Cts-Clinical and Translational Science最新文献

{"title":"Pharmacogenetic testing in primary care could bolster depression treatment: A value proposition","authors":"Nina R. Sperber,&nbsp;Megan C. Roberts,&nbsp;Sarah Gonzales,&nbsp;Lisa M. Bendz,&nbsp;Deborah Cragun,&nbsp;Susanne B. Haga,&nbsp;R. Ryanne Wu,&nbsp;Chioma Omeogu,&nbsp;Brystana Kaufman,&nbsp;Natasha J. Petry,&nbsp;Laura B. Ramsey,&nbsp;Ryley Uber","doi":"10.1111/cts.13837","DOIUrl":"10.1111/cts.13837","url":null,"abstract":"<p>Pharmacogenetic testing could reduce the time to identify a safe and effective medication for depression; however, it is underutilized in practice. Major depression constitutes the most common mental disorder in the US, and while antidepressant therapy can help, the current trial –and error approach can require patients to endure multiple medication trials before finding one that is effective. Tailoring the fit of pharmacogenetic testing with prescribers' needs across a variety of settings could help to establish a generalizable value proposition to improve likelihood of adoption. We conducted a study to explore the value proposition for health systems using pharmacogenetic testing for mental health medications through prescribers' real-world experiences using implementation science concepts and systematic interviews with prescribers and administrators from four health care systems. To identify a value proposition, we organized the themes according to the Triple Aim framework, a leading framework for health care policy which asserts that high-value care should focus on three key metrics: (1) better health care quality and (2) population-level outcomes with (3) reduced per capita costs. Primary care providers whom we interviewed said that they value pharmacogenetic testing because it would provide more information about medications that they can prescribe, expanding their ability to identify medications that best-fit patients and reducing their reliance on referrals to specialists; they said that this capacity would help meet patients' needs for access to mental health care through primary care. At the same time, prescribers expressed differing views about how pharmacogenetic testing can help with quality of care and whether their views about out-of-pocket cost would prevent them from offering it. Thus, implementation should focus on integrating pharmacogenetic testing into primary care and using strategies to support prescribers' interactions with patients.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.1,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13837","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141428202","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular identification of HLA-B75 serotype markers by qPCR: A more inclusive pharmacogenetic approach before carbamazepine prescription","authors":"Kanoot Jaruthamsophon,&nbsp;Pornsiri Sangmanee,&nbsp;Oradawan Plong-on,&nbsp;Chariyawan Charalsawadi,&nbsp;Chonlaphat Sukasem,&nbsp;Areerat Hnoonual","doi":"10.1111/cts.13867","DOIUrl":"10.1111/cts.13867","url":null,"abstract":"<p>Genetic screening for <i>HLA-B*15:02</i> before prescribing carbamazepine is standard practice to prevent severe cutaneous adverse reactions in Asian populations. These reactions are associated not only with this allele but also with closely related HLA-B75 serotype markers—<i>HLA-B*15:11</i> and <i>HLA-B*15:21—</i>which are prevalent in several Asian countries. However, a reliable method for identifying HLA-B75 serotype markers is still not available. We developed an in-house quantitative PCR (qPCR) for HLA-B75 screening and validated it using 303 anonymized DNA samples. Due to inadequate quality control, the qPCR results for 11 samples were excluded. We analyzed the sensitivity and specificity of the test using 93 HLA-typed samples. The concordance between the qPCR method and an established screening method was assessed using 199 HLA-screened samples tested for <i>HLA-B*15:02</i> at