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Background: There are many reported pharmacist‐led transitions of care (TOC) programs to address medication‐related problems (MRP) at discharge from the acute care setting. Most have identified time and labor resources as significant limitations. This study aims to assess the effectiveness of a medication risk score (MRS)‐driven clinical decision support system (CDSS) in identifying actionable MRPs and improving medication safety in the acute care discharge TOC setting. Methods: A cross‐sectional analysis was conducted in a cohort of 481 subjects discharged from the acute care setting. The MRS‐CDSS was utilized to identify MRPs and provide recommendations for risk reduction. The distribution of MRPs, recommendations, and their associations with MRS severity were analyzed. Additionally, the potential reduction in MRS per subject and its correlation with MRS severity were examined. Results: The median MRS reduction per subject was 2 points, while high/severe‐risk patients showed a median potential reduction of 7 points. Among the identified MRPs (n = 691), drug interaction, drug use without indication, and adverse drug reaction accounted for 89.7% of all MRPs. The top three recommendations, discontinue medication, change the time of administration, and start alternative therapy, represented 94.1% of all recommendations. Stratified analysis by MRS category revealed a significant increase in adverse drug reaction MRPs and recommendations to discontinue medications with higher MRS severity. The results were consistent with previous outpatient studies, supporting the MRS‐CDSS's ability to enhance medication safety. Conclusion: This study demonstrates that the MRS‐CDSS effectively identifies actionable MRPs and has the potential to substantially reduce overall pharmacotherapy regimen risk when applied during acute care discharge TOC. The findings support implementable recommendations directed at patient safety and the allocation of health care resources to high‐risk patients for maximum benefit. [ABSTRACT FROM AUTHOR]

Linezolid (LZD) has a longstanding reported association with the onset of serotonin toxicity (ST), secondary to drug–drug interactions with serotoninergic agents. There have been no conclusive data supporting the incidence or contributing risk factors to date. The study evaluated the incidence of ST in patients treated with LZD and serotonergic agents concomitantly versus LZD alone. The secondary objectives included a comparison of ST incidence in patients treated with one serotonergic agent + LZD versus two or more serotonergic agents + LZD. The studies used for this meta-analysis were retrieved from PubMed, Scopus, and Google Scholar. All studies including a comparison between LZD alone and LZD + a serotonergic agent published between 1 January 2000 and 1 October 2023 and meeting the quality standards were considered for inclusion. Fourteen studies were identified, with five meeting all inclusion and exclusion criteria with no significant heterogeneity. For the analysis of LZD monotherapy vs. SA combination therapy, four studies with 6025 patients total were analyzed and yielded an odds ratio of 1.78 (CI [1.04, 3.02]; I2 = 49%; GRADE certainty: low). Four studies and 2501 patients were included in the analysis of one versus more than one SA with an odds ratio of 5.18 (CI [1.05, 25.49]; I2 = 44.87; GRADE certainty: moderate). The Newcastle–Ottawa score, visual inspection of the funnel plot, and Egger's statistic were used to evaluate quality and heterogeneity. The Peto method was used to calculate the summary odds ratios. All analyses were performed using Comprehensive Meta-Analysis version 3.0 and R, while GRADE was used to evaluate the quality of the final recommendation. The number of concomitant serotonergic agents may play a role in the development of serotonin toxicity in patients prescribed linezolid. In patients requiring linezolid therapy and serotonergic agents, risk versus benefit analysis should pay attention to the number of interacting drugs. [ABSTRACT FROM AUTHOR]

Objective: Unknown etiology Background: Comorbidities and polypharmacy are difficult to manage, as polypharmacy hinders identification and prevention of medication-related problems. Risk for adverse drug events (ADEs) can be minimized through pharmacogenomic (PGx) testing and related therapeutic adjustments. Case Report: A 70-year-old woman with comorbidities and medications enrolled in the Program of All-inclusive Care for the Elderly presented with left lower extremity (LLE) pain, generalized weakness, and major depressive disorder. The provider requested a medication safety review, where the clinical pharmacist-recommended PGx testing given the LLE pain and weakness while taking a statin and inconsistent INR readings taking warfarin. The pharmacist recommended switching atorvastatin to pravastatin to minimize the risk for statin-associated ADEs due to CYP3A4 inhibition and switching fluoxetine to citalopram due to uncontrolled depression/anxiety and to mitigate drug-drug interactions with carvedilol to reduce the risk of orthostatic hypotension. Recommendations were accepted and upon follow-up the patient reported minor LLE pain and improved wellbeing on citalopram. Following PGx testing, the patient had decreased function at SLCO1B1 and was an intermediate metabolizer for CYP2C9 and CYP2D6. This case demonstrates how preemptive PGx testing would have identified drug-gene interactions (DGIs) at the time of prescribing and reduced the risk of statin-associated muscular symptoms, highlighting the utility of panel-based PGx testing in older adults at high risk for ADEs and/or therapy failure. Conclusions: Decreased function at SLCO1B1 increases exposure to statins, leading to statin-induced myalgias, as displayed in this case. PGx testing can help identify DGIs, choose optimal therapies in medically complex older adults, and minimize ADE risk. [ABSTRACT FROM AUTHOR]

Diazepam is a benzodiazepine widely prescribed for the management of patients with severe alcohol withdrawal syndrome to prevent agitation, withdrawal seizures, and delirium tremens. Despite standard dosing of diazepam, a subset of patients experience refractory withdrawal syndromes or adverse drug reactions, such as impaired motor coordination, dizziness, and slurred speech. The CYP2C19 and CYP3A4 enzymes play a key role in the biotransformation of diazepam. Given the highly polymorphic nature of the CYP2C19 gene, we reviewed the clinical impact of variants in the CYP2C19 gene on both the pharmacokinetics of diazepam and treatment outcomes related to the management of alcohol withdrawal syndrome. [ABSTRACT FROM AUTHOR]

