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Blinatumomab Trimer Formation: Insights From A Mechanistic PKPD Model Into The Implications For Switching From Infusion To Subcutaneous Dosing Regimen medRxiv. Pharmacol. Ther. Pub Date : 2024-03-13 Georgi I Kapitanov, Sarah A Head, David Flowers, Joshua F Apgar, Joshuaine Grant
Blinatumomab is a bispecific T-cell engager (BiTE) that binds to CD3 on T cells and CD19 on B cells. It has been approved for use in B-cell acute lymphoblastic leukemia (B-ALL) with a regimen that requires continuous infusion (cIV) for four weeks per treatment cycle. It is currently in clinical trials for Non-Hodgkin lymphoma (NHL) with cIV administration. Recently, there have been studies investigating
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ASSESSING THE NET FINANCIAL BENEFITS OF EMPLOYING DIGITAL ENDPOINTS IN CLINICAL TRIALS medRxiv. Pharmacol. Ther. Pub Date : 2024-03-09 Joseph A. DiMasi, Abigail Dirks, Zachary Smith, Sarah Valentine, Jennifer C. Goldsack, Thomas Metcalfe, Upinder Grewal, Lada Leyens, Ute Conradi, Daniel Karlin, Lesley Maloney, Kenneth A. Getz, Bert Hartog
Background: In the last few decades developers of new drugs, biologics, and devices have increasingly leveraged digital health technologies (DHTs) to assess clinical trial digital endpoints. To our knowledge, a comprehensive assessment of the financial net benefits of digital endpoints in clinical trials has not been conducted. Data and Methods: We obtained data from the Digital Medicine Society (DiMe)
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Publication bias in pharmacogenetics of statin-associated muscle symptoms, an umbrella review with a meta-epidemiological study medRxiv. Pharmacol. Ther. Pub Date : 2024-03-08 Arthur Gougeon, Ikram Aribi, Sofia Guernouche, Jean-Christophe Lega, James M. Wright, Céline Verstuyft, Audrey Lajoinie, François Gueyffier, Guillaume Grenet
Background: Statin-associated muscle symptoms (SAMS) are a major cause of treatment discontinuation. Adjusting statin dosages for solute carrier organic anion transporter family member 1B1 (SLCO1B1) genotype has been proposed to reduce SAMS. We hypothesized that the association between SLCO1B1 genotype and SAMS is misestimated because of publication bias. Methods: We searched for published systematic
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Predicting drug outcome of population via clinical knowledge graph medRxiv. Pharmacol. Ther. Pub Date : 2024-03-08 Maria Brbic, Michihiro Yasunaga, Prabhat Agarwal, Jure Leskovec
Optimal treatments depend on numerous factors such as drug chemical properties, disease biology, and patient characteristics to which the treatment is applied. To realize the promise of AI in healthcare, there is a need for designing systems that can capture patient heterogeneity and relevant biomedical knowledge. Here we present PlaNet, a geometric deep learning framework that reasons over population
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Determining the feasibility of linked claims and vaccination data for a Covid-vaccine pharmaco-epidemiological study in Germany - RiCO feasibility study protocol medRxiv. Pharmacol. Ther. Pub Date : 2024-03-07 Nina Timmesfeld, Peter Ihle, Robin Denz, Katharina Meiszl, Katrin Scholz, Doris Oberle, Ursula Drechsel-Baeuerle, Brigitte Keller-Stanislawski, Hans H. Diebner, Ingo Meyer
In Germany, there has been no population-level pharmaco-epidemiological study on the safety of the Covid-19 vaccines. One factor preventing such a study so far relates to challenges combining the different relevant data bodies on vaccination with suitable outcome data, specifically statutory health insurance claims data. Individual identifiers used across these data bodies are of unknown quality and
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Anticoagulation-related complications and their outcomes in hemodialysis patients with acute kidney injury at selected hospitals in Ethiopia. medRxiv. Pharmacol. Ther. Pub Date : 2024-02-29 Hanan Muzeyin Kedir, Abdella Birhan Yabeyu, Addisu Melkie Ejigu, Tamrat Assefa Tadesse, Eskinder Ayalew Sisay
Introduction: During hemodialysis (HD), the presence of clots in the dialyzer can diminish the effective surface area of the device. In severe cases, clot formation in the circuit can halt treatment and lead to blood loss in the system. Thus, ensuring proper anticoagulation during HD is crucial to prevent clotting in the circuit while safeguarding the patient from bleeding risks. This study aimed to
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What does it take to make progress in a disease? medRxiv. Pharmacol. Ther. Pub Date : 2024-02-29 Michael S Ringel, Julie Dethier, Michelle J. Davitt, Maria Denslow, R. Andrew Fowler, Sebastian C. Hasenfuss, Ulrik Schulze
In this paper, we investigate what conditions need to be in place to make progress in combating a disease using a case-control design: we compare cases (diseases with a successful therapy) to controls (diseases without a successful therapy). We find five conditions ('hurdles') must typically be cleared for success: (A) understanding of biological drivers, (B) ability to modulate biology, (C) availability
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Dynamic Clinical Success Rates for Drugs in the 21st Century medRxiv. Pharmacol. Ther. Pub Date : 2024-02-29 Ying Zhou, Yintao Zhang, Zhen Chen, Shijie Huang, Yinghong Li, Jianbo Fu, Hongning Zhang, Donghai Zhao, Xichen Lian, Yuan Zhou, Xinyi Shen, Yunqing Qiu, Lianyi Han, Feng Zhu
In clinical drug development, two fundamental questions remain unanswered: what is the success rate of drugs in clinical trial? how does such rate change over time? Herein, a systematic analysis on the dynamic change of drugs' clinical success rates (ClinSRs) using data from 20,398 clinical trial pipelines of 9,682 unique molecular entities during the past two decades was presented. Our analysis discovered
