首页 > 最新文献

Pharmacology Research & Perspectives最新文献

英文 中文
Changes in plasma alpha-1 acid glycoprotein following hemorrhagic trauma: Possible role in dose differences of ALM drug therapy in rat and pig resuscitation. 出血性创伤后血浆α-1酸性糖蛋白的变化:ALM药物治疗在大鼠和猪复苏中剂量差异的可能作用。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-01 DOI: 10.1002/prp2.1133
Hayley L Letson, Jodie L Morris, Geoffrey P Dobson

Introduction: The binding of drugs to plasma proteins is an important consideration in drug development. We have reported that the dose of adenosine, lidocaine, and magnesium (ALM) fluid therapy for resuscitation from hemorrhagic shock is nearly 3-times higher for pigs than rats. Since lidocaine strongly binds to serum alpha-1-acid glycoprotein (AGP), the aim of the study was to investigate the effect of hemorrhagic shock on levels of AGP in rats and pigs.

Materials and methods: Healthy adult male Sprague-Dawley rats and female crossbred pigs (n = 33 each) underwent tail vein and peripheral ear vein blood sampling, respectively, to collect plasma for AGP measurements. Rats (n = 17) and pigs (n = 16) underwent surgical instrumentation and uncontrolled hemorrhage via liver resection, and were treated with 3% NaCl ± ALM IV bolus followed 60 min later by 4 h 0.9% NaCl ± ALM IV drip. Rats were monitored for 72 h with blood samples taken post-surgery, and at 5.25, 24, and 72 h. Pigs were monitored for 6 h with blood samples taken post-surgery, and at 60 min and 6 h. Plasma AGP was measured with rat- and pig-specific enzyme-linked immunosorbent assay kits.

Results: Baseline AGP levels in rats were 3.91 μg/mL and significantly 83-fold lower than in pigs (325 μg/mL). Surgical instrumentation was associated with ~10-fold increases in AGP in rats and a 21% fall in pigs. AGP levels remained elevated in rats after hemorrhage and resuscitation (28-29 μg/mL). In contrast, no significant differences in plasma AGP were found in ALM- or Saline-treated pigs over the monitoring period.

Conclusions: We conclude that the trauma of surgery alone was associated with significant increases in AGP in rats, compared to a contrasting decrease in pigs. Higher levels of plasma AGP in pigs prior to hemorrhagic shock is consistent with the higher ALM doses required to resuscitate pigs compared with rats.

引言:药物与血浆蛋白的结合是药物开发中的一个重要考虑因素。据我们报道,猪失血性休克复苏时使用腺苷、利多卡因和镁(ALM)液的剂量几乎是大鼠的3倍。由于利多卡因能与血清α-1-酸糖蛋白(AGP)强结合,本研究的目的是研究失血性休克对大鼠和猪AGP水平的影响。材料和方法:健康成年雄性Sprague-Dawley大鼠和雌性杂交猪(n = 33个)分别接受尾静脉和耳周静脉血液采样,以收集血浆用于AGP测量。大鼠(n = 17) 和清管器(n = 16) 接受了手术器械治疗,并通过肝切除术控制出血,并接受了3%氯化钠治疗 ± ALM IV推注60 4分钟后 h 0.9%氯化钠 ± ALM IV滴漏。对大鼠进行了72次监测 h,术后采集血样,5.25、24和72 h.对猪进行6次监测 h,术后采集血样,60岁时 最小值和6 h.用大鼠和猪特异性酶联免疫吸附测定试剂盒测定血浆AGP。结果:大鼠AGP基线水平为3.91 μg/mL,显著低于猪的83倍(325 μg/mL)。手术器械与大鼠AGP增加约10倍和猪下降21%有关。大鼠在出血和复苏后AGP水平仍然升高(28-29 μg/mL)。相反,在监测期内,ALM或生理盐水处理的猪的血浆AGP没有发现显著差异。结论:我们得出的结论是,与猪的AGP显著降低相比,单独手术的创伤与大鼠AGP显著升高有关。与大鼠相比,失血性休克前猪血浆AGP水平较高与复苏猪所需的ALM剂量较高一致。
{"title":"Changes in plasma alpha-1 acid glycoprotein following hemorrhagic trauma: Possible role in dose differences of ALM drug therapy in rat and pig resuscitation.","authors":"Hayley L Letson,&nbsp;Jodie L Morris,&nbsp;Geoffrey P Dobson","doi":"10.1002/prp2.1133","DOIUrl":"10.1002/prp2.1133","url":null,"abstract":"<p><strong>Introduction: </strong>The binding of drugs to plasma proteins is an important consideration in drug development. We have reported that the dose of adenosine, lidocaine, and magnesium (ALM) fluid therapy for resuscitation from hemorrhagic shock is nearly 3-times higher for pigs than rats. Since lidocaine strongly binds to serum alpha-1-acid glycoprotein (AGP), the aim of the study was to investigate the effect of hemorrhagic shock on levels of AGP in rats and pigs.</p><p><strong>Materials and methods: </strong>Healthy adult male Sprague-Dawley rats and female crossbred pigs (n = 33 each) underwent tail vein and peripheral ear vein blood sampling, respectively, to collect plasma for AGP measurements. Rats (n = 17) and pigs (n = 16) underwent surgical instrumentation and uncontrolled hemorrhage via liver resection, and were treated with 3% NaCl ± ALM IV bolus followed 60 min later by 4 h 0.9% NaCl ± ALM IV drip. Rats were monitored for 72 h with blood samples taken post-surgery, and at 5.25, 24, and 72 h. Pigs were monitored for 6 h with blood samples taken post-surgery, and at 60 min and 6 h. Plasma AGP was measured with rat- and pig-specific enzyme-linked immunosorbent assay kits.</p><p><strong>Results: </strong>Baseline AGP levels in rats were 3.91 μg/mL and significantly 83-fold lower than in pigs (325 μg/mL). Surgical instrumentation was associated with ~10-fold increases in AGP in rats and a 21% fall in pigs. AGP levels remained elevated in rats after hemorrhage and resuscitation (28-29 μg/mL). In contrast, no significant differences in plasma AGP were found in ALM- or Saline-treated pigs over the monitoring period.</p><p><strong>Conclusions: </strong>We conclude that the trauma of surgery alone was associated with significant increases in AGP in rats, compared to a contrasting decrease in pigs. Higher levels of plasma AGP in pigs prior to hemorrhagic shock is consistent with the higher ALM doses required to resuscitate pigs compared with rats.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 5","pages":"e01133"},"PeriodicalIF":2.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b8/0b/PRP2-11-e01133.PMC10465298.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10206095","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}
引用次数: 0
Impact of amiodarone use on metoprolol concentrations, α-OH-metoprolol concentrations, metoprolol dosing and heart rate: A cross-sectional study. 胺碘酮的使用对美托洛尔浓度、α-OH美托洛尔的浓度、美托洛尔剂量和心率的影响:一项横断面研究。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-01 DOI: 10.1002/prp2.1137
Sabrina Robert, Marc-Olivier Pilon, Essaïd Oussaïd, Maxime Meloche, Grégoire Leclair, Martin Jutras, Marie-Josée Gaulin, Ian Mongrain, David Busseuil, Jean-Claude Tardif, Marie-Pierre Dubé, Simon de Denus

Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described "White" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.

