Evaluation of VBP15 a dissociative steroidal analogue on pain and inflammation

解离性类固醇类似物 VBP15 对疼痛和炎症的评价

• 批准号: 8722797
• 负责人: Jesse Damsker
• 金额: $ 22.5万
• 依托单位: REVERAGEN BIOPHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-23 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8722797
• 关键词: Acute Pain; Adherence; Adrenal Cortex Hormones; Adverse effects; Affect; Analgesics; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Biochemical; Biological Assay; Blinded; Blood Vessels; Brain; Cell Adhesion Molecules; Child; Clinical Trials; Collaborations; Data; Dexamethasone; Disease; Duchenne muscular dystrophy; Emergency Situation; Evaluation; Fiber; Fright; Future; Glucocorticoids; Goals; Histologic; Hospital Costs; Hospitalization; Human; Hyperalgesia; Hypoxia; Incidence; Inflammation; Inflammatory; Intervention; Kidney; Lead; Leukocytes; Lung; Measures; Mediating; Membrane; Methylprednisolone; Modeling; Morbidity - disease rate; Mus; Muscular Dystrophies; NF-kappa B; Necrosis; Nerve Fibers; Nociception; Opioid; Organ; Outcome; Outcome Measure; Pain; Pain Measurement; Pathology; Patients; Pharmaceutical Preparations; Phase I Clinical Trials; Phenotype; Property; Provider; Publishing; Recommendation; Research Personnel; Risk; Role; Safety; Sensory; Sickle Cell; Sickle Cell Anemia; Small Business Technology Transfer Research; Spleen; Steroids; Stroke; Symptoms; Testing; Therapeutic; Therapeutic Intervention; Therapeutics for Rare and Neglected Diseases; Time; Transactivation; Translations; United States National Institutes of Health; Up-Regulation; Visit; acute chest syndrome; afferent nerve; analog; care delivery; cytokine; health disparity; hospital readmission; inflammatory marker; man; mortality; mouse model; pain behavior; patient population; preclinical efficacy; preclinical evaluation; preclinical study; prednisolone; programs; public health relevance; response; sickling; vaso-occlusive pain

DESCRIPTION (provided by applicant): The treatment of pain in Sickle Cell Disease (SCD) is challenging for both patients and providers and is associated with significant disparities in healt care delivery. While the role of ongoing inflammation during vasooclusive crisis and pain is recognized, effective therapeutic interventions are lacking. Glucocorticoids, with their anti-inflammatory properties, in small clinical trials have been shown to reduce the duration of analgesic therapy in children with pain crisis, and in SCD patients admitted with acute chest syndrome, a course of dexamethasone decreased hospitalization time. However, clinicians hesitate to prescribe steroids to treat steroid-responsive conditions in SCD patients because their use is associated with complications that include increased risk of hospital readmission, rebound pain, strokes, avascular necrosis, and acute chest syndrome. Further, some steroid-responsive conditions such as asthma have a high incidence in SCD; however, because of known side-effects, clinicians hesitate to use disease-altering therapies such as steroids in SCD patients. In turn, SCD patients who have steroid-responsive conditions may receive less than ideal treatment. VBP15 is a first-in-man dissociative steroid that has optimized sub-activities of more traditional glucocorticoids, with increased efficacy and reduced side effects. VBP15 retains NFKB inhibition (transrepression) but loses GRE-mediated transactivation activities associated with side effect profiles of clinically used steroids. Preliminary data shows that VBP15 has the potential to favorably affect the alterations in pain response and some hematologic and histopathologic alterations observed in a murine model of SCD. The goal of this STTR proposal is to carry out a preclinical efficacy study of VBP15 to treat the altered pain response and to ameliorate the abnormal hematologic, biochemical, and inflammatory profiles in SCD mice.

描述（由申请人提供）：镰状细胞病（SCD）疼痛的治疗对患者和提供者都具有挑战性，并且与医疗保健服务的显著差异有关。虽然持续炎症在血管闭塞危象和疼痛中的作用已被认识，但缺乏有效的治疗干预。具有抗炎特性的糖皮质激素在小型临床试验中已被证明可缩短疼痛危象儿童的镇痛治疗持续时间，在因急性胸部综合征入院的SCD患者中，地塞米松疗程可缩短住院时间。然而，临床医生不愿意开类固醇来治疗SCD患者的类固醇反应性疾病，因为它们的使用与并发症有关，包括再入院、反跳痛、中风、缺血性坏死和急性胸部综合征的风险增加。此外，一些类固醇反应性疾病（例如哮喘）在SCD中的发病率很高;然而，由于已知的副作用，临床医生不愿在SCD患者中使用类固醇等改变疾病的疗法。反过来，患有类固醇反应性疾病的SCD患者可能接受不到理想的治疗。VBP 15是一种首次用于人体的解离性类固醇，具有更传统的糖皮质激素的优化子活性，具有更高的疗效和更低的副作用。VBP 15保留NF κ B抑制（反式阻遏），但失去与临床使用的类固醇的副作用谱相关的GRE介导的反式激活活性。初步数据显示，VBP 15具有有利地影响在SCD的鼠模型中观察到的疼痛反应的改变和一些血液学和组织病理学改变的潜力。该STTR提案的目标是进行VBP 15的临床前有效性研究，以治疗SCD小鼠中改变的疼痛反应并改善异常的血液学、生化和炎症特征。

项目成果

The corticosteroid compounds prednisolone and vamorolone do not alter the nociception phenotype and exacerbate liver injury in sickle cell mice.

• DOI: 10.1038/s41598-018-24274-6
• 发表时间: 2018-04-17
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Almeida LEF;Damsker JM;Albani S;Afsar N;Kamimura S;Pratt D;Kleiner DE;Quezado M;Gordish-Dressman H;Quezado ZMN
• 通讯作者: Quezado ZMN