Comparative simulation of intraperitoneal aminoglycoside regimens for patients with peritonitis on automated peritoneal dialysis.

BACKGROUND: Intraperitoneal (IP) aminoglycosides (AGs) continue to be the cornerstone of empiric management of peritonitis. AG dosing during automated peritoneal dialysis (APD), however, has not been well studied in patients with peritonitis. We sought to identify differences in AG exposure in the peritoneum and plasma for two different dosing regimens with little supporting evidence in patients on APD with peritonitis. METHODS: A retrospective design that utilised the peritoneal and plasma concentration-time data from a prior study of 18 continuous ambulatory peritoneal dialysis (CAPD) patients with peritonitis to generate an in silico peritoneal and plasma PK model. This model was then used to compare via simulation using Phoenix© WinNonlin Software with IP AG dosing for a loading-dose regimen (1.5 mg/kg first dose) versus a fixed-dose regimen (0.6 mg/kg/d) in patients on APD with peritonitis. RESULTS: Outcome measures were (1) percentage of time where peritoneal peak concentrations/minimal inhibitory concentration (MIC) ratio >10, (2) AUC/MIC > 74 and (3) plasma Cmin concentrations. Both regimens resulted in > 90% optimal peak/MIC ratio and AUC/MIC ratios on days 1 and 5 of the dose protocol. The loading-dose regimen resulted in IP exposures that were 2.5 times greater in the peritoneal compartment on day 1. By day 5, both protocols resulted in similar accumulation of AG plasma Cmin concentrations of 2.5-3.4 mg/L versus 2.4-3.3 mg/L, respectively, for the loading-dose regimen versus fixed-dose regimen. CONCLUSIONS: The current international guidelines for the treatment of peritoneal dialysis-associated peritonitis can continue to recommend the fixed-dose regimen for those on APD with the addition of plasma Cmin monitoring after 3 days to assess for drug accumulation.

Anticoagulation strategies in COVID-19 infected patients receiving ECMO support.

BACKGROUND: Hospitalized COVID-19 patients with hypoxemic respiratory failure may deteriorate despite invasive mechanical ventilation and thus require extracorporeal membrane oxygenation (ECMO) support. Unfractionated heparin (UFH) is the antithrombotic of choice, however, bivalirudin may offer more predictable pharmacokinetics resulting in consistent anticoagulant effects with lower bleeding and thrombotic occurrences. The aim of this study was to evaluate efficacy and safety outcomes in patients undergoing venovenous (VV) ECMO receiving bivalirudin or UFH-based anticoagulation. METHODS: This retrospective, single-center, observational cohort study included patients with confirmed COVID-19 infection requiring VV ECMO support receiving anticoagulation with UFH or bivalirudin. Primary endpoints were time to reach therapeutic aPTT, percent time spent in aPTT range, and the occurrence of thrombotic events over the entire course of ECMO support. Secondary endpoints included the incidence of major/minor bleeding, the ability to wean off ECMO support, in-hospital mortality, and length of stay. RESULTS: Twenty-two patients were included in the study (n = 10 UFH, n = 12 bivalirudin). Time to therapeutic aPTT was achieved faster with UFH (10 h vs. 20 h). The percentage time spent within the goal aPTT range was similar between UFH and bivalirudin (50% vs. 52%). Thrombotic events were significantly higher in the UFH group (40% DVT, 40% PE, 80% oxygenator thrombus in ECMO machine, 10% ischemic stroke) versus bivalirudin (8% DVT, 17% PE, 33% oxygenator thrombus, no ischemic strokes) (CI 95%, p = 0.04). The overall bleeding incidence was higher in the UFH arm (90% vs. 75%). The mortality rate was 90% in the UFH group and 58% in the bivalirudin group. The length of stay was similar between the two study arms. CONCLUSION: In hospitalized patients with COVID-19-associated acute respiratory distress syndrome (ARDS) on VV ECMO support, the use of bivalirudin showed to be a viable anticoagulation alternative in terms of efficacy compared to UFH and resulted in a favorable safety profile with lower rates of bleeding and thrombotic events.

Incidence of Venous Thromboembolism in Hospitalized COVID-19 Patients Receiving Thromboprophylaxis.

