Drugs in Research & Development最新文献

{"title":"Analysis of the US Safety Data for Edaravone (Radicava^®) From the Third Year After Launch.","authors":"Angela Genge,&nbsp;Benjamin Rix Brooks,&nbsp;Björn Oskarsson,&nbsp;Alexander Kalin,&nbsp;Ming Ji,&nbsp;Stephen Apple,&nbsp;Laura Bower","doi":"10.1007/s40268-022-00391-6","DOIUrl":"https://doi.org/10.1007/s40268-022-00391-6","url":null,"abstract":"<p><strong>Background: </strong>Amyotrophic lateral sclerosis (ALS) is a progressive and fatal neuromuscular disease with no curative therapies. Edaravone (Radicava^®) (Mitsubishi Tanabe Pharma Corporation, Tokyo, Japan), approved in the United States (US) for ALS in adults in 2017, was shown in a clinical trial to slow the rate of physical functional decline in ALS and is administered intravenously. The aim of this paper is to summarize the observed safety profile from real-world patient use during the first 3 years of edaravone availability in the US.</p><p><strong>Methods: </strong>Edaravone usage data were collected, and adverse events (AEs) were identified from a postmarketing safety database from August 8, 2017 through August 7, 2020 (cutoff date).</p><p><strong>Results: </strong>As of October 3, 2020, 5207 ALS patients had been treated with edaravone. As of August 7, 2020, the most commonly reported AEs included death (not specified), drug ineffective, disease progression, therapeutic response unexpected, fall, asthenia, fatigue, muscular weakness, gait disturbance, and dyspnea. The most commonly reported serious AEs (SAEs) included death (not specified), pneumonia, disease progression, ALS, fall, dyspnea, respiratory failure, device-related infection, hospitalization, and injection-site infection. There were 687 deaths, with 494 reported as death without specifying the cause. Deaths were most commonly attributed to ALS, disease progression, respiratory failure, or pneumonia. Review for administration-site reactions revealed 95 AEs, including 34 site infections, with 22 SAEs (all non-fatal). Five non-fatal SAEs of anaphylaxis were reported.</p><p><strong>Conclusion: </strong>In the postmarketing reporting to date, no new safety signals were identified beyond those already known from the edaravone clinical trial program.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"22 3","pages":"205-211"},"PeriodicalIF":3.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c0/8f/40268_2022_Article_391.PMC9433633.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40070552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Study of the Stability of Sandoz Rituximab Biosimilar Rixathon^®/Riximyo^® When Subjected for up to 21 Days to Ambient Storage.","authors":"Roman Borišek,&nbsp;André Mischo,&nbsp;Ida Šmid","doi":"10.1007/s40268-022-00393-4","DOIUrl":"https://doi.org/10.1007/s40268-022-00393-4","url":null,"abstract":"<p><strong>Aim: </strong>The purpose of this study was to evaluate the extended physicochemical and biological stability of Sandoz Rixathon®/Riximyo® (SDZ-RTX) after exposure to out-of-fridge (OOF) conditions.</p><p><strong>Materials and methods: </strong>The impact of the short-term temperature excursion on stability parameters of SDZ-RTX was simulated by subsequently exposing the three batches of SDZ-RTX (100 and 500 mg) to OOF conditions, (I) 25 ± 2 °C/60 ± 5% relative humidity (RH) and (II) 30 ± 2 °C/65 ± 5% RH, for up to 21 days after more than the claimed 36-month shelf-life storage in long-term conditions (5 ± 3 °C). Analytical methods used included the cation exchange chromatography (CEX), size exclusion chromatography (SEC), and non-reducing capillary electrophoresis-sodium dodecyl sulfate (nrCE-SDS), as well as biological activity by complement-dependent cytotoxicity (CDC)-bioactivity as well as further methods, for example, related to identity and pharmacopoeia test methods.