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BACKGROUND: Drug-induced QT prolongation (diLQT) is a feared side effect that could expose susceptible individuals to fatal arrhythmias. The occurrence of diLQT is primarily attributed to unintended drug interactions with cardiac ion channels, notably the hERG (human ether-a-go-go-related gene) channels that generate the delayed-rectifier potassium current (IKr) and thereby regulate the late repolarization phase. There is an important interindividual susceptibility to develop diLQT, which is of unknown origin but can be reproduced in patient-specific induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs). We aimed to investigate the dynamics of hERG channels in response to sotalol and to identify regulators of the susceptibility to developing diLQT. METHODS: We measured electrophysiological activity and cellular distribution of hERG channels after hERG blocker treatment in iPS-CMs derived from patients with highest sensitivity (HS) or lowest sensitivity (LS) to sotalol administration in vivo (ie, on the basis of the measure of the maximal change in QT interval 3 hours after administration). Specific small interfering RNAs and CAVIN1-T2A-GFP adenovirus were used to manipulate CAVIN1 expression. RESULTS: Whereas HS and LS iPS-CMs showed similar electrophysiological characteristics at baseline, the late repolarization phase was prolonged and IKr significantly decreased after exposure of HS iPS-CMs to low sotalol concentrations. IKr reduction was caused by a rapid translocation of hERG channel from the membrane to the cytoskeleton-associated fractions upon sotalol application. CAVIN1, essential for caveolae biogenesis, was 2× more highly expressed in HS iPS-CMs, and its knockdown by small interfering RNA reduced their sensitivity to sotalol. CAVIN1 overexpression in LS iPS-CMs using adenovirus showed reciprocal effects. We found that treatment with sotalol promoted translocation of the hERG channel from the plasma membrane to the cytoskeleton fractions in a process dependent on CAVIN1 (caveolae associated protein 1) expression. CAVIN1 silencing reduced the number of caveolae at the membrane and abrogated the translocation of hERG channel in sotalol-treated HS iPS-CMs. CAVIN1 also controlled cardiomyocyte responses to other hERG blockers, such as E4031, vandetanib, and clarithromycin. CONCLUSIONS: Our study identifies unbridled turnover of the potassium channel hERG as a mechanism supporting the interindividual susceptibility underlying diLQT development and demonstrates how this phenomenon is finely tuned by CAVIN1. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to summarize and meta-analyze existing evidence regarding the influence of CYP1A2 genotypes on the acute effects of caffeine for exercise performance and to investigate the interaction between genotype, dosage, and timing of caffeine supplementation. Methods: Six databases were searched for studies determining the effect of caffeine (except mouth rinsing) on exercise performance between CYP1A2 genotypes. Three-level meta-analyses were performed using standardized mean differences (SMD; Hedge's g) to determine the effect of caffeine on exercise outcomes within and between CYP1A2 genotypes (AA, AC, and CC). Meta-regressions were performed for dose, timing, and presence of reported conflict of interests (RCOI). A meta-analysis was also performed with placebo values to assess for imbalances between genotypes. Results: Thirteen studies, totaling 119 outcomes and 440 participants, were included (233 AA, 175 AC, ad 34 CC). Caffeine improved performance for AA (SMD = 0.30, 95% confidence interval [CI] = 0.21–0.39, P < 0.0001) and AC (SMD = 0.16, 95% CI = 0.06–0.25, P = 0.022) but worsened performance for CC (SMD = −0.22, 95% CI = −0.44 to −0.01, P < 0.0001). Dose affected only CC, with greater doses generating more positive SMD (CC–dose estimate: +0.19/1 mg·kg−1 body mass, 95% CI = 0.04–0.33, P = 0.01). Timing influenced only CC, with better performance with later onset of exercise after supplementation (CC–timing estimate: +0.01/min, 95% CI = 0.00–0.02, P = 0.02). RCOI only affected SMD of CC (CC–RCOI estimate: −0.57, 95% CI = −1.02 to −0.12, P = 0.01). After excluding studies with RCOI, no influence of genotype was seen (all P ≥ 0.19). Small, nonsignificant differences were seen in placebo between genotypes (SMD AA vs CC: −0.13; AA vs AC: −0.12; AC vs CC: −0.05; all P ≥ 0.26). Conclusions: Caffeine improved performance for AA and AC but worsened performance for CC. Dose and timing moderated the efficacy of caffeine for CC only. Caution is advised because baseline differences and studies with RCOI could have influenced these results. [ABSTRACT FROM AUTHOR]

