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.
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.
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