Cts-Clinical and Translational Science最新文献

{"title":"Implementing a pragmatic clinical trial to tailor opioids for chronic pain on behalf of the IGNITE ADOPT PGx investigators","authors":"Todd C. Skaar,&nbsp;Rachel A. Myers,&nbsp;Roger B. Fillingim,&nbsp;John T. Callaghan,&nbsp;Emily Cicali,&nbsp;Michael T. Eadon,&nbsp;Erica N. Elwood,&nbsp;Geoffrey S. Ginsburg,&nbsp;Sheryl Lynch,&nbsp;Khoa A. Nguyen,&nbsp;Aniwaa Owusu Obeng,&nbsp;Haesuk Park,&nbsp;Victoria M. Pratt,&nbsp;Marc Rosenman,&nbsp;Azita Sadeghpour,&nbsp;Saskia Shuman,&nbsp;Rajbir Singh,&nbsp;Emma M. Tillman,&nbsp;Simona Volpi,&nbsp;Kristin Wiisanen,&nbsp;Almut G. Winterstein,&nbsp;Carol R. Horowitz,&nbsp;Deepak Voora,&nbsp;Lori Orlando,&nbsp;Hrishikesh Chakraborty,&nbsp;Sara Van Driest,&nbsp;Josh F. Peterson,&nbsp;Larisa A. Cavallari,&nbsp;Julie A. Johnson,&nbsp;Paul R. Dexter,&nbsp;the IGNITE Pragmatic Trials Network","doi":"10.1111/cts.70005","DOIUrl":"10.1111/cts.70005","url":null,"abstract":"<p>Chronic pain is a prevalent condition with enormous economic burden. Opioids such as tramadol, codeine, and hydrocodone are commonly used to treat chronic pain; these drugs are activated to more potent opioid receptor agonists by the hepatic CYP2D6 enzyme. Results from clinical studies and mechanistic understandings suggest that CYP2D6-guided therapy will improve pain control and reduce adverse drug events. However, CYP2D6 is rarely used in clinical practice due in part to the demand for additional clinical trial evidence. Thus, we designed the ADOPT-PGx (A Depression and Opioid Pragmatic Trial in Pharmacogenetics) chronic pain study, a multicenter, pragmatic, randomized controlled clinical trial, to assess the effect of <i>CYP2D6</i> testing on pain management. The study enrolled 1048 participants who are taking or being considered for treatment with CYP2D6-impacted opioids for their chronic pain. Participants were randomized to receive immediate or delayed (by 6 months) genotyping of <i>CYP2D6</i> with clinical decision support (CDS). CDS encouraged the providers to follow the CYP2D6-guided trial recommendations. The primary study outcome is the 3-month absolute change in the composite pain intensity score assessed using Patient-Reported Outcomes Measurement Information System (PROMIS) measures. Follow-up will be completed in July 2024. Herein, we describe the design of this trial along with challenges encountered during enrollment.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-08-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70005","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037609","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":"Novel cathepsin C inhibitor, BI 1291583, intended for treatment of bronchiectasis: Phase I characterization in healthy volunteers","authors":"Philipp Badorrek,&nbsp;Claudia Diefenbach,&nbsp;Harald Kögler,&nbsp;Anastasia Eleftheraki,&nbsp;Friedeborg Seitz,&nbsp;Jens M. Hohlfeld","doi":"10.1111/cts.13891","DOIUrl":"10.1111/cts.13891","url":null,"abstract":"<p>Novel treatments are needed to reduce inflammation, improve symptoms, address exacerbations, and slow disease progression in bronchiectasis. Cathepsin C (CatC) inhibition promises to achieve this through reduction of neutrophil-derived serine protease (including neutrophil elastase [NE] and proteinase 3 [PR3]) activation. Here, we present the phase I characterization of the novel CatC inhibitor, BI 1291583. Five phase I trials of BI 1291583 in healthy subjects are presented: a single-rising-dose study (NCT03414008) and two multiple-rising-dose studies (NCT03868540 and NCT04866160) assessing the safety, tolerability, pharmacodynamics, and pharmacokinetics of BI 1291583; a food effect study (NCT03837964); and a drug–drug interaction study (NCT03890887) of BI 1291583 and itraconazole. BI 1291583 was safe and well tolerated across the doses tested in these trials. Most adverse events (AEs) were mild or moderate in intensity, with no serious AEs, AEs of special interest or deaths reported in any trial. Drug-related skin exfoliation was not reported more frequently in subjects treated with BI 1291583 compared with placebo. BI 1291583 was readily absorbed, and pharmacokinetics were supra-proportional over the dose ranges assessed. Additionally, BI 1291583 inhibited CatC in a dose-dependent manner, inhibited downstream NE activity, and decreased PR3 levels. No food effect was observed. Co-administration of multiple doses of itraconazole increased BI 1291583 exposure approximately twofold. Due to these promising phase I results, a multinational phase II program of BI 1291583 in adults with bronchiectasis is ongoing (Airleaf™ [NCT05238675], Clairafly™ [NCT05865886], and Clairleaf™ [NCT05846230]).