Background Pharmacogenomics is an emerging and affordable tool that may improve postoperative pain control. One challenge to successful pain control is the large interindividual variability among analgesics in their efficacy and adverse drug events. Whether preoperative pharmacogenomic testing is worthwhile for patients undergoing TKA is unclear. Questions/purposes (1) Are the results of preoperative pharmacogenetic testing associated with lower postoperative pain scores as measured by the Overall Benefit of Analgesic Score (OBAS)? (2) Do the results of preoperative pharmacogenomic testing lead to less total opioids given? (3) Do the results of preoperative pharmacogenomic testing lead to changes in opioid prescribing patterns? Methods Participants of this randomized trial were enrolled from September 2018 through December 2021 if they were aged 18 to 80 years and were undergoing primary TKA under general anesthesia. Patients were excluded if they had chronic kidney disease, a history of chronic pain or narcotic use before surgery, or if they were undergoing robotic surgery. Preoperatively, patients completed pharmacogenomic testing (RightMed, OneOME) and a questionnaire and were randomly assigned to the experimental group or control group. Of 99 patients screened, 23 were excluded, one before randomization; 11 allocated patients in each group did not receive their allocated interventions for reasons such as surgery canceled, patients ultimately undergoing spinal anesthesia, and change in surgery plan. Another four patients in each group were excluded from the analysis because they were missing an OBAS report. This left 30 patients for analysis in the control group and 38 patients in the experimental group. The control and experimental groups were similar in age, gender, and race. Pharmacogenomic test results for patients in the experimental group were reviewed before surgery by a pharmacist, who recommended perioperative medications to the clinical team. A pharmacist also assessed for clinically relevant drug-gene interactions and recommended drug and dose selection according to guidelines from the Clinical Pharmacogenomics Implementation Consortium for each patient enrolled in the study. Patients were unaware of their pharmacogenomic results. Pharmacogenomic test results for patients in the control group were not reviewed before surgery; instead, standard perioperative medications were administered in adherence to our institutional care pathways. The OBAS (maximum 28 points) was the primary outcome measure, recorded 24 hours postoperatively. A two-sample t-test was used to compare the mean OBAS between groups. Secondary measures were the mean 24-hour pain score, total morphine milligram equivalent, and frequency of opioid use. Postoperatively, patients were assessed for pain with a VAS (range 0 to 10). Opioid use was recorded preoperatively, intraoperatively, in the postanesthesia care unit, and 24 hours after discharge from the postanesthesia care unit. Changes in perioperative opioid use based on pharmacogenomic testing were recorded, as were changes in prescription patterns for postoperative pain control. Preoperative characteristics were also compared between patients with and without various phenotypes ascertained from pharmacogenomic test results. Results The mean OBAS did not differ between groups (mean 6 SD 4.7 6 3.7 in the control group versus 4.2 6 2.8 in the experimental group, mean difference 0.5 [95% CI -1.1 to 2.1]; p = 0.55). Total opioids given did not differ between groups or at any single perioperative timepoint (preoperative, intraoperative, or postoperative). We found no difference in opioid prescribing pattern. After adjusting for multiple comparisons, no difference was observed between the treatment and control groups in tramadol use (41% versus 71%, proportion difference 0.29 [95% CI 0.05 to 0.53]; nominal p = 0.02; adjusted p > 0.99). Conclusion Routine use of pharmacogenomic testing for patients undergoing TKA did not lead to better pain control or decreased opioid consumption. Future studies might focus on at-risk populations, such as patients with chronic pain or those undergoing complex, painful surgical procedures, to test whether pharmacogenomic results might be beneficial in certain circumstances. Level of Evidence Level I, therapeutic study. [ABSTRACT FROM AUTHOR]

The article focuses on the potential health benefits of anise (Pimpinella anisum L.) and its essential oil. Topics discussed include its traditional uses for relief of coughs, respiratory congestion, migraines, gastrointestinal distress, and colic; treatment of skin infections; as a tranquilizer and aphrodisiac; and its antioxidant, anti-inflammatory, and antimicrobial properties.

Direct oral anticoagulants (DOACs) are effective for both prevention and treatment of venous thromboembolism (VTE) and have favorable safety in comparison with warfarin. Although drug-drug interactions with DOACs are not as frequent as with warfarin, certain drugs can interfere with DOAC metabolism, affect DOAC efficacy, and potentially cause adverse reactions when used in combination with DOACs. The NP must determine which agent is most beneficial for the individual patient with VTE based on a number of factors. A knowledge of periprocedural management of DOACs will assist the NP in providing a smooth transition for patients undergoing minor and major procedures and surgeries. [ABSTRACT FROM AUTHOR]

The world's healthcare systems were forced to evaluate evolving evidence regarding the COVID-19 pandemic quickly. The technology used to improve patient outcomes and survival is rapidly evolving along with the virus. This article discusses new therapies developed to treat and prevent COVID-19 in qualifying patients. This article discusses new therapies developed to treat and prevent COVID-19 in qualifying patients. [ABSTRACT FROM AUTHOR]

HIV continues to affect certain populations disproportionately, including sexual and gender minorities, racial/ethnic minorities, and populations with limited resources in southern US states. New CDC guidelines include a recommendation to discuss HIV preexposure prophylaxis (PrEP) with all sexually active patients, which is likely to expand use. The guidelines also include important changes in PrEP monitoring and address PrEP telehealth. The FDA approved the first non-oral PrEP, long-acting injectable cabotegravir, in late 2021. However, PrEP continues to be underused. This article describes how to better employ PrEP in light of these recent significant changes. [ABSTRACT FROM AUTHOR]

Complementary and alternative medicines (CAM) are commonly used across the world by diverse populations and ethnicities but remain largely unregulated. Although many CAM agents are purported to be efficacious and safe by the public, clinical evidence supporting the use of CAM in heart failure remains limited and controversial. Furthermore, health care professionals rarely inquire or document use of CAM as part of the medical record, and patients infrequently disclose their use without further prompting. The goal of this scientific statement is to summarize published efficacy and safety data for CAM and adjunctive interventional wellness approaches in heart failure. Furthermore, other important considerations such as adverse effects and drug interactions that could influence the safety of patients with heart failure are reviewed and discussed. [ABSTRACT FROM AUTHOR]

Abstract: Response to analgesic therapy is influenced by several factors including genetics and drug-drug interactions. Pharmacogenetic (PGx) variants in the CYP2D6 gene modify response to opioids by altering drug metabolism. We sought to determine the potential impact of PGx testing on the care of Veterans with noncancer pain prescribed opioids metabolized by CYP2D6 (codeine, hydrocodone, or tramadol). A retrospective analysis was performed within the Veterans Health Administration evaluating prescription records for pain medications metabolized by CYP2D6 and interacting drugs from 2012 to 2017. Among 2,436,654 Veterans Health Administration pharmacy users with at least 1 opioid prescription, 34% met the definition of chronic use (longer than 90 days with more than 10 prescriptions or 120 days-supply). Opioids were commonly coprescribed with antidepressants interacting with CYP2D6 (28%). An estimated 21.6% (n = 526,905) of these patients are at an elevated risk of an undesirable response to their opioid medication based on predicted phenotypes and drug-drug interactions: 3.5% are predicted CYP2D6 ultrarapid metabolizers and at increased risk for toxicity, 5.4% are poor metabolizers at higher risk for nonresponse, and 12.8% are normal or intermediate metabolizers coprescribed a CYP2D6 inhibitor leading to phenoconversion into poor metabolizer. Despite the high rate of coprescription of opioids and interacting drugs, CYP2D6 testing was infrequent in the sample (0.02%), and chart review suggests that test results were used to optimize antidepressant treatments rather than pain medications. Using PGx testing combined with consideration of phenoconversion may allow for an enhanced precision medicine approach to pain management in Veterans. [ABSTRACT FROM AUTHOR]

