A Phase II trial of topical sodium nitrite in patients with sickle cell disease and leg ulcers

摘要 长期以来，腿部溃疡一直被认为是镰状细胞病的一种严重的、使人虚弱的并发症。 第一例SCD患者于1910年在北美被描述为腿部溃疡。流行率各不相同， 10岁前低，除SS外，其余各型均为低。它受地理位置的影响，有 在牙买加，SS患者的发病率高达75%，在北美，发病率为8%-10%。慢性阻塞性肺疾病的病因学 SCD和其他溶血性疾病中的溃疡是未知的-致密的镰状红细胞造成的机械性梗阻， 静脉压升高，细菌感染，自主神经控制异常，血管过度收缩 在依赖体位时，贫血程度与携氧能力下降均为 被认为是潜在的促成因素。 尽管取得了进展，但慢性小腿溃疡的发病率仍然是SCD患者的重大临床负担 使用羟基脲等疾病改良剂、输血和改善支持性护理。 镰状细胞病和腿部溃疡的患者有更严重的溶血性贫血的生物标志物，这是一种状态 与一氧化氮的生物利用度低有关。现有的治疗SCD溃疡的方法是 并不令人满意，而且主要是基于对普通人群中静脉和动脉溃疡的治疗。一个 Cochrane最近的综述确定了仅有六项针对镰状细胞病腿部疾病的前瞻性随机治疗试验 在过去的30年里--牙买加有4例，美国有2例。结果好坏参半；具有统计学意义 仅报道了局部应用Arg-Gly-Asp(RGD)多肽和静脉注射精氨酸可增加伤口闭合率 丁酸盐。由于这些药物仍处于早期药物开发阶段，患者几乎没有治疗选择。 可用。我们在广泛发表的文献的基础上选择了亚硝酸钠用于临床开发。 关于静脉和口服给药的安全性，其血管扩张特性，以及初步的 酸化亚硝酸盐治疗其他慢性皮肤溃疡患者的疗效报告。 在动物中，亚硝酸钠治疗促进缺血肢体的血运重建，保护缺血 心脏、肝脏和大脑的梗塞，并对心脏骤停介导的心脏和 脑部受伤。亚硝酸盐阴离子在体内通过在低氧组织中产生一氧化氮而起到血管扩张剂的作用。 张力和酸碱度，这些情况很可能出现在慢性伤口中。这个机制涉及到氧气- 血红蛋白或黄嘌呤氧化还原酶的亚硝酸还原酶活性依赖和pH依赖。 实验模型表明，一氧化氮在伤口愈合的早期和后期都有有益的作用。 包括增加细胞外基质的产生，免疫反应的调节和刺激 角质形成细胞的增殖、血管生成和杀菌特性。一氧化氮介导的必需物质 血管内稳态，包括血管扩张和抗血小板活性，并影响几种生长因子 参与内皮细胞的动态平衡。 我们已经完成了18例成人镰状细胞患者的剂量递增、安全性和耐受性的1期研究。 贫血和腿部溃疡。未发生3-4级不良事件、严重不良事件或剂量限制副反应。 效果。药代动力学分析显示亚硝酸钠的全身吸收较低。外用药物的应用 亚硝酸钠与伤口周围皮肤血流量的显著增加有关 激光散斑对比成像和通过红外热像仪增加伤口周围皮肤温度。 有趣的是，腿部溃疡大小(p=0.0012)和溃疡相关疼痛呈剂量依赖性减少。 (宝洁0.0001)。接受了最高浓度外用药物的三名患者的溃疡完全愈合 亚硝酸钠(1.8%和2%的奶油)。对疼痛的事后分析显示疼痛程度降低 (P=0.0048)和疼痛干预(P=0.0013)。 基于这些令人鼓舞的结果，我们建议进行一项前瞻性、双盲、随机的第二阶段试验。 其目标是： 1.进一步评估延长(10周)，每周两次的安全性和耐受性 外用亚硝酸钠在成人镰状细胞病和小腿疾病中的应用 一项随机、双盲、安慰剂对照的II期试验。 2.确定外用亚硝酸钠在促进创面愈合和 在接受类似治疗的患者中，与安慰剂相比，伤口处的疼痛有所减轻 伤口护理水平。 3.提高我们对腿部溃疡形成和延迟的病理生物学的认识 SCD患者的愈合情况。

Abstract Leg ulcerations have long been identified as a serious and debilitating complication of sickle cell disease (SCD).The first SCD patient described in North America in 1910 had leg ulcerations. Prevalence varies, being low before 10 years of age and in genotypes other than SS. It is influenced by geographical location, with occurrence as high as 75% in SS patients in Jamaica, and 8-10% in North America. The etiology of chronic ulcers in SCD and other hemolytic disorders is unknown - mechanical obstruction by dense sickled red cells, increased venous pressure, bacterial infections, abnormal autonomic control with excessive vasoconstriction when in dependent position, degree of anemia with decrease in oxygen carrying capacity, have all been proposed as potential contributing factors. Morbidity from chronic leg ulcers remains a substantial clinical burden in patients with SCD despite advances in care with disease-modifying agents such as hydroxyurea, blood transfusions, and improved supportive care. Patients with sickle cell disease and leg ulcers have biomarkers of more severe hemolytic anemia, a state associated with low bioavailability of nitric oxide. Existing therapeutic approaches for SCD ulcers are unsatisfactory, and are mostly based on treatments for venous and arterial ulcers in the general population. A recent Cochrane review identified only six prospective, randomized therapeutic trials for sickle cell disease leg ulcers over the past 30 years—four in Jamaica and two in the USA. Results were mixed; statistically significant increases in