Delivery of peptides for inducing voiding associated with neurological retention

递送肽以诱导与神经滞留相关的排尿

• 批准号: 8905338
• 负责人: LESLEY MARSON
• 金额: $ 22.49万
• 依托单位: DIGNIFY THERAPEUTICS, LLC
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-15 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8905338
• 关键词: Acute; Adverse effects; Affect; Agonist; Biological Assay; Bladder; Blood Circulation; Buffers; Calcitonin; Canis familiaris; Catheterization; Catheters; Cholinergic Agonists; Climacteric; Community Healthcare; Data; Data Analyses; Desmopressin; Development; Diabetes Mellitus; Dose; Drug Delivery Systems; Drug Formulations; Drug Kinetics; Enhancers; Evaluation; Experimental Designs; Feces; Film; Glycerol; Goals; Grant; Health; Health Care Costs; Health Status; Hospitalization; Human; Humidity; In Vitro; Incidence; Incontinence; Individual; Intestines; Intranasal Administration; Ionic Strengths; Life; Marketing; Measures; Mental Depression; Mental Health; Methods; Methylcellulose; Micturition Reflex; Modeling; Multiple Sclerosis; Neurogenic Bladder; Neurokinin A; Neurologic; Osmolalities; Output; Oxytocin; Parkinson' s Dementia; Pathway interactions; Patients; Peptides; Performance; Peripheral; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Pharmacotherapy; Phase; Plasticizers; Polymers; Pre-Clinical Model; Program Development; Quality of life; Rattus; Rectum; Safety; Sepsis; Site; Smooth Muscle; Software Design; Solvents; Spinal; Spinal Dysraphism; Spinal cord injury; Stroke; Substance K Receptor; TAC1 gene; Temperature; Testing; Therapeutic; Thick; Time; Urethra; Urinary Retention; Urinary tract infection; Urination; Urine; Variant; Work; absorption; analog; aqueous; awake; base; clinically relevant; cost; design; diabetic rat; dosage; human tissue; improved; in vivo; novel; phase 2 study; physical conditioning; physical property; pre-clinical; professor; public health relevance; rapid technique; receptor; research study; success

 DESCRIPTION (provided by applicant): Neurological conditions, such as multiple sclerosis, Parkinson's disease, dementia, spina bifida, diabetes, stroke, and spinal cord injury (SCI); can result in loss of voluntary control over bladder and bowel function, often producing both incontinence and retention of urine and stools in the same patient. This has a profound impact on the mental and physical health status and quality of life of patients as well as a large impact on health care costs. For example, urinary retention is generally irreversible and can be life threatening. The only available pharmacotherapy consists of cholinergic agonists, which have minimal efficacy and severe side effects. Consequently, patients catheterize themselves multiple times daily to empty their bladder. Catheter use is associated with increased incidence of urinary tract infections, sepsis, isolation, depression and hospitalization. An 'on demand', saf and effective, pharmaceutical alternative to catheterization would be a life-changing improvement in the daily routine of bladder management for patients, not to mention a significant reduction in individual and community health care costs. Similarly, 'on-demand' bowel control would provide substantial improvement in 'quality of life' for people with neurogenic bowel. Dignify Therapeutics is developing an 'on-demand, rapid-onset, short-duration, drug-induced voiding' therapy using an analogue of neurokinin A - [Lys5,MeLeu9,Nle10]-NKA(4-10) - (aka DTI-100). DTI-100 is a potent and selective agonist of the NK2 receptor, which induces powerful contractions of the human bladder and rectum in vitro and provides highly promising in vivo efficacy, safety, and pharmacodynamic (PD) profiles in various dog and rat models (spinal intact, SCI, and diabetes) following IV administration. Presently, the overarching objective of its development program is to discover a formulation that is more convenient for people with neurological conditions but maintains the therapeutic benefit of the IV formulation. The specific aims of the current Phase I application are to examine the suitability of an intranasal (IN) formulation and an orally- dissolving film (ODF) formulation. Based on previous work with systemic delivery of similar peptides from each of the formulations, it is anticipated that either may provide a stable dosage that provides rapid release, systemic absorption, and PD activity. The specific aims of this Phase I application are to compare stability and release rates of each formulation containing various media and to compare the in vivo activity of the most optimized formulations using a simple, but clinically relevant, anesthetized, acute spinal rat cystometry model. If positive results are obtained, detailed pharmacokinetic studies and testing in additional species and neuropathological models are proposed for Phase II studies.

 描述（由申请人提供）：神经系统疾病，如多发性硬化症、帕金森病、痴呆、脊柱裂、糖尿病、中风和脊髓损伤（SCI）;可导致对膀胱和肠功能的自主控制丧失，通常在同一患者中产生尿失禁和尿便潴留。这对患者的身心健康状况和生活质量产生了深远的影响，对医疗保健费用也产生了很大的影响。例如，尿潴留通常是不可逆的，并且可能危及生命。唯一可用的药物治疗包括胆碱能激动剂，其具有最小的功效和严重的副作用。因此，患者每天多次导尿以排空膀胱。导尿管的使用与尿路感染、败血症、隔离、抑郁和住院的发生率增加有关。一个“按需”，安全和有效的，药物替代导尿管将是一个改变生活的改善日常膀胱管理的病人，更不用说显着减少个人和社区的医疗保健费用。同样，“按需”排便控制将为神经性肠道患者的“生活质量”提供实质性改善。Dignify Therapeutics正在开发一种使用神经激肽A - [Lys 5，MeLeu 9，Nle 10]-NKA（4-10）-（又名DTI-100）类似物的“按需，快速起效，短持续时间，药物诱导的排尿”疗法。DTI-100是NK 2受体的强效和选择性激动剂，其在体外诱导人膀胱和直肠的强力收缩，并在IV给药后在各种犬和大鼠模型（脊柱完整、SCI和糖尿病）中提供非常有希望的体内疗效、安全性和药效学（PD）特征。目前，其总体目标是 开发计划的目的是发现一种对患有神经系统疾病的人更方便但保持IV制剂的治疗益处的制剂。当前I期申请的具体目的是检查鼻内（IN）制剂和口腔溶解膜（ODF）制剂的适用性。基于先前对来自每种制剂的类似肽的全身递送的研究，预期任一种都可以提供稳定的剂量，其提供快速释放、全身吸收和PD活性。该I期申请的具体目的是比较含有各种介质的每种制剂的稳定性和释放速率，并使用简单但临床相关的麻醉急性脊髓大鼠膀胱测压模型比较最优化制剂的体内活性。如果获得阳性结果，则需要进行详细的药代动力学研究和额外的检测。 物种和神经病理学模型提出了第二阶段的研究。