Comprehensive medication management (CMM) is increasingly provided by health care teams through telehealth or hybrid modalities. The purpose of this scoping literature review was to assess the published literature and examine the economic, clinical, and humanistic outcomes of CMM services provided by pharmacists via telehealth or hybrid modalities. This scoping review followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analysis extension for Scoping Reviews. Randomized controlled trials (RCTs) and observational studies were included if they: reported on economic, clinical, or humanistic outcomes; were conducted via telehealth or hybrid modalities; included a pharmacist on their interprofessional team; and evaluated CMM services. The search was conducted between January 1, 2000, and September 28, 2021. The search strategy was adapted for use in Medline (PubMed); Embase; Cochrane; Cumulative Index to Nursing and Allied Health Literature; PsychINFO; International Pharmaceutical Abstracts; Scopus; and grey literature. Four reviewers extracted data using a screening tool developed for this study and reviewed for risk of bias. Authors screened 3500 articles, from which 11 studies met the inclusion criteria (9 observational studies, 2 RCTs). In seven studies, clinical outcomes improved with telehealth CMM interventions compared to either usual care, face‐to‐face CMM, or educational controls, as shown by the statistically significant changes in chronic disease clinical outcomes. Two studies evaluated and found increased patient and provider satisfaction. One study described a source of revenue for a telehealth CMM service. Overall, study results indicate that telehealth CMM services, in select cases, may be associated with improved clinical outcomes, but the methods of the included studies were not homogenous enough to conclude that telehealth or hybrid modalities were superior to in‐person CMM. To understand the full impact on the Quadruple Aim, additional research is needed to investigate the financial outcomes of CMM conducted using telehealth or hybrid technologies. [ABSTRACT FROM AUTHOR]

Pharmacotherapy for major depressive disorder (MDD) typically consists of trial-and-error and clinician preference approaches, where patients often fail one or more antidepressants before finding an optimal regimen. Pharmacogenomics (PGx) can assist in prescribing appropriate antidepressants, thereby reducing the time to MDD remission and occurrence of adverse drug events. Since many antidepressants are metabolized by and/or inhibit cytochrome P450 enzymes (e.g., CYP2C19 or CYP2D6), drug-induced phenoconversion is common in patients on antidepressant combinations. This condition influences the interpretation of a patient's PGx results, overall risk of ineffective/adverse medication response due to multi-drug interactions, and the recommendations. This complex case describes a patient with MDD, generalized anxiety disorder, and chronic pain who experienced a fall due to excessive sedation following a prescribing cascade of fluoxetine, bupropion, and doxepin. These antidepressants delivered a significant additive sedative effect and interacted with the patient's hydrocodone, potentially contributing to uncontrolled pain, upward dose titration of hydrocodone, and a higher overall sedative burden. The PGx results and drug-induced phenoconversion described in this case report explain the patient's excessive sedation and possibly ineffective/toxic antidepressant and opioid treatment. This case report also illustrates how a more timely multi-drug interaction assessment (preferably in conjunction with preemptive PGx testing) may have informed a different prescribing pattern, reduced/avoided a prescribing cascade, and potentially prevented a drug-related fall. [ABSTRACT FROM AUTHOR]

Background: Given associations with serious cognitive and physical adverse effects (e.g., dementia, falls), strong anticholinergics, like urinary antimuscarinics (UAMs), should be avoided in older adults. This feasibility study aimed to (1) evaluate the implementation rate of pharmacists' recommendations intended to de‐escalate UAMs, (2) quantify the change in overall anticholinergic dosing exposure from these recommendations, and (3) investigate factors that predict recommendation implementation. Methods: This was a retrospective, observational, before‐and‐after study. Pharmacists (n = 18) devised strategies to de‐escalate UAMs in 187 participants (mean age 72.4 ± 9.4; 77.0% female; mean number of medications 12.9 ± 4.6) of 35 Programs of All‐Inclusive Care for the Elderly (PACE). PACE prescribers (non‐physicians and physicians) determined whether to implement recommendations. Implementation was defined as a change in the prescription records consistent with the pharmacist's recommendation at 2‐, 4‐, 6‐, and 9‐months post‐recommendation. Anticholinergic dosing exposure was measured at each time point using standardized daily doses (SDD). Multivariable logistic regression was used to identify factors that predicted recommendation implementation. Results: Across 9 months, recommendations were implemented in 118 out of 187 participants, yielding a 63.1% implementation rate. Of these, 77.1% (n = 91/118) implemented by month 2. Implementers' mean overall anticholinergic SDD decreased 65.4% from baseline (baseline: 2.6 [95% CI: 2.2, 3.0] to month 9: 0.9 [95% CI: 0.6,1.2], p < 0.001) whereas non‐implementers demonstrated no significant change (p = 0.52). Taking <10 baseline medications (OR 2.75; 95% CI: 1.09, 7.61); baseline UAM SDD ≥2 (OR 2.20; 95% CI: 1.11, 4.44); uncomplicated recommendations (OR 3.38; 95% CI: 1.67–7.03); and baseline calcium channel blocker use (OR 2.19; 95% CI: 1.09, 4.52) predicted implementation. Conclusion: Our high implementation rate indicates that pharmacists' recommendations to de‐escalate UAMs as a way to reduce overall anticholinergic exposure is feasible in medically complex, community‐dwelling older adults. Future research should investigate whether these recommendations benefit cognitive (e.g., delirium, dementia) and/or physical functioning (e.g., falls). [ABSTRACT FROM AUTHOR]

Utilizing pharmacogenomics (PGx) and integrating drug-induced phenoconversion to guide opioid therapies could improve the treatment response and decrease the occurrence of adverse drug events. Genetics contribute to the interindividual differences in opioid response. The purpose of this case report highlights the impact of a PGx-informed medication safety review, assisted by a clinical decision support system, in mitigating the drug–gene and drug–drug–gene interactions (DGI and DDGI, respectively) that increase the risk of an inadequate drug response and adverse drug events (ADEs). This case describes a 69-year-old female who was referred for PGx testing for uncontrolled chronic pain caused by osteoarthritis and neuropathy. The clinical pharmacist reviewed the PGx test results and medication regimen and identified several (DGIs and DDGIs, respectively) at Cytochrome P450 (CYP) 2C19 and CYP2D6. The recommendations were to: (1) switch tramadol to buprenorphine transdermal patch, an opioid with lower potential for ADEs, to mitigate a CYP2D6 DDGI; (2) gradually discontinue amitriptyline to alleviate the risk of anticholinergic side effects, ADEs, and multiple DDGIs; and (3) optimize the pregabalin. The provider and the patient agreed to implement these recommendations. Upon follow-up one month later, the patient reported an improved quality of life and pain control. Following the amitriptyline taper, the patient experienced tremors in the upper and lower extremities. When the perpetrator drug, omeprazole, was stopped, the metabolic capacity was no longer impeded; the patient experienced possible amitriptyline withdrawal symptoms due to the rapid withdrawal of amitriptyline, which was reinitiated and tapered off more slowly. This case report demonstrates a successful PGx-informed medication safety review that considered drug-induced phenoconversion and mitigated the risks of pharmacotherapy failure, ADEs, and opioid misuse. [ABSTRACT FROM AUTHOR]

