Discriminative stimulus properties of dextromethorphan in rats.

Male Sprague-Dawley rats were trained to discriminate dextromethorphan (DM, 30 mg/kg, ip) from saline using a standard two-lever, fixed ratio 10, food reinforcement procedure. The DM-saline discrimination was acquired, and a range of doses of DM produced a dose-related generalization to the DM-lever choice. Stimulus generalization tests were conducted with dextrorphan, an active metabolite of DM, and with drugs selected from different pharmacological families. Dextrorphan induced a full generalization to DM, but only at a dose higher than the DM training dose. Morphine, a mu opiate receptors agonist, and U 50488, a kappa opiate receptors agonist, failed to substitute for DM. Cyclazocine, a benzomorphan derivative, with high affinity for sigma receptors, was able to produce a complete generalization to DM, without a change in the number of rats responding. Dizocilpine (MK 801), a phencyclidine-like drug, produced a complete generalization, but only at a dose that markedly reduced the number of rats responding. Carbetapentane and caramiphen, antitussive drugs with high affinity for the 'specific DM receptors', failed to substitute for DM. These results show that the discriminative stimulus of DM, did not result primarily from its metabolism to dextrorphan; and the discriminative stimulus properties of DM appear to more closely resemble those of cyclazocine than those of the other drugs tested. This suggests a role of sigma receptors in the mediation of the DM stimulus. These experimental data are discussed with reference to the cyclazocine-like subjective effects produced in man by large doses of DM.

Antagonism of metergoline on the diuretic effect of cyclazocine and U-50488 drugs with a kappa agonist activity.

In rats receiving a normal saline load of 2.5 ml/100 g, sc, (moderately hydrated rats), injections of the serotonin (5-HT) antagonist, metergoline (0.25-1-4 mg/kg), resulted in a dose-dependent decrease in the urine output induced by a dose of 8 mg/kg of cyclazocine (a benzomorphan derivative, mixed kappa and sigma agonist) at the 2-h time period. The antagonist effect of metergoline (1 mg/kg) on cyclazocine doses ranging from 0.25 to 8 mg/kg, was observed only at 2 mg/kg higher doses. Other 5-HT receptor blockers, methysergide, pizotifen, cyproheptadine, caused a significant degree of antagonism. In rats receiving a saline load and a water load of 5.5 ml/100 g, ip (hyperhydrated rats), metergoline (1 mg/kg) completely antagonized the diuretic effect of cyclazocine (8 mg/kg) at the 4-h and 5-h time periods. Similarly, metergoline (1 and 4 mg/kg) administered in moderately hydrated rats, markedly decreased at the 2-h time period, the urine output produced by 5 mg/kg of U-50488 (a non benzomorphan derivative, highly selective kappa agonist), and in hyperhydrated rats, completely suppressed, at the 4-h and 5-h time periods the drug-induced diuresis. Metergoline administered alone had no effect on urine output in moderately hydrated rats or in hyperhydrated rats. These results suggest the hypothesis that 5-HT may be involved in the complex mechanisms of kappa agonist-induced diuresis in rats.

Pharmacokinetics of apomorphine in parkinsonian patients.

Apomorphine, a dopamine agonist, has been used efficiently in parkinsonian patients to treat severe levodopa-induced on-off phenomenon. Motor improvement has been obtained both with continuous subcutaneous (SC) infusions, and multiple SC injections. So as to assist in the understanding of the clinical results, we studied the peripheral pharmacokinetics of apomorphine in 20 patients after intravenous (IV) or SC injections in the anterior abdominal wall and in the thigh at various doses, or SC infusion. Plasma apomorphine levels were measured by high-performance liquid chromatography with electrochemical detection. After an SC injection in the abdominal wall, the Tmax was brief (16 +/- 11 min) the drug was rapidly cleared from the plasma and had a short plasma half-life (69.7 +/- 25.8 min). The AUC was similar following SC and IV injections, suggesting that apomorphine was completely absorbed from subcutaneous tissue. Inter-subject variability in drug absorption was large. We noticed a trend towards a more complete absorption following injection in the abdominal wall rather than in the thigh. In patients chronically treated by continuous SC infusion, the apparent plasma half-life was five times longer than that following SC or IV injections. These pharmacokinetic data may explain the rapid onset and brief duration of clinical effects, and the usefulness of individual titration for intermittent SC apomorphine injections, and the smoother motor response obtained with continuous SC infusions.

