Targeting mitochondrial dysfunction with elamipretide.

Although currently employed therapies for heart failure decrease overall mortality and improve patient quality of life temporarily, the disease is known to progress even for patients who receive all guideline-recommended therapies. This indicates that our concise understanding of heart failure and of disease progression is incomplete, and there is a need for new interventions that may augment, or even supplant, currently available options. A literature review reveals that an exciting, novel area of current research is focused on mitochondria, which are uniquely juxtaposed at the sites of both generation of high-energy molecules and initiation of programmed cell death. Elamipretide is being studied both to maintain cellular biogenetics and prevent reactive oxygen species-induced cell damage by targeting and stabilizing the cardiolipin-cytochrome c supercomplex. Thus far, elamipretide has been shown to increase left ventricular ejection fraction in dog models of heart failure with reduced ejection fraction and to prevent left ventricular remodeling in rats. In early-phase clinical trials, elamipretide administration has not resulted in any severe adverse events, and it has shown promising improvements in cardiac hemodynamics at highest doses. Nonetheless, additional studies are necessary to describe the long-term safety and efficacy of elamipretide.

Angiotensin II: A Review of Current Literature.

Up to one-third of all patients admitted to intensive care units carry a diagnosis of shock. The use of angiotensin II is becoming widespread in all forms of shock, including cardiogenic, after the U.S. Food and Drug Administration's (FDA's) initial approval for vasoplegic shock in 2017. Here, the authors review the literature on angiotensin II's mechanism of action, benefits, and future therapeutic opportunities.

Andexanet Alfa (Andexxa®) for the Reversal of Direct Oral Anticoagulants.

Andexanet alfa (Andexxa®) for the reversal of direct oral anticoagulants.

Edoxaban: an investigational factor xa inhibitor.

Edoxaban: an investigational factor Xa inhibitor.

Implementing and evaluating a veterans crisis line quality improvement initiative: The safety planning pilot program.

The Veterans Crisis Line (VCL) is part of the U.S. Department of Veterans Affairs' suicide prevention mission. In 2021, VCL assessed the impact of a pilot implementation project of conducting six-part safety plans (SPs) instead of VCL's usual risk mitigation plan. VCL responders offered to complete six-part SPs with eligible callers. Parametric and nonparametric methods compared call characteristics and Veteran Health Administration (VHA) utilization of eligible callers, by SP completion. We forecasted the operational impact of VCL-wide implementation. 27.37% (N = 448/1,637) of calls to designated responders were eligible for SPs. Of those, 27.23% (N = 122/448) completed SPs. Common barriers were call interruptions and the veteran declining. Among veteran callers who use VHA, SP completers were more likely to accept clinical referrals and had more outpatient mental health appointments before and after their VCL call. Calls involving SPs had a call plus documentation time 175% longer than eligible calls without SPs (87.78 vs. 49.66 min). If SPs were implemented VCL-wide, this would require 3-5(4.12%) more responders per hour to maintain current VCL call answer speed. SPs are adaptable to VCL; however, implementation presents logistical barriers. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Suicide mortality and related behavior following calls to the Veterans Crisis Line by Veterans Health Administration patients.

OBJECTIVES: To assess outcomes for Veterans Health Administration (VHA) patients following calls to the Veterans Crisis Line (VCL). METHODS: 158,927 VHA patients had an initial VCL call in 2010-2015 with documented identifiers. Multivariable proportional hazards regressions assessed risks of suicide and suicide-related behavior through 12 months. Covariates included age, sex, region, mental health encounters in the prior year, time of day, weekday/weekend status, call outcome, and responder determination of caller risk. RESULTS: Annualized suicide rates per 100,000 within 1, 3, 6, and 12 months were 797, 520, 387, and 298, respectively. Average age was 49.9 (SD = 15.2), 86.5% were male, 68.6% received mental health encounters in the prior year, and 5.9% had calls categorized as at high risk. Adjusting for covariates, suicide risk was greater among male callers and those with calls categorized as at high or moderate risk. CONCLUSIONS: Veterans Crisis Line serves a high-risk population at a critical time. Rates were particularly high within one month and remained substantially elevated through 12 months. Findings have directly informed ongoing efforts to enhance coordination between VCL and VHA to support suicide prevention.

Design of an in vitro biocatalytic cascade for the manufacture of islatravir.

