Evaluation of miltefosine for the treatment of dogs naturally infected with L. infantum (=L. chagasi) in Brazil

AbstractDogs naturally infected with Leishmania Infantum (=L. chagasi) were treated with miltefosine using different therapeutic regimens. The animals were evaluated for clinical evolution, biochemical parameters, parasite load (by real-time PCR), cytokine levels and humoral response. After treatment and during the following 24 months, there was progressive clinical improvement and complete recovery in 50% (7/14) of the treated animals. There was a decrease in the smear positivity of the bone marrow after treatment, and there was also a gradual and constant decrease in positive cultures at the end of the follow-up period. However, the PCR detection of parasite DNA remained positive. In general, all animals presented a significant increase in parasite load 6 months after treatment. The IFN-γ levels in all the groups tended to increase during follow-up period, regardless of the miltefosine dose administered. The IL-4 and IL-10 levels of the animals tended to decrease during follow-up, except after 300 days when only IL-10 increased. The serum antibodies identified antigens that ranged from 116kDa to less than 29kDa in the Western blot assay. Furthermore, 300 days after treatment, qualitative and quantitative differences in the antigen profiles were observed. Antigens of 97 and 46kDa were the most intensely recognized. Higher levels of antigen-specific Leishmania IgG were detected before and 300 days after treatment in all groups. Taking together, the improvement in the clinical symptoms was not followed by parasitological clearance, suggesting that treatment with miltefosine is not recommended, especially in endemic areas like Brazil, where children are the major victims and dogs are involved in the maintenance of the parasite cycle

Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, OPRM1, and COMT genotype and select opioid therapy

First published: 02 January 2021Opioids are mainly used to treat both acute and chronic pain. Several opioids are metabolized to some extent by CYP2D6 (codeine, tramadol, hydrocodone, oxycodone and methadone). Polymorphisms in CYP2D6 have been studied for an association with the clinical effect and safety of these drugs. Other genes which have been studied for their association with opioid clinical effect or adverse events include OPRM1 (mu receptor) and COMT (catechol-O-methyltransferase). This guideline updates and expands the 2014 Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and codeine therapy and includes a summation of the evidence describing the impact of CYP2D6, OPRM1 and COMT on opioid analgesia and adverse events. We provide therapeutic recommendations for the use of CYP2D6 genotype results for prescribing codeine and tramadol and describe the limited and/or weak data for CYP2D6 and hydrocodone, oxycodone and methadone and for OPRM1 and COMT for clinical use.Kristine R. Crews, Andrew A. Monte, Rachel Huddart, Kelly E. Caudle, Evan D. Kharasch, Andrea Gaedigk ... et al

Impact of liver inflammation on bile acid side chain shortening and amidation

Bile acid (BA) synthesis from cholesterol by hepatocytes is inhibited by inflammatory cytokines. Whether liver inflammation also affects BA side chain shortening and conjugation was investigated. In human liver cell lines (IHH, HepG2, and HepaRG), agonists of nuclear receptors including the farnesoid X receptor (FXR), liver X receptor (LXR), and peroxisome proliferator-activated receptors (PPARs) did not affect the expression of BA-related peroxisomal enzymes. In contrast, hepatocyte nuclear factor 4 alpha (HNF4 alpha) inhibition down-regulated acyl-CoA oxidase 2 (ACOX2). ACOX2 was repressed by fibroblast growth factor 19 (FGF19), which was prevented by extracellular signal-regulated kinase (ERK) pathway inhibition. These changes were paralleled by altered BA synthesis (HPLC-MS/MS). Cytokines able to down-regulate cholesterol-7 alpha-hydroxylase (CYP7A1) had little effect on peroxisomal enzymes involved in BA synthesis except for ACOX2 and bile acid-CoA:amino acid N-acyltransferase (BAAT), which were down-regulated, mainly by oncostatin M (OSM). This effect was prevented by Janus kinase (JAK) inhibition, which restored BA side chain shortening and conjugation. The binding of OSM to the extracellular matrix accounted for a persistent effect after culture medium replacement. In silico analysis of four databases (n = 201) and a validation cohort (n = 90) revealed an inverse relationship between liver inflammation and ACOX2/BAAT expression which was associated with changes in HNF4 alpha levels. In conclusion, BA side chain shortening and conjugation are inhibited by inflammatory effectors. However, other mechanisms involved in BA homeostasis counterbalance any significant impact on the serum BA profile