Pub Date : 2024-09-17DOI: 10.1101/2024.09.16.24313779
Jyotirmoy Sarker, Michael Kim, Samantha Patton, Przemyslaw Radwanski, Mark A Munger, KIBUM KIM
Background: Icosapent ethyl (ICP), an ethyl ester of eicosapentaenoic acid (EPA), and omega-3 acid ethyl esters (DHA/EPA), comprised of ethyl esters of EPA and doxosahexaenoic acid (DHA), are approved as adjunctive therapy to statins for reducing adverse cardiovascular events (CV) in patients with CV risks. However, there are concerns regarding a potential association between ICP and atrial fibrillation (AF). This study evaluated the incidence of AF onset between ICP and DHA/EPA when used as adjuvant therapy with statins. Methods and Results: This retrospective study utilized administrative healthcare claims to analyze adult AF-naïve patients from one year preceding their first prescription for ICP or DHA/EPA. These patients were followed for two years, spanning from2013-2021. AF incidence was assessed during active treatment with either ICP or DHA/EPA as adjunct statin therapy. A propensity score (PS) matched cohort controlled for baseline characteristics and the effect of calendar year on the use of ICP or DHA/EPA. The cumulative incidence of AF was estimated using a product-limit estimator and compared between groups using a Cox proportional hazards regression model. The PS-matched cohort included 17,638 participants with a mean age 56 years, predominantly male (65.7% ICP vs. 64.5% DHA/EPA). Over two years, the cumulative incidence of AF from ICP and DHA/EPA was 5.32% and 3.99% respectively, resulting in a HR of 1.242 (95% CI: 1.061 to 1.455). Conclusions: In adult AF-naïve patients, ICP, when compared to DHA/EPA in conjunction with statin therapy, was associated with a significantly higher significant risk of developing AF.
{"title":"Comparative Risk of the Onset of Atrial Fibrillation after Icosapent Ethyl versus Omega-3–Acid-Ethyl-Esters Adjuvant to Statins","authors":"Jyotirmoy Sarker, Michael Kim, Samantha Patton, Przemyslaw Radwanski, Mark A Munger, KIBUM KIM","doi":"10.1101/2024.09.16.24313779","DOIUrl":"https://doi.org/10.1101/2024.09.16.24313779","url":null,"abstract":"Background: Icosapent ethyl (ICP), an ethyl ester of eicosapentaenoic acid (EPA), and omega-3 acid ethyl esters (DHA/EPA), comprised of ethyl esters of EPA and doxosahexaenoic acid (DHA), are approved as adjunctive therapy to statins for reducing adverse cardiovascular events (CV) in patients with CV risks. However, there are concerns regarding a potential association between ICP and atrial fibrillation (AF). This study evaluated the incidence of AF onset between ICP and DHA/EPA when used as adjuvant therapy with statins. Methods and Results: This retrospective study utilized administrative healthcare claims to analyze adult AF-naïve patients from one year preceding their first prescription for ICP or DHA/EPA. These patients were followed for two years, spanning from2013-2021. AF incidence was assessed during active treatment with either ICP or DHA/EPA as adjunct statin therapy. A propensity score (PS) matched cohort controlled for baseline characteristics and the effect of calendar year on the use of ICP or DHA/EPA. The cumulative incidence of AF was estimated using a product-limit estimator and compared between groups using a Cox proportional hazards regression model. The PS-matched cohort included 17,638 participants with a mean age 56 years, predominantly male (65.7% ICP vs. 64.5% DHA/EPA). Over two years, the cumulative incidence of AF from ICP and DHA/EPA was 5.32% and 3.99% respectively, resulting in a HR of 1.242 (95% CI: 1.061 to 1.455). Conclusions: In adult AF-naïve patients, ICP, when compared to DHA/EPA in conjunction with statin therapy, was associated with a significantly higher significant risk of developing AF.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260061","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-17DOI: 10.1101/2024.09.14.24312736
Christopher L. Penney, Boulos Zacharie, Jean-Simon Duceppe
Abstract: Approximately 39 million people worldwide are living with Human Immunodeficiency Virus, HIV. However, the number of HIV infections is unevenly distributed with two thirds of global infections confined to Sub-Saharan Africa. Due to viral drug resistance, the most effective treatment requires a triple drug combination thereby adding to the complexity and cost of therapy. As such, many people living with HIV or at risk of infection do not have access to prevention or treatment of this potentially fatal disease. There is no cure for HIV [1]. Tucaresol is an orally active clinical stage drug which functions as a host targeted antiviral agent by controlled stimulation of CD4+ T helper immune cells. We report herein that Tucaresol also displays in-vitro activity against HIV. Although this antiviral activity is not potent, the excellent safety profile and bioavailability of Tucaresol, along with its low Molecular Weight, support attainment of relevant drug concentrations in man to achieve significant in-vivo activity. This is demonstrated by previously reported stabilization of viremia in a prior proof of concept phase 1b/2a HIV clinical trial [2]. It is possible that the significant in-vivo activity of Tucaresol arises from synergy between co-stimulation of CD4+ T helper cells and the direct activity against virally infected cells. A pan in-vitro viral screen of Tucaresol further revealed a weak, direct antiviral activity against human herpes virus 6B, human papillomavirus 11, measles virus and hepatitis B virus.