小型研究表明胺碘酮是细胞色素P450(CYP)2D6的弱抑制剂。CYP2D6的抑制导致酶代谢的药物浓度增加,如美托洛尔。考虑到美托洛尔和胺碘酮都具有β-肾上腺素能阻断特性,并且两种药物之间的适度相互作用会导致美托洛尔浓度增加,这可能会导致更高的心动过缓和房室传导阻滞风险。本研究的主要目的是评估在蒙特利尔心脏研究所医院队列中随机收集的患者的美托洛尔血浆浓度是否有助于确定胺碘酮和美托洛尔之间的适度药代动力学相互作用。我们对一项横断面研究进行了分析,该研究是蒙特利尔心脏研究所医院队列的一部分。所有参与者都是自称“白人”的成年人,美托洛尔是他们日常药物治疗方案的一部分。在接受美托洛尔治疗的999名患者中,36人同时服用胺碘酮。调整不同协变量后,胺碘酮的使用与较高的美托洛尔浓度有关(p = .0132)。一致地,胺碘酮的使用与较低的心率之间的相关性在调整了所有研究的协变量后是明显和显著的(p = .0001)。我们的研究结果强调,可以利用随机采集的单个血液样本来检测适度的药代动力学相互作用。
{"title":"Impact of amiodarone use on metoprolol concentrations, α-OH-metoprolol concentrations, metoprolol dosing and heart rate: A cross-sectional study.","authors":"Sabrina Robert,&nbsp;Marc-Olivier Pilon,&nbsp;Essaïd Oussaïd,&nbsp;Maxime Meloche,&nbsp;Grégoire Leclair,&nbsp;Martin Jutras,&nbsp;Marie-Josée Gaulin,&nbsp;Ian Mongrain,&nbsp;David Busseuil,&nbsp;Jean-Claude Tardif,&nbsp;Marie-Pierre Dubé,&nbsp;Simon de Denus","doi":"10.1002/prp2.1137","DOIUrl":"10.1002/prp2.1137","url":null,"abstract":"<p><p>Small studies suggest that amiodarone is a weak inhibitor of cytochrome P450 (CYP) 2D6. Inhibition of CYP2D6 leads to increases in concentrations of drugs metabolized by the enzyme, such as metoprolol. Considering that both metoprolol and amiodarone have β-adrenergic blocking properties and that the modest interaction between the two drugs would result in increased metoprolol concentrations, this could lead to a higher risk of bradycardia and atrioventricular block. The primary objective of this study was to evaluate whether metoprolol plasma concentrations collected at random timepoints from patients enrolled in the Montreal Heart Institute Hospital Cohort could be useful in identifying the modest pharmacokinetic interaction between amiodarone and metoprolol. We performed an analysis of a cross-sectional study, conducted as part of the Montreal Heart Institute Hospital Cohort. All participants were self-described \"White\" adults with metoprolol being a part of their daily pharmacotherapy regimen. Of the 999 patients being treated with metoprolol, 36 were also taking amiodarone. Amiodarone use was associated with higher metoprolol concentrations following adjustment for different covariates (p = .0132). Consistently, the association between amiodarone use and lower heart rate was apparent and significant after adjustment for all covariates under study (p = .0001). Our results highlight that single randomly collected blood samples can be leveraged to detect modest pharmacokinetic interactions.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 5","pages":"e01137"},"PeriodicalIF":2.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/64/dd/PRP2-11-e01137.PMC10512912.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41148366","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}
引用次数: 0
A phase I, single-center, open-label study to investigate the absorption, distribution, metabolism and excretion of encorafenib following a single oral dose of 100 mg [14 C] encorafenib in healthy male subjects. 一项I期、单中心、开放标签研究,旨在研究单次口服剂量100 mg[14 C]安可非尼用于健康男性受试者。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-01 DOI: 10.1002/prp2.1140
Lance Wollenberg, Erik Hahn, Jason Williams, Kevin Litwiler

Encorafenib is a novel kinase inhibitor of BRAF V600E as well as wild-type BRAF and CRAF and has received approval, in combination with binimetinib, to treat BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma or in combination with cetuximab to treat BRAF V600E mutation-positive colorectal cancer. The absorption, distribution, metabolism and excretion (ADME) of encorafenib was studied by administering [14 C] encorafenib (100 mg containing 90 μCi of radiolabeled material) to 4 healthy male subjects (NCT01436656). Following a single oral 100-mg dose of [14 C] encorafenib to healthy male subjects, the overall recovery of radioactivity in the excreta was ≥93.9% in all four subjects, indicating that good mass balance was achieved. An equal mean of 47.2% for the radioactivity dose was eliminated in the feces and urine. The percentage of the dose eliminated in the feces (5.0%) and urine (1.8%) as unchanged encorafenib was minor. Metabolism was found to be the major clearance pathway (~88% of the recovered radioactive dose) for encorafenib in humans and is predominantly mediated through N-dealkylation of the isopropyl carbamic acid methyl ester to form the primary phase 1 direct metabolite M42.5 (LHY746). Oral absorption was estimated from the radioactive dose recovered in the urine (47.2%) and the total radioactive dose recovered in the feces as metabolites (39%). Based on these values and the assumptions that encorafenib and its metabolites are stable in feces, the fraction of oral absorption was estimated to be at least ~86%.

