[Delayed convulsion after lidocaine instillation for bronchoscopy]. / Convulsion tardive après instillation de lidocaïne pour bronchoscopie.

INTRODUCTION: Lidocaine toxicity usually appears rapidly and is directly correlated with plasma concentrations of the drug. CASE REPORT: We report a case of a late neurologic toxicity occurring after instillation of lidocaine during fibre-optic bronchoscopy. A patient with bronchiolitis obliterans underwent a diagnostic bronchoscopy. She received multiples instillations of Xylocaine(®) 2% (lidocaine). Three and a half hours later, she had a tonic-clonic seizure. Seven hours later, this recurred. Lidocaine plasma levels were in the toxic range at the time of the first seizure (18.32µg/mL) with a significant decrease in the concentration noted 24hours later. CONCLUSION: The slow absorption of lidocaine into the blood from the bronchial tree explains the delayed neurologic toxicity. Our observation is a reminder that complications can occur due to high doses of lidocaïne administrated by instillation. Thus, if the recommended dose of lidocaine is exceeded, it is essential to monitor patients closely for a prolonged period, especially those with fibrosing lung disease in order to avoid possible late toxicity.

[Interaction between azole antifugals drugs and tacrolimus in four kidney transplant patients]. / Interaction médicamenteuse entre des antifongiques azolés et le tacrolimus chez quatre greffés rénaux.

Tacrolimus, an immunosuppressor indicated in solid organ transplantation, has a large inter- and intra-individual variability, a narrow therapeutic index and numerous drug interactions. It is metabolized in the enterocytes and the liver by CYP3A4. Association to enzymatic inhibitors like azole antifungals increase its blood levels and may increase its toxicity directly related to an increase of its blood concentration. We describe in this study four cases of drug interaction between tacrolimus and azole antifungals. These patients were renal transplanted in 2009 and treated with tacrolimus. For fungal infections, azole antifungals were added in these cases. Three were treated by fluconazole and one with voriconazole. By the risk of drug interaction occurrence, tacrolimus doses were decreased by two thirds in one case and by the third in the second case. This association leaded to an increase in tacrolimus concentration (1.33 to 2.45 times the initial concentration) in all patients. Side effects observed in our patients were liver toxicity in two cases, an increase in serum creatinin and an hyperglycemia were notified in all patients. An increase in tacrolimus concentration with about 1.33 times was observed in the case receiving fluconazole intravenously at the dose of 100mg one day out of two and with a tacrolimus doses decrease by two thirds. The patient had impaired renal function before fluconazole introduction. This suggests that in the presence of renal function alteration even low doses of fluconazole with an inhibition of only liver CYPA3A4 (without inhibition of intestinal CYP3A4 and P-gp) leads to an increase on tacrolimus concentration and occurrence of adverse effects related to tacrolimus toxicity. With the co-administration of azole antifugals, it is recommended to adjust tacrolimus dosage on the basis of therapeutic tacrolimus blood monitoring in order to maintain tacrolimus concentration in therapeutic range and to avoid adverse toxic effects.

[Auditory hallucinations due to voriconazole: Illustration by plasma monitoring]. / Hallucinations auditives induites par le voriconazole : illustration par le monitorage plasmatique.

Voriconazole is a second-generation azole antifungal that is widely indicated in the treatment of invasive aspergillosis. It is generally well tolerated. It has nevertheless numerous side effects like hepatotoxicity, photosensitivity, skin rashes, and visual disturbances. Hallucinations were also reported as side effects to voriconazole but auditory hallucinations were rarely reported and seem to be related to toxic voriconazole blood levels. We report, herein, a case of auditory hallucination with monitoring of voriconazole plasma concentration during hallucination and after its disappearance. A 38-year-old man was treated with intravenously voriconazole for a pulmonary aspergillosis. Seven days after the initiation of voriconazole, the patient presented a sudden history of auditory hallucination associated to incoherence and temporo-spatial disorientation. Therapeutic drug monitoring of voriconazole showed a plasmatic residual concentration (C0) of 7.5µg/mL (therapeutic interval: 1.4-1.8µg/mL) and a pic concentration (Cmax) of 9.83µg/mL (therapeutic interval: 2.1-4.8µg/ml). Voriconazole was then stopped and, two days later, symptomatology completely disappeared and at the same time levels of voriconazole decreased (C0=0.11µg/mL and Cmax=2.17µg/mL). We concluded in our case that the patient's auditory hallucinations were caused by voriconazole treatment. In fact, the sudden onset of hallucinations was concomitant with high plasmatic voriconazole levels, and since the medication was stopped, an important decrease of voriconazole levels was observed which was associated with a sudden disappearance of the auditory hallucinations.

Effect of liver hypothermic preservation: exploration and protection.

