Cts-Clinical and Translational Science最新文献

{"title":"Non-alkylating agents-induced gonadotoxicity in pre-pubertal males: Insights on the clinical and pre-clinical front","authors":"Sruthi Sriram,&nbsp;Tiago Macedo,&nbsp;Annelies Mavinkurve-Groothuis,&nbsp;Marianne van de Wetering,&nbsp;Leendert H. J. Looijenga","doi":"10.1111/cts.70075","DOIUrl":"https://doi.org/10.1111/cts.70075","url":null,"abstract":"<p>Whilst chemotherapy regimens have proven to be more successful for pediatric cancer patients over the years, their influence on long-term side effects is relatively poorly understood. One of the possible targets is the gonads, with gonadotoxic agents representing those that threaten the patient's ability to have children post surviving the primary disease treatment. Many risk stratification guidelines have categorized these agents based on the severity of their effect on the pre-pubertal testis. While the consensus is that those agents factored with a cyclophosphamide equivalent dosage pose the highest threat to fertility (e.g. alkylating agents), other agents might still contribute to a reduced testis function; especially in the case of combination therapies. Besides, it is important to note that studies deciphering the effect of other non-alkylating agents on the pre-pubertal testis lack standardized conclusions for clinically relevant outcomes. This makes it imperative to ensure the knowledge gap is addressed between the clinic and pre-clinic to understand potential gonadotoxic effects, ultimately leading to improved patient care. Therefore, this review will summarize the key findings in understanding the gonadotoxic effects of the most commonly researched non-alkylating agents: vincristine, etoposide, doxorubicin, and imatinib on the pre-pubertal testis.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142708166","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":"Randomized evaluation of the loss-of-function carboxylesterase 1 (CES1) G143E variant on clopidogrel and ticagrelor pharmacodynamics","authors":"Joshua P. Lewis,&nbsp;Kathleen A. Ryan,&nbsp;Elizabeth A. Streeten,&nbsp;Hilary B. Whitlatch,&nbsp;Melanie Daue,&nbsp;Keith Tanner,&nbsp;James A. Perry,&nbsp;Jeffrey R. O'Connell,&nbsp;Alan R. Shuldiner,&nbsp;Braxton D. Mitchell","doi":"10.1111/cts.70079","DOIUrl":"10.1111/cts.70079","url":null,"abstract":"<p>Antiplatelet therapy with a P2Y₁₂ receptor inhibitor, in combination with aspirin, is standard of care for medical management of patients with coronary artery disease, and flexibility in prescribing options among these medications offers great potential for individualizing patient care. Previously, we showed that a loss-of-function missense mutation (G143E) in carboxylesterase 1 (CES1), the primary enzyme responsible for clopidogrel degradation, significantly impacts on-clopidogrel platelet aggregation and recurrent cardiovascular event risk. In the current investigation, we conducted a prospective randomized crossover study of clopidogrel (75 mg/day for 7 days) and ticagrelor (180 mg/day for 7 days) in 50 individuals stratified by <i>CES1</i> G143E genotype (<i>N</i> = 34 143GG and 16 143GE) to determine the effect of drug choice on inhibition of platelet aggregation (IPA). Consistent with prior reports, we observed strong association between G143E and adenosine diphosphate-stimulated platelet aggregation following clopidogrel administration (IPA = 71.6 vs. 48.0% in 143E-allele carriers vs. non-carriers, respectively, <i>p</i> = 3.8 × 10⁻⁵). Similar significant effects on platelet aggregation were also noted between 143E-allele carriers versus non-carriers in response to stimulation with arachidonic acid (45.8 vs. 25.8%, <i>p</i> = 0.04), epinephrine (44.4 vs. 18.8%, <i>p</i> = 0.03), and collagen (5 μg/mL, 25.8 vs. 11.4%, <i>p</i> = 3.7 × 10⁻³). In contrast, no relationship between <i>CES1</i> G143E and IPA was observed following ticagrelor administration regardless of the platelet agonist used. Collectively, these data suggest that on-clopidogrel platelet aggregation is substantially modified by <i>CES1</i> G143E genotype, that this variant does not modify ticagrelor pharmacodynamics, and that more consistent inhibition of platelet aggregation may be achieved by using ticagrelor in patients who carry clopidogrel response-modifying alleles in <i>CES1</i>.