Pub Date : 2024-06-28DOI: 10.1101/2024.06.27.24309347
Chengliang Zhong, Shengxuan Guo, Qingyuan Liu, Deyang Sun, Boyang Wang, Siyuan Hu, Xinmin Li, Ying Ding, Bin Yuan, Jing Liu, Long Xiang, Nan Li, Zheng Xue, Yan Li, Yiqun Teng, Rongsong Yi, Shao Li, Rong Ma
Mycoplasma pneumoniae pneumonia (MPP) is a common type of pneumonia among school-aged children and adolescents. Jinzhen Oral Liquid (JZOL) and Azithromycin (AZ) are commonly used treatment options in traditional Chinese medicine (TCM) and Western medicine, respectively. There are several clinical and basic research reports on their solo effect against MPP, enabling their combined treatment to become possible. However, the mechanisms and specific pharmacodynamics of their combined therapy remain unclear. In this study, we conducted a mechanistic analysis of the combination of JZOL and AZ based on network target, elucidating their modular network regulatory mechanisms. The modular mechanisms involve four modules, including hormone response, cell differentiation and migration, signal transduction, oxygen and hypoxia response, centered by TNF signaling pathway-mediated regulation. Under the instruction of computational analysis, we conducted a randomized, double-blind, three-armed, parallel-controlled, multicenter clinical study of different doses of JZOL combined with AZ for the treatment of MPP in children. At the study endpoint, the median time to clinical recovery showed statistically significant differences, which were also observed between groups for time to complete fever remission, time to relief of cough/phlegm, effective rate of chest X-ray improvement, and rate of healing of TCM symptoms. During the treatment period, there were no statistically significant differences in the rates of adverse events, serious adverse events, or adverse reactions between the groups. Different doses of JZOL combined with AZ in the treatment of MPP in children have shown the effects of shortening the course of the disease, relieving the symptoms, and improving the prognosis. The research program composed of computational prediction and clinical trials can significantly accelerate the research and development process and identify more effective treatment with good safety, which is worthy of clinical promotion.
{"title":"Unveil the mechanism of Jinzhen Oral Liquid combined with Azithromycin in the treatment of Mycoplasma pneumoniae pneumonia based on Network pharmacology and clinical trials","authors":"Chengliang Zhong, Shengxuan Guo, Qingyuan Liu, Deyang Sun, Boyang Wang, Siyuan Hu, Xinmin Li, Ying Ding, Bin Yuan, Jing Liu, Long Xiang, Nan Li, Zheng Xue, Yan Li, Yiqun Teng, Rongsong Yi, Shao Li, Rong Ma","doi":"10.1101/2024.06.27.24309347","DOIUrl":"https://doi.org/10.1101/2024.06.27.24309347","url":null,"abstract":"Mycoplasma pneumoniae pneumonia (MPP) is a common type of pneumonia among school-aged children and adolescents. Jinzhen Oral Liquid (JZOL) and Azithromycin (AZ) are commonly used treatment options in traditional Chinese medicine (TCM) and Western medicine, respectively. There are several clinical and basic research reports on their solo effect against MPP, enabling their combined treatment to become possible. However, the mechanisms and specific pharmacodynamics of their combined therapy remain unclear. In this study, we conducted a mechanistic analysis of the combination of JZOL and AZ based on network target, elucidating their modular network regulatory mechanisms. The modular mechanisms involve four modules, including hormone response, cell differentiation and migration, signal transduction, oxygen and hypoxia response, centered by TNF signaling pathway-mediated regulation. Under the instruction of computational analysis, we conducted a randomized, double-blind, three-armed, parallel-controlled, multicenter clinical study of different doses of JZOL combined with AZ for the treatment of MPP in children. At the study endpoint, the median time to clinical recovery showed statistically significant differences, which were also observed between groups for time to complete fever remission, time to relief of cough/phlegm, effective rate of chest X-ray improvement, and rate of healing of TCM symptoms. During the treatment period, there were no statistically significant differences in the rates of adverse events, serious adverse events, or adverse reactions between the groups. Different doses of JZOL combined with AZ in the treatment of MPP in children have shown the effects of shortening the course of the disease, relieving the symptoms, and improving the prognosis. The research program composed of computational prediction and clinical trials can significantly accelerate the research and development process and identify more effective treatment with good safety, which is worthy of clinical promotion.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141502168","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 : 2024-06-25DOI: 10.1101/2024.06.25.24309486