NPs are likely to encounter patients using cannabis with therapeutic intent, with or without legal authorization. During the clinical history and assessment process, NPs need to engage in frank discussion about cannabis therapeutics, including the risks and benefits, evidence for use, dosing considerations, potential drug interactions, and harm reduction. [ABSTRACT FROM AUTHOR]

The mTOR-inhibitor everolimus is a precision drug with antiepileptogenic properties approved for treatment of epilepsy in persons with tuberous sclerosis complex (TSC) in combination with other antiseizure medications (ASMs). However, the pharmacokinetic variability of everolimus is scarcely described, and the available information on pharmacokinetic interactions is scarce. The purpose of this study was to investigate pharmacokinetic variability of everolimus in patients with TSC, and the impact of age, sex and comedication. In this retrospective observational study we used anonymized data from medical records of patients with TSC using everolimus in Norway and Denmark, 2012 to 2020. Long-term therapeutic drug monitoring (TDM) identified inter-patient and intra-patient variability. The study included 59 patients, (36 females (61%)), median age 22 (range 3-59 years). Polytherapy was used in 50 patients (85%). The most frequently used ASMs were lamotrigine (n = 21), valproate (n = 17), and levetiracetam (n = 13). Blood concentrations of everolimus were measured in all patients. Pharmacokinetic variability of everolimus between patients was extensive, as demonstrated by a 24-fold variability from minimum-maximum concentration/dose (C/D)-ratios. The coefficient of variation (CV) for intra-patient (n = 59) and inter-patient variability (n = 47, ≥3 measurements) was 40% and 43%, respectively. The C/D-ratio of everolimus was 50% lower in 13 patients (22%) using enzyme-inducing ASMs compared to the 30 patients who did not (0.7 vs 1.4 ng/mL mg, P < .05). Age and sex were not significantly associated with changes in C/D-ratios of everolimus. Long-term TDM identified extensive variability in concentrations over time for everolimus both within and between patients, where comedication with enzyme-inducing ASMs was an important contributing factor. The findings suggest a need for TDM in patients with TSC treated with everolimus., Competing Interests: The other authors have no conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: Preliminary evidence shows that concomitant administration of valproic acid can reduce the exposure to dolutegravir with limited clinical impacts. Here, we describe a male living with HIV who experienced a drastic reduction in dolutegravir trough concentrations a few weeks after starting valproic acid treatment as identified by therapeutic drug monitoring. Concomitantly, pharmacists recommended a supplementation of magnesium to improve insomnia., Case Report: A 62-year-old man with HIV on antiretroviral therapy with dolutegravir and lamivudine recently added valproic acid to clonazepam and sertraline to treat severe sleep disturbances. An 84% reduction in dolutegravir trough concentrations was observed compared with the previous outpatient visit (418 versus 2714 ng/mL), with values close to the minimum effective drug concentration (300 ng/mL). Considering this, we strongly discourage the use of magnesium., Conclusions: We are confident that our findings can contribute to a better understanding of the clinical problems that infectious disease physicians encounter in their daily management of people with HIV and how therapeutic drug monitoring may add value in this context. This case also highlights the importance of multidisciplinary services for the optimal management of polypharmacy in people with HIV., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: This review article explores the evidence regarding sugammadex (MSD Australia) and its potential interaction with hormonal contraceptives. The impact of recent clinical trials and review articles is examined., Recent Findings: Recent clinical data suggest that the interaction between sugammadex and estrogen and progesterone concentrations may not be clinically significant and may confer some protection against ovulation. There are no clinical trials reporting interactions between sugammadex and the exogenous hormonal compounds found in oral contraceptive pills. The method of contraception is an important consideration, as sugammadex theoretically affects oral and nonoral, and combined versus single agent methods differently. Two large retrospective database studies have reported two cases of pregnancy postoperatively in patients on hormonal contraceptives whose anesthetic included sugammadex., Summary: Strong clinical evidence to support or refute claims of a significant impact of sugammadex on contraceptive efficacy in women on contraception is lacking. The existing evidence does not suggest a basis for concern regarding the impact of sugammadex on contraception in the perioperative setting., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Competing Interests: The authors have no conflicts of interest to declare.

Background: AST-004, a small molecule agonist of the adenosine A1 and A3 receptors, is a potential cerebroprotectant for patients with acute stroke and is currently in clinical trials. Drug-drug interactions are critically important to assess in the context of acute stroke care. Lytic therapy with tPA (tissue-type plasminogen activator)-induced plasmin formation (alteplase) is the only available pharmacotherapy for acute stroke. Consequently, it is imperative to evaluate potential interactions between AST-004 and tPAs such as alteplase and tenecteplase., Methods: The interactions between AST-004 and tPAs were evaluated in 3 ways in preparation for AST-004 phase II trials. First, the metabolic stability of AST-004 was determined in the presence of alteplase and plasmin. Second, the potential for AST-004 to influence the thrombolytic efficacy of alteplase and tenecteplase was evaluated with an in vitro assay system utilizing a fluorogenic substrate of plasmin. Finally, the potential for AST-004 to influence the thrombolytic efficacy of alteplase was also determined with an in vitro thrombolysis assay of human blood thrombi., Results: Neither alteplase nor plasmin affected the stability of AST-004 in vitro. In 2 different in vitro systems, AST-004 had no effect on the ability of alteplase or tenecteplase to generate plasmin, and AST-004 had no effect on the thrombolytic efficacy of alteplase to lyse blood clots in human blood., Conclusions: These studies indicate that there will be no interactions between AST-004 and tPAs such as alteplase or tenecteplase in patients with stroke undergoing thrombolytic therapy., Competing Interests: Disclosures Drs Liston and Korinek are employees of Astrocyte Pharmaceuticals Inc. Dr Lechleiter is a co-founder of Astrocyte Pharmaceuticals Inc, and a science advisor. D. Solt is an employee of Thrombodyne MDEC, LLC.

