Beside nonsteroidal anti-inflammatory steroid drug use, antihypertensive medication and concomitant arteriosclerotic diseases are risk factors for colonic diverticular hemorrhage. Our results support the hypothesis of an altered arteriosclerotic vessel as the source of bleeding.

To examine the genetic factors influencing clozapine kinetics in vivo, 75 patients treated with clozapine were genotyped for CYPs and ABCB1 polymorphisms and phenotyped for CYP1A2 and CYP3A activity. CYP1A2 activity and dose-corrected trough steady-state plasma concentrations of clozapine correlated significantly (r = -0.61; P = 1 x 10), with no influence of the CYP1A2*1F genotype (P = 0.38). CYP2C19 poor metabolizers (*2/*2 genotype) had 2.3-fold higher (P = 0.036) clozapine concentrations than the extensive metabolizers (non-*2/*2). In patients comedicated with fluvoxamine, a strong CYP1A2 inhibitor, clozapine and norclozapine concentrations correlate with CYP3A activity (r = 0.44, P = 0.075; r = 0.63, P = 0.007, respectively). Carriers of the ABCB1 3435TT genotype had a 1.6-fold higher clozapine plasma concentrations than noncarriers (P = 0.046). In conclusion, this study has shown for the first time a significant in vivo role of CYP2C19 and the P-gp transporter in the pharmacokinetics of clozapine. CYP1A2 is the main CYP isoform involved in clozapine metabolism, with CYP2C19 contributing moderately, and CYP3A4 contributing only in patients with reduced CYP1A2 activity. In addition, ABCB1, but not CYP2B6, CYP2C9, CYP2D6, CYP3A5, nor CYP3A7 polymorphisms, influence clozapine pharmacokinetics.

Pharmacogenetic tests and therapeutic drug monitoring may considerably improve the pharmacotherapy of depression. The aim of this study was to evaluate the relationship between the efficacy of mirtazapine (MIR) and the steady-state plasma concentrations of its enantiomers and metabolites in moderately to severely depressed patients, taking their pharmacogenetic status into account. Inpatients and outpatients (n = 45; mean age, 51 years; range, 19-79 years) with major depressive episode received MIR for 8 weeks (30 mg/d on days 1-14 and 30-45 mg/d on days 15-56). Mirtazapine treatment resulted in a significant improvement in mean Hamilton Depression Rating Scale total score at the end of the study (P < 0.0001). There was no evidence for a significant plasma concentration-clinical effectiveness relationship regarding any pharmacokinetic parameter. The enantiomers of MIR and its hydroxylated (OH-MIR) and demethylated (DMIR) metabolites in plasma samples on days 14 and 56 were influenced by sex and age. Nonsmokers (n = 28) had higher mean MIR plasma levels than smokers (n = 17): S(+)-enantiomer of MIR, 9.4 (SD, 3.9) versus 6.2 (SD, 5.5) ng/mL (P = 0.005); R(-)-enantiomer of MIR, 24.4 (SD, 6.5) versus 18.5 (SD, 4.1) ng/mL (P = 0.003). Only in nonsmokers, plasma levels of S(+)-enantiomer of MIR and metabolites depended on the CYP2D6 genotype. Therefore, high CYP1A2 activity seen in smokers seems to mask the influence of the CYP2D6 genotype. In patients presenting the CYP2B6 *6/*6 genotype (n = 8), S-OH-MIR concentrations were higher those in the other patients (n = 37). Although it is not known if S-OH-MIR is associated with the therapeutic effect of MIR, the reduction of the Hamilton scores was significantly (P = 0.016) more pronounced in the CYP2B6 *6/*6-genotyped patients at the end of the study. The role of CYP2B6 in the metabolism and effectiveness of MIR should be further investigated.

The use of the cut-off values for LBP and CRP determined here would have avoided unnecessary antibiotic therapy in 14 and 11%, of patients respectively. CRP and LBP appear to be superior to IL-6 and WBC as diagnostic markers of bacterial gastrointestinal infection. Cut-off values may be a useful tool to support clinical decision-making on whether or not to initiate empiric antibiotic therapy.

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