安可拉芬尼是BRAF V600E以及野生型BRAF和CRAF的新型激酶抑制剂,并已获得批准与二甲替尼联合治疗BRAF V600 E或V600 K突变阳性的不可切除或转移性黑色素瘤,或与西妥昔单抗联合治疗BRAF-V600 E突变阳性的癌症。通过给药[14C]encorafenib(100 mg含90 μCi)给4名健康男性受试者(NCT01436656)。对健康男性受试者单次口服100 mg剂量[14 C]安可非尼后,四名受试者排泄物中放射性的总体回收率均≥93.9%,表明达到了良好的质量平衡。粪便和尿液中放射性剂量的平均值为47.2%。在粪便(5.0%)和尿液(1.8%)中消除的剂量百分比为未改变的安可芬尼,是很小的。代谢被发现是安可芬尼在人体内的主要清除途径(约为回收放射性剂量的88%),主要通过异丙基氨基甲酸甲酯的N-脱烷基作用介导,形成初级1相直接代谢产物M42.5(LHY746)。根据尿液中回收的放射性剂量(47.2%)和粪便中回收的代谢产物总放射性剂量(39%)估计口服吸收。基于这些值以及安克拉芬尼及其代谢物在粪便中稳定的假设,估计口服吸收率至少为~86%。
{"title":"A phase I, single-center, open-label study to investigate the absorption, distribution, metabolism and excretion of encorafenib following a single oral dose of 100 mg [<sup>14</sup> C] encorafenib in healthy male subjects.","authors":"Lance Wollenberg,&nbsp;Erik Hahn,&nbsp;Jason Williams,&nbsp;Kevin Litwiler","doi":"10.1002/prp2.1140","DOIUrl":"10.1002/prp2.1140","url":null,"abstract":"<p><p>Encorafenib is a novel kinase inhibitor of BRAF V600E as well as wild-type BRAF and CRAF and has received approval, in combination with binimetinib, to treat BRAF V600E or V600K mutation-positive unresectable or metastatic melanoma or in combination with cetuximab to treat BRAF V600E mutation-positive colorectal cancer. The absorption, distribution, metabolism and excretion (ADME) of encorafenib was studied by administering [<sup>14</sup> C] encorafenib (100 mg containing 90 μCi of radiolabeled material) to 4 healthy male subjects (NCT01436656). Following a single oral 100-mg dose of [<sup>14</sup> C] encorafenib to healthy male subjects, the overall recovery of radioactivity in the excreta was ≥93.9% in all four subjects, indicating that good mass balance was achieved. An equal mean of 47.2% for the radioactivity dose was eliminated in the feces and urine. The percentage of the dose eliminated in the feces (5.0%) and urine (1.8%) as unchanged encorafenib was minor. Metabolism was found to be the major clearance pathway (~88% of the recovered radioactive dose) for encorafenib in humans and is predominantly mediated through N-dealkylation of the isopropyl carbamic acid methyl ester to form the primary phase 1 direct metabolite M42.5 (LHY746). Oral absorption was estimated from the radioactive dose recovered in the urine (47.2%) and the total radioactive dose recovered in the feces as metabolites (39%). Based on these values and the assumptions that encorafenib and its metabolites are stable in feces, the fraction of oral absorption was estimated to be at least ~86%.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 5","pages":"e01140"},"PeriodicalIF":2.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10541456/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41168723","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}
引用次数: 0
Autocrine positive feedback of tumor necrosis factor from activated microglia proposed to be of widespread relevance in chronic neurological disease. 来自活化小胶质细胞的肿瘤坏死因子的自身分泌正反馈被认为与慢性神经疾病具有广泛的相关性。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-10-01 DOI: 10.1002/prp2.1136
Ian A Clark, Bryce Vissel

Over a decade's experience of post-stroke rehabilitation by administering the specific anti-TNF biological, etanercept, by the novel perispinal route, is consistent with a wide range of chronically diminished neurological function having been caused by persistent excessive cerebral levels of TNF. We propose that this TNF persistence, and cerebral disease chronicity, largely arises from a positive autocrine feedback loop of this cytokine, allowing the persistence of microglial activation caused by the excess TNF that these cells produce. It appears that many of these observations have never been exploited to construct a broad understanding and treatment of certain chronic, yet reversible, neurological illnesses. We propose that this treatment allows these chronically activated microglia to revert to their normal quiescent state, rather than simply neutralizing the direct harmful effects of this cytokine after its release from microglia. Logically, this also applies to the chronic cerebral aspects of various other neurological conditions characterized by activated microglia. These include long COVID, Lyme disease, post-stroke syndromes, traumatic brain injury, chronic traumatic encephalopathy, post-chemotherapy, post-irradiation cerebral dysfunction, cerebral palsy, fetal alcohol syndrome, hepatic encephalopathy, the antinociceptive state of morphine tolerance, and neurogenic pain. In addition, certain psychiatric states, in isolation or as sequelae of infectious diseases such as Lyme disease and long COVID, are candidates for being understood through this approach and treated accordingly. Perispinal etanercept provides the prospect of being able to treat various chronic central nervous system illnesses, whether they are of infectious or non-infectious origin, through reversing excess TNF generation by microglia.

十多年来,通过新的椎管外途径给予特异性抗肿瘤坏死因子生物制剂依那西普进行脑卒中后康复的经验与由持续过量的脑肿瘤坏死因子水平引起的广泛的慢性神经功能减退相一致。我们提出,这种TNF的持久性和脑疾病的慢性性在很大程度上源于这种细胞因子的正自分泌反馈回路,允许这些细胞产生的过量TNF引起的小胶质细胞活化的持久性。这些观察结果中的许多似乎从未被用来构建对某些慢性但可逆的神经疾病的广泛理解和治疗。我们提出,这种治疗方法可以让这些慢性激活的小胶质细胞恢复到正常的静止状态,而不是简单地中和这种细胞因子从小胶质细胞释放后的直接有害影响。从逻辑上讲,这也适用于以小胶质细胞活化为特征的各种其他神经疾病的慢性大脑方面。其中包括长期新冠肺炎、莱姆病、卒中后综合征、创伤性脑损伤、慢性创伤性脑病、化疗后、放疗后脑功能障碍、脑瘫、胎儿酒精综合征、肝性脑病、吗啡耐受的抗伤害感受状态和神经源性疼痛。此外,某些精神状态,无论是孤立的还是莱姆病和长期新冠肺炎等传染病的后遗症,都有可能通过这种方法被理解并得到相应的治疗。脊髓周围依那西普通过逆转小胶质细胞产生的过量TNF,有望治疗各种慢性中枢神经系统疾病,无论这些疾病是传染性的还是非传染性的。
{"title":"Autocrine positive feedback of tumor necrosis factor from activated microglia proposed to be of widespread relevance in chronic neurological disease.","authors":"Ian A Clark,&nbsp;Bryce Vissel","doi":"10.1002/prp2.1136","DOIUrl":"10.1002/prp2.1136","url":null,"abstract":"<p><p>Over a decade's experience of post-stroke rehabilitation by administering the specific anti-TNF biological, etanercept, by the novel perispinal route, is consistent with a wide range of chronically diminished neurological function having been caused by persistent excessive cerebral levels of TNF. We propose that this TNF persistence, and cerebral disease chronicity, largely arises from a positive autocrine feedback loop of this cytokine, allowing the persistence of microglial activation caused by the excess TNF that these cells produce. It appears that many of these observations have never been exploited to construct a broad understanding and treatment of certain chronic, yet reversible, neurological illnesses. We propose that this treatment allows these chronically activated microglia to revert to their normal quiescent state, rather than simply neutralizing the direct harmful effects of this cytokine after its release from microglia. Logically, this also applies to the chronic cerebral aspects of various other neurological conditions characterized by activated microglia. These include long COVID, Lyme disease, post-stroke syndromes, traumatic brain injury, chronic traumatic encephalopathy, post-chemotherapy, post-irradiation cerebral dysfunction, cerebral palsy, fetal alcohol syndrome, hepatic encephalopathy, the antinociceptive state of morphine tolerance, and neurogenic pain. In addition, certain psychiatric states, in isolation or as sequelae of infectious diseases such as Lyme disease and long COVID, are candidates for being understood through this approach and treated accordingly. Perispinal etanercept provides the prospect of being able to treat various chronic central nervous system illnesses, whether they are of infectious or non-infectious origin, through reversing excess TNF generation by microglia.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 5","pages":"e01136"},"PeriodicalIF":2.6,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/29/3a/PRP2-11-e01136.PMC10520644.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41130046","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}
引用次数: 0
Drug interactions of tacrolimus with letermovir and azole antifungals following hematopoietic stem cell transplantation: A retrospective observational analysis. 他克莫司与利特莫韦和唑类抗真菌药物在造血干细胞移植后的相互作用:回顾性观察分析。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-08-01 DOI: 10.1002/prp2.1120
Yuri Shinogi, Toshinori Hirai, Miki Ishibashi, Kazuko Ino, Isao Tawara, Takuya Iwamoto