Amy E. Pomeroy, Adam C. Palmer
Combinations of chemotherapies are used to treat many cancer types as they elicit higher cure rates and longer responses than single drugs. Several rationales contribute to the efficacy of combinations, including overcoming inter-patient and intra-tumor heterogeneity and improving efficacy through additive or synergistic pharmacological effects. We present a quantitative model that unifies these phenomena to simulate the clinical activity of curative combination therapies. This mechanistic simulation describes kinetics of tumor growth and death in response to treatment and outputs progression-free survival (PFS) distributions in patient populations. We applied this model to first-line combination therapy for Diffuse Large B-Cell Lymphoma, which is cured in most patients by the 5-drug combination RCHOP. This mechanistic model reproduced clinically observed PFS distributions, kinetics of tumor killing measured by circulating tumor DNA, and the adverse prognostic effect of tumor proliferation rate. The outcomes of nine phase 3 trials of new therapies combined with RCHOP were accurately predicted by the model, based on new therapies’ efficacies in trials in patients with relapsed or refractory disease. Finally, we used the model to explore how drug synergy and predictive biomarkers affect the chance of success of randomized trials. These findings show that curative combination therapies can be understood in quantitative and kinetic detail, and that predictive simulations can be used to aid the design of new treatment regimens and clinical trials in curative-intent settings.
与单一药物相比，联合化疗的治愈率更高，疗效更持久，因此被用于治疗多种癌症类型。联合用药的疗效有几个方面的原因，包括克服患者之间和肿瘤内部的异质性，以及通过相加或协同药理作用提高疗效。我们提出了一个量化模型，将这些现象统一起来，模拟治疗性联合疗法的临床活性。这种机理模拟描述了肿瘤生长和死亡对治疗的反应动力学，并输出了患者群体的无进展生存期（PFS）分布。我们将这一模型应用于弥漫大 B 细胞淋巴瘤的一线联合疗法，大多数患者都能通过五药联合疗法 RCHOP 治愈。这一机理模型再现了临床观察到的 PFS 分布、循环肿瘤 DNA 测定的肿瘤杀伤动力学以及肿瘤增殖率对预后的不利影响。根据新疗法在复发或难治性疾病患者试验中的疗效，该模型准确预测了九项新疗法联合 RCHOP 3 期试验的结果。最后，我们利用该模型探讨了药物协同作用和预测性生物标志物如何影响随机试验的成功几率。这些研究结果表明，我们可以从定量和动力学角度详细了解治疗性联合疗法，预测性模拟可用于帮助设计新的治疗方案和进行治疗性临床试验。
{"title":"A mechanistic model of curative combination therapy explains lymphoma clinical trial results","authors":"Amy E. Pomeroy, Adam C. Palmer","doi":"10.1101/2024.06.25.24309486","DOIUrl":"https://doi.org/10.1101/2024.06.25.24309486","url":null,"abstract":"Combinations of chemotherapies are used to treat many cancer types as they elicit higher cure rates and longer responses than single drugs. Several rationales contribute to the efficacy of combinations, including overcoming inter-patient and intra-tumor heterogeneity and improving efficacy through additive or synergistic pharmacological effects. We present a quantitative model that unifies these phenomena to simulate the clinical activity of curative combination therapies. This mechanistic simulation describes kinetics of tumor growth and death in response to treatment and outputs progression-free survival (PFS) distributions in patient populations. We applied this model to first-line combination therapy for Diffuse Large B-Cell Lymphoma, which is cured in most patients by the 5-drug combination RCHOP. This mechanistic model reproduced clinically observed PFS distributions, kinetics of tumor killing measured by circulating tumor DNA, and the adverse prognostic effect of tumor proliferation rate. The outcomes of nine phase 3 trials of new therapies combined with RCHOP were accurately predicted by the model, based on new therapies’ efficacies in trials in patients with relapsed or refractory disease. Finally, we used the model to explore how drug synergy and predictive biomarkers affect the chance of success of randomized trials. These findings show that curative combination therapies can be understood in quantitative and kinetic detail, and that predictive simulations can be used to aid the design of new treatment regimens and clinical trials in curative-intent settings.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141502171","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 : 2024-06-20DOI: 10.1101/2024.06.19.24309187