摘要：全球约有 3900 万人感染了人类免疫缺陷病毒（HIV）。然而，艾滋病毒感染人数分布不均，全球三分之二的感染病例集中在撒哈拉以南非洲地区。由于病毒的抗药性，最有效的治疗需要三联药物组合，从而增加了治疗的复杂性和成本。因此，许多艾滋病毒感染者或有感染风险的人无法预防或治疗这种可能致命的疾病。目前还没有治愈艾滋病病毒的方法[1]。Tucaresol 是一种处于临床阶段的口服活性药物，它通过控制对 CD4+ T 辅助免疫细胞的刺激，发挥宿主靶向抗病毒药物的作用。我们在此报告 Tucaresol 对 HIV 也具有体外活性。虽然这种抗病毒活性并不强，但 Tucaresol 具有出色的安全性和生物利用度，而且分子量较低，因此可以在人体内达到相关的药物浓度，从而实现显著的体内活性。之前报道的一项 1b/2a 期艾滋病临床试验中病毒血症的稳定情况就证明了这一点[2]。Tucaresol 的显著体内活性可能来自于对 CD4+ T 辅助细胞的协同刺激和对病毒感染细胞的直接活性。对 Tucaresol 的体外病毒筛选进一步发现，它对人类疱疹病毒 6B、人类乳头瘤病毒 11、麻疹病毒和乙型肝炎病毒具有微弱的直接抗病毒活性。
{"title":"Tucaresol: An Oral Candidate Drug With Two Distinct Antiviral Mechanisms.","authors":"Christopher L. Penney, Boulos Zacharie, Jean-Simon Duceppe","doi":"10.1101/2024.09.14.24312736","DOIUrl":"https://doi.org/10.1101/2024.09.14.24312736","url":null,"abstract":"Abstract: Approximately 39 million people worldwide are living with Human Immunodeficiency Virus, HIV. However, the number of HIV infections is unevenly distributed with two thirds of global infections confined to Sub-Saharan Africa. Due to viral drug resistance, the most effective treatment requires a triple drug combination thereby adding to the complexity and cost of therapy. As such, many people living with HIV or at risk of infection do not have access to prevention or treatment of this potentially fatal disease. There is no cure for HIV [1]. Tucaresol is an orally active clinical stage drug which functions as a host targeted antiviral agent by controlled stimulation of CD4+ T helper immune cells. We report herein that Tucaresol also displays in-vitro activity against HIV. Although this antiviral activity is not potent, the excellent safety profile and bioavailability of Tucaresol, along with its low Molecular Weight, support attainment of relevant drug concentrations in man to achieve significant in-vivo activity. This is demonstrated by previously reported stabilization of viremia in a prior proof of concept phase 1b/2a HIV clinical trial [2]. It is possible that the significant in-vivo activity of Tucaresol arises from synergy between co-stimulation of CD4+ T helper cells and the direct activity against virally infected cells. A pan in-vitro viral screen of Tucaresol further revealed a weak, direct antiviral activity against human herpes virus 6B, human papillomavirus 11, measles virus and hepatitis B virus.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142260059","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Aim: To compare the efficacy of a novel maxillofacial drug delivery technology with that of oral administration by analyzing the presence of administered metronidazole in plasma. Material & Methods: The patients reporting to the Dental outpatient department with acute pulpitis in relation to maxillary molar were examined and recruited for the study. All consenting patients fulfilling the inclusion criteria during the study period were included. The selected patients were randomly divided into two groups using computer generated sequence of random numbers. Group I In the control group patients, a single dose of 400 mg of metronidazole in the form of a tablet was administered through the oral route, after biomechanical preparation of root canals. Group II In the experimental group patients, 5mg of metronidazole in the form of an infusion solution was administered into the pulp cavity of a maxillary molar using the maxillofacial route and technology, after biomechanical preparation of root canals. The blood samples were collected at 15 minutes and 30 minutes after administration of metronidazole. The plasma samples were then analyzed for the presence of metronidazole using high performance liquid chromatography (HPLC). Results: Out of ten, 5 (50%) samples in the oral route group and all 9 (100%) samples in the maxillofacial route group had the presence of the drug (p = 0.033). There was no statistically significant difference in presence of the drug between 15 minutes and 30 minutes in the oral route (p = 1.0) and in the maxillofacial route (p = 0.687). Further, the mean value of the area under the HPLC curve after 15 minutes was found to be similar in both the groups (p = 0.4). At 30 minutes also the area under the HPLC curve between the groups was not statistically significant (p = 0.156) Conclusion: The maxillofacial drug delivery technique can be an effective alternate route for painless and controlled drug delivery.