wound closure were reported only for topical Arg-Gly-Asp (RGD) peptide and intravenous arginine butyrate. As these agents remain in early-phase drug development, patients have few therapeutic options available. We selected sodium nitrite for clinical development on the basis of the extensive published literature about its safety profile when administered intravenously and orally, its vasodilating properties, and preliminary reports of the efficacy of acidified nitrite in the treatment of other patient populations with chronic skin ulcers. In animals, sodium nitrite therapy promotes revascularization of ischemic limbs, protects against ischemic infarction of the heart, liver, and brain, and has a protective effect against cardiac arrest-mediated heart and brain injury. The nitrite anion acts as a vasodilator in vivo by generating nitric oxide in tissues with low oxygen tension and pH, conditions which are likely to be present in chronic wounds. The mechanism involves oxygen- dependent and pH-dependent nitrite reductase activity of hemoproteins or xanthine oxidoreductase. Experimental models suggest beneficial effects of nitric oxide in the early and late phases of wound healing, including increased extracellular matrix production, immune response modulation, and stimulation of keratinocyte cell proliferation, angiogenesis, and bactericidal properties. Nitric oxide mediates essential vascular homoeostasis, including vasodilation, and antiplatelet activity, and affects several growth factors involved in endothelial homoeostasis. We have completed a dose escalation, safety and tolerability phase 1 study in 18 adult patients with sickle cell anemia and leg ulcers. There were no grade 3–4 adverse events serious adverse events or dose-limiting side- effects. Pharmacokinetic analysis showed low systemic absorption of sodium nitrite. Application of topical sodium nitrite was associated with a significant increase in peri-wound cutaneous blood flow measured by laser speckle contrast imaging and increased peri-wound skin temperature by infrared thermography. Interestingly, there was a dose-dependent decrease in leg ulcer size (p=0.0012) and ulcer associated pain (p<0.0001). Ulcers healed completely in three patients who received the highest concentrations of topical sodium nitrite (the 1.8% and 2% cream). Post-hoc analysis of pain revealed decreased pain severity (p=0.0048) and pain interference (p=0.0013). On the basis of these encouraging results we propose a prospective, double blinded, randomized Phase II trial which aims at: 1. Further evaluate the safety and tolerability of prolonged (10 weeks), twice a week application of topical sodium nitrite in adult patients with sickle cell disease and leg ulcers in a randomized, double blind, placebo controlled Phase II trial. 2. Determine the effectiveness of topical sodium nitrite in accelerating wound healing and decrease pain at the wound site compared to placebo in patients receiving similar levels of wound care. 3. Improve our understanding of the pathobiology of leg ulcer formation and delayed healing in patients with SCD.