Clavulanic acid: a potential abuse-deterrent and CNS-active therapeutic

描述（由申请人提供）：b-内酰胺抗生素头孢曲松（CTX）显示出令人惊讶的抗谷氨酸作用。这导致其被鉴定为治疗CNS疾病的有希望的候选物。然而，医生和神经科学家越来越担心的是，CTX产生无法忍受的副作用，这将限制其作为CNS活性治疗剂的效用。问题是，在没有脑膜炎的情况下，CTX显示出很差的脑穿透性。因此，必须给予大剂量的CTX以实现抗谷氨酸作用，这是其对CNS疾病的功效的基础。这些大剂量增加了患者不良反应的风险。我们推测，一个有吸引力的替代CTX治疗是b-内酰胺酶抑制剂克拉维酸。CTX和克拉维酸都含有一个中心β-内酰胺环。β-内酰胺环是抗谷氨酸活性所必需的，因为含有该环的抗生素增强谷氨酸摄取，而缺少该环的抗生素则无效。与CTX相比，克拉维酸显示出几个有吸引力的特征，即增强的脑渗透性、在低100倍剂量下在动物中的CNS活性、可忽略的抗菌活性和更容易的给药途径（口服与血管内CTX）。我们的临床前实验提供了一个原理证明，即克拉维酸模拟CTX对谷氨酸过度传递引起的CNS疾病的疗效。两种b-内酰胺化合物在体外和体内测定中都显示出抗谷氨酸活性。它们还破坏啮齿动物的吗啡镇痛耐受性和可卡因自我给药，并在无脊椎动物中显示抗癫痫样活性。具体目标是：1）比较CLAV和CTX在耐受性、依赖性和成瘾性动物模型中的作用; 2）比较CLAV和CTX对药物未戒断和吗啡或可卡因依赖动物中谷氨酸功能的作用。拟议的行为和神经化学研究将首次全面调查CLAV在耐受性和成瘾动物模型中的作用，并测试总体假设，即脑渗透性b-内酰胺酶抑制剂，通过预期的抗谷氨酸盐特性，是有吸引力的和患者友好的替代b-内酰胺抗生素作为滥用威慑和CNS活性治疗。我们的总体方法是基于广泛持有的原则，即实验室和临床之间已被证明的捷径是为现有药物找到新的用途（即，克拉维酸）。由于现有的药物具有已知的药代动力学和安全性特征，并且经常被监管机构批准用于人类使用，因此任何新发现的用途都可以在II期临床试验中快速评估，这些临床试验通常持续两年，耗资1700万美元。通过这种方式，药物开发人员可以通过消除大部分毒理学和药代动力学评估来绕过将药物推向市场的总成本的近40%。利用这种经过验证的策略可以确定一种新的CNS活性治疗剂，其方式与丙戊酸用于治疗前列腺癌和NSAID用于治疗阿尔茨海默病的方式大致相同。 公共卫生相关性：β-内酰胺抗生素显示出令人惊讶的抗谷氨酸性质，这导致它们被鉴定为管理缺乏有效、安全和方便疗法的广泛CNS疾病的有希望的候选物，但是越来越多的人担心抗生素作为CNS活性治疗剂将仅具有有限的临床用途，因为它们产生通常导致患者停止治疗的副作用。我们假设克拉维酸是直接β-内酰胺类抗生素治疗的一种有吸引力的替代药物，克拉维酸是一种结构相似的β-内酰胺酶抑制剂，由于其增强的脑渗透性、可忽略的抗菌活性和方便的（口服）给药途径，可能提供更安全和更患者友好的治疗。我们希望我们经过验证的方法，即识别现有药物的新用途，将通过消除从头开始设计，合成，测试和开发药物时所需的大部分正常毒理学和药代动力学评估，以具有成本效益和及时的方式识别新型滥用威慑和CNS活性治疗剂。

DESCRIPTION (provided by applicant): The b-lactam antibiotic ceftriaxone (CTX) displays surprising anti-glutamate effects. This has led to its identification as a promising candidate to treat CNS diseases. However, a growing concern among physicians and neuroscientists is that CTX produces intolerable side effects that will limit its utility as a CNS-active therapeutic. The problem is that CTX displays poor brain penetrability in the absence of meningitis. Large doses of CTX must therefore be administered to achieve anti-glutamate effects that underlie its efficacy against CNS diseases. These large doses increase the risk of adverse effects in patients. We hypothesize that an attractive alternative to CTX therapy is the b-lactamase inhibitor clavulanic acid. CTX and clavulanic acid both contain a central b-lactam ring. The b-lactam ring is required for anti-glutamate activity because antibiotics containing the ring enhance glutamate uptake whereas those lacking the ring are ineffective. Compared to CTX, clavulanic acid displays several attractive features, namely enhanced brain penetrability, CNS activity in animals at 100-fold lower doses, negligible anti-bacterial activity, and easer administration route (oral versus intravascular for CTX). Our preclinical experiments provide a proof-of-principle that clavulanic acid mimics CTX efficacy against CNS diseases resulting from excessive glutamate transmission. Both b-lactam compounds display anti-glutamate activity in both in vitro and in vivo assays. They also disrupt morphine analgesic tolerance and cocaine self-administration in rodents and display anti-seizure-like activity in invertebrates. The Specific Aims are to: 1) Compare the effects of CLAV and CTX in animal models of tolerance, dependence, and addiction and 2) Compare effects of CLAV and CTX on glutamate function in drug-naove and morphine- or cocaine-dependent animals. The proposed behavioral and neurochemical studies will provide the first comprehensive investigation of CLAV effects in animal models of tolerance and addiction and test the overall hypothesis that brain penetrable b-lactamase inhibitors, through anticipated anti-glutamate properties, are attractive and patient-friendly alternatives to b-lactam antibiotics as abuse-deterrent and CNS-active therapeutics. Our overall approach is based on the widely held tenet that a proven short cut between the laboratory and clinic is to find a new use for an existing drug (i.e., clavulanic acid). Because existing drugs have known pharmacokinetics and safety profiles and are often approved by regulatory agencies for human use, any newly identified use can be rapidly evaluated in phase II clinical trials, which typically last two years and cost $17 million. In this way, drug developers can bypass almost 40% of the overall cost of bringing a drug to market by eliminating much of the toxicological and pharmacokinetic assessments. Utilization of this proven strategy here may identify a novel CNS-active therapeutic, in much the same way that valproic acid is used to manage prostate cancer and NSAIDs are used to manage Alzheimer's disease. PUBLIC HEALTH RELEVANCE: b-lactam antibiotics display surprising anti-glutamate properties that have led to their identification as promising candidates to manage a broad range of CNS diseases that lack efficacious, safe, and convenient therapies, but there is a growing concern that the antibiotics will be of only limited clinical utility as CNS-active therapeutics because they produce adverse effects which often lead to discontinuation of therapy by patients. We hypothesize that an attractive alternative to direct b-lactam antibiotic therapy is clavulanic acid, a structurally similar b-lactamase inhibitor that may provide a safer and more patient-friendly therapeutic because of its enhanced brain penetrability, negligible anti-bacterial activity, and convenient (oral) administration route. We expect that our proven approach, namely the identification of a new use for an existing drug, will identify a novel abuse-deterrent and CNS-active therapeutic in a cost effective and timely manner by eliminating much of the normal toxicological and pharmacokinetic assessments that are required when designing, synthesizing, testing, and developing a drug from scratch.