Pub Date : 2024-01-08DOI: 10.1101/2024.01.03.24300783
Xiao-Jian Zhou, Arantxa Horga, Adeep Puri, Lee Winchester, Maureen Montrond, Keith Pietropaolo, Bruce Belanger, Courtney V. Fletcher, Janet Hammond
Bemnifosbuvir (BEM, AT-527) is a novel oral guanosine nucleotide antiviral drug for the treatment of patients with COVID-19. Direct assessment of drug disposition in the lungs, via bronchoalveolar lavage, is necessary to ensure antiviral drug levels at the primary site of SARS-CoV-2 infection are achieved. We conducted a Phase 1 study in healthy subjects to assess the bronchopulmonary pharmacokinetics, safety, and tolerability of repeated doses of BEM. A total of 24 subjects were assigned to receive twice-daily (BID) BEM at doses of 275, 550, or 825 mg for up to 3.5 days. AT-511, the free base of BEM, was largely eliminated from the plasma within 6 h post dose in all dosing groups. Antiviral drug levels of BEM were consistently achieved in the lungs with BEM 550 mg BID. The mean level of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, measured in the epithelial lining fluid of the lungs was 0.62 µM at 4–5 h post dose. This exceeded the target in vitro 90% effective concentration (EC90) of 0.5 µM for antiviral drug exposure against SARS-CoV-2 replication in human airway epithelial cells. BEM was well tolerated across all doses tested, and most treatment-emergent adverse events reported were mild in severity and resolved. The favorable pharmacokinetics and safety profile of BEM demonstrates its potential as an oral antiviral treatment for COVID-19, with 550 mg BEM BID currently under further clinical evaluation in patients with COVID-19.
{"title":"Human bronchopulmonary disposition and plasma pharmacokinetics of oral bemnifosbuvir (AT-527), an experimental guanosine nucleotide prodrug for COVID-19","authors":"Xiao-Jian Zhou, Arantxa Horga, Adeep Puri, Lee Winchester, Maureen Montrond, Keith Pietropaolo, Bruce Belanger, Courtney V. Fletcher, Janet Hammond","doi":"10.1101/2024.01.03.24300783","DOIUrl":"https://doi.org/10.1101/2024.01.03.24300783","url":null,"abstract":"Bemnifosbuvir (BEM, AT-527) is a novel oral guanosine nucleotide antiviral drug for the treatment of patients with COVID-19. Direct assessment of drug disposition in the lungs, via bronchoalveolar lavage, is necessary to ensure antiviral drug levels at the primary site of SARS-CoV-2 infection are achieved. We conducted a Phase 1 study in healthy subjects to assess the bronchopulmonary pharmacokinetics, safety, and tolerability of repeated doses of BEM. A total of 24 subjects were assigned to receive twice-daily (BID) BEM at doses of 275, 550, or 825 mg for up to 3.5 days. AT-511, the free base of BEM, was largely eliminated from the plasma within 6 h post dose in all dosing groups. Antiviral drug levels of BEM were consistently achieved in the lungs with BEM 550 mg BID. The mean level of the guanosine nucleoside metabolite AT-273, the surrogate of the active triphosphate metabolite of the drug, measured in the epithelial lining fluid of the lungs was 0.62 µM at 4–5 h post dose. This exceeded the target <em>in vitro</em> 90% effective concentration (EC<sub>90</sub>) of 0.5 µM for antiviral drug exposure against SARS-CoV-2 replication in human airway epithelial cells. BEM was well tolerated across all doses tested, and most treatment-emergent adverse events reported were mild in severity and resolved. The favorable pharmacokinetics and safety profile of BEM demonstrates its potential as an oral antiviral treatment for COVID-19, with 550 mg BEM BID currently under further clinical evaluation in patients with COVID-19.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139411365","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}
Teicoplanin is an important antimicrobial agent for methicillin-resistant Staphylococcus aureus infections. To enhance its clinical effectiveness while preventing adverse effects, therapeutic drug monitoring (TDM) of teicoplanin trough concentration is recommended. Given the importance of the early achievement of therapeutic concentrations for treatment success, initial dosing regimens are deliberately designed based on patient information.