Clinicians caring for persons with mental illness should be aware of increased mortality, physical problems, and health disparities in this population. This article provides a brief overview of physical health problems in the context of mental illness as well as those related to psychotropic medications, and discusses strategies to manage treatment effectively. [ABSTRACT FROM AUTHOR]

Objective: To evaluate topiramate and etonogestrel pharmacokinetic interactions in contraceptive implant users.Methods: We conducted a prospective, noninferiority study with healthy women using etonogestrel implants continuously for 12-36 months. We measured baseline serum etonogestrel concentrations and then began a 6-week titrated topiramate regimen to standard migraine (100 mg/day) and epilepsy (400 mg/day) dosages. We repeated serum etonogestrel concentrations at 3 weeks (100 mg/day), 4 weeks (200 mg/day), and 6 weeks (400 mg/day) of topiramate therapy. We measured etonogestrel using a validated liquid chromatography-tandem, mass-spectrometry assay and tested for noninferiority (less than 30% decrease) in serum etonogestrel concentrations from baseline.Results: We enrolled 48 total participants; 32 completed 3 weeks, 31 completed 4 weeks, and 27 completed all follow-up visits. Participants' median age was 25.3 years (range 18.3-37.2), median body mass index (BMI) was 25.5 kg/m2 (range 18.7-42.2), and median duration of implant use was 24 months (range 12-36). Median etonogestrel concentrations were 142 pg/mL (range 76.2-771) at baseline, 126 pg/mL (range 72.4-585) at 3 weeks, 119 pg/mL (range 65.6-542) at 4 weeks, and 105 pg/mL (46.2-859) at 6 weeks. The 95% CIs for mean percent change in serum etonogestrel concentrations from baseline were [-37.3%+16.9%], [-45.4%+5.2%], and [-66.8%+24.8%] at 3 weeks, 4 weeks, and 6 weeks, respectively. Excluding one participant who had a serum etonogestrel concentration less than 90 pg/mL at baseline, 30.8% of participants (8/26, 95% CI 14.3-51.8%) had a serum etonogestrel concentration less than 90 pg/mL at 6 weeks.Conclusion: Though only a mild enzyme-inducing antiepileptic drug, concomitant topiramate use led to inferior serum etonogestrel concentrations among implant users, with a significant proportion reaching etonogestrel concentrations below the threshold for ovulatory suppression when taking antiepileptic dosages of topiramate.Funding Source: This study was primarily funded through an Investigator-Initiated Study grant from Merck Sharp & Dohme Corp [MISP#57073]. This work was also supported by NIH/NCATS CTSA Grant Number UL1 TR001082 and NICHD K12 Women's Reproductive Health Research Scholar Program (grant number 5K12HD001271-18).Clinical Trial Registration: ClinicalTrials.gov, NCT03335163. [ABSTRACT FROM AUTHOR]

The article discusses how nurse practitioners can safely and effectively prescribe the first extended-release injectable medication Cabenuva for human immunodeficiency virus-1 approved by the US Food and Drug Administration. It mentions that the use of long-acting injectable antiretroviral therapy can help prevent social stigma, improve patient privacy, and help maintain confidentiality.

Anise (Pimpinella anisum L. , family Apiaceae) is an aromatic annual herb native to the eastern Mediterranean region and western Asia. Although the small fruit is incorrectly referred to as a seed, nonetheless, the fruit is commonly known as aniseed. When ripe and dried, it is the popular spice. Aniseed and its essential oil are used in traditional therapies, for example, for relief of coughs, respiratory congestion, migraines, gastrointestinal distress, and colic; for treatment of skin infections; as a tranquilizer and aphrodisiac; and to improve lactation. Limited and preliminary clinical research has examined the efficacy of aniseed toward diabetes, dysmenorrhea, and menopausal hot flashes. Antioxidant, anti-inflammatory, and antimicrobial properties also were identified. The present narrative review summarizes human and animal studies reporting potential health benefits of aniseed and highlights areas for future research. [ABSTRACT FROM AUTHOR]

Background: Legalization of cannabis use and the evidence base supporting both risks and benefits of cannabinoids are expanding, but our understanding of health care professionals' (HCPs) knowledge about cannabis for medical purposes is limited. Understanding of the knowledge base and knowledge gaps about medical cannabis use is critical to advanced practice registered nurses (APRNs) because they are increasingly called on to manage patients taking multiple drugs, including prescribed and unprescribed cannabis and prescription cannabinoids. Purpose: The purpose of this study was to examine HCPs' knowledge of clinical cannabis, including laws and regulations; risks and harms; pharmacology; and effects on pain, multiple sclerosis spasticity, and seizures as assessed with written tests before an in-person, continuing medical education program. Methods: Total scores and differences among professions and topics were compared. Results: A total of 178 of the 226 program attendees completed the test (79%) (107 [47%] physicians, 30 [13%] APRNs, and 18 [8%] registered nurses). The mean test score was 63.2% (SD = 12.7%) without significant differences among professions (F (3, 174) = 1.53; p =.21) but with significant differences among topics (χ2(7, 1068) = 201.13; p <.001). The score was lowest for effects on seizures (43.8%) and with scores below 70% for all other areas except laws and regulations (85.7%). Implications for practice: There are substantial gaps in HCPs' knowledge about the clinical effects of cannabis, especially about risks and harms, pharmacology, and the effects on pain, multiple sclerosis spasticity, and seizures. Further education may help HCPs to understand the risks and benefits of cannabis and cannabinoids across conditions. [ABSTRACT FROM AUTHOR]

Fluoroquinolones (FQs) are highly effective, well-tolerated, broad-spectrum antibiotics, making them desirable treatment options for infections. However, their adverse reactions as well as recent trends in antibiotic susceptibility must be considered. This article discusses the spectrum of activity and adverse reactions of FQs to guide nurses in caring for patients receiving this class of antibiotics. This article discusses the spectrum of activity and adverse reactions of fluoroquinolones to guide nurses in caring for patients receiving this class of antibiotics. [ABSTRACT FROM AUTHOR]

