Prevention of postischaemic ventricular fibrillation by long term beta adrenoceptor blockade with acebutolol in the anaesthetised dog.

Acute occlusions of the proximal left circumflex coronary arteriovenous pedicle were performed in open chest anaesthetised dogs. Twenty eight dogs were randomly allocated to receive acebutolol (3 mg X kg-1 twice daily) or placebo given blindly by mouth for five days; a control group of 14 dogs without any pretreatment underwent the same procedure. Coronary ligations in the randomised study were performed during seven consecutive days, and four dogs were operated on each day. This schedule was chosen in order to measure acebutolol plasma concentrations just before ligation from 60 to 540 min after the last dose of the drug. Long term oral treatment with acebutolol protected against postischaemic ventricular fibrillation and significantly reduced the incidence of both early phase (0-10 min postocclusion) ventricular arrhythmias and ventricular fibrillation. As a result the outcome was significantly improved after 60 min of ischaemia in acebutolol compared with placebo treated animals. The results in the control animals were similar to those in the placebo treated dogs. The protective effect of long term oral treatment with acebutolol lasted for nine hours and was apparently independent of the plasma concentrations of the drug. These data show that improved outcome in this canine model is due to the prevention of ischaemia induced ventricular fibrillation by long term beta adrenoceptor blockade, which is able to overcome the effect, if any, of partial agonist activity of acebutolol. A direct myocardial anti-ischaemic effect might explain the effectiveness of long term oral treatment, which is independent of plasma concentrations of the drug.

Concentrations of heroin, 06-monoacetylmorphine, and morphine in a lethal case following an oral heroin overdose.

A case of lethal overdose by heroin ingestion is presented. The concentrations of drugs were measured several hours after death. Heroin, 06-monoacetylmorphine, and morphine were identified and quantitated in blood, urine, and gastrointestinal contents by gas chromatography-mass spectrometry and high-performance liquid chromatography. Concentrations of heroin, 06-monoacetylmorphine, and morphine were 109, 168, and 1140 ng/mL, respectively, in blood and 17, 12, and 425 ng/g, respectively, in gastrointestinal content. In urine, however, only morphine was detected at 3650 ng/mL.

Quantitation and ultraviolet spectrum identification of buflomedil in whole blood and plasma by HPLC.

Buflomedil, a vasodilating agent, was determined in whole blood or plasma by HPLC with papaverine as internal standard after absorption of the alkaline sample on an Extrelut column and elution with diethylether-methylene chloride (70:30, v/v). The eluate was evaporated and the residue was dissolved in 100 microL of the mobile phase; 20 microL of this solution were injected into a mu Bondapak C18 column (10 microns) using acetonitrile-0.125M potassium dihydrogen phosphate (40:60, v/v) as mobile phase and UV detection at 280 nm, followed by UV spectrum identification (between 200 and 350 nm) with a photodiode array detector. The method is rapid (giving response within 20 min), reproducible, selective, and sensitive. It can be applied for pharmacokinetic studies and for both clinical pharmacology and forensic toxicology.

A rapid HPLC procedure for the simultaneous determination of chloroquine, monodesethylchloroquine, diazepam, and nordiazepam in blood.

Chloroquine, monodesethylchloroquine, diazepam, and nordiazepam levels are simultaneously determined in whole blood or plasma by HPLC. Papaverine is used as internal standard, and the analysis is performed after protein-binding hydrolysis, absorption on Extrelut, and elution with diethyl ether/methylene chloride (70:30 v/v). UV detection is used at 343 nm for 12 min, then changed to 242 nm. There are two mobile phases with two flow rates. The procedure requires 30 min, is reproducible, sensitive (8-10 ng/mL for chloroquine and its metabolite, 4 ng/mL for diazepam and nordiazepam), and selective, especially towards other antimalarial agents and drugs like adrenaline or barbiturates, which may be used in chloroquine poisoning therapy. It can be used for pharmacokinetic studies, therapeutic control, to establish the diagnosis and prognosis of a chloroquine poisoning, and to follow and optimize treatment.

Toxicological analysis of sulpiride in a lethal poisoning case.

A fatality following ingestion of sulpiride is presented. The drug was identified and quantitated in postmortem blood by gas chromatography-mass spectrometry and high-performance liquid chromatography with diode-array detection. The concentration was 38 microg/mL, which was in excess of 34 times the therapeutic concentration of sulpiride. For other associated drugs, their concentrations were in their therapeutic ranges.