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A Cannabidiol/Terpene Formulation Increases Restorative Sleep in Insomniacs: A Double-Blind, Placebo-controlled, Randomized, Crossover Study medRxiv. Pharmacol. Ther. Pub Date : 2024-02-28 Michael Wang, Marcus Faust, Scott Abbott, Vikrant Patel, Eric Chang, John Clark, Nephi Stella, Paul Muchowski
Study Objectives: Cannabidiol (CBD) is increasingly used as a health supplement, though few human studies have demonstrated benefits. The primary objective of this study was to evaluate the effects of an oral CBD-terpene formulation on sleep physiology in insomniacs. Methods: In this double-blind, placebo-controlled, randomized clinical trial, 125 insomniacs received an oral administration of CBD (300
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Generation of realistic virtual adult populations using a model-based copula approach medRxiv. Pharmacol. Ther. Pub Date : 2024-02-23 Yuchen Guo, Tingjie Guo, Catherijne A.J. Knibbe, Laura B. Zwep, J.G. Coen van Hasselt
Incorporating realistic sets of patient-associated covariates, i.e., virtual populations, in pharmacometric simulation workflows is essential to obtain realistic model predictions. Current covariate simulation strategies often omit or simplify dependency structures between covariates. Copula models are multivariate distribution functions suitable to capture dependency structures between covariates
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TCMM: A Unified Database for Traditional Chinese Medicine Modernization and Therapeutic Innovations medRxiv. Pharmacol. Ther. Pub Date : 2024-02-21 Zhixiang Ren, Yiming Ren, Zeting Li, Huan Xu
Mining the potential of traditional Chinese medicine (TCM) in treating modern diseases requires a profound understanding of its action mechanism and a comprehensive knowledge system that seamlessly bridges modern medical insights with traditional theories. However, existing databases for modernizing TCM are plagued by varying degrees of information loss, which impede the multidimensional dissection
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Towards personalized nicotinamide mononucleotide supplementation: nicotinamide adenine dinucleotide concentration medRxiv. Pharmacol. Ther. Pub Date : 2024-02-21 Ajla Hodzic Kuerec, Weilan Wang, Lin Yi, Rongsheng Tao, Zhigang Lin, Aditi Vaidya, Sohal Pendse, Sornaraja Thasma, Niranjan Andhalkar, Ganesh Avhad, Vidyadhar Kumbhar, Andrea Britta Maier
Nicotinamide mononucleotide (NMN) is a precursor of nicotinamide adenine dinucleotide (NAD), which declines with age. Supplementation of NMN has been shown to improve blood NAD concentration. However, the optimal NMN dose remains unclear. This is a post-hoc analysis of a double-blinded clinical trial involving 80 generally healthy adults aged 40 to 65 years. The participants received a placebo or daily
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SAFETY, PHARMACOKINETICS, AND PHARMACODYNAMICS OF A CLC-1 INHIBITOR - A FIRST-IN-CLASS COMPOUND THAT ENHANCES MUSCLE EXCITABILITY: A PHASE I, SINGLE- AND MULTIPLE-ASCENDING DOSE STUDY medRxiv. Pharmacol. Ther. Pub Date : 2024-02-17 Titia Q Ruijs, Catherine M.K.E. de Cuba, Jules A.A.C. Heuberger, John Hutchison, Jane Bold, Thomas Groennebaek, Klaus G. Jensen, Eva Chin, Jorge Quiroz, Thomas K. Petersen, Peter Flagstad, Marieke L. de Kam, Michiel J. van Esdonk, Erica Klaassen, Robert J. Doll, Ingrid W. Koopmans, Annika A. de Goede, Thomas H Pedersen, Geert Jan Groeneveld
NMD670 is a first-in-class inhibitor of skeletal muscle-specific chloride channel ClC-1, developed to improve muscle weakness and fatigue in neuromuscular diseases. Preclinical studies show that ClC-1 inhibition enhances muscle excitability, improving muscle contractility and strength. We describe the first-in-human administration of ClC-1 inhibitor NMD670. In this randomized, double-blind, placebo-controlled
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Phenotypic models of drug-drug-gene interactions mediated by cytochrome drug-metabolizing enzymes medRxiv. Pharmacol. Ther. Pub Date : 2024-02-02 Roberto Viviani, Judith Berres, Julia C Stingl
Genetic polymorphisms in drug metabolizing enzymes and drug-drug interactions are major sources of inadequate drug exposure and ensuing adverse effects or insufficient responses. The current challenge in assessing drug-drug gene interactions (DDGI) for the development of precise dose adjustment recommendation systems is to take into account both simultaneously. Here, we analyze the static models of
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Medical Marijuana Had No Impact on Amphetamine Prescribing in Medicaid medRxiv. Pharmacol. Ther. Pub Date : 2024-01-30 Errien M. Williams, Mariam Camara, Jessica L. Goldhirsh, Brian J. Piper
Abstract: Due to the uncertainty of the health effects medical marijuana poses, states differ in their medical marijuana laws (MML). Long-term effects of marijuana are found to be like attention-deficit-hyperactive disorder (ADHD). With amphetamines being prescribed to treat ADHD symptoms we hypothesized that amphetamine prescriptions would increase in states implementing MML. The number of amphetamine
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Overcoming the discrepancies between RCTs and real-world data by accounting for Selection criteria, Operations, and Measurements of Outcome (SOMO) medRxiv. Pharmacol. Ther. Pub Date : 2024-01-23 Luca Marzano, Adam S. Darwich, Asaf Dan, Salomon Tendler, Rolf Lewensohn, Luigi De Petris, Jayanth Raghothama, Sebastiaan Meijer
The potential of real-world data to inform clinical trial design and supplement control arms has gained much interest in recent years. The most common approach relies on matching real-world patient cohorts to clinical trial baseline covariates using propensity score techniques. However, recent studies pointed out that there is a lack of replicability, generalisability, and consensus. Further, few studies
