In this overview, we discuss the discovery and development of topiramate (TPM) as an anticonvulsant, including notable aspects of its chemical, biologic, and pharmacokinetic properties. In particular, we highlight its anticonvulsant profile in traditional seizure tests and animal models of epilepsy and the results of recent electrophysiological and biochemical studies using cultured neurons that have revealed a unique combination of pharmacologic properties of TPM. Finally, we present a hypothesis for the mechanistic basis of the anticonvulsant activity of TPM, which proposes that TPM binds to certain membrane ion channel proteins at phosphorylation sites and thereby allosterically modulates channel conductance and secondarily inhibits protein phosphorylation.Topiramate (TPM; RWJ-17021-000, McN-4853) was originally synthesized as part of a research project to discover structural analogs of fructose-1,6-diphosphate capable of inhibiting the enzyme fructose 1,6-bisphosphatase, thereby blocking gluconeogenesis. Sulfamate derivatives of fructose were the initial focus of the synthetic effort because they contain unionized groups that might simulate phosphate binding to the enzyme and also facilitate access to the enzyme by enhancing membrane permeability.TPM was prepared as a synthetic intermediate in the project, and it is devoid of hypoglycemic activity. However, the structural resemblance of its 0-sulfamate moiety to the sulfonamide moiety in acetazolamide (and other arenesulfonamide anticonvulsants) prompted an evaluation of possible anticonvulsant effects. TPM was highly active in the traditional maximal electroshock seizure (MES) test in mice and rats and possessed a long duration of action (1-3). Furthermore, there was a wide separation between the effective anticonvulsant doses compared to those causing motor impairment. Development of TPM as an antiepileptic drug (AED) was subsequently pursued on the basis of its potency, duration of action, and high neuroprotective index.
Nonclinical rodent and nonrodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans, contributing to drug failures in the clinic. Here, we applied microengineered Organs-on-Chips technology to design a rat, dog, and human Liver-Chip containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. The Liver-Chip detected diverse phenotypes of liver toxicity, including hepatocellular injury, steatosis, cholestasis, and fibrosis, and species-specific toxicities when treated with tool compounds. A multispecies Liver-Chip may provide a useful platform for prediction of liver toxicity and inform human relevance of liver toxicities detected in animal studies to better determine safety and human risk.
Nonclinical rodent and non-rodent toxicity models used to support clinical trials of candidate drugs may produce discordant results or fail to predict complications in humans contributing to drug failures in the clinic. Here we applied microengineered Organ-on-Chip (Organ-Chip) technology to design rat, dog, and human Liver-Chips containing species-specific primary hepatocytes interfaced with liver sinusoidal endothelial cells, with or without Kupffer cells and hepatic stellate cells, cultured under physiological fluid flow. The Liver-Chips detected diverse phenotypes of liver toxicity including hepatocellular injury, steatosis, cholestasis, and fibrosis as well as species-specific toxicities when treated with tool compounds. Multi-species Liver-Chips may provide a useful platform for prediction of liver toxicity and inform human relevance of liver toxicities detected in animal studies to better determine safety and human risk.One Sentence Summary: Microengineered Organ-Chip technology has been used to design rat, dog and human Liver-Chips that recapitulate species-specific liver toxicities.
______________________________________________________________________________The U.S. Food and Drug Administration (FDA) and European Medicines Agency generally require the safety of new drug candidates to be evaluated in both a rodent and a nonrodent animal models, frequently rat and dog, before moving the new chemical entity (NCE) into human clinical trials. An analysis of 150 drugs that caused adverse events in humans found that regulatory testing in rats and dogs correctly predicted just 71% of toxicities in humans (1).Moreover, while gastrointestinal, hematological, and cardiovascular toxicities were predicted with a relatively high concordance, the ability to predict liver toxicities was much lower. This was further confirmed by a more recent survey comparing target organ toxicities in animal and first-in-human studies that also found a low concordance of liver toxicity between human and 3 animals (2). The poor prediction of liver toxicity in humans is driven by poor nonclinical to clinical translation and by rare idiosyncratic events that occur in large patient trials or at postmarketing. Thus, one of the major challenges the pharmaceutical and biotechnology industries face is selecting compounds with reduced risk for hepatotoxicity-the major cause for liver failure and drug attrition (3)(4)(5)(6). Given the scale of this challenge and its negative impact on healthcare costs and development of new therapeutics, there is a critical need for more predictive and human relevant alternatives to animal models. Here, we explored whether human microengineered Organ-on-Chip (Organ-Chip) technology, which has been shown to faithfully recapitulate the complex functions and pathophysiology of multiple human organs (7-11), may be used to design species-specific Liver-Chips that can be used to address this challenge.
Development and Characterization of rat, dog, and human Liver-ChipsSpecies-specific Liver-Chips lined by living rat,...
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