Alcohol relapse is the treatment target for medications development for alcohol dependence. Aticaprant, a selective and short-acting kappa-opioid receptor (KOR) antagonist, has recently been under development for new clinical implications (depression or anhedonia). Recent studies have also found that aticaprant reduces alcohol intake and prevents stress- triggered alcohol seeking in rodents via a KOR-mediated mechanism. Here, we further investigated whether aticaprant alone or in combination with naltrexone (mu-opioid receptor [MOR] antagonist) altered alcohol relapse-like drinking using a mouse alcohol deprivation effect (ADE) paradigm to mimic the relapse episodes in human alcoholics. A long-acting and selective KOR antagonist nor-BNI was used as a reference compound for the effects of the KOR antagonism on the ADE. After 3-week intermittent-access alcohol drinking (two-bottle choice, 24-h access every other day), male and female mice displayed excessive alcohol intake and then pronounced ADE after 1-week abstinence. Aticaprant alone decreased alcohol ADE in a dose- dependent manner (1-3 mg/kg) in both males and females. Aticaprant at a lower dose (0.3 mg/kg) than the effective one (3 mg/kg) combined with a low dose of naltrexone (1 mg/kg) reduced the ADE in both sexes, and the combination was effective after a multi-dosing regimen (5 daily injections during the abstinence) without development of tolerance, suggesting synergistic effects of the combination. In contrast, nor-BNI alone or with naltrexone had no effect on the ADE in either sex. Our present study suggests that a combination of clinically developed, short-acting KOR antagonist aticaprant with low-dose naltrexone has therapeutic potential in alcohol "relapse" treatment.
Clinical evidence is reviewed for the possible use of the adamantanes amantadine and memantine, for the prevention and/or treatment of COVID-19. Literature searches revealed three series of case reports authored by independent teams of international investigators. Subjects were comprised principally of patients receiving amantadine or memantine for several weeks as part of their treatment regimen for Parkinson’s disease, Multiple Sclerosis or Cognitive impairment prior to their infection by SARS-CoV-2. All patients tested positive for SARSCoV-2 confirmed by RT-PCR of nasopharyngeal swabs. Interestingly, the majority of cases manifested age-related vulnerabilities to COVID-19 as well as the presence of co-morbidities resulting from either severe neurological disorders or type-2 diabetes. Amantadine appeared to prevent the appearance of typical COVID-19related clinical manifestations of infectious disease in 23/24 cases. In addition, one patient with type-2 diabetes treated with amantadine for 14 days showed clear improvements in clinical status and in oxygen saturation levels; by day 6 he could breathe without the need for oxygen supplementation and was discharged from hospital on day 14. It is necessary to now confirm these findings by randomized controlled trials in order to objectively evaluate the use of these agents for the prevention and/or treatment of COVID-19.
Intensive efforts are underway in the search for novel antiviral agents and in the repurposing of existing antivirals with the potential to mitigate the effects of COVID-19. Amantadines represent a large family of tricyclic agents some of which are known to manifest efficacy against a range of viruses including influenza A and several human and animal coronaviruses including SARS-CoV and HCoV-OC43 with neuroinvasive characteristics. The adamantane derivative memantine improves clinical scores and motor disabilities while reducing HCoVOC43 viral replication in a dose-dependent manner. Anti-viral actions of memantine against HCoV are independent of the agent’s action as a non-competitive NMDA receptor antagonist. Amantadine and the novel spiroadamantane amine possess significant activity against coronavirus 229E. Mechanisms proposed to date to account for the antiSARS CoV-2 actions of adamantanes include blocking of the viroporin channel of the virus E protein preventing release of viral nucleus into the host-cell cytoplasm and down-regulation of the host protease CTSL and lysosomal disruption leading to decreased viral replication. Further investigations are now required including the assessment of other adamantanes as antivirals in the experimental setting and controlled clinical trials to assess their safety and efficacy for the prevention and treatment of COVID-19.
Widespread damage to the central and peripheral nervous systems resulting from COVID-19 is becoming well established. Features include impairments of the level [somnolence, stupor, coma] and content [confusion, delirium] of consciousness, impaired senses of taste, smell and vision as well as skeletal muscle manifestations. The neuroinvasive nature of SARS-CoV-2 may contribute to the acute respiratory failure of COVID-19. SARS-CoV-1 virus was detected in the brain of infected patients along with neuronal necrosis and glial hyperplasia. In SARS-CoV-2, modifications of crucial cellular pathways [mitochondrial function, proteolysis, lipid metabolism] known to be implicated in cellular aging and in neurodegenerative diseases occur. Adamantanes, [amantadine and the structurally-related memantine] are employed for the treatment of disorders of consciousness while also manifesting effective antiviral properties. Clinical studies and Case Reports at this early stage of COVID-19 reveal evidence of a protective effect of amantadine in infected patients with benefit being ascribed to amantadine's effects on viral release into the host cell via mechanisms involving the E channel of the virus or by the agent's down-regulation of the host protease Cathepsin L in addition to disruption of the lysosomal pathway. Memantine has potent neuroprotective actions in both wellestablished neurodegenerative diseases as well as in viral disorders in which it prevents neuronal cell loss and concomitantly reduces viral replication in a dose-dependent manner. Controlled clinical trials for the assessment of efficacy of these adamantanes for the prevention and treatment of COVID-19 are now indicated.