{"title":"A Novel Maxillofacial Technology for Drug Administration-A Randomized Controlled Trial Using Metronidazole.","authors":"SAJANI RAMACHANDRAN, RAVICHANDRAN KANDASAMY, KAVITA VERMA, JAYAHSHRI MURUGAN, JISHNU SUDHAKAR, HRIDWIK ADIYERI JANARDHANAN, ANOOP U.R","doi":"10.1101/2024.09.11.24313269","DOIUrl":"https://doi.org/10.1101/2024.09.11.24313269","url":null,"abstract":"Aim: To compare the efficacy of a novel maxillofacial drug delivery technology with that of oral administration by analyzing the presence of administered metronidazole in plasma.\u0000Material & Methods:\u0000The patients reporting to the Dental outpatient department with acute pulpitis in relation to maxillary molar were examined and recruited for the study. All consenting patients fulfilling the inclusion criteria during the study period were included.\u0000The selected patients were randomly divided into two groups using computer generated sequence of random numbers. Group I In the control group patients, a single dose of 400 mg of metronidazole in the form of a tablet was administered through the oral route, after biomechanical preparation of root canals.\u0000Group II In the experimental group patients, 5mg of metronidazole in the form of an infusion solution was administered into the pulp cavity of a maxillary molar using the maxillofacial route and technology, after biomechanical preparation of root canals.\u0000The blood samples were collected at 15 minutes and 30 minutes after administration of metronidazole. The plasma samples were then analyzed for the presence of metronidazole using high performance liquid chromatography (HPLC).\u0000Results:\u0000Out of ten, 5 (50%) samples in the oral route group and all 9 (100%) samples in the maxillofacial route group had the presence of the drug (p = 0.033). There was no statistically significant difference in presence of the drug between 15 minutes and 30 minutes in the oral route (p = 1.0) and in the maxillofacial route (p = 0.687). Further, the mean value of the area under the HPLC curve after 15 minutes was found to be similar in both the groups (p = 0.4). At 30 minutes also the area under the HPLC curve between the groups was not statistically significant (p = 0.156)\u0000Conclusion: The maxillofacial drug delivery technique can be an effective alternate route for painless and controlled drug delivery.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199746","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-09-04DOI: 10.1101/2024.09.02.24312967
Rodrigo Machado-Vieira, Trudy Millard Krause, Gregory Jones, Antonio L Teixeira, Lokesh Shahani, Scott Lane, Jair C. Soares, Chau N. Truong
Objectives To investigate the relationship between neuropsychiatric medication usage and COVID-19 outcomes before COVID-19 usage.
目的 调查使用 COVID-19 前神经精神科药物治疗与 COVID-19 结果之间的关系。
{"title":"Protective Effects of Psychiatric Medications against COVID-19 Mortality Before Vaccines","authors":"Rodrigo Machado-Vieira, Trudy Millard Krause, Gregory Jones, Antonio L Teixeira, Lokesh Shahani, Scott Lane, Jair C. Soares, Chau N. Truong","doi":"10.1101/2024.09.02.24312967","DOIUrl":"https://doi.org/10.1101/2024.09.02.24312967","url":null,"abstract":"<strong>Objectives</strong> To investigate the relationship between neuropsychiatric medication usage and COVID-19 outcomes before COVID-19 usage.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199875","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Purpose Colon cancer, one of the three deadliest cancers worldwide, has a high prevalence, especially in developing societies. Recently, our preclinical study demonstrated the strong anti-tumor effects of memantine on colon cancer in rats. This study aimed to investigate the effects of memantine (an NMDA receptor antagonist) in patients with metastatic colon cancer.