</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13891","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037634","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":"Reply to “A call for reporting of tumor-specific outcomes in studies of DPYD genotyping”","authors":"Nihal El Rouby,&nbsp;Josiah D. Allen,&nbsp;Megan Muldoon,&nbsp;Mollie Beck,&nbsp;Kristina Hesse,&nbsp;Nichlas Sebree,&nbsp;Robin Yoder,&nbsp;Stacey Ritter,&nbsp;Zuhair Alqahtani,&nbsp;Jaime Grund,&nbsp;Brooke Philips Holbrook","doi":"10.1111/cts.70008","DOIUrl":"10.1111/cts.70008","url":null,"abstract":"<p>We thank Dr. Tuteja for her letter to the editor on our recent publication: “Real-world implementation of <i>DPYD</i> and <i>UGT1A1</i> pharmacogenetic testing in a community-based cancer center.”<span>¹</span> Due to the small sample size in our exploratory analysis, we were unable to report the outcomes by cancer type. As rightly stated by the coauthors, only 6% of the tested patients had breast cancer, none of whom were <i>DPYD</i> variant carriers.</p><p>Fluoropyrimidine-based chemotherapy is used to treat various solid cancers, including gastrointestinal and breast cancer, where treatments like capecitabine are used for high-risk or advanced breast cancer cases.<span>²</span> As Dr. Tuteja pointed out, most research on <i>DPYD</i> outcomes focuses on gastrointestinal cancers, where the use of fluoropyrimidines is more prevalent. While <i>DPYD</i> testing is becoming standard in Europe, it still remains limited in the United States, leading to sparse data on outcomes by tumor type.</p><p>We advocate for routine <i>DPYD</i> testing before administering fluoropyrimidines due to the demonstrated risk of toxicity in large prospective studies and meta-analyses.<span>^{3, 4}</span> The recent data by Knikman <i>et al</i>.<span>⁵</span> showed that <i>DPYD</i>-guided dose reductions did not negatively impact cancer outcomes. The case of a breast cancer patient experiencing severe diarrhea from capecitabine in the authors' biobank data highlights the importance of <i>DPYD</i> testing for identifying these high-risk patients. This is especially crucial for debilitated patients for whom fluoropyrimidine may be the second or third line of treatment.</p><p>We agree that more data are needed to further assess tumor-specific outcomes. We propose that the solution to reporting such outcomes, as called for by the authors, would be through large collaborative, multi-site data from institutions that have implemented <i>DPYD</i> testing or those with biobanks. These large datasets allow for pooling data and analyzing outcomes separately by cancer type. This type of analysis is underway, and our institution, as well as other researchers, are in the process of collecting such data to evaluate the effectiveness and toxicity outcomes of <i>DPYD</i>-guided dosing. These large outcome-based analyses will further strengthen the evidence for <i>DPYD</i>-based prescribing to increase the adoption of testing.</p><p>No funding was received for this work.</p><p>The author declared no competing interests for this work.