کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8538789 | 1561120 | 2018 | 11 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Preclinical evaluation of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys
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کلمات کلیدی
موضوعات مرتبط
علوم زیستی و بیوفناوری
علوم محیط زیست
بهداشت، سم شناسی و جهش زایی
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![عکس صفحه اول مقاله: Preclinical evaluation of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys Preclinical evaluation of the mono-PEGylated recombinant human interleukin-11 in cynomolgus monkeys](/preview/png/8538789.png)
چکیده انگلیسی
The mono-PEGylated recombinant human interleukin-11 (rhIL-11) was evaluated for its pharmacology and toxicology profile in non-human primates. This PEGylated IL-11 (PEG-IL11) showed a much prolonged circulating half-life of 67 h in cynomolgus monkeys as compared to its un-PEGylated counterpart (~ 3 h) through subcutaneous administration, implicating that a single injection of the recommended dose will effectively enhance thrombopoiesis in humans for a much longer period of time compared to rhIL-11 in humans (t1/2 = 6.9 h). The toxicokinetics study of single dose and multiple doses showed that systemic exposure was positively correlated with the dosing level, implying that efficacy and toxicity were mechanism-based. A single high dose at 6.25 mg/kg through subcutaneous route revealed tolerable and transient toxicity. Multiple-dose in monkeys receiving 0.3 mg/kg weekly of the drug developed only mild to moderate toxicity. Major adverse events and immunogenicity in monkeys were only observed in the overdose groups. Bones were positively impacted; while reversible toxicities in heart, liver, kidney and lung observed were likely to be consequences of fluid retention. In summary, the PEG moiety on rhIL-11 did not elicit additional toxicities, and the drug under investigation was found to be well tolerated in monkeys after receiving a single effective dose of 0.1-0.3 mg/kg through subcutaneous delivery, which may be allometrically scaled to a future clinical dose at 30-100 μg/kg, creating a potential long acting, safer, and more convenient treatment approach based on rhIL-11.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Toxicology and Applied Pharmacology - Volume 342, 1 March 2018, Pages 39-49
Journal: Toxicology and Applied Pharmacology - Volume 342, 1 March 2018, Pages 39-49
نویسندگان
Kuo-Ming Yu, Johnson Yiu-Nam Lau, Manson Fok, Yuk-Keung Yeung, Siu-Ping Fok, Suxing Zhang, Peizhen Ye, Kezhi Zhang, Xiaobo Li, Juan Li, Qin Xu, Wing-Tak Wong, Qui-Lim Choo,