(1) Background: Adverse drug events and inappropriate use of medications lead to hospitalizations, medication-related morbidity, and mortality. This study examined whether a novel medication risk prediction tool, the MedWise Risk Score™, was associated with medication safety-related problem (MRP) identification and whether integration into an existing innovative transitions of care (TOC) service could decrease readmissions. (2) Methods: This retrospective comparator group study assessed patients discharged from a hospital in southern Arizona between January and December 2020. Participants were included in the study if they were 18 years of age or older, referred to the pharmacist for TOC services, and received a pharmacist consultation within one-week post discharge. Patients were categorized into two groups: (1) medication safety review (MSR)-TOC service (intervention) or (2) existing innovative TOC service (control). (3) Results: Of 164 participants, most were male (57%) and were between 70–79 years of age. Overall, there were significantly more drug-drug interactions (DDI) MRPs identified per patient in the intervention vs. control group for those who were readmitted (3.7 ± 1.5 vs. 0.9 ± 0.6, p < 0.001) and those who were not readmitted (2 ± 1.3 vs. 1.3 ± 1.2, p = 0.0120). Furthermore, of those who were readmitted, the average number of identified MRPs per patient was greater in the intervention group compared to the control (6.3 vs. 2.5, respectively, p > 0.05). Relative to the control, the readmission frequency was 30% lower in the treatment group; however, there was insufficient power to detect significant differences between groups. (4) Conclusions: The integration of a medication risk prediction tool into this existing TOC service identified more DDI MRPs compared to the previous innovative TOC service, which lends evidence that supports its ability to prevent readmissions. Future work is warranted to demonstrate the longitudinal impact of this intervention in a larger sample size. [ABSTRACT FROM AUTHOR]

Adverse drug events (ADEs) represent an expensive societal burden that disproportionally affects older adults. Therefore, value-based organizations that provide care to older adults—such as the Program of All-Inclusive Care for the Elderly (PACE)—should be highly motivated to identify actual or potential ADEs to mitigate risks and avoid downstream costs. We sought to determine whether PACE participants receiving medication risk mitigation (MRM) services exhibit improvements in total healthcare costs and other outcomes compared to participants not receiving structured MRM. Data from 2545 PACE participants from 19 centers were obtained for the years 2018 and 2019. We compared the year-over-year changes in outcomes between patients not receiving (control) or receiving structured MRM services. Data were adjusted based on participant multimorbidity and geographic location. Our analyses demonstrate that costs in the MRM cohort exhibited a significantly smaller year-to-year increase compared to the control (MRM: USD 4386/participant/year [95% CI, USD 3040–5732] vs. no MRM: USD 9410/participant/year [95% CI, USD 7737–11,084]). Therefore, receipt of structured MRM services reduced total healthcare costs (p < 0.001) by USD 5024 per participant from 2018 to 2019. The large majority (75.8%) of the reduction involved facility-related expenditures (e.g., hospital admission, emergency department visits, skilled nursing). In sum, our findings suggest that structured MRM services can curb growing year-over-year healthcare costs for PACE participants. [ABSTRACT FROM AUTHOR]

Polypharmacy of psychotropic medications predisposes older adults to adverse drug events (ADEs). One contributing factor is inhibition of metabolic pathways between substrates (competitive inhibition) or between substrates and inhibitors of the same cytochrome P450 (CYP450) isoforms. The purpose of this case report is to demonstrate observed sedation and difficulty concentrating from augmentation therapy for resistant major depressive disorder (MDD) and to highlight the value of clinical tools to identify opportunities for treatment optimization to reduce ADEs. The pharmacist identified significant medication burden and competitive inhibition of drug metabolism in the CYP450 system during a telehealth medication therapy management consultation with a 69-year-old male. The pharmacist recommended clinical monitoring and communicated concerns about medication-induced sedation, difficulty concentrating, and other medication-related problems (MRP) to providers. Several recommendations were implemented which helped improved patient's outcomes. Individualizing MDD pharmacotherapy based on pharmacokinetic and pharmacodynamic drug interactions and geriatric dosage considerations may lead to better outcomes and tolerability among older adults. [ABSTRACT FROM AUTHOR]

Patients are often faced with challenges when it comes to safe therapeutic options. An 89-year-old female with a history of arrhythmias and refractory gastroparesis complained of adverse drug events from her benzodiazepine. While performing a comprehensive medication review and a medication safety review using an advanced clinical decision support system, the pharmacist successfully tapered off the benzodiazepine to a safer alternative antidepressant indicated for the treatment of gastroparesis. Special attention was given to selecting drugs with less QT prolongation risk, based on her age, current drug regimen, previous medical history, and presence of polypharmacy. [ABSTRACT FROM AUTHOR]

Tramadol is an opioid medication used to treat moderately severe pain. Cytochrome P450 (CYP) 2D6 inhibition could be important for tramadol, as it decreases the formation of its pharmacologically active metabolite, O‐desmethyltramadol, potentially resulting in increased opioid use and misuse. The objective of this study was to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O‐desmethyltramadol pharmacokinetics using quinidine and metoprolol as prototypical perpetrator drugs. A physiologically based pharmacokinetic model for tramadol and O‐desmethyltramadol was developed and verified in PK‐Sim version 8 and linked to respective models of quinidine and metoprolol to evaluate the impact of allosteric and competitive CYP2D6 inhibition on tramadol and O‐desmethyltramadol exposure. Our results show that there is a differentiated impact of CYP2D6 inhibitors on tramadol and O‐desmethyltramadol based on their mechanisms of inhibition. Following allosteric inhibition by a single dose of quinidine, the exposure of both tramadol (51% increase) and O‐desmethyltramadol (52% decrease) was predicted to be significantly altered after concomitant administration of a single dose of tramadol. Following multiple‐dose administration of tramadol and a single‐dose or multiple‐dose administration of quinidine, the inhibitory effect of quinidine was predicted to be long (≈42 hours) and to alter exposure of tramadol and O‐desmethyltramadol by up to 60%, suggesting that coadministration of quinidine and tramadol should be avoided clinically. In comparison, there is no predicted significant impact of metoprolol on tramadol and O‐desmethyltramadol exposure. In fact, tramadol is predicted to act as a CYP2D6 perpetrator and increase metoprolol exposure, which may necessitate the need for dose separation. [ABSTRACT FROM AUTHOR]

