ABSTRACT
Background: Apremilast, an oral phosphodiesterase 4 inhibitor, is approved in the European Union for the treatment of moderate-to-severe chronic plaque psoriasis in adult patients refractory or contraindicated to or intolerant of other systemic therapies. Objectives: The APPRECIATE study assessed apremilast use in real-world practice and its clinical value to physicians and patients. APPRECIATE was a multinational, observational, retrospective, cross-sectional study. Methods: Apremilast effectiveness at 6 (±1) months was assessed on the basis of psoriasis severity and health-related quality-of-life scores and treatment satisfaction using physician/patient-reported outcomes, respectively. We report the Austrian cohort of 72 patients. Results: At 6 (±1) months, three-quarters of patients remained on apremilast, while physicians and patients reported treatment benefits across all psoriasis symptoms and manifestations. Of patients, the majority were satisfied with their treatment and achieved treatment goals considered most relevant. Patients' and physicians' perceptions of treatment effectiveness were aligned, and health-related quality-of-life scores indicated an improvement in the majority of patients. Apremilast tolerability was consistent with the known safety profile. Conclusions: Among psoriasis patients receiving apremilast in Austria, improvement in clinical outcomes were observed and satisfaction with apremilast treatment among patients and physicians was high. Registration: ClinicalTrials.gov NCT02740218.
ABSTRACT
The family of secreted aspartic proteinases is known as an important virulence factor of yeast infections by Candida albicans in particular, which is the most common fungal pathogen for humans with respect to systemic disease. Due to the continuing increase of drug resistant strains, these proteinases are currently considered as promising drug target candidates. Based on the known Sap2-substrate specificity data and X-ray analyses of Sap/inhibitor complexes, three libraries of inhibitors were designed and synthesized by modifying the structure of pepstatin A, a common non-selective aspartic proteinase inhibitor, at the P3, P2, or P2' position. These novel inhibitors showed high inhibitory potencies for the isoenzymes Sap1, Sap3, Sap5 and Sap6. Then, the affinity and selectivity of the peptide ligands were investigated by molecular modeling, highlighting new key structural information for the design of potent and selective anti-virulence agents targeting Candida albicans.
Subject(s)
Antifungal Agents/chemistry , Aspartic Acid Endopeptidases/antagonists & inhibitors , Candida albicans/enzymology , Fungal Proteins/antagonists & inhibitors , Models, Molecular , Pepstatins/chemistry , Antifungal Agents/chemical synthesis , Aspartic Acid Endopeptidases/chemistry , Drug Design , Fungal Proteins/chemistry , Isoenzymes/antagonists & inhibitors , Isoenzymes/chemistry , Pepstatins/chemical synthesis , Structure-Activity RelationshipABSTRACT
Modern tissue culture technology has made it possible to generate human skin equivalents that represent either epidermis or epidermis plus dermis (full-thickness skin) in vitro. Commercially available skin equivalents and in-house models are used for safety analysis of cosmetics and toxicity screening of various pharmaceutical compounds. Recently, tissue culture technology has also been used to develop in vitro models of skin disease, in particular to promote cutaneous drug research while sparing experimental animals. The spectrum of model diseases available covers a range from inflammatory disease to cancer. It has, thus, been possible to gain more insight into the role of active pharmaceutical ingredients of various dermatologically relevant drug classes as well as conventional and innovative formulations.
Subject(s)
Animal Testing Alternatives , Drug-Related Side Effects and Adverse Reactions , Models, Biological , Skin Diseases/drug therapy , Skin/drug effects , Animals , Drug Discovery , Epithelium/drug effects , Humans , Skin Diseases/etiology , Tissue Culture TechniquesABSTRACT
Stems of Opuntia ficus-indica (L.) Mill. (OFI) are traditionally used in Mexico to treat diabetes mellitus. Less research data are available for combinations of stem and fruit preparations. The present study was designed to investigate the effects of an aqueous extract prepared from the cladodes and a proprietary stem/fruit skin-blend (stem/fruit skin ratio 75/25) of OFI on blood glucose and plasma insulin in normal rats. A dose finding study with the traditional cladode OFI extract revealed that maximum effects on blood glucose and insulin were observed after oral administration in a dose range of 6-176 mg/kg. The proprietary OFI blend significantly lowered blood glucose levels in the glucose tolerance test to a similar extent (p < 0.05 vs control) as the traditional aqueous cladode extract when administered in a dose of 6 mg/kg. In contrast to the aqueous extract, the proprietary blend significantly increased basal plasma insulin levels (p < 0.01 vs control) indicating a direct action on pancreatic beta cells. The results suggest that both OFI extracts exert hypoglycemic activities in rats in doses as low as 6 mg/kg but that the effects of the proprietary stem/fruit blend were more pronounced in our model.
