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Industrial and environmental agents
Published in James W. Albers, Stanley Berent, Neurobehavioral Toxicology: Neurological and Neuropsychological Perspectives, 2005
James W. Albers, Stanley Berent
Adverse effects of long-term elemental mercury exposure at levels below those associated with overt toxicity have not been established (Chang, 1980). Shapiro et al. (1982, 1988) evaluated 298 dentists using an X-ray-fluorescent technique purported to estimate the body burden of mercury resulting from long-term mercury exposure. They identified seven dentists who had subclinical polyneuropathy, defined as reduced conduction velocities or amplitudes in two or more nerves. These seven dentists were among the 23 dentists who had the highest mercury levels. No evidence of polyneuropathy was detected among the control group of dentists without detectable mercury levels (Shapiro et al., 1982). Yet, in this study of dental personnel, few of the electrophysiologic measures differed among the high-mercury exposure group and the control group, and existing differences were small (Shapiro et al., 1988). The cross-sectional study was performed before weight, height, body mass index, and finger diameter were recognized as having important influence on electrodiagnostic studies. Three of the seven dentists with neuropathy had slowing of median conduction across the wrist, suggestive of carpal tunnel syndrome (Shapiro et al., 1988). This was hypothesized to reflect local damage at a common entrapment site due to a subclinical neuropathy. However, the diagnosis of median mononeuropathy in each reflected motor greater than sensory involvement, a finding atypical for carpal tunnel syndrome. Further, the frequency of median mononeuropathy in this group of dentists was not excessive, and below that expected among individuals exposed to cumulative trauma or repetitive hand activities (Werner, Albers, Franzblau, & Armstrong, 1994; Werner, Franzblau, Albers, & Armstrong, 1998; Werner et al., 1997). It is plausible that the median nerve abnormalities and the increased mercury levels reflect an increased level of dental activity in this group of dentists compared with remaining dentists. Increased activity would result in greater opportunity for cumulative wrist trauma and for mercury exposure. The hypothesis that subjects with subclinical or mild generalized polyneuropathy are predisposed to carpal tunnel syndrome has not been supported by subsequent study (Albers, Brown, Sima, Greene, & Tolrestat Study Group for EDIT, 1996).
Aldose reductase inhibitors: 2013-present
Published in Expert Opinion on Therapeutic Patents, 2019
Luca Quattrini, Concettina La Motta
Products that appeared to be promising during in vitro studies or in trials with animal models often failed to proceed any further showing uncertain results in clinical trials with humans. Their failure was often due to the emergence of adverse side effects: the clinical development of sorbinil (1, Figure 3), the progenitor of the hydantoin-based inhibitors, was discontinued because of hypersensitivity reactions related to the presence of hydantoin ring [17]. Tolrestat (2, Figure 3), the key representative of the carboxylic acid inhibitors class, displayed severe liver toxicity [18], and the same was also true for the parent acid zopolrestat (6, Figure 3) [19]. In addition, a significant number of compounds under investigation showed limited clinical efficacy, often caused by an inappropriate dosing schedule of the inhibitor or by an unfitting pharmacokinetic tethered with its absorption, distribution, metabolism, and excretion properties. The observed difficulties led to a general and understandable decrease of scientific interest on this enzyme and its inhibitors, which dragged out till the beginning of the 2000s (Figure 2).
Diabetic nephropathy: an insight into molecular mechanisms and emerging therapies
Published in Expert Opinion on Therapeutic Targets, 2019
Annabelle M. Warren, Søren T. Knudsen, Mark E. Cooper
Aldose reductase inhibitors (ARI) have demonstrated renoprotection in animal models of diabetic kidney disease for many decades [106]. A number of ARIs have been trialed in humans, with varying success. Clinical trials of the ARI tolrestat showed improvements in urinary albumin excretion and indeed it was approved for clinical use; however, it was later withdrawn due to severe hepatic toxicity [109,110]. An alternative ARI epalrestat has been shown to attenuate increases in urinary albumin excretion in diabetic patients without significant toxicity [111]. Epalrestat remains approved for use in some jurisdictions, but its modest impact has limited its uptake worldwide.
The time to develop treatments for diabetic neuropathy
Published in Expert Opinion on Investigational Drugs, 2021
A large program focused on the aldose reductase inhibitor tolrestat [72,73]. Tolrestat received approval for treatment of diabetic neuropathy in several countries, but the agent was eventually withdrawn after a phase 3 trial failed to achieve endpoints and signs of liver toxicity emerged [74].