Background: Patients taking medication with high anticholinergic and sedative properties are at increased risk of experiencing poor cognitive and physical outcomes. Therefore, precise quantification of the cumulative burden of their drug regimen is advisable. There is no agreement regarding which scale to use to simultaneously quantify the burden associated with medications. Objectives: The objective of this review was to assess the strengths and limitations of available tools to quantify medication-related anticholinergic burden and sedative load in older adults. We discuss specific limitations and agreements between currently available scales and models and propose a comprehensive table combining drugs categorized as high, moderate, low, or no anticholinergic or sedative activity as excerpted from the selected studies. Methods: A targeted search was carried out using the National Library of Medicine through PubMed using medical subject heading terms and text words around the following search terms: (anticholinergic OR sedative) AND (load OR burden OR scale) for studies published between 1 January 1945 and 5 June 2021. In addition, the following databases were searched using the same terms: MEDLINE-EBSCO, APA PsycInfo, CINAHL Plus, Cochrane Library, Scopus, OAIster, OVID-MEDLINE, Web of Science, and Google Scholar. Screening by titles was followed by an abstract and full-text review. After blind evaluation, agreement between reviewers was reached to establish drug characteristics and categories. Results: After 3163 articles were identified, 13 were included: 11 assigned risk scores to anticholinergic drugs and two to sedative drugs. Considerable variability between anticholinergic scales was observed; scales included between 27 and 548 drugs. We generated a comprehensive table combining the anticholinergic and sedative activities of drugs evaluated and proposed a categorization of these drugs based on available scientific and clinical evidence. Our table combines information about 642 drugs and categorizes 44, 25, 99, and 474 drugs as high, moderate, low, or no anticholinergic and sedative activity, respectively. Conclusions: Variability and inconsistency exists among scales used to categorize drugs with anticholinergic or sedative burden. In this review, we provide a comprehensive table that proposes a new categorization of these drugs. A longitudinal study will be required to validate the new proposed anticholinergic and sedative burden catalog in an evidence-based manner. [ABSTRACT FROM AUTHOR]

Cannabis products that contain the tetrahydrocannabinol (THC) cannabinoid are emerging as promising therapeutic agents for the treatment of medical conditions such as chronic pain. THC elicits psychoactive effects through modulation of dopaminergic neurons, thereby altering levels of dopamine in the brain. This case report highlights the complexity associated with medicinal cannabis and the health risks associated with its use. A 57-year-old male with Parkinson’s disease was experiencing worsening tremors and vivid hallucinations despite therapy optimization attempts. It was discovered that the patient took cannabis for chronic back pain, and a pharmacogenomics (PGx) test indicated the presence of variants for the COMT and HTR2A genes. These variants could increase dopamine levels and predispose patients to visual hallucinations. Once the cannabis was discontinued, the patient’s hallucinations began to slowly dissipate. Cannabis use continues to expand as it gains more acceptance legally and medicinally, but cannabis can affect the response to drugs. This patient case suggests that cannabis use in combination with dopamine-promoting drugs, especially in a patient with genetic variants, can increase the risk for vivid hallucinations. These conditions support the importance of considering herb–drug interactions and PGx data when performing a medication safety review. [ABSTRACT FROM AUTHOR]

Drug safety is generally established from clinical trials, by pharmacovigilance programs and during observational phase IV safety studies according to drug intended or approved indications. The objective of this study was to estimate the risk of potential adverse drug events (ADEs) associated with drugs repurposed for coronavirus disease 2019 (COVID‐19) treatment in a large‐scale population. Drug claims were used to calculate a baseline medication risk score (MRS) indicative of ADE risk level. Fictitious claims of repurposed drugs were added, one at a time, to patients' drug regimens to calculate a new MRS and compute a level of risk. Drug claims data from enrollees with Regence health insurance were used and sub‐payer analyses were performed with Medicare and commercial insured groups. Simulated interventions were conducted with hydroxychloroquine and chloroquine, alone or combined with azithromycin, and lopinavir/ritonavir, along with terfenadine and fexofenadine as positive and negative controls for drug‐induced Long QT Syndrome (LQTS). There were 527,471 subjects (56.6% women; mean [SD] age, 47 years [21]) were studied. The simulated addition of each repurposed drug caused an increased risk of ADEs (median MRS increased by two‐to‐seven points, p < 0.001). The increase in ADE risk was mainly driven by an increase in CYP450 drug interaction risk score and by drug‐induced LQTS risk score. The Medicare group presented a greater risk overall compared to the commercial group. All repurposed drugs were associated with an increased risk of ADEs. Our simulation strategy could be used as a blueprint to preemptively assess safety associated with future repurposed or new drugs. [ABSTRACT FROM AUTHOR]

Pharmacogenomic (PGx) information can guide drug and dose selection, optimize therapy outcomes, and/or decrease the risk of adverse drug events (ADEs). This report demonstrates the impact of a pharmacist-led medication evaluation, with PGx assisted by a clinical decision support system (CDSS), of a patient with multiple comorbidities. Following several sub-optimal pharmacotherapy attempts, PGx testing was recommended. The results were integrated into the CDSS, which supported the identification of clinically significant drug–drug, drug–gene, and drug–drug–gene interactions that led to the phenoconversion of cytochrome P450. The pharmacist evaluated PGx results, concomitant medications, and patient-specific factors to address medication-related problems. The results identified the patient as a CYP2D6 intermediate metabolizer (IM). Duloxetine-mediated competitive inhibition of CYP2D6 resulted in phenoconversion, whereby the patient’s CYP2D6 phenotype was converted from IM to poor metabolizer for CYP2D6 co-medication. The medication risk score suggested a high risk of ADEs. Recommendations that accounted for PGx and drug-induced phenoconversion were accepted. After 1.5 months, therapy changes led to improved pain control, depression status, and quality of life, as well as increased heart rate, evidenced by patient-reported improved sleep patterns, movement, and cognition. This case highlights the pharmacist’s role in using PGx testing and a CDSS to identify and mitigate medication-related problems to optimize medication regimen and medication safety [ABSTRACT FROM AUTHOR]