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70008","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142037635","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, pharmacodynamics, and safety of GS-3583, a FLT3 agonist Fc fusion protein, from single-ascending-dose phase I study in healthy participants","authors":"Anees M. Dauki,&nbsp;Nishanthan Rajakumaraswamy,&nbsp;Torsten Trowe,&nbsp;Winnie Weng,&nbsp;Kai-Wen Lin,&nbsp;Emon Elboudjwarej,&nbsp;Ann Ran-Ran Qin,&nbsp;Christian Schwabe,&nbsp;Michelle R. Kuhne,&nbsp;Ahmed A. Othman","doi":"10.1111/cts.70011","DOIUrl":"10.1111/cts.70011","url":null,"abstract":"<p>Conventional dendritic cells subtype 1 (cDC1) play a vital role in the priming and expansion of tumor-specific CD8+ T cells and their recruitment to tumor microenvironment. However, cDC1s are often underrepresented in the microenvironment. Systemic administration of Fms-like tyrosine kinase 3 ligand, a hematopoietic growth factor that binds to FLT3 on myeloid and lymphoid progenitor cells, leads to cDC1 expansion in the periphery and recruitment into the microenvironment. FLT3 pathway stimulation using GS-3583, a novel FLT3 agonistic Fc fusion protein, has the potential to promote T-cell mediated antitumor activity. This was a first-in-human, placebo-controlled study of GS-3583 in healthy participants to evaluate the safety, pharmacokinetics (PK), and pharmacodynamic (PD) of escalating single doses (75–2000 μg) of GS-3583. Each dose cohort enrolled 8–12 healthy participants who received GS-3583 or placebo as single IV infusion at 3:1 ratio. As part of the PD evaluation, the changes in the number of cDC1 cells were investigated. GS-3583 was well-tolerated in healthy participants up to the highest evaluated dose (2000 μg). There have been no serious or grade III or higher adverse events. PK analysis suggested a dose-dependent increase in GS-3583 exposure with target-mediated disposition characteristics at low doses. PD analysis shows that administration of GS-3583 resulted in transient, dose-dependent increases in cDC1 cells that returned to baseline within 3 weeks of drug administration. The pharmacokinetics and pharmacodynamics of GS-3583 following single dosing were characterized in this study which enabled subsequent phase Ib assessments in patients with advanced solid tumors.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70011","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142019460","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":"Challenges with sirolimus experimental data to inform QSP model of post-transplantation cyclophosphamide regimens","authors":"Ezhilpavai Mohanan,&nbsp;Guofang Shen,&nbsp;Suping Ren,&nbsp;Hsuan-Hao Fan,&nbsp;Kao Tang Ying Moua,&nbsp;Aleksandra Karolak,&nbsp;Russell C. Rockne,&nbsp;Ryotaro Nakamura,&nbsp;David A. Horne,&nbsp;Christopher G. Kanakry,&nbsp;Donald E. Mager,&nbsp;Jeannine S. McCune","doi":"10.1111/cts.70014","DOIUrl":"10.1111/cts.70014","url":null,"abstract":"<p>Dose optimization of sirolimus may further improve outcomes in allogeneic hematopoietic cell transplant (HCT) patients receiving post-transplantation cyclophosphamide (PTCy) to prevent graft-versus-host disease (GVHD). Sirolimus exposure–response association studies in HCT patients (i.e., the association of trough concentration with clinical outcomes) have been conflicting. Sirolimus has important effects on T-cells, including conventional (Tcons) and regulatory T-cells (Tregs), both of which have been implicated in the mechanisms by which PTCy prevents GVHD, but there is an absence of validated biomarkers of sirolimus effects on these cell subsets. Considering the paucity of existing biomarkers and the complexities of the immune system, we conducted a literature review to inform a quantitative systems pharmacology (QSP) model of GVHD. The published literature presented multiple challenges. The sirolimus pharmacokinetic models insufficiently describe sirolimus distribution to relevant physiological compartments. Despite multiple publications describing sirolimus effects on Tcons and Tregs in preclinical and human ex vivo models, consistent parameters relating sirolimus concentrations to circulating Tcons and Tregs could not be found. Each aspect presents a challenge in building a QSP model of sirolimus and its temporal effects on T-cell subsets and GVHD prevention. To optimize GVHD prevention regimens, phase I studies and systematic studies of immunosuppressant concentration–effect association are needed for QSP modeling.