</p><p><strong>Results: </strong>No notable changes were observed across all batches with respect to identity (charge and primary structure), pharmaceutical tests (clarity, visible and subvisible particles analytics, container appearance, degree of coloration, pH, osmolality, extractable volume, and container closure integrity testing), protein content by UV and microbiological parameters (sterility and bacterial endotoxins) under both OOF conditions. Only minor changes were observed for parameters evaluated via SEC, CEX, and nrCE-SDS. For potency (CDC-bioactivity) only one of the batches showed a relevant change. Even for these stability-indicating test methods, all analyzed parameters complied with the shelf-life specifications.</p><p><strong>Conclusion: </strong>SDZ-RTX is safe for use even under worst-case conditions, for example, after subjecting it for up to 21 days at OOF conditions (25 ± 2 °C/60 ± 5% RH or 30 ± 2 °C/65 ± 5% RH) after the batches had reached an age that was already beyond the claimed shelf-life.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"22 3","pages":"225-234"},"PeriodicalIF":3.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/af/60/40268_2022_Article_393.PMC9433506.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40686131","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effectiveness and Safety of Upadacitinib in the Treatment of Moderate-Severe Atopic Dermatitis: A Multicentric, Prospective, Real-World, Cohort Study.","authors":"Andrea Chiricozzi,&nbsp;Niccolò Gori,&nbsp;Alessandra Narcisi,&nbsp;Anna Balato,&nbsp;Alessio Gambardella,&nbsp;Michela Ortoncelli,&nbsp;Angelo Valerio Marzano,&nbsp;Riccardo Balestri,&nbsp;Giovanni Palazzo,&nbsp;Michele Pellegrino,&nbsp;Marco Romanelli,&nbsp;Giovanni Tripepi,&nbsp;Ketty Peris,&nbsp;Antonio Costanzo","doi":"10.1007/s40268-022-00396-1","DOIUrl":"https://doi.org/10.1007/s40268-022-00396-1","url":null,"abstract":"<p><strong>Background: </strong>The efficacy and safety of upadacitinib in atopic dermatitis (AD) have been defined in clinical trials, but no real-world data are currently available. We aimed to assess the safety and effectiveness of upadacitinib in a real-world AD patient cohort that mostly included patients who failed the available systemic therapies, including dupilumab.</p><p><strong>Methods: </strong>Prospective cohort study collecting data on upadacitinib-treated AD adult patients completing at least 16 weeks of therapy.</p><p><strong>Results: </strong>Forty-three patients showed rapid and marked response to upadacitinib with significant reduction of all disease severity scores since the first follow-up visit. At week 16, Eczema Area and Severity Index (EASI) 75, EASI 90, and EASI 100 response was observed in 97.5%, 82.1%, and 69.2% of patients, respectively. EASI 90 response reflected the achievement of a clear or almost clear condition (POEM 0-2), self-evaluated by 79.5% of patients. Patients' quality of life improved as suggested by the achievement of DLQI 0/1 by 38.5% of patients at week 4, and by 76.9% at week 16.</p><p><strong>Conclusion: </strong>Elevated effectiveness and favorable safety of upadacitinib were confirmed in patients unresponsive to dupilumab, who were not included in upadacitinib trials.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"22 3","pages":"245-252"},"PeriodicalIF":3.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/a5/e9/40268_2022_Article_396.PMC9362214.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40598046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antiplatelets Versus Anticoagulation in Cervical Artery Dissection: A Systematic Review and Meta-analysis of 2064 Patients.","authors":"Abdulrahman Ibrahim Hagrass, Bashar Khaled Almaghary, Mohamed Abdelhady Mostafa, Mohamed Elfil, Sarah Makram Elsayed, Amira A Aboali, Aboalmagd Hamdallah, Mohammed Tarek Hasan, Mohammed Al-Kafarna, Khaled Mohamed Ragab, Mohamed Fahmy Doheim","doi":"10.1007/s40268-022-00398-z","DOIUrl":"10.1007/s40268-022-00398-z","url":null,"abstract":"<p><strong>Background and objectives: </strong>In young people aged < 50 years, cervical artery dissection (CeAD) is among the most common causes of stroke. Currently, there is no consensus regarding the safest and most effective antithrombotic treatment for CeAD. We aimed to synthesize concrete evidence from studies that compared the efficacy and safety of antiplatelet (AP) versus anticoagulant (AC) therapies for CeAD.