Tacrolimus interacts with letermovir and azole antifungals, whereas letermovir has nonuniform effects on the pharmacokinetics of azole antifungals. We retrospectively investigated the interaction of tacrolimus (continuous infusion) with letermovir considering co-administered azole antifungals in adult hematopoietic stem cell transplantation patients. The extent of intraindividual variation in the ratio of tacrolimus concentration to dose normalized by body weight (C/D ratio) was investigated. The correlation between the C/D ratio and estimated glomerular filtration rate (eGFR) was analyzed. In 35 patients (795 points), the C/D ratio was higher in the tacrolimus plus letermovir period than in the tacrolimus alone period (1234.7 [566.2-2721.0] ng/mL/mg/kg vs. 564.4 [245.3-1861.3] ng/mL/mg/kg, p < .001). This trend was observed when co-administered with azole antifungals (n = 30, 1285.5 [662.7-2506.7] ng/mL/mg/kg vs. 547.1 [245.3-1861.3] ng/mL/mg/kg, p < .001), but not without azole antifungals (n = 5, 809.9 [566.2-1573.3] ng/mL/mg/kg vs. 616.1 [350.6-979.8] ng/mL/mg/kg, p = .125). For patients co-administered fluconazole, the tacrolimus C/D ratio increased in patients with letermovir than those without letermovir (n = 28, 1215.0 [662.7-2506.7] ng/mL/mg/kg vs. 529.9 [245.3-1654.4] ng/mL/mg/kg, p < .001). Tacrolimus C/D ratio did not correlate with eGFR under letermovir and fluconazole administrations (y = 0.1x + 1307.1, r = .008, p = .968). Close blood concentration monitoring of intravenous tacrolimus is required when patients administered letermovir and azole antifungals.

他克莫司与莱特莫韦和唑类抗真菌药物相互作用,而莱特莫韦对唑类抗真菌药物的药代动力学影响不均匀。我们回顾性地研究了他克莫司(持续输注)与利特莫韦在成人造血干细胞移植患者中联合使用唑类抗真菌药物的相互作用。研究了他克莫司浓度与体重归一化剂量之比(C/D比)的个体变异程度。分析C/D比值与肾小球滤过率(eGFR)的相关性。35例患者(795分)中,他克莫司联合莱特莫韦组C/D比值高于单用他克莫司组(1234.7 [566.2-2721.0]ng/mL/mg/kg vs. 564.4 [245.3-1861.3] ng/mL/mg/kg, p
{"title":"Drug interactions of tacrolimus with letermovir and azole antifungals following hematopoietic stem cell transplantation: A retrospective observational analysis.","authors":"Yuri Shinogi,&nbsp;Toshinori Hirai,&nbsp;Miki Ishibashi,&nbsp;Kazuko Ino,&nbsp;Isao Tawara,&nbsp;Takuya Iwamoto","doi":"10.1002/prp2.1120","DOIUrl":"https://doi.org/10.1002/prp2.1120","url":null,"abstract":"<p><p>Tacrolimus interacts with letermovir and azole antifungals, whereas letermovir has nonuniform effects on the pharmacokinetics of azole antifungals. We retrospectively investigated the interaction of tacrolimus (continuous infusion) with letermovir considering co-administered azole antifungals in adult hematopoietic stem cell transplantation patients. The extent of intraindividual variation in the ratio of tacrolimus concentration to dose normalized by body weight (C/D ratio) was investigated. The correlation between the C/D ratio and estimated glomerular filtration rate (eGFR) was analyzed. In 35 patients (795 points), the C/D ratio was higher in the tacrolimus plus letermovir period than in the tacrolimus alone period (1234.7 [566.2-2721.0] ng/mL/mg/kg vs. 564.4 [245.3-1861.3] ng/mL/mg/kg, p < .001). This trend was observed when co-administered with azole antifungals (n = 30, 1285.5 [662.7-2506.7] ng/mL/mg/kg vs. 547.1 [245.3-1861.3] ng/mL/mg/kg, p < .001), but not without azole antifungals (n = 5, 809.9 [566.2-1573.3] ng/mL/mg/kg vs. 616.1 [350.6-979.8] ng/mL/mg/kg, p = .125). For patients co-administered fluconazole, the tacrolimus C/D ratio increased in patients with letermovir than those without letermovir (n = 28, 1215.0 [662.7-2506.7] ng/mL/mg/kg vs. 529.9 [245.3-1654.4] ng/mL/mg/kg, p < .001). Tacrolimus C/D ratio did not correlate with eGFR under letermovir and fluconazole administrations (y = 0.1x + 1307.1, r = .008, p = .968). Close blood concentration monitoring of intravenous tacrolimus is required when patients administered letermovir and azole antifungals.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 4","pages":"e01120"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/e7/e0/PRP2-11-e01120.PMC10395274.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9933206","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}
引用次数: 0
Application of physiologically based pharmacokinetic modeling to understand real-world outcomes in patients receiving imatinib for chronic myeloid leukemia. 应用基于生理的药代动力学模型来了解接受伊马替尼治疗慢性髓性白血病患者的实际结果。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-08-01 DOI: 10.1002/prp2.1082
Josephine A Adattini, Jeffry Adiwidjaja, Annette S Gross, Andrew J McLachlan

