Cam M C, Cros G H, Serrano J J, Lazaro R, McNeill J H
Division of Pharmacology and Toxicology, Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, Canada.
Diabetes Res Clin Pract. 1993 May;20(2):111-21. doi: 10.1016/0168-8227(93)90004-o.
The vanadyl (+IV) form of vanadium has been demonstrated to have insulin-mimetic activity in vivo. In an effort to improve the poor gastrointestinal absorption of the ion, an organic complex of vanadyl (naglivan) was synthesized. We tested the antidiabetic effects of naglivan in rats made diabetic with streptozotocin (55 mg/kg, i.v.). Four days after the streptozotocin injection, one diabetic group (DVI) and a control group (CV) were treated with naglivan (50 mg/kg/day, equivalent to 0.06 mmol vanadium/kg/day) by oral gavage. Treatment in the DVI group was supplemented with daily insulin while a second diabetic group (DI) was administered daily titrated doses of insulin alone (Protamine Zinc, s.c.) to achieve stable euglycemia. The dose of exogenous insulin required to maintain normal glucose was significantly lower in the DVI group compared to the DI throughout the treatment period. At the end of week 3, exogenous insulin was withdrawn from both the DVI and DI groups, while naglivan treatment was continued in the CV and DVI groups for an additional 5 weeks. At termination, hearts were isolated and cardiac function (+dP/dt, -dP/dt and left ventricular developed pressure) was assessed in all the animals. After insulin was withdrawn, 4/8 DVI animals which continued to receive naglivan had consistent normoglycemia (as determined by % glycosylated hemoglobin) and an improved cardiac function. All the DI animals and 4/8 DVI rats were hyperglycemic and had depressed heart function despite having similar plasma insulin levels to the euglycemic DVI animals. As with vanadyl sulfate, there were no signs of long-term toxicity with regards to renal or liver function after 8 weeks of treatment. Thus, naglivan is an orally effective form of vanadyl with an oral potency 7.6 times greater than that of vanadyl sulfate (minimum effective dose: 0.06 mmol vanadium.kg-1.day-1) as compared to vanadyl sulfate (0.46 mmol vanadium.kg-1.day-1). The lack of incidence of diarrhea in either control or diabetic animals demonstrates that naglivan could be a more therapeutically desirable form of vanadyl.
钒的正四价氧钒形式已被证明在体内具有胰岛素模拟活性。为了改善该离子较差的胃肠道吸收情况，合成了一种氧钒有机复合物（那格列钒）。我们在经链脲佐菌素（55毫克/千克，静脉注射）诱导糖尿病的大鼠中测试了那格列钒的抗糖尿病作用。链脲佐菌素注射4天后，一个糖尿病组（DVI）和一个对照组（CV）通过口服灌胃给予那格列钒（50毫克/千克/天，相当于0.06毫摩尔钒/千克/天）。DVI组的治疗补充了每日胰岛素，而第二个糖尿病组（DI）单独给予每日滴定剂量的胰岛素（精蛋白锌胰岛素，皮下注射）以实现稳定的血糖正常。在整个治疗期间，与DI组相比，DVI组维持正常血糖所需的外源性胰岛素剂量显著更低。在第3周结束时，从DVI组和DI组中都撤掉了外源性胰岛素，而CV组和DVI组继续进行那格列钒治疗额外5周。在实验结束时，分离出心脏并评估所有动物的心脏功能（+dP/dt、-dP/dt和左心室舒张末压）。撤掉胰岛素后，继续接受那格列钒治疗的8只DVI动物中有4只血糖持续正常（通过糖化血红蛋白百分比确定）且心脏功能得到改善。所有DI组动物和8只DVI大鼠中的4只尽管血浆胰岛素水平与血糖正常的DVI动物相似，但仍出现高血糖且心脏功能降低。与硫酸氧钒一样，治疗8周后在肾功能或肝功能方面没有长期毒性迹象。因此，那格列钒是一种口服有效的氧钒形式，与硫酸氧钒（0.46毫摩尔钒/千克/天）相比，其口服效力比硫酸氧钒高7.6倍（最小有效剂量：0.06毫摩尔钒/千克/天）。在对照组或糖尿病动物中腹泻发生率均未出现，这表明那格列钒可能是一种更具治疗优势的氧钒形式。
