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Background: For extended-release drug formulations, effective half-life (t1/2eff) is a relevant pharmacokinetic parameter to inform dosing strategies and time to reach steady state. Tacrolimus, an immunosuppressant commonly used for the prophylaxis of organ rejection in transplant patients, is available as both immediate- and extended-release formulations. To the best of our knowledge, the t1/2eff of tacrolimus from these different formulations has not yet been assessed. The objective of this study was to characterize the t1/2eff and terminal half-life (t1/2z) of an extended-release once-daily tacrolimus formulation (LCPT) and twice-daily immediate-release tacrolimus (IR-Tac)., Methods: A noncompartmental analysis of pharmacokinetic data obtained from a phase 2 study in de novo kidney transplant recipients receiving either LCPT or IR-Tac was conducted. Intensive blood sampling was performed on days 1, 7, and 14, and tacrolimus whole blood concentrations were measured using a validated liquid chromatography with tandem mass spectrometry method. T1/2eff was estimated using within-participant accumulation ratios. T1/2z was estimated by linear regression of the terminal phase of the concentration versus time profile., Results: The median accumulation ratios of LCPT and IR-Tac on day 14 were 3.18 and 2.06, respectively.The median (interquartile range; IQR) t1/2eff for LCPT at day 14 of dosing was 48.4 (37.4-77.9) hours, whereas the t1/2z was 20.3 (17.6-22.9) hours. For IR-Tac, the median (IQR) t1/2eff and t1/2z on day 14 were 12.5 (8.8-23.0) hours and 12.2 (9.2-15.7) hours, respectively., Conclusions: Consistent with its prolonged release of tacrolimus, LCPT demonstrated a higher accumulation ratio and a longer t1/2eff compared with IR-Tac. These findings underscore the pharmacokinetic differences between different drug formulations of the same moiety and may help inform dose adjustments for LCPT in kidney transplantation., Competing Interests: J.D. Momper has received consulting fees from Veloxis Pharmaceuticals, Inc. B.M. Masters and S.J. Patel are employees of Veloxis Pharmaceuticals, Inc. R. Venkataramanan, A.S. Jantz, D.M. Cibrik, and K. Birdwell have no conflicts of interest to declare., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Arrestins are multifunctional proteins that regulate G-protein-coupled receptor (GPCR) desensitization, signaling, and internalization. The arrestin family consists of four subtypes: visual arrestin1, β-arrestin1, β-arrestin2, and visual arrestin-4. Recent studies have revealed the multifunctional roles of β-arrestins beyond GPCR signaling, including scaffolding and adapter functions, and physically interacting with non-GPCR receptors. Increasing evidence suggests that β-arrestins are involved in the pathogenesis of a variety of neurodegenerative diseases, including Alzheimer's disease (AD), frontotemporal dementia (FTD), and Parkinson's disease (PD). β-arrestins physically interact with γ-secretase, leading to increased production and accumulation of amyloid-beta in AD. Furthermore, β-arrestin oligomers inhibit the autophagy cargo receptor p62/SQSTM1, resulting in tau accumulation and aggregation in FTD. In PD, β-arrestins are upregulated in postmortem brain tissue and an MPTP model, and the β2AR regulates SNCA gene expression. In this review, we aim to provide an overview of β-arrestin1 and β-arrestin2, and describe their physiological functions and roles in neurodegenerative diseases. The multifaceted roles of β-arrestins and their involvement in neurodegenerative diseases suggest that they may serve as promising therapeutic targets., (© 2024. The Author(s).)