[Pharmacokinetics of methohexital given by constant rate intravenous infusion]. / Pharmacocinétique du méthohexital administré en perfusion intraveineuse à débit constant.

The pharmacokinetic characteristics of a constant rate methohexitone infusion were studied in young ASA 1 patients undergoing maxillofacial surgery. They were randomly assigned to two groups; group M patients (n = 7) were given 9 mg.kg-1.h-1 of methohexitone for one hour, and group MF patients (n = 7) 9 mg.kg-1.h-1 of methohexitone with 7 micrograms.kg-1.h-1 of fentanyl, also for one hour. Blood samples for determining methohexitone concentrations were obtained at various times, from before the start of the methohexitone infusion up to 19 h afterwards. In twelve patients, a two-compartment model was appropriate to characterize the decrease of methohexitone concentration; for the other two (one in each group), a three-compartment model was applied. There were no statistically significant differences between the two groups. Elimination half-life in group M was 3.22 +/- 1.96 h, and total plasma clearance 8.54 +/- 2.8 ml.kg-1.min-1. The wide variations in pharmacokinetic parameters between subjects may explain some unpredictable variations in duration of action of methohexitone. Fentanyl did not modify methohexitone pharmacokinetics, which remained of the first order. However, it potentiated the barbiturate's action: extubation was only possible after stopping the infusion for 39.4 min +/- 22 min in group MF, and 15.4 min +/- 6 min in group M (p less than 0.01). At that time, plasma concentrations were respectively 3.12 +/- 0.99 mg.l-1 (group MF) and 5.71 +/- 2.09 mg.l-1 (group M), (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of 6-mercaptopurine and its metabolites in plasma or serum by high performance liquid chromatography.

A sensitive and accurate reversed phase liquid chromatographic assay was developed for the determination of 6-mercaptopurine (6MP) (the active metabolite of azathioprine) in human plasma. The assay involved extraction into acetonitrile and dichloromethane from plasma pretreated with 0.038 M of dithiothreitol solution. The residue was analyzed by isocratic chromatography on a C18 analytical column with UV detection at 326 nm. The average extraction recovery of 6MP was 85%. The method has been applied successfully to the determination of 6MP and its metabolites in pharmacokinetic studies.

Bayesian estimation of cyclosporine clearance in bone marrow graft.

The dosage regimen of cyclosporine (CsA) can be individualized in patients by means of a test dose (TD) method in the few days before bone marrow graft. To simplify the test dosing protocol, we used a Bayesian estimation (BE) of CsA clearance requiring population data and partial kinetic information for a given patient. In the first part, 42 patients, aged 11-47 years, were given a 2-h infusion of CsA (4 mg.kg-1). CsA concentrations were determined in several blood samples. The obtained concentration-time curves were fitted according to a three-compartment model. Maximum likelihood estimation (MLE) allowed CsA determination of pharmacokinetic parameters. Early population parameters of CsA were determined using 22 TD by a two-stage method. In the remaining 20 patients, individual pharmacokinetic parameters were also computed by BE procedure, taking into account the above determined population parameters and CsA concentration determinations from three blood samples drawn at 5 and 30 min and 3 h after the end of TD infusion. In the second part, 16 patients were used to evaluate performance of BE in directly predicting target concentration values. Finally, early population characteristics were updated on the basis of 42 patients. Statistical comparisons between MLE and BE estimates of CsA clearance and between concentrations predicted after BE and those experimentally obtained showed that three blood CsA determinations allowed accurate clearance estimation and target concentration predictions. The method presented here can be used to calculate an individual CsA dosage regimen in real time, thus improving patient comfort.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurochemical actions of ethylketocyclazocine and ketocyclazocine in different regions of rat brain.

The effects of ethylketocyclazocine (EKC) and ketocyclazocine (KC), benzomorphan derivatives proposed as kappa opioid receptor agonists, were studied by measuring changes in the levels of dopamine (DA), noradrenaline (NA), 5-hydroxytryptamine (5-HT), and their major metabolites, DOPAC, HVA, MHPG-SO4, 5-HIAA, in different regions of rat brain. Doses ranging from 1 to 10 mg/kg were tested. EKC decreased the levels of DOPAC and HVA in striatum, and increased DA concentrations, EKC markedly increased the levels of MHPG-SO4 in hypothalamus, but not in cortex, midbrain and pons-medulla. There was a non-significant decrease in NA concentrations. EKC increased the levels of 5-HIAA in hypothalamus and also in cortex, midbrain and pons-medulla, while the levels of 5-HT were increased. On the whole, similar neurochemical effects were observed after KC administration. These data were discussed in relation to the behavioral actions caused in rats by EKC and KC, including the increase in food intake, and they raise the possibility that the hypothalamic noradrenergic system participate in feeding behavior of these drugs.

