Browsing by Subject "Clinical pharmacology"

Now showing 1 - 5 of 5
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    Agonist antibody to guanylate cyclase receptor NPR1 regulates vascular tone
    (Springer Nature, 2024) Dunn, Michael E.; Kithcart, Aaron; Kim, Jee Hae; Ho, Andre Jo-Hao; Franklin, Matthew C.; Romero Hernandez, Annabel; de Hoon, Jan; Botermans, Wouter; Meyer, Jonathan; Jin, Ximei; Zhang, Dongqin; Torello, Justin; Jasewicz, Daniel; Kamat, Vishal; Garnova, Elena; Liu, Nina; Rosconi, Michael; Pan, Hao; Karnik, Satyajit; Burczynski, Michael E.; Zheng, Wenjun; Rafique, Ashique; Nielsen, Jonas B.; De, Tanima; Verweij, Niek; Pandit, Anita; Locke, Adam; Chalasani, Naga; Melander, Olle; Schwantes-An, Tae-Hwi; Penn Medicine Biobank; Baras, Aris; Lotta, Luca A.; Musser, Bret J.; Mastaitis, Jason; Devalaraja-Narashimha, Kishor B.; Rankin, Andrew J.; Huang, Tammy; Herman, Gary; Olson, William; Murphy, Andrew J.; Yancopoulos, George D.; Olenchock, Benjamin A.; Morton, Lori; Medicine, School of Medicine
    Heart failure is a leading cause of morbidity and mortality1,2. Elevated intracardiac pressures and myocyte stretch in heart failure trigger the release of counter-regulatory natriuretic peptides, which act through their receptor (NPR1) to affect vasodilation, diuresis and natriuresis, lowering venous pressures and relieving venous congestion3-8. Recombinant natriuretic peptide infusions were developed to treat heart failure but have been limited by a short duration of effect9,10. Here we report that in a human genetic analysis of over 700,000 individuals, lifelong exposure to coding variants of the NPR1 gene is associated with changes in blood pressure and risk of heart failure. We describe the development of REGN5381, an investigational monoclonal agonist antibody that targets the membrane-bound guanylate cyclase receptor NPR1. REGN5381, an allosteric agonist of NPR1, induces an active-like receptor conformation that results in haemodynamic effects preferentially on venous vasculature, including reductions in systolic blood pressure and venous pressure in animal models. In healthy human volunteers, REGN5381 produced the expected haemodynamic effects, reflecting reductions in venous pressures, without obvious changes in diuresis and natriuresis. These data support the development of REGN5381 for long-lasting and selective lowering of venous pressures that drive symptomatology in patients with heart failure.
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    Influence of CYP2B6 Pharmacogenetics on Stereoselective Inhibition and Induction of Bupropion Metabolism by Efavirenz in Healthy Volunteers
    (American Society for Pharmacology and Experimental Therapeutics, 2022-07-07) Gufford, Brandon T.; Metzger, Ingrid F.; Bamfo, Nadia O.; Benson, Eric A.; Masters, Andrea R.; Lu, Jessica Bo Li; Desta, Zeruesenay; Medicine, School of Medicine
    We investigated the acute and chronic effects of efavirenz, a widely used antiretroviral drug, and CYP2B6 genotypes on the disposition of racemic and stereoisomers of bupropion (BUP) and its active metabolites, 4-hydroxyBUP, threohydroBUP and erythrohydroBUP. The primary objective of this study was to test how multiple processes unique to the efavirenz-CYP2B6 genotype interaction influence the extent of efavirenz-mediated drug-drug interaction (DDI) with the CYP2B6 probe substrate BUP. In a three-phase, sequential, open-label study, healthy volunteers (N=53) were administered a single 100 mg oral dose of BUP alone (control phase), with a single 600 mg oral efavirenz dose (inhibition phase), and after 17-days pretreatment with efavirenz (600 mg/day) (induction phase). Compared to the control phase, we show for the first time that efavirenz significantly decreases and chronically increases the exposure of hydroxyBUP and its diastereomers, respectively, and these interactions were CYP2B6 genotype dependent. Chronic efavirenz enhances the elimination of racemic BUP and its enantiomers as well as of