Opioids are powerful analgesics acting via the human μ‐opiate receptor (hMOR). Opioid use is associated with adverse effects such as tolerance, addiction, respiratory depression, and constipation. Two synthetic opioids, AH‐7921 and U‐47700 that were developed in the 1970s but never marketed, have recently appeared on the illegal drug market and in forensic toxicology reports. These agents were initially characterized for their analgesic activity in rodents; however, their pharmacology at hMOR has not been delineated. Thus, we synthesized over 50 chemical analogs based on core AH‐7921 and U‐47700 structures to assess for their ability to couple to Gα i signaling and induce hMOR internalization. For both the AH‐7921 and U‐47700 analogs, the 3,4‐dichlorobenzoyl substituents were the most potent with comparable EC 50 values for inhibition of cAMP accumulation; 26.49 ± 11.2 nmol L −1 and 8.8 ± 4.9 nmol L −1 , respectively. Despite similar potencies for Gα i coupling, these two compounds had strikingly different hMOR internalization efficacies: U‐47700 (10 μmol L −1 ) induced ~25% hMOR internalization similar to DAMGO while AH‐7921 (10 μmol L −1 ) induced ~5% hMOR internalization similar to morphine. In addition, the R , R enantiomer of U‐47700 is significantly more potent than the S , S enantiomer at hMOR. In conclusion, these data suggest that U‐47700 and AH‐7921 analogs have high analgesic potential in humans, but with divergent receptor internalization profiles, suggesting that they may exhibit differences in clinical utility or abuse potential.

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Metastatic bone disease is a common complication of advanced breast cancer. Recently, the results of a large randomized placebo-controlled trial demonstrated that monthly pamidronate infusions reduce the incidence of skeletal related events in these patients. In the current study, a cost-utility analysis was performed from a Canadian health care system perspective to estimate the incremental cost-effectiveness of pamidronate in patients with advanced breast cancer. Twenty-five advanced breast cancer patients who were bisphosphonate naYve and had developed skeletal related complications were identified. Total hospital resource consumption was then collected for all patients. This included direct costs for hospitalization and costs for radiation treatment to bone, surgery, analgesics, blood products, diagnostic imaging, paramedical services and all related physician fees. Treatment preferences were estimated from a random sample of 25 women selected from the general population and 25 female health care professionals, using the Time Trade-Off technique. The outcomes were then generated through a decision-analytic model. Over a 12-month period, total costs in the pamidronate arm were approximately 44% higher than those in the no-treatment alternative (Can$ 9,180 vs Can$ 6,380). When treatment preferences were incorporated into the analysis, the results of the decision model revealed an incremental pamidronate cost of $18,700 per quality-adjusted life year gained. The results of the sensitivity analysis suggested that this estimate was dependent on the cost of treating skeletal related events, particularly bone surgery. Even though pamidronate has a high drug acquisition cost, the results of the cost-utility analysis suggest that this agent does provide patients with a substantial quality-adjusted survival benefit at a reasonable cost to the Canadian health care system.

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Reductions in populations of both Pre-B cell (Hardy fractions D) and Pro-B cells (Hardy fractions B–C) have been described in association with murine lupus. Recent studies of B cell populations, based on evaluation of B cell differentiation markers, now allow the enumeration and enrichment of other stage specific precursor cells. In this study we report detailed analysis of the ontogeny of B cell lineage subsets in New Zealand black (NZB) and control strains of mice. Our data suggest that B cell development in NZB mice is partially arrested at the fraction A Pre–Pro B cell stage. This arrest at the Pre-Pro B cell stage is secondary to prolonged lifespan and greater resistance to spontaneous apoptosis. In addition, expression of the gene encoding the critical B cell development transcription factor BSAP is reduced in the Pre–Pro B cell stage in NZB mice. This impairment may influence subsequent B cell development to later stages, and thereby accounts for the down-regulation of the B cell receptor component Igα (mb-1). Furthermore, levels of expression of the Rug2, λ5 and Igβ (B29) genes are also reduced in Pre–Pro B cells of NZB mice. The decreased frequency of precursor B cells in the Pre–Pro B cell population occurs at the most primitive stage of B cell differentiation.