{"title":"Integration of pharmacists’ knowledge into a predictive model for teicoplanin dose planning","authors":"Tetsuo Matsuzaki, Tsuyoshi Nakai, Yoshiaki Kato, Kiyofumi Yamada, Tetsuya Yagi","doi":"10.1101/2023.12.14.23299934","DOIUrl":"https://doi.org/10.1101/2023.12.14.23299934","url":null,"abstract":"Teicoplanin is an important antimicrobial agent for methicillin-resistant <em>Staphylococcus aureus</em> infections. To enhance its clinical effectiveness while preventing adverse effects, therapeutic drug monitoring (TDM) of teicoplanin trough concentration is recommended. Given the importance of the early achievement of therapeutic concentrations for treatment success, initial dosing regimens are deliberately designed based on patient information.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138820179","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 : 2023-12-08DOI: 10.1101/2023.12.06.23299603
Shifang Li, Meijiao Gong
Growing evidence has revealed the associations between telomere length and diseases; however, the mechanisms behind these links are not fully understood. In this study, by applying proteome-wide Mendelian randomisation (MR), multiple sensitivity analyses, colocalization, single-cell RNA-sequencing, and mediation analysis, the potential mechanisms that link 4,907 plasma proteins, telomere length, and 8 diseases were identified. Following MR analysis for the effects of plasma protein levels on telomere length, 34 proteins were found to be causally related to telomere length. Among these, 8 proteins (PSMB4, PARP1, GDI2, MAX, GMPR2, ARPC1B, ATOX1, and NUDT5) were found to be well colocalized with telomere length (posterior probability >80%). 21 mediation pairs were revealed for the indirect effect of circulating proteins on 8 diseases via telomere length. Furthermore, 35 proteins, including CD8A, were found to be influenced by telomere length among 4,907 proteins. No significant mediation pairs for circulating proteins that mediate the effects of telomere length on disease have been identified. Overall, our study provided insights into understanding the biology of telomeres and prioritized the identified proteins as prospective intervention targets for the disease.
{"title":"Integrative proteogenomics study identifies the indirect effect of circulating proteins on 8 diseases via telomere length","authors":"Shifang Li, Meijiao Gong","doi":"10.1101/2023.12.06.23299603","DOIUrl":"https://doi.org/10.1101/2023.12.06.23299603","url":null,"abstract":"Growing evidence has revealed the associations between telomere length and diseases; however, the mechanisms behind these links are not fully understood. In this study, by applying proteome-wide Mendelian randomisation (MR), multiple sensitivity analyses, colocalization, single-cell RNA-sequencing, and mediation analysis, the potential mechanisms that link 4,907 plasma proteins, telomere length, and 8 diseases were identified. Following MR analysis for the effects of plasma protein levels on telomere length, 34 proteins were found to be causally related to telomere length. Among these, 8 proteins (PSMB4, PARP1, GDI2, MAX, GMPR2, ARPC1B, ATOX1, and NUDT5) were found to be well colocalized with telomere length (posterior probability >80%). 21 mediation pairs were revealed for the indirect effect of circulating proteins on 8 diseases via telomere length. Furthermore, 35 proteins, including CD8A, were found to be influenced by telomere length among 4,907 proteins. No significant mediation pairs for circulating proteins that mediate the effects of telomere length on disease have been identified. Overall, our study provided insights into understanding the biology of telomeres and prioritized the identified proteins as prospective intervention targets for the disease.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138564124","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 : 2023-12-07DOI: 10.1101/2023.12.05.23299140
Guang Yang, Cristina Alarcon, Catherine Chanfreau-Coffinier, Norm H Lee, Paula Friedman, Edith Nutescu, Matthew Tuck, Travis O'Brien, Li Gong, Teri E Klein, Kyong-Mi Chang, Philip S Tsao, David O Meltzer, Million Veteran Program, Sony Tuteja, Minoli A Perera
Clopidogrel, an anti-platelet drug, used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic episodes, with African Americans suffering disproportionately. The aim of this study was to identify biomarkers of clopidogrel resistance in African American patients. We conducted a genome-wide association study, including local ancestry adjustment, in 141 African Americans on clopidogrel to identify associations with high on-treatment platelet reactivity (HTPR). We validated genome-wide and suggestive hits in an independent cohort of African American clopidogrel patients (N = 823) from the Million Veterans Program (MVP) along with in vitro functional follow up. We performed differential gene expression (DGE) analysis in whole blood with functional follow-up in MEG-01 cells. We identified rs7807369, within thrombospondin 7A (THSD7A), as significantly associated with increasing risk of HTPR (p = 4.56 x 10-9). Higher THSD7A expression was associated with HTPR in an independent gene expression cohort of clopidogrel treated patients (p = 0.004) and supported by increased gene expression on THSD7A in primary human endothelial cells carrying the risk allele. Two SNPs (rs1149515 and rs191786) were validated in the MVP cohort. DGE analysis identified an association with decreased LAIR1 expression to HTPR. LAIR1 knockdown in a MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of LAIR1 in the Glycoprotein VI pathway. Notably, the CYP2C19 variants showed no association with clopidogrel response in the discovery or MVP cohorts. In summary, these finding suggest that other variants outside of CYP2C19 star alleles play an important role in clopidogrel response in African Americans.