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Pharmacogenomic diversity in psychiatry: Challenges and Opportunities in Africa medRxiv. Pharmacol. Ther. Pub Date : 2024-01-20 Muktar B. Ahmed, Anwar Mulugeta, Niran Okewole, Scott Clark, Conrad O. Iyegbe, Azmeraw T. Amare
Background Studies on the pharmacogenomic of psychiatric drugs have slowly identified genetic variations that influence drug metabolism and treatment outcomes, including response, remission, and side effects. However, most of these studies predominantly entered on populations of European descent. As a result, there remains a significant knowledge gap pertaining to the extent of pharmacogenomic diversity
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Clinical Prediction Models for Treatment Outcomes in Newly-diagnosed Epilepsy medRxiv. Pharmacol. Ther. Pub Date : 2024-01-13 Corey Ratcliffe, Vishnav Pradeep, Anthony Marson, Simon S. Keller, Laura J. Bonnett
Background Up to 35% of individuals diagnosed with epilepsy proceed to develop pharmacoresistant epilepsy, leading to persistent uncontrolled seizure activity that can directly, or indirectly, significantly degrade an individual’s quality of life. The factors underlying pharmacoresistance are unclear, but it has been hypothesised that repeated ictogenic activity is conducive to the development of a
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Generalizability in real-world trials medRxiv. Pharmacol. Ther. Pub Date : 2024-01-11 Anatol-Fiete Näher, Marvin Kopka, Felix Balzer, Matthias Schulte-Althoff
Real-world evidence (RWE) trials have a key advantage over conventional randomized controlled trials (RCTs) due to their possibly higher external validity. This allows for better generalizability of results to larger populations, which is essential for evidence-based decision making in clinical medicine, pharmacoepidemiology, and health policy. Random sampling of RWE trial participants is regarded
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Human bronchopulmonary disposition and plasma pharmacokinetics of oral bemnifosbuvir (AT-527), an experimental guanosine nucleotide prodrug for COVID-19 medRxiv. Pharmacol. Ther. Pub Date : 2024-01-08 Xiao-Jian Zhou, Arantxa Horga, Adeep Puri, Lee Winchester, Maureen Montrond, Keith Pietropaolo, Bruce Belanger, Courtney V. Fletcher, Janet Hammond
Bemnifosbuvir (BEM, AT-527) is a novel oral guanosine nucleotide antiviral drug for the treatment of patients with COVID-19. Direct assessment of drug disposition in the lungs, via bronchoalveolar lavage, is necessary to ensure antiviral drug levels at the primary site of SARS-CoV-2 infection are achieved. We conducted a Phase 1 study in healthy subjects to assess the bronchopulmonary pharmacokinetics
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First-in-human trial evaluating safety and pharmacokinetics of AT-752, a novel nucleotide prodrug with pan-serotype activity against dengue virus medRxiv. Pharmacol. Ther. Pub Date : 2024-01-04 Xiao-Jian Zhou, Jason Lickliter, Maureen Montrond, Laura Ishak, Keith Pietropaolo, Dayle James, Bruce Belanger, Arantxa Horga, Janet Hammond
AT-752 is a novel guanosine nucleotide prodrug inhibitor of the dengue virus (DENV) polymerase with sub-micromolar, pan-serotype antiviral activity. This Phase 1, double-blind, placebo-controlled, first-in-human study evaluated the safety, tolerability, and pharmacokinetics of ascending single and multiple oral doses of AT-752 in healthy subjects. AT-752 was well tolerated when administered as a single
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The TuberXpert project protocol: Towards a Clinical Decision Support System for therapeutic anti-tuberculosis medical drugs monitoring in Tanzania medRxiv. Pharmacol. Ther. Pub Date : 2023-12-24 Yann Thoma, Annie E. Cathignol, Yuan J. Pétermann, Margaretha L. Sariko, Bibie Said, Chantal Csajka, Monia Guidi, Stellah G. Mpagama
Introduction The End Tuberculosis (TB) Strategy requires a novel patient treatment approach contrary to the “one-size fits all” model. It is well known that each patient’s physiology is different and leads to various rates of drug elimination. Therapeutic Drug Monitoring (TDM) offers a way to manage drug dosage adaptation but requires trained pharmacologists, which is scarce in resource-limited settings
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Refining the impact of genetic evidence on clinical success medRxiv. Pharmacol. Ther. Pub Date : 2023-12-19 Eric Vallabh Minikel, Jeffrey L Painter, Coco Chengliang Dong, Matthew R Nelson
The cost of drug discovery and development is driven primarily by failure, with just ~10% of clinical programs eventually receiving approval. We previously estimated that human genetic evidence doubles the success rate from clinical development to approval. In this study we leverage the growth in genetic evidence over the past decade to better understand the characteristics that distinguish clinical
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Integration of pharmacists’ knowledge into a predictive model for teicoplanin dose planning medRxiv. Pharmacol. Ther. Pub Date : 2023-12-17 Tetsuo Matsuzaki, Tsuyoshi Nakai, Yoshiaki Kato, Kiyofumi Yamada, Tetsuya Yagi
Teicoplanin is an important antimicrobial agent for methicillin-resistant Staphylococcus aureus infections. To enhance its clinical effectiveness while preventing adverse effects, therapeutic drug monitoring (TDM) of teicoplanin trough concentration is recommended. Given the importance of the early achievement of therapeutic concentrations for treatment success, initial dosing regimens are deliberately
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DPYD genetic polymorphisms in non-European patients with severe fluoropyrimidine-related toxicity: A systematic review medRxiv. Pharmacol. Ther. Pub Date : 2023-12-11 Tsun Ho Chan, J. Eunice Zhang, Munir Pirmohamed
Background Pre-treatment DPYD screening is mandated in the UK and EU to reduce the risk of severe and potentially fatal fluoropyrimidine-related toxicity. Four DPYD gene variants which are more prominently found in Europeans are tested.