Songklanagarind Hospital, Songkhla, Thailand. All discordant results were confirmed by Sanger sequencing. The qPCR method demonstrated a sensitivity of 100% (95% confidence interval = 83.16%–100.00%) and a specificity of 100% (95% confidence interval = 95.07%–100.00%). Concordance analysis revealed a 96.5% agreement between methods (192/199; 44 positive and 148 negative results). All discordant results were due to HLA-B75 markers not being <i>HLA-B*15:02</i> (two samples with <i>HLA-B*15:11</i> and five samples with <i>HLA-B*15:21</i>). In conclusion, this qPCR method could be useful for identifying HLA-B75 carriers at risk of carbamazepine-induced reactions in Asian populations where carriers of <i>HLA-B*15:02</i>, <i>HLA-B*15:11</i>, or <i>HLA-B*15:21</i> are common.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13867","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Growth hormone treatment for neurologic symptoms of post-acute sequelae of COVID-19","authors":"Traver J. Wright,&nbsp;Melinda Sheffield-Moore,&nbsp;Richard B. Pyles,&nbsp;Kathleen M. Randolph,&nbsp;Kristen A. McGovern,&nbsp;Christopher P. Danesi,&nbsp;Sarah E. Lindsay,&nbsp;Mohammed F. Zaidan,&nbsp;Brent E. Masel,&nbsp;Randall J. Urban","doi":"10.1111/cts.13826","DOIUrl":"10.1111/cts.13826","url":null,"abstract":"<p>Following SARS-CoV-2 infection, some patients develop lingering neurologic symptoms of post-acute sequelae of COVID-19 (PASC) that commonly include fatigue and “brain fog.” PASC symptoms are also linked with reduced growth hormone (GH) secretion, but GH treatment has not been tested to relieve symptoms. We enrolled 13 adults with neurologic PASC symptoms and peak stimulated GH secretion less than 10 ng/mL (glucagon stimulation) in a pilot study to receive 9 months of daily GH injections and an additional 3 months of off-treatment assessment. We compared peak stimulated GH secretion at baseline and 12 months and assessed measures of cognition, metabolism, body composition, and physical performance over the first 6 months of treatment. Patient-reported outcomes of fatigue, quality of life, sleep, and mood were recorded at baseline and compared with timepoints at 6, 9, and 12 months. GH treatment was associated with significantly improved scores for Brief Fatigue Inventory, Multidimensional Fatigue Symptom Inventory, Quality of Life Assessment of Growth Hormone Deficiency in Adults, Profile of Mood States, and Beck Depression Inventory-II, with no significant change in Pittsburgh Sleep Quality Index. Six months of adjunct GH treatment was not associated with significant changes in cognition, body composition, resting energy expenditure, or physical performance. Peak stimulated GH secretion was not altered at 12 months following 9 months of GH treatment. GH treatment significantly improved neurologic symptoms in PASC patients but cognition, sleep, and physical performance were not significantly altered.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-06-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13826","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141421771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association of CYP2C19 genotypes with postoperative atrial fibrillation after coronary artery bypass surgery","authors":"Qin Jiang,&nbsp;Keli Huang,&nbsp;Lizhu Han,&nbsp;Hong Kong,&nbsp;Zhenglin Yang,&nbsp;Shengshou Hu","doi":"10.1111/cts.13862","DOIUrl":"10.1111/cts.13862","url":null,"abstract":"<p>This cohort study aims to assess the connection between cytochrome P450 family 2 subfamily C member 19 (CYP2C19) genotyping, platelet aggregability following oral clopidogrel administration, and the occurrence of postoperative atrial fibrillation (POAF) after off-pump coronary artery bypass graft (CABG) surgery. From May 2017 to November 2022, a total of 258 patients undergoing elective first-time CABG surgery, receiving 100 mg/day oral aspirin and 75 mg/day oral clopidogrel postoperatively, was included for