[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.

Cardioprotection and kallikrein-kinin system in acute myocardial ischaemia in mice.

1. Acute myocardial ischaemia and reperfusion trigger cardioprotective mechanisms that tend to limit myocardial injury. These cardioprotective mechanisms remain for a large part unknown, but can be potentiated by performing ischaemic preconditioning or by administering drugs such as angiotensin-I-converting enzyme (kininase II) inhibitors (ACEI). 2. This brief review summarizes the findings concerning the role of tissue kallikrein (TK), a major kinin-forming enzyme, kinins and kinin receptors in the cardioprotection afforded by ischaemic preconditioning (IPC) or by pharmacological postconditioning by drugs originally targeted at the renin-angiotensin system, ACEI and type 1 angiotensin-II receptor blockers (ARB) in acute myocardial ischaemia. Myocardial ischaemia was induced by left coronary occlusion and was followed after 30 min by a 3 h reperfusion period (IR), performed in vivo in mice. The role of the kallikrein-kinin system (KKS) was studied by using genetically engineered mice deficient in TK gene and their wild-type littermates, or by blocking B1 or B2 bradykinin receptors in wild-type mice using selective pharmacological antagonists. 3. Ischaemic preconditioning (three cycles: 3 min occlusion/5 min reperfusion) enhances the ability of the heart of wild-type mice to tolerate IR. Tissue kallikrein plays a major role in the cardioprotective effect afforded by IPC, which is largely reduced in TK-deficient mice. The B2 receptor is the main kinin receptor involved in the cardioprotective effect of IPC. 4. Tissue kallikrein is also required for the cardioprotective effects of pharmacological postconditioning with ACEI (ramiprilat) or ARB (losartan), which are abolished for both classes of drugs in TK-deficient mice. The B2 receptor mediates the cardioprotective effects of these drugs. Activation of angiotensin-II type 2 (AT2) receptor is involved in the cardioprotective effects of losartan, suggesting a functional coupling between AT2 receptor and TK during angiotensin-II type 1 (AT1) receptor blockade. 5. The demonstration of a cardioprotective effect of the KKS in acute myocardial ischaemia involving TK and the B2 receptor and playing a major role in IPC or pharmacological postconditioning by ACEI or ARB, suggests a potential therapeutic approach based on pharmacological activation of the B2 receptor.

Pharmacokinetics and pharmacodynamics of Linezolid in burn patients.

Burns induce complex physiological changes such as modification of distribution volume, increased clearance of elements and decrease of protein binding. The pharmacokinetics of many antibiotics may then be modified, which requires dose adjustment. We attempted to evaluate the pharmacokinetics of linezolid in burn patients at a standard dose of 600 mg intravenously thrice a day. A prospective study was conducted in a 20-bed adult burn ICU at a university-affiliated teaching hospital in Tunis. Thirteen adult burned patients with documented and/or suspected multi drug resistant (MDR) gram-positive bacterium-related infections were enrolled in the study. Our study suggests that linezolid dosing at 600mg thrice a day leads to adequate pharmacodynamic/pharmacokinetic exposure to linezolid with a Cmin > 2mg/l in 84.6% of cases, T > MIC in about 87.5% and AUC/MIC > 100 in 61.5% of cases. However, a high variability in linezolid serum concentrations with a substantial percentage of sub-therapeutic levels was observed in a few patients, 15% of cases. Therefore, therapeutic drug monitoring of linezolid might be helpful for adequate dosing of linezolid in burned patients, to avoid the risk of treatment failure or of dose-dependent toxicity.

Les brûlés présentent une augmentation du volume de distribution et une modification de la clairance de toutes les classes des antibiotiques. De ce fait, il est recommandé d'augmenter la dose de chaque antibiotique chez le brûlé. Le linézolide est recommandé à la dose de 600mg/12h chez les malades en réanimation. Ce travail est entrepris afin d'évaluer la pharmacocinétique du linézolide à la dose de 600mg/8h chez les brûlés. Une étude prospective a été menée dans le service de réanimation des brûlés de Tunis. Ont été inclu, les patients ayant une SCB ≥ 20% ayant une infection suspectée et/ou documentée à cocci à Gram positif multi-résistants. Notre étude suggère que l'administration de linézolide chez le brûlé à la dose de 600mg/8 h permet d'atteindre une meilleure pharmacocinétique, avec Cmin > 2mg/l dans 84,6% des cas, T > MIC dans 87,5% et un ratio AUC/MIC > 100 dans 61,5% des cas. Néanmoins, une variabilité des concentrations sériques de linézolide, avec des taux sub- thérapeutiques ont été notés chez 15% des patients. Le monitorage des taux sériques peut être utile lors de l'utilisation du linézolide chez les brûlés, afin d'éviter l'échec thérapeutique ou la toxicité, dose-dépendante..

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.