Evaluation of the Efficacy of Tofacitinib, a JAK Inhibitor, in Alleviating Sepsis-Induced Multiple Organ Dysfunction Syndrome.

IF 1.7 Q3 PHARMACOLOGY & PHARMACY Drug Research Pub Date : 2024-10-01 Epub Date: 2024-08-12 DOI:10.1055/a-2372-3446
Vaishnavi Singh, Kavita Joshi, Samit Chatterjee, Sameer Qureshi, Snigdha Siddh, Vandana Nunia
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Abstract

Sepsis, a life-threatening condition triggered by an uncontrolled response to infection, results in a systemic inflammatory response syndrome (SIRS) and the failure of multiple organs leading to multiple organ dysfunction (MODS). In the present study, we investigated the therapeutic potential of tofacitinib (TOFA), an FDA-approved inhibitor of JAK1 and JAK3 against sepsis, using a mouse model induced by cecal ligation puncture (CLP). Swiss albino mice were employed to replicate the CLP-induced sepsis model and were randomly divided into four groups: control, CLP, 150 mg/kg TOFA, and 300 mg/kg TOFA. Six hours after the last TOFA dose, we collected blood and tissue samples from the liver, lungs, kidneys, and spleen for histological analysis. Blood samples were used to assess granulocyte and lymphocyte percentages. Throughout the experiment, we monitored body weight and short-term survival. Our comparative histological analysis revealed that 150 mg/kg TOFA had a protective effect against multiple organ damage. Conversely, the study highlighted the harmful effects of 300 mg/kg TOFA, primarily due to liver and renal toxicity within this group. In summary, our findings demonstrate that tofacitinib at an optimal dose of 150 mg/kg showed promise as a potential therapeutic intervention for sepsis-induced multiple organ failure. However, caution is warranted when considering higher dosages.

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评估JAK抑制剂托法替尼在缓解败血症引发的多器官功能障碍综合征方面的疗效
败血症是一种因感染反应失控而引发的危及生命的疾病,会导致全身炎症反应综合征(SIRS)和多器官功能衰竭,从而引发多器官功能障碍(MODS)。在本研究中,我们利用盲肠结扎穿刺(CLP)诱导的小鼠模型,研究了托法替尼(TOFA)的治疗潜力,托法替尼是美国 FDA 批准的 JAK1 和 JAK3 抑制剂,可用于败血症的治疗。瑞士白化小鼠被用来复制CLP诱导的败血症模型,并被随机分为四组:对照组、CLP组、150毫克/千克TOFA组和300毫克/千克TOFA组。最后一次服用 TOFA 六小时后,我们采集血液和肝、肺、肾、脾组织样本进行组织学分析。血液样本用于评估粒细胞和淋巴细胞的百分比。在整个实验过程中,我们监测体重和短期存活率。我们的组织学对比分析表明,150 毫克/千克 TOFA 对多器官损伤具有保护作用。相反,该研究强调了 300 毫克/千克 TOFA 的有害作用,主要是由于该组的肝脏和肾脏毒性。总之,我们的研究结果表明,最佳剂量为 150 毫克/千克的托法替尼有望成为脓毒症诱发的多器官功能衰竭的潜在治疗干预措施。不过,在考虑更大剂量时应谨慎。
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来源期刊
Drug Research
Drug Research PHARMACOLOGY & PHARMACY-
CiteScore
3.50
自引率
0.00%
发文量
67
期刊介绍: Drug Research (formerly Arzneimittelforschung) is an international peer-reviewed journal with expedited processing times presenting the very latest research results related to novel and established drug molecules and the evaluation of new drug development. A key focus of the publication is translational medicine and the application of biological discoveries in the development of drugs for use in the clinical environment. Articles and experimental data from across the field of drug research address not only the issue of drug discovery, but also the mathematical and statistical methods for evaluating results from industrial investigations and clinical trials. Publishing twelve times a year, Drug Research includes original research articles as well as reviews, commentaries and short communications in the following areas: analytics applied to clinical trials chemistry and biochemistry clinical and experimental pharmacology drug interactions efficacy testing pharmacodynamics pharmacokinetics teratology toxicology.
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