We aimed to use physiologically based pharmacokinetic (PBPK) modeling and simulation to predict imatinib steady-state plasma exposure in patients with chronic myeloid leukemia (CML) to investigate variability in outcomes. A validated imatinib PBPK model (Simcyp Simulator) was used to predict imatinib AUCss , Css,min and Css,max for patients with CML (n = 68) from a real-world retrospective observational study. Differences in imatinib exposure were evaluated based on clinical outcomes, (a) Early Molecular Response (EMR) achievement and (b) occurrence of grade ≥3 adverse drug reactions (ADRs), using the Kruskal-Wallis rank sum test. Sensitivity analyses explored the influence of patient characteristics and drug interactions on imatinib exposure. Simulated imatinib exposure was significantly higher in patients who achieved EMR compared to patients who did not (geometric mean AUC0-24,ss 51.2 vs. 42.7 μg h mL-1 , p < 0.05; Css,min 1.1 vs. 0.9 μg mL-1 , p < 0.05; Css,max 3.4 vs. 2.8 μg mL-1 , p < 0.05). Patients who experienced grade ≥3 ADRs had a significantly higher simulated imatinib exposure compared to patients who did not (AUC0-24,ss 56.1 vs. 45.9 μg h mL-1 , p < 0.05; Css,min 1.2 vs. 1.0 μg mL-1 , p < 0.05; Css,max 3.7 vs. 3.0 μg mL-1 , p < 0.05). Simulations identified a range of patient (sex, age, weight, abundance of hepatic CYP2C8 and CYP3A4, α1 -acid glycoprotein concentrations, liver and kidney function) and medication-related factors (dose, concomitant CYP2C8 modulators) contributing to the inter-individual variability in imatinib exposure. Relationships between imatinib plasma exposure, EMR achievement and ADRs support the rationale for therapeutic drug monitoring to guide imatinib dosing to achieve optimal outcomes in CML.

我们的目的是使用基于生理的药代动力学(PBPK)建模和模拟来预测慢性髓性白血病(CML)患者的伊马替尼稳态血浆暴露,以研究结果的变异性。通过验证的伊马替尼PBPK模型(Simcyp Simulator)来预测CML患者(n = 68)的伊马替尼AUCss、Css、min和Css、max。使用Kruskal-Wallis秩和检验,根据临床结果(a)早期分子反应(EMR)的实现和(b)≥3级药物不良反应(adr)的发生来评估伊马替尼暴露的差异。敏感性分析探讨了患者特征和药物相互作用对伊马替尼暴露的影响。模拟伊马替尼暴露在患者明显高于EMR相比,患者没有(几何平均数AUC0-24,党卫军51.2 vs 42.7μg h mL-1 p党卫军,最小1.1 vs 0.9μg mL-1 p党卫军,最大3.4 vs 2.8μg mL-1 p 0-24,党卫军56.1 vs 45.9μg h mL-1 p党卫军,最小1.2 vs 1.0μg mL-1 p党卫军,最大3.7 vs 3.0μg mL-1 p浓度1酸性糖蛋白,肝脏和肾脏功能)和与药物因素(剂量,伴随CYP2C8调节剂)导致伊马替尼暴露的个体间变异性。伊马替尼血浆暴露、EMR实现和不良反应之间的关系支持治疗药物监测的基本原理,以指导伊马替尼给药,以实现CML的最佳结果。
{"title":"Application of physiologically based pharmacokinetic modeling to understand real-world outcomes in patients receiving imatinib for chronic myeloid leukemia.","authors":"Josephine A Adattini,&nbsp;Jeffry Adiwidjaja,&nbsp;Annette S Gross,&nbsp;Andrew J McLachlan","doi":"10.1002/prp2.1082","DOIUrl":"https://doi.org/10.1002/prp2.1082","url":null,"abstract":"<p><p>We aimed to use physiologically based pharmacokinetic (PBPK) modeling and simulation to predict imatinib steady-state plasma exposure in patients with chronic myeloid leukemia (CML) to investigate variability in outcomes. A validated imatinib PBPK model (Simcyp Simulator) was used to predict imatinib AUC<sub>ss</sub> , C<sub>ss,min</sub> and C<sub>ss,max</sub> for patients with CML (n = 68) from a real-world retrospective observational study. Differences in imatinib exposure were evaluated based on clinical outcomes, (a) Early Molecular Response (EMR) achievement and (b) occurrence of grade ≥3 adverse drug reactions (ADRs), using the Kruskal-Wallis rank sum test. Sensitivity analyses explored the influence of patient characteristics and drug interactions on imatinib exposure. Simulated imatinib exposure was significantly higher in patients who achieved EMR compared to patients who did not (geometric mean AUC<sub>0-24,ss</sub> 51.2 vs. 42.7 μg h mL<sup>-1</sup> , p < 0.05; C<sub>ss,min</sub> 1.1 vs. 0.9 μg mL<sup>-1</sup> , p < 0.05; C<sub>ss,max</sub> 3.4 vs. 2.8 μg mL<sup>-1</sup> , p < 0.05). Patients who experienced grade ≥3 ADRs had a significantly higher simulated imatinib exposure compared to patients who did not (AUC<sub>0-24,ss</sub> 56.1 vs. 45.9 μg h mL<sup>-1</sup> , p < 0.05; C<sub>ss,min</sub> 1.2 vs. 1.0 μg mL<sup>-1</sup> , p < 0.05; C<sub>ss,max</sub> 3.7 vs. 3.0 μg mL<sup>-1</sup> , p < 0.05). Simulations identified a range of patient (sex, age, weight, abundance of hepatic CYP2C8 and CYP3A4, α<sub>1</sub> -acid glycoprotein concentrations, liver and kidney function) and medication-related factors (dose, concomitant CYP2C8 modulators) contributing to the inter-individual variability in imatinib exposure. Relationships between imatinib plasma exposure, EMR achievement and ADRs support the rationale for therapeutic drug monitoring to guide imatinib dosing to achieve optimal outcomes in CML.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 4","pages":"e01082"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10326685/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9807933","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}
引用次数: 0
Investigation of the GnRH antagonist degarelix isomerization in biological matrices. GnRH拮抗剂在生物基质中脱链异构化的研究。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-08-01 DOI: 10.1002/prp2.1117
Lucia Ferrazzano, Alessandra Tolomelli, Ivan Guryanov, Marco Macis, Ulrich Abel, Antonio Ricci, Walter Cabri

One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impurities in the peptide drugs and their metabolites, which require the development of advanced analytical methods to properly assess their content. Here, we investigated the degradation of the potent long-acting GnRH antagonist degarelix in various biologic media by the tailor-made HPLC method, which allows precise determination of 5-Aph(Hyd)-degarelix isomer, an impurity found in the degarelix active pharmaceutical ingredient (API) during its manufacturing. Unexpectedly, we discovered a rapid and irreversible conversion of degarelix API into the corresponding hydantoin isomer in serum, suggesting that this impurity can be also a potential drug metabolite in vivo. This finding underlines the importance of the development of more accurate and performing analytical techniques to correctly characterize the chemical composition of the manufactured drugs and their behavior under physiological conditions.