BACKGROUND/AIMS: The principal aim of conservation is to maintain the viability of grafts. This requires the addition of a cellular protector allowing better conservation of the graft. The aim of this work is to evaluate the effect of trimetazidine (TMZ) addition to Wistar rat livers conserved in Krebs-Henseleit solution, compared to the livers preserved only in Krebs-Henseleit solution (24 h at 4 degrees C). METHODS: 40 Wistar female rats divided into 5 groups were used: the first group consists of nonpreserved livers, the second consists of livers preserved only in the Krebs-Henseleit solution, and the other 3 groups consist of livers preserved in Krebs solution with different concentrations of TMZ added (16.5, 49.5 and 165 microg/ml). RESULTS: The obtained results show an improvement in the state of the liver in the presence of a high concentration of TMZ, which approaches normal physiological conditions. We note a clear diminution of transaminase activities, as well as an amelioration in metabolic capacities of the liver if the mitochondrial esterase pathway is supported in Wistar rats by a reduction of histological injuries. CONCLUSION: A TMZ concentration of 165 microg/ml clearly restored the metabolic capacities of the liver. Indeed, TMZ limited the appearance of necrotic areas and almost suppressed apoptotic cells.

Comparison of three methods for cyclosporine therapeutic monitoring.

Cyclosporine (CsA) is an immunosuppressive drug used extensively in human transplants of solid organs or bone marrow as well as in the treatment of autoimmune diseases. To optimize immunosuppressive efficacy and minimize adverse reactions, blood CsA concentrations are monitored to allow appropriate dosage adjustments. To establish objective criteria to compare various techniques of CsA monitoring, we performed a detailed study over 5 months to compare and evaluate three immunoassays methods in comparison to the reference method of high-performance liquid chromatography (HPLC). Our study included 976 samples that were evaluated by: the COBAS INTEGRA 800 (Roche Laboratories); the V-Twin (Dade Behring Laboratories); and the AxSYM FPIA (Abbott Laboratories). Our results showed that all of the immunoassays yielded slightly higher concentrations than HPLC. However CsA concentrations obtained by AxSYM were most close to those of HPLC, so that this method seemed to be more specific than the other two.

[Fixed drug eruption induced by sulfaguanidine]. / Erythème pigmenté fixe à la sulfaguanidine.

INTRODUCTION: Fixed drug eruption is a lesion induced by drugs. The family of drugs usually incriminated are sulfonamides, tetracyclines and pyrazols. We describe nine cases of fixed drug eruption induced by sulfaguanidine, a sulfonamide with local action. CASE REPORTS: All the patients presented one or more fixed drug eruption reactivation lesions induced by sulfaguanidine as self-medication for diarrhea. The number of lesions increased in 7 cases after reactivation. The delay in occurrence of the fixed drug eruption decreased during the different episodes. The lesions predominated on the hands in 8 cases of 9. DISCUSSION: The sulfaguanidine must be added to the list of drug-induced fixed drug eruptions with limited absorption from the gastrointestinal tract.

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.

Doxorubicin concentrations in plasma and myocardium and their respective roles in cardiotoxicity.

Three hours after the intravenous infusion of doxorubicin (3 mg/kg over 15 min) to anesthetized dogs, the drug concentration was found much higher in the myocardium than in the plasma (about 4,000 ng/g, i.e., 50 times higher). After the intravenous infusion of doxorubicin (1.5 mg/kg over 15 min) to conscious dogs, the drug concentration appeared to decline very slowly in the myocardium, since it was close to 200 ng/g at the 7th day, whereas the plasma concentration had fallen to zero, and the drug was still detected in the cardiac tissue 21 days after the administration. As myocardial concentrations of doxorubicin persist long after plasma clearance is complete, the hazards of repeated administration, based on plasma kinetic patterns, must be emphasized.

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.

Doxorubicin concentration time course in the myocardium after single administration to the dog. Possible role in the cardiac effects.

Three hours after i.v. administration of doxorubicin, concentrations of the drug in the myocardium are much higher (about 50 times) and decrease much more slowly (drug still detected 21 days later) than those in the plasma, so that storage results from too early readministration, with possible toxic signs.

Protection against ventricular and atrial fibrillation by sotalol.

Sotalol is not only a beta blocker but a class III antiarrhythmic drug. Its possible antifibrillatory activity was therefore investigated in both the ventricles and atria of dog heart in situ, since vulnerability to fibrillation is not the same in both these parts of the myocardium. Fibrillation threshold was measured concurrently with the duration and amplitude of monophasic action potential, the effective refractory period, the conduction time in the contractile fibres, and after fibrillation had been triggered the fibrillation rate. Variables were measured at 5 and 10 min after sotalol had been given intravenously in closed chest dogs in three doses (1, 1, and 2 mg X kg-1) at 15 min interval. Sotalol produced a rise in fibrillation threshold that occurred simultaneously with a prolongation in monophasic action potential duration and effective refractory period of the contractile fibres and a slowing in fibrillation rate, whereas conduction time was not affected. The changes appeared, however, to be less pronounced in the ventricles than in the atria, in which vulnerability to fibrillation, normally increased by vagal tone, had been previously enhanced by acetylcholine. Sotalol antagonised the changes due to acetylcholine. In both the atria and the ventricles the first dose (1 mg X kg-1), which produced plasma concentrations of approximately 2 micrograms X ml-1 10 min after injection, produced a submaximal effect. Nevertheless, subsequent administrations increased the beneficial effects but not in proportion to the dose and plasma concentrations.