{"title":"Anti-cancer effect of memantine as adjunctive therapy in metastatic colon cancer: A pilot randomized controlled clinical trial","authors":"Kosar Jannesar, Yousef Roosta, Naser Masoudi, Rahim Asghari, Javad Rasouli, Hamid Soraya","doi":"10.1101/2024.09.01.24312896","DOIUrl":"https://doi.org/10.1101/2024.09.01.24312896","url":null,"abstract":"<strong>Purpose</strong> Colon cancer, one of the three deadliest cancers worldwide, has a high prevalence, especially in developing societies. Recently, our preclinical study demonstrated the strong anti-tumor effects of memantine on colon cancer in rats. This study aimed to investigate the effects of memantine (an NMDA receptor antagonist) in patients with metastatic colon cancer.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-30DOI: 10.1101/2024.08.28.24312707
Pauline Lanting, Robert Warmerdam, Jelle Slager, Harm Brugge, Taichi Ochi, Marloes Benjamins, Esteban A. Lopera, Soesma Jankipersadsing, Jody Gelderloos, Daphne Teuben, Dennis Hendriksen, Bart Charbon, Lennart Johansson, Thijs H. Oude Munnink, Nienke De Boer-Veger, Lifelines NEXT, Lifelines Cohort Study, Bob Wilffert, Morris Swertz, Daan J. Touw, Patrick Deelen, Nine V.A.M. Knoers, Jackie A.M. Dekens, Lude Franke
Pharmacogenomic (PGx) information is essential for precision medicine, enabling drug prescriptions to be personalized according to an individual's genetic background. Almost all individuals will carry a genetic marker that affects their drug response, so the ideal drug prescription for these individuals will differ from the population-level guidelines. Currently, PGx information is often not available at first prescription, reducing its effectiveness. Pharmacogenetic information is most often obtained using special assays, making it expensive and time-consuming to generate. We therefore hypothesized that we could also use genome-wide oligonucleotide genotyping arrays to generate comprehensive PGx information (PGx passports), thereby decreasing the cost and time required for PGx testing, and lowering the barrier to generating PGx information prior to first prescription. Taking advantage of existing genetic data generated in two biobanks, we developed and validated Asterix, a low-cost clinical-grade PGx passport pipeline for 12 PGx genes. In these biobanks we performed and clinically validated genetic variant calling and statistical phasing and imputation. In addition, we developed and validated a novel CYP2D6 copy number variant calling tool, foregoing the need to use separate PCR-based copy number detection. Ultimately, we returned 1227 PGx passports to biobank participants via a layperson-friendly app, improving knowledge of PGx among citizens. Our study demonstrates the feasibility of a low-cost clinical-grade PGx passport pipeline that could be readily implemented in clinical settings to enhance personalized healthcare, ensuring that patients receive the most effective and safe drug therapy based on their unique genetic makeup.