</p><p><strong>Methods: </strong>We searched major electronic databases/search engines from inception till September 2021. Cohort studies and randomized controlled trials (RCTs) comparing anticoagulants with antiplatelets for CeAD were included. A meta-analysis was conducted using articles that were obtained and found to be relevant. Mean difference (MD) with 95% confidence interval (CI) was used for continuous data and odds ratio (OR) with 95% CI for dichotomous data.</p><p><strong>Results: </strong>Our analysis included 15 studies involving 2064 patients, 909 (44%) of whom received antiplatelets and 1155 (56%) received anticoagulants. Our analysis showed a non-significant difference in terms of the 3-month mortality (OR 0.47, 95% CI 0.03-7.58), > 3-month mortality (OR 1.63, 95% CI 0.40-6.56), recurrent stroke (OR 0.97, 95% CI 0.46-2.02), recurrent transient ischaemic attack (TIA) (OR 0.93, 95% CI 0.44-1.98), symptomatic intracranial haemorrhage (sICH) (OR 0.38, 95% CI 0.12-1.19), and complete recanalization (OR 0.70, 95% CI 0.46-1.06). Regarding primary ischaemic stroke, the results favoured AC over AP among RCTs (OR 6.97, 95% CI 1.25-38.83).</p><p><strong>Conclusion: </strong>Our study did not show a considerable difference between the two groups, as all outcomes showed non-significant differences between them, except for primary ischaemic stroke (RCTs) and complete recanalization (observational studies), which showed a significant favour of AC over AP. Even though primary ischaemic stroke is an important outcome, several crucial points that could affect these results should be paid attention to. These include the incomplete adjustment for the confounding effect of AP-AC doses, frequencies, administration compliance, and others. We recommend more well-designed studies to assess if unnecessary anticoagulation can be avoided in CeAD.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"22 3","pages":"187-203"},"PeriodicalIF":2.2,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e3/82/40268_2022_Article_398.PMC9433613.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40598047","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bioavailability of Oniria^®, a Melatonin Prolonged-Release Formulation, Versus Immediate-Release Melatonin in Healthy Volunteers.","authors":"Manuel Román Martinez, Eva García Aguilar, Samuel Martin Vílchez, Javier González García, Sergio Luquero-Bueno, Paola Camargo-Mamani, Gina Mejia-Abril, Laura García-Castro, Alejandro de Miguel-Cáceres, Paula Saz-Leal, Francisco Abad-Santos, Concepcion Nieto Magro, Dolores Ochoa Mazarro","doi":"10.1007/s40268-022-00394-3","DOIUrl":"10.1007/s40268-022-00394-3","url":null,"abstract":"<p><strong>Background: </strong>Melatonin is an endogenous substance which plays a key role in sleep induction by reducing sleep onset latency; it has been approved by the European Food Safety Authority as a food supplement for exogenous administration. Oniria^® is a food supplement formulated as 1.98 mg of prolonged-release melatonin tablets; it displays a dual dissolution profile in vitro.</p><p><strong>Objectives: </strong>The main objective of the present study was to evaluate the relative oral bioavailability of Oniria^®, in comparison with immediate-release tablets (IRT) with a similar melatonin content as a reference. We also attempted to characterize the circadian rhythm of endogenous melatonin.</p><p><strong>Methods: </strong>We performed an open-label, cross-over, randomized, phase I clinical study with two sequences and three periods involving 14 healthy volunteers. We characterized the endogenous melatonin circadian profile (period 1) and pharmacokinetics (PK) of both Oniria^® and the reference melatonin (periods 2 and 3).