Antiretroviral therapies for HIV may cause systemic toxicities when coadministered with corticosteroids. Potential drug-drug interactions may occur, leading to iatrogenic Cushing syndrome or adrenal insufficiency. This article highlights the drug-drug interactions of antiretroviral therapies with corticosteroids. Practice implications are discussed. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to examine perioperative medication patterns surrounding major amputation surgeries. Design: A retrospective chart review of 216 cases of major amputations (transfemoral, hip disarticulation, hemipelvectomy, forequarter) at an academic hospital was conducted, examining medications, dosing changes, and drug-drug interaction warnings preoperatively and postoperatively. Results: Medications increased in 76.9% (166/216), remained the same in 10.6% (23/216), and decreased in 12.5% (27/216) of cases. Average number of medications was 7 preoperatively and 10 postoperatively. In 189 cases with preoperative medications present, postoperative dosing remained the same for 74.3%, increased for 9.2%, decreased for 7.6%, andwas unknown for 8.9% of medications. Increases in each of type C ("monitor therapy"), D ("consider therapy modification), and X ("avoid combination") drug-drug interaction warnings were seen respectively in 59.7%, 62.0%, and 5.1% of cases. Conclusion: Polypharmacy is involved preoperatively and increased postoperatively in most cases of major limb amputation, with agent dosing remaining the same or increased in most cases. Drug-drug interaction warnings also increase. These occur at a time of abrupt changes to the body's size, compartments, and physiologic responses. More research and clinical attention are warranted given anticipated changes in pharmacokinetics and pharmacodynamics. [ABSTRACT FROM AUTHOR]

The second of a two-part series, this article describes eight recently approved drugs, including the first drug approved for the treatment of SARS-CoV-2, a first-in-class HIV attachment inhibitor, and a new intravenous injection indicated for the treatment of acute pain in adults for whom other treatments are ineffective. [ABSTRACT FROM AUTHOR]

Background: Carbamazepine (CBZ) is an antiseizure medication known to induce the expression of cytochrome P4503A metabolic enzymes. Here, we describe a man living with HIV who underwent several changes in the daily dose of CBZ, which resulted in different induction effects on darunavir trough concentrations., Methods: A 59-year-old man with HIV, successfully undergoing maintenance antiretroviral treatment with darunavir/cobicistat once daily (combined with raltegravir), was prescribed CBZ for recurrent trigeminal neuralgia. Over subsequent months, the patient underwent various changes in the doses (from 200 to 800 mg/d) and trough concentrations (from 3.6 to 18.0 mg/L) of CBZ, guided by clinical response to trigeminal neuralgia., Results: A highly significant inverse association was observed between darunavir trough concentration and both CBZ dose or trough concentration (coefficient of determination >0.75, P < 0.0001). Ultimately, the darunavir dose was increased to 600 mg twice daily with ritonavir and dolutegravir to ensure optimal antiretroviral coverage, anticipating potential further uptitration of CBZ doses., Conclusions: The impact of CBZ on boosted darunavir exposure seemed to be dose- and concentration-dependent. The management of such drug-drug interactions in daily practice was facilitated through therapeutic drug monitoring. This case underscores the importance of a multidisciplinary approach that incorporates both antiretroviral and nonantiretroviral comedications contributing to the optimal management of polypharmacy in individuals living with HIV., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: The authors described tacrolimus dosing in a kidney transplant patient concurrently treated with phenobarbital, where measuring the tacrolimus area under the curve was necessary to achieve adequate drug exposure and improve kidney function., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: To evaluate the effect of metformin on the plasma levels of rifampicin, isoniazid, and pyrazinamide in patients with drug-sensitive pulmonary tuberculosis being treated with first-line antituberculosis treatment (ATT) and to assess the influence of gene polymorphisms on the metabolic pathway of metformin and plasma levels of antitubercular drugs., Methods: Nondiabetic adults aged 18-60 years with pulmonary tuberculosis were randomized to either the standard ATT (ATT group) or ATT plus metformin (METRIF group) groups in a phase IIB clinical trial. An intensive pharmacokinetic study with blood collection at 0 hour (predosing), followed by 1, 2, 4, 6, 8, and 12 hours after dosing was conducted during the first month of treatment in a subset of 60 study participants after a minimum of 14 doses. Plasma concentrations of rifampicin, isoniazid, pyrazinamide, and metformin were measured by high-performance liquid chromatography using validated methods, and pharmacokinetic parameters and OCT1 and MATE1 gene polymorphisms were compared between the groups., Results: Significant increases in the clearance of rifampicin, isoniazid, and pyrazinamide were observed in patients in the METRIF group (n = 29) compared with those in the ATT group (n = 31). The AA genotypes of the single-nucleotide polymorphism of rs2289669 ( MATE1 ) in the METRIF group showed a significantly decreased area under the concentration-time curve to the last observation point and increased clearance of rifampicin., Conclusions: Metformin altered rifampicin and isoniazid plasma concentrations in patients receiving antituberculosis treatment for pulmonary tuberculosis with little effect on sputum conversion at the end of treatment. Studies with larger sample sizes are needed to understand host drug-drug interactions., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology.)