Rationale: Female rodents consume more ethanol (EtOH) than males and exhibit greater aversion-resistant drinking in some paradigms. Ovarian hormones promote EtOH drinking but the contribution of ovarian hormones to aversion-resistant drinking has not been assessed., Objectives: We aimed to investigate the role of ovarian hormones to aversion-resistant drinking in female mice in a drinking in the dark (DID) task., Methods: Female C57BL/6 J mice first underwent an ovariectomy (OVX, n = 16) or sham (SHAM, n = 16) surgery. Four weeks following surgery, mice underwent a DID paradigm where they were given access to water and 15% EtOH 3 h into the dark cycle for up to 4 h across 15 drinking sessions. To assess frontloading behavior, bottles were weighed at 30 min, 2 h, and 4 h. Aversion-resistance was tested by adding escalating concentrations of quinine (0, 100, 250, and 500 µM) to the 15% EtOH bottle on sessions 16 - 19., Results: Removal of the ovaries reduced EtOH consumption in OVX subjects. When assessing aversion-resistant EtOH drinking, mice with ovarian hormones (SHAM) reduced consumption of 250 and 500 µM quinine in EtOH, while OVX subjects exhibited aversion-resistance at all quinine concentrations. OVX mice had greater frontloading for quinine + EtOH at higher concentrations of quinine., Conclusions: These results indicate that circulating ovarian hormones may be protective against the development of aversion-resistant EtOH drinking and call for further investigation of the role of ovarian hormones in models of addictive behavior., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Introduction: While substantial research has focused on the contribution of sex hormones to driving elevated levels of alcohol drinking in female rodents, fewer studies have investigated how genetic influences may underlie sex differences in this behavior., Methods: We used the Four Core Genotypes (FCG) mouse model to explore the contribution of sex chromosome complement (XX/XY) and gonad type [ovaries ( Sry- )/testes ( Sry+ )] to ethanol (EtOH) consumption and quinine-resistant drinking across two voluntary self-administration tasks: limited access consumption in the home cage and an operant response task., Results: For limited access drinking in the dark, XY/ Sry + (vs. XX/ Sry +) mice consumed more 15% EtOH across sessions while preference for 15% EtOH vs. water was higher in XY vs. XX mice regardless of gonad type. XY chromosomes promoted quinine-resistant drinking in mice with ovaries ( Sry- ) and the estrous cycle did not affect the results. In the operant response task, responding for EtOH was concentration dependent in all genotypes except XX/ Sry  + mice, which maintained consistent response levels across all concentrations (5-20%) of EtOH. When increasing concentrations of quinine (100-500 μM) were added to the solution, FCG mice were insensitive to quinine-punished EtOH responding, regardless of sex chromosome complement. Sry  + mice were further found to be insensitive to quinine when presented in water. Importantly, these effects were not influenced by sensitivity to EtOH's sedative effect, as no differences were observed in the time to lose the righting reflex or the time to regain the righting reflex between genotypes. Additionally, no differences in EtOH concentration in the blood were observed between any of the genotypes once the righting reflex was regained., Discussion: These results provide evidence that sex chromosome complement regulates EtOH consumption, preference, and aversion resistance and add to a growing body of literature suggesting that chromosomal sex may be an important contributor to alcohol drinking behaviors. Examination of sex-specific genetic differences may uncover promising new therapeutic targets for high-risk drinking., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sneddon, Masters, Ream, Fennell, DeMedio, Cash, Hollingsworth, Pandrangi, Thach, Shi and Radke.)

Introduction: Advanced liver disease or cirrhosis is associated with an increased risk of infections; however, the impact of high pretransplant model for end-stage liver disease (MELD) score on cytomegalovirus (CMV) viremia after liver transplantation is unknown., Methods: This single-center, retrospective, cohort study evaluated CMV high-risk (CMV immunoglobulin G D+/R-) liver transplant recipients who received valganciclovir prophylaxis for 3 months between 2009 and 2019. Patients were stratified by pretransplant MELD score of <35 (low MELD) and ≥35 (high MELD). The primary outcome was 12-month CMV viremia, and secondary outcomes included CMV resistance and tissue invasive disease, mortality, biopsy-proven acute rejection (BPAR), leukopenia, and thrombocytopenia. Multivariable Cox proportional-hazards modeling was used to assess the association of MELD score with the time to CMV viremia., Results: There were 162 and 79 patients in the low and high MELD groups, respectively. Pretransplant MELD score ≥35 was associated with an increased risk of CMV viremia (hazard ratio [HR] 1.73; confidence interval 1.06-2.82, p = .03). CMV viremia occurred at 162 ± 61 days in the low MELD group and 139 ± 62 days in the high MELD group. Although BPAR occurred early at 30 days (13-59) in the low-MELD group and at 18 days (11-66) in the high-MELD group (p = .56), BPAR was not associated with an increased risk of CMV viremia (HR 1.55 [0.93-2.60], p = .1)., Discussion: MELD scores ≥35 were associated with an increased hazards of CMV viremia. In liver transplant recipients with MELD scores ≥35 who are CMV high-risk, additional CMV intervention may be warranted., (© 2022 Wiley Periodicals LLC.)

