of both the rate of choline uptake and the incorporation of choline into acetylcholine in the rat diaphragm. Aldosterone has no such effects. It is concluded that the beneficial effect of glucocorticoids in the treatment of myasthenia gravis may be due not only to immunosuppression, but also to some direct effect on presynaptic events perhaps via a choline carrier or an enzyme of choline metabolism.

The selective dopamine D1 receptor agonist, SKF 81297, stimulates motor behaviour of MPTP-lesioned monkeys

The alleged selective, high efficacy dopamine D1 receptor agonist, SKF 81297 (0.05-0.3 mg/kg i.m.), induced rotational behaviour away from the lesion and stimulated use of the dominant right hand in unilaterally (left side) 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned rhesus monkeys (Macaca mulatta). The effects of SKF 81297 were completely blocked by the dopamine D1 receptor antagonist, SCH 23390 (0.05 mg/kg), but not by the dopamine D2 receptor antagonist, remoxipride (1 mg/kg), and were similar to those induced by the selective dopamine D2 agonist, LY 171555 (0.01 mg/kg). These results suggest a functional stimulatory role for the dopamine D1 receptor on motor behaviour in a non-human primate model of Parkinsons disease when stimulated with a high efficacy selective dopamine D1 receptor agonist.

A double‐blind, placebo‐controlled, dose‐ranging study to investigate the safety and efficacy of CY 208‐243 in patients with Parkinson's disease

We carried out a double-blind rising dose study of a D-l dopamine agonist, CY 208-243, in 6 parkinsonian patients. Deficits monitored by Columbia scores were significantly improved at single doses ranging from 5 to 40 mg, though efficacy was low. Used alone, CY 208-243 was not a satisfactory therapeutic agent, and toxicity data precluded further increases in dosage.

Effect of corticosteroids on sciatic nerve‐tibialis anterior muscle of rats treated with hemicholinium‐3 An experimental approach to a possible mechanism of action of corticosteroids in myasthenia gravis

We studied the effect of intraperitoneally administered corticosteroids on the neuromuscular transmission in the sciatic nerve-tibialis anterior muscle preparation of the anesthetized rat stimulated at a rate of 10 Hz. Administered simultaneously with hemicholinium-3 (HC-3), 80 pg per kilogram (that is, half the lethal dose for 50 percent survival), prednisolone and dexamethasone cause a marked reversal of the block of the neuromuscular transmission caused by HC-3. The effect of aldosterone is very small. The blocking action of d-tubocurarine is not antagonized by either prednisolone or dexamethasone. Choline provides total protection against the HC-3 blockade, whereas physostigmine, in a just sublethal dose, is ineffective. We tentatively conclude that in myasthenia gravis the carrier-mediated transport of choline into the nerve endings may be deficient and that the beneficial effect of corticosteroids in this condition is based on their ability to ameliorate the deficient choline transoort.

Penicillin concentrations in serum and CSF during high-dose intravenous treatment for neurosyphilis

Eight neurosyphilitic patients (two asymptomatic, six symptomatic) were treated with intravenously administered aqueous penicillin G, 0.15 million IU/kg body weight/24 hrs for 15 days. On the 8th day of treatment, penicillin concentrations were determined in serum and CSF samples collected at hourly intervals over a period of 8 hours, using a microbiological assay method. Serum concentrations ranged from 0.26 to 100 mg/l, while CSF concentrations ranged from 0.062 to 3.0 mg/l. These results indicate that, by ensuring penicillin concentrations in CSF, which are continuously above the minimal fully treponemicidal concentration during the course of treatment, this treatment regimen should provide an adequate therapy for asymptomatic and symptomatic neurosyphilis.

The effect of prednisolone on the rat phrenic nerve-diaphragm preparation treated with hemicholinium

Abstract Recent papers have reported the benificial action of corticosteroids in myasthenia gravis. The underlying mechanism of action is not known. In a preliminary investigation the effect of prednisolone on the rat phrenic nerve-diaphragm preparation was studied. It was shown that a relatively high stimulation rate which caused ‘fatigue’ of the preparation, prednisolone prevented the blocking effect of hemicholinium-3, but had no effect on the preparation prior to addition of hemicholinium.

The effect of cholinesterase inhibitors and corticosteroids on rat nerve-muscle preparations treated with hemicholinium-3

Corticosteroids improve muscle function impaired by hemicholinium-3 (HC-3). The effects of cholinesterase inhibitors either alone or in combination with the glucocorticoid dexamethasone were studied on nerve-muscle preparations treated with HC-3, both in vivo and in vitro. Administered simultaneously with HC-3 (80 μg/kg by i.p. injection, physostigmine (250–1500 μg/kg) caused a significant, dose-dependent reversal of the neuro-muscular transmission block caused by HC-3 in the sciatic nerve-tibialis anterior muscle preparation of the anaesthetized rat, stimulated at a rate of 10 Hz. The HC-3-blocked neuromuscular transmission was also antagonized by neostigmine (125 and 250 μg/kg). Under the same conditions physostigmine (1000 μg/kg) potentiated the effect of dexamethasone. After i.p. injection of physostigmine (125–1000 μg/kg) and neostigmine (62.5–250 μ/kg) respectively, the LD50 in rats was significantly increased. With physostigmine a sharp maximum was found at 250 μg/kg. Neostigmine, and to a lesser extent physostigmine antagonized the neuromuscular transmission inhibited by HC-3 in the in vitro phrenic nerve—diaphragm preparation of the rat. The HC-3-induced inhibition of both uptake of choline and its incorporation into acetylcholine was antagonized by physostigmine and neostigmine. This antagonism was not altered in the presence of dexamethasone 0.2 μM. The possible implications of these findings, and the mechanism underlying the effects seen with corticosteroids and cholinesterase inhibitors are discussed. It is concluded that under certain circumstances a nerve-muscle preparation treated with HC-3 may be an adequate model for myasthenia gravis.