Interaction between vagal and chemoreceptors afferents in ventilatory response to transient hypercapnia (awake rabbits).

The ventilatory response to a transient hypercapnia was studied in four awake rabbits maintained in a volume displacement plethysmograph : the increase in inspiratory volume (VI) was associated or not with an increase in inspiratory and expiratory durations (TI and TE). These ventilatory variations were consistent with the activation of the peripheral chemoreceptors by carbon dioxide (short latency of the initial response). After vagal blockade by local anaesthesia, relative ventilatory variations were not significantly different from those previously measured. Central activity seems an important factor reducing inhibitory vagal input and favouring peripheral chemoreceptor afferents.

Pattern of the ventilatory response to transient hypoxia in man: differences from transient hypercapnic test.

The pattern of change in ventilatory variables after inhalation of pure N2 for two breaths was studied in normal children and adults. In six subjects the trends of change were compared to the ventilatory response to transient hypercapnia. We observed differences in the patterns of increasing ventilation with an initial abrupt increase of tidal volume for transient hypoxia and a progressive change for hypercapnia. In both cases respiratory frequency was progressively but unsystematically enhanced. A highly significant positive correlation was demonstrated between individual sensitivities to CO2 and O2, with a greater response to hypercapnia (5.6 time) than to hypoxia. Finally, a very short-latency decrease in expiratory duration occurred in the first breath after inhalation of hypercapnic mixture, supporting the recent data of Cunningham et al. (1977).

Pulmonary mechanics during hypoxia in spontaneously breathing anesthetized rabbits.

Changes in lung mechanics were measured during hypoxia (FIO2 = 0.10 during 5 min) in spontaneously breathing anesthetized rabbits. In intact animals, hypoxia induced scattered variations in total lung resistance (RL) (decrease, increase or no alteration) and dynamic lung compliance (CL), whereas in carotid body denervated animals it was accompanied by an almost constant decrease in RL (-12%); but if a subsequent vagotomy was performed, there was no significant variation in RL. In animals which had been only vagotomized, CL decreased significantly during hypoxia (-23%) without any associated change in RL. So, the arterial chemoreceptor mediated bronchoconstrictor effects due to hypoxia could be normally masked by the dilator effects (metabolic and/or sympathetic) on the airways.

Assessment of the central chemosensitivity in man under transient or progressive hypercapnia.

In healthy man, the central chemosensitivity to CO2 was studied after depression of the arterial chemoreflex drive by inhalation of pure oxygen. The effectiveness of the functional decrease of arterial chemoreceptor function was assessed by the delayed hyperventilation which followed transient inhalation of hypercapnic gas mixtures for 3 or 5 breaths in hyperoxic conditions. In such a case the first significant increase in tidal volume (VT) occurred 13.9 +/- 3.2 (SE) sec later than the early change in this variable measured in normoxic conditions. The stimulus strength was estimated by the change in CO2 partial pressure in end-tidal alveolar gas (delta PETCO2). The central chemosensitivity (SCO2), defined as the ratio between change in ventilation (delta V) and delta PETCO2, was assessed either by transient inhalation of gas mixtures containing 5 to 8% CO2 in pure O2 ("varying transients") or by progressive hypercapnia (rebreathing in pure O2). In both cases, the first significant change in ventilation was due to an increase in VT, but, for a given delta PETCO2, VT changes were higher during rebreathing than after transient hypercapnia; (2) The respiratory frequency (fR) was progressively enhanced during rebreathing (shortening of expiratory duration in all cases and of inspiratory time in some subjects) but the ventilatory rhythm diminished after transient stimulation as soon as delta PETCO2 reached one kPa, and this was due to an increase in inspiratory duration; (3) The associated changes in VT and fR during rebreathing could explain that SCO2 values given by this method were 5.2 times greater than after transient hypercapnia ("varying tests"). The differences are discussed in terms of, (1) isolated changes in arterial PCO2 or associated decrease in pH of the cerebrospinal fluid; (2) changes in brain blood flow, and (3) stimulation of lung stretch receptors by the important increase in VT during rebreathing.

Lung reflexes in anaesthetized rabbits with elastase-induced emphysema.