The risk‐benefit ratio associated with the use of repurposed drugs to treat severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2)‐related infectious coronavirus disease 2019 (COVID‐19) is complicated because benefits are awaited, not proven. A thorough literature search was conducted to source information on the pharmacological properties of 5 drugs and 1 combination (azithromycin, chloroquine, favipiravir, hydroxychloroquine, remdesivir, and lopinavir/ritonavir) repurposed to treat COVID‐19. A risk assessment of drug‐induced long QT syndrome (LQTS) associated with COVID‐19 repurposed drugs was performed and compared with 23 well‐known torsadogenic and 10 low torsadogenic risk compounds. Computer calculations were performed using pharmacokinetic and pharmacodynamic data, including affinity to block the rapid component of the delayed rectifier cardiac potassium current (IKr) encoded by the human ether‐a‐go‐go gene (hERG), propensity to prolong cardiac repolarization (QT interval) and cause torsade de pointes (TdP). Seven different LQTS indices were calculated and compared. The US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database was queried with specific key words relating to arrhythmogenic events. Estimators of LQTS risk levels indicated a very high or moderate risk for all COVID‐19 repurposed drugs with the exception for azithromycin, although cases of TdP have been reported with this drug. There was excellent agreement among the various indices used to assess risk of drug‐induced LQTS for the 6 repurposed medications and 23 torsadogenic compounds. Based on our results, monitoring of the QT interval shall be performed when some COVID‐19 repurposed drugs are used, as such monitoring is possible for hospitalized patients or with the use of biodevices for outpatients. [ABSTRACT FROM AUTHOR]

Heart failure (HF) causes pathological changes in multiple organs, thus affecting the pharmacokinetics (PK) of drugs. The aim of this study was to investigate the PK of candesartan in patients with HF while examining significant covariates and their related impact on estimated clearance using a population PK (Pop‐PK) modeling approach. Data from a prospective, multicenter study were used. Modeling and simulations were conducted using Nonlinear Mixed‐Effects Modeling (NONMEM) and R software. A total of 281 white patients were included to develop the Pop‐PK model. The final model developed for apparent oral clearance (CL/F) included weight, estimated glomerular filtration rate (eGFR), and diabetes, which partly explained its interindividual variability. The mean CL/F value estimated was 7.6 L/h (1.7–22.6 L/h). Simulations revealed that an important decrease in CL/F (> 25%) is obtained with the combination of the factors retained in the final model. Considering these factors, a more individualized approach of candesartan dosing should be investigated in patients with HF. [ABSTRACT FROM AUTHOR]

Precision medication entails selecting the precise medication, dose, and timing of administration. Multi‐drug interactions and genetics significantly affect precision medication. In this article, we present two simulated cases for real‐world applications of precision medication. Clinicians may need to acquire additional skills to apply the principles illustrated by these cases. [ABSTRACT FROM AUTHOR]

We conducted a comprehensive in vivo study evaluating the influence of type 2 diabetes (T2D) on major cytochrome P450 (CYP450) activities. These activities were assessed in 38 T2D and 35 non‐T2D subjects after a single oral administration of a cocktail of probe drugs: 100 mg caffeine (CYP1A2), 100 mg bupropion (CYP2B6), 250 mg tolbutamide (CYP2C9), 20 mg omeprazole (CYP2C19), 30 mg dextromethorphan (CYP2D6), 2 mg midazolam (CYP3As), and 250 mg chlorzoxazone (alone; CYP2E1). Mean metabolic activity for CYP2C19, CYP2B6, and CYP3A was decreased in subjects with T2D by about 46%, 45%, and 38% (P < 0.01), respectively. CYP1A2 and CYP2C9 activities seemed slightly increased in subjects with diabetes, and no difference was observed for CYP2D6 or CYP2E1 activities. Several covariables, such as inflammatory markers (interleukin (IL)‐1ß, IL‐6, gamma interferon, and tumor necrosis factor alpha), genotypes, and diabetes‐related and demographic‐related factors were considered in our analyses. Our results indicate that low chronic inflammatory status associated with T2D modulates CYP450 activities in an isoform‐specific manner. [ABSTRACT FROM AUTHOR]

The relevance of endogenous 4β‐hydroxycholesterol (4β‐OHC) plasma concentrations or of the 4β‐OHC/total cholesterol concentration ratio (4β‐OHC ratio) as surrogate markers of cytochrome P450 3A (CYP3A) activity was evaluated in individuals with (n = 38) or without (n = 35) type 2 diabetes (T2D). Midazolam was used as a comparator to validate exploratory measures of phenotypic CYP3A activity. Metabolic ratios of orally administered midazolam in nondiabetic and diabetic populations correlated significantly with 4β‐OHC (rs = 0.64 and 0.48; P ≤ 0.003) and 4β‐OHC ratio (rs = 0.69 and 0.46; P ≤ 0.003), respectively. Activity of CYP3A was lower in the T2D population compared with nondiabetic subjects; this decrease was reflected in 4β‐OHC concentrations (24.33 vs. 12.58 ng/mL; P < 0.0001) and 4β‐OHC ratio (0.13 vs. 0.09 (× 104); P < 0.0002). These results suggest that 4β‐OHC should be considered as a valid, convenient, and easy to use endogenous biomarker of CYP3A activity in patients. [ABSTRACT FROM AUTHOR]

Aims: To characterize mRNA expression levels (17 cytochromes P450) and activity (9 isoforms) of major cytochromes P450 expressed throughout the human small intestine. Methods: Tissue samples were obtained from 9 deceased subjects and intestinal sections (n = 10) were isolated for each subject. Relative mRNA expression levels were determined using quantitative real‐time PCR. Intestinal microsomes were prepared from 5 subsections: duodenum, jejunum (proximal and mid‐jejunum) and ileum (proximal and mid‐ileum) regions. In vitro incubations were performed with various cytochrome P450 probe substrates: bupropion (CYP2B6), repaglinide (CYP2C8), tolbutamide (CYP2C9), S‐mephenytoin (CYP2C19), bufuralol (CYP2D6), chlorzoxazone (CYP2E1), ebastine (CYP2J2), midazolam (CYP3A4/5) and lauric acid (CYP4A11). Metabolite formation was assessed using validated liquid chromatography–tandem mass spectrometry assays. Results: Cytochrome P450 mRNA levels ranked as follows: CYP3A4 > CYP2C9 > CYP2C19 > CYP2J2 > CYP4F2. Cytochrome P450 mRNA transcripts showed different patterns in their relative expression from 1 region to the other but CYP3A4, CYP2C9, CYP2C19 and CYP2J2 displayed the highest levels of mRNA expression (>5%) in all intestinal sections. Cytochrome P450 activities were greater in proximal part of the small intestine with the jejunum showing the greatest drug‐metabolism activity. Spearman's correlation analyses indicated that cytochrome P450 mRNA expressions and corresponding cytochrome P450 activities in the human intestine were moderately associated for CYP2C19, CYP2D6 and CYP4A11 (rs = 0.44–0.56). Conclusions: Our study provides new and additional information on the expression and activities of selected cytochromes P450 in various sections of the human small intestine. [ABSTRACT FROM AUTHOR]

