piperidines and teriflunomide

Topics: Acetanilides; Adrenergic beta-Agonists; Anti-Asthmatic Agents; Anti-Retroviral Agents; Bronchodilator Agents; Citrates; Crotonates; Drug Approval; Humans; Hydroxybutyrates; Immunosuppressive Agents; Laxatives; Nitriles; Organometallic Compounds; Peptides; Picolines; Piperidines; Pyrimidines; Pyrroles; Quinolones; Receptors, Guanylate Cyclase-Coupled; Thiazoles; Toluidines; Tropanes

Translational animal models are essential in the prediction of the efficacy and side effects of new chemical entities. We have carried out a thorough study of three distinct disease-modifying antirheumatic drugs (DMARDs) in an adjuvant-induced arthritis (AIA) model in the rat and critically appraised the results in the context of the reported clinical experience in rheumatoid arthritis (RA) patients.. Teriflunomide - a dihydroorotate dehydrogenase (DHODH) inhibitor; AL8697 - a selective p38 MAPK inhibitor; and tofacitinib - a Janus kinase (JAK) inhibitor; were selected as representatives of their class and dose-response studies carried out using a therapeutic 10-day administration scheme in arthritic rats. Paw swelling and body weight were periodically monitored, and joint radiology and histology, lymph organ weight and haematological and biochemical parameters evaluated at study completion.. All three drugs demonstrated beneficial effects on paw swelling, bone lesions and splenomegalia, with p38 inhibition providing the best anti-inflammatory effect and JAK inhibition the best DMARD effect. Leukopenia, body weight loss and gastrointestinal toxicity were dose-dependently observed with teriflunomide treatment. p38 MAPK inhibition induced leukocytosis and increased total plasma cholesterol. JAK inhibition, normalized platelet, reticulocyte and neutrophil counts, and alanine aminotransferase (ALT) levels while inducing lymphopenia and cholesterolemia.. This multiparametric approach can reveal specific drug properties and provide translational information. Whereas the complex profile for p38 inhibition in AIA is not observed in human RA, immunosuppressants such as DHODH and JAK inhibitors show DMARD properties and side effects seen in both AIA and RA.

Topics: Animals; Antirheumatic Agents; Arthritis, Experimental; Benzamides; Bridged Bicyclo Compounds, Heterocyclic; Crotonates; Dihydroorotate Dehydrogenase; Dose-Response Relationship, Drug; Edema; Enzyme Inhibitors; Gastrointestinal Tract; Half-Life; Hydroxybutyrates; Hypercholesterolemia; Immunosuppressive Agents; Janus Kinases; Joints; Leukocyte Disorders; Male; Nitriles; Oxidoreductases Acting on CH-CH Group Donors; p38 Mitogen-Activated Protein Kinases; Piperidines; Pyrimidines; Pyrroles; Rats; Rats, Wistar; Splenomegaly; Toluidines; Weight Loss

The aim of this work was to investigate the effect of the stability of hydrogen-bonded ion pairs with organic amines on transdermal penetration of teriflunomide (TEF). Five organic amines, diethylamine (DEtA), triethylamine (TEtA), diethanolamine (DEA), triethanolamine (TEA), and N-(2'-hydroxyethanol)-piperdine (NP), were chosen to form ion pairs with TEF separately, and the passage of each TEF ion pair through the rabbit skin was evaluated in vitro. FTIR and (1)H NMR spectroscopy were performed to confirm the formation of ion pairs between TEF and organic amines in solution. The stability parameter of ion pairs in terms of ion-pair lifetimes (T(life)) was calculated from the NMR data. TEF could form ion pairs with these amines via hydrogen bond. The formation of ion pairs enhanced the percutaneous absorption of TEF except TEF-DEA. It was found that, for most studied organic amines, the longer the ion-pair lifetime, the higher the flux of skin permeation. The stability of TEF ion pairs was a pivotal factor influencing the skin permeation of TEF.

Topics: Administration, Cutaneous; Amines; Animals; Crotonates; Hydrogen Bonding; Hydroxybutyrates; In Vitro Techniques; Nitriles; Palmitates; Piperidines; Rabbits; Skin Absorption; Toluidines