Sarraa Al-Mahdi, Jignna Patel, James Sweatman, Robert Oakley, Reya Shah, Joseph Standing, Dagan O Lonsdale
Background & aim: Co-amoxiclav is a commonly used antibiotic, the dose administered during renal replacement therapy may be subtherapeutic. This study aims to describe the current literature on the pharmacokinetics and pharmacodynamics of co-amoxiclav in patients undergoing renal replacement therapy. Method: We carried out a systematic review of the available literature in MEDLINE, Embase, Pubmed, and Google Scholar from inception to Oct 2023. Studies were included if they reported pharmacokinetic data on adults given amoxicillin or clavulanic acid during renal replacement therapy. Results: Seven studies were identified which were published between 1984 to 2021. Variability was observed in the characteristics of the studies, the renal replacement therapy settings, the drug exposure, drug assay methods, and the analysis of the pharmacokinetic parameters. Conclusion: Further pharmacokinetic-pharmacodynamic studies are needed on co-amoxiclav during renal replacement therapy.
{"title":"A systematic review of the effect of renal replacement therapy on the pharmacokinetics of co-amoxiclav","authors":"Sarraa Al-Mahdi, Jignna Patel, James Sweatman, Robert Oakley, Reya Shah, Joseph Standing, Dagan O Lonsdale","doi":"10.1101/2024.06.19.24309187","DOIUrl":"https://doi.org/10.1101/2024.06.19.24309187","url":null,"abstract":"Background & aim: Co-amoxiclav is a commonly used antibiotic, the dose administered during renal replacement therapy may be subtherapeutic. This study aims to describe the current literature on the pharmacokinetics and pharmacodynamics of co-amoxiclav in patients undergoing renal replacement therapy. Method: We carried out a systematic review of the available literature in MEDLINE, Embase, Pubmed, and Google Scholar from inception to Oct 2023. Studies were included if they reported pharmacokinetic data on adults given amoxicillin or clavulanic acid during renal replacement therapy. Results: Seven studies were identified which were published between 1984 to 2021. Variability was observed in the characteristics of the studies, the renal replacement therapy settings, the drug exposure, drug assay methods, and the analysis of the pharmacokinetic parameters. Conclusion: Further pharmacokinetic-pharmacodynamic studies are needed on co-amoxiclav during renal replacement therapy.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141502169","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 : 2024-06-20DOI: 10.1101/2024.06.19.24309024
Nina-Francesca Parrella, Aron T Hill, Peter G Enticott, Tanita Botha, Sarah Catchlove, Luke Downey, Talitha C Ford
Cannabidiol (CBD), a non-intoxicating compound derived from the cannabis plant, has garnered increasing attention as a potential pharmacological therapeutic for autistic children. We conducted a randomised double-blind, placebo-controlled, crossover trial to understand whether oral CBD oil can improve behaviours in this population, with a primary focus on social relating outcomes, along with anxiety and parental stress. A total of 29 children (18 male), aged 5 to 12 years (M = 9.62 years, SD = 2.05), diagnosed with autism spectrum disorder, completed the study. Participants received weight-based dosing of CBD oil (10 mg/kg/day) or placebo oil over two 12-week intervention periods (crossover), separated by an 8-week washout period. Outcome measures included the Social Responsiveness Scale-2 (SRS-2; primary outcome), PROMIS Social Relating, Anxiety, and Sleep, Developmental Behaviour Checklist-2 (DBC-2), Vineland 3, and Autism Parenting Stress Index (APSI; secondary outcomes). There was no significant effect observed for the primary outcome measure (SRS-2) for CBD oil relative to placebo oil after 12 weeks, (p=.125). Significant improvements were observed in secondary measures of social functioning (PROMIS-Social, DBC-2 Social Relating; p<.05) and anxiety symptoms (PROMIS Anxiety, DBC-2 Anxiety; p<.05), while there was also a reduction in parental stress (p<.05). Safety and tolerability data indicated that two children experienced gastrointestinal discomfort while taking CBD. This pilot trial represents preliminary evidence for the potential therapeutic effects of CBD in autism. While further research is needed to confirm and extend these findings, the results suggest that CBD may be a promising intervention for addressing one of autism's core symptoms: social relating. Future studies with larger sample sizes are needed to fully evaluate the efficacy and safety of CBD for autistic children.