</p><p><strong>Results: </strong>Two phases were clearly differentiated in the PK profile of Oniria^®. An initial one, from dosing up to 2 h, and a delayed one from 2 to 11 h post-administration. During the initial phase, both melatonin formulations were equivalent, with a C_max value close to 4000 pg/mL. However, in the delayed phase, Oniria^® showed significantly higher melatonin concentrations than the IRT (three times higher at 4-6 h post-administration). Moreover, Oniria^® exhibited concentrations above the endogenous melatonin peak of 80 pg/mL for up to 2.5 h versus the reference formulation, potentially suggesting an effect of Oniria^®, not only in the induction of sleep, but also in the maintenance.</p><p><strong>Conclusion: </strong>Oniria^® could be a highly promising food supplement, not only for sleep induction but also for the maintenance of sleep.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"22 3","pages":"235-243"},"PeriodicalIF":2.2,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/fa/ef/40268_2022_Article_394.PMC9433621.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40665668","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between Acid-Suppressive Drugs and Clinical Outcomes in Patients with Nonvalvular Atrial Fibrillation.","authors":"Hideki Arai, Shinichiro Ueda, Kazutaka Uchida, Fumihiro Sakakibara, Norito Kinjo, Mari Nezu, Takeshi Morimoto","doi":"10.1007/s40268-022-00392-5","DOIUrl":"10.1007/s40268-022-00392-5","url":null,"abstract":"<p><strong>Purpose: </strong>Acid-suppressive drugs (ASDs) are often prescribed for patients with nonvalvular atrial fibrillation (NVAF) taking oral anticoagulants (OACs). However, the risk-benefit balance of ASDs prescription for patients with NVAF taking OACs is still unclear. This study aimed to assess the association between ASDs and clinical outcomes in patients taking OACs for NVAF.</p><p><strong>Methods: </strong>This study is a subanalysis of an historical registry study from 71 centers in Japan. We included patients taking vitamin K antagonists for NVAF and excluded those with mechanical heart valves or a history of pulmonary thrombosis or deep vein thrombosis. We registered consecutive patients in February 2013 and followed them up until February 2017. The primary outcomes were ischemic events, major bleedings, and all-cause mortality. Ischemic stroke, acute myocardial infarction, and hemorrhagic stroke comprised the secondary outcomes.</p><p><strong>Results: </strong>We included 7826 patients with a mean age of 73 years, 5274 (67%) of whom were males. The adjusted hazard ratios (95% confidence intervals) for ischemic events, major bleedings, and all-cause mortality in the ASD group compared with the no-ASD group were 0.998 (0.78-1.27), 0.98 (0.81-1.18), and 1.22 (1.02-1.47), respectively, while those for ischemic stroke, acute myocardial infarction, and hemorrhagic stroke were 0.96 (0.74-1.24), 0.82 (0.36-1.88), and 1.17 (0.69-1.99), respectively.</p><p><strong>Conclusions: </strong>ASDs were significantly associated with all-cause mortality in patients with NVAF taking OACs.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"22 3","pages":"213-222"},"PeriodicalIF":2.2,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/65/f1/40268_2022_Article_392.PMC9433614.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40605408","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Association between Acid-Suppressive Drugs and Clinical Outcomes in Patients with Nonvalvular Atrial Fibrillation.","authors":"Hideki Arai,&nbsp;Shinichiro Ueda,&nbsp;Kazutaka Uchida,&nbsp;Fumihiro Sakakibara,&nbsp;Norito Kinjo,&nbsp;Mari Nezu,&nbsp;Takeshi Morimoto","doi":"10.1007/s40268-022-00401-7","DOIUrl":"https://doi.org/10.1007/s40268-022-00401-7","url":null,"abstract":"","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"22 3","pages":"223"},"PeriodicalIF":3.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/44/48/40268_2022_Article_401.PMC9433611.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40636628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: The Pitfalls of Abnormal Laboratory Value Interpretation in Vaccine Clinical Trials: The Example of Asymptomatic Transient Neutropenia.","authors":"Venanzio Vella,&nbsp;Johannes E Schmidt,&nbsp;Giulia Luna Cilio,&nbsp;Iris De Ryck,&nbsp;Audino Podda,&nbsp;Valentino Conti,&nbsp;Joachim Auerbach","doi":"10.1007/s40268-022-00395-2","DOIUrl":"https://doi.org/10.1007/s40268-022-00395-2","url":null,"abstract":"","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"22 3","pages":"253"},"PeriodicalIF":3.