Pub Date : 2022-09-01Epub Date: 2022-08-03DOI: 10.1007/s40268-022-00398-z
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
Background and objectives: 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.
Methods: 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.
Results: 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).
Conclusion: 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.
背景和目标:方法:我们检索了从开始到 2021 年 9 月的主要电子数据库/搜索引擎。包括队列研究和随机对照试验(RCT),这些研究比较了抗凝剂和抗血小板治疗 CeAD 的效果。利用获得的相关文章进行荟萃分析。连续数据采用平均差(MD)和 95% 置信区间(CI),二分数据采用几率比(OR)和 95% 置信区间:我们的分析包括 15 项研究,涉及 2064 名患者,其中 909 人(44%)接受了抗血小板治疗,1155 人(56%)接受了抗凝治疗。02)、复发性短暂性缺血性发作(TIA)(OR 0.93,95% CI 0.44-1.98)、症状性颅内出血(sICH)(OR 0.38,95% CI 0.12-1.19)和完全再通(OR 0.70,95% CI 0.46-1.06)。在原发性缺血性中风方面,RCTs 的结果显示 AC 优于 AP(OR 6.97,95% CI 1.25-38.83):我们的研究并未显示两组间存在显著差异,因为所有结果均显示两组间无显著差异,只有原发性缺血性卒中(研究性试验)和完全再通(观察性研究)显示 AC 明显优于 AP。尽管原发性缺血性中风是一项重要结果,但仍需注意可能影响这些结果的几个关键点。其中包括对 AP-AC 剂量、频率、给药依从性等混杂效应的调整不完全。我们建议开展更多精心设计的研究,以评估在 CeAD 中是否可以避免不必要的抗凝。
{"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":null,"pages":null},"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":"Correction: 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/s40268-022-00401-7","DOIUrl":"https://doi.org/10.1007/s40268-022-00401-7","url":null,"abstract":"","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"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}
Purpose: 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.
Methods: 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.
Results: 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.
Conclusions: ASDs were significantly associated with all-cause mortality in patients with NVAF taking OACs.
{"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":null,"pages":null},"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}
Pub Date : 2022-09-01Epub Date: 2022-08-22DOI: 10.1007/s40268-022-00395-2
Venanzio Vella, Johannes E Schmidt, Giulia Luna Cilio, Iris De Ryck, Audino Podda, Valentino Conti, Joachim Auerbach
{"title":"Correction: The Pitfalls of Abnormal Laboratory Value Interpretation in Vaccine Clinical Trials: The Example of Asymptomatic Transient Neutropenia.","authors":"Venanzio Vella, Johannes E Schmidt, Giulia Luna Cilio, Iris De Ryck, Audino Podda, Valentino Conti, 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":null,"pages":null},"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}
Pub Date : 2022-09-01Epub Date: 2022-08-25DOI: 10.1007/s40268-022-00397-0
Luay Alkazmi, Hayder M Al-Kuraishy, Gaber El-Saber Batiha, Gomaa Mostafa-Hedeab, Michel De Waard, Jean-Marc Sabatier, Saeed M Kabrah, Hebatallah M Saad, Ali I Al-Gareeb, Jesus Simal-Gandara
{"title":"Roxadustat for SARS-CoV-2 Infection: Old Signaling Raised New Hopes.","authors":"Luay Alkazmi, Hayder M Al-Kuraishy, Gaber El-Saber Batiha, Gomaa Mostafa-Hedeab, Michel De Waard, Jean-Marc Sabatier, Saeed M Kabrah, Hebatallah M Saad, Ali I Al-Gareeb, 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":null,"pages":null},"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}
Background and objective: Upacicalcet sodium hydrate is a novel small-molecule calcimimetic and has potential as a therapeutic agent for secondary hyperparathyroidism. We assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of a single intravenous dose of upacicalcet in Japanese healthy adults.
Method: This was a single-center, double-blinded, randomized, placebo-controlled, dose-escalation study. For each cohort, eight subjects were randomly assigned at a ratio of 3:1 to receive a single injection of placebo or upacicalcet 0.01, 0.1, 1.0, or 2.5 mg.
