Journal of Pharmacology and Experimental Therapeutics最新文献

{"title":"New potential ligand-receptor axis involved in tissue repair as therapeutic targets in progressive multiple sclerosis.","authors":"Eugenio Antonio Carrera Silva, Jorge Correale, Carla Rothlin, Juan Manuel Ortiz Wilczyñski","doi":"10.1124/jpet.124.002254","DOIUrl":"https://doi.org/10.1124/jpet.124.002254","url":null,"abstract":"<p><p>Progressive multiple sclerosis (PMS) represents the worsening phase of the disease by accumulative neurodegeneration and disability, mainly refractory to current treatments. The therapeutic options remain challenging based partially on the lack of understanding of the pathogenic mechanisms but also because the early dogma was centered on neuroinflammation, overshadowing the critical role of the tissue repair process. The tissue repair target should necessarily start early in disease development and PMS should combine anti-inflammatory and neuroprotective therapeutic strategies. Increasing preclinical evidence, together with the new era of omics applied on frozen human brain tissue, shed light on some ligand receptors axis, such as GAS6/TYRO3 and PROS1/AXL required to dampen inflammation, promote tissue repair and engage remyelination, at the early stages of multiple sclerosis (MS) as a critical step in preventing or stopping neurodegeneration. Here, we will discuss those receptor/ligand pairs that could be targetable for therapeutic intervention in progressive MS disease. <b>Significance Statement</b> The aim for PMS should be to combine anti-inflammatory and neuroprotective therapeutic strategies based on early intervention. The TYRO3, AXL, and MERTK (TAM) signaling axis, particularly GAS6/TYRO3 and PROS1/AXL, which are involved in tempering inflammation, promoting tissue repair, and engaging remyelination, could significantly benefit patients at the early PMS.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391380","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"COSMIC Database and Structural Modeling Analysis of CYP2D6 Mutations in Human Cancers.","authors":"Kennedy Kuchinski, Nathaniel King, Julia Driggers, Kylie Lawson, Martin Vo, Shayne Skrtic, Connor Slattery, Rebecca Lane, Emma Simone, Stephen A Mills, Wilber Escorcia, Hanna Wetzel","doi":"10.1124/jpet.124.002136","DOIUrl":"https://doi.org/10.1124/jpet.124.002136","url":null,"abstract":"<p><p>Single nucleotide polymorphisms (SNPs) in cytochrome P450 (CYP450) enzymes alter the metabolism of a variety of drugs. Numerous medications, including chemotherapies, are metabolized by CYP450 enzymes, making the expression of this suite of enzymes in tumor cells relevant to prescription regimens for cancer patients. We analyzed the characteristics of mutations of the CYP2D6 enzymes in cancer patients obtained from the Catalogue of Somatic Mutations in Cancer (COSMIC), including mutation type, age of the patient, tissue type, and histology. Mutations were analyzed through the Cancer-Related Analysis of Variants Toolkit (CRAVAT) software along with CHASM and VEST4 algorithms to determine the likelihood of being a driver and/or pathogenic mutation. For mutations with significant CHASM and VEST4 scores, structural analysis of each corresponding mutant protein was performed. The effect of each mutation was evaluated for its impact on the overall protein stability and ligand binding using Foldit Standalone and SwissDock, respectively. Structural analysis revealed that several missense mutations in CYP2D6 resulted in altered stability after energy minimization. Three missense mutations of CYP2D6 significantly altered docking stability and those located on alpha-helices near the docking site had a more significant impact than those not found in secondary protein structures. In conclusion, we have identified a series of mutations to CYP2D6 enzymes with possible relevance to cancer pathologies. <b>Significance Statement</b> CYP2D6 is responsible for the metabolism of many anti-cancer drugs. This study identified and characterized a series of mutations in the CYP2D6 enzyme that occurred in tumors. We found it likely that many of these mutations would alter enzyme function, leading to changes in drug metabolism in the tumor. We provide a basis for predicting the likelihood of a patient carrying these mutations to identify patients who may benefit from a precision medicine approach to drug selection and dosing.