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70014","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142005735","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":"Predicting progression-free survival from measurable residual disease in chronic lymphocytic leukemia","authors":"Florencia A. Tettamanti,&nbsp;Holly Kimko,&nbsp;Shringi Sharma,&nbsp;Giovanni Di Veroli","doi":"10.1111/cts.13905","DOIUrl":"10.1111/cts.13905","url":null,"abstract":"<p>Association between measurable residual disease (MRD) and survival outcomes in chronic lymphocytic leukemia (CLL) has often been reported. However, limited quantitative analyses over large datasets have been undertaken to establish the predictive power of MRD. Here, we provide a comprehensive assessment of published MRD data to explore the utility of MRD in the prediction of progression-free survival (PFS). We undertook two independent analyses, which leveraged available published data to address two complimentary questions. In the first, data from eight clinical trials was modeled via a meta-regression approach, showing that median PFS can be predicted from undetectable MRD rates at 3–6 months of post-treatment. The resulting model can be used to predict the probability of technical success of a planned clinical trial in chemotherapy. In the second, we investigated the evidence for predicting PFS from competing MRD metrics, for example baseline value and instantaneous MRD value, via a joint modeling approach. Using data from four small studies, we found strong evidence that including MRD metrics in joint models improves predictions of PFS compared with not including them. This analysis suggests that incorporating MRD is likely to better inform individual progression predictions. It is therefore proposed that systematic MRD collection should be accompanied by modeling to generate algorithms that inform patients' progression.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.13905","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142009911","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":"First-in-human study evaluating safety, pharmacokinetics, and pharmacodynamics of lorundrostat, a novel and highly selective aldosterone synthase inhibitor","authors":"Hidetoshi Shimizu,&nbsp;Michael A. Tortorici,&nbsp;Yoshiyasu Ohta,&nbsp;Kei Ogawa,&nbsp;Sheikh Mohammed Ashfaq Rahman,&nbsp;Aya Fujii,&nbsp;Yuki Hiraga,&nbsp;Mizue Kawai,&nbsp;Kanami Sugimoto-Kawabata,&nbsp;Mattheus (Thijs) van Iersel,&nbsp;Jan Jaap van Lier,&nbsp;Stephen Djedjos,&nbsp;B. T. Slingsby,&nbsp;David M. Rodman","doi":"10.1111/cts.70000","DOIUrl":"https://doi.org/10.1111/cts.70000","url":null,"abstract":"<p>Dysregulation of the mineralocorticoid hormone aldosterone is an increasingly prevalent cause of hypertension. Aldosterone synthase (CYP11B2) shares 93% homology to 11β-hydroxylase (CYP11B1), which produces cortisol. Lorundrostat, a highly selective inhibitor of CYP11B2, is a potential safe and effective treatment for aldosterone-dependent, uncontrolled hypertension, including treatment-resistant hypertension. Lorundrostat showed highly selective inhibition of CYP11B2 in vitro, with 374-fold selectivity for CYP11B2 vs. CYP11B1. A first-in-human study of single ascending doses ranging from 5 to 800 mg and multiple ascending doses ranging from 40 to 360 mg once daily was conducted in healthy participants. After single- and multiple-dose administration, lorundrostat plasma levels peaked 1–3 h after administration with a <i>t</i>_1/2 of 10–12 h. Plasma aldosterone decreased up to 40% with single 100-mg to 200-mg doses and up to 70% with single 400 to 800-mg doses. Plasma aldosterone returned to baseline within 16 h after single 100-mg doses and multiple once-daily 120-mg doses. Lorundrostat demonstrated a favorable safety profile in healthy participants. Dose- and exposure-dependent inhibition of renal tubular sodium reabsorption was observed across a clinically relevant dose range with no suppression of basal or cosyntropin-stimulated cortisol production and only a modest increase in mean serum potassium.