Background: The purpose of this study was to investigate the association between anticoagulant dosing intensity in coronavirus disease 2019 (COVID-19) infected patients and its outcomes on venous thromboembolism (VTE) and all-cause mortality. Methods: This is a retrospective observational study that examined different anticoagulation regimens among COVID-19 patients for prophylaxis of VTE. Primary outcomes of the study were VTE incidence and all-cause mortality for patients receiving prophylaxis-intensity (PPX) and therapeutic-intensity (TX) anticoagulation. Secondary outcomes were incidence of hemorrhagic events and hospital length of stay. Patients were matched (1:1) based on age and Charlson comorbidity score. Sub-group analyses evaluated outcomes within critically ill patients, between specific anticoagulant agents and comorbid conditions. Results: The primary outcome of VTE occurred in six patients within the prophylactic dose group and eight patients in the therapeutic-intensity dose group (risk ratio (RR): 2.02 (95% confidence interval (CI): 0.7 - 5.2); P = 0.2). Bleeding occurred in 15 (11%) patients in the prophylactic group and 27 (19%) patients in the therapeutic group (RR: 0.5 (95% CI: 0.3 - 1.0); P < 0.049). Hospital length of stay was shorter by 4 days in those treated with prophylactic-intensity anticoagulation (P = 0.003). Intensive care unit admission and ventilation were negatively correlated with mortality in a multivariate analysis. Conclusions: Among hospitalized COVID-19 patients, the use of therapeutic-intensity anticoagulation did not show any benefits in reducing the occurrence of VTE. An increase in mortality and in the incidence of hemorrhagic events was statistically significant in the therapeutic-intensity group. Future prospective studies are warranted to evaluate anticoagulation therapy in COVID-19 infected patients.

Identification of Inappropriate Antibiotic Orders During Implementation of a Multidisciplinary Antimicrobial Stewardship Program Within the Primary Care Setting.

OBJECTIVE: The aim of the study was to describe implementation of an outpatient antibiotic stewardship program at primary care practices in South Florida and the proportion of appropriate and inappropriate orders and reasons for inappropriateness during the intervention. METHODS: An antibiotic stewardship committee at a large hospital system implemented aspects of The Core Elements of Outpatient Antibiotic Stewardship at outpatient facilities in 2018. Interventions included an education/awareness campaign directed at prescribers (audit and feedback, routine education at prescribers' meetings, availability of updated guidelines in a shared drive and antibiogram via intranet) and patients (posters, tear-off sheets on symptom relief for viral illness). Orders were evaluated using clinical documentation, current antibiogram, and Infectious Diseases Society of America guidelines. An appropriate order was defined as a correct antibiotic and dose/frequency and duration of therapy. An inappropriate antibiotic order was defined as not meeting 1 or more of the abovementioned conditions. Descriptive statistics assessed the data. RESULTS: In this retrospective review of 2934 oral antibiotic orders from January 1 to December 31, 2018, 2565 (87.4%) were necessary while 369 (12.6%) were unnecessary. Of 2565 necessary orders, 1448 (56.5%) were appropriate while 1117 (43.5%) were inappropriate. Of 1117 inappropriate orders, 24.9% had all 3 conditions; 41.5% of inappropriate orders were solely due to wrong duration of therapy. CONCLUSIONS: Although our institution demonstrated commitment to optimizing antibiotic prescribing by providing resources to clinicians and patients about evidence-based antibiotic prescribing, inappropriate antibiotic prescribing was persistent. The interventions used must continue to evolve and include point-of-care access to guidelines and clinical decision support tools.

impact of a Pharmacy-Led Transitions of Care Program Within a Primary Care-Based Accountable Care Organization.

OBJECTIVE: To assess the impact of pharmacist-led transitions of care program on 30-day readmission rates in the accountable care organization (ACO) primary care setting. DESIGN: Retrospective cohort study. SETTING: Two primary care provider (PCP) offices with an ACO in South Florida. PATIENTS, PARTICIPANTS: Adult Medicare patients who completed a post-discharge follow-up visit at two primary care offices within an ACO from July to December 2017. INTERVENTIONS: To supplement postdischarge visits with a PCP, the pharmacy services were also provided two days per week with a PCP. The comparator groups were patients who only saw a PCP or those who saw a PCP and pharmacist. MAIN OUTCOME MEASUREMENTS: The primary outcome was hospital readmission or emergency department visit within 30 days. RESULTS: A total of 190 subjects were included. There were 113 patients in the PCP group and 77 patients in the PCP/pharmacist group. There was a reduction in the primary outcome when comparing the PCP-only versus PCP/pharmacist groups (6.2% versus 3.9%; P = 0.74). CONCLUSION: Involving pharmacists in patient transitions of care in the primary care setting may be beneficial as previous studies have demonstrated. Further studies evaluating pharmacy services in emerging health care models are needed in order to most effectively utilize the expertise of the pharmacy team.

