School of Pharmaceutical Sciences , University of Geneva & University of Lausanne , CMU - 1 rue Michel Servet , 1211 Geneva 4 , Switzerland.
Apidel SA, 29 Quai du Mont Blanc , 1201 Geneva , Switzerland.
Mol Pharm. 2018 Mar 5;15(3):1192-1202. doi: 10.1021/acs.molpharmaceut.7b01028. Epub 2018 Feb 15.
The objective was to investigate whether mineralocorticoid receptor antagonism using a novel topical micellar formulation of spironolactone could prevent glucocorticoid-induced delayed corneal wound healing in New Zealand white rabbits. Spironolactone micelles (0.1%, w/v) with a mean number weighted diameter of 20 nm were prepared using a pegylated copolymer (mPEG-dihexPLA) and showed a preliminary stability of at least 12 months at 5 °C. Preclinical studies in New Zealand white rabbits demonstrated that the 0.1% spironolactone micellar formulation was well-tolerated since no reaction was observed in the cornea following multiple daily instillation over 5 days. As expected, the preclinical studies also confirmed that dexamethasone significantly delayed epithelial wound healing as compared to untreated control (percentage re-epithelialization after day 4: 84.6 ± 13.9% versus 99.5 ± 1.0% for the control, p < 0.05). However, the addition of the 0.1% spironolactone micellar formulation significantly improved the extent of re-epithelialization, countering the dexamethasone induced delayed wound healing with a percentage re-epithelialization that was statistically equivalent to the control (96.9 ± 7.3% versus 99.5 ± 1.0%, p > 0.05). The biodistribution study provided insight into the ocular metabolism of spironolactone and hence the relative contributions of the parent molecule and its two principal metabolites, 7α-thiomethylspironolactone and canrenone, to the observed pharmacological effects. Comparison of the efficacies of spironolactone and potassium canrenoate (a water-soluble precursor of canrenone) in overcoming the dexamethasone-induced delayed wound healing confirmed that the former had greater efficacy. The results pointed to the greater potency of 7α-thiomethylspironolactone over canrenone as a mineralocorticoid receptor antagonist, which explained its superior ability in countering the glucocorticoid-induced overactivation that was responsible for the delayed wound healing. In conclusion, the preliminary results supported the above-mentioned hypothesis suggesting that coadministration of mineralocorticoid receptor antagonists to patients under glucocorticoid therapy might prevent the deleterious effects of glucocorticoids on complex corneal wound healing processes.
目的是研究一种新型局部米糠醇螺内酯能否预防糖皮质激素诱导的新西兰白兔角膜延迟愈合。螺内酯胶束（0.1%，w/v）的平均数加权直径为 20nm，采用聚乙二醇化共聚物（mPEG-二己 PLA）制备，在 5°C 下至少稳定 12 个月。新西兰白兔的临床前研究表明，0.1%螺内酯胶束制剂耐受性良好，因为在连续 5 天每天多次滴注后，角膜无反应。正如预期的那样，临床前研究还证实，与未治疗的对照组相比，地塞米松显著延迟上皮伤口愈合（第 4 天的再上皮化百分比：84.6±13.9%与对照组的 99.5±1.0%相比，p<0.05）。然而，添加 0.1%螺内酯胶束制剂显著改善了再上皮化程度，对抗了地塞米松诱导的延迟伤口愈合，再上皮化百分比与对照组统计学等效（96.9±7.3%与对照组的 99.5±1.0%相比，p>0.05）。生物分布研究提供了螺内酯的眼部代谢以及母体分子及其两种主要代谢物 7α-硫甲基螺内酯和坎利酮对观察到的药理作用的相对贡献的见解。比较螺内酯和钾坎利酮（坎利酮的水溶性前体）在克服地塞米松诱导的延迟伤口愈合中的功效，证实前者的功效更大。结果表明，7α-硫甲基螺内酯作为盐皮质激素受体拮抗剂的效力大于坎利酮，这解释了其在对抗糖皮质激素诱导的过度激活方面的优越能力，这种过度激活是导致延迟伤口愈合的原因。总之，初步结果支持了上述假设，即糖皮质激素治疗患者联合使用盐皮质激素受体拮抗剂可能预防糖皮质激素对复杂角膜伤口愈合过程的有害影响。