肽药物设计的主要目标之一是在保持生物活性的同时改善肽的药代动力学,这可以通过对肽一级结构的复杂修饰来实现。然而,这些变化往往导致多肽药物及其代谢产物中形成特殊杂质,这就需要发展先进的分析方法来正确评估其含量。在这里,我们研究了有效的长效GnRH拮抗剂degarelix在各种生物介质中的降解,通过定制的高效液相色谱方法,可以精确测定5-Aph(Hyd)-degarelix异构体,这是在degarelix活性药物成分(API)生产过程中发现的杂质。出乎意料的是,我们发现degarelix API在血清中快速且不可逆地转化为相应的海因异构体,这表明该杂质在体内也可能是一种潜在的药物代谢物。这一发现强调了发展更准确和更有效的分析技术以正确表征制造药物的化学成分及其在生理条件下的行为的重要性。
{"title":"Investigation of the GnRH antagonist degarelix isomerization in biological matrices.","authors":"Lucia Ferrazzano,&nbsp;Alessandra Tolomelli,&nbsp;Ivan Guryanov,&nbsp;Marco Macis,&nbsp;Ulrich Abel,&nbsp;Antonio Ricci,&nbsp;Walter Cabri","doi":"10.1002/prp2.1117","DOIUrl":"https://doi.org/10.1002/prp2.1117","url":null,"abstract":"<p><p>One of the main objectives of peptide drug design is the improvement of peptide pharmacokinetics with maintaining biological activity, which can be achieved by the complex modifications of the primary structure of the peptides. However, these changes often lead to the formation of peculiar impurities in the peptide drugs and their metabolites, which require the development of advanced analytical methods to properly assess their content. Here, we investigated the degradation of the potent long-acting GnRH antagonist degarelix in various biologic media by the tailor-made HPLC method, which allows precise determination of 5-Aph(Hyd)-degarelix isomer, an impurity found in the degarelix active pharmaceutical ingredient (API) during its manufacturing. Unexpectedly, we discovered a rapid and irreversible conversion of degarelix API into the corresponding hydantoin isomer in serum, suggesting that this impurity can be also a potential drug metabolite in vivo. This finding underlines the importance of the development of more accurate and performing analytical techniques to correctly characterize the chemical composition of the manufactured drugs and their behavior under physiological conditions.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 4","pages":"e01117"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10350552/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9891068","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}
引用次数: 0
How to approach a study in ethnopharmacology? Providing an example of the different research stages for newcomers to the field today. 如何进行民族药理学研究?为今天这个领域的新手提供了一个不同研究阶段的例子。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-08-01 DOI: 10.1002/prp2.1109
Fabien Schultz, Leif-Alexander Garbe

Ethnopharmacology seeks to investigate humankind's use of natural materials, such as plants, fungi, microorganisms, animals, and minerals, for medicinal purposes. In this highly interdisciplinary field, which can be described as a bridge between the natural/medical and socio-cultural sciences, pharmacological, anthropological, and socio-cultural research methods are often applied, along with methods from other branches of science. When entering the field of ethnopharmacology as a newcomer, student, or early career researcher today, the tremendous amount of scientific publications, and even classical books from this field and related scientific disciplines, can be overwhelming. Ethnopharmacology has evolved over the past decades, and new key topics, such as the decolonization of the field, issues on intellectual property and benefit-sharing, species conservation, the preservation of traditional knowledge, the protection of indigenous communities, science outreach, and climate change, have become important and urgent aspects of the field that must not be disregarded by today's ethnopharmacologists. One of the questions of newcomers will be, "Where to begin?" This review article offers a brief (and certainly not comprehensive) introduction to the science of ethnopharmacology, highlighting some of its past most notable achievements and future prospects. In addition, this article provides an example for newcomers to the field of how to address different stages that may be involved in conducting ethnopharmacological field and lab studies, including early-stage drug discovery and community work. The example presented summarizes a series of studies conducted in the remote Greater Mpigi region of Uganda, located in East Africa. Stages of ethnopharmacological research described include ethnobotanical surveying and fieldwork, the pharmacological assessment of activity with diverse targets in the laboratory, and the transfer of results back to indigenous communities, that is, non-financial benefit sharing as a potential best practice example. As a result of this research example, a total of six original research articles have been published on the medicinal application and ethnopharmacology of 16 plant species from the Ugandan study site, offering a large quantity of results. These six publications reflect the multifaceted nature of the interdisciplinary science of ethnopharmacology, which may serve as a reference point and inspiration for newcomers to design and conduct their own independent ethnopharmacological research endeavors at other study sites. Major bottlenecks and solutions are provided, and the current social media channels with educational ethnopharmacological content are briefly introduced.

民族药理学旨在调查人类利用天然材料,如植物、真菌、微生物、动物和矿物进行药用的情况。在这个高度跨学科的领域,它可以被描述为自然/医学和社会文化科学之间的桥梁,药理学,人类学和社会文化研究方法经常被应用,以及其他科学分支的方法。今天,当一个新人、学生或早期职业研究者进入民族药理学领域时,大量的科学出版物,甚至是来自这个领域和相关科学学科的经典书籍,都是压倒性的。民族药理学在过去的几十年里不断发展,新的关键主题,如该领域的非殖民化,知识产权和利益分享问题,物种保护,传统知识的保存,土著社区的保护,科学推广和气候变化,已经成为该领域重要和紧迫的方面,今天的民族药理学家不能忽视。新来者的问题之一是,“从哪里开始?”这篇综述文章提供了一个简短的(当然不是全面的)介绍民族药理学的科学,突出了一些过去最显著的成就和未来的展望。此外,本文还为新进入该领域的人提供了一个例子,说明如何处理可能涉及进行民族药理学领域和实验室研究的不同阶段,包括早期药物发现和社区工作。所举的例子总结了在东非乌干达偏远的大姆皮吉地区进行的一系列研究。所描述的民族药理学研究的阶段包括民族植物学调查和实地调查,实验室中不同目标活动的药理学评估,以及将结果转移回土著社区,即非经济利益分享作为潜在的最佳实践示例。通过这一研究实例,共发表了6篇关于乌干达研究地点16种植物的药用和民族药理学的原创研究文章,提供了大量的结果。这六份出版物反映了民族药理学跨学科科学的多面性,可以作为新来者在其他研究地点设计和开展自己独立的民族药理学研究的参考点和灵感。提供了主要瓶颈和解决方案,并简要介绍了目前具有教育民族药理学内容的社交媒体渠道。
{"title":"How to approach a study in ethnopharmacology? Providing an example of the different research stages for newcomers to the field today.","authors":"Fabien Schultz,&nbsp;Leif-Alexander Garbe","doi":"10.1002/prp2.1109","DOIUrl":"https://doi.org/10.1002/prp2.1109","url":null,"abstract":"<p><p>Ethnopharmacology seeks to investigate humankind's use of natural materials, such as plants, fungi, microorganisms, animals, and minerals, for medicinal purposes. In this highly interdisciplinary field, which can be described as a bridge between the natural/medical and socio-cultural sciences, pharmacological, anthropological, and socio-cultural research methods are often applied, along with methods from other branches of science. When entering the field of ethnopharmacology as a newcomer, student, or early career researcher today, the tremendous amount of scientific publications, and even classical books from this field and related scientific disciplines, can be overwhelming. Ethnopharmacology has evolved over the past decades, and new key topics, such as the decolonization of the field, issues on intellectual property and benefit-sharing, species conservation, the preservation of traditional knowledge, the protection of indigenous communities, science outreach, and climate change, have become important and urgent aspects of the field that must not be disregarded by today's ethnopharmacologists. One of the questions of newcomers will be, \"Where to begin?\" This review article offers a brief (and certainly not comprehensive) introduction to the science of ethnopharmacology, highlighting some of its past most notable achievements and future prospects. In addition, this article provides an example for newcomers to the field of how to address different stages that may be involved in conducting ethnopharmacological field and lab studies, including early-stage drug discovery and community work. The example presented summarizes a series of studies conducted in the remote Greater Mpigi region of Uganda, located in East Africa. Stages of ethnopharmacological research described include ethnobotanical surveying and fieldwork, the pharmacological assessment of activity with diverse targets in the laboratory, and the transfer of results back to indigenous communities, that is, non-financial benefit sharing as a potential best practice example. As a result of this research example, a total of six original research articles have been published on the medicinal application and ethnopharmacology of 16 plant species from the Ugandan study site, offering a large quantity of results. These six publications reflect the multifaceted nature of the interdisciplinary science of ethnopharmacology, which may serve as a reference point and inspiration for newcomers to design and conduct their own independent ethnopharmacological research endeavors at other study sites. Major bottlenecks and solutions are provided, and the current social media channels with educational ethnopharmacological content are briefly introduced.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 4","pages":"e01109"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/b9/c6/PRP2-11-e01109.PMC10375576.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9895647","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}
引用次数: 1
Intravenous ibuprofen in postoperative pain and fever management in adults: A systematic review and meta-analysis of randomized controlled trials. 静脉注射布洛芬治疗成人术后疼痛和发热:随机对照试验的系统回顾和荟萃分析。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-08-01 DOI: 10.1002/prp2.1123
Pengxiang Zhou, Lu Chen, Ente Wang, Lanzhi He, Shuxia Tian, Suodi Zhai