{"title":"Investigation of genomic and transcriptomic risk factors in clopidogrel response in African Americans.","authors":"Guang Yang, Cristina Alarcon, Catherine Chanfreau-Coffinier, Norm H Lee, Paula Friedman, Edith Nutescu, Matthew Tuck, Travis O'Brien, Li Gong, Teri E Klein, Kyong-Mi Chang, Philip S Tsao, David O Meltzer, Million Veteran Program, Sony Tuteja, Minoli A Perera","doi":"10.1101/2023.12.05.23299140","DOIUrl":"https://doi.org/10.1101/2023.12.05.23299140","url":null,"abstract":"Clopidogrel, an anti-platelet drug, used to prevent thrombosis after percutaneous coronary intervention. Clopidogrel resistance results in recurring ischemic episodes, with African Americans suffering disproportionately. The aim of this study was to identify biomarkers of clopidogrel resistance in African American patients. We conducted a genome-wide association study, including local ancestry adjustment, in 141 African Americans on clopidogrel to identify associations with high on-treatment platelet reactivity (HTPR). We validated genome-wide and suggestive hits in an independent cohort of African American clopidogrel patients (N = 823) from the Million Veterans Program (MVP) along with in vitro functional follow up. We performed differential gene expression (DGE) analysis in whole blood with functional follow-up in MEG-01 cells. We identified rs7807369, within thrombospondin 7A (THSD7A), as significantly associated with increasing risk of HTPR (p = 4.56 x 10-9). Higher THSD7A expression was associated with HTPR in an independent gene expression cohort of clopidogrel treated patients (p = 0.004) and supported by increased gene expression on THSD7A in primary human endothelial cells carrying the risk allele. Two SNPs (rs1149515 and rs191786) were validated in the MVP cohort. DGE analysis identified an association with decreased LAIR1 expression to HTPR. LAIR1 knockdown in a MEG-01 cells resulted in increased expression of SYK and AKT1, suggesting an inhibitory role of LAIR1 in the Glycoprotein VI pathway. Notably, the CYP2C19 variants showed no association with clopidogrel response in the discovery or MVP cohorts. In summary, these finding suggest that other variants outside of CYP2C19 star alleles play an important role in clopidogrel response in African Americans.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138556917","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 : 2023-12-07DOI: 10.1101/2023.12.05.23299561
Sophie samuel, Kyndol Craver, Charles Miller, Brittany Pelsue, Catherine Gonzalez, Teresa Annette Allison, Brain Gulbis, Huimahn Alex Choi, Seokhum Kim
Background: Acute ischemic stroke (AIS) is a major health challenge, often resulting in long-term disability and death. This study assesses the impact of renin-angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) on AIS patient mortality compared to non-RAS antihypertensive medications. Methods: This retrospective cohort study, conducted at Memorial Hermann–Texas Medical Center in Houston, Texas, from August 31, 2017, to August 31, 2022, examined AIS patient mortality. We used a cohort design, evaluating the effects of RAS inhibitors, either alone or in combination with beta-blockers (BBs), while exploring interactions, including those related to end-stage renal disease (ESRD) and serum creatinine levels. Eligible subjects included AIS patients aged 18 or older with specific AIS subtypes who received in-patient antihypertensive treatment. Missing data were addressed using imputation, followed by Inverse Probability of Treatment Weighting (IPTW) to achieve covariate balance. Our primary outcome was mortality rates. Statistical analyses involved cross-sectional and longitudinal approaches, including generalized linear models, G-computation, and discrete time survival analysis over a 20-day follow-up period. Results: In our study of 3058 AIS patients, those using RAS inhibitors had significantly lower in-hospital mortality (2.2%) compared to non-users (12.1%), resulting in a relative risk (RR) of 0.18 (95% CI 0.12-0.26). Further analysis using G-computation revealed a marked reduction in mortality risk associated with RAS inhibitors (Risk 0.0281 vs. 0.0913, Risk Difference (RD) of 6.31% or 0.0631, 95% CI 0.046-0.079). Subgroup analysis demonstrated notable benefits, with individuals having creatinine levels below and above 1.3 mg/dL exhibiting statistically significant RD (RD -0.0510 vs. -0.0895), and a significant difference in paired comparison (-0.0385 or 3.85%, CI 0.023-0.054). Additionally, longitudinal analysis confirmed a consistent daily reduction of 0.93% in mortality risk associated with the intake of RAS inhibitors. Conclusion: RAS inhibitors are associated with a significant reduction in in-hospital mortality in AIS patients, suggesting potential clinical benefits in improving patient outcomes.
