Development of a first-in-class therapeutic for producing 'on-demand' voiding

项目摘要(摘要) 衰老和糖尿病，以及许多神经系统疾病，如多发性硬化症、帕金森氏症 疾病、脊柱裂、中风和脊髓损伤(SCI)可导致随意排尿和 需要间歇性导尿才能排尿。导管的使用与发病率的增加有关 健康问题，主要是反复尿路感染、败血症、尿路创伤和 住院治疗。一种短效、有效和安全的产品，可以“按需”排尿，可以提供 神经原性膀胱管理的范式转变，可以减少或消除 间歇性导尿术。 Diguify Treeutics正在开发一种新的药物治疗方法DTI-100，以提供一种“按需、快速起效、 短期、药物诱导的排尿疗法“适用于那些不能自愿排尿的人。当给药时 DTI-100对大鼠、狗和小型猪静脉注射或皮下注射快速诱发膀胱 排尿。然而，静脉和SC给药途径对于每天多次给药可能是不切实际的 神经原性膀胱症患者需要使用。因此，鼻腔(IN)和口腔崩解 DTI-100的片剂(ODT)正在开发中。初步研究表明，有效的 使用ODT和IN均可实现血药浓度和剂量依赖性的膀胱收缩 配方。 这一快速通道SBIR方案的第一阶段将使用重复剂量和排尿效率测量 在有意识的小型猪中，具有与人类相似的皮下、鼻和口腔组织的物种，以识别 未来临床研究中使用的首选配方和给药途径(IN或ODT)。同相 2、该配方将根据FDA监管指南进行优化和生产。这个 优化后的最终配方将用于小型猪和大鼠的临床前体内试验，以 描述药理作用机制，以及强制性的一般毒性研究 需要提交研究用新药(IND)申请和在#年启动研究 人类。在适当的支持下，我们的产品可以作为治疗剂在未来五到五年内上市 七年了。

PROJECT SUMMARY (ABSTRACT) Aging and diabetes, as well as many neurological conditions, such as multiple sclerosis, Parkinson's disease, spina bifida, stroke, and spinal cord injury (SCI), can result in loss of voluntary voiding of urine and require intermittent bladder catheterization for voiding. Catheter use is associated with increased incidence of health problems, predominately repeated urinary tract infections, sepsis, urethral trauma and hospitalization. A short-acting, effective, and safe product that induces “on-demand” voiding would provide a paradigm shift in the management of neurogenic bladder and could reduce or eliminate the need for intermittent catheterization. Dignify Therapeutics is developing a novel drug treatment, DTI-100, to provide an “on-demand, rapid-onset, short-duration, drug-induced, voiding therapy” for those who cannot void voluntarily. When administered intravenously (IV) or subcutaneously (SC) to rats, dogs, and minipigs, DTI-100 rapidly induces bladder voiding. However IV and SC routes of administration may be impractical for the multiple daily dosing that will be required by individuals with neurogenic bladder. Therefore, intranasal (IN) and orally-disintegrating tablet (ODT) formulations of DTI-100 are being developed. Preliminary studies have shown that efficacious plasma concentrations and dose-dependent bladder contractions can be achieved using both ODT and IN formulations. Phase 1 of this fast-track SBIR proposal will use repeated dosing and measurements of voiding efficiency in conscious minipigs, a species with subcutaneous, nasal, and oral tissues similar to humans, to identify the preferred formulation and route of administration (IN or ODT) for use in future clinical studies. In Phase 2, this formulation will be optimized and manufactured according to FDA regulatory guidelines. The optimized final formulation will then be used for preclinical in vivo testing in minipigs and rats to characterize the pharmacological mechanism of action, as well as for mandatory general toxicity studies required for submission of an investigational new drug (IND) application and the initiation of studies in humans. With proper support, our product could be available as a therapeutic agent with the next five to seven years.