Clinical and genetic influencing factors on clozapine pharmacokinetics in Tunisian schizophrenic patients.

Clozapine (Clz) is an atypical antipsychotic, which its pharmacokinetics can be influenced by several factors. The CYP1A2 and CYP2C19, major enzymes implicated in Clz metabolism, present an interethnic variation on their activity caused by single nucleotide polymorphisms (SNPs). The present study investigated the influence of genetic and nongenetic factors on Clz pharmacokinetics in a southern Mediterranean population. We included adult Tunisian schizophrenic patients having received Clz and undergone a therapeutic drug monitoring (TDM) of Clz by morning C0 monitoring. The genomic DNA was extracted using a salting-out procedure. CYP1A2*1F (rs762551;-163C>A), CYP1A2*1C (rs2069514;-3860 G>A) and CYP 2C19*2 (rs4244285; 681G>A) was analyzed using PCR-RFLP. Fifty-one patients were enrolled in the study. The mutant allele (CYP1A2*1F) was the most frequently detected (58.8%). For CYP1A2*1F, Clz dose-normalized (C0/D ratio) was as high as 1.28 ± 0.37 in CC versus 0.67 ± 0.32 ng mL-1 per mg day-1 in AA group (p < 0.001). The influence of genetic (CYP1A2*1F, CYP1A2*1C and CYP2C19*2) and nongenetic parameters (age, weight, gender, tobacco, coffee, and alcohol consumption) on the variation of the Clz C0/D ratio was investigated. Only the CYP1A2*1 F polymorphism correlates significantly with the Clz C0/D variation and could explain 24% of its variability. Our data support a critical role of the CYP1A2 -163C>A on the variation of Clz exposure in Tunisian schizophrenic patients. Considering its narrow therapeutic range, CYP1A2 genotyping combined with TDM of Clz may improve efficacy and safety of this drug. Further studies are needed to investigate this issue.

Piroxicam-induced fixed drug eruption: Cross-reactivity with meloxicam.

BACKGROUND: Non-steroidal anti-inflammatory drugs constitute a main cause of fixed drug eruption (FDE). A few cases of piroxicam-induced FDE have been reported; however, the cross-reactivity among oxicams has rarely been evaluated. OBJECTIVES: To describe a series of patients with piroxicam-induced FDE, mostly confirmed by a positive patch test reaction, in whom cross-reactivity to meloxicam was assessed. METHODS: We included all cases of piroxicam-induced FDE diagnosed in the department of pharmacovigilance of Monastir. Patch tests for piroxicam and meloxicam were performed in the involved skin according to the European Network on Drug Allergy recommendations. Oral provocation tests (OPTs) were performed for patients with negative skin test results. RESULTS: Seven patients were included in this study. FDE was multiple for five patients and solitary for two. Bullous eruption was noticed in two cases. Lesional patch tests for piroxicam gave positive results in six patients. To assess cross-reactivity with meloxicam, this was patch tested. The test gave a positive result in only one patient. OPTs with meloxicam gave positive results in two patients with negative patch test results. CONCLUSION: Meloxicam is not a safe alternative for the treatment of piroxicam-induced FDE, and OPTs can be used to confirm tolerance before this drug is prescribed as a safer alternative.

Albendazole-induced associated acute hepatitis and bicytopenia.

Acute hepatitis induced by albendazole is rarely reported. We describe herein an original case of acute hepatitis associated with bicytopenia after albendazole intake. This paper is the first to describe a possible association of a hematologic disorder and acute hepatitis, both induced by albendazole therapy.

Interest of therapeutic drug monitoring of aminoglycosides administered by a monodose regimen.