1. The objective of our study was to develop and validate a cocktail approach to allow the simultaneous characterization of various CYP450-mediated oxidations by human heart microsomes for nine probe drug substrates, namely, 7-ethoxyresorufin, bupropion, repaglinide, tolbutamide, bufuralol, chlorzoxazone, ebastine, midazolam and dodecanoic acid. 2. The first validation step was conducted using recombinant human CYP450 isoenzymes by comparing activity measured for each probe drug as a function of (1) buffer used, (2) selectivity towards specific isoenzymes and (3) drug interactions between probes. Activity was all measured by validated LC-MSMS methods. 3. Two cocktails were then constituted with seven of the nine drugs and subjected to kinetic validation. Finally, all probe drugs were incubated with human heart microsomes prepared from ventricular tissues obtained from 12 patients undergoing cardiac transplantation. 4. Validated cocktail #1 including bupropion, chlorzoxazone, ebastine and midazolam was used to characterize CYP2B6-, 2E1-, 2J2- and 3A5-mediated metabolism in human hearts. 5. Cocktail #2 which includes bufuralol, 7-ethoxyresorufin and repaglinide failed the validation step. Substrates in cocktail #2 as well as tolbutamide and dodecanoic acid had to be incubated separately because of their physico-chemical characteristics (solubility and ionization) or drug interactions. 6. Activity in HHM was the highest towards ebastine, chlorzoxazone and tolbutamide. [ABSTRACT FROM AUTHOR]

Introduction Diabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to variability in the functional activity of drug-metabolising enzymes including cytochromes P450 (CYP450s). CYP450 is a superfamily of enzymes responsible for xenobiotic metabolism. Knowledge must be gained on the impact of T2DM and related inflammatory processes on drug metabolism and its consequences on drug response. The aim of this study is to characterise the activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in T2DM versus non-T2DM subjects following the administration of a cocktail of probe drug substrates. Methods and analysis This single-centre clinical study proposes the first detailed characterisation of T2DM impacts on major CYP450 drug-metabolising enzyme activities. We intend to recruit 42 patients with controlled T2DM (A1C≤7%), 42 patients with uncontrolled T2DM (A1C>7%) and 42 non-diabetic control subjects. The primary objective is to determine and compare major CYP450 activities in patients with T2DM versus nondiabetic subjects by dosing in plasma and urine probe drug substrates and metabolites following the oral administration of a drug cocktail: caffeine (CYP1A2), bupropion (CYP2B6), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4/5). Secondary objectives will evaluate the influence of variables such as glycaemia, insulinaemia, genetic polymorphisms and inflammation. The value of an endogenous biomarker of CYP3A activity is also evaluated. The first patient was recruited in May 2015 and patients will be enrolled up to completion of study groups. Ethics and dissemination Approval was obtained from the ethic review board of the CHUM research centre (Montreal, Canada). Trial registration number NCT02291666. [ABSTRACT FROM AUTHOR]

Many drugs can cause unexpected muscle disorders, often necessitating the cessation of an effective medication. Inhibition of monocarboxylate transporters (MCTs) may potentially lead to perturbation of L-lactic acid homeostasis and muscular toxicity. Previous studies have shown that statins and loratadine have the potential to inhibit L-lactic acid efflux by MCTs (MCT1 and 4). The main objective of this study was to confirm the inhibitory potentials of atorvastatin, simvastatin (acid and lactone forms), rosuvastatin, and loratadine on L-lactic acid transport using primary human skeletal muscle cells (SkMC). Loratadine (IC50 31 and 15 μM) and atorvastatin (IC50 ∼130 and 210 μM) demonstrated the greatest potency for inhibition of L-lactic acid efflux at pH 7.0 and 7.4, respectively (∼2.5-fold L-lactic acid intracellular accumulation). Simvastatin acid exhibited weak inhibitory potency on L-lactic acid efflux with an intracellular lactic acid increase of 25-35%. No L-lactic acid efflux inhibition was observed for simvastatin lactone or rosuvastatin. Pretreatment studies showed no change in inhibitory potential and did not affect lactic acid transport for all tested drugs. In conclusion, we have demonstrated that loratadine and atorvastatin can inhibit the efflux transport of L-lactic acid in SkMC. Inhibition of L-lactic acid efflux may cause an accumulation of intracellular L-lactic acid leading to the reported drug-induced myotoxicity. [ABSTRACT FROM AUTHOR]

Various diseases such as type 2 diabetes (T2D) may alter drug clearance. The objective of this study was to evaluate the effects of T2D on CYP450 expressions and activities using high-fat diet (HFD) as a model of obesity-dependent diabetes in C57BL6 mice. The cyp450 mRNA expression levels for 15 different isoforms were determined in the liver and extra-hepatic tissues (kidneys, lungs and heart) of HFD-treated animals (n = 45). Modulation of cyp450 metabolic activities by HFD was assessed using eight known substrates for specific human ortholog CYP450 isoforms: in vitro incubations were conducted with liver and extra-hepatic microsomes. Expression levels of cyp3a11 and cyp3a25 mRNA were decreased in the liver (>2-14-fold) and kidneys (>2-fold) of HFD groups which correlated with a significant reduction in midazolam metabolism (by 21- and 5-fold in hepatic and kidney microsomes, respectively, p < 0.001). HFD was associated with decreased activities of cyp2b and cyp2c subfamilies in all organs tested except in the kidneys (for tolbutamide). Other cyp450 hepatic activities were minimally or not affected by HFD. Taken together, our data suggest that substrate-dependent and tissue-dependent modulation of cyp450 metabolic capacities by early phases of T2D are observed, which could modulate drug disposition and pharmacological effects in various tissues. [ABSTRACT FROM AUTHOR]

The article presents abstracts on the study of xenobiotics which include the use of liver microsomal stability assay for assessing the metabolic liability of drug candidates, analytical method to determine a major residue in bovine milk, and analysis of human cytochrome using doses of probe drugs.

