Liver Allocation to Non-U.S. Citizen Non-U.S. Residents: An Ethical Framework for a Last-in-Line Approach.

The incidence of non-U.S. citizen non-U.S. resident patients coming to the United States specifically for deceased donor liver transplantation raises compelling ethical questions that require careful consideration. The inclusion of these often financially and/or socially privileged patients in the pool of potential candidates for an absolutely scarce and life-saving liver transplant may exacerbate disparities already existing in deceased donor liver allocation. In addition, their inclusion on organ transplant waiting lists conflicts with recognized ethical principles of justice and reciprocity. Moreover, preliminary data suggest that public awareness of this practice could discourage organ donation, thereby worsening an already profound supply-demand gulf. Finally, U.S. organ allocation policies and statutes are out of step with recently promulgated international transplant guidelines, which prioritize self-sufficiency of organ programs. This article analyzes each of these ethical conflicts within the context of deceased donor liver transplantation and recommends policy changes that align the United States with international practices that discourage this scenario.

The do-not-resuscitate order: associations with advance directives, physician specialty and documentation of discussion 15 years after the Patient Self-Determination Act.

BACKGROUND: Since the passage of the Patient Self-Determination Act, numerous policy mandates and institutional measures have been implemented. It is unknown to what extent those measures have affected end-of-life care, particularly with regard to the do-not-resuscitate (DNR) order. METHODS: Retrospective cohort study to assess associations of the frequency and timing of DNR orders with advance directive status, patient demographics, physician's specialty and extent of documentation of discussion on end-of-life care. RESULTS: DNR orders were more frequent for patients on a medical service than on a surgical service (77.34% vs 64.20%, p = 0.02) and were made earlier in the hospital stay for medicine than for surgical patients (adjusted mean ratio of time from DNR orders to death versus total length of stay 0.30 for internists vs 0.21 for surgeons, p = 0.04). 22.18% of all patients had some form of an advance directive in their chart, yet this variable had no impact on the frequency or timing of DNR ordering. Documentation of DNR discussion was significantly associated with the frequency of DNR orders and the time from DNR to death (2.1 days with no or minimal discussion vs 2.8 days with extensive discussion, p<0.01). CONCLUSIONS: The physician's specialty continues to have a significant impact on the frequency and timing of DNR orders, while advance directive status still has no measurable impact. Additionally, documentation of end-of-life discussions is significantly associated with varying DNR ordering rates and timing.

O6-alkylguanine-DNA alkyltransferase inactivation by ester prodrugs of O6-benzylguanine derivatives and their rate of hydrolysis by cellular esterases.

To modulate the bioavailability and perhaps improve the tumor cell selectivity of O6-alkylguanine-DNA alkyltransferase (AGT) inactivators, pivaloyloxymethyl ester derivatives of O6-benzylguanine (BG) were synthesized and tested as AGT inactivators and as substrates for cellular esterases. The potential prodrugs examined were the 7- and 9-pivaloyloxymethyl derivatives of O6-benzylguanine (7- and 9-esterBG), and of 8-aza-O6-benzylguanine (8-aza-7-esterBG and 8-aza-9-esterBG) and the 9-pivaloyloxymethyl derivative of 8-bromo-O6-benzylguanine (8-bromo-9-esterBG). The benzylated purines were all potent inactivators of the pure AGT and of the AGT activity in HT29 cells and cell extracts. Each ester was at least 75 times less potent than the corresponding benzylated purine against the pure human AGT. In contrast, the activities of esters and their respective benzylated purine were similar in crude cell extracts and in intact cells. The increase in potency of esters in cellular extracts could be explained by a conversion of the respective prodrug to the more potent benzylated purine in the presence of cellular esterases. The apparent catalytic activity (Vmax/Km) of liver microsomal esterase for 8-azaBG ester prodrugs was 70-130 times greater than for BG prodrugs and 10-20 times greater than for 8-bromo-9-esterBG. Tumor cell hydrolysis of the esters varied considerably as a function of cell type and prodrug structure. These data suggest that these or related prodrugs may be advantageous for selective AGT inactivation in certain tumor types.