threo- and erythro-hydroBUP and their diastereomers, suggesting additional novel mechanisms underlying efavirenz interaction with BUP. The effects of efavirenz and genotypes were nonstereospecific. In conclusion, acute and chronic administration of efavirenz inhibits and induces CYP2B6 activity. Efavirenz-BUP interaction is complex involving time- and CYP2B6 genotype-dependent inhibition and induction of primary and secondary metabolic pathways. Our findings highlight important implications to the safety and efficacy of BUP, study design considerations for future efavirenz interactions, and individualized drug therapy based on CYP2B6 genotypes. Significance Statement: The effects of acute and chronic doses of efavirenz on the disposition of racemic and stereoisomers of BUP and its active metabolites were investigated in healthy volunteers. Efavirenz causes an acute inhibition, but chronic induction of CYP2B6 in a genotype dependent manner. Chronic efavirenz induces BUP reduction and the elimination of BUP active metabolites. Efavirenz's effects were non-stereospecific. These data reveal novel mechanisms underlying efavirenz DDI with BUP and provide important insights into time- and CYP2B6 genotype dependent DDIs.
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    Propoxyphene, Norpropoxyphene, and Proadifen (SKF-525A) Are Mechanism Based Inhibitors of CYP3A4, CYP3A5, and CYP3A in Human Liver Microsomes
    (2009-03-18T18:37:57Z) Riley, Anna Ruth; Queener, Sherry F.; Jones, David R.; Flockhart, David A.; Willis, Lynn R.
    The purpose of this study is to determine if propoxyphene and norpropoxyphene are mechanism-based (irreversible) inhibitors of CYP3A, and to determine if propoxyphene and norpropoxyphene are reversible inhibitors of CYP3A. Mechanismbased inhibition is a type of irreversible inhibition that results from an inhibitor or its metabolite binding to an enzyme during drug metabolism, which renders the enzyme nonfunctional. Propoxyphene is an analgesic that is frequently prescribed in the United States and Europe. It is metabolized by CYP3A enzymes, and is an irreversible inhibitor of CYP3A4. The major metabolite of propoxyphene is norpropoxyphene, which has not been extensively studied for enzyme inhibition. Proadifen (SKF-525a) is not a marketed drug, but it is a known CYP inhibitor that is structurally similar to propoxyphene and norpropoxyphene. Propoxyphene, norpropoxyphene, and proadifen were characterized in these studies with CYP3A4(+b5), CYP3A5(+b5) and pooled human liver microsomes. Time-dependent and concentration-dependent loss of activity of CYP3A was measured by formation of testosterone product. Propoxyphene and norpropoxyphene exhibited the greatest inhibition with CYP3A in human liver microsomes, followed by CYP3A4(+b5), and CYP3A5(+b5). Both compounds formed metabolic-inhibitor complexes with vi CYP3A4(+b5) and CYP3A5(+b5), but not with human liver microsomes. Proadifen was a more potent inhibitor of CYP3A4(+b5) than of human liver microsomes and CYP3A5(+b5). The KI values of propoxyphene and CYP3A4(+b5) and human liver microsomes fall within the range of reported therapeutic blood levels of propoxyphene, with reversible inhibition constants (Ki values) above therapeutic blood concentrations for propoxyphene and norpropoxyphene. The KI values of norpropoxyphene and CYP3A4(+b5) and human liver microsomes are higher than most reported blood levels, except for blood levels after repeated dosing of propoxyphene at high concentrations. The predicted change in the area under the plasma concentration versus time curve of an orally administered CYP3A substrate with propoxyphene (AUC'po/AUCpo) was calculated for common CYP3A substrates. The AUC'po/AUCpo ratios are four to twenty-five times higher with co-administration of propoxyphene based on in vitro kinetic parameters. Propoxyphene and norpropoxyphene may cause adverse events when chronically administered at high doses and/or when co-administered with other CYP3A substrates.