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Integrative proteogenomics study identifies the indirect effect of circulating proteins on 8 diseases via telomere length medRxiv. Pharmacol. Ther. Pub Date : 2023-12-08 Shifang Li, Meijiao Gong
Growing evidence has revealed the associations between telomere length and diseases; however, the mechanisms behind these links are not fully understood. In this study, by applying proteome-wide Mendelian randomisation (MR), multiple sensitivity analyses, colocalization, single-cell RNA-sequencing, and mediation analysis, the potential mechanisms that link 4,907 plasma proteins, telomere length, and
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Investigation of genomic and transcriptomic risk factors in clopidogrel response in African Americans. medRxiv. Pharmacol. Ther. Pub Date : 2023-12-07 Guang Yang, Cristina Alarcon, Catherine Chanfreau-Coffinier, Norm H Lee, Paula Friedman, Edith Nutescu, Matthew Tuck, Travis O'Brien, Li Gong, Teri E Klein, Kyong-Mi Chang, Philip S Tsao, David O Meltzer, Million Veteran Program, Sony Tuteja, Minoli A Perera
Clopidogrel, an anti-platelet drug, used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic episodes, with African Americans suffering disproportionately. The aim of this study was to identify biomarkers of clopidogrel resistance in African American patients. We conducted a genome-wide association study, including local ancestry adjustment
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Mendelian randomization analysis supports Factors II and XI as actionable anticoagulant targets medRxiv. Pharmacol. Ther. Pub Date : 2023-12-07 Eloi Gagnon, Estonian Biobank research Team, Arnaud Girard, Jérome Bourgault, Erik Abner, Dipender Gill, Sébastien Thériault, Marie-Claude Vohl, André Tchernof, patrick mathieu, Benoit J Arsenault
Background: Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in patients undergoing prolonged anticoagulation. New safer anticoagulant targets are needed. Methods: We performed two-sample Mendelian randomization (MR) and genetic colocalization to prioritize
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Effect of RAS Inhibitors in Acute Ischemic Stroke to Improve Outcomes: A Cross Sectional and Longitudinal Analysis. medRxiv. Pharmacol. Ther. Pub Date : 2023-12-07 Sophie samuel, Kyndol Craver, Charles Miller, Brittany Pelsue, Catherine Gonzalez, Teresa Annette Allison, Brain Gulbis, Huimahn Alex Choi, Seokhum Kim
Background: Acute ischemic stroke (AIS) is a major health challenge, often resulting in long-term disability and death. This study assesses the impact of renin-angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) on AIS patient mortality compared to non-RAS antihypertensive medications. Methods: This retrospective cohort study, conducted at
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SLCO1B1 functional variants and statin-induced myopathy in people with recent genealogical ancestors from Africa: a population-based real-world study. medRxiv. Pharmacol. Ther. Pub Date : 2023-12-03 Sook Wah Yee, Tanushree Haldar, Mark Kvale, Jia Yang, Michael P Douglas, Akinyemi Oni-Orisan
Background: Clinical pharmacogenetic implementation guidelines for statin therapy are derived from evidence of primarily Eurocentric study populations. Functional SLCO1B1 variants that are rare in these study populations have not been investigated as a determinant of statin myotoxicity and are thus missing from guideline inclusion. Objective: Determine the relationship between candidate functional
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Thyroid hyperplasia and neoplasm adverse events associated with GLP-1 receptor agonists in FDA Adverse Event Reporting System medRxiv. Pharmacol. Ther. Pub Date : 2023-11-24 Tigran Makunts, Haroutyun Joulfayan, Ruben Abagyan
Glucagon receptor-like peptide receptor agonists, GLP-1 RAs, are one of the most commonly used drugs for type-2 diabetes mellitus. The clinical guidelines recommend GLP-1 RAs as adjunct to diabetes therapy in patients with chronic kidney disease, presence or risk of atherosclerotic cardiovascular disease, obesity, and other cardiometabolic conditions. The weight loss seen in clinical trials has been
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Availability, market share and price of quality assured artemisinin-based combination therapies in private drug outlets after over a decade of Copayment mechanism in Uganda. medRxiv. Pharmacol. Ther. Pub Date : 2023-11-18 Moses Ocan, Winnie Nambatya, Caroline Otike, Loyce Nakalembe, Sam Nsobya
Background Malaria remains one of the leading causes of morbidity, and mortality in Uganda. A large proportion of malaria symptomatic patients seek healthcare in the private sector. However, availability and affordability are major barriers to access to effective treatment. The private sector copayment mechanism in Uganda aims to increase availability and affordability of antimalarial agents. Our study
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Identification of therapeutic targets for 18 clinical diseases by integrating human plasma proteome with genome medRxiv. Pharmacol. Ther. Pub Date : 2023-11-17 Shifang Li, Meijiao Gong