Impact of pharmacy-supported interventions on proportion of patients receiving non-indicated acid suppressive therapy upon discharge: A systematic review and meta-analysis.

OBJECTIVE: Conduct a systematic review and meta-analysis to estimate the impact of pharmacy-supported interventions on the proportion of patients discharged from the hospital on inappropriate acid suppressive therapy (AST). METHODS: To identify studies, the following databases were systematically searched on October 14th, 2018 and repeated on September 12th, 2019: Ovid MEDLINE(R) and In-Process & Other Non-Indexed Citations and Daily, Embase.com, CINAHL, Web of Science, Cochrane CENTRAL (EBSCO), and ClinicalTrials.gov. Eligible studies consisted of adults, intervention and historical/usual care groups, description of active pharmacy-supported intervention, and proportion of patients discharged on inappropriate AST. Qualitative assessments and quantitative analyses were performed. Modified funnel plot analysis assessed heterogeneity. Preferred reporting items of systematic reviews and meta-analyses (PRISMA) methodology was used to evaluate studies in this review. RESULTS: Seventeen publications resulting in 16 studies were included in the review. Using random effects model, meta-analysis showed a significant reduction in the odds of being discharged on inappropriate AST from the hospital in the pharmacist-supported intervention arm versus comparator (Odds Ratio 0.33 [95%CI 0.20 to 0.53]), with significant heterogeneity (I2 = 86%). Eleven studies favored pharmacy-supported interventions, four were inconclusive and one favored usual care. Using modified funnel plot analysis, our final evaluation was distilled to 11 studies and revealed a similar outcome (OR 0.36 [95%CI 0.27 to 0.48]), but with less heterogeneity (I2 = 36%). CONCLUSION: This systematic review and meta-analysis showed that pharmacy-supported interventions were associated with a significantly reduced probability of patients discharged on inappropriate AST. However, heterogeneity was high and may affect interpretation of results. Using funnel plot optimization method, three positive and two negative studies were objectively removed from analyses, resulting in a similar effect size, but with less heterogeneity. To improve study quality, future researchers should consider utilizing a pre-post, multi-arm, prospective design with sampling randomization, training of data extractors (preferably two extractors), re-evaluating a small dataset to check for agreement and providing a comprehensive methodology in subsequent publications.

Impact of pharmacist-led heart failure tool kits on patient-reported self-care behaviors in a primary care-based accountable care organization.

OBJECTIVE: The goal of this project is to evaluate the impact of a pharmacist-led heart failure (HF) intervention, using an educational toolkit, on patient-reported self-care maintenance, management, and confidence at 30 days. SETTING: Three Accountable Care Organization (ACO) primary care provider offices in South Florida from January to March 2018. PRACTICE DESCRIPTION: Each primary care clinic was staffed with at least 1 physician, nurse practitioners, a clinical pharmacy faculty member, pharmacy residents and students, and ancillary staff. Pharmacists spent approximately 2 days per week in clinic. PRACTICE INNOVATION: At the time of this project, no formalized management program for HF patients existed within the clinics. An educational toolkit was designed, reviewed, and approved by the team of pharmacists and ACO providers before use within the clinics, and included educational material outlining common causes of HF exacerbation, symptoms of HF, symptom management strategies, medication action plan, self-management instructions, medication adherence tips, and a weight-management log sheet. EVALUATION: A prospective, pretest and posttest observational project was conducted at the 3 clinical sites for eligible patients. The Self-Care for Heart Failure Index (SCHFI, v.6.2) tool was used to evaluate self-care practices and adequacy of maintenance, management, and confidence at baseline as compared with 30 days. RESULTS: Twelve participants completed the initial interview and 30-day follow-up. SCHFI scores for self-maintenance (63-68, P = 0.04) and self-management (38-58, P = 0.01) significantly improved from baseline, whereas self-confidence scores showed an increase, but was not statistically significant (80-82, P = 0.58). All self-care behaviors saw a nonstatistically significant improvement in percentage of patients achieving adequacy. CONCLUSION: Pharmacists and educational toolkits in the ACO primary care setting may improve self-maintenance, self-management, and self-confidence behaviors in patients with HF.

