Liver and peripheral blood concentration ratio (L/P) as a marker of postmortem drug redistribution: a literature review

The liver to peripheral blood (L/P) ratio, based upon review of previously published works, was evaluated as a marker of postmortem redistribution (PMR). Literature supported the proposed model that drugs exhibiting an L/P ratio of less than 5 are prone to little or no PMR, while those with an L/P ratio greater than 20–30 have propensity for significant redistribution. Many antidepressants, including both tricyclic antidepressants and selective serotonin re-uptake inhibitors, were markedly differentiated from drugs previously verified to be free from, or exhibit little, PMR. The magnitude of the liver to blood concentrations also appeared to provide an advantage over the conventional central to peripheral blood ratio model of PMR by demonstrating a wide range of values (1.6–97) for interpretation of drugs’ potential for, and variations in, redistribution.     

Transplantation at the Nexus of Behavioral Economics and Health Care Delivery

The transplant surgeon's decision to accept and utilize an organ typically is made within a constrained time window, explicitly cognizant of numerous health‐related risks and under the potential influence of considerable regulatory and institutional pressures. This decision affects the health of two distinct populations, those patients receiving organ transplants and those waiting to receive a transplant; it also influences the physician's life and their institute's productivity. The numerous, at times nonaligned, incentives established by the complex clinical and regulatory environment, have been derived specifically to influence physicians’ behaviors, and though well intended, may lead to responses that are nonoptimal when considering the myriad stakeholders being influenced. This may compromise the quality of care provided to the population at risk, and has potential to influence the physician–patient relationship. A synergistic collaboration between transplant physicians and economists that is focused on this decision environment may help to alleviate these strains. This viewpoint discusses behavioral economic principles and how they might be applied to transplantation. Specifically, the previous medical decision‐making literature on transplantation will be reviewed and a discussion on how a behavioral model of physician decision making can be utilized will be explored. To date this approach has not been integrated into transplantation decision making.     

IL-1 regulates in vivo C-X-C chemokine induction and neutrophil sequestration following endotoxemia

The influx of neutrophils into tissues in response to inflammatory stimuli involves C-X-C chemokines. Interleukin-1 (IL-1) stimulates chemokine production in vitro, but its role in vivo on chemokine production is not as clearly understood. We hypothesized that IL-1 mediates in vivo tissue C-X-C chemokine production induced by systemic lipopolysaccharide (LPS). IL-1 activity was blocked by IL-1 receptor antagonist (IL-1Ra). Rats were injected with Salmonella typhi LPS (0.5 mg/kg) with and without prior administration of IL-1Ra. Cytokine-induced neutrophil chemoattractant-1 (CINC-1) and macrophage inflammatory protein-2 (MIP-2) protein and mRNA levels, tissue neutrophil accumulation, and indices of organ injury were measured. LPS administration resulted in increased plasma, lung, and liver IL-1beta that was decreased by Il-1Ra. LPS also induced an increase in plasma, lung, and liver CINC-1 and MIP-2 protein and mRNA. However, IL-1Ra had no effect on LPS-induced plasma or lung tissue CINC-1 levels. In contrast, IL-1Ra pretreatment did significantly decrease CINC-1 protein expression in the liver (45% decrease) and MIP-2 protein expression in plasma (100% decrease), lung (72% decrease) and liver (100% decrease) compared to LPS- treated controls. Steady-state mRNA levels by Northern blot analysis of both CINC-1 and MIP-2 in lung and liver were similar to the protein findings. Pretreatment with IL-1Ra also resulted in a 47% and 59% decrease in lung and liver neutrophil accumulation, respectively, following LPS. In addition, indices of both lung and liver injury were decreased in animals pretreated with IL-1Ra. In summary, LPS induces IL-1beta and MIP-2 expression in the lung and liver, both of which are IL-1 dependent. Although lung neutrophil accumulation in both lung and liver after LPS is also IL-1 mediated, lung CINC-1 levels were unaffected by IL-1Ra. These data suggest that IL-1 regulates tissue chemokine expression and neutrophil accumulation after LPS.     

Surgical intervention for drug-resistant ventricular tachycardia

Endocardial resection was required in 26 patients with sustained drug-resistant ventricular tachycardia. The early mortality rate (within 30 days after operation) was 12%. Two deaths were the result of low cardiac output, and the third death was related to recurrent ventricular septal defect after septal endocardial resection. The survivors of endocardial resection were followed up from 6 to 92 months (mean 43). There were no recurrences of ventricular arrhythmias, and patients did not require antiarrhythmic drug therapy. The late mortality rate after endocardial resection was 19%. There were two late cardiac-related deaths (unrelated to arrhythmias) and three late deaths from noncardiac causes. Complete endocardial resection successfully ablates drug-resistant ventricular tachycardia, but is associated with an increased perioperative mortality rate in those patients who have severely depressed left ventricular function without a well defined left ventricular aneurysm.     

Antiphospholipid antibodies. Risk assessments for solid organ, bone marrow, and tissue transplantation

The literature pertaining to transplantation of solid organs, bone marrow, and other tissues in aPL-positive patients has been reviewed. The effects that aPL have relative to BMT are altogether different than those ascribed to solid organs and tissues. By definition, the transplantation of allogeneic bone marrow serves to reconstitute the recipient with a completely new and genetically different repertoire of antibody-producing cells. Previously aPL-positive bone marrow recipients become aPL-negative subsequent to transplantation assuming that the marrow donor is aPL-negative. These observations are the basis for contemporary experimental approaches to curing certain autoimmune diseases with BMT. Similarly, it would follow that an aPL-negative patient provided cells from an aPL-positive donor could become aPL-positive and suffer increased risk for thrombosis. From the data provided in most of the non-bone marrow publications, the presence of aPL should be considered a grave risk factor for any potential solid organ or tissue transplant candidate. Peritoneal dialysis patients seem to be at maximal risk. Given the serious emotional and economic impact of irreversible thrombotic loss suffered by organ transplant recipients, these factors alone should justify the modest expense of pretransplant aPL screening. In the United States, the average cost of losing a kidney transplant to aPL-associated thrombosis was estimated from 1996 data to be $82,000. The cost of losing a heart or liver is measured not only in dollars but often in the patient's life. The encouraging news, however, is that once aPL are identified before transplantation, prophylactic anticoagulation seems to be capable of forestalling untoward aPL-associated allograft events. Clearly, much remains to be discovered in exploring the pathobiologic characteristics of aPL in the laboratory as well as in neutralizing their procoagulant effects at the bedside.