Clinical and Translational Science最新文献

{"title":"The economics of moonshots: Value in rare disease drug development.","authors":"Nathan Yates, Jennifer Hinkel","doi":"10.1111/cts.13270","DOIUrl":"https://doi.org/10.1111/cts.13270","url":null,"abstract":"The authors review the literature surrounding the economics of rare disease drug development and access before advancing the case for novel approaches to funding treatments. To fund the next stage of rare disease drugs, which will likely center on gene therapies and molecular medicine, they discuss value frameworks as well as patient- led models of finance, and how these may fit into the existing frameworks in the US to incentivize rare disease drug development and access.","PeriodicalId":501617,"journal":{"name":"Clinical and Translational Science","volume":" ","pages":"809-812"},"PeriodicalIF":3.9,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e3/63/CTS-15-809.PMC9010265.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40326992","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Response to \"iPTH is not a significant factor influencing the tacrolimus C/D ratio\".","authors":"Ryota Tanaka, Yosuke Suzuki, Hiroshi Watanabe, Takashi Fujioka, Kenshiro Hirata, Toshitaka Shin, Tadasuke Ando, Hiroyuki Ono, Ryosuke Tatsuta, Hiromitsu Mimata, Toru Maruyama, Hiroki Itoh","doi":"10.1111/cts.13242","DOIUrl":"https://doi.org/10.1111/cts.13242","url":null,"abstract":"We welcome Westphal et al.’s response to our recent publication. As they point out, our1 and Hirata et al.2 previous retrospective studies have very small sample sizes of 48 and 12 patients, respectively. In our paper, time points of measurements for tacrolimus (TAC) and intact parathyroid hormone (iPTH) were not standardized, and logistic regression analysis did not partition TAC concentration/ dose (per body weight) ratio (C/D) into a binary dependent variable. Additionally, we did not investigate the influence of other uremic toxins, such as indoxyl sulfate, that accumulate in renal failure and may induce downregulation of cytochrome P450 (CYP) 3A protein expression.3 Other factors, such as FGF23, ionized calcium, phosphorus, and vitamin D levels, that fluctuate in secondary hyperparathyroidism were also not evaluated. Therefore, as described in the limitation section of our report, we cannot rule out the possibility that iPTH correlates positively with other molecules that accumulate in renal failure and partially mediates elevation of TAC C/D. Westphal et al. found that there was no correlation between iPTH and TAC C/D using a large number of 393 kidney transplant recipients. However, this letter does not seem to rule out the influence of concomitant drugs, such as CYP3A inhibitors and inducers. According to the report by Hirata et al.,2 the positive correlation of iPTH level with TAC C/D was confirmed by excluding patients who received these concomitant drugs. In addition, our previous study found that the correlation coefficient of both factors increased from r = 0.305 to 0.428 by excluding these patients.1 However, kidney transplant recipients take multiple medications for primary and comorbidities, some of which have CYP3A inhibitory activity. Thus, we also consider that iPTH levels may not correlate with TAC C/D in the entire patients who undergo kidney transplantation. Furthermore, as described in the limitation section of our report, there are racial differences in the prevalence of CYP3A5*1 carrier4 and iPTH concentration.5 Hence, our results cannot be generalized to other ethnicities. Moreover, TAC is a typical substrate for Pglycoprotein. The bioavailability of TAC varies due to the difference in the expression level of Pglycoprotein.6 Therefore, C/D alone cannot completely assess the metabolic activity of TAC. It is still controversial that iPTH may reduce the metabolic activity of TAC by decreasing the expression level of CYP3A. However, a large sample study by Béranger et al. suggests that iPTH is not a major driver of the TAC C/D ratio in kidney transplant recipients.","PeriodicalId":501617,"journal":{"name":"Clinical and Translational Science","volume":" ","pages":"807-808"},"PeriodicalIF":3.9,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/2c/a6/CTS-15-807.PMC9010249.