Alcohol use and high-risk alcohol drinking behaviours among women are rapidly rising. In rodent models, females typically consume more ethanol (EtOH) than males. Here, we used the four core genotypes (FCG) mouse model to investigate the influence of gonadal hormones and sex chromosome complement on EtOH drinking behaviours. FCG mice were given access to escalating concentrations of EtOH in a two-bottle, 24-h continuous access drinking paradigm to assess consumption and preference. Relapse-like behaviour was measured by assessing escalated intake following repeated cycles of deprivation and re-exposure. Twenty-four-hour EtOH consumption was greater in mice with ovaries (Sry-), relative to those with testes, and in mice with the XX chromosome complement, relative to those with XY sex chromosomes. EtOH preference was higher in XX versus XY mice. For both consumption and preference, the influences of the Sry gene and sex chromosomes were concentration dependent. Escalated intake following repeated cycles of deprivation and re-exposure emerged only in XX mice (vs. XY). Mice with ovaries (Sry- FCG mice and C57BL/6J females) were also found to consume more water than mice with testes. These results demonstrate that aspects of EtOH drinking behaviour may be independently regulated by sex hormones and chromosomes and inform our understanding of the neurobiological mechanisms which contribute to EtOH dependence in male and female mice. Future investigation of the contribution of sex chromosomes to EtOH drinking behaviours is warranted. We used the FCG mouse model to investigate the influence of gonadal hormones and sex chromosome complement on EtOH drinking behaviours, including the alcohol deprivation effect. Escalated intake following repeated cycles of deprivation and re-exposure emerged only in XX mice (vs. XY). These results demonstrate that aspects of EtOH drinking behaviour may be independently regulated by sex hormones and chromosomes., (© 2022 Society for the Study of Addiction.)

Background: Elderly patients are the fastest growing population requiring renal replacement therapy. As previous studies have shown a survival benefit of kidney transplantation compared to dialysis for end-stage renal disease, we sought to evaluate if this survival benefit extends to octogenarians., Methods: This was a single-center retrospective cohort study of renal allograft recipients ≥80 years transplanted from 1999 to 2014 who were compared to patients listed during the same period that did not proceed to transplantation. A secondary matched group was selected from the UNOS transplant waitlist database. The primary outcome was patient survival. Secondary outcomes included graft survival and rejection incidence., Results: Thirty-three transplanted patients were compared to 71 patients waitlisted at our center and 66 patients from the UNOS database. Patients in the study group were transplanted 20.8 ± 16.1 months after listing. Patient survival was 87.8% at 6 months and 1 year and 71.4% at 3 years. Kidney transplantation was associated with a significant decrease in the risk of death after listing (HR: 0.22, CI: 0.11-0.45, P < .001)., Conclusion: With escalating life expectancy, kidney transplantation is a suitable treatment option in eligible octogenarians., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Recently, it has been shown that panniculectomy concurrent to living donor renal transplantation is a safe option for management of renal transplant recipients with a large focal pannus. This combined management requires precise coordination of teams. We describe the technique, timing, and sequence for combined renal transplantation and panniculectomy., Methods: We conducted a retrospective chart review of adult patients (≥18 years old) who underwent simultaneous living donor renal transplantation-panniculectomy from 2015 to 2019. A multi-team approach that included urology, transplant, and plastic surgery was used to perform the combined operations. Typically, the plastic surgery team initiates the operation by performing the panniculectomy. This is followed by kidney transplantation and graft anastomosis. The plastic surgery team then completes the operation with closure of the wound., Results: Twenty patients were identified. Most were male (12:8) with a mean age of 55 years and an average body mass index of 35 kg/m. The mean total operative duration was 394 minutes. On average, 17% of operating time was devoted to panniculectomy. At 90 days follow-up, there was 100% graft survival and all patients had primary graft function. There was a 25% wound complications rate and a 15% reoperation rate., Conclusion: By performing panniculectomy first in the sequence, concurrent panniculectomy provides wide exposure and a large operative field for transplantation. Wound closure by plastic surgeons may mitigate the high complication rate commonly seen in obese patients with end-stage renal disease. Future studies are needed to evaluate the cost-benefit of the combined living donor renal transplantation-panniculectomy.