The proteome is an abundant source of potential therapeutic targets, and a comprehensive evaluation of proteins as therapeutic targets for a wide range of diseases is required. By screening 4,907 plasma proteins, we conducted a systematically two-sample proteome-wide Mendelian randomisation (MR) study to uncover potential therapeutic targets for 18 clinical diseases. Following MR analysis and stringent
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Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome medRxiv. Pharmacol. Ther. Pub Date : 2023-11-16 Martina Vinicki, Tea Pribic, Frano Vuckovic, Azra Frkatovic-Hodzic,, Isaac Plaza-Andrade, Francisco Tinahones, Joseph Raffaele, Jose Carlos Fernandez-Garcia, Gordan Lauc
With aging, there is a correlation between a decline in the body′s ability to maintain regular functioning and greater susceptibility to age-related diseases. Therapeutic interventions targeting the underlying biological changes of aging hold promise for preventing or delaying multiple age-related diseases. Metformin, a drug commonly used for diabetes treatment, has emerged as a potential gerotherapeutic
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Effectiveness and safety of drugs in pregnancy: evidence from drug target Mendelian randomization medRxiv. Pharmacol. Ther. Pub Date : 2023-11-06 Ciarrah-Jane Shannon Barry, Venexia Walker, Christy Burden, Alexandra Havdahl, Neil M Davies
Limited information exists regarding the impact of pharmacotherapy in pregnancy due to ethical concerns of unintended foetal harm. We investigate genetically proxied intrauterine antihypertensive exposure on offspring outcomes, including gestational age and birthweight, using two-sample multivariable Mendelian randomization. Higher levels of maternal protein targets for calcium channel blockers increased
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Oxytocin-augmented modular-based group intervention for loneliness: A proof-of-concept randomized-controlled trial medRxiv. Pharmacol. Ther. Pub Date : 2023-10-30 Ruben Berger, Rene Hurlemann, Simone G. Shamay-Tsoory, Alisa Kantermann, Maura Brauser, Jessica Gorni, Maike Luhmann, Elisabeth Schramm, Johannes Schultz, Alexandra Philipsen, Jana Lieberz, Dirk Scheele
Introduction: Loneliness poses a significant health problem and existing psychological interventions have shown only limited positive effects on loneliness. Based on preliminary evidence for impaired oxytocin signaling in trait-like loneliness, the current proof-of-concept study used a randomized, double-blind, placebo-controlled design to probe intranasal oxytocin (OT) as an adjunct to a short-term
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HAI-VECT(SCD): AI-Humanoid Enabled Virtual Clinical Trial for Sickle Cell Disease medRxiv. Pharmacol. Ther. Pub Date : 2023-10-18 Wayne Robert Danter
Background: Sickle Cell Disease (SCD) remains a globally important disorder with limited therapeutic options. This study utilizes the advanced capabilities of the DeepNEU platform v8.2 and aiHumanoid (Pat. Pend.) simulations to evaluate potential drug combinations for treating SCD, focusing on vaso-occlusive events (VOE) and associated secondary outcomes. Methods: Using data from 25 virtual patients
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Concentration-effect relationships of plasma caffeine on EEG delta power and cardiac autonomic activity during human sleep medRxiv. Pharmacol. Ther. Pub Date : 2023-10-14 Diego M. Baur, Dario A. Dornbierer, Hans-Peter Landolt
Acute caffeine intake affects brain and cardiovascular physiology, yet the concentration-effect relationships on the electroencephalogram (EEG) and cardiac autonomic activity during sleep are poorly understood. To tackle this question, we simultaneously quantified the plasma caffeine concentration with ultra-high-performance liquid chromatography, as well as the EEG, heart rate and high-frequency (0
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40 Hz Light Flickering Promotes Sleep through Cortical Adenosine Signaling medRxiv. Pharmacol. Ther. Pub Date : 2023-10-09 Yan He, Xuzhao Zhou, Tao Xu, Zhaofa Wu, Wei Guo, Xi Xu, Yuntao Liu, Yi Zhang, Huiping Shang, Zhimo Yao, Zewen Li, Zhihui Li, Tao Feng, Shaomin Zhang, Rodrigo Cunha, Zhi-Li Huang, Yulong Li, Xiaohong Cai, Jia Qu, Jiang-Fan Chen
Flickering light stimulation has emerged as a promising non-invasive neuromodulation strategy to alleviate neuropsychiatric disorders. However, the lack of a neurochemical underpinning has hampered its therapeutic development. Here, we demonstrate that light flickering triggered an immediate and sustained increase (up to 3 hours after flickering) in extracellular adenosine levels in the primary visual
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Effect of ginger supplementation on the fecal microbiome in subjects with prior colorectal adenoma medRxiv. Pharmacol. Ther. Pub Date : 2023-10-05 Ajay Prakash, Nathan Rubin, Christopher Staley, Guillaume Onyeaghala, Ya-Feng Wen, Aasma Shaukat, Ginger Milne, Robert Straka, Timothy R Church, Anna Prizment
Ginger has been associated with a decreased incidence of colorectal cancer (CRC) through reduction in inflammatory pathways and inhibition of tumor growth. Recent pre-clinical models have implicated changes in the gut microbiome as a possible mediator of the ginger effect on CRC. We hypothesized that, in adults previously diagnosed with a colorectal adenoma, ginger supplementation would alter the fecal
