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Biomedical subjects

Q Timour

Publications and source records attributed to Q Timour.

52 records · Page 3Linked to original sources
PubMed1988

[Systemic toxicity of local anesthetics. Pharmacokinetic and pharmacodynamic factors].

Local anaesthetics can have systemic adverse effects, mostly affecting the central nervous system and the heart. The physicochemical characteristics of the different local anaesthetics are recalled, for they determine the relationship between structure, activity and toxicity. The pharmacokinetic factors involved in the toxic effects of local anaesthetics, whether the drug is given in a single extravascular dose or, accidentally, within a blood vessel, are discussed. The toxic effects of repeated administrations of local anaesthetics depend on the metabolism of the drug as well as on pharmacokinetic factors. Possible maximal doses and drug interactions are also discussed. The mechanism of action of local anaesthetics, which block the sodium channel, explains their tissue toxicity and, more specifically, their central nervous and cardiovascular toxicities, which are more pronounced for the more potent local anaesthetic agents (bupivacaine, etidocaine). Systemic maternal effects and transplacental passage probably explain their foetal toxicity. Specific toxic effects are seen with some drugs, such as methaemoglobinaemia and allergic reactions (rarely for amide agents). Overall, local anaesthetic accidents are rare, but they must be prevented.

Anesthesia, Intravenous↗
PubMed1988

Haemodynamic effects of high plasma concentrations of bupivacaine in the dog.

The threshold concentrations responsible for circulatory collapse were experimentally investigated by intravenously infusing the drug at high rates (0.2 and 0.3 mg kg-1 min-1 over 20 min, and 0.4 mg kg-1 over 10 min) to 11 anaesthetized and ventilated dogs. Bupivacaine plasma concentrations at the time of haemodynamic measurements were, respectively, 4303 +/- 46, 5829 +/- 615, and 8930 +/- 689 ng ml-1 (means +/- SEM). Cardiac output appeared to be the first and the most affected of the haemodynamic variables studied. Its reduction was already significant with the 0.2 mg kg-1 min-1 bupivacaine infusion, whereas mean systolic blood pressure remained unchanged because of the compensatory increase in vascular resistance. The fall of cardiac output was enhanced by the rise in bupivacaine infusion rate, with simultaneous substantial decreases in left ventricular pressure and LV dP/dt max. At this stage, the increase in systemic vascular resistance was less marked than at low infusion rates, and was not sufficient to prevent hypotension. The variations of mean pulmonary blood pressure and pulmonary capillary wedge pressure did not reach statistical significance, and the absence of significant change in mean pulmonary blood pressure at the time cardiac output was reduced reflected the increase in pulmonary vascular resistance. These results suggest that high plasma concentrations of bupivacaine exert a depressant effect on cardiac contractions earlier than on arteriolar tone.

Animals↗
PubMed1987

Electrophysiological study in the dog of the risk of cardiac toxicity of bupivacaine.

The risk of toxic effects on the heart of bupivacaine following several kinds of locoregional anaesthesia has been investigated in the dog in situ heart by determining conduction time and effective refractory period in the various parts of the conduction system and the ventricular muscle, as well as the discharge rate of the sinus node. Bupivacaine, i.v. infused at 3 rates, 0.2, 0.3 and 0.4 mg X kg-1 X min-1, proved to have depressant effects on conduction, automatism and excitability. It slows down conduction in all the parts of the myocardium, considerably at high stimulation frequencies, but always much more in the His-Purkinje system and the ventricular contractile fibres than in the atrioventricular node, because it tends to block the sodium rather than the calcium or potassium channel. Its effect remain more moderate, indeed, on sinus automatism and atrial and mainly ventricular refractoriness. Its danger lies, therefore, in the inhibition of conduction, with atrioventricular or His bundle branch block, but more frequently reentrant arrhythmias, likely to result in ventricular fibrillation. However: these alterations are observed with very high plasma levels (about 4 to 9 micrograms X ml-1), much higher than usual peak concentrations following spinal anaesthesia (0.10 micrograms X ml-1) or even epidural anaesthesia or brachial plexus block (1.20 micrograms X ml-1); reversal of these alterations occurs rapidly (reduction by 50% within 30 min for instance), when they have not led to ventricular fibrillation or they have not been associated with circulatory collapse.