Minimal Physiologically Based Pharmacokinetic Model of Intravenously and Orally Administered Delta-9-Tetrahydrocannabinol in Healthy Volunteers.

BACKGROUND AND OBJECTIVES: Lack of information on the pharmacokinetics of the active moiety of Cannabis or the metabolites of delta-9-tetrahydrocannabinol (THC) does not seem to be discouraging medical or recreational use. Cytochrome P450 (CYP) 2C9, the primary enzyme responsible for THC metabolism, has two single nucleotide polymorphisms-Arg144Cys (*2) and Ile359Leu (*3). In the Caucasian population, allelic frequency is between 0.08 and 0.14 for CYP2C9*2 and between 0.04 and 0.16 for CYP2C9*3. In vitro data suggest that metabolic capacity for the variants CYP2C9*2 and CYP2C9*3 is about one-third compared to wild-type CYP2C9. Previous work has suggested exposure to the terminal metabolite is genetically determined. We therefore sought to characterize the pharmacokinetics of THC and its major metabolites 11-hydroxy-delta-9-tetrahydrocannabinol (THC-OH) and 11-nor-9-carboxy-delta-9-tetrahydrocannabinol (THC-COOH) in healthy volunteers with known CYP2C9 status by non-compartmental analysis (NCA), compartmental modeling (CM) and minimal physiologically based pharmacokinetic (mPBPK) modeling. METHODS: Blood samples drawn for THC, THC-OH and THC-COOH after a single intravenous (IV) bolus of 0.1 mg/kg (0.32 µM/kg) THC were analyzed using a validated LC-MS/MS method. NCA generated initial estimates and CM and the mPBPK model were then fit to plasma concentration data using non-linear mixed-effects modeling. Blood samples from orally dosed (10, 25 and 50 mg) THC brownies were added to validate the model. RESULTS: THC can be described as a high hepatic extraction ratio drug with blood flow-dependent metabolism not restricted by protein binding. THC hepatic clearance is dependent on the CYP2C9 genetic variant in the population. High extraction drugs display route-dependent metabolism. When administered via the IV or inhalation routes, induction or inhibition of CYP2C9 should be non-contributory as the elimination of THC is dependent only on liver blood flow. THC-OH is also a high extraction ratio drug, but its hepatic clearance is significantly impacted by the hepatic diffusional barrier that impedes its access to hepatic CYP2C9. THC-COOH is glucuronidated and renally cleared; subjects homozygous for CYP2C9*3 have reduced exposure to this metabolite as a result of the polymorphism reducing THC production, the hepatic diffusional barrier impeding egress from the hepatocyte, and increased renal clearance. CONCLUSION: It has recently been reported that the terminal metabolite THC-COOH is active, implying the exposure difference in individuals homozygous for CYP2C9*3 may become therapeutically relevant. Defining the metabolism of THC in humans is important, as it is increasingly being used as a drug to treat various diseases and its recreational use is also rising. We have used NCA, CM, and mPBPK modeling of THC and its metabolites to partially disentangle the complexity of cannabis disposition in humans.

Incidence of Acute Kidney Injury in Intermittent Versus Continuous Infusion of Polymyxin B in Hospitalized Patients.

Background: Studies evaluating the risk of developing acute kidney injury (AKI) with different dosing strategies of polymyxin B are limited. Objectives: To compare the incidence of AKI in patients treated with intermittent versus continuous polymyxin B therapy. Secondary objectives included time to onset of AKI, hospital length of stay (LOS), and all-cause hospital mortality. Variables associated with an increased risk of AKI were evaluated. Methods: A retrospective record review was conducted at a single center in Puerto Rico. Adult patients (≥18 years old) treated with polymyxin B (first course) for at least 48 hours from 2013-2015 were evaluated. Patients with a creatinine clearance <10 mL/min and/or on renal replacement were excluded. Results: A total of 69 patients were included: 42 in the continuous infusion and 27 in the intermittent dosing group. Incidence of AKI was not significantly different between the groups (intermittent 41% vs continuous 31%, P = 0.4). No difference was found in the onset of nephrotoxicity, hospital LOS, or all-cause hospital mortality. Variables associated with increased risk of AKI were baseline serum creatinine, age, and intensive care unit admission. Patients with a body mass index (BMI) >25 kg/m2 on polymyxin B via continuous infusion had a significantly higher cumulative incidence of AKI (P = 0.016). Conclusion and Relevance: No difference in the risk of polymyxin B nephrotoxicity was found between intermittent and continuous infusion administration. Administration of polymyxin B via a continuous infusion may result in a higher risk of AKI in patients with a BMI >25 kg/m2.

