M. T. Rosseel

Plasma levels in man of nitroglycerin after buccal administration

levels may be increased for a longer time in the former group than in the latter, since we observed that the anticataleptic action of L-dopa was shorter in rats pretreated with Ro 4-4602, and the action decreased during the 2 h observation period. Spiroperidol-induced catalepsy seems to be particularly resistant to the antagonistic action of L-dopa and is not antagonized by apomorphine (unpublished results). We would like to thank Dr. Janssen for generous giftsof spiroperidol andpimozide.

Isosorbide, isomannide and isoidide dinitrate: Urinary excretion in the rat

Abstract In rats given the dinitrates of isosorbide, isomannide and isoidide orally, urinary excretion products were studied by gas chromatography and thin layer chromatography. The unchanged dinitrates are excreted in small amounts; the different mononitrates and denitrated alcohols are also present; the mononitrates are conjugated to a large extent. After administration of isosorbide dinitrate, isoidide mononitrate and isoidide are excreted in the urine, and after isomannide dinitrate administration, 5-isosorbide mononitrate and isosorbide can be found. This inversion of configuration from the endo- to the exo-position could be due to the formation of a carbonyl intermediate or to a backside displacement mechanism.

Therapeutic effectivenss and plasma levels of aprindine, a new antidysrhythmic drug

Summary41 patients with stable, frequent, chronic premature ventricular contractions have been treated with aprindine, and its therapeutic effectiveness evaluated by continuous electrocardiographic recording on tape. Excellent results (total suppression of the dysrhythmia) were obtained in 29 patients (71%), in whom the minimal effective plasma level ranged from 0.73 to 2.55 µg/ml (mean 1.35 µg/ml). Neurological side effects developed in 9 patients (22%), with plasma levels from 1.19 to 4.13 µg/ml (mean 2.65 µg/ml). The value of plasma level determinations is discussed.

Binding to serum α1-acid glycoprotein and effect of β-adrenoceptor antagonists in rats with inflammation

1 The β‐blocking effect of 4 β‐adrenoceptor antagonists with different pharmacokinetic properties was studied after intravenous and intraportal administration to control rats and to rats with experimental inflammation. 2 In rats with inflammation the effects of propranolol and oxprenolol, which are mainly bound to α‐acid glycoprotein (α1‐AGP), were significantly less after intravenous administration, but not after intraportal administration. In contrast, for metoprolol and atenolol, which are only negligibly serum bound, no difference was observed between control rats and rats with inflammation for either route of administration. 3 Total and unbound serum concentrations of propranolol were measured 20 min after intravenous and intraportal administration. 4 After intravenous administration, in the rats with inflammation total concentrations of propranolol were more than twice, and unbound concentrations less than half those of control rats. After intraportal administration the total concentrations were 8 times, and the unbound concentrations 3 times higher in the rats with inflammation. 5 There was a significant correlation between the β‐blocking effect and the unbound concentrations of propranolol after intravenous administration, but not after intraportal administration. The latter finding is probably because the unbound concentrations were supramaximal.

Fate of isosorbide dinitrate and mononitrates in patients with renal failure

SummaryIsosorbide dinitrate 10 mg, isosorbide 5-mononitrate 5 mg and isosorbide 2-mononitrate 5 mg were administered orally to subjects with and without renal failure, and the plasma concentrations of isosorbide dinitrate and of both the mononitrates were measured. There was no striking difference in plasma concentration as a function of time between subjects with and without renal failure, except for a somewhat higher isosorbide 5-mononitrate concentration after administration of this metabolite to uraemic patients.

Severe diltiazem poisoning with intestinal pseudo-obstruction: case report and toxicological data

This case report concerns a 30-year-old man who survived a 4.2 g diltiazem overdose. He sustained vasoplegic shock with a junctional escape rhythm which required high doses of norepinephrine and epinephrine. Among other complications, ileus with paralytic intestinal pseudo-obstruction developed on day three. Cecal distention was demonstrated by abdomen computed tomodensitometry. The ileus resolved on day seven following the poisoning. Diltiazem plasma concentrations were determined during the first three days. The possible role of other medications, activated charcoal and sufentanil, is noted.