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11583987/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142693798","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":"What motivates people with type 2 diabetes mellitus to participate in clinical trials from home?","authors":"Julia Kopanz,&nbsp;Bart Lagerwaard,&nbsp;Magdalena Beran,&nbsp;Jorien Veldwijk,&nbsp;Julia K. Mader,&nbsp;Tina Pöttler,&nbsp;Dietrich Tews,&nbsp;Diederick E. Grobbee,&nbsp;Mira G. P. Zuidgeest,&nbsp;the Trials@Home consortium","doi":"10.1111/cts.70070","DOIUrl":"10.1111/cts.70070","url":null,"abstract":"<p>Decentralized clinical trials (DCTs), in which all or part of the trial activities are moved to the participants' immediate surroundings, promise to improve trial conduct. However, no evidence is available on what motivates people to participate in DCTs. Our aim was to determine the drivers and perceptions for participation in clinical trials with different decentralization levels in persons with type 2 diabetes mellitus. Five focus groups were conducted utilizing the nominal group technique in the Netherlands (<i>n</i> = 1), Germany (<i>n</i> = 1), and Austria (<i>n</i> = 3) with four to six participants per group. The focus groups were analyzed using thematic analysis. Of the 26 participants (10 females, median age: 66 years [IQR: 62–72]) 42% had previously participated in a trial, and almost all had internet access at home (96%). A total of seven main themes regarding participation in clinical trials (location, time investment, contact with healthcare professionals (HCPs), digital technologies, data collection, perceived risk, and motivation) were identified, of which a total of 20 drivers emerged. Perceptions regarding trial participation differed widely among participants, and individual preferences influenced which drivers were considered more important by participants. Flexibility of location and time spent on the trial were identified as the most motivating factors for participation in DCTs. Some drivers, such as digital infrastructure, digital literacy, home visits, personal interaction, and relationship with HCPs were perceived as both enablers and barriers, depending on personal preferences. However, most of the potential barriers regarding DCTs may be resolved by addressing them in the design of future DCTs.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11582682/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142689529","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":"Effects of statins in patients with coronary artery spasm: A nationwide population-based study","authors":"Yu-Ching Lee,&nbsp;Ming-Jui Hung,&nbsp;Tien-Hsing Chen,&nbsp;Chun-Tai Mao,&nbsp;Chi-Tai Yeh,&nbsp;Nicholas G. Kounis,&nbsp;Ian Y. Chen,&nbsp;Patrick Hu,&nbsp;Ming-Yow Hung","doi":"10.1111/cts.70087","DOIUrl":"10.1111/cts.70087","url":null,"abstract":"<p>Controversies regarding the benefits of statin treatment on clinical outcomes in coronary artery spasm (CAS) without obstructive coronary artery disease (CAD) persist due to limited data. In this retrospective nationwide population-based cohort study from the Taiwan National Health Insurance Research Database during the period 2000–2012, the matched cohorts consisted of 12,000 patients with CAS. After propensity score matching with 1:1 ratio, 2216 patients were eligible for outcome analysis in either statin or nonstatin group, with the mean follow-up duration of 4.8 and 4.6 years, respectively. Statin users versus nonusers had a significantly reduced risk of major adverse cardiovascular events (MACEs) (6.7% vs. 9.5%, hazard ratio [HR] 0.68; 95% confidence interval [CI] 0.55–0.84) and all-cause mortality (6.0% vs. 7.6%; HR 0.77; 95% CI 0.61–0.96). While the results of MACEs were mainly contributed by cardiovascular death (1.9% vs. 3.2%; HR 0.56; 95% CI 0.38–0.83) and ischemic stroke (3.8% vs. 5.4%; subdistribution HR 0.69; 95% CI 0.52–0.91), they were primarily driven by reductions in ischemic but not hemorrhagic stroke. The benefit of statins was significantly pronounced in patients with hypertension and diabetes. Nevertheless, the effect on MACEs was consistent irrespective of age, sex, dyslipidemia, and mental disorder. Statins significantly reduced the risk of MACEs and all-cause mortality in CAS patients. The benefit of statin therapy in reducing MACEs appeared to be linear, with greater risk reduction with higher doses and longer duration without upper threshold, reflecting the dose-dependent relationship of statins with MACEs in CAS patients.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11579374/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142683099","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":"High-dose intranasal insulin in an adaptive dose-escalation study in healthy human participants","authors":"Florian Schmitzberger,&nbsp;Jennifer Fowler,&nbsp;Cindy H. Hsu,&nbsp;Manjunath P. Pai,&nbsp;Robert W. Neumar,&nbsp;William J. Meurer,&nbsp;Robert Silbergleit","doi":"10.1111/cts.70071","DOIUrl":"https://doi.org/10.1111/cts.70071","url":null,"abstract":"<p>Intranasal insulin is a putative neuroprotective therapy after cardiac arrest, but safety in humans at doses extrapolated from animal models is unknown. This phase I, open-label adaptive dose-escalation