{"title":"Effects of Cannabidiol on Social Relating, Anxiety, and Parental Stress in Autistic Children: A Randomised Controlled Crossover Trial","authors":"Nina-Francesca Parrella, Aron T Hill, Peter G Enticott, Tanita Botha, Sarah Catchlove, Luke Downey, Talitha C Ford","doi":"10.1101/2024.06.19.24309024","DOIUrl":"https://doi.org/10.1101/2024.06.19.24309024","url":null,"abstract":"Cannabidiol (CBD), a non-intoxicating compound derived from the cannabis plant, has garnered increasing attention as a potential pharmacological therapeutic for autistic children. We conducted a randomised double-blind, placebo-controlled, crossover trial to understand whether oral CBD oil can improve behaviours in this population, with a primary focus on social relating outcomes, along with anxiety and parental stress. A total of 29 children (18 male), aged 5 to 12 years (M = 9.62 years, SD = 2.05), diagnosed with autism spectrum disorder, completed the study. Participants received weight-based dosing of CBD oil (10 mg/kg/day) or placebo oil over two 12-week intervention periods (crossover), separated by an 8-week washout period. Outcome measures included the Social Responsiveness Scale-2 (SRS-2; primary outcome), PROMIS Social Relating, Anxiety, and Sleep, Developmental Behaviour Checklist-2 (DBC-2), Vineland 3, and Autism Parenting Stress Index (APSI; secondary outcomes). There was no significant effect observed for the primary outcome measure (SRS-2) for CBD oil relative to placebo oil after 12 weeks, (p=.125). Significant improvements were observed in secondary measures of social functioning (PROMIS-Social, DBC-2 Social Relating; p<.05) and anxiety symptoms (PROMIS Anxiety, DBC-2 Anxiety; p<.05), while there was also a reduction in parental stress (p<.05). Safety and tolerability data indicated that two children experienced gastrointestinal discomfort while taking CBD. This pilot trial represents preliminary evidence for the potential therapeutic effects of CBD in autism. While further research is needed to confirm and extend these findings, the results suggest that CBD may be a promising intervention for addressing one of autism's core symptoms: social relating. Future studies with larger sample sizes are needed to fully evaluate the efficacy and safety of CBD for autistic children.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141502056","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}
Abstract Background Hallucinogens attract research as alternatives to the commonly used medications to treat major depressive and anxiety disorders. Aims Assess hallucinogens' efficacy for managing depressive and anxiety symptoms and evaluate their safety profiles. Method In five databases, we searched for randomized controlled trials of hallucinogens targeting depressive and anxiety symptoms. We performed a meta-analysis using a random effects model when data permitted it. The protocol of the review is registered in PROSPERO; CRD42022341325. Results Psilocybin produced a rapid and sustained reduction in depressive and anxiety symptoms in patients with major depressive disorder, severe, and in patients with life-threatening cancer. A decrease in depressive symptoms was observed with 3, 4-methylenedioxymethamphetamine (MDMA), primarily in patients with life-threatening cancer, autism spectrum disorder, and post-traumatic stress disorder. MDMA reduced social anxiety symptoms. However, MDMA's effect size was either negligible or negative for anxiety symptoms overall. Ayahuasca reduced depressive symptoms in individuals with treatment-resistant major depressive and personality disorders. Lysergic acid diethylamide (LSD) reduced anxiety symptoms in individuals with life-threatening cancer. Psilocybin's adverse effects were noticeable for elevated blood pressure, headaches, and panic attacks. For MDMA, elevated blood pressure, headaches, panic attacks, and feeling cold were noticeable. Conclusions Psilocybin, MDMA, ayahuasca, and LSD appear to have the potential to reduce depressive and anxiety symptoms. Adverse effects are noticed. Rigorous randomized controlled studies with larger sample sizes utilizing outcome measures instruments with better reliability and validity are warranted.