Colchicine-an anti-inflammatory alkaloid-has assumed an important role in the management of cardiovascular inflammation ≈3500 years after its first medicinal use in ancient Egypt. Primarily used in high doses for the treatment of acute gout flares during the 20th century, research in the early 21st century demonstrated that low-dose colchicine effectively treats acute gout attacks, lowers the risk of recurrent pericarditis, and can add to secondary prevention of major adverse cardiovascular events. As the first Food and Drug Administration-approved targeted anti-inflammatory cardiovascular therapy, colchicine currently has a unique role in the management of atherosclerotic cardiovascular disease. The safe use of colchicine requires careful monitoring for drug-drug interactions, changes in kidney and liver function, and counseling regarding gastrointestinal upset. Future research should elucidate the mechanisms of anti-inflammatory effects of colchicine relevant to atherosclerosis, the potential role of colchicine in primary prevention, in other cardiometabolic conditions, colchicine's safety in cardiovascular patients, and opportunities for individualizing colchicine therapy using clinical and molecular diagnostics., Competing Interests: Disclosures L.F. Buckley has received consulting fees from Kiniksa Pharmaceuticals and speaker fees from Boehringer Ingelheim Pharmaceuticals, Inc, and Eli Lilly and Company through ASHP Advantage. P. Libby is an unpaid consultant to, or involved in clinical trials for, Amgen, AstraZeneca, Baim Institute, Beren Therapeutics, Esperion Therapeutics, Genentech, Kancera, Kowa Pharmaceuticals, Medimmune, Merck, Moderna, Novo Nordisk, Novartis, Pfizer, and Sanofi-Regeneron. P. Libby is a member of the scientific advisory board for Amgen, Caristo Diagnostics, Cartesian Therapeutics, CSL Behring, DalCor Pharmaceuticals, Dewpoint Therapeutics, Eulicid Bioimaging, Kancera, Kowa Pharmaceuticals, Olatec Therapeutics, Medimmune, Novartis, PlaqueTec, TenSixteen Bio, Soley Therapeutics, and XBiotech, Inc. P. Libby’s laboratory has received research funding in the last 2 years from Novartis, Novo Nordisk, and Genentech. P. Libby is on the Board of Directors of XBiotech, Inc. P. Libby has a financial interest in Xbiotech, a company developing therapeutic human antibodies, in TenSixteen Bio, a company targeting somatic mosaicism and clonal hematopoiesis of indeterminate potential to discover and develop novel therapeutics to treat age-related diseases, and in Soley Therapeutics, a biotechnology company that is combining artificial intelligence with molecular and cellular response detection for discovering and developing new drugs, currently focusing on cancer therapeutics. P. Libby’s interests were reviewed and are managed by Brigham and Women’s Hospital and Mass General Brigham in accordance with their conflicts-of-interest policies.

Competing Interests: The authors have no conflicts of interest to report associated with this work.

Purpose: Sulthiame is an antiseizure medication increasingly used for epilepsy. The aim of this study was to investigate the pharmacokinetic variability of sulthiame in children and adults with epilepsy with respect to age, comedication, dose, serum concentration, and biochemical markers of toxicity in a clinical setting., Method: Retrospective quantitative data from the therapeutic drug monitoring (TDM) database at the Section for Clinical Pharmacology, the National Center for Epilepsy, Norway (2015-2021), were used., Results: TDM data from 326 patients (127 female/199 male) were included [mean age, 11.4 (range 2-44) years; mean weight, 41 (range 14-109) kg]. Interindividual pharmacokinetic variability in the concentration/(dose/body weight) (C/(D/kg)) ratio was 16-fold; intraindividual variability was up to 8-fold (coefficient of variation = 10%-78%). Young children (younger than 6 years) had a significantly lower C/(D/kg) ratio than older age groups ( P < 0.05). Various comedications did not significantly affect the C/(D/kg) ratio, possibly owing to the small sample size. However, CYP2C19-mediated inhibition by sulthiame was indicated because patients using clobazam and sulthiame (n = 28) had a 3.5-fold higher N-desmethylclobazam C/(D/kg) ratio than those using neutral comedication (n = 45; P < 0.001). Patients with pH values below the adjusted normal range (7.32-7.42; n = 15) had a 33% higher sulthiame concentration than those with normal pH values (n = 22; P < 0.05). Blood gas measurements, especially pH, may serve as markers of toxicity and can be used in combination with clinical data when toxicity is suspected., Conclusions: This study revealed the extensive intraindividual and interindividual pharmacokinetic variability of sulthiame, with age as a contributing factor. Sulthiame has clinically relevant interactions with clobazam. The use of TDM and pH as a biochemical marker may contribute to individualized and safe sulthiame treatment., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Zuranolone (Zurzuvae) is the first oral medication approved to treat postpartum depression in adult women. Nurses should teach patients to avoid driving for at least 12 hours after each dose. [ABSTRACT FROM AUTHOR]

Potential of MDMA-assisted therapy for PTSD... Some antidopaminergic antiemetics may increase stroke risk... Statins may lower risk for Parkinson disease... Updates on cardio-oncology drug interactions... First drug approved for recurrent yeast infections... New approval for ulcerative colitis treatment [ABSTRACT FROM AUTHOR]

Pre-exposure prophylaxis (PrEP) is an HIV preventive service and treatment that is continuing to evolve. With the availability of in-house lab screenings and simplified testing protocols, primary care providers are in a unique position to initiate and provide the added layer of HIV protection for their patients. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to determine the effects of a 5-yr exercise intervention on metabolic syndrome (MetS) and health-related variables and medication use for MetS management. Methods: Participants were randomly assigned to an exercise intervention (n = 25, 54 ± 2 yr, 20% women) or control group (n = 26, 54 ± 2 yr, 38% women). The intervention lasted 4 months per year and consisted of high-intensity interval training on a cycloergometer thrice a week. Outcomes were MetS z-score and medication use score, MetS-related variables (including blood pressure, blood glucose homeostasis, and lipid profile), and cardiorespiratory fitness (CRF, as determined by maximal oxygen uptake). Results: MetS z-score was similarly reduced over time in both groups (P = 0.244 for group--time interaction). A quasi-significant and significant group--time interaction was found for MetS number of factors (P = 0.004) and CRF (P < 0.001), respectively. Thus, MetS factors tended to decrease over time only in the exercise group with no change in the control group, whereas CRF increased from baseline to 5-yr assessment in the exercise group (by 1.1MET, P < 0.001) but decreased in the control group (-0.5MET, P = 0.025).Medicine use score increased twofold frombaseline to 5-yr follow-up in the control group (P < 0.001) but did not significantly change (10%, P = 0.52) in the exercise group (P < 0.001 for group--time interaction). The proportion of medicated patients who had to increase antihypertensive (P < 0.001), glucose-lowering (P = 0.036), or total medication (P < 0.0001) over the 5-yr period was lower in the exercise than that in the control group. Conclusions: Exercise training can attenuate the increase in medication that would be otherwise required to manage MetS over a 5-yr period. [ABSTRACT FROM AUTHOR]

