The Link between Oxidative Stress, Mitochondrial Dysfunction and Neuroinflammation in the Pathophysiology of Alzheimer's Disease: Therapeutic Implications and Future Perspectives.

Alzheimer's disease (AD), the most common form of dementia, has increasing incidence, increasing mortality rates, and poses a huge burden on healthcare. None of the currently approved drugs for the treatment of AD influence disease progression. Many clinical trials aiming at inhibiting amyloid plaque formation, increasing amyloid beta clearance, or inhibiting neurofibrillary tangle pathology yielded inconclusive results or failed. Meanwhile, research has identified many interlinked vicious cascades implicating oxidative stress, mitochondrial dysfunction, and chronic neuroinflammation, and has pointed to novel therapeutic targets such as improving mitochondrial bioenergetics and quality control, diminishing oxidative stress, or modulating the neuroinflammatory pathways. Many novel molecules tested in vitro or in animal models have proven efficient, but their translation into clinic needs further research regarding appropriate doses, delivery routes, and possible side effects. Cell-based therapies and extracellular vesicle-mediated delivery of messenger RNAs and microRNAs seem also promising strategies allowing to target specific signaling pathways, but need further research regarding the most appropriate harvesting and culture methods as well as control of the possible tumorigenic side effects. The rapidly developing area of nanotechnology could improve drug delivery and also be used in early diagnosis.

Comparison of Tolerability and Impact on Metabolic Profiles of Antiretroviral Regimens Containing Darunavir/Ritonavir or Darunavir/Cobicistat in Romanian HIV Infected Patients.

The management of the side effects caused by the antiretroviral therapy is one of the main problems facing clinicians. The patient's tolerability and safety influence the success of the therapy. This retrospective study assesses the tolerability and impact on metabolic profiles of antiretroviral regimens containing darunavir/ritonavir (DRV/r) versus those containing darunavir/cobicistat (DRV/c), in routine clinical practice. The database of Prof. Dr Matei Bals of the National Institute of Infectious Diseases (INBI MB) was studied for the period 2017-2020, allowing the inclusion in the study of 462 HIV-infected patients who received the current regimen at least three months before evaluation. The following parameters were collected and analyzed: significant medical history, associated diseases, serum levels for profile evaluation: carbohydrate, lipidic, serum level of liver and pancreatic enzymes, serum markers of cardiac function, coagulation, and renal function. DRV/c (800 mg/150 mg, once daily) administrated in combination with other antiretroviral (ARV) in HIV-1 infected subjects proved to be better tolerated and with a lower impact on metabolic profile than DRV/r (600 mg/100 mg, twice daily). Patients in DRV/r group are significantly more at risk of developing, over time, side effects and metabolic impairments than those in DRV/c group, in all body functions studied, with statistically significant differences (p < 0.05) between the two groups. Laboratory data were correlated with patient's demographic and clinical characteristics and statistically significant outcomes have been found, proving that a personalized regimen is needed to minimize the ART side effects and to maximize the success of therapy. The results of the study showed that DRV/c, associated with other antiretroviral drugs in the regimens of Romanian HIV infected subjects, have a more favorable metabolic profile than those containing DRV/r.