RJX 可改善糖尿病大鼠的伤口愈合。
RJX Improves Wound Healing in Diabetic Rats.
机构信息
Drug Discovery Program, Reven Pharmaceuticals, Westminster, CO, United States.
Department of Developmental Therapeutics, Immunology, and Integrative Medicine, Ares Pharmaceuticals, St. Paul, MN, United States.
出版信息
Front Endocrinol (Lausanne). 2022 Jun 2;13:874291. doi: 10.3389/fendo.2022.874291. eCollection 2022.
BACKGROUND
We recently reported the clinical safety profile of RJX, a well-defined intravenous GMP-grade pharmaceutical formulation of anti-oxidant and anti-inflammatory vitamins as active ingredients, in a Phase 1 study in healthy volunteers (ClinicalTrials.gov Identifier: NCT03680105) (Uckun et al., Front. Pharmacol. 11, 594321. 10.3389/fphar.2020.594321). The primary objective of the present study was to examine the effects of GMP-grade RJX on wound and burn injury healing in diabetic rats.
METHODS
In the present study, a rat model of T2DM was used that employs HFD in combination with a single injection of STZ intraperitoneally (i.p) at a moderate dose level (45 mg/kg). Anesthetized diabetic rats underwent full-thickness skin excision on the back or were subjected to burn injury a heated brass probe and then started on treatments with normal saline (NS = vehicle) or RJX administered intraperitoneal injections for three weeks.
FINDINGS
Notably, diabetic rats treated with the 1.25 mL/kg or 2.5 mL/kg RJX (DM+RJX groups) rapidly healed their wounds as fast as non-diabetic control rats. Inflammatory cell infiltration in the dermis along with fibrin and cell debris on the epithelial layer persisted for up to 14 days in the DM+NS group but not in RJX-treated groups. The histopathological score of wound healing on days 7 and 14 was better in diabetic rats treated with RJX than diabetic rats treated with NS and comparable to the scores for non-diabetic healthy rats consistent with an accelerated healing process. The residual wound area of RJX-treated rats was significantly smaller than that of NS-treated diabetic rats at each evaluation time point (P<0.001). The accelerating effect of RJX on diabetic wound healing was dose-dependent. We obtained similar results in the burn injury model. Our results demonstrate that RJX - at a dose level >10-fold lower than its clinical maximum tolerated dose (MTD) - accelerates the healing of excision wounds as well burn injury in diabetic rats.
背景
我们最近报告了 RJX 的临床安全性概况，RJX 是一种经过良好定义的静脉内 GMP 级别的抗氧化和抗炎维生素药物制剂，作为活性成分，在健康志愿者的 I 期研究中（ClinicalTrials.gov 标识符：NCT03680105）（Uckun 等人，Front. Pharmacol. 11, 594321. 10.3389/fphar.2020.594321）。本研究的主要目的是研究 GMP 级 RJX 对糖尿病大鼠创伤和烧伤愈合的影响。
方法
本研究采用 T2DM 大鼠模型，该模型采用高脂肪饮食（HFD）与腹腔内（i.p）单次注射中等剂量 STZ（45mg/kg）相结合。麻醉后的糖尿病大鼠背部进行全层皮肤切除，或用加热的黄铜探头进行烧伤，然后开始用生理盐水（NS=载体）或 RJX 进行腹腔注射治疗，持续 3 周。
结果
值得注意的是，用 1.25ml/kg 或 2.5ml/kg RJX（DM+RJX 组）治疗的糖尿病大鼠的伤口愈合速度与非糖尿病对照大鼠一样快。在 DM+NS 组中，真皮中的炎症细胞浸润以及上皮层中的纤维蛋白和细胞碎片持续长达 14 天，但在 RJX 治疗组中则不然。用 RJX 治疗的糖尿病大鼠的伤口愈合组织学评分在第 7 天和第 14 天均优于用 NS 治疗的糖尿病大鼠，与非糖尿病健康大鼠的评分相当，表明愈合过程加快。在每个评估时间点，用 RJX 治疗的大鼠的残余伤口面积均明显小于用 NS 治疗的糖尿病大鼠（P<0.001）。RJX 对糖尿病伤口愈合的加速作用呈剂量依赖性。我们在烧伤模型中获得了类似的结果。我们的结果表明，RJX - 剂量水平比其临床最大耐受剂量（MTD）高 10 倍以上 - 可加速糖尿病大鼠的切伤愈合和烧伤愈合。
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