analysis. These patients were categorized based on CYP2C19 genotyping. Platelet aggregability was assessed serially using multiple-electrode aggregometry before CABG, 1 and 5 days after the procedure, and before discharge. The incidences of POAF were compared using the log-rank test for cumulative risk. CYP2C19 genotyping led to categorization into CYP2C19*1*1 (WT group, <i>n</i> = 123) and CYP2C19*2 or *3 (LOF group, <i>n</i> = 135). Baseline characteristics and operative data showed no significant differences between the two groups. The incidence of POAF after CABG was 42.2% in the LOF group, contrasting with 22.8% in the WT group (hazard risk [HR]: 2.061; 95% confidence interval [CI]: 1.347, 3.153; <i>p</i> = 0.0013). Adenosine diphosphate-stimulated platelet aggregation was notably higher in the LOF group compared to the WT group 5 days after CABG (30.4% ± 6.5% vs. 17.9% ± 4.1%, <i>p</i> &lt; 0.001), remaining a similar higher level at hospital discharge (25.6% ± 6.1% vs. 12.2% ± 3.5%, <i>p</i> &lt; 0.001). The presence of CYP2C19 LOF was linked to a higher incidence of POAF and relatively elevated platelet aggregation after CABG surgery under the same oral clopidogrel regimen.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-06-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13862","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141321932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rationale and design for a pragmatic randomized trial to assess gene-based prescribing for SSRIs in the treatment of depression","authors":"Lindsay J. Hines,&nbsp;Russell A. Wilke,&nbsp;Rachel Myers,&nbsp;Carol A. Mathews,&nbsp;Michelle Liu,&nbsp;Jordan F. Baye,&nbsp;Natasha Petry,&nbsp;Emily J. Cicali,&nbsp;Benjamin Q. Duong,&nbsp;Erica Elwood,&nbsp;Leslie Hulvershorn,&nbsp;Khoa Nguyen,&nbsp;Michelle Ramos,&nbsp;Azita Sadeghpour,&nbsp;R. Ryanne Wu,&nbsp;Lloyda Williamson,&nbsp;Kristin Wiisanen,&nbsp;Deepak Voora,&nbsp;Rajbir Singh,&nbsp;Kathryn V. Blake,&nbsp;James W. Murrough,&nbsp;Simona Volpi,&nbsp;Geoffrey S. Ginsburg,&nbsp;Carol R. Horowitz,&nbsp;Lori Orlando,&nbsp;Hrishikesh Chakraborty,&nbsp;Paul Dexter,&nbsp;Julie A. Johnson,&nbsp;Todd C. Skaar,&nbsp;Larisa H. Cavallari,&nbsp;Sara L. Van Driest,&nbsp;Josh F. Peterson,&nbsp;the IGNITE Pragmatic Trials Network","doi":"10.1111/cts.13822","DOIUrl":"10.1111/cts.13822","url":null,"abstract":"<p>Specific selective serotonin reuptake inhibitors (SSRIs) metabolism is strongly influenced by two pharmacogenes, <i>CYP2D6</i> and <i>CYP2C19</i>. However, the effectiveness of prospectively using pharmacogenetic variants to select or dose SSRIs for depression is uncertain in routine clinical practice. The objective of this prospective, multicenter, pragmatic randomized controlled trial is to determine the effectiveness of genotype-guided selection and dosing of antidepressants on control of depression in participants who are 8 years or older with ≥3 months of depressive symptoms who require new or revised therapy. Those randomized to the intervention arm undergo pharmacogenetic testing at baseline and receive a pharmacy consult and/or automated clinical decision support intervention based on an actionable phenotype, while those randomized to the control arm have pharmacogenetic testing at the end of 6-months. In both groups, depression and drug tolerability outcomes are assessed at baseline, 1 month, 3 months (primary), and 6 months. The primary end point is defined by change in Patient-Reported Outcomes Measurement Information System (PROMIS) Depression score assessed at 3 months versus baseline. Secondary end points include change inpatient health questionnaire (PHQ-8) measure of depression severity, remission rates defined by PROMIS score &lt; 16, medication adherence, and medication side effects. The primary analysis will compare the PROMIS score difference between trial arms among those with an actionable <i>CYP2D6</i> or <i>CYP2C19</i> genetic result or a CYP2D6 drug–drug interaction. The trial has completed accrual of 1461 participants, of which 562 were found to have an actionable phenotype to date, and follow-up will be complete in April of 2024.