Allocation of faculty and curricular time to the teaching of transitions of care concepts by colleges of pharmacy.

INTRODUCTION: To determine the allocation of faculty and curricular time to the teaching of transitions of care (ToC) concepts by colleges of pharmacy (COPs) to equip students with the necessary skills for the provision of these services. METHODS: A novel 15-question anonymous electronic survey was sent to 136 pharmacy practice chairpersons. RESULTS: Response rate was 26.5% (n = 36). Of these, 47% employed ToC faculty while 44% are not actively recruiting for that position in the foreseeable future. Median total curriculum hours dedicated to teaching ToC was four (interquartile range two to 10 hours). Medication reconciliation skills were taught didactically and via interactive lab sessions by 53% of respondents. Only 11% offered an interdisciplinary ToC program. A significant association between not having ToC faculty and lack of implementation of ToC concepts within a pharmacy curriculum (p = 0.02, Fisher's Exact) and practice site (p = 0.045, Pearson's) was observed. Barriers to adopting ToC within the curriculum (e.g., uncertainty of placement within curriculum, resistance by faculty and administrators) and at a practice site (e.g., inadequate infrastructure to accommodate ToC delivery, ToC faculty unavailability and resistance by other health care providers) were reported. DISCUSSION AND CONCLUSIONS: This study demonstrated that COPs devote curricular time to ToC activities and involve dedicated faculty in the provision of these services. Several barriers to employing ToC faculty and planning additional time in the curriculum for teaching these skills were identified. Future research should determine the best methods for training students to ensure competence in performing ToC tasks.

Difficulty and discrimination indices of multiple-choice examination items in a college of pharmacy therapeutics and pathophysiology course sequence.

OBJECTIVE: The purpose of this study was to identify differences in difficulty and discrimination among multiple-choice examination items with regard to format and content in pharmacy therapeutics and pathophysiology (TP) courses. METHODS: Items from a TP course sequence were categorized by format and content by a faculty committee using the Delphi technique. Difficulty was not normally distributed; therefore, a logit transformation was employed. Difficulty and discrimination were analysed using one-way analysis of variance, with post hoc Bonferroni correction for pairs, to detect differences. KEY FINDINGS: A total of 516 items were included, with approximately 233 students answering each item. Case-based items were statistically more difficult than Standard (P=0.0007) or Statement items (P=0.001) and more discriminatory than Standard items (P=0.015). Dosing items were more difficult (P=0.013) and discriminating (P=0.02) than therapeutics items. CONCLUSIONS: Case-based items appear to have been more difficult than other items and may provide greater discrimination than Standard items.

Improvement in surrogate endpoints by a multidisciplinary team in a mobile clinic serving a low-income, immigrant minority population in South Florida.

To determine effect on surrogate endpoints for cardiovascular disease (CVD), we performed a retrospective chart review of 114 patients seen by a multidisciplinary team that provided primary care services in a mobile clinic over 12 months. Eligible patients had outcomes available for at least six months. Mixed effect modeling examined variation in surrogate markers for CVD: blood pressure (BP), heart rate, and body mass index. Repeated measures ANOVA compared lipids, hemoglobin A1c, and medication use from baseline and throughout study. Most patients were female (75%), Haitian (76%), and low-income ($747/month) with average age 63 years. Common diagnoses were hypertension (82%) and hyperlipidemia (63%). Significant reduction in systolic BP, total- and LDL-cholesterol, and hemoglobin A1c were found (p<.05). Use of ACE-inhibitors, beta-blockers, diuretics, aspirin, metformin, and statins increased significantly (p<.05). Mobile clinic with a multidisciplinary team improved surrogate endpoints over 12 months in underserved, low-income, mostly foreign-born, Haitian population in U.S.

External validation of aminoglycoside models used in web calculators and clinical decision support systems after laboratory conversion to serum creatinine isotope dilution mass spectrometry assay.