study explores the maximum tolerated dose of intranasal insulin in healthy human participants. Placebo or insulin at doses from 0 to 1000 units was given to healthy participants intranasally on repeated weekly visits. Serum glucose, insulin, and C-peptide levels were measured serially at 0, 15, 30, 60, 120, 180, and 240 min after administration. Twenty-four participants (12 female, median age 53, IQR 35–61) were enrolled. There was minimal change in average serum glucose after administration of intranasal insulin. Average serum insulin increased slightly in a dose-dependent manner, reaching maximum concentrations at 15 min. C-peptide decreased over time from administration in all groups. One participant had severe hypoglycemia (24 mg/dL at 45 min) and a different participant had mild hypoglycemia (51 mg/dL at 30 min), both after receiving 600 U intranasal insulin. Hypoglycemic episodes were associated with increases in serum insulin. Both participants continued in the study without hypoglycemia after additional doses. High-dose intranasal insulin up to 1000 U was generally well tolerated, with minimal measurable systemic absorption and without significant aggregate changes in mean glucose. Idiosyncratic episodic systemic absorption and hypoglycemia require further study and additional caution in potential clinical application. Further study of its target engagement and efficacy as a neuroprotective therapy after cardiac arrest at these doses is warranted.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70071","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666037","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":"Integrating real-world data and machine learning: A framework to assess covariate importance in real-world use of alternative intravenous dosing regimens for atezolizumab","authors":"Bianca Vora,&nbsp;Ashutosh Jindal,&nbsp;Erick Velasquez,&nbsp;James Lu,&nbsp;Benjamin Wu","doi":"10.1111/cts.70077","DOIUrl":"https://doi.org/10.1111/cts.70077","url":null,"abstract":"<p>The increase in the availability of real-world data (RWD), in combination with advances in machine learning (ML) methods, provides a unique opportunity for the integration of the two to explore complex clinical pharmacology questions. Here we present a recently developed RWD/ML framework that utilizes ML algorithms to understand the influence and importance of various covariates on the use of a given dose and schedule for drugs that have multiple approved dosing regimens. To demonstrate the application of this framework, we present atezolizumab as a use case on account of its three approved alternative intravenous (IV) dosing regimens. As expected, the real-world use of atezolizumab has generally been increasing since 2016 for the 1200 mg every 3 weeks regimen and since 2019 for the 1680 mg every 4 weeks regimen. Out of the ML algorithms evaluated, XGBoost performed the best, as measured by the area under the precision–recall curve, with an emphasis on the under-sampled class given the imbalance in the data. The importance of features was measured by Shapley Additive exPlanations (SHAP) values and showed metastatic breast cancer and use of protein-bound paclitaxel as the most correlated with the use of 840 mg every 2 weeks. Although patient usage data for alternative IV dosing regimens are still maturing, these analyses provide initial insights on the use of atezolizumab and set up a framework for the re-analysis of atezolizumab (at a future data cut) as well as application to other molecules with approved alternative dosing regimens.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666036","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":"Use cases of registry-based randomized controlled trials—A review of the registries' contributions and constraints","authors":"Nadine Kubesch,&nbsp;Sneha Gaitonde,&nbsp;Uarda Petriti,&nbsp;Elisabeth Bakker,&nbsp;Swati Basu,&nbsp;Laura Ellen Birks,&nbsp;Elodie Aubrun,&nbsp;Sieta T. de Vries,&nbsp;Rahel Schneider","doi":"10.1111/cts.70072","DOIUrl":"https://doi.org/10.1111/cts.70072","url":null,"abstract":"<p>Registry-based randomized controlled trials (RRCTs) can combine the advantages of registries with those of randomization. This review aimed to expand the current knowledge on RRCT utilization and implementation by providing a comprehensive overview of RRCT use cases. A targeted literature search was conducted through July 2023 to identify articles on RRCTs. Information regarding the RRCT characteristics, their utilization, and the registries' contributions and the constraints faced was extracted. Descriptive statistics were used. We identified 102 RRCTs in 110 publications. RRCTs were mostly performed for the assessment of medical devices or surgical/clinical procedures (<i>n</i> = 45), followed by drugs (<i>n</i> = 30). More than half of the RRCTs were conducted in the Nordic countries (<i>n</i> = 58) and the most used registry types were health service registries/administrative health data (<i>n</i> = 63), followed by disease registries (<i>n</i> = 46). Approximately half of the RRCTs (<i>n</i> = 53) utilized additional data sources aside from registry data. The contribution of a registry to the RRCT was mostly for data collection and study follow-up (<i>n</i> = 90–92), followed by patient recruitment (<i>n</i> = 56–61), and randomization (<i>n</i> = 28–38), with varying levels of transparency in reporting. We collated author-reported constraints related to the used registries into four overarching themes, that is, data availability and completeness, data quality, representativeness, and registry infrastructure and accessibility. This review shows that RRCTs are already used in different domains and geographic regions. Guidelines on structured and transparent reporting of RRCT methods and the optimal use are, however, needed to inform decision-making by health authorities and to reach their full potential.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70072","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666035","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":"Accumulation of endogenous Muse cells in the myocardium and its pathophysiological role in patients with fulminant myocarditis","authors":"Shigeru Toyoda,&nbsp;Masashi Sakuma,&nbsp;Kazuyuki Ishida,&nbsp;Yoshihiro Kushida,&nbsp;Ryoichi Soma,&nbsp;Hidehito Takayama,&nbsp;Kazumi Akimoto,&nbsp;Mari Dezawa,&nbsp;Teruo Inoue","doi":"10.1111/cts.70067","DOIUrl":"10.1111/cts.70067","url":null,"abstract":"<p>Multi-lineage differentiating stress-enduring (Muse) cells, identified as pluripotent surface marker SSEA-3(+) cells, are stress tolerant endogenous pluripotent-like stem cells, and are involved in tissue repair. However, the significance of Muse cells in acute myocarditis has not been evaluated. In the present study, we counted Muse cells/area in biopsied myocardial tissue samples from 17 patients with fulminant myocarditis, and 6 with non-inflammatory myocardial disease as controls. Compared with controls, patients with fulminant myocarditis had significantly more Muse cells (<i>p</i> = 0.00042). Patients with mechanical circulatory support (<i>p</i> = 0.006) and myocardial degeneration (<i>p</i> = 0.023) had significantly more Muse cells than those without them. The Muse cell number was correlated with acute phase CK-MB level (<i>ρ</i> = 0.547, <i>p</i> = 0.029), indicating the severity of myocardial injury, and was also correlated with acute/recovery phase ratio of CK-MB (<i>ρ</i> = 0.585, <i>p</i> = 0.023) and cardiac troponin I (<i>ρ</i> = 0.498, <i>p</i> = 0.047) levels, indicating resilience of myocardial injury. In fulminant myocarditis, the Muse cell number was associated with the severity of clinical features in the acute phase, and also with the recovery from myocardial damage in the chronic phase. Endogenous Muse cells might be mobilized and accumulate to the myocardial tissues in fulminant myocarditis, and might participate in the repair of injured myocardium.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cts.70067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629891","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":"Toward an effective translational science engine","authors":"Octavian C. Ioachimescu,&nbsp;Reza Shaker","doi":"10.1111/cts.70069","DOIUrl":"10.1111/cts.70069","url":null,"abstract":"&lt;p&gt;The journey of innovation and scientific discovery toward widespread clinical implementation is often meandrous, with many roadblocks, changeovers, or transitions. The traditional funded research pathway starts from ideation, request for application, and funding of the basic science or laboratory-based exploration (T0), to early-phase translational investigation in humans (T1), to clinical studies on patients in various practice settings (T2), then exploration of health in different communities (T3), to global approaches in the larger population (T4), and eventually to societal outputs via regulatory changes, policy, or new health systems' creation (T5). Unfortunately, the linear process of translation may encounter strictures at every stage of the way (Figure 1a). This is perhaps not surprising, as the linear nature of a very complex process conforms to the well-known theory of constraints, as articulated by Goldratt.&lt;span&gt;&lt;sup&gt;1&lt;/sup&gt;&lt;/span&gt; Additionally, the well-known pipeline model of translation (Figure 1a) does not include bidirectional flows of knowledge, for example, transitions from laboratory to clinic, community, or population and sometimes back to the laboratory. One can argue that the cartography of translation is not even a continuous function, as temporal disruptions may lead to dead ends, abandoned paths, wasted opportunities, unsurmountable funding gaps, or overt unrealized discoveries.