{"title":"Rapid and prolonged antidepressant and antianxiety effects of psychedelics and 3, 4-methylenedioxy-methamphetamine. A systematic review and meta-analysis","authors":"Dimy Fluyau, Vasanth Kattalai Kailasam, Neelambika Revadigar","doi":"10.1101/2024.06.17.24308787","DOIUrl":"https://doi.org/10.1101/2024.06.17.24308787","url":null,"abstract":"Abstract\u0000Background\u0000Hallucinogens attract research as alternatives to the commonly used medications to treat major depressive and anxiety disorders.\u0000Aims\u0000Assess hallucinogens' efficacy for managing depressive and anxiety symptoms and evaluate their safety profiles.\u0000Method\u0000In five databases, we searched for randomized controlled trials of hallucinogens targeting depressive and anxiety symptoms. We performed a meta-analysis using a random effects model when data permitted it. The protocol of the review is registered in PROSPERO; CRD42022341325.\u0000Results\u0000Psilocybin produced a rapid and sustained reduction in depressive and anxiety symptoms in patients with major depressive disorder, severe, and in patients with life-threatening cancer. A decrease in depressive symptoms was observed with 3, 4-methylenedioxymethamphetamine (MDMA), primarily in patients with life-threatening cancer, autism spectrum disorder, and post-traumatic stress disorder. MDMA reduced social anxiety symptoms. However, MDMA's effect size was either negligible or negative for anxiety symptoms overall. Ayahuasca reduced depressive symptoms in individuals with treatment-resistant major depressive and personality disorders. Lysergic acid diethylamide (LSD) reduced anxiety symptoms in individuals with life-threatening cancer. Psilocybin's adverse effects were noticeable for elevated blood pressure, headaches, and panic attacks. For MDMA, elevated blood pressure, headaches, panic attacks, and feeling cold were noticeable. Conclusions\u0000Psilocybin, MDMA, ayahuasca, and LSD appear to have the potential to reduce depressive and anxiety symptoms. Adverse effects are noticed. Rigorous randomized controlled studies with larger sample sizes utilizing outcome measures instruments with better reliability and validity are warranted.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141502170","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 : 2024-06-15DOI: 10.1101/2024.06.14.24308941
Dawud N Ellayan
Purpose Examine the effect of AMPK activation in addition to OCT2 competitive blockage through metformin concomitant treatment on the incidence rate of nephrotoxicity in adult head and neck cancer patients treated with cisplatin-based chemoradiation. Methods A single center retrospective three to one controlled study in HNSCC patients treated at a single academic health center between January 1st 2015 to December 31st 2021. Patients treated with cisplatin based chemoradiation regimen at a dose of either 40 mg/m2 weekly, or 100 mg/m2 every 3 weeks for a total of 7 weeks were identified and were divided into two cohorts; Cohort A with patients who received concomitant metformin therapy, where concomitant is defined as taken prior to the time of cisplatin start and continued during treatment. And cohort B with a control group of patients who did not receive metformin during cisplatin treatment. Results 18 patients were enrolled retrospectively in cohort A and 54 in cohort B. Our data shows a lower incidence of nephrotoxicity than reported in historical controls. However, no statistically significant differences were identified in direct comparison between the two cohorts. Conclusion Our data reaffirms the higher risk of nephrotoxicity for patients on Q3weeks regimen compared to weekly regimen, however, we were unable to show a statistically significant effect in direct comparison between the cohorts due to sample size limitation.