The rise in direct oral anticoagulant (DOAC) use means nurses must understand the reversal of these agents in case of bleeding. Depending on bleed severity, as well as other criteria, pharmacologic reversal can be considered in place of supportive care alone. Knowledge of literature surrounding DOAC reversal is crucial. [ABSTRACT FROM AUTHOR]

Background: Accurate estimation of conception is critical in the assessment of the effects of drugs used during pregnancy or to prevent pregnancy. In a novel application, we studied the effectiveness of oral contraceptives (OCs), where misclassification of conception relative to OC exposure may obscure effect estimates.Methods: We studied OC failure, in a large claims database, among women who used antiepileptic drugs with metabolizing enzyme-inducing properties (carbamazepine or oxcarbazepine), which reduce OC's effectiveness or enzyme-neutral properties (lamotrigine or levetiracetam), with no expected impact on OC effectiveness. We compared conception rates in women 12-48 years of age concomitantly using OCs and enzyme-inducing drugs with rates in concomitant users of OCs and enzyme-neutral drugs. We measured conception with a validated algorithm that estimates gestational age based on pregnancy endpoints. We estimated relative and attributable risk using generalized estimating equation models after standardized mortality ratio weighting.Results: We identified 89,777 concomitant use episodes with adjusted contraceptive failure rates of 1.6 (95% confidence interval (CI) = 1.4, 1.8) per 100 person-years among users of enzyme-neutral drugs and 18,964 episodes with a rate of 2.3 (1.9, 2.8) among users of enzyme-inducing drugs. The relative risk of conception for enzyme-inducing group was 1.4 (1.1, 1.8), and the rate difference was 0.7 (0.2, 1.2).Conclusions: OCs in combination with antiepileptic drugs that interact with metabolic enzymes were associated with increased contraceptive failure rates. Measurement of conception in claims data had adequate accuracy to uncover a strong drug-drug interaction, offering promise for broader application in comparative effectiveness studies on hormonal contraceptives to inform clinical and regulatory decisionmaking. [ABSTRACT FROM AUTHOR]

The primary aim of the study is to discuss the potential interactions between venetoclax and common drugs used in department of hematology and the corresponding effects on the efficacy and safety of venetoclax treatment. Here, we report an acute myeloid leukemia patient treated with venetoclax and posaconazole, and the dose of venetoclax was adjusted due to drug interactions. Clinical pharmacists actively participated in treatment of this patient to provide pharmacy care to assist clinicians to identify the venetoclax-induced liver function impairment and give timely management. The case reported here is hoped to provide reference for clinical venetoclax treatment in patients with such disease. Clinical pharmacists should actively participate in clinical treatment, actively screen potential drug interactions, strengthen cooperation and communication with doctors, provide patients with high-quality pharmaceutical services, and establish clinical pharmacists' status in the multidisciplinary treatment of tumor., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: The authors have no conflicts of interest to declare.

Background: To mitigate increased risk of premature cardiovascular disease in antiretroviral therapy (ART) suppressed adults living with HIV (PWH), low-dose methotrexate (LDMTX) was evaluated in a multicenter randomized placebo controlled clinical trial of 176 PWH taking various ART regimens (ACTG A5314). Given shared methotrexate (MTX) and tenofovir (TFV) pharmacokinetic (PK) pathways, a substudy was conducted to investigate whether LDMTX alters TFV exposure. Methods: Adults virally suppressed on ART for >24 weeks were randomized to LDMTX or placebo. The first 66 participants taking a tenofovir disoproxil fumarate-containing regimen underwent intensive PK sampling over 24 hours after the second dose of LDMTX 10 mg or placebo. TFV and MTX levels were quantified using validated mass spectrometry methods. TFV PK between LDMTX and placebo groups were compared and MTX PK was characterized. Results: Forty-eight participants completed this substudy (n = 20 on LDMTX and 28 on placebo). Baseline characteristics were balanced except for protease inhibitor (PI)-use (25% in LDMTX and 43% in placebo groups). For TFV, AUC6 (primary endpoint), and AUC24,imputed, Cmax, and Cmin (secondary endpoints) were on average 22%, and 24%, 27%, and 31% less in the LDMTX versus placebo groups, with reductions in secondary endpoints reaching statistical significance. Additional analyses suggested a greater reduction in the absence of PI although not significant. Conclusion: Lower TFV AUC24,imputed and Cmax indicates that LDMTX reduces TFV exposure in PWH. However, this change was modest, not warranting a change in TFV dosing at this time. Further studies of TFV PK with LDMTX, especially without PI co-administration, are warranted. [ABSTRACT FROM AUTHOR]

Migraine headaches can be a disabling condition for patients. Fortunately, most patients can be successfully managed in the outpatient setting, however, there are a number of patients who may not respond to the abortive treatments that they have been prescribed. These patients often present to the emergency department (ED) for further assistance with the management of their condition. Migraines are the fourth most common cause of ED visits and are associated with an estimated annual cost of $17 billion in the United States. Familiarity with abortive treatments is critical for providers in the ED as are treatments, such as valproic acid, that may be considered in patients who do not respond to other treatment options. Many providers are more familiar with the role of valproic acid in the treatment of mood and seizure disorders, but its tolerability and the successes reported in the primary literature make it a reasonable consideration for patients with migraine who fail to respond to other therapies. This article briefly summarizes the therapies considered first line for abortive treatment in the setting of migraines and provides an overview of the primary literature describing the use of valproic acid in these patients. [ABSTRACT FROM AUTHOR]