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Discovery of Ancestry-Specific Variants Associated with Clopidogrel Response among Caribbean Hispanics. medRxiv. Pharmacol. Ther. Pub Date : 2023-10-02 Guang Yang, Pablo González, Mariangeli Moneró, Kelvin Carrasquillo, Jessicca Y. Renta, Dagmar Fredy Hernandez-Suarez, Mariana R. Botton, Kyle Melin, Stuart Scott, Gualberto Ruaño, Abiel Roche-Lima, Cristina Alarcon, Marylyn Ritchie, Minoli Perara, Jorge Duconge
Background. High on-treatment platelet reactivity (HTPR) with clopidogrel is predictive of ischemic events in adults with coronary artery disease. Despite strong data suggesting HTPR varies with ethnicity, including clinical and genetic variables, no genome-wide association study (GWAS) of clopidogrel response has been performed among Caribbean Hispanics. This study aimed to identify genetic predictors
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SAFETY ASSESSMENT OF LUTEIN AND ZEAXANTHIN SUPPLEMENTATION AND ITS EFFECTS ON BLOOD GLUCOSE LEVELS, KIDNEY FUNCTIONS, LIVER FUNCTIONS AND BONE HEALTH - A RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED CLINICAL STUDY medRxiv. Pharmacol. Ther. Pub Date : 2023-09-29 Vadiraj GB, C A Anzar, Joseph MV, Sundaram R, Prasad CP, Bineesh Eranimose, Shobith Jagadeesh
Objective: HbA1c, a major marker for the sugar levels in the blood, is the litmus test for people who are on the verge of entering the diabetic zone and for those who are already affected by this disease. Oral hypoglycemic agents are the fine line of treatment in such cases. Nutraceutical and herbal supplements can be utilized as a prophylactic to keep such diseases at bay. Lutein, a carotenoid from
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Exploring the effects of Dasatinib, Quercetin, and Fisetin on DNA methylation clocks: a longitudinal study on senolytic interventions medRxiv. Pharmacol. Ther. Pub Date : 2023-09-26 Edwin Lee, Natalia Carreras-Gallo, Leilani Lopez, Logan Turner, Aaron Lin, Tavis L Mendez, Hannah Went, Alan Tomusiak, Eric Verdin, Michael Corley, Lishomwa Ndhlovu, Ryan Smith, Varun B Dwaraka
Senolytics, small molecules targeting cellular senescence, have emerged as potential therapeutics to enhance health span. However, their impact on epigenetic age remains unstudied. This study aimed to assess the effects of Dasatinib and Quercetin (DQ) senolytic treatment on DNA methylation (DNAm), epigenetic age, and immune cell subsets. In a Phase I pilot study, 19 participants received DQ for 6 months
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Antimicrobial susceptibility testing reveals reduced susceptibility to azithromycin and other antibiotics in Legionella pneumophila serogroup 1 isolates from Portugal medRxiv. Pharmacol. Ther. Pub Date : 2023-09-26 Corrado Minetti, Rachael Barton, Caitlin Farley, Brad Owen Spiller, Raquel Esaguy Rodrigues, Paulo Goncalves
Background: Although not fully investigated, studies show that Legionella pneumophila can develop antibiotic resistance. As there is limited data available for Portugal, we determined the antibiotic susceptibility profile of Portuguese L. pneumophila serogroup 1 (LpnSg1) isolates against antibiotics used in the clinical practice in Portugal. Methods: Minimum inhibitory concentrations (MICs) were determined
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Pharmacokinetic effects of a single-dose nutritional ketone ester supplement on brain ketone and glucose metabolism in alcohol use disorder medRxiv. Pharmacol. Ther. Pub Date : 2023-09-26 Xinyi Li, Anthony J Young, Lais S Pereira-Rufino, Zhenhao Shi, Juliana I Byanyima, Sianneh Vesslee, Rishika Reddy, Timothy Pond, Mark Elliott, Ravinder Reddy, Robert K Doot, Jan-Willem van der Veen, Henry Kranzler, Jacob G Dubroff, Corinde E Wiers
Introduction: Acute alcohol intake decreases brain glucose metabolism and increases brain uptake of acetate, a metabolite of alcohol. Individuals with alcohol use disorder (AUD) show elevated brain acetate metabolism at the expense of glucose, a shift in energy utilization that persists beyond acute intoxication. We recently reported that nutritional ketosis and administration of ketone bodies as an
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Repurposing of rituximab biosimilars to treat B cell mediated autoimmune diseases medRxiv. Pharmacol. Ther. Pub Date : 2023-09-25 Agata Agata Mostkowska, Guy Rousseau, Noel Raynal
Rituximab, the first monoclonal antibody approved for the treatment of lymphoma, eventually became one of the most popular and versatile drugs ever in terms of clinical application and revenue. Since its patent expiration, and consequently, the loss of exclusivity of the original biologic, its repurposing as an off-label drug has increased dramatically, propelled by the development and commercialization
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Atazanavir/ritonavir increased tizoxanide exposure from oral nitazoxanide through pharmacokinetic interaction in healthy volunteers medRxiv. Pharmacol. Ther. Pub Date : 2023-09-22 Abdulafeez Akinloye, Timothy Oyedeji, Oluwasegun Eniayewu, Babatunde Adeagbo, Oluseye Bolaji, Steve Rannard, Andrew Owen, Adeniyi Olagunju