Action Potentials↗
PubMedDate not supplied

[Sudden death during anesthesia: human error, drug related or cardiac death?].

We carried out a retrospective analysis of 1500 forensic autopsies following sudden unexpected cardiac death. This analysis showed a group of 43 cases that could have been related to surgery and/or anaesthesia. Pathological examination revealed the existence of cardiac lesions in 40 cases: arrhythmogenic right ventricular cardiomyopathy (14 cases), coronary artery disease (9 cases), cardiomyopathy (8 cases), structural abnormalities of the His bundle (7 cases), mitral valve prolapse (1 case) and acute myocarditis (1 case). These disorders are compatible with a paroxysmal (rhythmic) phenomenon at the origin of the cardiac arrest. Identification of the cause of death in a patient who was presumed to be at low risk may provide major relief to the patient's family and the medical staff.

Adolescent↗
PubMedDate not supplied

[Cardiotoxicity of 5-fluorouracil: report of 6 cases].

5-fluorouracil (5-FU), a fluoropyrimidine antimetabolite, is widely used in the treatment of cancers of the digestive tract and breast. The clinical cardiotoxicity of 5-FU was first reported in 1975. Adverse cardiac effects include coronary disorders, heart failure and sudden death of suspected cardiac origin. Six new cases are reported, including 5 cases of angina and one of heart failure. The patients, 4 males and 2 females, were 26 to 71 years of age (mean: 56.2). They had no medical history of heart failure, myocardial ischemia or electrocardiographic anomalies prior to 5-FU treatment. Three patients had hypertension of whom one had had type-II diabetes mellitus for the past 20 years. Clinical symptoms included chest pain in 4 patients and heart failure in one, whereas the last patient had ECG changes with no associated clinical symptoms. Clinical symptoms of angina totally disappeared after the cessation of 5-FU administration, but heart failure was alleviated only after the introduction of digitalis, a converting-enzyme inhibitor and a diuretic. It has been estimated that 1.6% of patients treated with 5-FU develop adverse cardiac effects. Patients at greater risk are those with a history of ischemic cardiac disease, thoracic radiotherapy or high-dose 5-FU therapy. The mechanism involved is not clearly elucidated. Spasms of the coronary arteries or toxic inflammation of the myocardium have been suspected. These 6 new cases confirm the potential for cardiotoxicity of 5-FU and the need for careful cardiac monitoring of treated patients.

Adult↗
PubMedDate not supplied

Calcium channel modulators and susceptibility to ischaemic ventricular fibrillation: modification of cellular calcium overload.

The effects of the calcium channel modulators, Bay k 8644, infused i.v. at a rate of 2.5 micrograms/kg/min, and diltiazem, injected i.v. in a dose of 0.5 mg/kg, on the susceptibility to fibrillation induced by ischaemia, were investigated in anaesthetized, open-chest pigs. Ischaemia was produced, under ventricular pacing at constant high rate (180 beats/min), by transient complete occlusion of the left anterior descending coronary artery, near its origin. It was maintained till the triggering of fibrillation. The propensity to fibrillation was judged from the time elapsing between the onset of occlusion and the onset of fibrillation (time to fibrillation). In addition to the surface electrocardiogram, conduction time and monophasic action potential were recorded in the ventricular contractile fibres, as were dP/dtmax in the left ventricle and blood pressure in the carotid artery. At the end of a 10 min infusion, Bay k 8644 lowered to a large extent (about 40%) the time to fibrillation, which returned to its control values within the following 20 min. Conversely, diltiazem increased the time to fibrillation by a factor 4 or 5 at 5 min after its administration. This time to fibrillation remained substantially increased 25 min later. These changes were not associated with alterations in conduction time or monophasic action potential duration in the absence of ischaemia, but with significant alterations in myocardial contractility and blood pressure: in the direction of an increase with Bay k 8644 and of a decrease with diltiazem. These results are in agreement with the enhancement by Bay k 8644 and the prevention by diltiazem of cell calcium overload which is at present recognized as being the essential determinant of the fibrillatory process.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMedDate not supplied

