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Pharmacological Management of Amyotrophic Lateral Sclerosis
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Shalini Mani, Chahat Kubba, Tanya Sharma, Manisha Singh
Treatment of ALS using anti-excitotoxins is still in active research phase and has shown a promising clinical outcome (Venkova-Hristova et al., 2017). The benzothiazole compound R-pramipexole came into view as a drug from research on Parkinson’s disease that can save dopaminergic neurons from glutamate excitotoxicity. The neuroprotective effects observed to be triggered downstream from the glutamate-gated receptors and further intended to perform action in the mitochondria (Izumi et al., 2007). Thus, potential neuroprotective compounds are hypothesized to have a considerable clinical benefit in ALS patients. Unsurprisingly, therapeutic approach that belongs to this class has recruited numerous patients in their respective phase 3 trials. Clinical trials with TCH346 (Miller et al., 2007) and olesoxime (Lenglet et al., 2014) have recruited more than 500 patients each, with dexpramipexole (Cudkowicz et al., 2011) and xaliproden (Lacomblezetal, 2004) recruiting more than 1000 and 2000 patients, respectively. Dexpramipexole falls under the category of compounds termed as benzothiazoles, which shows a broad range of biological activity. As per studies conducted in preclinical models, dexpramipexole has demonstrated its neuroprotective activity in CNS to be dependent on the function of mitochondrial (Alavian et al., 2012), including the improvement in survivability of SOD1G93A mouse model (Bennett et al., 2014). However, this compound was not capable to exhibit its therapeutic effects in ALS (Cudkowiczetal., 2013).
Advances in disease-modifying pharmacotherapies for the treatment of amyotrophic lateral sclerosis
Published in Expert Opinion on Pharmacotherapy, 2020
R Hergesheimer, D Lanznaster, P Vourc’h, Cr Andres, Se Bakkouche, S Beltran, H Blasco, P Corcia, P Couratier
The case of dexpramipexole demonstrates this pattern of false-positive results. It presents neuroprotective effects mainly by inhibiting dysfunctional leak conductance of the inner mitochondrial membrane (Figure 1) [42]. In SOD-1 mice, one study showed a therapeutic effect [43], which supported the transition to human clinical trials. The phase II study reported promising results in both reduction in functional decline and mortality rate [44]. However, the long-awaited phase III trial failed to show any efficacy [45]. In fact, a later study reevaluating the effect of dexpramipexole in the same mouse model [46] could not recognize any beneficial outcome. The authors argued that the initial preclinical study was underpowered by a lack of balance for sex, age, weight, and littermate in treated cohorts. Furthermore, Vieira and others [46] minimized experimenter bias by conducting an observer-blinded study, unlike the first one.
Emerging drugs for eosinophilic esophagitis
Published in Expert Opinion on Emerging Drugs, 2018
Robert D. Pesek, Sandeep K. Gupta
Dexpramipexole, which has been shown to improve mitochondrial function, was initially developed for use in amyotrophilc lateral sclerosis (ALS) but was also found to have a significant impact on blood eosinophils [98]. In a phase II clinical trial of 102 subjects with ALS, a significant reduction in peripheral eosinophils was seen within 1 month in subjects that received dexpramipexole, compared to controls [99]. This decline was dose-dependent and was as great as 78.9% in some subjects. In the following phase III trial, 76.8% of subjects receiving dexpramipexole had a 50% or greater decline in peripheral eosinophils after 6 months of treatment [100]. There are no current studies for the use of dexpramipexole in EoE, but there are pending trials in hypereosinophilic syndrome (ClinicalTrials.gov Identifier: NCT02101138) and a recently completed trial in nasal polyposis (ClinicalTrials.gov Identifier: NCT02217332).
Mepolizumab for the treatment of chronic rhinosinusitis with nasal polyps in adults
Published in Expert Review of Respiratory Medicine, 2023
Josh Neposlan, Leigh J Sowerby, Ameen Biadsee
Beyond biologics, dexpramipexole, a novel therapeutic studied for use in ALS, is another agent that has been studied for use in patients with CRSwNP. Incidentally found to reduce eosinophil levels in ALS patients, further trials have shown that despite lowering both blood and tissue eosinophil levels, it failed to confer an associated reduction in polyp or symptom scores in patients with CRSwNP [27]. It follows that eosinophilia does not act alone in promoting polyp formation, a process which ultimately remains unclear [2,4].