Result: The plasma concentration of upacicalcet increased in a dose-dependent manner. Upacicalcet rapidly disappeared from plasma after administration. The half-life of upacicalcet was approximately 1-2 h. The major excretion route of upacicalcet was via urine. Serum intact parathyroid hormone decreased in accordance with the upacicalcet dose, from the lowest dose of 0.01 mg. Gastrointestinal disorders occurred in one patient in the 1.0 mg group and in five patients in the 2.5 mg group. All adverse events were nonserious, and no symptomatic hypocalcemia occurred.
Conclusion: This study showed that upacicalcet acted as a calcimimetic and was excreted in the urine unchanged with little metabolism. Moreover, upacicalcet is a small molecule and has a small volume of distribution. In addition, less than 50% of upacicalcet binds to human plasma proteins. These findings suggest that upacicalcet administered to patients undergoing hemodialysis might be expected to have a long excretion period and sustained pharmacological effect.
{"title":"First-in-Human Phase I Study of the Novel Injectable Calcimimetic Agent Upacicalcet in Healthy Adult Japanese Participants.","authors":"Fumihiko Koiwa, Rie Yazawa, Masafumi Fukagawa, Daisuke Honda, Tadao Akizawa","doi":"10.1007/s40268-022-00385-4","DOIUrl":"https://doi.org/10.1007/s40268-022-00385-4","url":null,"abstract":"<p><strong>Background and objective: </strong>Upacicalcet sodium hydrate is a novel small-molecule calcimimetic and has potential as a therapeutic agent for secondary hyperparathyroidism. We assessed the pharmacokinetics, pharmacodynamics, safety, and tolerability of a single intravenous dose of upacicalcet in Japanese healthy adults.</p><p><strong>Method: </strong>This was a single-center, double-blinded, randomized, placebo-controlled, dose-escalation study. For each cohort, eight subjects were randomly assigned at a ratio of 3:1 to receive a single injection of placebo or upacicalcet 0.01, 0.1, 1.0, or 2.5 mg.</p><p><strong>Result: </strong>The plasma concentration of upacicalcet increased in a dose-dependent manner. Upacicalcet rapidly disappeared from plasma after administration. The half-life of upacicalcet was approximately 1-2 h. The major excretion route of upacicalcet was via urine. Serum intact parathyroid hormone decreased in accordance with the upacicalcet dose, from the lowest dose of 0.01 mg. Gastrointestinal disorders occurred in one patient in the 1.0 mg group and in five patients in the 2.5 mg group. All adverse events were nonserious, and no symptomatic hypocalcemia occurred.</p><p><strong>Conclusion: </strong>This study showed that upacicalcet acted as a calcimimetic and was excreted in the urine unchanged with little metabolism. Moreover, upacicalcet is a small molecule and has a small volume of distribution. In addition, less than 50% of upacicalcet binds to human plasma proteins. These findings suggest that upacicalcet administered to patients undergoing hemodialysis might be expected to have a long excretion period and sustained pharmacological effect.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e1/02/40268_2022_Article_385.PMC9167405.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40330559","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}
Pub Date : 2022-06-01Epub Date: 2022-02-17DOI: 10.1007/s40268-022-00383-6
Matthew W McCarthy
Lysins are bacteriophage-derived enzymes that degrade essential components of bacteria. Exebacase (Lysin CF-301) is an attractive antimicrobial agent because it demonstrates rapid bacteriolytic activity against staphylococcal species, including Staphylococcus aureus, has a low resistance profile, eradicates biofilms, and acts synergistically with other antibiotics. Combinations including exebacase and standard of care antibiotics represent an alternative to antibiotic monotherapies currently used to treat invasive staphylococcal infections. This manuscript reviews what is known about exebacase and explores how this novel agent may be used in the future to treat human bacterial pathogens.
