[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.

[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.

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.

Blockade by verapamil of cholinergic effects on atrial specialised tissue in the anaesthetised dog.

The effects of verapamil were studied in anaesthetised dogs administered dextromoramide intrathecally to provide background vagal tone. Measurements were made of spontaneous heart rate, and, in paced hearts, of conduction times in atrial muscle, the atrioventricular node (A-V node) and His-Purkinje system by means of His bundle potential recording. The effective refractory period (ERP) of A-V node was measured by the extrastimulus method. In atropinised and vagotomised animals, verapamil reduced sinus rate and increased A-V nodal conduction time. In dogs high vagal tone after dextromoramide, however, verapamil increased sinus rate and reduced A-V nodal ERP. After dextromoramide alone, A-V block was observed at an atrial pacing rate of 150 beats X min-1, but after verapamil 1:1 A-V conduction was restored. The decrease in conduction velocity in the A-V node due to ACh was neither attenuated nor enhanced by verapamil.

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.

Centrally mediated cardiovascular effects of nicergoline in the dog compared to those of clonidine.

The intracisternal administration of nicergoline (5 micrograms/kg) or clonidine (4 micrograms/kg) in chloralose-anesthetized dogs induced significant decreases in blood pressure and heart rate. The same dose of nicergoline induced similar effects on atropine-pretreated dogs. Guanethidine pretreatment (30 mg/kg i.v. the day before) prevented the hypotension but not the bradycardia induced by clonidine. Guanethidine prevented both the hypotension and the bradycardia induced by nicergoline. Thus, nicergoline, unlike clonidine, does not increase cardiac parasympathetic activity. When administered by the same route at the same doses, nicergoline did not change the slope and reduced the amplitude whereas clonidine increased both the slope and the amplitude of the heart period vs. blood pressure curve obtained by intravenous administration of phenylephrine. Taken together, these results suggest that nicergoline and clonidine probably act on different structures within the central nervous system.

Biphasic effect of a gradual rise in plasma calcium concentration on vulnerability to fibrillation.

The possible potentiation by a rise in plasma calcium concentration of the effects of acetylcholine (ACh) on the atrial myocardium was investigated, mainly with a view to define the increase in vulnerability to fibrillation by hypercalcaemia. The effective refractory period (ERP) of the atrial myocardium, the atrial fibrillation threshold (AFT) and the atrial fibrillation rate (AFR) were measured repeatedly before and during the intravenous infusion of calcium at the rates of 0.025, 0.050 and 0.100 mmol . kg-1 . min-1 in dogs whose heart was, in addition, submitted to a cholinergic influence. 1. As long as the rise in plasma calcium concentration did not reach 100% approximately, this influence was enhanced considerably: in particular, ACh shortened ERP and raised AFR to a much larger extent, so that it resulted in fibrillation with a minor electrical stimulation. 2. When the rise in plasma calcium concentration exceeded 100%, hypercalcaemia became inhibitory of the effects of ACh, with a reversal in the modification of all the parameters, AFT especially, and, finally, prevention or even conversion to sinus rhythm of fibrillation.

Potentiation by hypokalemia of the effects of acetylcholine on the canine heart in situ.

In the heart in situ of vagotomized dogs, atrioventricular conduction was studied by the His bundle potential recording, sinus rate continuously registered and the effective refractory period (ERP) of the atrial muscle measured by the extrastimulus method. The modifications induced by the acute lowering of plasma potassium concentration from 3.5 to 2.0 mmol/l obtained by hemodialysis appeared to be similar to those due to parasympathetic stimulation and the effects of hypokalemia and acetylcholine (ACh) on the atrioventricular (A-V) and sinoatrial nodes as well as on the atrial contractile tissue gave rise to potentiation. Intraaortically injected near coronary ostia in a dose lower than liminal dose, ACh enhanced to a large extent all the phenomena elicited by hypokalemia, since the variations respectively observed under the influence of hypokalemia alone and the combination of hypokalemia and ACh were as follows: lengthening of conduction time in the A-V node by 100 and 180%, reduction of sinus rate by 10 and 20%, shortening of the atrial ERP by 20 and 40%.

[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.