{"title":"Low-cost generation of clinical-grade layperson-friendly pharmacogenetic passports using oligonucleotide arrays","authors":"Pauline Lanting, Robert Warmerdam, Jelle Slager, Harm Brugge, Taichi Ochi, Marloes Benjamins, Esteban A. Lopera, Soesma Jankipersadsing, Jody Gelderloos, Daphne Teuben, Dennis Hendriksen, Bart Charbon, Lennart Johansson, Thijs H. Oude Munnink, Nienke De Boer-Veger, Lifelines NEXT, Lifelines Cohort Study, Bob Wilffert, Morris Swertz, Daan J. Touw, Patrick Deelen, Nine V.A.M. Knoers, Jackie A.M. Dekens, Lude Franke","doi":"10.1101/2024.08.28.24312707","DOIUrl":"https://doi.org/10.1101/2024.08.28.24312707","url":null,"abstract":"Pharmacogenomic (PGx) information is essential for precision medicine, enabling drug prescriptions to be personalized according to an individual's genetic background. Almost all individuals will carry a genetic marker that affects their drug response, so the ideal drug prescription for these individuals will differ from the population-level guidelines. Currently, PGx information is often not available at first prescription, reducing its effectiveness. Pharmacogenetic information is most often obtained using special assays, making it expensive and time-consuming to generate. We therefore hypothesized that we could also use genome-wide oligonucleotide genotyping arrays to generate comprehensive PGx information (PGx passports), thereby decreasing the cost and time required for PGx testing, and lowering the barrier to generating PGx information prior to first prescription. Taking advantage of existing genetic data generated in two biobanks, we developed and validated Asterix, a low-cost clinical-grade PGx passport pipeline for 12 PGx genes. In these biobanks we performed and clinically validated genetic variant calling and statistical phasing and imputation. In addition, we developed and validated a novel CYP2D6 copy number variant calling tool, foregoing the need to use separate PCR-based copy number detection. Ultimately, we returned 1227 PGx passports to biobank participants via a layperson-friendly app, improving knowledge of PGx among citizens. Our study demonstrates the feasibility of a low-cost clinical-grade PGx passport pipeline that could be readily implemented in clinical settings to enhance personalized healthcare, ensuring that patients receive the most effective and safe drug therapy based on their unique genetic makeup.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199750","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1101/2024.08.26.24312616
Timothy J Atkinson, Justin Petway, Whitney L Forbes, Hannah Thorfinnson, Maj Ryan C Costantino, Laura Elisabeth Gressler
Importance: Cardiovascular disease (CVD) is a major global health concern, responsible for a significant proportion of deaths annually. Despite the widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs) in managing various conditions, their association with cardiovascular events poses a challenge, and existing guidelines lack a reliable risk prediction tool. This study addresses the critical need for an evidence-based instrument to assess the likelihood of NSAID-induced cardiovascular events, that provides clinicians with valuable decision support to improve safety in their use for pain management, especially in patients vulnerable to cardiovascular events. Objective: To develop a practical risk scoring tool, NSAID Induced Cardiovascular Events (NAÏVE), for estimating the risk of serious cardiovascular events associated with NSAID use. Design: Retrospective nested case-control study Setting: The study leveraged data from the DAVINCI database, integrating electronic health records, administrative data, and clinical data from both the Veterans Health Administration (VHA) and the Department of Defense (DoD). Participants: The study cohort consisted of individuals with at least one NSAID pharmacy claim, with cases defined as those experiencing non-fatal myocardial infarction, non-fatal stroke, or new heart failure. Interventions: Development of the NAÏVE risk scoring tool involved a comprehensive analysis of demographic, clinical, and prescription-related variables, including NSAID exposure, comorbidities, and medication history. Main Outcomes/Measures: The primary outcome was the first occurrence of a cardiovascular event. Results: The study cohort comprised 231,967 cases and 2,319,670 controls, identified from individuals with at least one NSAID pharmacy claim between October 1, 2016, and September 30, 2020. The risk index, NAÏVE, demonstrated strong discriminatory ability and calibration, with a C-statistic of 0.88. Variables such as age, NSAID exposure, comorbidities, and medication history were associated with increased odds of NSAID-induced cardiovascular events. Conclusions/Relevance: NAÏVE is the first evidence-based risk scoring tool providing clinicians with valuable decision support for assessing the potential risk of serious cardiovascular events associated with NSAID use. It fills a crucial gap in clinical practice, allowing for transparent discussions with patients and shared decision-making regarding NSAID prescriptions. Further validation and prospective testing are warranted for broader applicability.