[The role of serotonin in the behavioral changes induced in the rat by cyclazocine]. / Rôle de la sérotonine dans les modifications comportementales produites chez le rat par la cyclazocine.

Cyclazocine is a benzomorphan derivative, considered as a mixed kappa and and sigma opioid receptor agonist. In experimental study with rats, cyclazocine is known to increase locomotor activity and to produce a bizarre behavioral syndrome including head swaying, backward walking, circling. The present study was undertaken to investigate the effects of various drugs modifying the serotoninergic neuronal systems, upon the locomotor activity and the abnormal behaviors induced by cyclazocine. Pretreatment with p-chlorophenylalanine (PCPA, 400 mg/kg, 72, 48, 24 hr) resulted in an inhibition of the three abnormal behaviors. Pretreatment with p-chloromethylamphetamine (PCMA, 15 mg/kg, 24 hr) antagonized head swaying, backward walking and markedly enhanced locomotor activity. In the contrary, pretreatment with PCMA (2.5 mg/kg, 15 min) resulted in enhanced abnormal behavioral responses to cyclazocine. L-tryptophan (50 mg/kg), 5-hydroxytryptophan (5-HTP, 50 mg/kg), or pargyline (50 mg/kg) inhibited abnormal behaviors and decreased locomotor activity. Serotonin antagonists with affinity fir both 5-HT1 and 5-HT2 receptors, metergoline (0.25-1 mg/kg), methysergide (1-5 mg/kg), amitriptyline (5-20 mg/kg), dl-propranolol (10-40 mg/kg) blocked head swaying and backward walking; only methysergide inhibited circling. All these drugs, except methysergide, markedly enhanced the cyclazocine-induced locomotor activity. In contrast, ketanserine (0.5-2 mg/kg) and pirenperone (0.05-0.2 mg/kg), serotonin antagonists with selective affinity for 5-HT2 receptors had no effects on the abnormal behaviors and locomotor activity. Taken together, these results suggest that a serotoninergic mediation is involved in the cyclazocine-induced abnormal behaviors, and that serotonin exerts an inhibitory control on the locomotor activity produced by the drug. These effects are probably associated with 5-HT1 receptors. Further experiments have shown that the drugs having being able to potentiate cyclazocine-induced locomotor activity, similarly potentiate the locomotor activity induced by levallorphan, morphinan derivative with cyclazocine-like properties but do not enhance the hyperactivity produced by a low dose of morphine. The data reported here, provide a contribution to the informations concerning the neuromediation of the effects of mixed kappa and sigma agonists and allow to compare the mechanism of action of cyclazocine with those of other psychotomimetic drugs.

Effects of acute administration of cyclazocine on the metabolism of biogenic amines in different regions of rat brain.

The effects of cyclazocine on the metabolism of dopamine (DA), noradrenaline (NA) and 5-hydroxytryptamine (5-HT) in regions of rat brain were studied by measuring changes in the levels of the monoamines and their major metabolites. Doses ranging from 4-32 mg/kg were tested. Rats were sacrificed 1 or 2 h after administration of the drug, according to the experiment. Administration of cyclazocine significantly decreased DA concentration and increased the levels of DOPAC and HVA in striatum. Cyclazocine decreased the levels of NA, and markedly increased the levels of MHPG-SP4 and 5-HIAA in cortex, hypothalamus, midbrain and pons-medulla, while little change in 5-HT concentration, except a decrease after the highest dose, was observed. These changes in the metabolism of the monoamines differed in their amplitude and temporal nature. The possible roles of dopaminergic, noradrenergic and serotoninergic neurons in different brain regions are discussed in relation to modifications of locomotor activity and the induction of bizarre behavior resulting from cyclazocine administration in rats. These investigations may add to the understanding of the mechanism of psychotomimetic effects produced in man by this drug.

Routine identification and determination of 11 barbiturates in biological samples.

