Interactions between neuroleptics and CYP2C6 in rat liver--in vitro and ex vivo study

The aim of the present study was to investigate the influence of classic and atypical neuroleptics on the activity of rat CYP2C6 measured as a rate of warfarin 7-hydroxylation. The reaction was studied in control liver microsomes in the presence of neuroleptics, as well as in microsomes of rats treated intraperitoneally for one day or two weeks (twice a day) with pharmacological doses (mg/kg) of the drugs (promazine, levomepromazine, thioridazine, perazine 10, chlorpromazine, haloperidol 0.3, risperidone 0.1, sertindole 0.05), in the absence of the neuroleptics in vitro. Some of the neuroleptics added in vitro to control liver microsomes decreased the activity of CYP2C6. Sertindole and levomepromazine (Ki = 25 and 31 microM, respectively) were the most potent inhibitors of the rat CYP2C6 among the drugs studied. Their effects were more pronounced than those of the other phenothiazines tested: thioridazine and chlorpromazine (Ki = 88 and 91 microM, respectively), promazine and perazine (Ki = 322 and 341 microM, respectively), risperidone (Ki = 414 microM) or haloperidol (Ki = 606 microM). The investigated neuroleptics--when given to rats in vivo for one day or two weeks--did not produce any indirect effect on CYP2C6 via other mechanisms, except for levomepromazine, which increased the activity of the enzyme after 24-h exposure. Therefore, the direct inhibitory effect of levomepromazine on CYP2C6 may be attenuated by an indirect mechanism at the beginning of the neuroleptic therapy. In summary, the obtained results show direct inhibitory effects of some phenothiazine neuroleptics and sertindole on the activity of CYP2C6 in vitro in rat liver microsomes. Considering relatively high pharmacological doses and therapeutic concentrations of phenothiazines, it seems that the inhibitory effect of levomepromazine (and other phenothiazines with Ki values below 100 microM) found in vitro may be of physiological and pharmacological importance in vivo.     

An easy and versatile method of coverage for distal tibial soft tissue defects

BACKGROUND: The distally based superficial sural artery flap, first described as a distally based neuroskin flap by Masquelet et al., is a skin island flap supplied by the vascular axis of the sural nerve. In the difficult area of defects in the lower leg and the ankle and heel region, it has a wide variety of indications, even in the vascularly compromised patients. It has the largest arc of rotation of all flaps that have been described in this region. The most important advantage is that it does not compromise a major artery. It is simple to dissect and has a low donor morbidity. METHODS: We reported our experience with this new flap in 15 cases and also described a new indication for the patients with neglected ruptures of the Achilles tendon. RESULTS: In 13 patients, the flap was successfully transferred. In two cases, partial necrosis of the flap ensued, which healed with secondary intention. CONCLUSION: This flap deserves a high degree of interest in the reconstructive armamentarium of the trauma surgeon.