{"title":"Generation of Risk Score for Serious Non-Steroidal Anti-Inflammatory Drug (NSAID) Induced Cardiovascular Events (NAÏVE) among Active-Duty Service Members and Veterans","authors":"Timothy J Atkinson, Justin Petway, Whitney L Forbes, Hannah Thorfinnson, Maj Ryan C Costantino, Laura Elisabeth Gressler","doi":"10.1101/2024.08.26.24312616","DOIUrl":"https://doi.org/10.1101/2024.08.26.24312616","url":null,"abstract":"Importance: Cardiovascular disease (CVD) is a major global health concern, responsible for a significant proportion of deaths annually. Despite the widespread use of nonsteroidal anti-inflammatory drugs (NSAIDs) in managing various conditions, their association with cardiovascular events poses a challenge, and existing guidelines lack a reliable risk prediction tool. This study addresses the critical need for an evidence-based instrument to assess the likelihood of NSAID-induced cardiovascular events, that provides clinicians with valuable decision support to improve safety in their use for pain management, especially in patients vulnerable to cardiovascular events. Objective: To develop a practical risk scoring tool, NSAID Induced Cardiovascular Events (NAÏVE), for estimating the risk of serious cardiovascular events associated with NSAID use. Design: Retrospective nested case-control study Setting: The study leveraged data from the DAVINCI database, integrating electronic health records, administrative data, and clinical data from both the Veterans Health Administration (VHA) and the Department of Defense (DoD). Participants: The study cohort consisted of individuals with at least one NSAID pharmacy claim, with cases defined as those experiencing non-fatal myocardial infarction, non-fatal stroke, or new heart failure. Interventions: Development of the NAÏVE risk scoring tool involved a comprehensive analysis of demographic, clinical, and prescription-related variables, including NSAID exposure, comorbidities, and medication history. Main Outcomes/Measures: The primary outcome was the first occurrence of a cardiovascular event. Results: The study cohort comprised 231,967 cases and 2,319,670 controls, identified from individuals with at least one NSAID pharmacy claim between October 1, 2016, and September 30, 2020. The risk index, NAÏVE, demonstrated strong discriminatory ability and calibration, with a C-statistic of 0.88. Variables such as age, NSAID exposure, comorbidities, and medication history were associated with increased odds of NSAID-induced cardiovascular events. Conclusions/Relevance: NAÏVE is the first evidence-based risk scoring tool providing clinicians with valuable decision support for assessing the potential risk of serious cardiovascular events associated with NSAID use. It fills a crucial gap in clinical practice, allowing for transparent discussions with patients and shared decision-making regarding NSAID prescriptions. Further validation and prospective testing are warranted for broader applicability.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-28DOI: 10.1101/2024.08.27.24312677
Zishan Jiwani, Simon Goldberg, Jack Stroud, Jacob Young, John Curtin, John D. Dunne, Otto Simonsson, Christian A. Webb, Robin Carhart-Harris, Marco Schlosser
Introduction: Meditation practice and psychedelic use have attracted increasing attention in the public sphere and scientific research. Both methods induce non-ordinary states of consciousness that may have significant therapeutic benefits. Thus, there is growing scientific interest in potential synergies between psychedelic use and meditation practice with some research suggesting that psychedelics may benefit meditation practice. The present study examined individual, psychedelic-related, and meditation-related factors to determine under what conditions meditators perceive psychedelic use as beneficial for their meditation practice. Method: Participants (N = 863) who had reported psychedelic use and a regular meditation practice (at least 3 times per week during the last 12 months) were included in the study. To accommodate a large number of variables, machine learning (i.e., elastic net, random forest) was used to analyze the data. Results: Most participants (n = 634, 73.5%) found psychedelic use to have a positive influence on their quality of meditation. Twenty-eight variables showed significant zero-order associations with perceived benefits even following a correction. Elastic net had the best performance (R2 = .266) and was used to identify the most important features. Across 53 variables, the model found that greater use of psychedelics, intention setting during psychedelic use, agreeableness, and exposure to N,N-Dimethyltryptamine (N,N-DMT) were most likely to be associated with the perception that psychedelics benefit meditation practice. The results were consistent across several different approaches used to identify the most important variables (i.e., Shapley values, feature ablation). Discussion: Results suggest that most meditators found psychedelic use to have a positive influence on their meditation practice, with: 1) regularity of psychedelic use, 2) the setting of intentions for psychedelic use, 3) having an agreeable personality, and 4) reported use of N,N-DMT being the most likely predictors of perceiving psychedelic use as beneficial. Longitudinal designs and randomized trials manipulating psychedelic use are needed to establish causality.