A very easy, reliable and specific gas-chromatographic method for identification and dosage of 11 barbiturates in plasma is presented. Methylene unit values determined on two types of column (one polar, one non-polar) allows very accurate identification with a minimum risk of error due to fluctuations in operating conditions. Sensitivity of the method is 0.5 microgram/ml plasma with a flame ionization detector. Derivatization procedure is complete, without any degradation phenomenon as tested by mass spectrometry. Such a method can be easily used as routine procedure for toxicological or pharmacological applications.

[Electrophysiological effects of the combined administration of digoxin and propranolol in man]. / Effets électrophysiologiques chez l'homme de l'association digoxine-propranolol.

The electrophysiological effects of the combined administration of digoxin and propranolol were studied in 40 patients, compared with the effects of digoxin alone and considered in relation to anomalies of the conduction pathways. The cycle of the sinus node was only lengthened by digoxin in patients who had an anomaly of sinus node function. In contrast the addition of propranolol always increased it (from 1 109 +/- 53 ms to 1 232 +/- 58 ms). Sinus node recovery time was only increased by combined administration (from 1 331 +/- 101 ms to 1 450 +/- 68 ms). Changes in sino-atrial conduction intervals were not very marked. The AH interval was increased by digoxin (from 97 +/- 4 ms to 109 +/- 6 ms), with propranolol exerting a synergistic effect (119 +/- 6 ms). When there was pre-existing supra-His block only combined administration increased the conduction defect. The HV interval and QRS duration were not altered. The effective atrial refractory period was increased by combined administration (from 264 +/- 10 ms to 304 +/- 14 ms) except in subjects who had supra-His block. The effective refractory period of the AV node (385 +/- 26 ms) was increased by digoxin (450 +/- 37 ms). This effect was potentiated by propranolol (478 +/- 34 ms) except in those subjects who had supra-His block. In three cases in which there were two conduction pathways at A V node level the refractory periods of the rapid and slow pathways were increased by digoxin, with a synergistic effect from propranolol. The ventriculo-atrial conduction time changed from 151 +/- 24 ms to 172 +/- 22 ms following digoxin, then to 193 +/- 34 ms after the addition of propranolol.

Plasma O-methyldopa in levodopa-induced dyskinesias. A bioclinical investigation.

The peripheral metabolism of Dopa has been studied in correlation with the clinical occurrence of Leyodopa-induced dyskinesias in Parkinson patients. Within the group of patients treated with a peripheral decarboxylase inhibitor (PDI), the combination of all the plasma levels of O-Methyldopa from patients with dyskinesias shows significantly higher values than those from patients without dyskinesias. For Dopa itself, no significant differnece can be detected. Such high O-Methyldopa levels seem to be due to a progressive accumulation of this compound and not to a higher degree of formation. In contrast, no significantly different Dopa or O-Methyldopa levels are found within the group of patients treated with L-Dopa alone. These results are discussed in relation to some of the suspected mechanisms involved in Levodopa-induced dyskinesias.

[Results of determination of plasma methoxydopa in parkinsonian patients with or without dyskinesia induced by L-Dopa]. / Résultats des dosages de la méthoxydopa plasmatique chez les parkinsoniens avec ou sans dyskinésies induites par la L-DOPA.

Horary plasmatic dosages of Dopa and metabolites in 30 treated parkinsonian patients have shown that, within the group of patients treated with L-Dopa combined with an extracerebral decarboxylase inhibitor, highly significant by increased plasmatic O-methyl-dopa levels can be found in patients with dyskinesias compared with those without dyskinesias. On the contrary, in these two subgroups of patients, plasmatic Dopa levels are not significantly different. By comparing some favoured Dopa and O-methyl-dopa levels between these two subgroups of patients, it seems more likely, that the elevated plasmatic O-methyl-dopa levels are due to an progressive accumulation on of its compound than to an excessive formation from Dopa.

Does O-methyl-dopa play a role in levodopa-induced dyskinesias?

Clinically scored levodopa-induced dyskinesias were correlated with plasma dopa and O-methyl-dopa levels determined every hour during one day in 30 Parkinsonian-treated patients. In patients treated with a combination of L-dopa and a peripheral decarboxylase inhibitor (PDI), those with dyskinesias have very high plasma O-methyl-dopa levels compared with those who have no dyskinesias. In contrast, no significantly different plasma dopa levels are found in these two subgroups of patients, leaving open the question of the possible involvement of such elevated plasma O-methyl-dopa levels in favouring dyskinesias.