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CYP2C19 converts the tricyclic antidepressant imipramine to its active metabolite desipramine, which is subsequently inactivated by CYP2D6. The novel CYP2C19*17 allele causes ultrarapid metabolism of CYP2C19 substrates. We genotyped 178 depressed patients on imipramine for CYP2C19*17, and measured steady-state imipramine and desipramine plasma concentrations. Mean dose-corrected imipramine plasma concentration was significantly dependent on CYP2C19 genotype (Kruskal–Wallis test, P=0.01), with circa 30% lower levels in CYP2C19*17/*17 individuals compared with CYP2C19*1/*1 (wild-type) patients. The mean dose-corrected imipramine+desipramine plasma concentrations and imipramine/desipramine ratios were not significantly different between genotype subgroups (Kruskal–Wallis tests, P0.12). In a multivariate analysis, we found a significant, but limited effect (P=0.035, η2=0.031) of the CYP2C19*17 genotype on imipramine+desipramine concentrations. Although the CYP2C19*17 allele is associated with a significantly increased metabolism of imipramine, CYP2C19*17 genotyping will, in our view, not importantly contribute to dose management of patients on imipramine therapy guided by imipramine+desipramine plasma concentrations. [ABSTRACT FROM AUTHOR]

Islet transplantation is associated with a high rate of early graft failure caused by early immune attack and poor functionality of islets. Apoptosis of islet cells appears soon after islet isolation and primarily involves the beta-cell. The purpose of this study was to determine the effect of ligation to extracellular matrix (ECM) proteins on survival of the islets of Langerhans following islet isolation. Islets that had been cultured for 24 h on collagen type I showed an islet survival of 59.7 +/- 8.7%, while islets that had been cultured on collagen type IV and laminin showed an islet survival of 88.6 +/- 10.3 and 94.3 +/- 5.6%, respectively. Islets that had been pretreated with anti-beta1 antibodies and argenin-glycin-aspartic acid (RGD) peptides showed a decrease in the level of apoptosis by a factor of 2.5 and 3.1, respectively, and an increase of phospho-Akt Ser 473 activity by a factor of 3.1 and 2.9, respectively, compared with untreated islets. When detached from their natural ECM surrounding in the pancreas, islet cells undergo apoptosis, unless islets are cultured on collagen IV or laminin or treated with anti-beta1 integrin antibodies or RGD peptides to mimic ECM ligation. These results indicate that inhibition of anoikis may offer opportunities to improve function and viability of islet cells. [ABSTRACT FROM AUTHOR]