&lt;/p&gt;&lt;p&gt;In 2011, NIH created the NCATS in order to pursue, encourage, catalyze, and grow funding opportunities for &lt;i&gt;disruptive translational innovation&lt;/i&gt;, using both intra- and extramural mechanisms.&lt;span&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/span&gt; In the current NCATS' strategic plan, one aim is to accelerate translation by addressing both scientific and operational barriers, recognizing that innovation, creativity, and technology can aid and accelerate &lt;i&gt;translational science&lt;/i&gt; and &lt;i&gt;translational research&lt;/i&gt; efforts, including identification of new opportunities to pursue effective and efficient transitions or translations through teamwork and transdisciplinary collaboration.&lt;span&gt;&lt;sup&gt;3&lt;/sup&gt;&lt;/span&gt; Translational science is an eclectic discipline that studies the translational &lt;i&gt;processes and operations&lt;/i&gt; in order to establish their scientific governing principles, mechanisms, and inner-workings, moving translation from empiricism to predictivity.&lt;span&gt;&lt;sup&gt;4&lt;/sup&gt;&lt;/span&gt; It has been asserted that moving an intervention or innovation in the well-described develop–demonstrate–disseminate cycle all the way to public health requires sometimes no &lt;20 distinct scientific disciplines, each with its own language, heuristics, frameworks, or specific outcomes.&lt;span&gt;&lt;sup&gt;4, 5&lt;/sup&gt;&lt;/span&gt;&lt;/p&gt;&lt;p&gt;We contend that the traditional translational pipeline model can be successfully modified (Figure 1b) so that linearity and unidirectionality are corrected by a hybrid serial–parallel system of communicating vessels, with finely tuned firepower (i.e., adequate local res","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561134/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142631046","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 randomized, placebo-controlled first-in-human study of oral TQS-168 in healthy volunteers: Assessment of safety, tolerability, pharmacokinetics, pharmacodynamics, and food effect","authors":"Jonas Hannestad,&nbsp;Steven Smith,&nbsp;Andrew Lam,&nbsp;Janet Hurt,&nbsp;Nicole Harada,&nbsp;Richard Kim,&nbsp;Abhirup Das,&nbsp;Juliana Brunello,&nbsp;Gareth Whitaker,&nbsp;David Chalmers,&nbsp;Faria Senjoti,&nbsp;Wu Lin,&nbsp;James Coghill,&nbsp;Yogesh Bansal,&nbsp;Sharan Sidhu,&nbsp;Vanessa Zann,&nbsp;Enchi Liu","doi":"10.1111/cts.70064","DOIUrl":"10.1111/cts.70064","url":null,"abstract":"<p>TQS-168, a first-in-class small-molecule inducer of peroxisome proliferator-activated receptor gamma coactivator 1-alpha gene expression, is in development for the treatment of amyotrophic lateral sclerosis. A single-ascending-dose (SAD) and multiple-ascending-dose (MAD) study of TQS-168 was carried out in healthy male subjects to investigate safety, tolerability, pharmacokinetics (PK), food effect, and preliminary pharmacodynamic effects (PD). Since solubility enhancement could be beneficial, assessment of three formulations was incorporated into the study using an integrated rapid manufacturing and clinical testing approach. Dosing in the SAD part was initiated with a crystalline methylcellulose (MC) suspension, and then spray-dried dispersion (SDD) and hot-melt extrusion (HME) suspensions were evaluated. The HME and SDD formulations showed two and fourfold higher exposure than the MC suspension, respectively, and the SDD formulation was selected for progression to subsequent SAD and MAD cohorts, in which there was further investigation of the food effect on exposure in addition to assessments of safety, tolerability, PK, and PD. <i>C</i>_max and AUC plasma exposures of TQS-168 were supra-proportional at higher doses, irrespective of formulation. Median <i>T</i>_max for TQS-168 occurred between 0.5 and 4.0 h post-dose and occurred later with higher doses. Geometric mean half-lives (<i>T</i>_1/2) for TQS-168 were independent of formulation and food, ranging from 3.2 to 10.5 h following single doses and 4.1 to 7.3 h following multiple doses. Food blunted TQS-168 <i>C</i>_max but had minimal impact on AUC. TQS-168 was considered to be safe and generally well tolerated following single and multiple oral doses. The SDD formulation was selected for future patient studies.</p>","PeriodicalId":50610,"journal":{"name":"Cts-Clinical and Translational Science","volume":"17 11","pages":""},"PeriodicalIF":3.1,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11559592/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142629938","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}