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142391378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction to “Comments on: Increasing Enzyme Mannose-6-Phosphate Levels but Not Miglustat Coadministration Enhances the Efficacy of Enzyme Replacement Therapy in Pompe Mice”","authors":"American Society for Pharmacology and Experimental Therapeutics","doi":"10.1124/jpet.123.002014err","DOIUrl":"https://doi.org/10.1124/jpet.123.002014err","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255507","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding Cisplatin Pharmacokinetics and Toxicodynamics to Predict and Prevent Kidney Injury.","authors":"Lauren E Thompson, Melanie S Joy","doi":"10.1124/jpet.124.002287","DOIUrl":"https://doi.org/10.1124/jpet.124.002287","url":null,"abstract":"<p><p>Cisplatin is a common platinum-based chemotherapeutic that induces acute kidney injury (AKI) in about 30% of patients. Pharmacokinetic/toxicodynamic (PKTD) models of cisplatin-induced AKI have been used to understand risk factors and evaluate potential mitigation strategies. While both traditional clinical biomarkers of kidney function [e.g. serum creatinine (SCr), blood urea nitrogen (BUN), estimated glomerular filtration rate (eGFR), and creatinine clearance (CrCl)] and newer subclinical biomarkers of kidney injury [e.g. urinary kidney injury molecule 1 (KIM-1), beta-2 microglobulin (B2M), neutrophil gelatinase-associated lipocalin (NGAL), calbindin, etc.] can be used to detect cisplatin-induced AKI, published PKTD models are limited to using only traditional clinical biomarkers. Previously identified risk factors for cisplatin nephrotoxicity have included dose, age, sex, race, body surface area, genetics, concomitant medications, and comorbid conditions. However, the relationships between concentrations and PK of platinum and biomarkers of kidney injury have not been well elucidated. This review discusses the evaluation of cisplatin-induced nephrotoxicity in clinical studies, mouse models, and <i>in vitro</i> models, and examines the available human PK and TD data. Improved understanding of the relationships between platinum PK and TD, in the presence of identified risk factors, will enable the prediction and prevention of cisplatin kidney injury. <b>Significance Statement</b> As cisplatin treatment continues to cause AKI in a third of patients, it is critical to improve the understanding of the relationships between platinum PK and nephrotoxicity as assessed by traditional clinical and contemporary subclinical TD markers of kidney injury. Prediction and prevention of cisplatin-induced nephrotoxicity will be advanced by the evolving development of PKTD models that incorporate kidney injury biomarkers with enhanced sensitivity and include covariates that can impact risk of developing cisplatin-induced AKI.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142348896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<b>Contrasting the Reinforcing Effects of the Novel Dopamine Transport Inhibitors JJC8-088 and JJC8-091 in Monkeys: Potential Translation to Medication Assisted Treatment</b>.","authors":"Mia I Allen, Omeed Rahimi, Bernard N Johnson, Jianjing Cao, Amy Hauck Newman, Michael A Nader","doi":"10.1124/jpet.124.002356","DOIUrl":"https://doi.org/10.1124/jpet.124.002356","url":null,"abstract":"<p><p>Despite considerable efforts, there remains no FDA-approved medications for cocaine use disorder (CUD). One strategy to mitigate cocaine craving and relapse is to elevate dopamine (DA). The DA transport inhibitor and releaser <i>d</i>-amphetamine has been shown to decrease cocaine self-administration (SA), although it has abuse liability. Recently, several modafinil analogues reduced cocaine SA in rats and monkeys, including JJC8-088, characterized as \"cocaine like\" in rats, and JJC8-091, characterized as \"atypical\" and not SA by rats. The present studies evaluated the reinforcing effects of both compounds in monkeys under several conditions. For Experiment 1, four male cocaine-experienced rhesus monkeys self-administered cocaine (0.001-0.3 mg/kg/injection), JJC8-088 (0.001-0.3 mg/kg/injection), and JJC8-091 (0.1-3.0 mg/kg/injection) under a progressive-ratio (PR) schedule of reinforcement. Both JJC