{"title":"A single center retrospective study to examine the effect of concomitant metformin treatment on cisplatin induced nephrotoxicity in adult HNSCC patients between 2015-2021","authors":"Dawud N Ellayan","doi":"10.1101/2024.06.14.24308941","DOIUrl":"https://doi.org/10.1101/2024.06.14.24308941","url":null,"abstract":"Purpose Examine the effect of AMPK activation in addition to OCT2 competitive blockage through metformin concomitant treatment on the incidence rate of nephrotoxicity in adult head and neck cancer patients treated with cisplatin-based chemoradiation.\u0000Methods\u0000A single center retrospective three to one controlled study in HNSCC patients treated at a single academic health center between January 1st 2015 to December 31st 2021. Patients treated with cisplatin based chemoradiation regimen at a dose of either 40 mg/m2 weekly, or 100 mg/m2 every 3 weeks for a total of 7 weeks were identified and were divided into two cohorts; Cohort A with patients who received concomitant metformin therapy, where concomitant is defined as taken prior to the time of cisplatin start and continued during treatment. And cohort B with a control group of patients who did not receive metformin during cisplatin treatment. Results\u000018 patients were enrolled retrospectively in cohort A and 54 in cohort B. Our data shows a lower incidence of nephrotoxicity than reported in historical controls. However, no statistically significant differences were identified in direct comparison between the two cohorts. Conclusion\u0000Our data reaffirms the higher risk of nephrotoxicity for patients on Q3weeks regimen compared to weekly regimen, however, we were unable to show a statistically significant effect in direct comparison between the cohorts due to sample size limitation.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141502055","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 : 2024-05-31DOI: 10.1101/2024.05.30.24308244
Katherine N. Theken, Soumita Ghosh, Carsten Skarke, Susanne Fries, Nicholas F. Lahens, Dimitra Sarantopoulou, Gregory R. Grant, Garret A. FitzGerald, Tilo Grosser
Background Non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of adverse cardiovascular events via suppression of cyclooxygenase (COX)-2-derived prostacyclin (PGI2) formation in heart, vasculature, and kidney. The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial and other large clinical studies compared the cardiovascular risk of traditional NSAIDs (i.e. naproxen), which inhibit both COX isozymes, with NSAIDs selective for COX-2 (i.e. celecoxib). However, whether pharmacologically equipotent doses were used - that is, whether a similar degree of COX-2 inhibition was achieved - was not considered. We compared drug target inhibition and blood pressure response to celecoxib at the dose used by most patients in PRECISION with the lowest recommended naproxen dose for osteoarthritis, which is lower than the dose used in PRECISION.
{"title":"Degree of Cyclooxygenase-2 Inhibition Modulates Blood Pressure Response to Celecoxib and Naproxen","authors":"Katherine N. Theken, Soumita Ghosh, Carsten Skarke, Susanne Fries, Nicholas F. Lahens, Dimitra Sarantopoulou, Gregory R. Grant, Garret A. FitzGerald, Tilo Grosser","doi":"10.1101/2024.05.30.24308244","DOIUrl":"https://doi.org/10.1101/2024.05.30.24308244","url":null,"abstract":"<strong>Background</strong> Non-steroidal anti-inflammatory drugs (NSAIDs) increase the risk of adverse cardiovascular events via suppression of cyclooxygenase (COX)-2-derived prostacyclin (PGI<sub>2</sub>) formation in heart, vasculature, and kidney. The Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen Or Naproxen (PRECISION) trial and other large clinical studies compared the cardiovascular risk of traditional NSAIDs (i.e. naproxen), which inhibit both COX isozymes, with NSAIDs selective for COX-2 (i.e. celecoxib). However, whether pharmacologically equipotent doses were used - that is, whether a similar degree of COX-2 inhibition was achieved - was not considered. We compared drug target inhibition and blood pressure response to celecoxib at the dose used by most patients in PRECISION with the lowest recommended naproxen dose for osteoarthritis, which is lower than the dose used in PRECISION.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141252426","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 : 2024-05-31DOI: 10.1101/2024.05.30.24308216
Haraldur Þorsteinsson, Hannes A. Baukmann, Hildur S. Sveinsdóttir, Dagmar Þ. Halldórsdóttir, Bartosz Grzymala, Courtney Hillman, Jude Rolfe-Tarrant, Matthew O. Parker, Justin L. Cope, Charles N. J. Ravarani, Marco F. Schmidt, Karl Æ. Karlsson
ADHD is a chronic neurodevelopmental disorder which significantly affects life outcomes. First-line treatments carry the risk of adverse side effects and present a high abuse potential, coupled with a 25% rate of non-response, necessitating novel treatments. Here, we validate amlodipine as an ADHD treatment using model rats and zebrafish and human genetic data. Amlodipine reduced hyperactivity in the Open Field Test in SHR rats and reduced both hyperactivity and impulsivity in the 5-Choice Serial Reaction Time Task in adgrl3.1-/-zebrafish. We show that amlodipine also passes the blood brain barrier and reduces telencephalic activation. Mendelian Randomization analysis using human genetic data revealed significant associations between ADHD and genetic variations in the subunits of L-type calcium channels (α1-C; CACNA1C, β1; CACNB1, α2δ3; CACNA2D3), and the combined genes targeted by amlodipine. Finally, we show that amlodipine mitigates key ADHD symptoms in a cohort of people with a high ADHD genetic liability. Given its well-tolerated profile, its efficacy in mitigating both hyperactivity and impulsivity across different species, coupled with genetic evidence from human data, the potential utility of amlodipine as a novel treatment for human ADHD is compelling.