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f3/26/40268_2022_Article_395.PMC9433636.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40718116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roxadustat for SARS-CoV-2 Infection: Old Signaling Raised New Hopes.","authors":"Luay Alkazmi,&nbsp;Hayder M Al-Kuraishy,&nbsp;Gaber El-Saber Batiha,&nbsp;Gomaa Mostafa-Hedeab,&nbsp;Michel De Waard,&nbsp;Jean-Marc Sabatier,&nbsp;Saeed M Kabrah,&nbsp;Hebatallah M Saad,&nbsp;Ali I Al-Gareeb,&nbsp;Jesus Simal-Gandara","doi":"10.1007/s40268-022-00397-0","DOIUrl":"https://doi.org/10.1007/s40268-022-00397-0","url":null,"abstract":"","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"22 3","pages":"183-186"},"PeriodicalIF":3.0,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/39/a3/40268_2022_Article_397.PMC9403957.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40638793","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Preclinical and Toxicology Studies of BRD5529, a Selective Inhibitor of CARD9.","authors":"Theodore J Kottom, Kyle Schaefbauer, Eva M Carmona, Eunhee S Yi, Andrew H Limper","doi":"10.1007/s40268-022-00389-0","DOIUrl":"10.1007/s40268-022-00389-0","url":null,"abstract":"<p><strong>Background: </strong>The caspase recruitment domain-containing protein 9 (CARD9) inhibitor BRD5529 has been shown to be an effective in vitro inhibitor of Pneumocystis β-glucan-induced proinflammatory signaling, suggesting its viability as a candidate for preliminary anti-Pneumocystis drug testing in the rodent Pneumocystis pneumonia (PCP) model.</p><p><strong>Methods: </strong>Mice were injected intraperitoneally (IP) daily with either vehicle or BRD5529 at 0.1 or 1.0 mg/kg for 2 weeks. Mouse weights were taken daily. At day 14, mice were euthanized, weighed, and analyzed by flexiVent™ for lung stiffness. Lungs, liver, and kidney were then harvested for hematoxylin and eosin (H&E) staining and pathology scoring. Lung samples were further analyzed for proinflammatory cytokines via enzyme-linked immunosorbent assay (ELISA) and extracellular matrix generation via quantitative polymerase chain reaction (qPCR). Blood collection postmortem was performed for blood chemistry analysis. Furthermore, administration of BRD5529 prior to the intratracheal inoculation of fungal β-glucans, which are known proinflammatory mediators via the Dectin-1-CARD9 pathway, resulted in significant reductions in lung tissue interleukin-6 and tumor necrosis factor-α, suggesting the exciting possibility of the use of this CARD9 inhibitor as an additional therapeutic tool in fungal infections.</p><p><strong>Results: </strong>BRD5529 at both IP doses resulted in no significant changes in daily or final weight gain, and analysis of lung stiffness by flexiVent™ showed no significant differences between the groups. Furthermore, ELISA results of proinflammatory cytokines showed no major differences in the respective groups. qPCR analysis of extracellular matrix transcripts were statistically similar. Examination and pathology scoring of H&E slides from lung, liver, and kidney in all groups, as well as subsequent pathology scoring, showed no significant change. Blood chemistry analysis revealed similar, non-significant patterns.</p><p><strong>Conclusions: </strong>In our initial general safety and toxicology assessments, BRD5529 displayed no inherent safety concerns in the analyzed parameters. These data support broader in vivo testing of the inhibitor as a timed adjunct therapy to the deleterious proinflammatory host immune response often associated with anti-Pneumocystis therapy.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":"22 1","pages":"165-173"},"PeriodicalIF":3.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9167333/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"48641677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}