Abstract— Four black and white female Saluki puppies developed variably severe hypotrichosis in black haired areas. Histologically, follicles in black haired areas were dilated with keratin and clumps of melanin pigment, and were irregularly shaped. Melanin pigment was also clumped in hair shafts, basal layer of epidermis, epithelial cells of hair bulbs and macrophages around follicles, especially at the base. White haired areas were normal grossly and histologically. Light microscopic examination of dehydrated and cleared primary black hair shafts from one Saluki with black hair follicular dysplasia and primary blue hair shafts from two blue Doberman pinschers with color mutant alopecia revealed that the blue Dobermans had many more visible macromelanosomes than the Saluki. On scanning electron microscopy, cuticular abnormalities were identified in some white and all black hairs from the Saluki. Several black hairs had shallow, oval defects in the superficial cortex. Blue hairs from one Doberman had similar, but more extensive changes. Résumé— Quatre chiots femelles Saluki noirs et blancs ont développé une hypotrichose plus ou moins étendue des zones de poils noirs. Sur le plan histologique, les follicules pileux des zones de poils noirs étalent dilatés, de forme irrégulière et obstrué par des bouchons de keratine et de mélanine. Des pigments mélaniques en motte sont aussi retrouvés dans la lumière des poits, les cellules basales de l'epiderme, les cellules épithéliales de bulbes pileux et les macrophages entourant les follicules pileux. Les zones de poils blancs étaient normales, tant macroscopiquement que micrioscopiquement. L'examen en microscopie optique de poils noirs primaires deshydratés et éclaircis provenant d'un de ces Saluki et de deux Doberman atteints d'alopécle des mutants de couleur a révélé un beaucoup plus grand nombre de macromélanosomes chez les Dobermans que chez le Saluki. En microscopie électronique à balayage des anomalies de la cuticule ont été observées sur quelques poils blancs et tous les poils noirs des Salukis. Plusieurs poils noirs présentaiert des déformations ovales peu profondes de la cuticule. Les poils bleus des Dobermans présentaient le même type de déformation, mais de façon plus étendue. Zusammenfassung— Vier schwarz‐weiße weibliche Salukiwelpen entwickelten abwechselnd eine schwere Hypotrichose in den schwarzgefärbten Fellbezirken. Im histologischen Bild waren die Follikel in den schwarzgefärbten Fellbezirken durch Keratin und Melaninpigmentklumpen dilatiert sowie unregelmäßig geformt. Das Melaninpigment war in den Haarschäften, in der Basalzellschicht der Epidermis, den Epitheizellen der Haarbulbi und den Makrophagen um die Follikel, besonders an der Basis, ebenfalls zusammengekiumpt. Die weißen Fellbezirke waren makroskopisch und histologisch unverändert. Die lichtmikroskopische Untersuchung von dehydrierten und aufgehellten Schäften schwarzer Primärhaare eines Salukis mit follikulärer Dysplasie schwarzer Haare und der Untersuchung der Haarschäfte blauer Primärhaare zweie...

BackgroundOptions are limited for patients with atopic dermatitis (AD) who do not respond to topical treatments. Antifolate therapy with systemic methotrexate improves the disease, but is associated with adverse effects. The investigational antifolate LD-aminopterin may offer improved safety. It is not known how antifolate dose and dosing frequency affect efficacy in AD, but a primary mechanism is thought to involve the antifolate-mediated accumulation of 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR). However, recent in vitro studies indicate that AICAR increases then decreases as a function of antifolate concentration. To address this issue and understand how dosing affects antifolate efficacy in AD, we examined the efficacy and safety of different oral doses and schedules of LD-aminopterin in the canine model of AD.Methods and FindingsThis was a multi-center, double-blind trial involving 75 subjects with canine AD randomized to receive up to 12 weeks of placebo, once-weekly (0.007, 0.014, 0.021 mg/kg) or twice-weekly (0.007 mg/kg) LD-aminopterin. The primary efficacy outcome was the Global Score (GS), a composite of validated measures of disease severity and itch. GS improved in all once-weekly cohorts, with 0.014 mg/kg being optimal and significant (43%, P<0.01). The majority of improvement was seen by 8 weeks. In contrast, GS in the twice-weekly cohort was similar to placebo and worse than all once-weekly cohorts. Adverse events were similar across all treated cohorts and placebo.ConclusionsOnce-weekly LD-aminopterin was safe and efficacious in canine AD. Twice-weekly dosing negated efficacy despite having the same daily and weekly dose as effective once-weekly regimens. Optimal dosing in this homologue of human AD correlated with the concentration-selective accumulation of AICAR in vitro, consistent with AICAR mediating LD-aminopterin efficacy in AD.