compounds functioned as reinforcers with equal reinforcing strength to cocaine. Although JJC8-091 was less potent than cocaine, JJC8-088 and cocaine had similar potencies. For Experiment 2, one male and two females drug-naïve cynomolgus monkeys responded on a fixed-ratio schedule of food reinforcement. JJC8-091 was self-administered at rates higher than saline in all three monkeys. In Experiment 3, monkeys from Experiment 2 responded under a concurrent drug vs. food choice paradigm and given access to cocaine or JJC8-091 under these conditions. At doses equal to or one-half log-units higher than doses used in Experiment 2, cocaine, but not JJC8-091, was chosen over food. Together, these results demonstrate that while JJC8-091 may be reinforcing under some conditions, its reinforcing strength, in the presence of an alternative reinforcer, is substantially less than cocaine. <b>Significance Statement</b> JJC8-088 and JJC8-091 have shown efficacy is reducing cocaine self-administration in rats and in nonhuman primates. This study found that both compounds maintained self-administration in monkeys responding under several conditions. However, when given access to an alternative reinforcer during the self-administration session, JJC8-091 was not reinforcing, suggesting that JJC8-091 may be a viable candidate for CUD since, in the human population, alternatives to drug use are often available.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289740","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<b>Efficacy of Fluoxetine and (<i>R,S)</i> Ketamine in Attenuating Conditioned Fear Behaviors in Male Mice</b>.","authors":"Megan Wells, Jan Hoffmann, Autumn Stage, Isabella Enger, Jayme Pomper, Lily Briggs, Amber LaCrosse","doi":"10.1124/jpet.124.002252","DOIUrl":"https://doi.org/10.1124/jpet.124.002252","url":null,"abstract":"<p><p>Post-traumatic stress disorder (PTSD) is caused by exposure to a traumatic or stressful event. Symptoms related to this disorder include persistent re-experiencing of memories and fear generalization. Current pharmacological treatments for PTSD are insufficient, with fewer than 30% of patients reporting symptom remission. This study aims to determine the efficacy of acute (<i>R,S)</i> ketamine and chronic fluoxetine (FLX) in reducing fear memory and fear generalization. In rodents, fear conditioning (FC) is commonly used in the literature to induce behaviors related to symptoms of PTSD, and the open field test (OFT) can assess anxiety and fear generalization behaviors during the exploration of a novel environment. In this study, FC consisted of a white noise cue stimulus and four inescapable foot shocks. Treatments began 4 hours after FC. Fear and anxiety behaviors were recorded during re-exposure to the FC stimuli at 24 hours and 2 weeks. The OFT was conducted one day before the last FC re-exposure. Results support the combined use of acute ketamine and chronic FLX as a treatment for reducing behaviors indicative of fear memory during re-exposure at 2 weeks, but not behaviors indicative of anxiety and fear generalization in the OFT. FLX alone was most effective in reducing behaviors related to fear generalization. This study contributes to the existing literature on pharmacological treatment for fear and anxiety behaviors relating to fear memory and fear generalization. Continued research is necessary to replicate results, optimize treatment protocols, and investigate the molecular adaptations to trauma and treatment. <b>Significance Statement</b> Up to 6% of people in the United States will develop PTSD within their lifetime, and less than half of those individuals will find relief from their symptoms given the current therapeutic options. This study offers preliminary support for the efficacy of ketamine and FLX in reducing PTSD-like behaviors induced by fear-conditioning in mice. Compared to current standard treatments, results indicate the potential for a more effective therapeutic option for those with stress-related disorders, such as PTSD.