Enzyme-catalyzed reactions have begun to transform pharmaceutical manufacturing, offering levels of selectivity and tunability that can dramatically improve chemical synthesis. Combining enzymatic reactions into multistep biocatalytic cascades brings additional benefits. Cascades avoid the waste generated by purification of intermediates. They also allow reactions to be linked together to overcome an unfavorable equilibrium or avoid the accumulation of unstable or inhibitory intermediates. We report an in vitro biocatalytic cascade synthesis of the investigational HIV treatment islatravir. Five enzymes were engineered through directed evolution to act on non-natural substrates. These were combined with four auxiliary enzymes to construct islatravir from simple building blocks in a three-step biocatalytic cascade. The overall synthesis requires fewer than half the number of steps of the previously reported routes.

Design and Delivery of Clinical Pharmacokinetics in Colleges and Schools of Pharmacy.

Objective. To describe how clinical pharmacokinetics is being delivered across curricula in pharmacy programs, including the curricular position of clinical pharmacokinetic topics, topics currently taught, and instructional methods used in delivering the course content. Methods. A survey was distributed to one representative faculty member from each pharmacy college who was most able to answer questions about their institution's delivery of clinical pharmacokinetic material. Results. Responses were collected from 82 out of the 108 pharmacy colleges who participated in the study. Clinical pharmacokinetics was integrated within other courses through the curriculum in 41% of colleges and includes a substantial amount of math-based material. The most common instructional methods were lectures and practice with actual pharmacokinetic cases. The majority of the schools used examinations and quizzes to determine students' grades. Certain drugs remain popular (ie, aminoglycosides, vancomycin, digoxin) while others have fallen out of favor (ie, procainamide, phenytoin, theophylline). Various methods were used to deliver the material and assess student learning. Conclusion. The delivery of clinical pharmacokinetic material has changed in the recent past across pharmacy colleges in the United States. Spreading clinical pharmacokinetics throughout the curriculum while maintaining the math-centric nature of the material has occurred. Clinical pharmacokinetics is a changing field and these results can be used to compare an institution's current content and delivery methods with other institutions. These aggregate results may be useful for schools that are redesigning their curriculum or are considering doing so.

Medical resident choices of electronic drug information resources.

OBJECTIVE: To determine medical residents' day-to-day use of drug information resources since their choices of these resources, when faced with common questions, are unknown. METHODS: An online survey including simulated drug information questions was administered to 146 medical residents in the Department of General Internal Medicine during July 2012. Residents were given a wide range of choices in drug information resources to answer these questions and were instructed to select what they would choose in actual practice. A score was assigned to each resource corresponding to a "best," "intermediate," or "not good" choice. RESULTS: Seventy-three respondents completed the survey and results were analyzed for statistical significance. Fifty-seven percent of respondents reported receiving no formal training regarding drug information. Statistical analyses revealed there were no significant differences in performance based on postgraduate year (P = .43) or extent of prior training (P = .45). Individual question responses revealed a generally infrequent selection of "best" choices. Less than 10% of the respondents chose the "best" answer for drug information questions related to drug interactions, herbal supplements, adverse events, and medication identification. CONCLUSION: Further training in drug information resource selection is warranted in the medical residency program to increase the frequency of use of higher quality resources.

Modification of a pharmacokinetics course design to improve student performance.

OBJECTIVE: To determine if the addition of weekly quizzes or reducing the number of faculty members teaching improved third-year (P3) pharmacy students' final grades in a clinical pharmacokinetics course. DESIGN: Four sections of a pharmacokinetics and pharmacodynamics course were divided according to the number of faculty members teaching the course and the administration of weekly quizzes. Two sections were taught by 6 faculty members and 2 were taught by 3 faculty members. Also, 1 section in each group received weekly quizzes, creating a 2-by-2 design. ASSESSMENT: The performance of the 201 P3 students enrolled in the course was assessed by comparing the average of 3 examination grades while excluding quiz grades. The mean final grade of classes in which quizzes were not administered was lower than that for classes in which quizzes were administered (p=0.019). The mean final grade in classes taught by 3 faculty members vs 6 faculty members was higher, but not significantly. A positive significant correlation existed between performance in a prerequisite biopharmaceutics class and this advanced class. CONCLUSION: Making minor modifications to the delivery of a course, such as number of quizzes administered and number of faculty members teaching the course, had a positive impact on student performance. Grades in a prerequisite course may enable earlier identification of students at risk of poor performance in advanced courses.

Sustainable practices in medicinal chemistry: current state and future directions.

The medicinal chemistry subgroup of the American Chemical Society's Green Chemistry Institute Pharmaceutical Roundtable (ACS GCI PR) offers a perspective on the current state of environmentally sustainable practices in medicinal chemistry with the aim of sharing best practices more widely and highlighting some potential future developments.

