A low oral dose of midazolam can be used to phenotype CYP3A, either by the determination of total 1'OH-midazolam/midazolam ratios at 30 min or by the determination of midazolam plasma levels between 1.5 h and 4 h after its administration.

Clozapine (CLO), an atypical antipsychotic, depends mainly on cytochrome P450 1A2 (CYP1A2) for its metabolic clearance. Four patients treated with CLO, who were smokers, were nonresponders and had low plasma levels while receiving usual doses. Their plasma levels to dose ratios of CLO (median; range, 0.34; 0.22 to 0.40 ng x day/mL x mg) were significantly lower than ratios calculated from another study with 29 patients (0.75; 0.22 to 2.83 ng x day/mL x mg; P < 0.01). These patients were confirmed as being CYP1A2 ultrarapid metabolizers by the caffeine phenotyping test (median systemic caffeine plasma clearance; range, 3.85; 3.33 to 4.17 mL/min/kg) when compared with previous studies (0.3 to 3.33 mL/min/kg). The sequencing of the entire CYP1A2 gene from genomic DNA of these patients suggests that the -164C > A mutation (CYP1A2*1F) in intron 1, which confers a high inducibility of CYP1A2 in smokers, is the most likely explanation for their ultrarapid CYP1A2 activity. A marked (2 patients) or a moderate (2 patients) improvement of the clinical state of the patients occurred after the increase of CLO blood levels above the therapeutic threshold by the increase of CLO doses to very high values (ie, up to 1400 mg/d) or by the introduction of fluvoxamine, a potent CYP1A2 inhibitor, at low dosage (50 to 100 mg/d). Due to the high frequency of smokers among patients with schizophrenia and to the high frequency of the -164C > A polymorphism, CYP1A2 genotyping could have important clinical implications for the treatment of patients with CLO.

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In the postmenopausal period, women's genital organs undergo several changes and female hormones, as well as modification of vascular reactivity to various stimuli, play a major role in this process. We studied the modification of uterine vascularity consequent to spontaneous or artificially induced menopause, with gonadotropin releasing hormone (GnRH) analogs. Flow velocity waveforms of the uterine arteries were detected using a color Doppler imaging system with a transvaginal probe; the pulsatility index was calculated. The study group consisted of 15 women observed before and after 6 months of treatment with GnRH analogs (triptorelin 3.75 mg depot every 4 weeks intramuscularly) for uterine fibromyomata; 20 women after 5 years of spontaneous menopause; and 20 healthy and normally menstruating women in the late luteal phase. We found a significant difference among the three groups with a progressive increase of the pulsatility index in spontaneous menopausal women. This phenomenon may be due to a different hormonal pattern which exists in spontaneous and artificially induced menopause (increase of gonadotropin level in the former and decrease in the latter), and to a decrease of vascular compliance caused by progressive sclerosis of the vasal walls.

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