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142289741","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lenacapavir Exhibits Atropisomerism-Mechanistic Pharmacokinetics and Disposition Studies of Lenacapavir Reveal Intestinal Excretion as a Major Clearance Pathway.","authors":"Jim Zheng, Bing Lu, Gavin Carr, Judy Mwangi, Kelly Wang, Jia Hao, Kelly McLennan Staiger, Nathan Kozon, Bernard P Murray, Mohammad Bashir, Mark A Gohdes, Winston C Tse, Scott Schroeder, Michael Graupe, John O Link, Jungjoo Yoon, Anna Chiu, William Rowe, Bill J Smith, Raju Subramanian","doi":"10.1124/jpet.124.002302","DOIUrl":"10.1124/jpet.124.002302","url":null,"abstract":"<p><p>Lenacapavir (LEN), a long-acting injectable, is the first approved human immunodeficiency virus type 1 capsid inhibitor and one of a few Food and Drug Administration-approved drugs that exhibit atropisomerism. LEN exists as a mixture of two class 2 atropisomers that interconvert at a fast rate (half-life < 2 hours) with a ratio that is stable over time and unaffected by enzymes or binding to proteins in plasma. LEN exhibits low systemic clearance (CL) in nonclinical species and humans; however, in all species, the observed CL was higher than the in vitro predicted CL. The volume of distribution was moderate in nonclinical species and consistent with the tissue distribution observed by whole-body autoradiography in rats. LEN does not distribute to brain, consistent with being a P-glycoprotein (P-gp) substrate. Mechanistic drug disposition studies with [¹⁴C]LEN in intravenously dosed bile duct-cannulated rats and dogs showed a substantial amount of unchanged LEN (31%-60% of dose) excreted in feces, indicating that intestinal excretion (IE) was a major clearance pathway for LEN in both species. Coadministration of oral elacridar, a P-gp inhibitor, in rats decreased CL and IE of LEN. Renal excretion was < 1% of dose in both species. In plasma, almost all radioactivity was unchanged LEN. Low levels of metabolites in excreta included LEN conjugates with glutathione, pentose, and glucuronic acid, which were consistent with metabolites formed in vitro in H<i>μ</i>rel hepatocyte cocultures and those observed in human. Our studies highlight the importance of IE for efflux substrates that are highly metabolically stable compounds with slow elimination rates. SIGNIFICANCE STATEMENT: LEN is a long-acting injectable that exists as conformationally stable atropisomers. Due to an atropisomeric interconversion rate that significantly exceeds the in vivo elimination rate, the atropisomer ratio of LEN remains constant in circulation. The disposition of LEN highlights that intestinal excretion has a substantial part in the elimination of compounds that are metabolically highly stable and efflux transporter substrates.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141906875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Methocinnamox is a Potent and Long-Acting Antagonist that can Prevent and Reverse Opioid-Induced Respiratory Depression.","authors":"James A Carr,Daniel J Morgan","doi":"10.1124/jpet.124.002205","DOIUrl":"https://doi.org/10.1124/jpet.124.002205","url":null,"abstract":"","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.5,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142255551","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Levetiracetam Prevents Neurophysiological Changes and Preserves Cognitive Function in the Human Immunodeficiency Virus (HIV)-1 Transactivator of Transcription Transgenic Mouse Model of HIV-Associated Neurocognitive Disorder.","authors":"Ashley N Ewens, Alexander Pilski, Shayne D Hastings, Chris Krook-Magnuson, Steven M Graves, Esther Krook-Magnuson, Stanley A Thayer","doi":"10.1124/jpet.124.002272","DOIUrl":"10.1124/jpet.124.002272","url":null,"abstract":"<p><p>Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) affects nearly half of the 39 million people living with HIV. HAND symptoms range from subclinical cognitive impairment to dementia; the mechanisms that underlie HAND remain unclear and there is no treatment. The HIV protein transactivator of transcription (TAT) is thought to contribute to HAND because it persists in the central nervous system and elicits neurotoxicity in animal models. Network hyperexcitability is associated with accelerated cognitive decline in neurodegenerative disorders. Here we show that the antiepileptic drug levetiracetam (LEV) attenuated aberrant excitatory synaptic transmission, protected synaptic plasticity, reduced seizure susceptibility, and preserved cognition in inducible TAT (iTAT) transgenic male mice. iTAT mice had an increased frequency