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39798191","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-dose of LC51-0255, a selective S1P₁ receptor modulator, showed dose-dependent and reversible reduction of absolute lymphocyte count in humans.","authors":"Sang Won Lee,&nbsp;Inyoung Hwang,&nbsp;Jaeseong Oh,&nbsp;SeungHwan Lee,&nbsp;In-Jin Jang,&nbsp;Kyung-Sang Yu","doi":"10.1111/cts.13227","DOIUrl":"https://doi.org/10.1111/cts.13227","url":null,"abstract":"<p><p>Reducing the peripheral absolute lymphocyte count (ALC) is a promising therapeutic approach in treating autoimmune diseases. LC51-0255 is a sphingosine-1-phosphate 1 receptor modulator, which is known to decrease the peripheral ALC. We aimed to assess the pharmacokinetics (PKs), pharmacodynamics (PDs), safety, and tolerability profiles of LC51-0255 after a single oral administration in healthy subjects. A randomized, double-blind, placebo-controlled, dose-escalation study was conducted in 50 healthy subjects. Each subject orally received LC51-0255 (0.25, 0.5, 1, 2, or 4 mg) or its matching placebo in an 8:2 ratio. Blood and urine samples were collected to assess the PKs, and PDs was evaluated using peripheral ALC and 24-h hourly heart rate data. Safety and tolerability were assessed by monitoring treatment emergent adverse events (TEAEs), vital signs, 12-lead electrocardiogram (ECG), continuous 24-h ECG (via Holter monitoring), clinical laboratory tests, ophthalmologic tests, pulmonary function tests, and physical examinations. A single dose of LC51-0255 reduced ALC and heart rate in a reversible and dose-dependent manner. Systemic exposure of LC51-0255 increased dose-dependently and its half-life ranged from 72.2 to 134.0 h. ALC and the systemic exposure of LC51-0255 seemed to be negatively correlated. LC51-0255 was well-tolerated up to 2 mg, and the most common TEAE was bradycardia. The results of this study suggest that LC51-0255 can be developed into a beneficial treatment option for autoimmune disease.</p>","PeriodicalId":501617,"journal":{"name":"Clinical and Translational Science","volume":" ","pages":"1074-1083"},"PeriodicalIF":3.9,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9010277/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39945862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evidence-time dilemma in a pandemic with high mortality: Can outcome-driven decision making on vaccines prevent deaths?","authors":"Klaus Eckhardt","doi":"10.1111/cts.13155","DOIUrl":"https://doi.org/10.1111/cts.13155","url":null,"abstract":"When the first vaccines were authorized for coronavirus disease 2019 (COVID19) in December 2020, its death toll exceeded 2,500,000 deaths globally. Basic science showed an unprecedented pace in its response to the virus with the synthesis of mRNA1273 (Spikevax), the active substance of a COVID19 vaccine, on January 13, 3 weeks prior to the first confirmed death in the United States. Can regulatory science accelerate access to vaccinations, prevent deaths, and overcome the evidence– time dilemma in future pandemics? The death toll of the COVID19 pandemic has only been exceeded by the Spanish Flu in 1918. Early in the first wave of the pandemic, a highly disproportionate distribution of COVID19 infections and deaths was observed between the age groups with a disproportionately high case fatality rate in the elderly subpopulation (&lt;1% in &lt;64yearold, 8.0% in 70– 79yearold, and 14.8% in &gt;80yearold subjects).1 Already at the start of the pandemic, it was obvious that effective vaccines will be the ultimate tool to control the COVID19 pandemic and bring societies back to normality. So, science excelled with the severe acute respiratory syndromecoronavirus 2 (SARSCoV2) virus genome being sequenced on January 11, the active substance, mRNA1273, synthesized on January 13, 2020.2 By December 2020, with an unprecedented speed of less than a year, the mRNA1273 and the BNT162 (Comirnaty) vaccine were developed and granted an Emergency Use Authorization (EUA) in the United States.2,3 In April 2020, the International Coalition of Medicines Regulatory Authorities (ICMRA) discussed aspects for COVID19 therapeutic developments, including clinical trials, realworld evidence (RWE), and compassionate use. They expressed the need for robust evidence to establish safety and efficacy for the proposed medicines, leading to timely regulatory decisions and thus guiding clinicians in defining the best treatment options for COVID19 to serve the patients’ needs in the fastest fashion possible.4 In support of the EUA, the pivotal clinical evidence was generated in large randomized controlled trials (RCTs) in an idealworld setting, in the broad adult population, with prevention as the primary end point (starting in July 2020).2 Due to the limited availability of the first two authorized COVID19 vaccines, the United States and almost all other countries prioritized the elderly in the vaccination process. This decision was based on modeling approaches revealing that mortality is minimized in scenarios where the subpopulation with the highest risk of COVID19related deaths is vaccinated first, already established for influenza vaccinations. Unfortunately, in a pandemic with such high mortality, there is an evidence– time dilemma; during the clinical evidence generation, the death toll continues to rise in the real world. Knowing that the second wave is often bigger than the first and was expected to start in autumn 2020 and last until spring 2021 further emphasizes the limited time.","PeriodicalId":501617,"journal":{"name":"Clinical and Translational Science","volume":" ","pages":"5-8"},"PeriodicalIF":3.9,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/58/86/CTS-15-5.PMC8653071.