A significant proportion of psychiatric patients will be treated with psychotropic drugs metabolized by cytochrome P450 2D6 and 2C19 (CYP2D6 and CYP2C19) throughout their illness.¹ Both enzymes are encoded by genetically polymorph genes, CYP2D6 (OMIM 124030) and CYP2C19 (OMIM 124020). Their phenotypic expression is mostly determined by the number of functional alleles, and it divides populations into phenotype groups with different drug metabolizing capacities, ranging from poor metabolizers (PMs) to intermediate metabolizers (IMs), extensive metabolizers (EMs), and ultrarapid metabolizers (UMs). Genetic differences in drug metabolism of these enzymes is associated with both treatment failure and adverse drug reactions in psychiatric patients but also with distinctive prescription patterns and health care costs.^2-4

Per- and polyfluoroalkyl substances (PFAS) are heat and stain resisting chemicals. They are persistent, bioaccumulating and spread ubiquitously. Many hotspots where humans are exposed to high levels of PFAS have been reported. A few small observational studies in humans suggest that treatment with an Anion Exchange Resin (AER) decreases serum PFAS. This first clinical controlled crossover study aimed to assess whether AER decreases perfluorooctanesulfonic acid (PFOS) in highly exposed adults. An open label 1:1 randomized treatment sequence crossover study with allocation to oral AER (cholestyramine 4 g three times daily) or observation for 12 weeks was conducted among citizens from a PFAS hotspot. Main inclusion criteria was serum PFOS > 21 ng/mL. Primary endpoint was change in serum PFOS levels between treatment and observational period. In total, 45 participants were included with a mean age of 50 years (SD 13). Serum PFOS baseline median was 191 ng/mL (IQR: 129-229) and decreased with a mean of 115 ng/mL (95 % CI: 89-140) on treatment, and 4.3 ng/mL in observation period corresponding to a decrease of 60 % (95 % CI: 53-67; p < 0.0001). PFHxS, PFOA, PFNA and PFDA decreased during treatment between 15 and 44 %. No serious adverse events were reported. Oral treatment with AER significantly lowered serum PFOS concentrations suggesting a possible treatment for enhancing elimination of PFOS in highly exposed adults.

Background: The costs of biologic treatment per patient with rheumatoid arthritis (RA) are about 100 times the costs of treatment with a combination of conventional disease modifying anti‐rheumatic drugs (DMARDs). Despite this, biologic agents have not been proven superior. We compared the effects of combination DMARD therapies with and without biologic agents as therapy for patients with rheumatoid arthritis. Methods: Eight randomized controlled trials published in 10 articles were selected from a systematic literature search of 1676 identified studies and integrated in a meta‐analysis. These trials compared combinations of DMARDs versus a tumor necrosis factor α inhibitor (TNFi) plus methotrexate. Two reviewers independently entered data into standardized extraction forms. The combined effect measures were compared by means of the inverse variance method (continuous data) and the Mantel Haenzel method (dichotomous data) using a random effect model. Results: The primary outcome, radiographic progression score, did not differ between the combination DMARD group and the TNFi group, neither during the second year (‐0.09U [‐0.61, 0.44]) of treatment nor during the first two years (0.66U [‐0.12, 1.43]). There were significant differences in radiographic progression score, ACR50 and ACR70 response criteria at 6 months in favor of TNFi treatment, but these differences were not present in patients treated with an initial steroid course and disappeared at 24 months irrespective of the use of steroids. Conclusion: The difference between DMARD combination treatments including or excluding TNF inhibitors is small. Due to the enormous cost‐differences RA guidelines should recommend combination DMARD treatment before initiation of TNF inhibitors.

Carboxylesterase 1 (CES1) metabolizes methylphenidate and other drugs. CES1 gene variation only partially explains pharmacokinetic (PK) variability. Biomarkers predicting the PKs of drugs metabolized by CES1 are needed. We identified lipids in plasma from 44 healthy subjects that correlated with CES1 activity as determined by PK parameters of methylphenidate including a ceramide (q value = 0.001) and a phosphatidylcholine (q value = 0.005). Carriers of the CES1 143E allele had decreased methylphenidate metabolism and altered concentration of this phosphatidylcholine (q value = 0.040) and several high polyunsaturated fatty acid lipids (PUFAs). The half‐maximal inhibitory concentration (IC₅₀) values of chenodeoxycholate and taurocholate were 13.55 and 19.51 μM, respectively, consistent with a physiological significance. In silico analysis suggested that bile acid inhibition of CES1 involved both binding to the active and superficial sites of the enzyme. We initiated identification of metabolites predicting PKs of drugs metabolized by CES1 and suggest lipids to regulate or be regulated by this enzyme.

GS-441524 is an adenosine analog and the parent nucleoside of the prodrug remdesivir, which has received emergency approval for treatment of COVID-19. Recently, GS-441524 has been proposed to be effective in the treatment of COVID-19, perhaps even being superior to remdesivir for treatment of this disease. Evaluation of the clinical effectiveness of GS-441524 requires understanding of its uptake and intracellular conversion to GS-441524 triphosphate, the active antiviral substance. We here discuss the potential impact of these pharmacokinetic steps of GS-441524 on the formation of its active antiviral substance and effectiveness for treatment of COVID-19. Available protein expression data suggest that several adenosine transporters are expressed at only low levels in the epithelial cells lining the alveoli in the lungs, i.e., the alveolar cells or pneumocytes from healthy lungs. This may limit uptake of GS-441524. Importantly, cellular uptake of GS-441524 may be reduced during hypoxia and inflammation due to decreased expression of adenosine transporters. Similarly, hypoxia and inflammation may lead to reduced expression of adenosine kinase, which is believed to convert GS-441524 to GS-441524 monophosphate, the perceived rate-limiting step in the intracellular formation of GS-441524 triphosphate. Moreover, increases in extracellular and intracellular levels of adenosine, which may occur during critical illnesses, has the potential to competitively decrease cellular uptake and phosphorylation of GS-441524. Taken together, tissue hypoxia and severe inflammation in COVID-19 may lead to reduced uptake and phosphorylation of GS-441524 with lowered therapeutic effectiveness as a potential outcome. Hypoxia may be particularly critical to the ability of GS-441524 to eliminate SARS-CoV-2 from tissues with low basal expression of adenosine transporters, such as alveolar cells. This knowledge may also be relevant to treatments with other antiviral adenosine analogs and anticancer adenosine analogs as well.