{"title":"Effect of RAS Inhibitors in Acute Ischemic Stroke to Improve Outcomes: A Cross Sectional and Longitudinal Analysis.","authors":"Sophie samuel, Kyndol Craver, Charles Miller, Brittany Pelsue, Catherine Gonzalez, Teresa Annette Allison, Brain Gulbis, Huimahn Alex Choi, Seokhum Kim","doi":"10.1101/2023.12.05.23299561","DOIUrl":"https://doi.org/10.1101/2023.12.05.23299561","url":null,"abstract":"Background: Acute ischemic stroke (AIS) is a major health challenge, often resulting in long-term disability and death. This study assesses the impact of renin-angiotensin system (RAS) inhibitors (angiotensin-converting enzyme inhibitors and angiotensin receptor blockers) on AIS patient mortality compared to non-RAS antihypertensive medications.\u0000Methods: This retrospective cohort study, conducted at Memorial Hermann–Texas Medical Center in Houston, Texas, from August 31, 2017, to August 31, 2022, examined AIS patient mortality. We used a cohort design, evaluating the effects of RAS inhibitors, either alone or in combination with beta-blockers (BBs), while exploring interactions, including those related to end-stage renal disease (ESRD) and serum creatinine levels. Eligible subjects included AIS patients aged 18 or older with specific AIS subtypes who received in-patient antihypertensive treatment. Missing data were addressed using imputation, followed by Inverse Probability of Treatment Weighting (IPTW) to achieve covariate balance. Our primary outcome was mortality rates. Statistical analyses involved cross-sectional and longitudinal approaches, including generalized linear models, G-computation, and discrete time survival analysis over a 20-day follow-up period.\u0000Results: In our study of 3058 AIS patients, those using RAS inhibitors had significantly lower in-hospital mortality (2.2%) compared to non-users (12.1%), resulting in a relative risk (RR) of 0.18 (95% CI 0.12-0.26). Further analysis using G-computation revealed a marked reduction in mortality risk associated with RAS inhibitors (Risk 0.0281 vs. 0.0913, Risk Difference (RD) of 6.31% or 0.0631, 95% CI 0.046-0.079). Subgroup analysis demonstrated notable benefits, with individuals having creatinine levels below and above 1.3 mg/dL exhibiting statistically significant RD (RD -0.0510 vs. -0.0895), and a significant difference in paired comparison (-0.0385 or 3.85%, CI 0.023-0.054). Additionally, longitudinal analysis confirmed a consistent daily reduction of 0.93% in mortality risk associated with the intake of RAS inhibitors.\u0000Conclusion: RAS inhibitors are associated with a significant reduction in in-hospital mortality in AIS patients, suggesting potential clinical benefits in improving patient outcomes.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138556796","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 : 2023-12-07DOI: 10.1101/2023.12.05.23299567
Eloi Gagnon, Estonian Biobank research Team, Arnaud Girard, Jérome Bourgault, Erik Abner, Dipender Gill, Sébastien Thériault, Marie-Claude Vohl, André Tchernof, patrick mathieu, Benoit J Arsenault
Background: Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in patients undergoing prolonged anticoagulation. New safer anticoagulant targets are needed. Methods: We performed two-sample Mendelian randomization (MR) and genetic colocalization to prioritize anticoagulant targets with the strongest efficacy (venous thromboembolism [VTE] prevention) and safety (low bleeding risk) profiles. We leveraged three large-scale plasma protein datasets (deCODE, n=35,559; Fenland n = 10,708; ARIC n= 7,213) and one liver gene expression dataset (n =246) to evaluate evidence for a causal effect of 26 coagulation cascade plasma proteins on VTE from a new genome-wide association meta-analysis of 44,232 VTE cases and 847,152 controls (from the UK Biobank, FinnGen and Estonian Biobank), stroke subtypes (from UK Biobank and International Stroke Genetics consortium 73,652 cases and 1,234,808 controls), bleeding outcomes (FinnGen, n=309,154) and over one million parental lifespans (UK Biobank and LifeGen consortium). Results: Genetically predicted reductions in