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39467081","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dose Selection in a Pandemic: A Framework Informed by the FDA Animal Rule.","authors":"Kunyi Wu,&nbsp;Kimberly L Bergman","doi":"10.1111/cts.12936","DOIUrl":"https://doi.org/10.1111/cts.12936","url":null,"abstract":"Effective treatment approaches in a pandemic such as COVID-19 hinge on expeditious identification of sound dosing strategies. Informed by experience with the Food and Drug Administration (FDA) Animal Rule, this commentary illustrates a framework for leveraging and integrating clinical pharmacology information for dose selection to treat novel infections in a public health emergency setting.","PeriodicalId":501617,"journal":{"name":"Clinical and Translational Science","volume":" ","pages":"5-7"},"PeriodicalIF":3.9,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/cts.12936","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38612195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evolving Role for Pharmacotherapy in NAFLD/NASH.","authors":"Suzanna L Attia,&nbsp;Samir Softic,&nbsp;Marialena Mouzaki","doi":"10.1111/cts.12839","DOIUrl":"https://doi.org/10.1111/cts.12839","url":null,"abstract":"<p><p>Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent, dynamic disease that occurs across the age spectrum and can lead to cirrhosis and hepatocellular carcinoma. There are currently no US Food and Drug Administration (FDA) approved treatments for NAFLD; however, this is a field of active research. This review summarizes emerging pharmacotherapies for the treatment of adult and pediatric NAFLD. Investigated pharmacotherapies predominantly target bile acid signaling, insulin resistance, and lipid handling within the liver. Three drugs have gone on to phase III trials for which results are available. Of those, obeticholic acid is the single agent that demonstrates promise according to the interim analyses of the REGENERATE trial. Obeticholic acid showed reduction of fibrosis in adults with nonalcoholic steatohepatitis (NASH) taking 25 mg daily for 18 months (n = 931, reduction in fibrosis in 25% vs. 12% placebo, P < 0.01). Ongoing phase III trials include REGENERATE and MAESTRO-NASH, which investigates thyroid hormone receptor-β agonist MGL-3196. Outcomes of promising phase II trials in adults with NASH are also available and those have investigated agents, including the fibroblast growth factor (FGF)19 analogue NGM282, the GLP1 agonist liraglutide, the FGF21 analogue Pegbelfermin, the sodium glucose co-transporter 2 inhibitor Empagliflozin, the ketohexokinase inhibitor PF-06835919, the acetyl-coenzyme A carboxylase inhibitor GS-0976, and the chemokine receptor antagonist Cenicriviroc. Completed and ongoing clinical trials emphasize the need for a more nuanced understanding of the phenotypes of subgroups within NAFLD that may respond to an individualized approach to pharmacotherapy.</p>","PeriodicalId":501617,"journal":{"name":"Clinical and Translational Science","volume":" ","pages":"11-19"},"PeriodicalIF":3.9,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/cts.12839","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38089245","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Priority Review Vouchers: GAO Report Provides Scant Evidence of Success.","authors":"Robert J Meyer","doi":"10.1111/cts.12878","DOIUrl":"https://doi.org/10.1111/cts.12878","url":null,"abstract":"","PeriodicalId":501617,"journal":{"name":"Clinical and Translational Science","volume":" ","pages":"8-10"},"PeriodicalIF":3.9,"publicationDate":"2021-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/cts.12878","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"38398996","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Building communities of practice: the research nurse round table.","authors":"Mary E Larkin,&nbsp;Catherine A Griffith,&nbsp;Linda Pitler,&nbsp;Lauren Donahue,&nbsp;Amy Sbrolla","doi":"10.1111/j.1752-8062.2012.00435.x","DOIUrl":"https://doi.org/10.1111/j.1752-8062.2012.00435.x","url":null,"abstract":"<p><p>This paper shares the experience of establishing a research nurse forum aimed at knowledge sharing, problem solving, and community building from the perspective of a group of clinical research nurses at Massachusetts General Hospital (MGH), a tertiary care center in Boston, -Massachusetts. We report on a sequence of developmental steps taken to create this forum as an example of best practice for research nurses. Logistical considerations, mission and goals, as well as outcomes and implications for practice are described, with the intent that others interested in building similar forums can replicate aspects of this model within their own practice settings.