{"title":"Can Psychedelic Use Benefit Meditation Practice? Examining Individual, Psychedelic, and Meditation-Related Factors","authors":"Zishan Jiwani, Simon Goldberg, Jack Stroud, Jacob Young, John Curtin, John D. Dunne, Otto Simonsson, Christian A. Webb, Robin Carhart-Harris, Marco Schlosser","doi":"10.1101/2024.08.27.24312677","DOIUrl":"https://doi.org/10.1101/2024.08.27.24312677","url":null,"abstract":"Introduction: Meditation practice and psychedelic use have attracted increasing attention in the public sphere and scientific research. Both methods induce non-ordinary states of consciousness that may have significant therapeutic benefits. Thus, there is growing scientific interest in potential synergies between psychedelic use and meditation practice with some research suggesting that psychedelics may benefit meditation practice. The present study examined individual, psychedelic-related, and meditation-related factors to determine under what conditions meditators perceive psychedelic use as beneficial for their meditation practice.\u0000Method: Participants (N = 863) who had reported psychedelic use and a regular meditation practice (at least 3 times per week during the last 12 months) were included in the study. To accommodate a large number of variables, machine learning (i.e., elastic net, random forest) was used to analyze the data. Results: Most participants (n = 634, 73.5%) found psychedelic use to have a positive influence on their quality of meditation. Twenty-eight variables showed significant zero-order associations with perceived benefits even following a correction. Elastic net had the best performance (R2 = .266) and was used to identify the most important features. Across 53 variables, the model found that greater use of psychedelics, intention setting during psychedelic use, agreeableness, and exposure to N,N-Dimethyltryptamine (N,N-DMT) were most likely to be associated with the perception that psychedelics benefit meditation practice. The results were consistent across several different approaches used to identify the most important variables (i.e., Shapley values, feature ablation).\u0000Discussion: Results suggest that most meditators found psychedelic use to have a positive influence on their meditation practice, with: 1) regularity of psychedelic use, 2) the setting of intentions for psychedelic use, 3) having an agreeable personality, and 4) reported use of N,N-DMT being the most likely predictors of perceiving psychedelic use as beneficial. Longitudinal designs and randomized trials manipulating psychedelic use are needed to establish causality.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-26DOI: 10.1101/2024.08.25.24312421
Ming Sun, Martijn L Manson, Anne-Grete Martson, Jacob Bodilsen, Elizabeth CM de Lange, Tingjie Guo
Acyclovir is a primary treatment for central nervous system (CNS) infections caused by herpes simplex virus (HSV) and varicella-zoster virus (VZV). However, patient outcomes remain suboptimal with high mortality and morbidity, following current dosing guidelines. Given the lack of alternative therapies, there is a pressing need to optimize acyclovir dosing, especially since initial regimens were developed in the 1980s with incomplete pharmacokinetic data in the CNS. This study aimed to evaluate both current and alternative acyclovir dosing regimens using a full Bayesian physiologically-based pharmacokinetic (PBPK) model tailored for viral encephalitis. We developed a CNS PBPK model to simulate acyclovir concentrations in plasma, brain extracellular fluid (ECF), and subarachnoid space (SAS). Drug efficacy was assessed using two pharmacokinetic targets, 50%fT>IC50 and Cmin>IC50, with a safety threshold set at 25 mg/L in plasma. The standard dosing regimen (10 mg/kg TID) yielded sufficient acyclovir exposure in plasma, brain extracellular fluid (ECF), and subarachnoid space (SAS) compartments based on the 50%fT>IC50 target. However, it did not consistently meet the Cmin>IC50 target, indicating potential suboptimal exposure in these compartments when evaluated against this criterion. Notably, a higher probability of target attainment (PTA) was generally observed in the brain ECF and SAS compared to plasma. Increasing the dosing frequency to QID improved target attainment but exceeded the toxicity threshold at 20 mg/kg. Our findings suggest that a dosing regimen of 10 mg/kg or 15 mg/kg QID may offer a more effective and safer approach for managing CNS infections compared to the other tested alternative dosing regimens.