BACKGROUND: Although the once-daily regimen of aminoglycosides (AG) is considered as predominantly used by many centers, the level of evidence of Therapeutic Drug Monitoring (TDM) of AG in cases of once-daily has not been clearly defined. The objective of this study is to evaluate the impact of TDM in achievement or maintaining target serum concentrations in patients receiving once-daily administration of AG. METHODS: We performed a retrospective analysis of data from patients having received a once daily amikacin or gentamicin and underwent routine TDM. A longitudinal follow up was performed. Data were analyzed according to the adhesion or not to recommendations. A logistic regression was performed in order to evaluate the effect of covariates (age, gender, weight, creatinine clearance [CLcr], TDM-based dose adjustment, weighted dose of AG) on the achievement of non-toxic Cmin. RESULTS: A total 437 blood samples issued from 324 patients were analyzed. The cut-off value of Clcr associated with a risk of toxic Cmin was≤41.66mL/min (OR: 11.29; 95%CI: 7.21-17.61; P<0.0001). Eighty-eight patients (27.1%) have at least two sampling points. The univariate analysis showed that the age, weight, CLcr and TDM-based dose adjustment were found to be significant factors in the achievement of non-toxic Cmin. In multivariate analysis, only TDM-based dose adjustment remains a significant factor in the achievement of non-toxic Cmin (OR: 6.66; 95%CI: 2.26-19.63; P=0.0006). CONCLUSION: Our study demonstrates the usefulness of TDM-based dosing adjustment of AG antibiotics in achieving nontoxic trough concentrations, particularly in critically ill patients, as they are prone to a renal impairment.

Colloidal silica-induced hypersensitivity: myth or reality.

BACKGROUND: Many excipients have been reported to induce drug hypersensitivity (e.g. colouring additives, preservatives). Colloidal silica has never been reported to induce drug hypersensitivity reactions. CASE REPORT: We report herein a 40-year-old patient who developed a skin eruption 2 days after Voltarene(®) (diclofenac) intake, confirmed by a positive patch test. Investigation of cross reactivity, assessed by patch testing to other non steroidal anti-inflammatory drugs, have showed a positive reaction only to piroxicam (Piroxen(®)), ketoprofen (Oki(®)) and indometacin (Indocid(®)). A hypersensivity to colloidal silica, a common excipient, was suspected. A patch test to this compound was performed showing a positive reaction. CONCLUSION: Colloidal silica, a compound widely used in drug manufacturing, could be another culprit excipient in inducing skin hypersensitivity reactions.

Ecological systems as computer networks: Long distance sea dispersal as a communication medium between island plant populations.

Ecological systems are known to exchange genetic material through animal species migration and seed dispersal for plants. Isolated plant populations have developed long distance dispersal as a means of propagation which rely on meteorological such as anemochory and hydrochory for coast, island and river bank dwelling species. Long distance dispersal by water, in particular, in the case of water current bound islands, calls for the analogy with computer networks, where each island and nearby mainland site plays the role of a network node, the water currents play the role of a transmission channel, and water borne seeds as data packets. In this paper we explore this analogy to model long distance dispersal of seeds among island and mainland populations, when traversed with water currents, in order to model and predict their future genetic diversity. The case of Pancratium maritimum L. populations in Tunisia is used as a proof of concept, where their genetic diversity is extrapolated.

Modeling hydrochory effects on the Tunisian island populations of Pancratium maritimum L. using colored Petri nets.

Hydrochory, the seed dispersal by water, is a strategy used by many aquatic and some terrestrial plants to move into areas appropriate for establishment. In this paper we model the hydrochory effects on the Tunisian island populations of Pancratium maritimum L. using colored Petri nets. Nineteen Tunisian coastal sites were considered including fourteen mainland and five island sites. The model was simulated for 400 thousand Atlantic Tunisian Current cycles (years). Snapshots of the island population's genetic makeup were taken for 50, 200 and 400 thousand years. The evolution of the obtained dendrograms showed a clear divide between the northern and southern island populations according to their estimated genetic make-up for the considered simulation durations. Hydrochory is not only with important ecological consequences, such as maintaining the populations of P. maritimum but also it may move species into areas appropriate for establishment. In this context, in situ and ex situ conservation measures of P. maritimum populations should be adopted very fast.