PMC:6582309 / 56518-58912 JSONTXT

{"project":"2_test","denotations":[{"id":"31249505-15795058-38601771","span":{"begin":257,"end":261},"obj":"15795058"},{"id":"31249505-15795058-38601773","span":{"begin":541,"end":545},"obj":"15795058"},{"id":"31249505-16044670-38601775","span":{"begin":921,"end":925},"obj":"16044670"},{"id":"31249505-20930279-38601776","span":{"begin":1099,"end":1103},"obj":"20930279"},{"id":"31249505-18300284-38601777","span":{"begin":1281,"end":1285},"obj":"18300284"},{"id":"31249505-26401704-38601778","span":{"begin":1304,"end":1308},"obj":"26401704"},{"id":"31249505-29318971-38601779","span":{"begin":1492,"end":1496},"obj":"29318971"},{"id":"31249505-15795058-38601780","span":{"begin":1740,"end":1744},"obj":"15795058"},{"id":"31249505-11108188-38601781","span":{"begin":1926,"end":1930},"obj":"11108188"},{"id":"31249505-21145918-38601783","span":{"begin":2266,"end":2270},"obj":"21145918"}],"text":"Testing the same compounds in dogs and humans provided similar findings also in other studies. CP-118,954, an acetylcholinesterase inhibitor, showed minimal cognitive enhancing effects in dogs and human clinical trials were discontinued (Studzinski et al., 2005). Donepezil administration enhanced memory in dogs (Araujo et al., 2011a). Phenserine, an acetylcholinesterase inhibitor which also inhibits synthesis of Aβ and acts as a cognitive enhancing therapeutic, improved learning and working memory in geriatric dogs (Studzinski et al., 2005; Araujo et al., 2011a). Its administration showed similar results in Phase II human clinical trials, suggesting its effectiveness in improving memory in AD patients, but in Phase III human clinical trial, with patients with mild to moderate AD, no significant differences between the phenserine treated and placebo groups were noticed and the trial was discontinued (Thatte, 2005). There has been further discussions if this trial, and several other AD trials, failed due to procedural errors rather than due to a lack of drug efficacy (Winblad et al., 2010). In more recent studies patients with mild AD showed improvement in cognition following phenserine treatments, this was mirrored also by an increase in CSF Aβ40 (Kadir et al., 2008; Nordberg et al., 2015). There is another mode of action of phenserine in AD, namely inhibition of neuronal self-induced preprogrammed cell death, which further clinical trials might pursue (Becker et al., 2018). Ampakine (drug that alters the glutaminergic system) also failed in human AD trials and in dogs with age-associated memory disorder and dementia showed insignificant memory-enhancing effects after treatment with ampakine (Studzinski et al., 2005). Dogs, treated with adrafinil, a mild central nervous system stimulant used to relieve excessive sleepiness and inattention in elderly patients, were more attentive (Siwak et al., 2000). Cholinergic hypofunction might play a role in age-dependent cognitive decline in dogs (Araujo et al., 2011b), this was determined by administration of muscarinic cholinergic receptor antagonist scopolamine, which induces transient memory impairment. Similar findings were presented for aged and demented humans (Schliebs and Arendt, 2011). All these suggest that dogs might be a very good preclinical model for developing and testing new drugs for AD in humans."}

{"project":"0_colil","denotations":[{"id":"31249505-15795058-737196","span":{"begin":257,"end":261},"obj":"15795058"},{"id":"31249505-15795058-737198","span":{"begin":541,"end":545},"obj":"15795058"},{"id":"31249505-16044670-737200","span":{"begin":921,"end":925},"obj":"16044670"},{"id":"31249505-20930279-737201","span":{"begin":1099,"end":1103},"obj":"20930279"},{"id":"31249505-18300284-737202","span":{"begin":1281,"end":1285},"obj":"18300284"},{"id":"31249505-26401704-737203","span":{"begin":1304,"end":1308},"obj":"26401704"},{"id":"31249505-29318971-737204","span":{"begin":1492,"end":1496},"obj":"29318971"},{"id":"31249505-15795058-737205","span":{"begin":1740,"end":1744},"obj":"15795058"},{"id":"31249505-11108188-737206","span":{"begin":1926,"end":1930},"obj":"11108188"},{"id":"31249505-21145918-737208","span":{"begin":2266,"end":2270},"obj":"21145918"}],"text":"Testing the same compounds in dogs and humans provided similar findings also in other studies. CP-118,954, an acetylcholinesterase inhibitor, showed minimal cognitive enhancing effects in dogs and human clinical trials were discontinued (Studzinski et al., 2005). Donepezil administration enhanced memory in dogs (Araujo et al., 2011a). Phenserine, an acetylcholinesterase inhibitor which also inhibits synthesis of Aβ and acts as a cognitive enhancing therapeutic, improved learning and working memory in geriatric dogs (Studzinski et al., 2005; Araujo et al., 2011a). Its administration showed similar results in Phase II human clinical trials, suggesting its effectiveness in improving memory in AD patients, but in Phase III human clinical trial, with patients with mild to moderate AD, no significant differences between the phenserine treated and placebo groups were noticed and the trial was discontinued (Thatte, 2005). There has been further discussions if this trial, and several other AD trials, failed due to procedural errors rather than due to a lack of drug efficacy (Winblad et al., 2010). In more recent studies patients with mild AD showed improvement in cognition following phenserine treatments, this was mirrored also by an increase in CSF Aβ40 (Kadir et al., 2008; Nordberg et al., 2015). There is another mode of action of phenserine in AD, namely inhibition of neuronal self-induced preprogrammed cell death, which further clinical trials might pursue (Becker et al., 2018). Ampakine (drug that alters the glutaminergic system) also failed in human AD trials and in dogs with age-associated memory disorder and dementia showed insignificant memory-enhancing effects after treatment with ampakine (Studzinski et al., 2005). Dogs, treated with adrafinil, a mild central nervous system stimulant used to relieve excessive sleepiness and inattention in elderly patients, were more attentive (Siwak et al., 2000). Cholinergic hypofunction might play a role in age-dependent cognitive decline in dogs (Araujo et al., 2011b), this was determined by administration of muscarinic cholinergic receptor antagonist scopolamine, which induces transient memory impairment. Similar findings were presented for aged and demented humans (Schliebs and Arendt, 2011). All these suggest that dogs might be a very good preclinical model for developing and testing new drugs for AD in humans."}