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

描述(申请人提供)：β-内酰胺类抗生素头孢曲松(CTX)具有惊人的抗谷氨酸作用。这使得它被确定为治疗中枢神经系统疾病的有前途的候选药物。然而，医生和神经科学家越来越担心的是，CTX会产生无法忍受的副作用，限制其作为中枢神经系统活性治疗药物的效用。问题是，在没有脑膜炎的情况下，CTX显示出较差的脑穿透性。因此，必须给予大剂量的环磷酰胺，以达到抗谷氨酸的效果，这是其治疗中枢神经系统疾病的基础。这些大剂量会增加患者出现不良反应的风险。我们推测，CTX治疗的一个有吸引力的替代方案是b-内酰胺酶抑制剂克拉维酸。环磷酰胺和克拉维酸都含有一个中心的b-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可增强谷氨酸的摄取，而没有该环的抗生素则无效。与环磷酰胺相比，克拉维酸表现出几个吸引人的特点，即增强了脑通透性，在动物体内的中枢神经系统活性降低了100倍，抗菌活性可以忽略不计，给药途径更容易(环磷酰胺口服与血管内注射相比)。我们的临床前实验提供了克拉维酸模拟CTX对谷氨酸过度传递引起的中枢神经系统疾病的疗效的原理证明。两种β-内酰胺类化合物在体外和体内试验中都显示出抗谷氨酸的活性。它们还扰乱了啮齿动物对吗啡的止痛耐受性和可卡因的自我给药，并在无脊椎动物中表现出抗癫痫样活动。其具体目的是：1)比较CLAV和CTX在耐受、依赖和成瘾动物模型中的作用；2)比较CLAV和CTX对药物依赖和吗啡或可卡因依赖动物谷氨酸功能的影响。拟议的行为和神经化学研究将首次在耐受和成瘾的动物模型中提供CLAV效应的全面调查，并检验脑透性β-内酰胺酶抑制剂通过预期的抗谷氨酸特性是有吸引力的和患者友好的B-内酰胺类抗生素的替代药物，作为滥用威慑和中枢神经系统活性治疗药物。我们的总体方法是基于一个被广泛接受的原则，即实验室和临床之间公认的捷径是为现有药物(即克拉维酸)找到新的用途。由于现有药物具有已知的药代动力学和安全性特征，并且经常得到监管机构的批准用于人类，因此任何新确定的用途都可以在第二阶段临床试验中快速评估，该试验通常持续两年，费用为1700万美元。通过这种方式，药物开发商可以省去大部分毒理学和药代动力学评估，从而绕过将药物推向市场的近40%的总成本。在这里利用这一经过验证的策略可能会确定一种新的中枢神经系统活性治疗方法，就像丙戊酸用于治疗前列腺癌和非类固醇抗炎药用于治疗阿尔茨海默病一样。

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.