F2 blood levels were associated with lower VTE risk (OR [odds ratio] per 1 standard deviation [SD] lower F2=0.44, 95% CI=0.38-0.51, p=2.6E-28) and cardioembolic stroke risk (OR = 0.55, 95% CI=0.39-0.76, p=4.2e-04) but not with bleeding (OR = 1.13, 95% CI=0.93-1.36, p=2.2e-01). Genetically predicted F11 reduction were associated with lower risk of VTE (OR = 0.61, 95% CI=0.58-0.64, p=4.1e-85) and cardioembolic stroke (OR = 0.77, 95% CI=0.69-0.86, p=4.1e-06), but not with bleeding (OR = 1.01, 95% CI=0.95-1.08, p=7.5e-01) (Figure 3). These MR associations were concordant across the three blood protein datasets and the hepatic gene expression dataset as well as three different MR and colocalization analyses. Conclusion: These results provide strong genetic evidence that F2 and F11 may represent safe and efficacious therapeutic targets to prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.
{"title":"Mendelian randomization analysis supports Factors II and XI as actionable anticoagulant targets","authors":"Eloi Gagnon, Estonian Biobank research Team, Arnaud Girard, Jérome Bourgault, Erik Abner, Dipender Gill, Sébastien Thériault, Marie-Claude Vohl, André Tchernof, patrick mathieu, Benoit J Arsenault","doi":"10.1101/2023.12.05.23299567","DOIUrl":"https://doi.org/10.1101/2023.12.05.23299567","url":null,"abstract":"Background: Anticoagulants are routinely used by millions of patients worldwide to prevent blood clots. Yet, problems with anticoagulant therapy remain, including a persistent and cumulative bleeding risk in patients undergoing prolonged anticoagulation. New safer anticoagulant targets are needed. Methods: We performed two-sample Mendelian randomization (MR) and genetic colocalization to prioritize anticoagulant targets with the strongest efficacy (venous thromboembolism [VTE] prevention) and safety (low bleeding risk) profiles. We leveraged three large-scale plasma protein datasets (deCODE, n=35,559; Fenland n = 10,708; ARIC n= 7,213) and one liver gene expression dataset (n =246) to evaluate evidence for a causal effect of 26 coagulation cascade plasma proteins on VTE from a new genome-wide association meta-analysis of 44,232 VTE cases and 847,152 controls (from the UK Biobank, FinnGen and Estonian Biobank), stroke subtypes (from UK Biobank and International Stroke Genetics consortium 73,652 cases and 1,234,808 controls), bleeding outcomes (FinnGen, n=309,154) and over one million parental lifespans (UK Biobank and LifeGen consortium). Results: Genetically predicted reductions in F2 blood levels were associated with lower VTE risk (OR [odds ratio] per 1 standard deviation [SD] lower F2=0.44, 95% CI=0.38-0.51, p=2.6E-28) and cardioembolic stroke risk (OR = 0.55, 95% CI=0.39-0.76, p=4.2e-04) but not with bleeding (OR = 1.13, 95% CI=0.93-1.36, p=2.2e-01). Genetically predicted F11 reduction were associated with lower risk of VTE (OR = 0.61, 95% CI=0.58-0.64, p=4.1e-85) and cardioembolic stroke (OR = 0.77, 95% CI=0.69-0.86, p=4.1e-06), but not with bleeding (OR = 1.01, 95% CI=0.95-1.08, p=7.5e-01) (Figure 3). These MR associations were concordant across the three blood protein datasets and the hepatic gene expression dataset as well as three different MR and colocalization analyses. Conclusion: These results provide strong genetic evidence that F2 and F11 may represent safe and efficacious therapeutic targets to prevent VTE and cardioembolic strokes without substantially increasing bleeding risk.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138556791","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 : 2023-12-03DOI: 10.1101/2023.12.02.23299324
Sook Wah Yee, Tanushree Haldar, Mark Kvale, Jia Yang, Michael P Douglas, Akinyemi Oni-Orisan