多动症是一种严重影响生活质量的慢性神经发育障碍。一线治疗方法存在不良副作用的风险，且滥用可能性高，再加上25%的无应答率，因此需要新型治疗方法。在此，我们利用模型大鼠、斑马鱼和人类基因数据验证了氨氯地平作为多动症治疗药物的有效性。氨氯地平能降低SHR大鼠在开阔地测试中的多动性，并能降低adgrl3.1-/-斑马鱼在5选1连续反应时间任务中的多动性和冲动性。我们的研究表明，氨氯地平还能通过血脑屏障，减少端脑激活。利用人类基因数据进行的孟德尔随机分析表明，多动症与 L 型钙通道亚基（α1-C；CACNA1C、β1；CACNB1、α2δ3；CACNA2D3）的基因变异以及氨氯地平所针对的组合基因之间存在显著关联。最后，我们表明，氨氯地平可减轻多动症高遗传倾向人群的主要多动症症状。鉴于氨氯地平具有良好的耐受性，在不同物种中都具有缓解多动和冲动的功效，再加上来自人类数据的遗传学证据，氨氯地平作为治疗人类多动症的新型疗法的潜在作用令人信服。
{"title":"Validation of L-Type Calcium Channel Blocker Amlodipine as a Novel ADHD Treatment through Cross-Species Analysis, Drug-Target Mendelian Randomization, and clinical evidence from medical records","authors":"Haraldur Þorsteinsson, Hannes A. Baukmann, Hildur S. Sveinsdóttir, Dagmar Þ. Halldórsdóttir, Bartosz Grzymala, Courtney Hillman, Jude Rolfe-Tarrant, Matthew O. Parker, Justin L. Cope, Charles N. J. Ravarani, Marco F. Schmidt, Karl Æ. Karlsson","doi":"10.1101/2024.05.30.24308216","DOIUrl":"https://doi.org/10.1101/2024.05.30.24308216","url":null,"abstract":"ADHD is a chronic neurodevelopmental disorder which significantly affects life outcomes. First-line treatments carry the risk of adverse side effects and present a high abuse potential, coupled with a 25% rate of non-response, necessitating novel treatments. Here, we validate amlodipine as an ADHD treatment using model rats and zebrafish and human genetic data. Amlodipine reduced hyperactivity in the Open Field Test in SHR rats and reduced both hyperactivity and impulsivity in the 5-Choice Serial Reaction Time Task in <em>adgrl3.1<sup>-/-</sup></em>zebrafish. We show that amlodipine also passes the blood brain barrier and reduces telencephalic activation. Mendelian Randomization analysis using human genetic data revealed significant associations between ADHD and genetic variations in the subunits of L-type calcium channels (α1-C; CACNA1C, β1; CACNB1, α2δ3; CACNA2D3), and the combined genes targeted by amlodipine. Finally, we show that amlodipine mitigates key ADHD symptoms in a cohort of people with a high ADHD genetic liability. Given its well-tolerated profile, its efficacy in mitigating both hyperactivity and impulsivity across different species, coupled with genetic evidence from human data, the potential utility of amlodipine as a novel treatment for human ADHD is compelling.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141252425","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 : 2024-05-29DOI: 10.1101/2024.05.28.24307823
Brandon Harkonen, Anthony Cuttitta, James Henderson, Valerie Gavrila, Jey Mckibbin, Sherrie Luttman, Wendy Benedict, Lindsey R. Kelley, Scott A. Flanders, Hae Mi Choe, Geoffrey D Barnes
Purpose The initiation of specialty medications is associated with patient access challenges and clinician burden. This intervention invested resources upstream of the prescription being written. The evaluation assessed the impact on patient and clinician experience.
