prednisolone (Orapred ODT / Predonine)

Carbonyl Reductase 1 regulates prednisolone clearance and modifies its adverse effect profile.

Pofi Riccardo R, Potter Tom T, Coll Sergi S, Othonos Nantia N et al.

Prednisolone is widely prescribed but associated with marked interindividual variability in adverse effects. While 11β-hydroxysteroid dehydrogenase (11β-HSD) enzymes regulate glucocorticoid activation, the contribution of alternative clearance pathways remains unclear. We aimed to characterize prednisolone metabolism beyond 11β-HSD enzymes, define the roles of carbonyl reductase 1 (CBR-1) and AKR1C1, and assess the clinical relevance of specific metabolites. Post-hoc targeted metabolomic analysis of a randomized, double-blind, placebo-controlled trial combined with mechanistic in vitro overexpression studies. Thirty healthy male volunteers from the TICSI trial (NCT03111810) and HEK293 cells overexpressing CBR-1 or AKR1C1 were studied. Participants received prednisolone (20 mg daily for one week) with placebo or the selective 11β-HSD1 inhibitor AZD4017. In vitro, transfected HEK293 cells were treated with prednisolone or prednisone. Steroid metabolites were quantified by targeted LC-MS/MS, and associations with glucose disposal and osteocalcin were assessed. 20β-reduced metabolites were major contributors to prednisolone clearance. In vitro, CBR-1 preferentially reduced prednisone, with 20β-dihydro-prednisone accounting for up to 78% of its clearance, whereas AKR1C1 had minimal impact. In vivo, 11β-HSD1 inhibition reduced prednisolone exposure without a compensatory rise in prednisone, with a relative increase in CBR-1-mediated 20β-reduction. Higher circulating 20β-dihydro-prednisone at 4 hours independently predicted improved glucose disposal and higher osteocalcin levels. CBR-1 is a key determinant of prednisolone and prednisone clearance in humans and is associated with clinically relevant metabolic and skeletal outcomes. Circulating 20β-dihydro-prednisone may serve as an informative biomarker of glucocorticoid exposure and adverse effect risk, supporting metabolite-guided approaches to glucocorticoid therapy.

Combination Therapy of Vinblastine, Prednisolone, Methotrexate, and 6-Mercaptopurine as a Front-Line Therapy for Adult Patients With Langerhans Cell Histiocytosis.

Sato Aki A, Yusa Nozomi N, Tanaka Yukihisa Y, Ogawa Miho M et al.

Comparison of the efficacy of TXNDC5 monoclonal antibody versus conventional drugs in the treatment of intestinal fibrosis associated with inflammatory bowel disease.

Liu Jiawei J, Zhang Lin L, Li Xianghui X, Yang Mi M

To compare the therapeutic efficacy of a thioredoxin domain-containing protein 5 (TXNDC5) monoclonal antibody (mAb) against prednisolone and sulfasalazine in DSS-induced IBD-related intestinal fibrosis mouse models. A total of 48 C57BL/6 mice were randomly divided into four model groups (Group A-D, 12 animals per group), while seven extra mice were assigned to the blank control group. Intestinal fibrosis was induced in mice of Groups A to D via recurrent administration of 2% DSS solution. On day 26 post-modeling, five mice from each model group were sacrificed to validate model success, and the leftover animals were treated with corresponding drugs or saline for 14 successive days. Multiple detection indexes were assessed in this study, consisting of body weight, DAI score, colonic morphological features, serum levels of transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α), collagen deposition level as well as colonic TXNDC5 expression. One-way ANOVA coupled with Tukey's post hoc test was applied for all statistical analyses. The TXNDC5 mAb group presented better weight restoration and earlier DAI remission. It obtained longer colon length, lower colon weight, decreased serum inflammatory cytokines and milder collagen accumulation relative to the two conventional drug groups (all P < 0.05). Meanwhile, TXNDC5 mRNA and protein expression were significantly downregulated in the mAb group compared with prednisolone and sulfasalazine groups. No statistical difference was found between the two traditional medication groups. At the experimental doses adopted in the present study, TXNDC5 mAb showed more pronounced anti-inflammatory and anti-fibrotic effects than prednisolone in DSS-induced mice. However, due to the potentially sub-therapeutic sulfasalazine dose, its comparative superiority over sulfasalazine cannot be established from the current data. These findings should be considered preliminary and hypothesis-generating, requiring further validation in optimized experimental settings.

Eosinophilic Gastroenteritis during Tocilizumab Treatment for Castleman Disease.

Kaneko Hiromitsu H, Hayashino Kenta K, Kobayashi Hiroki H, Fujiwara Yuki Y et al.

Eosinophilic gastroenteritis (EGE) is a rare inflammatory disorder characterized by eosinophilic infiltration of the gastrointestinal tract and its associated symptoms. We report a case of EGE in a patient with idiopathic multicentric Castleman disease and asthma, who developed gastrointestinal symptoms and eosinophilia during tocilizumab therapy. Endoscopy revealed marked gastric mucosal injury and biopsy confirmed eosinophilic infiltration. Despite normal intestinal endoscopic findings, the biopsy specimens revealed eosinophilic infiltration. The discontinuation of tocilizumab and initiation of prednisolone resulted in complete symptom resolution, suggesting that the onset of EGE may have been associated with tocilizumab treatment.