Background: Clinical pharmacogenetic implementation guidelines for statin therapy are derived from evidence of primarily Eurocentric study populations. Functional SLCO1B1 variants that are rare in these study populations have not been investigated as a determinant of statin myotoxicity and are thus missing from guideline inclusion. Objective: Determine the relationship between candidate functional SLCO1B1 variants and statin-induced myopathy in people with recent genealogical ancestors from Africa. Design: Population-based pharmacogenetic study using real-world evidence from electronic health record-linked biobanks Setting: Various health care settings Participants: Self-identified white and Black statin users with genome-wide genotyping data available. Measurements: Primarily, the odds of statin-induced myopathy + rhabdomyolysis. Secondarily, total bilirubin levels. Thirdly, cell-based functional assay results. Results: Meta-analyses results demonstrated an increased risk of statin-induced myopathy + rhabdomyolysis with c.481+1G>T (odds ratio [OR] = 3.27, 95% confidence interval [CI] 1.43-7.46, P=.005) and c.1463G>C (OR = 2.45, 95% CI 1.04-5.78, P=.04) for Black participants. For White participants, c.521T>C was also significantly associated with increased risk of statin-induced myopathy + rhabdomyolysis (OR = 1.41, 95% CI 1.20-1.67, P=5.4x10-5). This effect size for c.521T>C was similar in the Black participants, but did not meet the level of statistical significance (OR = 1.47, 95% CI 0.58-3.73, P=0.41). Supporting evidence using total bilirubin as an endogenous biomarker of SLCO1B1 function as well as from cell-based functional studies corroborated these findings. Limitations: Data limited to severe statin myotoxicity events. Conclusion: Our findings implicate Afrocentric SLCO1B1 variants on preemptive pharmacogenetic testing panels, which could have an instant impact on reducing the risk of statin-associated myotoxicity in historically excluded groups. Primary Funding Source: National Institutes of Health, Office of the Director - All of Us (OD-AoURP)
{"title":"SLCO1B1 functional variants and statin-induced myopathy in people with recent genealogical ancestors from Africa: a population-based real-world study.","authors":"Sook Wah Yee, Tanushree Haldar, Mark Kvale, Jia Yang, Michael P Douglas, Akinyemi Oni-Orisan","doi":"10.1101/2023.12.02.23299324","DOIUrl":"https://doi.org/10.1101/2023.12.02.23299324","url":null,"abstract":"Background: Clinical pharmacogenetic implementation guidelines for statin therapy are derived from evidence of primarily Eurocentric study populations. Functional SLCO1B1 variants that are rare in these study populations have not been investigated as a determinant of statin myotoxicity and are thus missing from guideline inclusion.\u0000Objective: Determine the relationship between candidate functional SLCO1B1 variants and statin-induced myopathy in people with recent genealogical ancestors from Africa.\u0000Design: Population-based pharmacogenetic study using real-world evidence from electronic health record-linked biobanks\u0000Setting: Various health care settings\u0000Participants: Self-identified white and Black statin users with genome-wide genotyping data available.\u0000Measurements: Primarily, the odds of statin-induced myopathy + rhabdomyolysis. Secondarily, total bilirubin levels. Thirdly, cell-based functional assay results.\u0000Results: Meta-analyses results demonstrated an increased risk of statin-induced myopathy + rhabdomyolysis with c.481+1G>T (odds ratio [OR] = 3.27, 95% confidence interval [CI] 1.43-7.46, P=.005) and c.1463G>C (OR = 2.45, 95% CI 1.04-5.78, P=.04) for Black participants. For White participants, c.521T>C was also significantly associated with increased risk of statin-induced myopathy + rhabdomyolysis (OR = 1.41, 95% CI 1.20-1.67, P=5.4x10-5). This effect size for c.521T>C was similar in the Black participants, but did not meet the level of statistical significance (OR = 1.47, 95% CI 0.58-3.73, P=0.41). Supporting evidence using total bilirubin as an endogenous biomarker of SLCO1B1 function as well as from cell-based functional studies corroborated these findings.\u0000Limitations: Data limited to severe statin myotoxicity events. Conclusion: Our findings implicate Afrocentric SLCO1B1 variants on preemptive pharmacogenetic testing panels, which could have an instant impact on reducing the risk of statin-associated myotoxicity in historically excluded groups.\u0000Primary Funding Source: National Institutes of Health, Office of the Director - All of Us (OD-AoURP)","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138534832","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 : 2023-11-18DOI: 10.1101/2023.11.17.23298706