{"title":"Implementation of an Enhanced Medication Access Workflow within a Health System Specialty Pharmacy: Impact on Patient & Clinician Experience","authors":"Brandon Harkonen, Anthony Cuttitta, James Henderson, Valerie Gavrila, Jey Mckibbin, Sherrie Luttman, Wendy Benedict, Lindsey R. Kelley, Scott A. Flanders, Hae Mi Choe, Geoffrey D Barnes","doi":"10.1101/2024.05.28.24307823","DOIUrl":"https://doi.org/10.1101/2024.05.28.24307823","url":null,"abstract":"<strong>Purpose</strong> The initiation of specialty medications is associated with patient access challenges and clinician burden. This intervention invested resources upstream of the prescription being written. The evaluation assessed the impact on patient and clinician experience.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141189371","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 : 2024-05-08DOI: 10.1101/2024.05.06.24306555
Diego Valderrama, Olga Teplytska, Luca Marie Koltermann, Elena Trunz, Eduard Schmulenson, Achim Fritsch, Ulrich Jaehde, Holger Fröhlich
A variety of classical machine learning approaches have been developed over the past ten years with the aim to individualize drug dosages based on measured plasma concentrations. However, the interpretability of these models is challenging as they do not incorporate information on pharmacokinetic (PK) drug disposition. In this work we compare well-known population PK modelling with classical and a newly proposed scientific machine learning (SciML) framework, which combines knowledge on drug disposition with data-driven modelling. Our approach lets us estimate population PK parameters and their inter-individual variability (IIV) using multimodal covariate data of each patient. A dataset of 549 fluorouracil (5FU) plasma concentrations as example for an intravenously administered drug and a dataset of 308 sunitinib concentrations as example for an orally administered drug were used for analysis. Whereas classical machine learning models were not able to describe the data sufficiently, the proposed model allowed us to obtain highly accurate predictions even for new patients. Additionally, we demonstrated that our model could outperform traditional population PK models in terms of accuracy and greater flexibility when learning population parameters if given enough training data.
{"title":"Scientific machine learning for predicting plasma concentrations in anti-cancer therapy","authors":"Diego Valderrama, Olga Teplytska, Luca Marie Koltermann, Elena Trunz, Eduard Schmulenson, Achim Fritsch, Ulrich Jaehde, Holger Fröhlich","doi":"10.1101/2024.05.06.24306555","DOIUrl":"https://doi.org/10.1101/2024.05.06.24306555","url":null,"abstract":"A variety of classical machine learning approaches have been developed over the past ten years with the aim to individualize drug dosages based on measured plasma concentrations. However, the interpretability of these models is challenging as they do not incorporate information on pharmacokinetic (PK) drug disposition. In this work we compare well-known population PK modelling with classical and a newly proposed scientific machine learning (SciML) framework, which combines knowledge on drug disposition with data-driven modelling. Our approach lets us estimate population PK parameters and their inter-individual variability (IIV) using multimodal covariate data of each patient. A dataset of 549 fluorouracil (5FU) plasma concentrations as example for an intravenously administered drug and a dataset of 308 sunitinib concentrations as example for an orally administered drug were used for analysis. Whereas classical machine learning models were not able to describe the data sufficiently, the proposed model allowed us to obtain highly accurate predictions even for new patients. Additionally, we demonstrated that our model could outperform traditional population PK models in terms of accuracy and greater flexibility when learning population parameters if given enough training data.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-05-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140925516","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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