QRS widening and QT prolongation are associated with bupropion. The objectives were to elucidate its cardiac electrophysiological properties. Patch-clamp technique was used to assess the IKr-, IKs-, and INa-blocking effects of bupropion. Langendorff retroperfusion technique on isolated guinea-pig hearts was used to evaluate the MAPD90-, MAP amplitude-, phase 0 d V/d t-, and ECG-modulating effects of bupropion and of two gap junction intercellular communication inhibitors: glycyrrhetinic acid and heptanol. To evaluate their effects on cardiac intercellular communication, fluorescence recovery after photobleaching (FRAP) technique was used. Bupropion is an IKr blocker. IC50 was estimated at 34 μ m. In contrast, bupropion had hardly any effect on IKs and INa. Bupropion had no significant MAPD90-modulating effect. However, as glycyrrhetinic acid and heptanol, bupropion caused important reductions in MAP amplitude and phase 0 d V/d t. A modest but significant QRS-widening effect of bupropion was also observed. FRAP experiments confirmed that bupropion inhibits gap junctional intercellular communication. QT prolongation during bupropion overdosage is due to its IKr-blocking effect. QRS widening with bupropion is not related to cardiac sodium channel block. Bupropion rather mimics the QRS-widening, MAP amplitude- and phase 0 d V/d t -reducing effect of glycyrrhetinic acid and heptanol. Unlike class I anti-arrhythmics, bupropion causes cardiac conduction disturbances by reducing cardiac intercellular coupling. [ABSTRACT FROM AUTHOR]

Propafenone and its 5-hydroxy metabolite exhibit different electrophysiological properties. Objectives of the CAQ-PAF study were (1) to develop a strategy favoring propafenone instead of 5-hydroxypropafenone in plasma following oral administration of propafenone and (2) to evaluate the potential of low-dose quinidine to chronically inhibit CYP2D6. Patients (n = 102) with atrial fibrillation received propafenone 150 mg 3 times daily with either quinidine 100 mg twice daily or placebo. Throughout the study (follow-up, 199 ± 155 days), quinidine successfully inhibited CYP2D6: propafenone concentrations were 3 times higher in patients receiving quinidine (1033 ± 611 ng/mL vs 328 ± 229 ng/mL; P < .001). Moreover, 80% (n = 10) of patients with propafenone levels greater than 1500 ng/mL were in sinus rhythm at 1 year. In contrast, recurrence of atrial fibrillation occurred in 22 of 23 patients with propafenone levels less than 1000 ng/mL (P < .0001). Thus, chronic inhibition of CYP2D6 is achievable with low-dose quinidine in humans. Increased plasma levels of propafenone may be highly beneficial to prevent recurrence of atrial fibrillation. [ABSTRACT FROM PUBLISHER]

The angiotensin-converting enzyme (ACE) gene is a candidate genetic locus for coronary artery disease (CAD). Studies investigating the relationship between the ACE–insertion/deletion (I/D) gene polymorphism and myocardial infarction (MI) have been inconsistent. The authors hypothesized that age may be an important modulating factor in this relationship. ACE-I/D allele and genotype distribution was determined in 3 groups: 104 men with a first MI at a young age (≤45 years old), 271 healthy young men (≤30 years old), and 28 healthy elderly men (>65 years old). All participants were French descendants from Quebec City, Canada. Frequency distribution of the ACE alleles and genotypes was similar among the healthy young, the healthy elderly, and the MI patients (P > .05). However, when considering the age at the time of the MI (≤40, ≤35, or ≤30 years old), a significant age-dependent effect with the prevalence of the ACE-DD genotype was found, as it increased by 22%, 61%, and 157%, respectively, compared with the healthy young group (P < .05). Similar observations were obtained versus the healthy elderly men (P < .05). The ACE-I/D polymorphism seems to be a genetic risk factor for MI in young men and becomes an important modulator of MI risk at a young age. [ABSTRACT FROM PUBLISHER]

Background: Tissue-specific expression of CYP450s can regulate the intracellular concentration of drugs and explain intersubject variability in drug action. The overall objective of our study was to determine in a large cohort of samples, mRNA levels and CYP450 activity expressed in the human heart. Methodology: CYP450 mRNA levels were determined by RTPCR in left ventricular samples (n = 68) of explanted hearts from patients with end-stage heart failure. Samples were obtained from ischemic and non-ischemic hearts. In some instances (n = 7), samples were available from both the left and right ventricles. A technique for the preparation of microsomes from human heart tissue was developed and CYP450-dependent activity was determined using verapamil enantiomers as probedrug substrates. Principal Findings: Our results show that CYP2J2 mRNA was the most abundant isoform in all human heart left ventricular samples tested. Other CYP450 mRNAs of importance were CYP4A11, CYP2E1, CYP1A1 and CYP2C8 mRNAs while CYP2B6 and CYP2C9 mRNAs were present at low levels in only some of the hearts analyzed. CYP450 mRNAs did not differ between ischemic and non-ischemic hearts and appeared to be present at similar levels in the left and right ventricles. Incubation of verapamil with heart microsomes led to the formation of nine CYP450-dependent metabolites: a major finding was the observation that stereoselectivity was reversed compared to human liver microsomes, in which the R-enantiomer is metabolized to a greater extent. Conclusions: This study determined cardiac mRNA levels of various CYP450 isozymes involved in drug metabolism and demonstrated the prevalent expression of CYP2J2 mRNA. It revealed that cardiomyocytes can efficiently metabolize drugs and that cardiac CYP450s are highly relevant with regard to clearance of drugs in the heart. Our results support the claim that drug metabolism in the vicinity of a drug effector site can modulate drug effects. [ABSTRACT FROM AUTHOR]

Background: Adequate platelet inhibition before percutaneous coronary intervention (PCI) reduces periprocedural and long-term ischemic complications. Reduced response to clopidogrel has been associated with subsequent major adverse cardiovascular events. Strategies to optimize platelet inhibition pre-PCI are under investigation. This study evaluated the effect on platelet aggregation of four different dosing regimens of clopidogrel given before elective PCI in a randomized, prospective, double-blind, and placebo-controlled design. Methods: One hundred twenty participants were randomized to one of four groups of clopidogrel: (a) 300 mg on the day prior to angiography; (b) 600 mg on the day prior to angiography; (c) 300 mg followed by 75 mg daily started 1 week prior to angiography; and (d) 300 mg followed by 150 mg daily started 1 week prior to angiography. Platelet aggregation was assessed by light transmission aggregometry (LTA) after stimulation with adenosine diphosphate 20 μM at baseline and at the time of diagnostic coronary angiography. The absolute change in platelet aggregation between these two time points was considered the main outcome measure. Results: At the time of diagnostic coronary angiography, the 300-mg/150-mg daily regimen achieved the greatest decrease in platelet aggregation (37 ± 19%), while the 300 mg regimen provided the smallest (20 ± 22%), an absolute difference between the two groups of 17.2 ± 5.1% (P = 0.005). Conclusions: A 300-mg loading dose of clopidogrel followed by 150 mg daily for 1 week prior to coronary angiography provides more effective platelet inhibition, as defined by LTA, compared to the standard 300-mg loading dose regimen at the time of coronary intervention. [ABSTRACT FROM AUTHOR]

The article presents a study on the effect of gender as a predisposing factor in prolonged QT intervals during cardiac repolarization with the use of potassium channel blockers. The study administered the blockers Indapamide, domperidone and Verapamil to male and female prepubertal guinea pigs. Results showed that females administered with indapamide exhibited a prolonged monophasic action duration at 90% repolarisation (MAPD90) while no gender-related differences were observed for domperidone blockers and verpamil treatment.