{"title":"Exebacase: A Novel Approach to the Treatment of Staphylococcal Infections.","authors":"Matthew W McCarthy","doi":"10.1007/s40268-022-00383-6","DOIUrl":"https://doi.org/10.1007/s40268-022-00383-6","url":null,"abstract":"<p><p>Lysins are bacteriophage-derived enzymes that degrade essential components of bacteria. Exebacase (Lysin CF-301) is an attractive antimicrobial agent because it demonstrates rapid bacteriolytic activity against staphylococcal species, including Staphylococcus aureus, has a low resistance profile, eradicates biofilms, and acts synergistically with other antibiotics. Combinations including exebacase and standard of care antibiotics represent an alternative to antibiotic monotherapies currently used to treat invasive staphylococcal infections. This manuscript reviews what is known about exebacase and explores how this novel agent may be used in the future to treat human bacterial pathogens.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/4c/0a/40268_2022_Article_383.PMC9167414.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"39931909","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}
Pub Date : 2022-06-01Epub Date: 2022-04-29DOI: 10.1007/s40268-022-00389-0
Theodore J Kottom, Kyle Schaefbauer, Eva M Carmona, Eunhee S Yi, Andrew H Limper
Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.
{"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":null,"pages":null},"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}
Pub Date : 2022-06-01DOI: 10.1007/s40268-022-00384-5
Liangying Gan, Panpan Xie, Yan Tan, Gang Wei, Xiaojuan Yuan, Zhifei Lu, Raymond Pratt, Yongchun Zhou, Ai-Min Hui, Kexin Li, Yi Fang, Li Zuo
Background and objective: Anemia caused by iron depletion is common in patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD-5HD) patients. To maintain the iron levels, external administration of iron is essential. Ferric pyrophosphate citrate (FPC) is a novel, water-soluble complex iron salt. The present study was conducted to evaluate the pharmacokinetic (PK) parameters and safety of FPC in adult healthy Chinese subjects and patients with CKD-5HD.
Methods: Two open-label, single-center studies were conducted in healthy subjects and patients with CKD-5HD. Healthy subjects received a single intravenous dose of 6.5 mg FPC solution, while CKD-5HD patients were randomized to two different sequences of FPC administration at two sequential hemodialysis (HD) treatments (dose 1 and dose 2). Patients received 27.2 mg of FPC at a dialysate concentration of 95 μg/L for 4 h or a single 6.5 mg dose of FPC administered intravenously via the pre-dialyzer blood circuit. The primary objective was to determine the PK parameters of total serum iron (Fetot), while the secondary objective was the safety of the FPC solution. PK parameters were calculated using Phoenix WinNonlin 8.1 and other parameters were analyzed using SAS 9.4 software. Comparison between HD dose 2 and HD dose 1 was performed using the Wilcoxon rank-sum test and analysis of variance (ANOVA).
Results: A total of 14 healthy subjects with a mean age of 30.8 ± 5.92 years and 12 HD patients with a mean age of 54.3 ± 16.47 years were included. In healthy subjects, the peak serum concentration was reached at the end of infusion of FPC, with an adjusted mean maximum concentration (Cmax,) of 33.46 ± 4.83 μmol/L at a mean time to reach Cmax (Tmax) of 4.09 ± 0.19 h. In patients with CKD-5HD, the adjusted mean Cmax of HD dose 2 was 25.37 ± 4.30 μmol/L at a Tmax, of 3.09 ± 0.32 h, whereas the Cmax, of HD dose 1 was 24.59 ± 4.77 μmol/L at a Tmax, of 3.96 ± 0.26 h. The Fetot concentration-time curves were observed to be similar for both administration methods (HD doses 1 and 2), while the PK parameters differed significantly for Tmax (p = 0.001; baseline correction) and area under the concentration-time curve from time zero to time t (AUCt) [p = 0.031 for cycle variance; without baseline correction] between HD doses 1 and 2. The geometric mean ratios (HD dose 1/HD dose 2) for Cmax and AUCt were within the 85-125% range (Cmax 96.56%; AUCt 96.07%). A total of three and two incidences of adverse events were reported in healthy subjects and patients with CKD-5HD, respectively.