COVID-19, a symptom complex of respiratory failure induced by a highly infectious pathogen, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has been classified as a pandemic. As of April 15, 2020, there have been 2 million people diagnosed with the viral infection and 130 000 deaths globally. It is highly likely that the number of infections is underrepresented secondary to variations in testing and reporting strategies globally. In this short review, we aim to summarize the current understanding of SARS-CoV-2 as it pertains to cardiovascular disease. We discuss the basis of cardiac pathophysiology and address some of the clinical scenarios that cardiovascular physicians may face. We introduce the concept of conservative management of acute coronary syndromes and address some complications such as myocarditis, heart failure, and cardiac arrhythmias that may be relevant for the management of patients presenting with COVID-19. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID-19) has resulted in an unprecedented pandemic, challenging practitioners to identify safe and effective therapeutic options in a limited amount of time. The rapid genomic sequencing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) provided a significant number of therapeutic targets. Repurposed and investigational agents are being studied for use in COVID-19. Although knowledge is rapidly expanding in regard to COVID-19 and there is promise with a few agents, there are no definitely proven effective therapies at this time. Supportive care remains the mainstay of therapy while ongoing clinical trials are being conducted. [ABSTRACT FROM AUTHOR]

Patients with Parkinson's disease (PD) face unique challenges when admitted to the hospital. The nature of the disease, complexity of the pharmacotherapeutic home regimens, and the medication-related policies of institutionalized care all contribute to the challenges patients and providers face. In addition, medication errors are common in this population. Incorrectly ordered or omitted home medications or delayed administration can have significant negative consequences including worsening of PD symptoms, dopamine agonist withdrawal syndrome, or malignant or hyperpyrexia syndrome. Also, this patient population may commonly encounter contraindicated medications ordered during their hospitalizations. These medication misadventures negatively affect patient care, which may lead to increased length of stay and significant adverse sequalae. Nurses, pharmacists, and other health care providers can help ease the anxiety of patients and their families by taking detailed medication histories, restarting home medication regimens, customizing medication administration to fit patients' needs, and screening patient profiles for drug-drug and drug-disease interactions. Education of hospital staff regarding the unique needs of this patient population and seeking the advice of specialists in PD can also promote improved patient care. [ABSTRACT FROM AUTHOR]

Approximately one third of patients coinfected with HIV and hepatitis Cvirus (HCV) who initiate direct-acting antivirals (DAAs) for HCV treatment may have to switch antiretroviral therapy (ART) because of drug interactions. ART switches can negatively affect quality of life, increase HIV symptom burden, and delay HCV therapy. Approaches to identify ART/DAA drug interactions that minimize the impact of switching ART are urgently needed. Nurses can lead the way in addressing this new and major need. We provide a guide for registered nurses and nurse practitioners who care for patients coinfected with HIV and HCV to identify HIV/HCV drug interactions and manage ART/DAA coadministration when needed. [ABSTRACT FROM AUTHOR]

Background: Self-controlled designs, both case-crossover and self-controlled case series, are well suited for evaluating outcomes of drug-drug interactions in electronic healthcare data. Their comparative performance in this context, however, is unknown.Methods: We simulated cohorts of patients exposed to two drugs: a chronic drug (object) and a short-term drug (precipitant) with an associated interaction of 2.0 on the odds ratio scale. We analyzed cohorts using case-crossover and self-controlled case series designs evaluating exposure to the precipitant drug within person-time exposed to the object drug. Scenarios evaluated violations of key design assumptions: (1) time-varying, within-person confounding; (2) time trend in precipitant drug exposure prevalence; (3) nontransient precipitant exposure; and (4) event-dependent object drug discontinuation.Results: Case-crossover analysis produced biased estimates when 30% of patients persisted on the precipitant drug (estimated OR 2.85) and when the use of the precipitant drug was increasing in simulated cohorts (estimated OR 2.56). Self-controlled case series produced biased estimates when patients discontinued the object drug following the occurrence of an outcome (estimated incidence ratio [IR] of 2.09 [50% of patients stopping therapy] and 2.22 [90%]). Both designs yielded similarly biased estimates in the presence of time-varying, within-person confounding.Conclusion: In settings with independent or rare outcomes and no substantial event-dependent censoring (<50%), self-controlled case series may be preferable to case-crossover design for evaluating outcomes of drug-drug interactions. With frequent event-dependent drug discontinuation, a case-crossover design may be preferable provided there are no time-related trends in drug exposure. [ABSTRACT FROM AUTHOR]

Auvelity, an extended-release fixed combination of dextromethorphan and bupropion, is approved for the treatment of major depressive disorder in adults. Like all antidepressants, dextromethorphan–bupropion carries a boxed warning that it may increase the risk of suicidal thoughts and behaviors in pediatric and young adult patients. Seizures can also occur and are more likely at higher doses. The most common adverse effects of dextromethorphan–bupropion include dizziness, nausea, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, hyperhidrosis, anxiety, constipation, decreased appetite, and insomnia. [ABSTRACT FROM AUTHOR]

Rationale: Linezolid itself is rarely reported to cause blood pressure elevation, and it is rare to report that linezolid causes hypertensive urgency., Patients Concerns: This case report describes a 38-year-old man who developed acute hypertension after a postoperative foot infection that was treated with linezolid antitherapy. Hypertensive urgency occurred without obvious potential interaction between linezolid and drugs. After receiving appropriate treatment and stopping medication, the patient's blood pressure returned to normal and did not recur., Diagnoses: Hypertensive crises occurred during the treatment of linezolid., Interventions: After stopping linezolid, the patient's blood pressure gradually returned to normal., Outcomes: The patient's blood pressure returned to normal on the 26th day after stopping linezolid, and no abnormal blood pressure was found in the follow-up 2 months after discharge., Lessons: Linezolid is rarely reported to cause elevated blood pressure, even though it may occur in the absence of obvious drug interactions. Case reported fewer reasons may be for clinicians statistically insignificant or notice, and hypertensive urgency often lead to clinical risk, should be given enough attention to clinical. Pay attention to blood pressure monitoring during use, when there is abnormal increase in blood pressure, should consider adverse drug reactions, give timely discontinuation and give symptomatic treatment., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)