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    Strategies prescribers and pharmacists use to identify and mitigate adverse drug reactions in inpatient and outpatient care: a cognitive task analysis at a US Veterans Affairs Medical Center
    (BMJ, 2022-02-21) Nguyen, Khoa Anh; Militello, Laura G.; Ifeachor, Amanda; Arthur, Karen J.; Glassman, Peter A.; Zillich, Alan J.; Weiner, Michael; Russ-Jara, Alissa L.; Medicine, School of Medicine
    Objective: To develop a descriptive model of the cognitive processes used to identify and resolve adverse drug reactions (ADRs) from the perspective of healthcare providers in order to inform future informatics efforts SETTING: Inpatient and outpatient care at a tertiary care US Veterans Affairs Medical Center. Participants: Physicians, nurse practitioners and pharmacists who report ADRs. Outcomes: Descriptive model and emerging themes from interviews. Results: We conducted critical decision method interviews with 10 physicians and 10 pharmacists. No nurse practitioners submitted ADR incidents. We generated a descriptive model of an ADR decision-making process and analysed emerging themes, categorised into four stages: detection of potential ADR, investigation of the problem's cause, risk/benefit consideration, and plan, action and follow-up. Healthcare professionals (HCPs) relied on several confirmatory or disconfirmatory cues to detect and investigate potential ADRs. Evaluating risks and benefits of related medications played an essential role in HCPs' pursuits of solutions CONCLUSIONS: This study provides an illustrative model of how HCPs detect problems and make decisions regarding ADRs. The design of supporting technology for potential ADR problems should align with HCPs' real-world cognitive strategies, to assist fully in detecting and preventing ADRs for patients.
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    Using naltrexone to validate a human laboratory test system to screen new medications for alcoholism (TESMA)- a randomized clinical trial
    (Springer Nature, 2023-04-05) Spreer, Maik; Grählert, Xina; Klut, Ina-Maria; Al Hamdan, Feras; Sommer, Wolfgang H.; Plawecki, Martin H.; O’Connor, Sean; Böttcher, Michael; Sauer, Cathrin; Smolka, Michael N.; Zimmermann, Ulrich S.; Psychiatry, School of Medicine
    This registered clinical trial sought to validate a laboratory test system devised to screen medications for alcoholism treatment (TESMA) under different contingencies of alcohol reinforcement. Forty-six nondependent, but at least medium-risk drinkers were given the opportunity to earn intravenous infusions of ethanol, or saline, as rewards for work in a progressive-ratio paradigm. Work demand pattern and alcohol exposure dynamics were devised to achieve a gradual shift from low-demand work for alcohol (WFA) permitting quickly increasing breath alcohol concentrations (BrAC) to high-demand WFA, which could only decelerate an inevitable decrease of the previously earned BrAC. Thereby, the reward contingency changed, modeling different drinking motivations. The experiment was repeated after at least 7 days of randomized, double-blinded treatment with naltrexone, escalated to 50 mg/d, or placebo. Subjects treated with naltrexone reduced their cumulative WFA (cWFA) slightly more than participants receiving placebo. This difference was not statistically significant in the preplanned analysis of the entire 150 min of self-administration, i.e., our primary endpoint (p = 0.471, Cohen's d = 0.215). Naltrexone serum levels correlated with change in cWFA (r = -0.53; p = 0.014). Separate exploratory analyses revealed that naltrexone significantly reduced WFA during the first, but not the second half of the experiment (Cohen's d = 0.643 and 0.14, respectively). Phase-dependent associations of WFA with changes in subjective stimulation, wellbeing and desire for alcohol suggested that the predominant reinforcement of WFA was positive during the first phase only, and might have been negative during the second. We conclude that the TESMA is a safe and practical method. It bears the potential to quickly and efficiently screen new drugs for their efficacy to attenuate positively reinforced alcohol consumption. It possibly also provides a condition of negative reinforcement, and for the first time provides experimental evidence suggesting that naltrexone's effect might depend on reward contingency.