Moses Ocan, Winnie Nambatya, Caroline Otike, Loyce Nakalembe, Sam Nsobya
Background Malaria remains one of the leading causes of morbidity, and mortality in Uganda. A large proportion of malaria symptomatic patients seek healthcare in the private sector. However, availability and affordability are major barriers to access to effective treatment. The private sector copayment mechanism in Uganda aims to increase availability and affordability of antimalarial agents. Our study assessed the availability, price, and market share of quality assured artemisinin-based combination therapies (QAACTs) in private drug outlets after over a decade of copayment mechanism in the private sector in Uganda. Methods This was a cross-sectional survey of anti-malarial agents in private drug outlets in high (Tororo, and Apac districts) and low (Kabale and Mbarara districts) malaria transmission settings. Following the WHO/HAI criteria, an audit of the antimalarial agents was done using a checklist to determine availability, price, and market share of QAACTs. Data was entered in Epi-data and analyzed in STATA ver 14.0 at 95% confidence level. Results A total of twenty-eight (28) private drug outlets (pharmacies and drug shops) were included in the survey. One in seven Artemisinin-based combination therapies (ACTs) in the drug outlets were quality assured (QAACTs). Artemether-lumefantrine (AL), 8.9% (11/124) and Artesunate-Amodiaquine (AQ), 7.3% (9/124) were the only QAACTs present in the drug outlets at the time of the survey. The majority, 86.1%% (124/144) of antimalarial agents present in stock in the drug outlets were artemisinin based. The most common, 38.9% (56/144) ACT in the drug outlets was Dihydroartemisinin-Piperaquine (DHP). Most, 69.4% (100/144) of the antimalarial agents were in high malaria transmission settings. The cost of ACT antimalarial agents is high in the country, USD 1.4 (Artemether-Lumefantrine, AL), USD 2.4 (Dihydroartemisinin-Piperaquine, DP), the first line and second-line agents respectively for treatment of uncomplicated malaria in Uganda. There was a statistically significant difference between the dispensing price of the ‘Green leaf’ ACTs and the recommended price (p<0.001). Conclusion Quality assured artemisinin-based combination therapies (QAACTs) are not common in private drug outlets in low and high malaria transmission settings. All the drug outlets had at least one ACT antimalarial agent present on the day of the survey. The dispensing price of QAACTs was significantly higher than the recommended markup price. There is need for awareness creation, surveillance, and monitoring of the implementation of Copayment mechanism in the country.
疟疾仍然是乌干达发病和死亡的主要原因之一。很大一部分有疟疾症状的病人到私营部门寻求保健。然而，可获得性和可负担性是获得有效治疗的主要障碍。乌干达私营部门共同支付机制的目的是增加抗疟疾药物的可得性和可负担性。我们的研究评估了在乌干达私营部门实施了十多年的共同支付机制后，私营药店中有质量保证的以青蒿素为基础的联合疗法(QAACTs)的可得性、价格和市场份额。方法对疟疾高发地区(托罗罗和Apac地区)和低发地区(卡巴莱和姆巴拉拉地区)私营药品销售点的抗疟药物情况进行横断面调查。按照世卫组织/国际卫生组织的标准，使用清单对抗疟药物进行了审计，以确定QAACTs的可得性、价格和市场份额。在Epi-data中输入数据，并在STATA ver 14.0中以95%置信水平进行分析。结果调查共包括28家私营药品销售点(药店和药店)。药店销售的以青蒿素为基础的联合疗法(ACTs)有七分之一是质量有保证的(QAACTs)。调查时各药品网点仅存在青蒿素-甲氨苯曲明(AL)，占8.9%(11/124)和青蒿素-阿莫地喹(AQ)，占7.3%(9/124)。药店库存抗疟药中以青蒿素类为主，占86.1%(124/144)。以双氢青蒿素-哌喹(DHP)最为常见，占38.9%(56/144)。在疟疾高传播环境中使用的抗疟药物最多，为69.4%(100/144)。在乌干达，以青蒿素为基础的联合治疗抗疟药物的成本很高，用于治疗无并发症疟疾的一线和二线药物分别为1.4美元(青蒿素-氨苯曲明，AL)和2.4美元(双氢青蒿素-哌喹，DP)。“绿叶”ACTs的配药价格与推荐价格之间存在统计学显著差异(p<0.001)。结论在疟疾低传播和高传播环境中，以青蒿素为基础的有质量保证的联合疗法(QAACTs)在私营药品销售点并不常见。所有药品销售点在调查当天至少有一种以青蒿素为基础的抗疟药。QAACTs的配药价格明显高于推荐加价。有必要提高认识，监督和监测共同支付机制在该国的实施情况。
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Pub Date : 2023-11-16DOI: 10.1101/2023.11.14.23298497
Martina Vinicki, Tea Pribic, Frano Vuckovic, Azra Frkatovic-Hodzic,, Isaac Plaza-Andrade, Francisco Tinahones, Joseph Raffaele, Jose Carlos Fernandez-Garcia, Gordan Lauc