Conclusion: FPC showed a good PK and safety profile and hence can be used as maintenance therapy for patients with CKD-5HD by choosing a better method of administration based
{"title":"Pharmacokinetics and Safety of Ferric Pyrophosphate Citrate in Chinese Subjects with and without Hemodialysis-Dependent Stage 5 Chronic Kidney Disease.","authors":"Liangying Gan, Panpan Xie, Yan Tan, Gang Wei, Xiaojuan Yuan, Zhifei Lu, Raymond Pratt, Yongchun Zhou, Ai-Min Hui, Kexin Li, Yi Fang, Li Zuo","doi":"10.1007/s40268-022-00384-5","DOIUrl":"https://doi.org/10.1007/s40268-022-00384-5","url":null,"abstract":"<p><strong>Background and objective: </strong>Anemia caused by iron depletion is common in patients with hemodialysis-dependent stage 5 chronic kidney disease (CKD-5HD) patients. To maintain the iron levels, external administration of iron is essential. Ferric pyrophosphate citrate (FPC) is a novel, water-soluble complex iron salt. The present study was conducted to evaluate the pharmacokinetic (PK) parameters and safety of FPC in adult healthy Chinese subjects and patients with CKD-5HD.</p><p><strong>Methods: </strong>Two open-label, single-center studies were conducted in healthy subjects and patients with CKD-5HD. Healthy subjects received a single intravenous dose of 6.5 mg FPC solution, while CKD-5HD patients were randomized to two different sequences of FPC administration at two sequential hemodialysis (HD) treatments (dose 1 and dose 2). Patients received 27.2 mg of FPC at a dialysate concentration of 95 μg/L for 4 h or a single 6.5 mg dose of FPC administered intravenously via the pre-dialyzer blood circuit. The primary objective was to determine the PK parameters of total serum iron (Fe<sub>tot</sub>), while the secondary objective was the safety of the FPC solution. PK parameters were calculated using Phoenix WinNonlin 8.1 and other parameters were analyzed using SAS 9.4 software. Comparison between HD dose 2 and HD dose 1 was performed using the Wilcoxon rank-sum test and analysis of variance (ANOVA).</p><p><strong>Results: </strong>A total of 14 healthy subjects with a mean age of 30.8 ± 5.92 years and 12 HD patients with a mean age of 54.3 ± 16.47 years were included. In healthy subjects, the peak serum concentration was reached at the end of infusion of FPC, with an adjusted mean maximum concentration (C<sub>max,</sub>) of 33.46 ± 4.83 μmol/L at a mean time to reach C<sub>max</sub> (T<sub>max</sub>) of 4.09 ± 0.19 h. In patients with CKD-5HD, the adjusted mean C<sub>max</sub> of HD dose 2 was 25.37 ± 4.30 μmol/L at a T<sub>max,</sub> of 3.09 ± 0.32 h, whereas the C<sub>max,</sub> of HD dose 1 was 24.59 ± 4.77 μmol/L at a T<sub>max,</sub> of 3.96 ± 0.26 h. The Fe<sub>tot</sub> concentration-time curves were observed to be similar for both administration methods (HD doses 1 and 2), while the PK parameters differed significantly for T<sub>max</sub> (p = 0.001; baseline correction) and area under the concentration-time curve from time zero to time t (AUC<sub>t</sub>) [p = 0.031 for cycle variance; without baseline correction] between HD doses 1 and 2. The geometric mean ratios (HD dose 1/HD dose 2) for C<sub>max</sub> and AUC<sub>t</sub> were within the 85-125% range (C<sub>max</sub> 96.56%; AUC<sub>t</sub> 96.07%). A total of three and two incidences of adverse events were reported in healthy subjects and patients with CKD-5HD, respectively.</p><p><strong>Conclusion: </strong>FPC showed a good PK and safety profile and hence can be used as maintenance therapy for patients with CKD-5HD by choosing a better method of administration based","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f7/8b/40268_2022_Article_384.PMC9167373.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10250876","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}
Pub Date : 2022-06-01DOI: 10.1007/s40268-022-00387-2
Simona De Gregori, Francesco Falaschi, Alessia Ballesio, Alessandra Fusco, Elisa Cremonte, Roberta Canta, Umberto Sabatini, Mariadelfina Molinaro, Carlo Soffiantini, Alba Nardone, Alessandro Vicentini, Annalisa De Silvestri, Antonio Di Sabatino
Background and objective: Hydroxychloroquine was widely used during the severe acute respiratory syndrome coronavirus 2 pandemic as an antiviral drug. Most previous pharmacokinetic/pharmacodynamic studies on hydroxychloroquine were conducted on healthy volunteers or patients receiving long-term therapy. There are no studies on the elimination of hydroxychloroquine after short-term treatments. Hydroxychloroquine is known to have a pro-arrhythmic effect through QT interval prolongation, but data in this setting are not conclusive. Our aims were to estimate the time needed for hydroxychloroquine concentrations (CHCQ) to drop to a safe concentration (500 ng/mL) after a short-term therapeutic cycle and to correlate the corrected QT interval with CHCQ.
