Association between polypharmacy and dementia - A systematic review and metaanalysis.

Objective: The association between polypharmacy and dementia is controversial. This systematic review and meta-analysis aims to summarize existing literature concerning the association between polypharmacy and dementia. Methods: A systematic literature review was performed by searching the EMBASE, PubMed, Scopus and International Pharmaceutical Abstract databases using terms related to polypharmacy and dementia. A meta-analysis was performed using random effect models. Results: Seven studies were included in this meta-analysis. The included studies were of medium to high quality with a potential for publication bias. A strong association between polypharmacy and dementia was found (pooled adjusted risk ratio (aRR) = 1.30 (95% CI: 1.16-1.46), I2 = 68%). Excessive polypharmacy was also strongly associated with dementia (pooled aRR = 1.52 (95% CI: 1.39-1.67), I2 = 24%). Conclusion: Pooled risk estimates from this meta-analysis showed that polypharmacy was associated with dementia. Although the causality of the relationship cannot be concluded from this analysis, the finding encourages the use of multidimensional assessment tools for dementia that includes the number of medications as a component.

A systematic review and meta-analysis of the association between vitamin A intake, serum vitamin A, and risk of liver cancer.

BACKGROUND: Previous evidence supports that vitamin A decreases the risk of several types of cancer. However, the association between vitamin A and liver cancer is inconclusive. AIM: This systematic review and meta-analysis summarizes the existing literature, discussing the association between vitamin A intake, serum vitamin A, and liver cancer in adult populations. METHODS: A systematic literature review was performed by searching the EMBASE, PubMed, Scopus and International Pharmaceutical Abstract databases using terms related to vitamin A (e.g. retinol, α-carotene, ß-carotene, and ß-cryptoxanthin) and hepatic cancer without applying any time restriction. A meta-analysis was performed using random effect models. RESULTS: The meta-analysis of five studies showed no association between serum retinol and liver cancer (pooled risk ratio = 1.90 (0.40-9.02); n = 5 studies, I2 = 92%). In addition, the systematic review of studies from 1955 to July 2017 found studies that indicated no association between the intake and serum level of α-carotene ( n = 2) and ß-cryptoxanthin ( n = 1) and the risk of liver cancer. Further, the associations between retinol intake ( n = 3), ß-carotene intake ( n = 3), or serum ß-carotene ( n = 3) and liver cancer were inconclusive. CONCLUSIONS: Current information on the association between vitamin A intake and liver cancer or serum vitamin A and liver cancer are limited. Most studies demonstrated no association between dietary vitamin A and the risk of liver cancer. However, the finding was based on a small number of studies with potential publication bias. Therefore, large observational studies should be conducted to confirm these associations.

An anti-TNF-glucocorticoid receptor modulator antibody-drug conjugate is efficacious against immune-mediated inflammatory diseases.

Glucocorticoids (GCs) are efficacious drugs used for treating many inflammatory diseases, but the dose and duration of administration are limited because of severe side effects. We therefore sought to identify an approach to selectively target GCs to inflamed tissue. Previous work identified that anti-tumor necrosis factor (TNF) antibodies that bind to transmembrane TNF undergo internalization; therefore, an anti-TNF antibody-drug conjugate (ADC) would be mechanistically similar, where lysosomal catabolism could release a GC receptor modulator (GRM) payload to dampen immune cell activity. Consequently, we have generated an anti-TNF-GRM ADC with the aim of inhibiting pro-inflammatory cytokine production from stimulated human immune cells. In an acute mouse model of contact hypersensitivity, a murine surrogate anti-TNF-GRM ADC inhibited inflammatory responses with minimal effect on systemic GC biomarkers. In addition, in a mouse model of collagen-induced arthritis, single-dose administration of the ADC, delivered at disease onset, was able to completely inhibit arthritis for greater than 30 days, whereas an anti-TNF monoclonal antibody only partially inhibited disease. ADC treatment at the peak of disease was also able to attenuate the arthritic phenotype. Clinical data for a human anti-TNF-GRM ADC (ABBV-3373) from a single ascending dose phase 1 study in healthy volunteers demonstrated antibody-like pharmacokinetic profiles and a lack of impact on serum cortisol concentrations at predicted therapeutic doses. These data suggest that an anti-TNF-GRM ADC may provide improved efficacy beyond anti-TNF alone in immune mediated diseases while minimizing systemic side effects associated with standard GC treatment.

Nilotinib Alters the Efflux Transporter-Mediated Pharmacokinetics of Afatinib in Mice.

Small-molecule tyrosine kinase inhibitors (TKIs) are novel anticancer agents with enhanced selectivity and superior safety profiles than conventional chemotherapeutics. A major shortcoming in TKI therapy is the development of acquired resistance. An important resistance mechanism is reduced intracellular drug accumulation due to an overexpression of efflux transporters such as P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP) in cancer cells. TKIs have dual roles as substrates and inhibitors of Pgp and BCRP; thus, combination TKI therapy could potentially reverse efflux transporter-mediated TKI resistance. In the present study, the effect of 14 TKIs on Pgp-, Bcrp1-, and BCRP-mediated afatinib efflux was investigated in vitro. Nilotinib was a potent inhibitor of Pgp, Bcrp1, and BCRP, with EC50 values of 2.22, 2.47, and 0.692 µM, respectively. Consequently, the pharmacokinetics of afatinib with and without the coadministration of nilotinib was determined in mice plasma and various tissues. Nilotinib increased afatinib AUC by 188% in plasma, and this altered tissue AUC by -38.8% to +221%. Nilotinib also decreased the clearance of afatinib by 65.3%, from 609 to 211 mL/h. Further studies are warranted to assess nilotinib's chemosensitizing effect in tumor xenograft models.