Possible role of drug interactions in bupivacaine-induced problems related to intraventricular conduction disorders.

Clinically, bupivacaine has depressant effects on intraventricular conduction that may lead to serious atrioventricular blocks or reentrant arrhythmias at plasma levels below those required to produce these effects experimentally (2-3 micrograms/ml instead of 8-10 micrograms/ml). The difference could be due to drugs present in the blood at the time of regional anesthesia that similarly inhibit conduction. This hypothesis was examined in 30 anesthesized, closed-chest dogs by measuring conduction time in the ventricular contractile fibers as well as effective refractory period under pacing at a constant, relatively high (180 beats/minute) rate. Changes in sinus rate were limited, as well as changes in ventricular effective refractory period and blood pressure regardless of the drug tested. In contrast, cibenzoline, disopyramide, and propranolol increased conduction time and lengthened QRS duration. Clomipramine appeared to prolong conduction time and widen QRS only moderately in therapeutic doses, whereas verapamil did not manifest noticeable effects on conduction. Caution is therefore recommended in regional anesthesia with bupivacaine in subjects being treated with cardiovascular drugs, such as cibenzoline, disopyramide, and propranolol and their congeners, or even by tricyclic antidepressants.

Animals↗
PubMedDate not supplied

Frequency- and time-dependent depression of ventricular distal conduction by two novel antiarrhythmic drugs, cibenzoline and flecainide.

The effects of two novel antiarrhythmic drugs, cibenzoline and flecainide, known to exert potent inhibitory effects on sodium channel, were investigated on intraventricular conduction in anaesthetized, closed-chest dogs. During this study, in which the heart was electrically stimulated, the pacing period was gradually reduced in the 500-200 msec range, and the pacing rate was abruptly altered (2 sec) or sustained (8 to 10 sec) in order to study the possible frequency- and time-dependency of the depression of conduction. In addition to the electrocardiogram, the conduction time was recorded in the ventricular contractile tissue between an electrode advanced to the apex and the pacing electrode positioned near the base. Effective refractory period (ERP) was concurrently measured according to the extrastimulus method, and the monophasic action potential (MAP) recorded. The drugs were infused at a rate of 0.2 mg/kg/min over a 10 min period after a 4.0 mg/kg loading dose. Conduction time was lengthened by approximately 50% at low frequencies and 100% at high frequencies. Widening of the ORS complexes paralleled this lengthening, whereas the drugs tended only to prolong ERP, without preventing its shortening induced by acceleration. Cardiac disorders were aggravated when high pacing rates were maintained for 8 to 10 sec.

Action Potentials↗
PubMedDate not supplied

[Demonstration of the fibrillatory effect of class I anti-arrhythmia agents based on the time of fibrillation onset and electrical threshold in myocardial ischemia].

In recent clinical studies, certain class I antiarrhythmic drugs (flecaïnide, lidocaïne) appeared to be responsible for an increase in mortality, when used to treat ventricular arrhythmias occurring after or during infarction. Experimentally, in pigs whose rate of ventricular beats was kept constant by pacing, all the studied class I antiarrhythmic drugs, disopyramide, lidocaïne and flecaïnide, proved to be to a variable degree capable of shortening time to onset of fibrillation (TOF) elicited by controlled myocardial ischemia. Fibrillation occurred at the end of the decline, under the influence of ischemia, of electrical fibrillation threshold (EFT) down to near 0 mA. The fall of EFT to this level was checked by ischemias of increasing duration to be hastened by the cited antiarrhythmic drugs. In other words, these drugs exert a profibrillatory effect in the ischemic heart.