of spontaneous excitatory postsynaptic currents in hippocampal slice recordings and impaired long-term potentiation, a form of synaptic plasticity that underlies learning and memory. Two-week administration of LEV by osmotic minipump prevented both impairments. Kainic acid administered to iTAT mice induced a higher maximum behavioral seizure score, longer seizure duration, and shorter latency to first seizure, consistent with a lower seizure threshold. LEV treatment prevented these in vivo signs of hyperexcitability. Lastly, in the Barnes maze, iTAT mice required more time to reach the goal, committed more errors, and received lower cognitive scores relative to iTAT mice treated with LEV. Thus, TAT expression drives functional deficits, suggesting a causative role in HAND. As LEV not only prevented aberrant synaptic activity in iTAT mice but also prevented cognitive dysfunction, it may provide a promising pharmacological approach to the treatment of HAND. SIGNIFICANCE STATEMENT: Approximately half of people living with human immunodeficiency virus (HIV) also suffer from HIV-associated neurocognitive disorder (HAND), for which there is no treatment. The HIV protein transactivator of transcription (TAT) causes toxicity that is thought to contribute to HAND. Here, the antiepileptic drug levetiracetam (LEV) prevented synaptic and cognitive impairments in a TAT-expressing mouse. LEV is widely used to treat seizures and is well-tolerated in humans, including those with HIV. This study supports further investigation of LEV-mediated neuroprotection in HAND.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141766411","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effect of Vascular Senescence on the Efficacy and Safety of Warfarin: Insights from Rat Models and a Prospective Cohort Study.","authors":"Haobin Li, Jing Liu, Qing Liang, Yan Yu, Guangchun Sun","doi":"10.1124/jpet.124.002265","DOIUrl":"10.1124/jpet.124.002265","url":null,"abstract":"<p><p>Warfarin, with its narrow therapeutic range, requires the understanding of various influencing factors for personalized medication. Vascular senescence, marked by vascular stiffening and endothelial dysfunction, has an unclear effect on the efficacy and safety of warfarin. Based on previous studies, we hypothesized that vascular senescence increases the risk of bleeding during warfarin therapy. This study aimed to explore these effects using animal models and clinical cohorts. We established rat models of vascular senescence and calcification using d-galactose, vitamin D, and nicotine. After validating the models, we examined changes in the international normalized ratio (INR) at fixed warfarin doses (0.20 and 0.35 mg/kg). We found that vascular senescence caused significantly elevated INR values and increased bleeding risk. In the prospective clinical cohort study (NCT06428110), hospitalized warfarin patients with standard dose adjustments were divided into vascular senescence and control groups based on ultrasound and computed tomography diagnosis. Using propensity score matching to exclude the influence of confounding factors, we found that the vascular senescence group had lower steady-state warfarin doses and larger dose adjustments, with a higher probability of INR exceeding the therapeutic range. The vascular senescence group tended to experience more bleeding or thromboembolic/ischemic events during 1 year of follow-up, while there was no statistical difference. In conclusion, vascular senescence leads to unstable INR values and increases higher bleeding risk during warfarin therapy, highlighting the importance of considering vascular senescence in future precision warfarin therapies. SIGNIFICANCE STATEMENT: Many factors influence warfarin efficacy; however, the effect of vascular senescence remains unclear. This study aimed to investigate the effects of vascular senescence on the efficacy and safety of warfarin. Through both rat models and clinical cohort studies, our findings indicated that vascular senescence may compromise the stability of warfarin, presenting challenges in maintaining its efficacy and safety.</p>","PeriodicalId":16798,"journal":{"name":"Journal of Pharmacology and Experimental Therapeutics","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141878929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}