Use of Argatroban during multi-organ procurement: pharmacokinetics and sequelae in recipient of transplanted liver

Abstract:  This report illustrates potential concerns regarding the administration of Argatroban (AGN), a small molecule, direct thrombin inhibitor, within the setting of multi-organ procurement (MOP). Herein, we outline the case of a large AGN bolus to the donor during MOP, and the passive transfer of a coagulopathy to the recipient of the transplanted liver. From this, we conclude that caution should be exercised when AGN is used in the setting of MOP.     

The roles of alcohol and alcohol expectancy in the dampening of responses to hyperventilation among high anxiety sensite young adults

Previous research suggests that high anxiety sensitivity (AS) young adults are particularly sensitive to alcohol's dampening effects on their responses to arousal-induction challenge [Alcohol.: Clin. Exp. Res. 24 (2000) 1656.]. This sensitivity to alcohol reward may place high AS individuals at increased risk for alcohol abuse. Over-and-above alcohol's pharmacological effects, tension-reduction expectancies might contribute to alcohol's reactivity-dampening effects in high-AS individuals. The present study examined the role of alcohol and alcohol expectancy factors by activating expectancies experimentally. Forty-eight high-AS young adults were randomly assigned to one of three beverage conditions: alcohol (pharmacology plus expectancy), placebo (expectancy only), and control (no pharmacology and no expectancy). Following beverage consumption and absorption, participants underwent a 3-min voluntary hyperventilation challenge. Replicating and extending previous findings, participants in the alcohol condition showed dampened affective and somatic responses to the challenge, and marginally dampened cognitive responses to the challenge, compared to both placebo and control participants. However, placebo participants did not display dampened responses to the challenge relative to control beverage condition participants. Additional analyses suggested that activation of tension-reduction expectancies might have contributed to an “inverse placebo” effect among high-AS participants administered placebo. Implications of the results for future research and for the prevention and treatment of alcohol problems among high-AS individuals are discussed.     

Everolimus for renal cell carcinoma: predictive factors for response and future directions

Mammalian target of rapamycin (mTOR) inhibitors have emerged as a major addition to the therapeutic armamentarium for renal cell carcinoma. Temsirolimus extended survival when employed as frontline therapy for poor-risk advanced renal cell carcinoma. Everolimus has demonstrated improved progression-free survival for all risk groups of RCC in the salvage setting following other anti-angiogenic agents. Preliminary data indicates that baseline activation of the mTOR signaling pathway and increased FDG-PET uptake as well as early pharmacodynamic modulations of the mTOR pathway and down-modulation of FDG-PET uptake may predict for the activity of mTOR inhibitors. Ongoing trials are attempting to validate these data with everolimus therapy for metastatic RCC and may enable the goal of personalized therapy.     

Novel treatment options for refractory germ cell tumors

Although testicular germ cell tumors (GCTs) are a model for a curable neoplasm, a significant proportion will relapse and require salvage therapy. While currently available conventional and high-dose chemotherapy salvage regimens attain durable complete remissions in a significant proportion of patients, the long-term outcomes are still suboptimal in this young population. Several novel agents are being evaluated for recurrent germ cell tumors, including chemotherapeutic and biologic agents, notably anti-angiogenic agents. A better understanding of biology may lead to enhanced outcomes for cisplatin-refractory patients with germ cell tumors.     

Short-term leptin infusion does not affect circulating levels of LH, testosterone or cortisol in food-restricted pubertal male rhesus macaques

OBJECTIVES: Although the adipocyte protein leptin has been implicated in the control of reproductive function in rodents, its role in primate reproductive physiology is poorly understood. Because primates in puberty show nighttime LH secretion and there is considerable evidence that the fertile state requires adequate nutrition, we reasoned that animals on the verge of reproductive competence would respond to leptin infusions by secreting LH. Food restriction reduces circulating leptin levels and slows or stops the GnRH pulse generator. Therefore, we examined the endocrine effects of leptin infusions in food-restricted male pubertal primates during the night when they normally secrete LH. In addition, we investigated the effect of leptin on in vitro testosterone production by Leydig cells. SUBJECTS: Four pubertal male rhesus macaques (Macaca mulatta), 4-5.5 kg in weight (2.5-4-year-old) were examined in this study. Leydig cells from adult male rats were to investigate in vitro effects of leptin. DESIGN: To document that animals had entered puberty, blood samples were collected from each of the four animals at 15-minute intervals for 15 h both during the day and at night. Since at this age animals secrete LH mainly at night, blood samples were collected at 15-minute intervals from each of the four animals on two separate occasions for 15 h between 1500 and 0600h. During the experiment, animals were feeding from 0800 to 0830h, cages were completely cleaned of food at 0900h and the afternoon meal was not given to individual animals on the day they were studied. One of the studies served as the control (food restricted group) and during the other, 2 mg (n = 4) or 0.3 mg (n = 3) of recombinant human leptin was administered intravenously during 2000-0100h (food restricted plus leptin group). Blood samples (1 ml) were collected through the indwelling catheter and immediately transferred from the plastic syringe into chilled glass tubes containing 10 microl 14% EDTA. The samples were centrifuged at 5-h intervals and the plasma withdrawn and stored frozen at - 20 degrees C in polypropylene vials until assays were performed. MEASUREMENTS: Bioactive LH was determined and testosterone, cortisol and leptin were measured by radioimmunoassay. RESULTS: During daytime experiments in these animals, LH pulses were sometimes observed late in the day and generally continued for 12-15 h. Food-restricted pubertal males showed delayed or absent LH pulses. Short-term leptin administration to food-restricted male rhesus macaques had no effect on LH, testosterone, or cortisol levels either during or after the infusion. Leptin also had no direct effect on basal or LH-stimulated testosterone production in Leydig cells. CONCLUSIONS: Our data support the notion that leptin is not the missing signal for the acute suppression of reproductive hormones secretion in food-restricted primates.