This study aims to evaluate the efficacy and safety of multiple or single-dosage intravenous ibuprofen (IVIB) in managing postoperative pain and fever in adults who are unable to take oral medications. A systematic review and meta-analysis was conducted based on randomized controlled trials (RCTs) comparing IVIB with placebo or other analgesic and antipyretic medications for postoperative pain and fever management. Data were collected from 8 main databases from the inception to June 2022. Risk of bias assessment was performed, and the GRADE methodology was used to assess the certainty of pooled evidence. Primary outcomes included visual analogue scale (VAS) scores within 24 h postoperative and reduction of temperature. Meta-analyses were conducted to calculate the mean difference (MD) or risk ratios (RR) and 95% CIs. As a result, a total of twenty-three RCTs with 3716 participants were included. For postoperative pain, with moderate-to-low certainty evidence, IVIB was associated with lower postoperative VAS scores than placebo, with MD ranging from -3.53 (95% CI, -4.32 to -2.75) at 0 min to -0.96 (95% CI, -1.35 to -0.57) at 24 h. Compared with intravenous acetaminophen, IVIB demonstrated lower VAS scores (MD, -1.54 at 0 min; -0.36 at 24 h). For fever, IVIB showed satisfactory antipyretic efficiency in a short period of time, but no difference was observed between IVIB and intravenous acetaminophen. IVIB was well-tolerated for both pain and fever management. In conclusion, moderate-to-low certainty evidence supports the use of IVIB for adults with postoperative pain and fever who are unable to take oral medications.

本研究旨在评估多次或单次静脉注射布洛芬(IVIB)治疗无法口服药物的成人术后疼痛和发热的疗效和安全性。在随机对照试验(rct)的基础上,对IVIB与安慰剂或其他镇痛和解热药物进行了系统回顾和荟萃分析,以治疗术后疼痛和发烧。数据收集自项目启动至2022年6月期间的8个主要数据库。进行偏倚风险评估,并使用GRADE方法评估合并证据的确定性。主要结果包括术后24 h内视觉模拟评分(VAS)和体温下降。进行meta分析以计算平均差异(MD)或风险比(RR)和95% ci。结果,共纳入23项随机对照试验,共3716名受试者。对于术后疼痛,有中等到低确定性证据表明,IVIB与术后VAS评分相关,其MD范围为0分钟时的-3.53 (95% CI, -4.32至-2.75)至24小时时的-0.96 (95% CI, -1.35至-0.57)。与静脉注射对乙酰氨基酚相比,IVIB的VAS评分较低(MD, 0 min时-1.54;-0.36, 24小时)。对于发热,IVIB在短时间内表现出满意的退热效果,但IVIB与静脉注射对乙酰氨基酚之间无差异。IVIB对疼痛和发热管理均具有良好的耐受性。总之,中等至低确定性证据支持对术后疼痛和发热且无法口服药物的成人使用IVIB。
{"title":"Intravenous ibuprofen in postoperative pain and fever management in adults: A systematic review and meta-analysis of randomized controlled trials.","authors":"Pengxiang Zhou,&nbsp;Lu Chen,&nbsp;Ente Wang,&nbsp;Lanzhi He,&nbsp;Shuxia Tian,&nbsp;Suodi Zhai","doi":"10.1002/prp2.1123","DOIUrl":"https://doi.org/10.1002/prp2.1123","url":null,"abstract":"<p><p>This study aims to evaluate the efficacy and safety of multiple or single-dosage intravenous ibuprofen (IVIB) in managing postoperative pain and fever in adults who are unable to take oral medications. A systematic review and meta-analysis was conducted based on randomized controlled trials (RCTs) comparing IVIB with placebo or other analgesic and antipyretic medications for postoperative pain and fever management. Data were collected from 8 main databases from the inception to June 2022. Risk of bias assessment was performed, and the GRADE methodology was used to assess the certainty of pooled evidence. Primary outcomes included visual analogue scale (VAS) scores within 24 h postoperative and reduction of temperature. Meta-analyses were conducted to calculate the mean difference (MD) or risk ratios (RR) and 95% CIs. As a result, a total of twenty-three RCTs with 3716 participants were included. For postoperative pain, with moderate-to-low certainty evidence, IVIB was associated with lower postoperative VAS scores than placebo, with MD ranging from -3.53 (95% CI, -4.32 to -2.75) at 0 min to -0.96 (95% CI, -1.35 to -0.57) at 24 h. Compared with intravenous acetaminophen, IVIB demonstrated lower VAS scores (MD, -1.54 at 0 min; -0.36 at 24 h). For fever, IVIB showed satisfactory antipyretic efficiency in a short period of time, but no difference was observed between IVIB and intravenous acetaminophen. IVIB was well-tolerated for both pain and fever management. In conclusion, moderate-to-low certainty evidence supports the use of IVIB for adults with postoperative pain and fever who are unable to take oral medications.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 4","pages":"e01123"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c9/fa/PRP2-11-e01123.PMC10395276.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9933209","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}
引用次数: 0
Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis. TAK1和JAK1/3在类风湿性关节炎CIA模型中不同炎症信号作用的描述。
IF 2.6 4区 医学 Q2 PHARMACOLOGY & PHARMACY Pub Date : 2023-08-01 DOI: 10.1002/prp2.1124
Robert Freeze, Kelly W Yang, Timothy Haystead, Philip Hughes, Scott Scarneo

Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by hyperactive immune cells within the joints, which leads to inflammation, bone degeneration, and chronic pain. For several decades, frontline immunomodulators such as the anti-tumor necrosis factor (TNF) biologics adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade) have successfully managed disease progression for many patients. However, over time, patients become refractory to these treatments requiring chronic disease to be managed with conventional and more problematic disease modifying antirheumatic drugs such as methotrexate and hydroxychloroquine, and corticosteroids. Due to the large proportion of patients who continue to fail on frontline biologic therapies, there remains an unmet need to derive novel alternative targets with improved efficacy and safety profiles to treat RA. Recent advances in the field have defined novel targets that play important roles in RA pathology, including the Janus activated kinase (JAK) and transforming growth factor beta activated kinase-1 (TAK1). Although three inhibitors of the JAK signaling pathway have been approved for the treatment of moderately to severely active RA in patients who failed on one or more anti-TNFs, at present, no FDA approved TAK1 treatments exist. Our recent discovery of a highly potent and selective, orally bioavailable TAK1 inhibitor has provided insight into the therapeutic potential of this protein kinase as a novel target for RA. Here, we show the distinct cytokine signaling of tofacitnib (Xeljanz; JAK1/3 inhibitor) compared to HS-276 (TAK1 inhibitor) in lipopolysaccharide (LPS) challenged THP-1 cells. Furthermore, in the collagen induced arthritis pre-clinical mouse model of RA, both tofacintib and HS-276 attenuated disease activity score and inflammatory cytokines in the serum. Overall, our results delineate the distinct cytokine signaling of JAK1/3 and TAK1 targeted therapies in vitro and in vivo and suggest that selective TAK1 inhibitors may provide superior therapeutic relief in RA with fewer adverse events.

类风湿性关节炎(RA)是一种复杂的自身免疫性疾病,其特征是关节内免疫细胞过度活跃,导致炎症、骨变性和慢性疼痛。几十年来,抗肿瘤坏死因子(TNF)生物制剂阿达木单抗(Humira)、依那西普(Enbrel)和英夫利昔单抗(Remicade)等一线免疫调节剂已成功控制了许多患者的疾病进展。然而,随着时间的推移,患者对这些治疗变得难治,需要用传统的、更有问题的疾病改良性抗风湿药物(如甲氨蝶呤和羟氯喹)和皮质类固醇来治疗慢性病。由于在一线生物治疗中仍有很大一部分患者失败,因此仍有未满足的需求,即开发出具有改善疗效和安全性的新的替代靶点来治疗RA。该领域的最新进展已经确定了在RA病理中发挥重要作用的新靶点,包括Janus活化激酶(JAK)和转化生长因子β活化激酶-1(TAK1)。尽管JAK信号通路的三种抑制剂已被批准用于治疗一种或多种抗TNF失败的患者的中度至重度活动性RA,但目前还没有FDA批准的TAK1治疗方法。我们最近发现了一种高效、选择性、口服生物可利用的TAK1抑制剂,这为该蛋白激酶作为RA新靶点的治疗潜力提供了见解。在这里,我们展示了在脂多糖(LPS)攻击的THP-1细胞中,与HS-276(TAK1抑制剂)相比,托法替尼(Xeljanz;JAK1/3抑制剂)的不同细胞因子信号传导。此外,在胶原诱导的RA关节炎临床前小鼠模型中,托法提布和HS-276都降低了血清中的疾病活性评分和炎性细胞因子。总的来说,我们的结果描述了JAK1/3和TAK1靶向治疗在体外和体内的不同细胞因子信号传导,并表明选择性TAK1抑制剂可以在RA中提供更好的治疗缓解,不良事件更少。
{"title":"Delineation of the distinct inflammatory signaling roles of TAK1 and JAK1/3 in the CIA model of rheumatoid arthritis.","authors":"Robert Freeze,&nbsp;Kelly W Yang,&nbsp;Timothy Haystead,&nbsp;Philip Hughes,&nbsp;Scott Scarneo","doi":"10.1002/prp2.1124","DOIUrl":"10.1002/prp2.1124","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is a complex autoimmune disease characterized by hyperactive immune cells within the joints, which leads to inflammation, bone degeneration, and chronic pain. For several decades, frontline immunomodulators such as the anti-tumor necrosis factor (TNF) biologics adalimumab (Humira), etanercept (Enbrel), and infliximab (Remicade) have successfully managed disease progression for many patients. However, over time, patients become refractory to these treatments requiring chronic disease to be managed with conventional and more problematic disease modifying antirheumatic drugs such as methotrexate and hydroxychloroquine, and corticosteroids. Due to the large proportion of patients who continue to fail on frontline biologic therapies, there remains an unmet need to derive novel alternative targets with improved efficacy and safety profiles to treat RA. Recent advances in the field have defined novel targets that play important roles in RA pathology, including the Janus activated kinase (JAK) and transforming growth factor beta activated kinase-1 (TAK1). Although three inhibitors of the JAK signaling pathway have been approved for the treatment of moderately to severely active RA in patients who failed on one or more anti-TNFs, at present, no FDA approved TAK1 treatments exist. Our recent discovery of a highly potent and selective, orally bioavailable TAK1 inhibitor has provided insight into the therapeutic potential of this protein kinase as a novel target for RA. Here, we show the distinct cytokine signaling of tofacitnib (Xeljanz; JAK1/3 inhibitor) compared to HS-276 (TAK1 inhibitor) in lipopolysaccharide (LPS) challenged THP-1 cells. Furthermore, in the collagen induced arthritis pre-clinical mouse model of RA, both tofacintib and HS-276 attenuated disease activity score and inflammatory cytokines in the serum. Overall, our results delineate the distinct cytokine signaling of JAK1/3 and TAK1 targeted therapies in vitro and in vivo and suggest that selective TAK1 inhibitors may provide superior therapeutic relief in RA with fewer adverse events.</p>","PeriodicalId":19948,"journal":{"name":"Pharmacology Research & Perspectives","volume":"11 4","pages":"e01124"},"PeriodicalIF":2.6,"publicationDate":"2023-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/9f/9f/PRP2-11-e01124.PMC10415874.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9997425","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}
引用次数: 0
期刊
Pharmacology Research & Perspectives
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1