BACKGROUND: Models to predict gentamicin t(½) from serum creatinine (SCr) estimated creatinine clearance (CrCl) are currently being incorporated into smart-device applications and clinical decision support modules without external validation. OBJECTIVE: The aim of this study was to determine whether such models remain viable after conversion to isotope dilution mass spectrometry (IDMS) SCr assay. METHODS: This study analyzed data from retrospective reviews of the medical records of nonobese adults receiving the aminoglycoside gentamicin and having ≥2 evaluable serum gentamicin concentrations after laboratory IDMS SCr conversion, from January 2008 to August 2009, at a tertiary care hospital in Florida. A literature search found a number of cited aminoglycoside models. This group of models was classified as group 1. The World Wide Web was also searched for the term aminoglycoside dosing calculators, with 6 models found and referred to as group 2. Predictive performance measures were used to compare the model results with the t(½) calculated from gentamicin concentrations using the Nelder-Mead algorithm. RESULTS: The records of 39 patients met the inclusion criteria (23 men, 16 women; age range, 18-86 years; range of estimated CrCl, 55-115 mL/min) and provided the "gold standard" aminoglycoside t(½). A gentamicin t(½) was predicted from several published models (group 1) and from other models used in online smart-device applications (group 2) and clinical decision modules. The median (interquartile range) root mean square errors were 0.48 (0.44 to 0.65) and 0.48 (0.45 to 0.70) hours from group-1 and -2 models, respectively. The median mean relative prediction errors were 9% (-14% to +13%) and 11% (+1% to +21%) from groups 1 and 2. The median mean absolute prediction errors were 21% (19% to 28%) and 21% (20% to 30%) from groups 1 and 2. Adjusting SCr by +20% improved the predictive ability in 3 of 12 cited models and in 5 of 6 models used in applications. CONCLUSIONS: Models to predict gentamicin t(½) should be externally validated at one's institution before use. The findings from the present study provide a framework for conducting external validation.

Incidence and predictors of nephrotoxicity associated with intravenous colistin in overweight and obese patients.

Intravenous colistin is used to treat resistant Gram-negative infections and is associated with nephrotoxicity. In overweight and obese adults, a paucity of data exists regarding the incidence and predictors of such toxicity. A retrospective nested case-control study was performed over 35 months for patients receiving intravenous colistin for ≥ 72 h with a body mass index (BMI) of ≥ 25 kg/m(2). The objective was to investigate the incidence and predictors of nephrotoxicity. Severity of acute kidney injury was defined by RIFLE (risk, injury, failure, loss, and end-stage kidney disease) criteria. Dosing and mortality were secondarily investigated. Forty-two patients met the inclusion criteria, and 20 (48%) developed nephrotoxicity. Patients with toxicity were in the risk (15%), injury (5%), and failure (80%) categories based on RIFLE criteria. A logistic regression model identified four predictors of colistin-associated nephrotoxicity: a BMI of ≥ 31.5 kg/m(2) (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.15 to 8.35), diabetes (OR, 2.11; 95% CI, 0.84 to 5.29), the length of hospitalization in days prior to receipt of colistin (OR, 1.04; 95% CI, 0.99 to 1.08), and age (OR, 1.08; 95% CI, 1.00 to 1.17). Among all of the patients, dosing based on the actual body weight and excessive dosing due to the use of the actual body weight were frequent at 64% and 92%, respectively. The 30-day all-cause in-hospital mortality rate was 40% in the toxicity group and 14% in the nontoxicity group (P = 0.14). Patients receiving intravenous colistin should be monitored for nephrotoxicity, especially when the BMI exceeds 31.5 kg/m(2). Prospective, randomized, controlled trials are warranted to further examine nephrotoxicity incidence and predictors and appropriate dosing strategies in this population.

The impact of student-faculty ratio on pharmacy faculty scholarship.

OBJECTIVE: To determine the relationship and impact of student-faculty ratio on scholarship of pharmacy faculty members. METHODS: The number and rank of faculty members, pharmacy program characteristics, and faculty productivity data were collected to determine the impact of student-faculty ratio on faculty scholarship. RESULTS: Faculty scholarship was not predicted by student-faculty ratio. Factors impacting positively on faculty productivity included National Institutes of Health funding; presence of clinical associate professors, instructors, and lecturers; and programs located in public universities. CONCLUSIONS: Faculty productivity is not related to the student-faculty ratio, wherein more faculty members and fewer students equates to increased scholarship. However, public universities may have different infrastructures which are associated with greater academic productivity compared to private institutions. Additionally, utilizing instructors and clinical or nontenure-track faculty members can significantly increase scholarship among faculty members.

Simvastatin-ezetimibe-induced hepatic failure necessitating liver transplantation.