The impact of pharmacist interventions on the inappropriate use of acid-suppression therapy.

OBJECTIVE: The inappropriate use of acid-suppression therapy (AST) in non-intensive care unit patients contributes to inappropriate polypharmacy, drug interactions, community- and hospital-acquired pneumonia, and increased health care expenditures for institutions and individuals. The purpose of this study was to determine whether clinical pharmacist interventions significantly decreased the rate of inappropriately used AST. DESIGN: A single group, pre-test post-test. SETTING: The Geriatric Evaluation and Management unit in the St. Louis Veterans Affairs Medical Center. PATIENTS: All patients admitted between July 1, 2006, through April 30, 2007 (control group), and May 1, 2007, through February 28, 2008 (PharmD group), were evaluated. All patients with a minimum length of stay of seven days were eligible for inclusion. Data were obtained from the Computerized Patient Record System regarding the use of proton-pump inhibitors, histamine-2 receptor antagonists, sucralfate, and the indication for these therapies. INTERVENTIONS: A clinical pharmacist was present during the weekly interdisciplinary team rounds to make recommendations in the intervention group, compared with a nonpharmacist control group. OUTCOME MEASURES: The percent of patients on these therapies without an appropriate indication (International Classification of Diseases, 9th Revision) were identified from the chart review, and comparisons were made between the control and PharmD groups. RESULTS: A total of 142 and 151 patients were admitted during the control and PharmD arms, respectively. Of these patients, 117 in each group were eligible for inclusion in the analysis. The primary outcome, the number of patients receiving AST prior to discharge without an appropriate indication, occurred 46.2% (54/117) versus 23.9% (28/117) (P = 0.001) in the control and PharmD groups, respectively. CONCLUSIONS: This study examined the impact of pharmacists' active participation in interdisciplinary team rounds compared with a nonpharmacist control group. These results demonstrate pharmacist participation associated with potential cost savings and improved patient care.

Effect of acetaminophen on international normalized ratio in patients receiving warfarin therapy.

Warfarin is known to have extensive interactions with many classes of drugs. The literature suggesting a relevant interaction between acetaminophen and warfarin is inconsistent. Considering the ubiquitous use of acetaminophen, a review of the effects on international normalized ratio (INR) in patients taking warfarin was necessary. Thus, we performed a search of the PubMed (1966-November 2010) and International Pharmaceutical Abstracts (1970-November 2010) databases to review the available literature addressing an acetaminophen-warfarin interaction and its possible mechanisms. A sample of case reports, in addition to all English-language studies were evaluated, and relevant references were examined for additional articles. Reports of nonwarfarin coumarin anticoagulants were excluded. Published documentation reporting an interaction between acetaminophen and warfarin is limited. Small prospective studies of various designs and case studies describe aberrant INR results in patients using acetaminophen while receiving warfarin. These INR elevations typically involved acetaminophen ingestion of at least 2 g/day for several consecutive days. In several small prospective studies, INR results were elevated to a statistically significant extent that would require a change in warfarin dosing and monitoring in clinical practice. The mechanism for this interaction remains to be elucidated yet is suggested to occur through alterations in hepatic metabolism. The use of moderate-to-high doses of acetaminophen while receiving warfarin results in supra-therapeutic INRs in some patients. The characteristics that may predispose a patient to this interaction are unclear, yet the widespread use of acetaminophen calls for enhanced clinician awareness and reinforcement of patient education about this interaction.

Biocatalytic asymmetric synthesis of chiral amines from ketones applied to sitagliptin manufacture.

Pharmaceutical synthesis can benefit greatly from the selectivity gains associated with enzymatic catalysis. Here, we report an efficient biocatalytic process to replace a recently implemented rhodium-catalyzed asymmetric enamine hydrogenation for the large-scale manufacture of the antidiabetic compound sitagliptin. Starting from an enzyme that had the catalytic machinery to perform the desired chemistry but lacked any activity toward the prositagliptin ketone, we applied a substrate walking, modeling, and mutation approach to create a transaminase with marginal activity for the synthesis of the chiral amine; this variant was then further engineered via directed evolution for practical application in a manufacturing setting. The resultant biocatalysts showed broad applicability toward the synthesis of chiral amines that previously were accessible only via resolution. This work underscores the maturation of biocatalysis to enable efficient, economical, and environmentally benign processes for the manufacture of pharmaceuticals.