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13822","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141302057","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical versus fixed warfarin dosing and the impact on quality of anticoagulation (The ClinFix trial)","authors":"Amr M. Fahmi,&nbsp;Ahmed El Bardissy,&nbsp;Mohamed Omar Saad,&nbsp;Mohamed Nabil Elshafei,&nbsp;Loulia Bader,&nbsp;Ahmed Mahfouz,&nbsp;Mohamed Kasem,&nbsp;Osama Abdelsamad,&nbsp;Abdelnasser Elzouki,&nbsp;Christina L. Aquilante,&nbsp;Fatima Mraiche,&nbsp;Ezeldin Soaly,&nbsp;Ihab El Madhoun,&nbsp;Nidal Asaad,&nbsp;Abdulrahman Arabi,&nbsp;Eman Alhmoud,&nbsp;Hazem Elewa","doi":"10.1111/cts.13797","DOIUrl":"10.1111/cts.13797","url":null,"abstract":"<p>Different dosing strategies exist to initiate warfarin, most commonly fixed warfarin dosing (FWD), clinical warfarin dosing (CWD), and genetic-guided warfarin dosing (GWD). Landmark trials have shown GWD to be superior when compared to FWD in the EU-PACT trial or CWD in the GIFT trial. COAG trial did not show differences between GWD and CWD. We aim to compare the anticoagulation quality outcomes of CWD and FWD. This is a prospective cohort study with a retrospective comparator. Recruited subjects in the CWD (prospective) arm were initiated on warfarin according to the clinical dosing component of the algorithm published in www.warfarindosing.org. The primary efficacy outcome was the percentage time in the therapeutic range (PTTR) from day 3 to 6 till day 28 to 35. The study enrolled 122 and 123 patients in the CWD and FWD, respectively. The PTTR did not differ statistically between CWD and FWD (62.2 ± 26.2% vs. 58 ± 25.4%, <i>p</i> = 0.2). There was also no difference between both arms in the percentage of visits with extreme subtherapeutic international normalized ratio (INR) (&lt;1.5; 15 ± 18.3% vs. 16.8 ± 19.1%, <i>p</i> = 0.44) or extreme supratherapeutic INR (&gt;4; 7.7 ± 14.7% vs. 7.5 ± 12.4%, <i>p</i> = 0.92). We conclude that CWD did not improve the anticoagulation quality parameters compared to the FWD method.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13797","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141302056","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mortality factors and antibiotic options in carbapenem-resistant Enterobacterales bloodstream infections: Insights from a high-prevalence setting with co-occurring NDM-1 and OXA-48","authors":"Palat Karnmueng,&nbsp;Preecha Montakantikul,&nbsp;Taniya Paiboonvong,&nbsp;Rongpong Plongla,&nbsp;Tanittha Chatsuwan,&nbsp;Supatat Chumnumwat","doi":"10.1111/cts.13855","DOIUrl":"10.1111/cts.13855","url":null,"abstract":"<p>Bloodstream infections (BSI) caused by carbapenem-resistant Enterobacterales (CRE) are associated with a high mortality rate. This study aimed to investigate factors associated with 14-day mortality and identify a potential treatment option. A retrospective cohort study was conducted on patients with CRE-BSI in Thailand from 2015 to 2020. The multivariate Cox proportional-hazards model was employed to identify factors influencing 14-day mortality. Out of 134 diagnosed cases of CRE-BSI, the all-cause 14-day mortality rate was 35.1%. The most prevalent organism isolated was <i>Klebsiella pneumoniae</i> (85.8%), followed by <i>Escherichia coli</i> (11.9%). Among the 60 isolates tested for carbapenemase genes, the majority exhibited co-occurring <i>bla</i>_NDM-1 and <i>bla</i>_OXA-48 (51.7%), followed by <i>bla</i>_OXA-48 (31.7%) and <i>bla</i>_NDM-1 (15.0%). In the multivariate analysis, neutropenia (adjusted hazard ratio [aHR] 2.55; 95% confidence interval [95%CI] 1.28–5.06; <i>p</i> = 0.008), sepsis/septic shock (aHR 3.02; 95%CI 1.33–6.86; <i>p</i> = 0.008), and previous metronidazole exposures (aHR 3.58; 95%CI 1.89–6.71; <i>p</i> &lt; 0.001) were identified as independent factors for 14-day mortality. The fosfomycin-based regimen was found to be protective (aHR 0.37; 95%CI 0.15–0.92; <i>p</i> = 0.032). In patients with CRE-BSI, particularly in regions with a high occurrence of co-occurring <i>bla</i>_NDM-1 and <i>bla</i>_OXA-48, neutropenia, sepsis/septic shock, and previous metronidazole exposures emerged as independent risk factors for mortality. Moreover, the fosfomycin-based regimen showed an improvement in the survival rate.