Abstract Serum aminotransferase elevations are a commonly known adverse effect of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (statin) therapy. However, hepatotoxic events have not been widely published with ezetimibe or the combination agent simvastatin-ezetimibe. We describe a 70-year-old Hispanic woman who developed fulminant hepatic failure necessitating liver transplantation 10 weeks after conversion from simvastatin 40 mg/day to simvastatin 10 mg-ezetimibe 40 mg/day. The patient's lipid panel had been maintained with simvastatin for 18 months before the conversion without evidence of hepatotoxicity. A routine laboratory work-up 10 weeks after conversion revealed elevated serum aminotransferase levels. Simvastatinezetimibe and escitalopram (which she was taking for depression) were discontinued, and other potential causes of hepatotoxicity were excluded. A repeat work-up revealed further elevations in aminotransferase levels, and liver biopsy revealed evidence of moderate-to-severe drug toxicity. She underwent liver transplantation with an uneventful postoperative course. Her aminotransferase levels returned to normal by postoperative day 23, and her 2-year follow-up showed no adverse events. Ezetimibe undergoes extensive glucuronidation by uridine diphosphate glucoronosyltransferases (UGT) in the intestine and liver and may have inhibited the glucuronidation of simvastatin hydroxy acid, resulting in increased simvastatin exposure and subsequent hepatotoxicity. To our knowledge, this is the first case report of simvastatin-ezetimibe-induced liver failure that resulted in liver transplantation. We postulate that the mechanism of the simvastatinezetimibe-induced hepatotoxicity is the increased simvastatin exposure by ezetimibe inhibition of UGT enzymes. Clinicians should be aware of potential hepatotoxicity with simvastatin-ezetimibe especially in elderly patients and should carefully monitor serum aminotransferase levels when starting therapy and titrating the dosage.

Solifenacin succinate for the treatment of symptoms of overactive bladder.

BACKGROUND: Overactivity of the bladder detrusor muscle can result in urinary urgency, frequency, and incontinence. Antimuscarinic agents are the treatment of choice, as they reduce the contractility of this muscle. Solifenacin succinate (SOL) is a competitive muscarinic-receptor antagonist approved by the US Food and Drug Administration in late 2004 for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. OBJECTIVE: This article reviews the current primary literature concerning the pharmacokinetics, efficacy, and tolerability of SOL in the treatment of OAB. METHODS: Pertinent English-language articles were identified through a search of MEDLINE (1966-week 4, 2006), EMBASE (1991-first quarter of 2006), Current Contents/Clinical Medicine (week 10, 2005-week 9, 2006), the Cochrane Database of Systematic Reviews, MICROMEDEX Healthcare Series, and International Pharmaceutical Abstracts (1970-present). The search terms were overactive bladder, urinary incontinence, solifenacin, YM905, pharmacokinetics, and cost. RESULTS: SOL is highly lipophilic (50:1 octanol:water distribution at pH 7.0), completely orally bioavailable, and 98% protein bound. It is metabolized by the cytochrome P450 3A isozyme, and approximately 50% of a dose is eliminated renally as parent compound, with 1 active and 3 inactive metabolites. In two 12-week Phase III studies, patients receiving SOL 5 or 10 mg had significant reductions compared with placebo in the numbers of voids (P < or = 0.01), incontinence episodes (P < or = 0.05), and urgency episodes (P < or = 0.01) per 24 hours; the volume voided per micturition was significantly increased (P < or = 0.01). In a study that compared SOL 5 and 10 mg with tolterodine extended release 4 mg, both agents were associated with significant reductions in the number of voids per 24 hours (-2.45 and -2.24 episodes, respectively; P = 0.004 for noninferiority). In a study of pooled data from two 12-week studies, patients who received SOL 5 or 10 mg reported significant improvements in a number of quality-of-life domains (P < or = 0.05). In a pooled analysis of 4 studies, the most common adverse effects (occurring in > or =3% of any group) in patients receiving SOL 5 mg (n = 266) and 10 mg (n = 612) were dry mouth (10.9% and 27.1%, respectively), constipation (5.3% and 12.9%), and blurred vision (4.5% and 4.7%). CONCLUSIONS: In the studies reviewed, SOL was effective in the treatment of OAB with urge incontinence. Adverse effects included dry mouth, constipation, and blurred vision. Further studies are needed to determine the efficacy and tolerability of SOL in patients with hepatic or renal impairment.