Characterization of a novel non-steroidal glucocorticoid receptor agonist optimized for topical treatment

Eirefelt, Stefan; Stahlhut, Martin; Svitacheva, Naila; Carnerup, Martin A.; Rosa, Joel Correa da; Ewald, David Adrian; Marstrand, Troels; Krogh-Madsen, Mikkel; Dünstl, Georg; Dack, Kevin N.; Ollerstam, Anna; Norsgaard, Hanne

doi:10.1038/s41598-022-05471-w

Cited by 8 publications

(3 citation statements)

References 38 publications

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“…A topical use of GCs is common in this context and the drug repertoire has been constantly growing. For example, a new non-steroidal GR agonist LEO134310 has been recently characterized with an advantage of a rapid deactivation in the blood [ 55 ]. In addition, inhaled GCs have been SoC in asthma and COPD for many years.…”

Section: Know Your Drug and Its Targetsmentioning

confidence: 99%

Renaissance of glucocorticoids in critical care in the era of COVID-19: ten urging questions

et al. 2022

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The 40-year-old experience with glucocorticosteroids (GCs) in the context of severe infections is complex and troublesome. Recently, however, a clear indication for GCs in severe COVID-19 has been established. This may constitute a harbinger of a wider use of GCs in critical illnesses. A fundamental prerequisite of such an action is a better understanding of the heterogeneity of critical illness and GCs operationalization within the precision medicine approach. In this perspective, we formulate ten major questions regarding the use of GCs in critical illness. Answering them will likely facilitate a new era of effective and personalized GCs use in modern critical care.

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Section: Know Your Drug and Its Targetsmentioning

confidence: 99%

Renaissance of glucocorticoids in critical care in the era of COVID-19: ten urging questions

et al. 2022

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“…The SEGRA LEO134310 demonstrated efficacy after topical application in human and mouse skin models, with significantly less skin atrophy compared to classical steroids. Safety, tolerability, and pharmacodynamics effects of LEO134310 were evaluated in a phase 1b study in adults with chronic plaque psoriasis, but the data have not yet been published [ 55 , 57 ].…”

Section: Discussionmentioning

confidence: 99%

Skin Anti-Inflammatory Potential with Reduced Side Effects of Novel Glucocorticoid Receptor Agonists

Flori,

Mosca,

Kovacs

et al. 2023

IJMS

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Glucocorticoids (GCs) are commonly used in the treatment of inflammatory skin diseases, although the balance between therapeutic benefits and side effects is still crucial in clinical practice. One of the major and well-known adverse effects of topical GCs is cutaneous atrophy, which seems to be related to the activation of the glucorticoid receptor (GR) genomic pathway. Dissociating anti-inflammatory activity from atrophogenicity represents an important goal to achieve, in order to avoid side effects on keratinocytes and fibroblasts, known target cells of GC action. To this end, we evaluated the biological activity and safety profile of two novel chemical compounds, DE.303 and KL.202, developed as non-transcriptionally acting GR ligands. In primary keratinocytes, both compounds demonstrated anti-inflammatory properties inhibiting NF-κB activity, downregulating inflammatory cytokine release and interfering with pivotal signaling pathways involved in the inflammatory process. Of note, these beneficial actions were not associated with GC-related atrophic effects: treatments of primary keratinocytes and fibroblasts with DE.303 and KL.202 did not induce, contrarily to dexamethasone—a known potent GC—alterations in extracellular matrix components and lipid synthesis, thus confirming their safety profile. These data provide the basis for evaluating these compounds as effective alternatives to the currently used GCs in managing inflammatory skin diseases.

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“…The Göttingen Minipig is the commonly used pig strain by the pharmaceutical industry, as they are genetically coherent and well-characterized, and by using the same strain, pharmaceutical companies can rely on historical control data when interpreting findings in drug safety studies ( 9 ). Minipigs have already been used as animal models for several clinical indications such as cardiovascular ( 10 ), dental conditions ( 11 ), diabetes ( 12 ), heart disease ( 13 ), skin conditions ( 14 , 15 ), and acute and chronic intestinal inflammation ( 2 , 16 ). Furthermore, the neonatal Göttingen Minipig shares a striking number of developmental similarities with human neonates ( 17 – 21 ).…”

Section: Introductionmentioning

confidence: 99%

Development of a neonatal Göttingen Minipig model for dose precision in perinatal asphyxia: technical opportunities, challenges, and potential further steps

Stroe,

Van Bockstal,

Valenzuela

et al. 2023

Front. Pediatr.

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Animal models provide useful information on mechanisms in human disease conditions, but also on exploring (patho)physiological factors affecting pharmacokinetics, safety, and efficacy of drugs in development. Also, in pediatric patients, nonclinical data can be critical for better understanding the disease conditions and developing new drug therapies in this age category. For perinatal asphyxia (PA), a condition defined by oxygen deprivation in the perinatal period and possibly resulting in hypoxic ischemic encephalopathy (HIE) or even death, therapeutic hypothermia (TH) together with symptomatic drug therapy, is the standard approach to reduce death and permanent brain damage in these patients. The impact of the systemic hypoxia during PA and/or TH on drug disposition is largely unknown and an animal model can provide useful information on these covariates that cannot be assessed separately in patients. The conventional pig is proven to be a good translational model for PA, but pharmaceutical companies do not use it to develop new drug therapies. As the Göttingen Minipig is the commonly used pig strain in nonclinical drug development, the aim of this project was to develop this animal model for dose precision in PA. This experiment consisted of the instrumentation of 24 healthy male Göttingen Minipigs, within 24 h of partus, weighing approximately 600 g, to allow the mechanical ventilation and the multiple vascular catheters inserted for maintenance infusion, drug administration and blood sampling. After premedication and induction of anesthesia, an experimental protocol of hypoxia was performed, by decreasing the inspiratory oxygen fraction (FiO2) at 15%, using nitrogen gas. Blood gas analysis was used as an essential tool to evaluate oxygenation and to determine the duration of the systemic hypoxic insult to approximately 1 h. The human clinical situation was mimicked for the first 24 h after birth in case of PA, by administering four compounds (midazolam, phenobarbital, topiramate and fentanyl), frequently used in a neonatal intensive care unit (NICU). This project aimed to develop the first neonatal Göttingen Minipig model for dose precision in PA, allowing to separately study the effect of systemic hypoxia versus TH on drug disposition. Furthermore, this study showed that several techniques that were thought to be challenging or even impossible in these very small animals, such as endotracheal intubation and catheterization of several veins, are feasible by trained personnel. This is relevant information for laboratories using the neonatal Göttingen Minipig for other disease conditions or drug safety testing.

show abstract

Characterization of a novel non-steroidal glucocorticoid receptor agonist optimized for topical treatment

Cited by 8 publications

References 38 publications

Renaissance of glucocorticoids in critical care in the era of COVID-19: ten urging questions

Renaissance of glucocorticoids in critical care in the era of COVID-19: ten urging questions

Skin Anti-Inflammatory Potential with Reduced Side Effects of Novel Glucocorticoid Receptor Agonists

Development of a neonatal Göttingen Minipig model for dose precision in perinatal asphyxia: technical opportunities, challenges, and potential further steps

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