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70000","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994267","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":"Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry – Informing optimal antiplatelet strategies","authors":"Larisa H. Cavallari,&nbsp;Craig R. Lee,&nbsp;Francesco Franchi,&nbsp;Ellen C. Keeley,&nbsp;Joseph S. Rossi,&nbsp;Cameron D. Thomas,&nbsp;Yan Gong,&nbsp;Caitrin W. McDonough,&nbsp;Petr Starostik,&nbsp;Maryam J. Al Saeed,&nbsp;Latonya Been,&nbsp;Natasha Kulick,&nbsp;Jean Malave,&nbsp;Ian R. Mulrenin,&nbsp;Anh B. Nguyen,&nbsp;Joshua N. Terrell,&nbsp;Grace Tillotson,&nbsp;Amber L. Beitelshees,&nbsp;Almut G. Winterstein,&nbsp;George A. Stouffer,&nbsp;Dominick J. Angiolillo","doi":"10.1111/cts.70004","DOIUrl":"10.1111/cts.70004","url":null,"abstract":"<p>Dual antiplatelet therapy (DAPT) with aspirin and a P2Y₁₂ receptor inhibitor (clopidogrel, prasugrel, or ticagrelor) is indicated after percutaneous coronary intervention (PCI) to reduce the risk of atherothrombotic events. Approximately 30% of the US population has a <i>CYP2C19</i> no-function allele that reduces the effectiveness of clopidogrel, but not prasugrel or ticagrelor, after PCI. We have shown improved outcomes with the integration of <i>CYP2C19</i> genotyping into clinical care to guide the selection of prasugrel or ticagrelor in <i>CYP2C19</i> no-function allele carriers. However, the influence of patient-specific demographic, clinical, and other genetic factors on outcomes with genotype-guided DAPT has not been defined. In addition, the impact of genotype-guided de-escalation from prasugrel or ticagrelor to clopidogrel in patients without a <i>CYP2C19</i> no-function allele has not been investigated in a diverse, real-world clinical setting. The Precision Antiplatelet Therapy after Percutaneous Coronary Intervention (Precision PCI) Registry is a multicenter US registry of patients who underwent PCI and clinical <i>CYP2C19</i> testing. The registry is enrolling a diverse population, assessing atherothrombotic and bleeding events over 12 months, collecting DNA samples, and conducting platelet function testing in a subset of patients. The registry aims to define the influence of African ancestry and other patient-specific factors on clinical outcomes with <i>CYP2C19</i>-guided DAPT, evaluate the safety and effectiveness of <i>CYP2C19-</i>guided DAPT de-escalation following PCI in a real-world setting, and identify additional genetic influences of clopidogrel response after PCI, with the ultimate goal of establishing optimal strategies for individualized antiplatelet therapy that improves outcomes in a diverse, real-world population.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70004","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141989330","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":"Dose-dependent induction of CYP3A activity by St. John's wort alone and in combination with rifampin","authors":"Nicolas Hohmann,&nbsp;Anna S. Friedrichs,&nbsp;Jürgen Burhenne,&nbsp;Antje Blank,&nbsp;Gerd Mikus,&nbsp;Walter E. Haefeli","doi":"10.1111/cts.70007","DOIUrl":"https://doi.org/10.1111/cts.70007","url":null,"abstract":"<p>The dose dependence of the effect of enzyme inducers and the effect of the combined administration of two inducers that exert their effect via the same induction pathway (pregnane X receptor) have not been well studied. Using oral midazolam microdoses (30 μg), we have investigated CYP3A4 induction by St. John's wort (SJW) in 11 healthy volunteers using low (300 mg/day containing 7.48 mg hyperforin), therapeutic (900 mg/day), and supratherapeutic doses of SJW (1800 mg/day) for 14 days. SJW was then co-administered with rifampin (600 mg/day) for a further 7 days to evaluate the effect of the combined administration of two inducers. In addition, intravenous midazolam microdoses (10 μg) were administered before SJW, at SJW 1800 mg/day, and during administration of the two inducers to assess the hepatic contribution to total induction (semi-simultaneous administration). Administration of SJW increased oral midazolam clearance 1.96-fold (300 mg/day), 3.86-fold (900 mg/day), and 5.62-fold (1800 mg/day), and 17.5-fold after the addition of rifampin. Concurrently, the clearance of intravenous midazolam increased 2.05-fold (1800 mg/day) and 2.93-fold (SJW + rifampin). These results show that rifampin significantly enhances the induction of the highest SJW doses both hepatically and overall and suggest that these metabolic effects occur predominantly in the gut. These findings also suggest that in drug interactions involving strong and moderate enzyme inducers, the perpetrator effects of the strong inducer are decisive for the interaction.