The effects of elastase-induced emphysema on vagal pulmonary reflexes were studied in seven rabbits, given 600 IU of porcine pancreatic elastase intratracheally (E group), and eight untreated rabbits (U group) under pentobarbital anaesthesia. The presence of emphysema was confirmed by histological and pathological criteria and by documented changes in lung mechanics seven months after treatment. The strength of the Hering-Breuer inflation reflex (HBIR), indicative of pulmonary stretch receptor excitability, was unchanged in the U group, but was significantly increased in the E group at inflation volumes greater than the tidal volume (VT) range, as she slope of the curve relating HBIR to inflation volume was significantly steeper (0.40 vs 0.22 ml-1; p less than 0.05). The early ventilatory response (first 3 breaths) to right atrial injections of phenyldiguanide (20 and 30 micrograms X kg-1 i.v.) was used as an indication of the excitability of lung receptors with non-myelinated vagal afferents. This response, characterized by a significant decrease in expiratory duration (TE) without effect on VT or inspiratory time (TI), was not significantly different between the E and U groups. The overall pattern of breathing in the E group showed a significant decrease in VT associated with an increase in TI.

Cold-induced bronchospasm in normal and sensitized rabbits.

In anesthetized, paralyzed and artificially ventilated rabbits, changes in lung resistance induced by cooling the inspired air were studied under dry air conditions. Airway response to cold was measured in normal animals and in rabbits sensitized to bovine serum albumin. The magnitude of cold-induced bronchospasm was significantly greater in sensitized than in normal rabbits but the time course for recovery of control lung resistance during rewarming was the same in both groups and lasted longer than 4 min. Inhalation of a nebulized aerosol of sodium cromoglycate (SCG) markedly reduced cold-induced bronchospasm and shortened the recovery period, which then lasted only 20 to 30 sec. Vagotomy abolished the airway response to cold air in all cases and this was observed whether the vagus nerves were cut before or after SCG inhalation. SCG or vagotomy exerted the same effect on the response to cold air in normal or sensitized rabbits. Sensitized animals showed an hyperresponsiveness to histamine as well as to cold air. These results suggest that cold-induced bronchospasm results from a vagally mediated reflex whose effects are only enhanced and prolonged by a local release of humoral factors, linked to the reflex path. The increased response to cold air in the sensitized rabbits seems to correspond to non-specific hyperresponsiveness of bronchial smooth muscle rather than to an increased local release of inflammatory mediators.

Increased ventilatory chemosensitivity induced by domperidone, a dopamine antagonist, in healthy humans.

Respiratory and cardiovascular effects of domperidone (0.1 mg X kg-1 i.v.) and placebo given on separate test days to eleven healthy volunteers were assessed in a double-blind study. Domperidone caused no significant change in ventilation, heart rate and blood pressure while they were resting and breathing room air. However, it produced an increase in the slope of the hypoxia-induced ventilatory response, from 2.35 +/- 1.10 to 3.71 +/- 2.91 1 X min-1 per 1% decrease in SaO2 (mean +/- SD; p less than 0.05). We conclude that domperidone augments hypoxic responsiveness in humans, presumably by blocking the dopaminergic receptors that modulate the activity of carotid body chemoreceptors, as it does not readily cross the blood-brain barrier.

Spontaneous and provoked resistance to isoproterenol in isolated human bronchi.

Cumulative concentration-response curves to isoproterenol were constructed in 74 preparations of human airways (group A) contracted with acetylcholine (80% of maximal contraction). In 52 bronchi (group A1), the maximal relaxation to isoproterenol represented at least 70% of the acetylcholine contraction (average 98% +/- 3) and the mean concentration (+/- SD) causing 50% of the relaxation (EC50) was 6.0 X 10(-8)M +/- 0.8. Resistance to isoproterenol (significant decrease of the maximal relaxation and right shift of the concentration-response curve) was provoked in 25 preparations by incubating them with isoproterenol (concentration 100 times higher than the individual EC50) for 30 min. The response to isoproterenol remained stable over the same time interval in eight control preparations. Incubation with isoproterenol did not modify the relaxing response to theophylline (n = 8). Indomethacin had no effect on the resistance provoked by isoproterenol incubation (n = 11). Incomplete relaxation to isoproterenol (maximal relaxation averaging 47% +/- 2 of the acetylcholine contraction) was observed in 22 preparations (group A2; mean EC50 = 1 X 10(-6)M +/- 0.2, significantly different [p less than 0.001] from group A1). Such preparations could be completely relaxed by theophylline (n = 7). For the whole group A, a significant negative correlation was found between isoproterenol EC50 and the magnitude of the maximal relaxation to isoproterenol (expressed as percent of acetylcholine contraction). There was no significant correlation between acetylcholine EC50 and isoproterenol maximum relaxation. Spontaneous resistance to isoproterenol was neither related to the technique of isoproterenol administration (cumulative versus noncumulative; n = 11) nor the magnitude of acetylcholine contraction (70% and 95% of maximal contraction; 14 bronchi, group B).