Aims: Nitazoxanide is a broad–spectrum antiviral with potential application in a number of viral infections. Its use is limited by gastrointestinal side effects associated with increasing dose. In this study, we investigated the possibility of enhancing the exposure of its active metabolite, tizoxanide, through pharmacokinetic interaction with atazanavir/ritonavir. Method: This was a crossover drug–drug
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Drug-induced liver injury associated with elexacaftor/tezacaftor/ivacaftor from the FDA Adverse Event Reporting System (FAERS) medRxiv. Pharmacol. Ther. Pub Date : 2023-09-17 Alan Shi, Harold Nguyen, Chiaoyun Benson Kuo, Paul M Beringer
Introduction: The efficacy and safety of elexacaftor/tezacaftor/ivacaftor (ETI) have been established in prospective clinical trials. Liver function test elevations were observed in a greater proportion of patients receiving ETI compared with placebo; however, the relatively small number of patients and short duration of study preclude detection of rare but clinically significant associations with
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Association between Haloperidol use and Risk of Rheumatoid Arthritis medRxiv. Pharmacol. Ther. Pub Date : 2023-09-12 Vidya Ambati, Tammy Cummings, Praveen Yerramothu, Joseph Nguyen, S Scott Sutton, Brian Werner, Joseph Magagnoli
Haloperidol is an anti-psychotic used for the treatment of schizophrenia or Tourette disorder. Here we report, by studying three large administrative health insurance databases, that haloperidol use is associated with a reduced risk of developing rheumatoid arthritis. A meta-analysis revealed a 31% reduced hazard of incident rheumatoid arthritis among individuals with schizophrenia or Tourette disorder
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Effect of cannabigerol on sleep and quality of life in Veterans: A decentralized, randomized, placebo-controlled trial medRxiv. Pharmacol. Ther. Pub Date : 2023-09-01 Chris R Emerson, Courtney E Webster, Eric J Daza, Brett G Klamer, Meghasyam Tummalacherla
Background/Objective: This decentralized, randomized, triple-blind, placebo-controlled study evaluated the efficacy and safety of an oral cannabigerol (CBG) formulation in Veterans with sleep issues. Methods: After inclusion, randomization and a two-week run-in phase, participants received CBG (25 mg daily for two weeks, escalated to 50 mg daily for a further two weeks) or placebo. The primary endpoint
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Pharmacokinetics-based identification of antiviral compounds of Rheum palmatum rhizomes and roots (Dahuang) medRxiv. Pharmacol. Ther. Pub Date : 2023-08-30 Nan-Nan Tian, Ling-Ling Ren, Ya-Xuan Zhu, Jing-Ya Sun, Jun-Lan Lu, Jia-Kai Zeng, Feng-Qing Wang, Fei-Fei Du, Xi-He Yang, Shu-Ning Ge, Rui-Min Huang, Wei-Wei Jia, Chuan Li
The potential of Dahuang to eliminate lung pathogens was often highlighted in Wenyi Lun. This investigation aimed to identify potential antiviral compounds of herbal component Dahuang (Rheum palmatum rhizomes and roots) of LianhuaQingwen capsule, with respect to their systemic exposure and lung reachability. Circulating Dahuang compounds were identified in human volunteers receiving LianhuaQingwen
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Psilocybin desynchronizes brain networks medRxiv. Pharmacol. Ther. Pub Date : 2023-08-24 Joshua S Siegel, Subha Subramanian, Demetrius A Perry, Benjamin P Kay, Evan M Gordon, Timothy O Laumann, Ravi V Chacko, Travis R Reneau, Nicholas V Metcalf, Christine Horan, Julie A Schweiger, Dean Wong, David Bender, Jonah Padawer-Curry, Charles L Raison, Robin Carhart-Harris, Marcus E Raichle, Eric J Lenze, Abraham Z Snyder, Nico U.F. Dosenbach, Ginger E Nicol
The relationship between the acute effects of psychedelics and their persisting neurobiological and psychological effects is poorly understood. Here, we tracked brain changes with longitudinal precision functional mapping in healthy adults before, during, and for up to 3 weeks after oral psilocybin and methylphenidate (17 MRI visits per participant) and again 6+ months later. Psilocybin disrupted connectivity
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Mediation and Longitudinal Analysis to interpret the association between clozapine pharmacokinetics, pharmacogenomics, and absolute neutrophil count. medRxiv. Pharmacol. Ther. Pub Date : 2023-08-24 Siobhan K Lock, Sophie E Legge, Djenifer B. Kappel, Isabella Rachel Willcocks, Marinka Helthuis, John Jansen, James T. R. Walters, Michael J Owen, Michael C O'Donovan, Antonio F Pardiñas
Clozapine is effective at reducing symptoms of treatment-resistant schizophrenia, but it can also induce several adverse outcomes including neutropenia and agranulocytosis. We used linear mixed-effect models and structural equation modelling to determine whether pharmacokinetic and genetic variables influence absolute neutrophil count in a longitudinal UK-based sample of clozapine users not currently
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The Clinical Effectiveness of One-Dose HPV Vaccine: A meta-analysis of 902,368 vaccinated women medRxiv. Pharmacol. Ther. Pub Date : 2023-08-23 Didik Setiawan, Nunuk Aries Nurulita, Sudewi Mukaromah, Maarten J Postma