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70007","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994235","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":"Expression and prognostic potential of osteopontin splice variants in malignant melanoma","authors":"Gabriela Ribeiro Silva,&nbsp;Luciana Bueno Ferreira,&nbsp;Etel Rodrigues Pereira Gimba","doi":"10.1111/cts.70002","DOIUrl":"https://doi.org/10.1111/cts.70002","url":null,"abstract":"&lt;p&gt;We read with great interest the article recently published by Koroknai et al.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; entitled “Expression pattern of osteopontin isoforms in malignant melanoma cell lines,” in which the expression of five OPN splice variants (OPN-SV) has been described in melanoma cell lines, providing new insights into this previously underexplored issue regarding osteopontin in melanoma research.&lt;/p&gt;&lt;p&gt;The authors found that the five OPN-SV presented higher expression levels in melanoma metastasis (MM) compared with melanoma primary (MP)-derived cell lines, although they did not reach statistical significance. They also observed that MM cell lines significantly express higher levels of all five OPN-SV in relation to those derived from primary superficial spreading melanoma (SSM), and between SSM and nodular melanoma (NM)-derived cell lines. These findings corroborate previous ones from the same group, in which &lt;i&gt;OPNa&lt;/i&gt;, &lt;i&gt;OPNb&lt;/i&gt;, and &lt;i&gt;OPNc&lt;/i&gt; are expressed at higher levels in metastatic tumor tissues compared with primary lesions.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; However, the recently described &lt;i&gt;OPN4&lt;/i&gt; and &lt;i&gt;OPN5&lt;/i&gt; variants presented low expression levels in both metastatic and primary tumor tissue samples, as opposed to data found in melanoma cell lines. The authors emphasized the association of &lt;i&gt;OPNc&lt;/i&gt; at higher levels with invasive behavior. Consistent with these data, Jambor et al.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; reported a significant positive correlation between &lt;i&gt;OPNc&lt;/i&gt; expression and the presence of metastasis.&lt;/p&gt;&lt;p&gt;Building upon these findings, we further explored these data by analyzing skin cutaneous melanoma (SKCM) samples using the TSVdb database (http://www.tsvdb.com/). We found that metastatic SKCM samples significantly express higher levels of these five OPN-SV compared with primary melanoma tumors (Figure 1). Our data in tumor samples corroborate data regarding melanoma-derived cell lines for the five OPN-SV reported by Koroknai et al., in contrast to previous data showing that &lt;i&gt;OPN4&lt;/i&gt; and &lt;i&gt;OPN5&lt;/i&gt; isoforms are downregulated in melanoma subtypes.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Altogether, these data provide evidence that not only &lt;i&gt;OPNa&lt;/i&gt;, &lt;i&gt;OPNb&lt;/i&gt;, and &lt;i&gt;OPNc&lt;/i&gt; are overexpressed in metastatic melanoma tissues in comparison with primary tumors, but also &lt;i&gt;OPN4&lt;/i&gt; and &lt;i&gt;OPN5&lt;/i&gt;, further evidencing that all five OPN-SV could be associated with an unfavorable prognosis in melanoma. Further research should elucidate how each OPN-SV could contribute to a worse prognosis in melanoma cancer, as reported for total osteopontin.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; The involvement of each OPN-SV in melanoma progression is key to a better understanding of this disease and for the development of new therapeutic approaches, considering their specific expression patterns and roles in each step of tumor progression.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;Funding for the works described was provided by the FAPERJ, CNPq, CAPES, and","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 8","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70002","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994234","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}