{"title":"Revisiting acyclovir dosing for viral encephalitis using a Bayesian PBPK modeling approach","authors":"Ming Sun, Martijn L Manson, Anne-Grete Martson, Jacob Bodilsen, Elizabeth CM de Lange, Tingjie Guo","doi":"10.1101/2024.08.25.24312421","DOIUrl":"https://doi.org/10.1101/2024.08.25.24312421","url":null,"abstract":"Acyclovir is a primary treatment for central nervous system (CNS) infections caused by herpes simplex virus (HSV) and varicella-zoster virus (VZV). However, patient outcomes remain suboptimal with high mortality and morbidity, following current dosing guidelines. Given the lack of alternative therapies, there is a pressing need to optimize acyclovir dosing, especially since initial regimens were developed in the 1980s with incomplete pharmacokinetic data in the CNS. This study aimed to evaluate both current and alternative acyclovir dosing regimens using a full Bayesian physiologically-based pharmacokinetic (PBPK) model tailored for viral encephalitis. We developed a CNS PBPK model to simulate acyclovir concentrations in plasma, brain extracellular fluid (ECF), and subarachnoid space (SAS). Drug efficacy was assessed using two pharmacokinetic targets, 50%fT>IC50 and Cmin>IC50, with a safety threshold set at 25 mg/L in plasma. The standard dosing regimen (10 mg/kg TID) yielded sufficient acyclovir exposure in plasma, brain extracellular fluid (ECF), and subarachnoid space (SAS) compartments based on the 50%fT>IC50 target. However, it did not consistently meet the Cmin>IC50 target, indicating potential suboptimal exposure in these compartments when evaluated against this criterion. Notably, a higher probability of target attainment (PTA) was generally observed in the brain ECF and SAS compared to plasma. Increasing the dosing frequency to QID improved target attainment but exceeded the toxicity threshold at 20 mg/kg. Our findings suggest that a dosing regimen of 10 mg/kg or 15 mg/kg QID may offer a more effective and safer approach for managing CNS infections compared to the other tested alternative dosing regimens.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199748","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-08-22DOI: 10.1101/2024.08.22.24312416
Han Yan, Shanbiao Hu, Hedong Zhang, Yangang Zhou, Rao Fu, Ping Xu, Hualin Cai, Xi Li, Gongbin Lan
Kidney transplantation recipients (KTRs) represent a vulnerable population for COVID-19 infection and severe disease. Nirmatrelvir-ritonavir has demonstrated efficacy in treating COVID-19 among KTRs, and interacts with tacrolimus leading to a precipitous increase in tacrolimus blood levels when co-administered, potentially resulting in toxicity. This study conducted a real-world analysis of KTRs treated with nirmatrelvir-ritonavir for COVID-19 to investigate the relationship between tacrolimus levels and dosing during and within 10 days post-discontinuation of nirmatrelvir-ritonavir. In the experimental group, tacrolimus was initiated at 20-25% of the baseline dose 48 hours after discontinuation of nirmatrelvir-ritonavir, with daily increments of 20-25% until the baseline dose was restored. The patients who did not adhere to the experimental protocol were included in the control group. Findings indicated that withholding tacrolimus 12 hours prior to commencing nirmatrelvir-ritonavir maintained tacrolimus blood levels above 83% of the baseline throughout the nirmatrelvir-ritonavir treatment period. Compared to the control group, the experimental group achieved target trough concentrations of tacrolimus more rapidly and maintained a higher proportion within the therapeutic range (p=0.029), and exhibited significantly lower rates of adverse events (p<0.001). This investigation provides a safe and effective pharmacological strategy for KTRs infected with COVID-19, enabling the safe co-administration of nirmatrelvir-ritonavir and tacrolimus.
{"title":"Optimized tacrolimus dosing strategy in kidney transplant recipients receiving nirmatrelvir-ritonavir for COVID-19","authors":"Han Yan, Shanbiao Hu, Hedong Zhang, Yangang Zhou, Rao Fu, Ping Xu, Hualin Cai, Xi Li, Gongbin Lan","doi":"10.1101/2024.08.22.24312416","DOIUrl":"https://doi.org/10.1101/2024.08.22.24312416","url":null,"abstract":"Kidney transplantation recipients (KTRs) represent a vulnerable population for COVID-19 infection and severe disease. Nirmatrelvir-ritonavir has demonstrated efficacy in treating COVID-19 among KTRs, and interacts with tacrolimus leading to a precipitous increase in tacrolimus blood levels when co-administered, potentially resulting in toxicity. This study conducted a real-world analysis of KTRs treated with nirmatrelvir-ritonavir for COVID-19 to investigate the relationship between tacrolimus levels and dosing during and within 10 days post-discontinuation of nirmatrelvir-ritonavir. In the experimental group, tacrolimus was initiated at 20-25% of the baseline dose 48 hours after discontinuation of nirmatrelvir-ritonavir, with daily increments of 20-25% until the baseline dose was restored. The patients who did not adhere to the experimental protocol were included in the control group. Findings indicated that withholding tacrolimus 12 hours prior to commencing nirmatrelvir-ritonavir maintained tacrolimus blood levels above 83% of the baseline throughout the nirmatrelvir-ritonavir treatment period. Compared to the control group, the experimental group achieved target trough concentrations of tacrolimus more rapidly and maintained a higher proportion within the therapeutic range (p=0.029), and exhibited significantly lower rates of adverse events (p<0.001). This investigation provides a safe and effective pharmacological strategy for KTRs infected with COVID-19, enabling the safe co-administration of nirmatrelvir-ritonavir and tacrolimus.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142199749","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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