The selective glucocorticoid receptor agonist mapracorat displays a favourable safety–efficacy ratio for the topical treatment of inflammatory skin diseases in dogs

Bäumer, Wolfgang; Roßbach, Kristine; Schmidt, Bernard

doi:10.1111/vde.12315

Cited by 10 publications

(6 citation statements)

References 15 publications

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“…GCs are potent anti‐inflammatory agents that have immune‐modulating activity (Cain & Cidlowski, ) and are often used for symptom relief (Tabas & Glass, ; Zhernakova, Withoff, & Wijmenga, ). However, the use of either short‐duration, high‐dose GCs or chronic GC maintenance therapy is associated with well‐known multi‐systemic side effects (Baumer, Rossbach, & Schmidt, ; Saridomichelakis & Olivry, ; Viviano, ).…”

Section: Introductionmentioning

confidence: 99%

Mycophenolic acid in patients with immune‐mediated inflammatory diseases: From humans to dogs

Klotsman

Sathyan

Anderson

et al. 2018

Vet Pharm & Therapeutics

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Mycophenolic acid (MPA), a noncompetitive, selective and reversible inhibitor of inosine 5′‐monophosphate dehydrogenase (IMPDH), is an immunosuppressive agent that has a long history in medicine. Mechanistically, the inhibition of IMPDH leads to the selective and eventual arrest of T‐ and B‐lymphocyte proliferation. Mycophenolate mofetil (MMF), the first MPA‐based product to receive marketing approval over two decades ago, was originally indicated for the prophylaxis of organ rejection in human transplant patients. Given its broad immunosuppressive properties and ability to selectively inhibit lymphocyte division and effector functions, the clinical utility of MPA was subsequently explored in a host of autoimmune diseases. Human clinical studies have shown MPA to be safe and effective and support its off‐label administration for immune‐mediated diseases such as lupus, myasthenia gravis and atopic dermatitis. MMF became generically available in the United States in 2008, and its clinical utility is increasingly being explored as a treatment option for dogs with immune‐mediated diseases. This review summarizes the available literature for MPA pharmacokinetics and pharmacodynamics, and the current status of MPA as a treatment for client‐owned dogs diagnosed with immune‐mediated diseases.

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Section: Introductionmentioning

confidence: 99%

Mycophenolic acid in patients with immune‐mediated inflammatory diseases: From humans to dogs

Klotsman

Sathyan

Anderson

et al. 2018

Vet Pharm & Therapeutics

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“…A comparison of the Mrgprs repertoires in dog and human revealed that dogs have MRGPR×2 and MRGPRD . Intradermal injection of compound 48/80 provokes immediate wheal and flare reactions in dogs and is considered a test system to evaluate drug efficacy in an immediate type hypersensitivity, such as glucocorticoids . The i.d.…”

Section: Discussionmentioning

confidence: 99%

Dose‐dependent pruritogenic and inflammatory effects of intradermal injections of histamine, compound 48/80 and anti‐canine IgE in healthy dogs

Banović

Denley

Blubaugh

2019

Veterinary Dermatology

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Background Scratching behaviours associated with intradermal (i.d.) injection of pruritogens such as histamine and compound 48/80 into the skin of mice and humans is the commonly used model to advance itch research and drug development. The predictive validity of this model is poorly documented in dogs. Objectives To evaluate the dose‐dependent effects of pruritogenic substances, each with a different mechanism of action, in healthy dogs. Animals Ten healthy laboratory beagles. Methods and materials All dogs were video‐recorded for 30 min post‐injection (mpi) of i.d. goat anti‐canine IgE (4 and 25 μg/site), histamine and compound 48/80 (50, 100, 200, 400 μg/site); two buffered saline injections served as controls. Two blinded investigators reviewed the pruritic behaviours of all video recordings. Global wheal scores were evaluated at 30 min by a blinded investigator. Results All dogs showed wheal and erythema at the pruritogen injection site; global wheal scores at 30 min of each substance significantly increased at all concentrations compared to control (P ≤ 0.05). A blinded evaluation revealed that all pruritogens induced mild acute pruritic behaviours at the site of injection. There was no injection site pain seen in any dog. Compared to controls, injections of pruritogens did not significantly affect the pruritic seconds or occurrence of pruritic episodes for any of the substances. Conclusions and clinical significance These preliminary results suggest that i.d. injections of the studied pruritogens can induce cutaneous wheal and flare response in healthy dogs; but inconsistencies occur in the induction of itch, even with the different concentrations of pruritogens.

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“…The first successful attempt at testing the activation/ repression hypothesis was reported by Vayssiere et al in 1997: the authors described several SEGRAM that separated in vitro TA and TR GR functions (RU24858, RU40066, and RU24782) [64]. Next generation of SEGRAM, compounds ZK245186 (Mapracorat/BOL-303242-X) and AL-438, demonstrated the affinity to GR close to Dex, the inhibition of the expression of inflammatory cytokines IL-1, IL-2, IL-8, prostaglandin-E2 and E-selectin as well as the antiinflammatory therapeutic activity in vivo but exhibiting less undesirable effects than synthetic Gcs [54,[65][66][67]. Other synthetic SEGRAMs, compounds CpdX and CpdX-D3 related to Mapracorat, also demonstrated promising results in in vivo studies [68,69].…”

Section: Development Of Dissociating Selective Gr Activators/ Modulat...mentioning

confidence: 99%

The long winding road to the safer glucocorticoid receptor (GR) targeting therapies

et al. 2022

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Glucocorticoids (Gcs) are widely used to treat inflammatory diseases and hematological malignancies, and despite the introduction of novel anti-inflammatory and anti-cancer biologics, the use of inexpensive and effective Gcs is expected to grow. Unfortunately, chronic treatment with Gcs results in multiple atrophic and metabolic side effects. Thus, the search for safer glucocorticoid receptor (GR)-targeted therapies that preserve therapeutic potential of Gcs but result in fewer adverse effects remains highly relevant. Development of selective GR agonists/modulators (SEGRAM) with reduced side effects, based on the concept of dissociation of GR transactivation and transrepression functions, resulted in limited success, and currently focus has shifted towards partial GR agonists. Additional approach is the identification and inhibition of genes associated with Gcs specific side effects. Others and we recently identified GR target genes REDD1 and FKBP51 as key mediators of Gcs-induced atrophy, and selected and validated candidate molecules for REDD1 blockage including PI3K/Akt/mTOR inhibitors. In this review, we summarized classic and contemporary approaches to safer GR-mediated therapies including unique concept of Gcs combination with REDD1 inhibitors. We discussed protective effects of REDD1 inhibitors against Gcs–induced atrophy in skin and bone and underlined the translational potential of this combination for further development of safer and effective Gcs-based therapies.

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The selective glucocorticoid receptor agonist mapracorat displays a favourable safety–efficacy ratio for the topical treatment of inflammatory skin diseases in dogs

Cited by 10 publications

References 15 publications

Mycophenolic acid in patients with immune‐mediated inflammatory diseases: From humans to dogs

Mycophenolic acid in patients with immune‐mediated inflammatory diseases: From humans to dogs

Dose‐dependent pruritogenic and inflammatory effects of intradermal injections of histamine, compound 48/80 and anti‐canine IgE in healthy dogs

The long winding road to the safer glucocorticoid receptor (GR) targeting therapies

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