Background: Cytomegalovirus (CMV) outcomes with valganciclovir prophylaxis in renal transplant recipients experiencing delayed graft function (DGF) are unclear., Methods: This single center, retrospective, cohort study of CMV high-risk (D+/R- with alemtuzumab induction) deceased donor renal transplant recipients receiving valganciclovir prophylaxis assessed CMV outcomes in patients experiencing DGF (n = 72) versus those with immediate graft function (IGF; n = 66)., Results: Cytomegalovirus viremia by 12 months occurred at similar rates in the IGF and DGF groups (30.3% vs 26.4%, respectively, P = 0.71) with 89.7% (35/39) of all cases classified as CMV disease. The median time to CMV viremia post transplant was day 141 and 138 in the IGF and DGF groups, respectively (P = 0.30). The incidence of biopsy-proven acute rejection (BPAR) was higher in the DGF group (18.1% vs 4.6%, P = 0.02) with BPAR preceding CMV in only 1 patient. There was no significant difference in graft loss (1.5% vs 4.2%, P = 0.62) or patient survival (98.5% vs 95.8%, P = 0.62) at 1 year between the IGF and DGF groups, respectively., Conclusion: Valganciclovir prophylaxis in patients experiencing DGF yielded similar CMV outcomes up to 1-year post transplant when compared to use in patients with IGF., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Panniculectomy can be performed as a prophylactic procedure preceding transplantation to enable obese patients to meet criteria for renal transplantation. No literature exists on combined renal transplant and panniculectomy surgery (LRT-PAN). We describe our 8-year experience performing LRT-PAN. A retrospective chart review of all patients who had undergone LRT-PAN from 2010 to 2018 was conducted. Data were collected on patient demographics, allograft survival and function, and postoperative course. Fifty-eight patients underwent LRT-PAN. All grafts survived, with acceptable function at 1 year. Median length of stay was 4 days with a mean operative duration of 363 minutes. The wound complication rate was 24%. Ninety-day readmission rate was 52%, with medical causes as the most common reason for readmission (45%), followed by wound (32%) and graft-related complications (23%). Body mass index, diabetes status, and previous immunosuppression did not influence wound complication rate or readmission (P = .7720, P = .0818, and P = .4830, respectively). Combining living donor renal transplant and panniculectomy using a multidisciplinary team may improve access to transplantation, particularly for the obese and postobese population. This combined approach yielded shorter-than-expected hospital stays and similar wound complication rates, and thus should be considered for patients in whom transplantation might otherwise be withheld on the basis of obesity., (© 2019 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background Given the complexity of solid organ transplant recipients, a multidisciplinary approach is required. To promote medication safety and enable providers to focus on the medical and surgical needs of these patients, our department of pharmacy created a collaborative practice agreement between physicians and pharmacists. Through this agreement, credentialed pharmacists are empowered to provide inpatient services including initiation and adjustment of medications through independent review of laboratory results after multidisciplinary rounds. Objective To evaluate the effect of our collaborative practice agreement on clinical care and institutional finances. Setting An inpatient setting at a large academic medical center. Methods Three transplant pharmacists entered all clinical interventions made on abdominal transplant recipients between September and October 2013 into Quantifi ® , a software application that categorizes and assigns a cost savings value based on impact and type of intervention. Main outcome measure The main outcome measures in this study were number and categorization of interventions, as well as estimated cost savings to the institution. Results There were 1060 interventions recorded, an average of 20 interventions per pharmacist per day. The most common interventions were pharmacokinetic evaluations (36%) and dose adjustments (19%). Over the time period, these interventions translated into an estimated savings of $107,634.00, or an annual cost savings of $373,131.20 per pharmacist, or a cost-benefit ratio of 2.65 to the institution. Conclusions Based on our study, implementation of a collaborative practice agreement enables credentialed pharmacists to make clinically and financially meaningful interventions in a complex patient population.