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13855","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141297164","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A comprehensive Thai pharmacogenomics database (TPGxD-1): Phenotype prediction and variants identification in 942 whole-genome sequencing data","authors":"Shobana John,&nbsp;Sommon Klumsathian,&nbsp;Paravee Own-eium,&nbsp;Jakris Eu-ahsunthornwattana,&nbsp;Thanyachai Sura,&nbsp;Donniphat Dejsuphong,&nbsp;Piyamitr Sritara,&nbsp;Prin Vathesatogkit,&nbsp;Nartthawee Thongchompoo,&nbsp;Wiphaporn Thabthimthong,&nbsp;Nuttinee Teerakulkittipong,&nbsp;Wasun Chantratita,&nbsp;Chonlaphat Sukasem","doi":"10.1111/cts.13830","DOIUrl":"10.1111/cts.13830","url":null,"abstract":"<p>Computational methods analyze genomic data to identify genetic variants linked to drug responses, thereby guiding personalized medicine. This study analyzed 942 whole-genome sequences from the Electricity Generating Authority of Thailand (EGAT) cohort to establish a population-specific pharmacogenomic database (TPGxD-1) in the Thai population. Sentieon (version 201808.08) implemented the GATK best workflow practice for variant calling. We then annotated variant call format (VCF) files using Golden Helix VarSeq 2.5.0 and employed Stargazer v2.0.2 for star allele analysis. The analysis of 63 very important pharmacogenes (VIPGx) reveals 85,566 variants, including 13,532 novel discoveries. Notably, we identified 464 known PGx variants and 275 clinically relevant novel variants. The phenotypic prediction of 15 VIPGx demonstrated a varied metabolic profile for the Thai population. Genes like <i>CYP2C9</i> (9%), <i>CYP3A5</i> (45.2%), <i>CYP2B6</i> (9.4%), <i>NUDT15</i> (15%), <i>CYP2D6</i> (47%) and <i>CYP2C19</i> (43%) showed a high number of intermediate metabolizers; <i>CYP3A5</i> (41%), and <i>CYP2C19</i> (9.9%) showed more poor metabolizers. <i>CYP1A2</i> (52.7%) and <i>CYP2B6</i> (7.6%) were found to have a higher number of ultra-metabolizers. The functional prediction of the remaining 10 VIPGx genes reveals a high frequency of decreased functional alleles in <i>SULT1A1</i> (12%), <i>NAT2</i> (84%), and <i>G6PD</i> (12%). <i>SLCO1B1</i> reports 20% poor functional alleles, while <i>PTGIS</i> (42%), <i>SLCO1B1</i> (4%), and <i>TPMT</i> (5.96%) showed increased functional alleles. This study discovered new variants and alleles in the 63 VIPGx genes among the Thai population, offering insights into advancing clinical pharmacogenomics (PGx). However, further validation is needed using other computational and genotyping methods.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13830","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141297163","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of single-dose rivaroxaban under fed state in obese vs. non-obese subjects: An open-label controlled clinical trial (RIVOBESE-PK)","authors":"Majdoleen Alalawneh,&nbsp;Ahmed Awaisu,&nbsp;Ibtihal Abdallah,&nbsp;Hazem Elewa,&nbsp;Mohammed Danjuma,&nbsp;Kamal M. Matar,&nbsp;Akram M. ElKashlan,&nbsp;Yasser Elshayep,&nbsp;Fathy Ibrahim,&nbsp;Ousama Rachid","doi":"10.1111/cts.13853","DOIUrl":"10.1111/cts.13853","url":null,"abstract":"<p>The evidence of rivaroxaban's pharmacokinetics in obese compared with non-obese populations remains inconclusive. We aimed to compare the pharmacokinetic profile of rivaroxaban between obese and non-obese populations under fed state. Participants who