Methods: We collected blood samples and electrocardiograms of patients who underwent short-term therapy with hydroxychloroquine during drug intake and after discontinuation. Hydroxychloroquine concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry and analysed with a linear regression model to estimate the elimination time of the drug after its discontinuation. We conducted a multivariate analysis of the corrected QT interval correlation with CHCQ.
Results: Our data suggest that short-term hydroxychloroquine courses can generate significant CHCQ persisting above 500 ng/mL up to 16 days after discontinuation of treatment. Corrected QT interval prolongation significantly correlates with CHCQ.
Conclusions: The study confirms the long half-life of hydroxychloroquine and its effect on the corrected QT interval even after short-term courses of the drug. This can inform the clinician using hydroxychloroquine treatments that it would be safer to start or re-initiate treatments with corrected QT interval-prolonging potential 16 days after hydroxychloroquine discontinuation.
{"title":"Hydroxychloroquine Blood Concentrations Can Be Clinically Relevant Also After Drug Discontinuation.","authors":"Simona De Gregori, Francesco Falaschi, Alessia Ballesio, Alessandra Fusco, Elisa Cremonte, Roberta Canta, Umberto Sabatini, Mariadelfina Molinaro, Carlo Soffiantini, Alba Nardone, Alessandro Vicentini, Annalisa De Silvestri, Antonio Di Sabatino","doi":"10.1007/s40268-022-00387-2","DOIUrl":"https://doi.org/10.1007/s40268-022-00387-2","url":null,"abstract":"<p><strong>Background and objective: </strong>Hydroxychloroquine was widely used during the severe acute respiratory syndrome coronavirus 2 pandemic as an antiviral drug. Most previous pharmacokinetic/pharmacodynamic studies on hydroxychloroquine were conducted on healthy volunteers or patients receiving long-term therapy. There are no studies on the elimination of hydroxychloroquine after short-term treatments. Hydroxychloroquine is known to have a pro-arrhythmic effect through QT interval prolongation, but data in this setting are not conclusive. Our aims were to estimate the time needed for hydroxychloroquine concentrations (C<sub>HCQ</sub>) to drop to a safe concentration (500 ng/mL) after a short-term therapeutic cycle and to correlate the corrected QT interval with C<sub>HCQ</sub>.</p><p><strong>Methods: </strong>We collected blood samples and electrocardiograms of patients who underwent short-term therapy with hydroxychloroquine during drug intake and after discontinuation. Hydroxychloroquine concentrations were determined by high-performance liquid chromatography-tandem mass spectrometry and analysed with a linear regression model to estimate the elimination time of the drug after its discontinuation. We conducted a multivariate analysis of the corrected QT interval correlation with C<sub>HCQ</sub>.</p><p><strong>Results: </strong>Our data suggest that short-term hydroxychloroquine courses can generate significant C<sub>HCQ</sub> persisting above 500 ng/mL up to 16 days after discontinuation of treatment. Corrected QT interval prolongation significantly correlates with C<sub>HCQ</sub>.</p><p><strong>Conclusions: </strong>The study confirms the long half-life of hydroxychloroquine and its effect on the corrected QT interval even after short-term courses of the drug. This can inform the clinician using hydroxychloroquine treatments that it would be safer to start or re-initiate treatments with corrected QT interval-prolonging potential 16 days after hydroxychloroquine discontinuation.</p>","PeriodicalId":49258,"journal":{"name":"Drugs in Research & Development","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/70/5d/40268_2022_Article_387.PMC9103606.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10598180","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}