[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.

[Pharmacologic study of monohydrated caffeine in the treatment of apnoea of premature infant]. / Etude pharmacologique de la caféine monohydratée dans le traitement des apnées du prématuré

UNLABELLED: Monohydrated caffeine was the only respiratory xanthine available in our country to treat apnea of premature infant. The aim of this study was to evaluate plasma levels of this molecule at dosages of 20 mg/kg (equal to 18 mg/kg of caffeine base) as a loading dose and 5 mg(-1) kg(-1) (equal to 4.5 mg(-1) kg(-1) of caffeine base) as a maintenance dose. PATIENTS AND METHODS: The study was prospective including premature infants less than 34 weeks of gestational age born between the 1st of july 2001 and 15th december 2001 and receiving monohydrated caffeine to prevent apnea. Each premature infant has received orally a loading dose of 20 mg/kg in the first hours of life followed, 24 h after, by a maintenance dose orally once a day of 5 mg/kg until 35 weeks of post-conceptional age. Caffeinemia plasma levels were measured by high performance liquid chromatography immediately before the second dose to determine the loading residual rate and immediately before the sixth dose to determine the maintenance residual rate. RESULTS: Twenty-one premature infants were included. Their medium term was 31.4 weeks (27.4-33.3 weeks), birth weight was 1684 g (1000-2800 g) and sex-ratio M/F was 1.3. Fifteen infants (71.4%) have presented apnea with an average of 4.1 episodes per infant and per day. Tolerance of the medicament was good in all cases. The medium loading residual rate was 3.26 microg/ml (1.75-7.80) and the medium maintenance residual rate was 4.26 microg/ml (2.13-7.64). CONCLUSION: Prescribed at a dosage close to twice the recommendations of the literature, monohydrated caffeine does not provide efficient plasma rates. This is probably due to a difference in its oral bio-availability compared with caffeine citrate and further study with greater dosages is needed to appreciate its efficacy.

[The risk of falling due to benzodiazepine administration, alone or in combination, in elderly subjects]. / Le risque de chutes lié à l'administration de benzodiazépines seules ou associées, chez le sujet âgé.

Benzodiazepines are well tolerated by young adults whereas in elderly people they are less safe and globally induce more central nervous system side-effects and falls. Falls result from a decrease of vigilance and an alteration of postural reflex. This latter includes the reception of sensory information and central integration modulated mainly by dopaminergic D2 receptors and motor stimulation. Benzodiazepines act simultaneously on the three stages, decreasing their efficacy. The risk increases when certain other drugs are coprescribed, especially synergistic drugs such as another psycholeptic drug, an aminoside or a centrally active antihypertensive drug. Thus their co-prescription with a benzodiazepine increases the risk of falls. The pharmacokinetic parameters of benzodiazepines may be modified or remain constant during ageing. The choice of molecules whose parameters do not vary seems advisable. Whatever the selected benzodiazepine, it is obvious that it must be administered at the lowest possible dose, this dose being increased only if necessary, the overall prescription being time limited.

[Are sigma receptors implicated in ischemic injury?]. / Les récepteurs sigma sont-ils impliqués dans les lésions d'ischémie?

Sigma receptors are present in many organs and several functions are allotted to them but the specificity of their effect remains to be established. Indeed, all the molecules known to interact with these receptors also have affinities for other receptors. Recently, sigma-1 receptors were implied in the processes of cellular protection, several of their ligands showing a neuroprotector effect in various models of cerebral ischaemia. S-16950, a trimetazidine derivative, is a powerful anti-ischaemic drug on a hepatic model of ischaemia-reperfusion. It is structurally closely related to SA4503, a sigma receptor ligand showing also an anti-ischaemic action. Our study shows that S-16950 inhibits the binding of [3H]pentazocine, a selective sigma-1 receptor radioligand, to rat brain membranes with a high affinity (IC50 = 7 nM). This affinity is equivalent to the most potent sigma ligand such as haloperidol. Its affinity is 170 times higher for the sigma-1 subtype than for the sigma-2 subtype. The effect of Gpp[NH]p on S-16950 inhibition of [3H]pentazocine binding and the potentiation of the convulsivant effect of cocaine under the action of S-16950 suggest that this molecule may act as an agonist. These results indicate that S-16950 is a new sigma ligand and reinforce the assumption of a link between sigma receptors and a cytoprotective activity.