Animals↗
PubMedDate not supplied

Vulnerability to ventricular fibrillation related to ischaemia: comparison of the acute effects of beta-blockers and calcium antagonists.

A comparative evaluation of beta-blockers and calcium antagonists as protective agents against ventricular fibrillation related to myocardial ischaemia, was attempted in the pig heart in situ of anaesthetized, open-chest animals, subjected to a temporary complete occlusion of the left anterior descending coronary artery near its origin. This occlusion resulted in fibrillation occurring after a time depending on the vulnerability to the fibrillatory process. As this time to onset of fibrillation does normally not exceed a few minutes, its determination could be achieved repeatedly in the course of an experiment, in the absence and presence of drugs such as beta-blockers and calcium antagonists. When propranolol (0.05 mg/kg, i.v.) and verapamil (0.05 mg/kg, i.v.) abolished tachycardia produced by isoproterenol (0.25 micrograms/kg/min), the triggering of fibrillation was delayed in either case: in animals under atrial pacing at a rate close to the sinus rate on each determination, time to fibrillation was prolonged from about 160 to 400 sec by propranolol and from 160 to 640 sec by verapamil, with a return to control values within 60 min. Under ventricular pacing at a constant high rate (180 beats/min), no change was observed in time to fibrillation after propranolol (0.025 or 0.050 mg/kg), whereas verapamil, in the same conditions and in the same doses, multiplied this time by about 4 and 6, respectively. Consequently, propranolol and verapamil are likely to protect against fibrillation immediately after i.v. injection, but the protection due to propranolol is only indirect and a consequence of bradycardia which tends to increase the polarization of the muscular fibres, whereas verapamil adds to the same influence a direct preventive action by avoiding a cellular calcium overload in these fibres, which is responsible for the depolarization and fluctuations of their membrane potential.

Animals↗
PubMedDate not supplied

[Comparative study of different classes of anti-arrhythmia agents on the vulnerability of ischemic ventricular fibrillation].

A comparative study of the various classes of antiarrhythmic drugs as agents protecting against ischaemia-induced ventricular fibrillation was undertaken in the pig in situ heart, in anaesthetized animals which were subjected to complete temporary occlusion of the left anterior descending coronary artery. This occlusion resulted in fibrillation after a time which varied in inverse ratio to vulnerability to fibrillation. However, as this time did not exceed a few minutes, time to onset of fibrillation could be repeatedly measured in the course of an experiment, in the absence or in the presence of an antiarrhythmic drug. Under ventricular pacing at a constant rate, 180 beats/min, all the class I antiarrhythmic drugs, flecainide, disopyramide and lidocaine, in clinical dose range, reduced time to fibrillation to a large extent (25 to 50%) at the maximum of their action, with gradual return to control values within less than one hour. The enhancement of vulnerability to fibrillation was accompanied by reduction in intraventricular conduction velocity and fibrillation rate. With the same ventricular pacing, no change was observed in time to fibrillation under the influence of propranolol or amiodarone. As for verapamil, it lengthened this time considerably, up to 600%. However, bradycardia produced in usual circumstances ensures a real protection against ischaemic fibrillation with propranolol and amiodarone and enhances protection directly exerted by verapamil.

Animals↗
PubMedDate not supplied

Disappearance with ischaemic depolarization of the antifibrillatory activity in a sodium channel blocker and appearance in calcium channel blocker.