[Pressure-volume relationship in the right ventricle]. / A propos des relations pression-volume dans le ventricule droit

The curve of the pressure-volume relationships of the right ventricular cavity is not a mono-exponential one. It can be characterized by the presence of two successive segments: linear and exponential. The points that constitute the first of them could not be subjected to Starling's law. This is material for the physiopathology of the tamponade.

[Tension-volume relationship of the wall of the isolated right ventricle]. / Relations tension-volume de la paroi du ventricule droit isolé

The variations of tension on the wall of the isolated right verticle have been observed on 18 dogs. The Tension/Volume curve we got can be superimposed to that obtained by pressures. The wall of the right ventricle itself (the radius of the curve in the cavity and the wall-thickness) seems to vary only with the changes in its tension in a rather small part of the curve.

[Intrarectal clonazepam in children. Plasma and CSF levels]. / Clonazépam intrarectal chez l'enfant. Taux plasmatique et dans le LCR.

Eleven children with seizures were treated with clonazepam by rectal route. Thirty minutes after the administration, the plasma (8 to 28 ng/ml) and CSF (0.9 to 2.26 ng/ml) levels were satisfactory and correlated with a good clinical result. Since the tolerance of the drug was excellent, clonazepam appears to be as useful as diazepam in the management of childhood seizures.

Simultaneous determination of dextromoramide, propoxyphene and norpropoxyphene in necropsic whole blood by liquid chromatography.

Dextromoramide, propoxyphene and its main metabolite, norpropoxyphene, were determined in blood after solid-liquid extraction by means of an HPLC method using photodiode-array detection. Two cases of fatal overdose resulting from abuse of the two drugs are presented. In case 1 the necropsic whole blood contained dextromoramide at toxic level (194 ng ml-1) and propoxyphene (614 ng ml-1) and norpropoxyphene (1100 ng ml-1) within the therapeutic range; the death could be due to the combined effect of the two analgesics and, perhaps, other associated drugs. In case 2, the necropsic whole blood concentrations of propoxyphene and norpropoxyphene were 4330 and 3800 ng ml-1, respectively, and could be considered as lethal.

[The curve of the intraventricular pressure-volume relationships is not mono-exponential]. / La courbe des relations pression-volume intraventriculaire n'est pas une mono-exponentielle

The graphic and statistic investigations have let us to assert that the right ventricular P/V relationship's curve is characterized by two successive segments: linear and exponential respectively. We have proposed an interpretation based on Roach's and Burton's works. Interest of information about this curve is double: 1) it is a function of the ventricular cavity volume; 2) it gives a general idea about the mode of ventricular filling.

Comparative reflex action of histamine, acetylcholine and serotonin on dog airways.

To dissociate airway stimulation from airway response, a segment of the cervical trachea was isolated from the rest of the bronchial tree in 15 anesthetized dogs; nerve and blood supplies of the segment were preserved. Patency of the intrathoracic airways was assessed with lung resistance (RL) measurements. When doses of aerosolized histamine (His), acetylcholine (ACh) and serotonin (Ser) causing comparable increases in RL were delivered into the intrathoracic airways, concomitant increases in pressure were recorded in the tracheal segment (indicating constriction) with His being the most effective. When the hypoxemia accompanying His- and ACh-induced bronchoconstriction was prevented by inhaling an air-oxygen mixture, the tracheal response persisted (2 dogs). Vagotomy decreased the RL response to His, ACh and Ser and abolished tracheal response (13 dogs). The tracheal response was still abolished when larger doses of His and ACh were given in order to induce an increase in RL similar to that observed before vagotomy (7 dogs). These data suggest the existence of a positive feed-back mechanism in the airways, pharmacological bronchoconstriction causing vagally mediated reflex bronchoconstriction. Direct stimulation of lung irritant receptors by histamine may explain the larger degree of reflex bronchoconstriction observed with this agent.