With aging, there is a correlation between a decline in the body′s ability to maintain regular functioning and greater susceptibility to age-related diseases. Therapeutic interventions targeting the underlying biological changes of aging hold promise for preventing or delaying multiple age-related diseases. Metformin, a drug commonly used for diabetes treatment, has emerged as a potential gerotherapeutic agent due to its established safety record and preclinical and clinical data on its anti-aging effects. Glycosylation, one of the most common and complex co- and post-translational protein modifications, plays a crucial role in regulating protein function and has been linked to aging and various diseases. Changes in IgG glycosylation patterns have been observed with age, and these alterations may serve as valuable biomarkers for disease predisposition, diagnosis, treatment monitoring, and overall health assessment. In this study, we analyzed the IgG glycosylation patterns of individuals under treatment with metformin, testosterone, metformin plus testosterone and placebo, and investigated the longitudinal changes in glycosylation over time. We observed statistically significant differences in the IgG glycome composition between participants on testosterone therapy and placebo, with decreased agalactosylation and increased galactosylation and sialylation. However, metformin therapy did not result in statistically significant changes in glycosylation patterns. These findings contribute to our understanding of the impact of therapeutic interventions on IgG glycosylation and confirm the value of IgG glycosylation as a significant biomarker, capable of assessing biological age using the GlycanAge index and providing insight into overall health compared to chronological age.
{"title":"Effects of testosterone and metformin on the GlycanAge index of biological age and the composition of the IgG glycome","authors":"Martina Vinicki, Tea Pribic, Frano Vuckovic, Azra Frkatovic-Hodzic,, Isaac Plaza-Andrade, Francisco Tinahones, Joseph Raffaele, Jose Carlos Fernandez-Garcia, Gordan Lauc","doi":"10.1101/2023.11.14.23298497","DOIUrl":"https://doi.org/10.1101/2023.11.14.23298497","url":null,"abstract":"With aging, there is a correlation between a decline in the body′s ability to maintain regular functioning and greater susceptibility to age-related diseases. Therapeutic interventions targeting the underlying biological changes of aging hold promise for preventing or delaying multiple age-related diseases. Metformin, a drug commonly used for diabetes treatment, has emerged as a potential gerotherapeutic agent due to its established safety record and preclinical and clinical data on its anti-aging effects. Glycosylation, one of the most common and complex co- and post-translational protein modifications, plays a crucial role in regulating protein function and has been linked to aging and various diseases. Changes in IgG glycosylation patterns have been observed with age, and these alterations may serve as valuable biomarkers for disease predisposition, diagnosis, treatment monitoring, and overall health assessment. In this study, we analyzed the IgG glycosylation patterns of individuals under treatment with metformin, testosterone, metformin plus testosterone and placebo, and investigated the longitudinal changes in glycosylation over time. We observed statistically significant differences in the IgG glycome composition between participants on testosterone therapy and placebo, with decreased agalactosylation and increased galactosylation and sialylation. However, metformin therapy did not result in statistically significant changes in glycosylation patterns. These findings contribute to our understanding of the impact of therapeutic interventions on IgG glycosylation and confirm the value of IgG glycosylation as a significant biomarker, capable of assessing biological age using the GlycanAge index and providing insight into overall health compared to chronological age.","PeriodicalId":501447,"journal":{"name":"medRxiv - Pharmacology and Therapeutics","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138534829","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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