The Safety and Efficacy of Roflumilast Cream 0.15% and 0.05% in Patients With Atopic Dermatitis: Randomized, Double-Blind, Phase 2 Proof of Concept Study.

BACKGROUND: Patients with atopic dermatitis (AD) need safe and effective topical treatments. OBJECTIVE: To assess safety and efficacy of roflumilast cream in patients with mild to moderate AD. METHODS: In this phase 2, proof of concept trial, patients (N=136) aged ≥12 years with AD were randomized to once-daily roflumilast cream 0.15%, roflumilast cream 0.05%, or vehicle cream for 4 weeks. Absolute change from baseline in Eczema Area and Severity Index (EASI) score at week 4 (primary endpoint), percentage change and responder rates, Validated Investigator Global Assessment-AD (vIGA-AD), and safety were assessed. RESULTS: At week 4, mean absolute changes in EASI were −6.4 (P=0.097 vs vehicle), −6.0 (P=0.356), and −4.8 with roflumilast 0.15%, roflumilast 0.05%, and vehicle, respectively. Significant improvements were observed for percentage change from baseline in EASI, patients reaching 75% improvement in EASI, and patients achieving vIGA-AD score of “clear” or “almost clear.” Treatment-related adverse events (AEs) occurred in 2 (2.2%) patients receiving roflumilast (mild rash and moderate application site pain). Only 1 (1.1%) patient receiving roflumilast discontinued study/drug due to an AE. LIMITATIONS: Small number of patients. CONCLUSIONS: Results support additional larger clinical trials of roflumilast cream to assess its potential as a once-daily, nonsteroidal topical AD treatment. CLINICALTRIALS: gov identifier NCT03916081 J Drugs Dermatol. 2023;22(2):139-147. doi:10.36849/JDD.7295.

Roflumilast Cream Improves Signs and Symptoms of Plaque Psoriasis: Results from a Phase 1/2a Randomized, Controlled Study.

Background: Roflumilast cream (ARQ-151) is a highly potent, selective phosphodiesterase-4 inhibitor in development for once-daily topical treatment of chronic plaque psoriasis. Objectives: To assess the safety and efficacy of once-daily roflumilast cream 0.5% and 0.15% in patients with chronic plaque psoriasis. Methods: This phase 1/2a study enrolled a single-dose, open-label cohort (Cohort 1: 0.5% cream applied to 25 cm² psoriatic plaques), and a 28-day, double-blinded cohort (Cohort 2: 1:1:1 randomization to roflumilast cream 0.5%, 0.15%, or vehicle). Patients had chronic plaque psoriasis of >6 months' duration with ≤5% body surface area involvement. Outcomes included safety (adverse events) and efficacy (percentage change in the Target Plaque Severity Score [TPSS] × Target Plaque Area [TPA]) at week 4. Results: For Cohorts 1 (n=8) and 2 (n=89), adverse events (all mild/moderate; none severe or serious) were similar between active arms and vehicle. Treatment-related events were confined to the application site, without differences between drug and vehicle. No patient discontinued treatment due to adverse events. The primary efficacy endpoint was met for both roflumilast cream doses: TPSS×TPA improvement at week 4 was statistically significant for roflumilast 0.5% (P=0.0007) and 0.15% (P=0.0011) versus vehicle; significance was reached as early as 2 weeks. For both roflumilast cream doses, 66%-67% improvement from baseline was observed at week 4, without reaching a plateau, versus 38% improvement for vehicle. Conclusion: Roflumilast cream was safe and highly effective at doses of 0.5% and 0.15% and represents a potential novel once-daily topical therapy for the treatment of chronic plaque psoriasis. ClinicalTrials.gov NCT03392168. J Drugs Dermatol. 2020;19(8): doi:10.36849/JDD.2020.5370.

Novel Square Arrangements in Tetranuclear and Octanuclear Iron(III) Complexes with Asymmetric Iron Environments Created by the Unsymmetric Bridging Ligand N,N,N'-Tris((N-methyl)-2-benzimidazolylmethyl)-N'-methyl-1,3-diamino-2-propanol.

The synthesis and characterization of novel tetranuclear and octanuclear iron(III) complexes with structures based on a nearly square arrangement of four iron ions are reported. Reaction of ferric nitrate, sodium acetate, and the unsymmetrical binucleating ligand HBMDP, where HBMDP is N,N,N'-tris((N-methyl)-2-benzimidazolylmethyl)-N'-methyl-1,3-diamino-2-propanol, in acetone/water yields the tetranuclear iron complex [Fe(4)(&mgr;-O)(2)(&mgr;-BMDP)(2)(&mgr;-OAc)(2)](4+), which exhibits coordination number asymmetry. The structure of [Fe(4)(&mgr;-O)(2)(&mgr;-BMDP)(2)(&mgr;-OAc)(2)](NO(3))(3)(OH).12H(2)O has been determined by single-crystal X-ray diffraction. Each (&mgr;-BMDP) ligand spans two iron(III) ions and causes these ions to become structurally distinct. Within this binuclear unit one iron atom is five-coordinate with distorted square pyramidal geometry and an N(2)O(3) donor set, while the other iron is six-coordinate with distorted octahedral geometry and an N(3)O(3) donor set. Two of these binuclear units are linked through a pair of oxo and acetato bridges to form the centrosymmetric tetranuclear complex. The coordinatively nonequivalent iron atoms exhibit distinct Mössbauer spectroscopic parameters and produce a pair of doublets at 80 K. The iron(III) centers are coupled antiferromagnetically with a room-temperature moment of 1.9 &mgr;(B) per iron with J = -103.3 cm(-)(1), zJ' = -105.9 cm(-)(1). The properties of the unsymmetric cation [Fe(4)(&mgr;-O)(2)(&mgr;-BMDP)(2)(&mgr;-OAc)(2)](4+) are similar to those observed for binuclear iron proteins with comparable coordinative inequivalence. Efforts to increase the solubility of [Fe(4)(&mgr;-O)(2)(&mgr;-BMDP)(2)(&mgr;-OAc)(2)](4+) by metathesis with sodium tetrafluoroborate resulted in the isolation of crystals of a new octanuclear iron species, [Fe(8)(&mgr;-O)(4)(&mgr;-BMDP)(4)(OH)(4)(&mgr;-OAc)(4)](BF(4))(3)(OH).2CH(3)CN.8H(2)O( )()(2), which has also been characterized by single-crystal X-ray diffraction. The asymmetric unit consists of an Fe(2)(&mgr;-O)(&mgr;-BMDP)(&mgr;-OAc)(OH) group which is externally bridged via the oxo ions to form a molecular square with four of the eight iron ions at the corners. Both iron sites are six-coordinate with distorted octahedral geometry. One has an N(2)O(4) donor set; the other has an N(3)O(3) donor set.

Pure-rotational spectrometry: a vintage analytical method applied to modern breath analysis.

Pure-rotational spectrometry (PRS) is an established method, typically used to study structures and properties of polar gas-phase molecules, including isotopic and isomeric varieties. PRS has also been used as an analytical tool where it is particularly well suited for detecting or monitoring low-molecular-weight species that are found in exhaled breath. PRS is principally notable for its ultra-high spectral resolution which leads to exceptional specificity to identify molecular compounds in complex mixtures. Recent developments using carbon aerogel for pre-concentrating polar molecules from air samples have extended the sensitivity of PRS into the part-per-billion range. In this paper we describe the principles of PRS and show how it may be configured in several different modes for breath analysis. We discuss the pre-concentration concept and demonstrate its use with the PRS analyzer for alcohols and ammonia sampled directly from the breath.