Background: The expression and activity of P-glycoproteins due to genetic or environmental factors may have a significant impact on drug disposition, drug effectiveness or drug toxicity. Hence, characterization of drug disposition over a wide range of conditions of these membrane transporters activities is required to better characterize drug pharmacokinetics and pharmacodynamics. This work aims to improve our understanding of the impact of P-gp activity modulation on tissue distribution of P-gp substrate. Methods: A PBPK model was developed in order to examine activity and expression of P-gp transporters in mouse brain and heart. Drug distribution in these tissues was first represented by a wellstirred (WS) model and then refined by a mechanistic transport-based (MTB) model that includes P-gp mediated transport of the drug. To estimate transport-related parameters, we developed an original three-step procedure that allowed extrapolation of in vitro measurements of drug permeability to the in vivo situation. The model simulations were compared to a limited set of data in order to assess the model ability to reproduce the important information of drug distributions in the considered tissues. Results: This PBPK model brings insights into the mechanism of drug distribution in non eliminating tissues expressing P- gp. The MTB model accounts for the main transport mechanisms involved in drug distribution in heart and brain. It points out to the protective role of P-gp at the blood-brain barrier and represents thus a noticeable improvement over the WS model. Conclusion: Being built prior to in vivo data, this approach brings an interesting alternative to fitting procedures, and could be adapted to different drugs and transporters. The physiological based model is novel and unique and brought effective information on drug transporters. [ABSTRACT FROM AUTHOR]

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • The progression and pharmacological response of heart failure-affected patients are subject to interindividual variability. • It is also acknowledged that the genotype frequency of certain gene polymorphisms varies across different ethnic groups and that a difference in gene polymorphism frequencies between healthy and heart failure patients seems to exist. WHAT THIS STUDY ADDS • This study investigated associations between 10 gene polymorphisms of RAAS-related genes with an individual's susceptibility to heart failure. • Our data suggest that the angiotensinogen (AGT) 235 single nucleotide polymorphism (SNP) may be associated with heart failure in our population and that the AGT(M174)-AGT(T235) haplotype, as well as the AGT/angiotensin-converting enzyme (ACE) gene combination, may play an important role in disease predisposition. AIMS Racial differences in survival outcomes point towards a genetic role in the pathophysiology of heart failure. Furthermore, contemporary evidence links genetics to heart failure (HF) predisposition. We tested for a difference in prevalence of 10 renin-angiotensin-aldosterone system (RAAS)-related gene polymorphisms between a homogenous population of HF patients and healthy controls. METHODS One hundred and eleven healthy volunteers and 58 HF patients were included in this study. The healthy control group consisted of males aged between 18 and 35 years old. The HF group consisted of patients (89.7% male) who were 63.8 ± 7.9 years old, were in New York Heart Association (NYHA) class II-III and had a documented left ventricular ejection fraction (LVEF) ≤ 40% within the previous 6 months. Despite being treated maximally for their condition with angiotensin-converting-enzyme (ACE)-inhibitors and β-adrenoceptor blockers, they continued to be symptomatic and, as such, were a highly specialized and homogeneous patient population. Both groups were composed of Canadian Caucasians. The analyzed polymorphisms were: ACE (I/D), angiotensin-II-receptor-type-1 (AGTR1)(A1166C), angiotensinogen (AGT)(M235T and T174M), endothelial-nitric-oxide-synthase (eNOS)(T-786C and Glu298Asp), adrenergic-receptor-â2 (ADRB2)(Gln27Glu), bradykinin-receptor-β2 (BDKRB2)(+9/−9), aldosterone-synthase (CYP11B2)(T-344C) and adducin-1 (ADD1)(Gly460Trp). RESULTS The AGT (T235) allele ( P = 0.0025, OR 2.02, 95% CI 1.24, 3.30) was found to be more prevalent in our HF group. The AGT (174M)-AGT (235T) haplotype was also associated with the HF phenotype ( P = 0.0069). Exploratory evaluation of gene-gene combinations revealed an indicative association of the AGT (T235)/ACE(D) combined polymorphisms in the HF group ( P = 0.02, OR 2.12, 95% CI 1.11, 4.06). CONCLUSIONS This study demonstrates that the SNPs of AGT may be associated with HF in our population and that the AGT/ACE gene combination may play an important role in disease predisposition. [ABSTRACT FROM AUTHOR]

Prolongation of the QT interval has been observed during treatment with olanzapine, a thienobenzodiazepine antipsychotic agent. Our objectives were 1) to characterize the effects of olanzapine on cardiac repolarization and 2) to evaluate effects of olanzapine on the major time-dependent outward potassium current involved in cardiac repolarization, namely IKr (IKr: rapid component of the delayed rectifier potassium current). Isolated, buffer-perfused guinea pig hearts (n=40) were stimulated at different pacing cycle lengths (150-250 msec) and exposed to olanzapine at concentrations ranging from 1 to 100µM. Olanzapine increased monophasic action potential duration measured at 90% repolarization (MAPD90) in a concentration-dependent manner by 6.7 ± 0.7 msec at 3 µM but by 26.0 ± 4.3 msec at 100 µM (250 msec cycle length). Increase in MAPD90 was also reverse frequency dependent; 30 µM olanzapine increased MAPD90 by 28.0 ± 6.2 msec at a pacing cycle length of 250msec but by only 18.9 ± 2.2 msec at a pacing cycle length of 150 msec. Experiments in HERG-transfected (HERG: human ether-a-gogo-related gene) HEK293 cells (n=36) demonstrated concentration-dependent block of the rapid component (IKr) of the delayed rectifier potassium current: tail current was decreased 50% at olanzapine 3.8 µM. Olanzapine possesses direct cardiac electrophysiological effects similar to those of class III anti-arrhythmic drugs. These effects were observed at concentrations that can be measured in patients under conditions of impaired drug elimination such as renal or hepatic insufficiency, during co-administration of other CYP1A2 substrates/inhibitors or after drug overdose. These results offer a new potential explanation for QT prolonging effects observed during olanzapine treatment in patients. [ABSTRACT FROM AUTHOR]