Abstract Introduction Although the effectiveness of the HPV vaccine has been comprehensively described, adherence to dosing and limited budget is one of the causes of delay in HPV vaccination implementation in a country. A one-dose HPV vaccine could possibly solve those issues since several studies show promising results. Areas covered This is a systematic review and meta-analysis focusing on the effectiveness
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Prevalence and Prescribers’ Knowledge of Psychotropic Polypharmacy in the Bono, Bono East, and Ahafo Regions, Ghana. medRxiv. Pharmacol. Ther. Pub Date : 2023-08-20 ANTWI JOSEPH BARIMAH, James Dumba, Mohammed Mohammed Ibrahim, Solomon Saka Allotey, Semefa Alorvi, William Appertey, Luke Sopaal, Frank Acheampong, Benjamin Pulle Niriwa
The use of psychotropic medications for treating simple and complex psychological and emotional problems is common and relevant among prescribers. This, therefore, come with the tendency to prescribe many medications to a patient on a single visit due to varied reasons. The study, therefore, sought to ascertain the prevalence and prescribers' knowledge of psychotropic polypharmacy. A quantitative,
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Characterization and Genome Sequencing of a Novel Lytic Bacteriophage Infecting Hospital-Associated Carbapenem-Resistant Klebsiella pneumoniae Strain from Dhaka, Bangladesh medRxiv. Pharmacol. Ther. Pub Date : 2023-08-15 NSU Genome Research Institute (NGRI), North South University, Muhammad Maqsud Hossain
Background: Multidrug-resistant bacterial pathogens pose a grave threat to global health, with Klebsiella pneumoniae being a particular concern due to its hypervariable extracellular matrix capsule and frequent development of extended-spectrum β-lactamases and other antibiotic defenses. Treating K. pneumoniae-induced infections with antibiotics is becoming increasingly challenging, necessitating the
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Pharmacotherapy for Children and adolescents with overweight and obesity: a systematic review and network meta-analysis of randomized controlled trials medRxiv. Pharmacol. Ther. Pub Date : 2023-08-09 Li Luo, Tingting Huang, Hui Wang, Jianglin Zhao, Yunyun Qi, Zijing Yan, Chunmei Zhu, Chufeng Wang, Na Su, Ting Xu, Shengzhao Zhang
Background: Overweight and obesity are widespread among children and adolescents. We aimed to summarize the evidence for the pharmacotherapy as an adjunct to lifestyle interventions in overweight or obese children and adolescents by comparing the benefits and harms. Methods: RCTs (randomized controlled trials) were sourced from PubMed, Embase (using the OVID platform), the Cochrane Library (CENTRAL)
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Prognosis and personalized in-silico prediction of treatment efficacy in cardiovascular and chronic kidney disease: a proof-of-concept study medRxiv. Pharmacol. Ther. Pub Date : 2023-08-06 Mayra Alejandra Jaimes Campos, Iván Andújar, Felix Keller, Gert Mayer, Peter Rossing, Jan A Staessen, Christian Delles, Joachim Beige, Griet Glorieux, Andrew Clark, William Mullen, Joost P Schanstra, Antonia Vlahou, Kasper Rossing, Karlheinz Peter, Alberto Ortiz, Archie Campbell, Frederik Persson, Agnieszka Latosinska, Harald Mischak, Justyna Siwy, Joachim Jankowski
kidney and cardiovascular diseases are responsible for a large fraction of population morbidity and mortality. Early, targeted, personalized intervention represents the ideal approach to cope with this challenge. Proteomic/peptidomic changes are largely responsible for onset and progression of these diseases and should hold information about optimal means for treatment and prevention. We investigated
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A dose-finding study to guide use of verapamil as an adjunctive therapy in tuberculosis medRxiv. Pharmacol. Ther. Pub Date : 2023-08-05 Chandrasekaran Padmapriyadarsini, John Szumowski, Nabila Akbar, Prema Shanmugasundaram, Anilkumar Jain, Marasamy Bathragiri, Manoranjan Pattnaik, Jyotirmayee Turuk, Ramesh Karunaianantham, Senthilkumar Balakrishnan, Sangamitra Pati, Hemanth KA Kupparam, Manoj Rathore, Jegadeesh Raja, Raghu Naidu, John Horn, Laura Whitworth, Roger Sewell, Lalita Ramakrishnan, Soumya Swaminathan, Paul Edelstein
Induction of mycobacterial efflux pumps is a cause of Mycobacterium tuberculosis (Mtb) drug tolerance, a barrier to shortening antitubercular treatment. Verapamil inhibits Mtb efflux pumps that mediate tolerance to rifampin, a cornerstone of tuberculosis treatment. Mycobacterial efflux pump inhibition by verapamil also limits Mtb growth in macrophages in the absence of antibiotic treatment. These findings
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Factors associated with therapeutic inertia in individuals with type 2 diabetes mellitus started on basal insulin medRxiv. Pharmacol. Ther. Pub Date : 2023-07-16 Sharmin Shabnam, Clare Gillies, Melanie J. Davies, Terry Dex, Eka Melson, Kamlesh Khunti, David Webb, Francesco Zaccardi, Samuel Seidu
Aim In this study we aim to identify the risk factors for treatment inertia in patients with type 2 diabetes mellitus (T2DM) who have been recently started on basal insulin (BI). Methods Using UK CPRD GOLD, we identified adults with T2DM with suboptimal glycaemia (HbA1c within 12 months of BI ≥7% (≥53 mmol/mol)). We used multivariable Cox regression model to describe the association between patient