met the study's eligibility criteria were assigned into one of two groups: obese (body mass index ≥35 kg/m²) or non-obese (body mass index 18.5–24.9 kg/m²). A single dose of rivaroxaban 20 mg was orally administered to each participant. Nine blood samples over 48 h, and multiple urine samples over 18 h were collected and analyzed for rivaroxaban concentration using ultra-performance liquid chromatography coupled with tandem mass detector. Pharmacokinetic parameters were determined using WinNonlin software. Thirty-six participants were recruited into the study. No significant changes were observed between obese and non-obese participants in peak plasma concentration, time to reach peak plasma concentration, area under the plasma concentration–time curve over 48 h or to infinity, elimination rate constant, half-life, apparent volume of distribution, apparent clearance, and fraction of drug excreted unchanged in urine over 18 h. Rivaroxaban's exposure was similar between the obese and non-obese subjects, and there were no significant differences in other pharmacokinetic parameters between the two groups. These results suggest that dose adjustment for rivaroxaban is probably unwarranted in the obese population.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13853","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141285258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The adiponectin-derived peptide ALY688 protects against the development of metabolic dysfunction-associated steatohepatitis","authors":"Zhe Huang,&nbsp;Hye Kyoung Sung,&nbsp;Xingqun Yan,&nbsp;Shiyu He,&nbsp;Leigang Jin,&nbsp;Qin Wang,&nbsp;Xuerui Wu,&nbsp;Henry H. Hsu,&nbsp;Angelica Pignalosa,&nbsp;Kathryn Crawford,&nbsp;Gary Sweeney,&nbsp;Aimin Xu","doi":"10.1111/cts.13760","DOIUrl":"10.1111/cts.13760","url":null,"abstract":"<p>Metabolic dysfunction-associated steatohepatitis (MASH) is the severe form of non-alcoholic fatty liver disease which has a high potential to progress to cirrhosis and hepatocellular carcinoma, yet adequate effective therapies are lacking. Hypoadiponectinemia is causally involved in the pathogenesis of MASH. This study investigated the pharmacological effects of adiponectin replacement therapy with the adiponectin-derived peptide ALY688 (ALY688-SR) in a mouse model of MASH. Human induced pluripotent stem (iPS) cell-derived hepatocytes were used to test cytotoxicity and signaling of unmodified ALY688 in vitro. High-fat diet with low methionine and no added choline (CDAHF) was used to induce MASH and test the effects of ALY688-SR in vivo. Histological MASH activity score (NAS) and fibrosis score were determined to assess the effect of ALY688-SR. Transcriptional characterization of mice through RNA sequencing was performed to indicate potential molecular mechanisms involved. In cultured hepatocytes, ALY688 efficiently induced adiponectin-like signaling, including the AMP-activated protein kinase and p38 mitogen-activated protein kinase pathways, and did not elicit cytotoxicity. Administration of ALY688-SR in mice did not influence body weight but significantly ameliorated CDAHF-induced hepatic steatosis, inflammation, and fibrosis, therefore effectively preventing the development and progression of MASH. Mechanistically, ALY688-SR treatment markedly induced hepatic expression of genes involved in fatty acid oxidation, whereas it significantly suppressed the expression of pro-inflammatory and pro-fibrotic genes as demonstrated by transcriptomic analysis. ALY688-SR may represent an effective approach in MASH treatment. Its mode of action involves inhibition of hepatic steatosis, inflammation, and fibrosis, possibly via canonical adiponectin-mediated signaling.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":null,"pages":null},"PeriodicalIF":3.9,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13760","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141285259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}