Results obtained in the prevention of ventricular fibrillation secondary to myocardial ischaemia are unexpected. Profibrillatory properties might be manifested by Class I antiarrhythmic drugs, normally antifibrillatory. Clear antifibrillatory properties might be manifested by calcium channel blockers, the antifibrillatory effects of which are normally questionable. Therefore, the action of a Class I antiarrhythmic drug, flecainide, and of a calcium channel blocker, verapamil, on the vulnerability to ischaemic ventricular fibrillation was assessed in anaesthetized, open-chest pigs by ventricular fibrillation threshold. Ventricular fibrillation threshold was determined with trains of diastolic stimuli of 100 msec duration, delivered at a rate of 180 beats/min (near that of the ventricular tachycardia), by a subepicardial electrode inserted into the area that could be subjected to ischaemia. Before determining this threshold, ventricles were paced at the same rate, particularly during the ischaemic periods. Ischaemia was produced by complete occlusion of the left anterior descending coronary artery, either at its origin or half-way from it, over increasing periods. The monophasic action potential and conduction time were recorded in the ischaemic area. Before ischaemia, flecainide was adapted to rais the ventricular fibrillation threshold, in spite of a lengthening of the conduction time. Verapamil was devoid of any influence on these parameters. The antifibrillatory effect of flecainide disappeared with ischaemia, which reduced the ventricular fibrillation threshold down to near 0 mA, with triggering of the spontaneous fibrillation at this level: this reduction was no longer counteracted and even hastened by flecainide, becomes finally profibrillatory. Verapamil, on the contrary, delayed the fall in ventricular fibrillation threshold, maintained far from 0 mA, with prevention of fibrillation, unless the occlusion was maintained over a much longer period. Verapamil similarly delayed the shortening of the monophasic action potential duration and the lengthening of the conduction time, preceding fibrillation and leading to it. Consequently, ischaemic depolarization is apparently responsible for the loss of antifibrillatory activity in a sodium blocker, such as flecainide, and the development of antifibrillatory activity in a calcium blocker, since the sodium channel is activated only at high potentials, whereas the calcium channel is activated at lower potentials.

Animals↗
PubMedDate not supplied

Prevention by calcium antagonists of profibrillatory effects of class I antiarrhythmic drugs in acute myocardial ischemia: study in pig heart in situ.

Class I antiarrhythmic drugs do not decrease, but increase, the risk of ventricular fibrillation in the ischemic myocardium. On the contrary, vulnerability to fibrillation related to ischemia appears to be substantially reduced by calcium antagonists. We assessed whether the calcium antagonist diltiazem (0.50 mg/kg bolus plus 0.02 mg/kg/min infusion) could prevent the profibrillatory effect or even partially restore the antifibrillatory effect of a class I antiarrhythmic drug, flecainide (1 mg/kg bolus plus 0.04 mg/kg/min infusion) in the ischemic myocardium of anesthetized, open-chest pigs. Ischemia was obtained by completely occluding the left anterior descending coronary artery near its origin. Vulnerability to fibrillation was assessed by electrical fibrillation threshold (EFT), measured with diastolic impulses of 100 msec duration delivered at a rate of 180 beats/minute. Diltiazem did not oppose the rise in EFT induced by flecainide in the absence of ischemia (6.8 +/- 1.2 to 9.9 +/- 0.9 mA, p<0.001). It limited the fall in EFT observed under the dual influence of ischemia and flecainide (4.2 +/- 0.9 vs 1.3 +/- 0.6 mA, p<0.001). By reducing calcium entry into myocardial fibers, diltiazem delayed ischemic depolarization, as evidenced by reduced shortening of the monophasic action potential duration from 215 +/- 7 to 200 +/- 4 msec, instead of 178 +/- 6 (p<0.001), and reduced lengthening of intraventricular conduction time from 33 +/- 5 to 43 +/- 4 msec, instead of 53 +/- 4 (p<0.01). Therefore, diltiazem is likely to prevent the loss and even the reversal of the antifibrillatory properties of flecainide due to myocardial ischemia in dosages that do not adversely affect myocardial contractility or atrioventricular conduction to a large extent.

Animals↗