</p>","PeriodicalId":501617,"journal":{"name":"Clinical and Translational Science","volume":" ","pages":"428-31"},"PeriodicalIF":3.9,"publicationDate":"2012-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1752-8062.2012.00435.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30978328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A pilot metabolic profiling study in serum of patients with chronic kidney disease based on (1) H-NMR-spectroscopy.","authors":"Suwen Qi,&nbsp;Xin Ouyang,&nbsp;Linqian Wang,&nbsp;Wujian Peng,&nbsp;Jinli Wen,&nbsp;Yong Dai","doi":"10.1111/j.1752-8062.2012.00437.x","DOIUrl":"https://doi.org/10.1111/j.1752-8062.2012.00437.x","url":null,"abstract":"<p><strong>Background: </strong>Chronic kidney disease (CKD) is the end point of a number of renal and systemic diseases. The metabolomics with a highly multiplexed and efficient manner is a challenging goal in nephrology.</p><p><strong>Methods: </strong>A (1) H-NMR based metabolomics approach was applied to establish a human CKD serum metabolic profile. Serum samples were obtained from CKD patients with four stages (N= 80) and healthy controls (N= 28). The data acquired by CMPG spectrum were further processed by pattern recognition (PR) analysis. Principal components analysis (PCA) and partial least-squares-discriminant analysis (PLS-DA) was capable of clustering the disease groups and establishing disease-specific metabolites profile.</p><p><strong>Results: </strong>The classification models could grade CKD patients with considerably high value of Q(2) and R(2) . The significant endogenous metabolites that contributed to distinguish CKD in different stages included the products of glycolysis (glucose, lactate), amino acids (valine, alanine, glutamate, glycine), organic osmolytes (betaine, myo-inositol, taurine, glycerophosphcholine), and so on. Based on these metabolites, the model for diagnosing patients with CKD achieved the sensitivity and specificity of 100%.</p><p><strong>Conclusion: </strong>The study illustrated that serum metabolic profile was altered in response to renal dysfunction and the progression of CKD. The identified metabolic biomarkers may provide useful information for the diagnosis of CKD, especially in early stages.</p>","PeriodicalId":501617,"journal":{"name":"Clinical and Translational Science","volume":" ","pages":"379-85"},"PeriodicalIF":3.9,"publicationDate":"2012-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1752-8062.2012.00437.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30979932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A characterization and targeting of the infarct border zone in a swine model of myocardial infarction.","authors":"Jason M Duran,&nbsp;Sharven Taghavi,&nbsp;Remus M Berretta,&nbsp;Catherine A Makarewich,&nbsp;Thomas Sharp Iii,&nbsp;Tim Starosta,&nbsp;Foram Udeshi,&nbsp;Jon C George,&nbsp;Hajime Kubo,&nbsp;Steven R Houser","doi":"10.1111/j.1752-8062.2012.00432.x","DOIUrl":"https://doi.org/10.1111/j.1752-8062.2012.00432.x","url":null,"abstract":"<p><strong>Introduction: </strong>Novel therapies for myocardial infarction (MI) involving stem cells, gene therapy, biomaterials, or revascularization strategies have shown promise in animal studies and clinical trials, but results have been limited partially due to the injection of therapeutics into ischemic myocardium that cannot support their mechanism of action. Accurate targeting of therapeutics precisely to the infarct border zone (BZ) may be essential for effective repair of the ischemic heart.</p><p><strong>Methods: </strong>Ischemia-reperfusion MI was induced in Yorkshire swine by inflation of an angioplasty balloon in the left anterior descending coronary artery. Fluorescent microspheres were injected into the BZ under NOGA catheter guidance, and this location was identified grossly then examined by immunohistochemistry and Western analysis.</p><p><strong>Results: </strong>Analysis of the infarct zone two hours post-MI revealed a frankly necrotic region devoid of contractile proteins with marked activation of caspase-3. The NOGA-defined BZ closely approximates the grossly-defined BZ and contains intact myocytes and vasculature. Western analysis detected Akt expression and levels of Ca(2+) handling proteins equivalent to that of viable tissues.</p><p><strong>Conclusions: </strong>Histological and Western analysis revealed that NOGA mapping precisely identifies grossly and molecularly defined infarct BZ at a location where there are still viable cells and vessels capable of supporting novel therapeutic strategies.</p>","PeriodicalId":501617,"journal":{"name":"Clinical and Translational Science","volume":" ","pages":"416-21"},"PeriodicalIF":3.9,"publicationDate":"2012-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1752-8062.2012.00432.x","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"30978326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}