Development and validation of a high-performance liquid chromatographic method for the determination of γ-hydroxybutyric acid in rat plasma

A method for the determination of gamma-hydroxybutyric acid (GHB) in rat plasma was developed using solid-phase extraction (SPE) and high-performance liquid chromatography (HPLC) with UV detection. GHB was isolated from plasma using strong anion-exchange SPE columns. The chromatographic separation was performed on a C18 Aqua column. The lower limit of quantification was 10 microg/ml using 60 microl of plasma. The linearity of the calibration curves was satisfactory as indicated by correlation coefficients of >0.990. The within-day and between-day precision were <10% (n=24), the accuracy was nearly 101%. Plasma concentrations in rats after GHB infusion determined by HPLC-UV were compared with the corresponding concentrations determined with a validated gas chromatographic-mass spectrometric method by orthogonal distance regression. A good correlation was observed and a t-test indicated no significant differences from 0 and 1 for the intercept and slope, respectively.

Intrapleural quinacrine instillation for recurrent pneumothorax or persistent air leak

From 1982 to 1990, 27 patients with recurrent pneumothorax or persistent air leak (28 episodes) underwent pleurodesis with intrapleural administration of quinacrine, according to a standardized scheme. A first evaluation was done about 1 month after the intervention. In August 1990, all patients were invited for a second check-up. In 4 patients quinacrine plasma concentrations were determined. There was one early failure. No late recurrences were observed. Neither serious nor late complications were seen with our low-dose regimen. Transient fever was the only constant side effect. In contrast to other chemicals proposed for pleurodesis, quinacrine did not cause major pain. Only very low quinacrine plasma concentrations (peak, < 10 ng/mL) were found. In conclusion, chemical pleurodesis with quinacrine can be considered a safe and effective treatment. The number of administrations as well as the dosage are important to prevent morbidity and recurrence.

Meptazinol (Wy 22811), a new analgesic: preliminary pharmacokinetic data.

The authors report on the pharmacokinetic profile of a new analgesic, meptazinol, from studies of plasma and urine levels after intravenous injection in 4 healthy volunteers. Conjugated product is formed very soon after injection and its concentration changes little over the period studied compared with the unchanged product where a fast, then a relatively slow phase of decline can easily be distinguished, suggesting a two compartment open system model. Meptazinol is predominantly eliminated in this conjugated form by urinary excretion of the metabolites. Excretion is very rapid in the first few hours after dosing and elimination is almost completed after 24 hours.

Relationship between gamma‐hydroxybutyrate plasma concentrations and its electroencephalographic effects in the rat

In view of the potential interest in an objective parameter for the depth of coma in intoxications with the recreational drug gamma‐hydroxybutyrate (GHB), we have studied the relationship between the plasma concentrations and the electroencephalographic (EEG) changes induced by GHB in the rat. Fifteen rats randomly received either 150 (n = 3), 200 (n = 6) or 300 mg kg−1 (n = 6) GHB over 5 min, followed by a supramaximal dose of 450 mg kg−1 over 5 min at the end of the experiment. Plasma concentrations were determined with HPLC. The EEG was continuously recorded and the amplitude in the 15.5–30 Hz frequency band was quantified using aperiodic analysis. The plasma concentration‐time profiles were fitted to a two‐compartment model with Michaelis‐Menten elimination. The pharmacokinetic parameters Vmax, Km and the apparent volume of distribution (Vd) proved to be independent of the dose and the mean pooled values were Vmax 2068 ± 140 μg mL−1 kg−1, Km 58 ± 16 μg mL−1 and Vd 476 ± 12 mL kg−1. The EEG amplitude in the 15.5–30 Hz frequency band displayed a monophasic inhibition and the effect‐plasma concentration curve showed hysteresis. This hysteresis between EEG effect and plasma concentrations was minimized by simultaneous calculation of hypothetical effect‐site concentrations and fitting the effect vs effect‐site concentration curve to a sigmoid inhibitory Emax model. The descriptors of this Emax model (Emax, EC50, ke,0, γ and E0) were independent of the dose with an equilibration half‐life t½ke,0 of 5.6 ± 0.3 min (mean value of the pooled results of the 5‐min treatment groups). To investigate the origin of this hysteresis, a dose of 600 mg kg−1 GHB was infused over either 45 or 60 min each in three animals. The hysteresis was much less pronounced with 45 min than with 5 min and was absent with 60‐min infusions. This indicated that the hysteresis was due to a distribution delay between the central compartment and the effect site. This study showed that the concentration‐effect relationship of GHB could be characterized in individual rats using aperiodic analysis in the 15.5–30 Hz frequency band.