Intrathecal Delivery of GABAmide to Reduce Spasticity

鞘内输送 GABA 酰胺以减少痉挛

• 批准号: 6338391
• 负责人: Jay Merlin Meythaler
• 金额: $ 11.49万
• 依托单位: NEURORECOVERY, INC.
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-20 至 2002-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6338391
• 关键词: antispasmodic agents; brain injury; drug design /synthesis /production; drug screening /evaluation; gamma aminobutyrate; hypertonia; injection /infusion; laboratory rat; nonhuman therapy evaluation; sensorimotor system; spasm; spinal cord injury

DESCRIPTION(Adapted from applicant's abstract): One of the most disabling sequelae to brain injury (BI), stroke, cerebral palsy (CP), spinal cord injury (SCI), spinal degenerative diseases such as multiple sclerosis (MS) and familial spastic paraparesis is the development of spastic hypertonia. The systemic delivery of gamma-amino-butyric acid (GABA) agonists has been successfully utilized for decades to reduce the spastic hypertonia. The GABA-B agonist baclofen has been delivered intrathecally into the cerebrospinal fluid surrounding the spinal cord. Side effects associated with systemic delivery are minimized with intrathecal administration. Gamma-amino-butyramide hydrochloride (GABAmide), which is an active metabolite of Progabide, is both a GABA-A as well as a GABA-B receptor agonist. We propose to conduct the final stage of pre-clinical testing of a drug, GABAmide. The effective intrathecal dose would be less than 1/100 to l /1000 of the necessary systemic delivery. Because of its broader receptor effects than baclofen, it is likely that intrathecally delivered GABAmide would be more than baclofen. Our preliminary studies in rats confirm that intrathecal GABAmide reduces spasticity at low doses. Proposed is a double-blind randomized crossover trial of intrathecally delivered GABAmide versus baclofen and normal saline in a rat model. This is to develop further knowledge on appropriate dosing and efficacy, before starting phase I human trials. PROPOSED COMMERCIAL APPLICATION: This would allow the development of a competitor to intrathecally delivered baclofen, which currently can run from $825 to over $1000 per refill kit. (pumps are refilled every one to three months). In US today, there are thousands of patients with implanted pumps that deliver intrathecal baclofen to treat disabling spastic hypertonia from SCI, MS, TBI, stroke, or CP. Development of a more effective alternative to intrathecally-delivered baclofen would allow for a significant profit and still decrease the cost of this effective treatment system.

描述（根据申请人的摘要改编）： 脑损伤（BI），中风，脑瘫最残疾的后遗症之一 （CP），脊髓损伤（SCI），脊柱退行性疾病，例如多种 硬化症（MS）和家族性痉挛性模拟是痉挛的发展 高血压。 γ-氨基丁酸（GABA）激动剂的全身递送 数十年来已成功使用以减少痉挛性高渗。 GABA-B激动剂巴氯芬已持胸表递送到 脊髓周围的脑脊液。相关的副作用 通过鞘内给药将系统性输送最小化。 γ-氨基丁胺盐酸盐（Gabamide），这是一种活性代谢物 Progabide既是GABA-A，也是GABA-B受体激动剂。我们建议 为了进行药物临床前测试的最后阶段，Gabamide。这 有效鞘内剂量将小于1/100的必要剂量 系统性交付。由于其受体效应比Baclofen更广泛，因此 固定的递送加巴酰胺可能不仅仅是巴氯芬。我们的 大鼠的初步研究证实，鞘内加巴胺会减少 低剂量的痉挛。提议的是一项双盲随机跨界试验 大鼠的固定固定递送的Gabamide与巴氯芬和正常盐水 模型。这是为了建立有关适当给药和功效的进一步知识， 在开始I阶段的人类试验之前。 拟议的商业应用： 这将使竞争对手的发展能够暂时交付Baclofen，这是 目前，每个补充工具包的价格从825美元到1000美元以上。 （每一到三个 几个月）。 今天在我们中，有成千上万的植入泵患者提供 鞘内巴氯芬治疗SCI，MS，TBI，中风或CP的残疾痉挛性高血压。 开发一种更有效的替代固定递送的baclofen的替代方法 获得可观的利润，并且仍然降低了这种有效的治疗系统的成本。