Sensorimotor changes following acute exposure to carbamazepine and phenytoin in male Wistar rats

Introduction: The use of antiepileptic drugs (AEDs) such as carbamazepine and phenytoin are part of strategies for the management of epilepsy. Acute exposure of epileptic patients to AEDs can cause sensory impairment. Aim: This study seeks to assess sensorimotor changes in male Wistar rats upon single-large dose exposure to carbamazepine, phenytoin and their mixture. Methods: 24 male Wistar rats (160-210 g) were randomly separated to four groups with 6 rats each. Groups I, II and III was given distilled water (2 ml/kg), carbamazepine (1950 mg/kg); and phenytoin (820 mg/kg) respectively, while Group IV (CBZ+PHY) was co-exposed to carbamazepine (1950 mg/kg) and phenytoin (820 mg/kg). The treatment was orally administered once by gavage (on Day(D) 1), then followed by weekly monitoring of body weight, clinical signs and neurobehavioural parameters for four weeks (D0, D1, D7, D14, D21 and D28). Results: The body weight revealed insignificant improvement (p > 0.05) in all groups. A significantly (p < 0.05) lower grooming frequency, increased locomotor activity and a reduction in the frequency of urination and defecation were recorded in the CBZ and PHY groups. Also, the number of missed rungs, inclined plane and grip fore-paw time reduced significantly (p < 0.05) in CBZ, PHY and CBZ+PHY groups. Significance: A single large dose of CBZ, PHY and their combination caused anxiogenic and sensorimotor impairment.

Single Large Dose (15 Mg/Kg) Amphotericin B Lipid Complex (L-AmB) as Prophylaxis of Fungal Infections during Induction Chemotherapy in Acute Non Lymphoid Leukemia (ANLL).

In ANLL, during intensive induction,invasive fungal infections (IFI) related to prolonged neutropenia,mucosal damage,steroids, geographical and center variations is the main factor wich can influence disease outcome The optimal prophylactic regimen has not yet to be identified. The AmB lipid formulations let to treat IFI in refractory or intolerant patients. The efficacy of these drugs appears to be related both to improved tissue penetration along with sustained bioactivity of drug levels in lung, brain, kidneys, liver and spleen.(Anaissie et al.2004).On this basis,, in a cohort of adult (>18y) ANLL patients,during induction,we applied a pilot study for IFI prophylaxis in the aim to test the efficacy and safety of a single large dose of L-AmB.The primary endpoint was to evaluate the incidence of documented or suspected fungal infection during and up to four weeks after prophylaxis discontinuation.PATIENTS: From September 2004 to May 2005 18 consecutive adult ANLL (4 APL) patients −12 M,6 F, median age 56 y (range 39–75)- entered in this study. Intensive induction chemotherapy included standard /high dose cytosine-arabinoside + antracyclines +etoposide or fludarabine and retinoic acid + antracyclines in the 4 APL. METHODS: The criteria of inclusion were:1)neutropenia (PMN <0.5 109/L) longer than 10 days 2) initial surveillance coltures, mannano and galattomammano antigens negative 3) no fever and/or clinical infection features. At the day after induction end, patients received L-AmB(AMBISOME, GILEAD®) at the dosage of 15 mg/kg i.v as single dose. A second single dose was repeated after 15 days in those cases which were persistently neutropenic,but did not meet the criteria of suspected fungal infections. RESULTS:13 (72%) patients achieved complete hematological remission,1 was resistant and 4 died during induction aplasia. (2 for Aspergillosis). Overall median neutropenia duration was 22 d (range 17 – 45). The median dosage of L- AmB administered was 900 mg x dose( range 750 – 900);a second single dose at the same dosage was given in four cases. During L-AmB infusion, 2 patients had CTC grade II allergy, treated by i.v. steroids, thus drug infusion could be completed; no patient had renal or hepatic toxicity.Of the 18 enrolled patients,14 (80%) met the primary endpoint of the studys since none of them developed fungal infection, while the remaining 4 cases had IFI: 2 Candida spp.sepsis and 2 invasive Aspergillosis.On the basis of these encouraging clinical results, in further consecutive 5 patients we tested L-AmB PK profile at the following times: 0,12,24 hour,7th and 14 th day from drug administration.The median L-AmB PK results (lower standard rate 0,15mg/l + − standard deviation) are: 0 h < 0,15 1 h 8,92 +/− 4,25 4 h 51,26 +/− 26,7 24 h 3,92 +/− 11,77 7° d 1,39 +/− 1,97 14° d 0,27 +/− 0,092 CONCLUSION:despite the low number of patients involved,in our experience a single large L-AmB dose (15mg/kg) did show an effective and safe approach for the IFI prophylaxis, since 80% of treated patients did not experience fungal infection;furthemore preliminary kinetic results show high plasma levels that are slowly eliminated. These data have to be confirmed in larger series of ANLL adult patients to define which may be the best dosage to achieve a good and prolonged tissue concentrations.