Putative antimicrobial-associated phototoxicity in three dogs.

This case series describes putative doxycycline phototoxicity in three dogs, with one also undergoing a possible sulfamethoxazole phototoxic reaction.

Cette série de cas décrit la possible phototoxicité de la doxycycline chez trois chiens, à laquelle s'ajouterait une possible réaction phototoxique au sulfaméthoxazole chez l'un des chiens.

Está serie de casos describe una posible reacción de fototoxicidad en tres perros, junto con otro también sufriendo una posible reacción fototóxica por administración de sulfametoxazol.

Esta série de casos descreve a fototoxicidade putativa da doxiciclina em três cães, sendo que um também passou por uma possível reação de fototoxicidade por sulfametoxazol.

Cytokine expression in feline allergic dermatitis and feline asthma.

BACKGROUND: The pathogenesis of feline allergic dermatitis (FAD) is unclear, with several differences from allergic dermatitis in dogs and humans. HYPOTHESIS/OBJECTIVES: To survey cytokine expression levels in healthy cats and cats affected with allergic dermatitis or asthma. ANIMALS: Formalin-fixed, paraffin-embedded skin biopsies from 22 cats with allergic dermatitis and 21 cats without allergic dermatitis were used for cutaneous assays. Serum was obtained from 17 healthy cats, 18 cats with allergic dermatitis, and 18 cats with a presumptive diagnosis of asthma. METHODS AND MATERIALS: Cutaneous mRNA expression was evaluated with quantitative PCR [interleukin (IL)-31 and IL-31 Receptor A] and RNA in situ hybridisation (ISH) [IL-5, IL-31, IL-31RA, IL-33 and Oncostatin M receptor (OSMR)-ß]. IL-31 protein concentrations were evaluated in serum with an enzyme-linked immunosorbent assay. Serum levels of 19 additional cytokines were evaluated using a Luminex panel. RESULTS: IL-31, IL-31RA, IL-5 and IL-33 mRNA expression were either expressed in low quantities or undetectable in most samples. By contrast, OSMR-ß expression was significantly higher in the skin of allergic versus healthy cats (P < 0.0001). Although serum IL-31 was detected in a larger number of cats with allergic dermatitis than healthy cats, and concentrations appeared to be higher in cats with allergies, this difference was not statistically significant. Cats affected by asthma also exhibited insignificantly higher concentrations of IL-31 in the serum. CONCLUSIONS AND CLINICAL RELEVANCE: Our results suggest that feline allergic diseases may exhibit different pathomechanisms from allergic diseases affecting other species. These findings are useful in guiding further therapeutic development toward targets that may have a role in the pathogenesis of feline allergic skin disease.

Benzoxazolinone aryl sulfonamides as potent, selective Nav1.7 inhibitors with in vivo efficacy in a preclinical pain model.

Studies on human genetics have suggested that inhibitors of the Nav1.7 voltage-gated sodium channel hold considerable promise as therapies for the treatment of chronic pain syndromes. Herein, we report novel, peripherally-restricted benzoxazolinone aryl sulfonamides as potent Nav1.7 inhibitors with excellent selectivity against the Nav1.5 isoform, which is expressed in the heart muscle. Elaboration of initial lead compound 3d afforded exemplar 13, which featured attractive physicochemical properties, outstanding lipophilic ligand efficiency and pharmacological selectivity against Nav1.5 exceeding 1000-fold. Key structure-activity relationships associated with oral bioavailability were leveraged to discover compound 17, which exhibited a comparable potency/selectivity profile as well as full efficacy following oral administration in a preclinical model indicative of antinociceptive behavior.

Clinical and microscopic features of generalized discoid lupus erythematosus in dogs (10 cases).

BACKGROUND: Generalized discoid lupus erythematosus (GDLE) is a newly recognized canine variant of chronic cutaneous lupus erythematosus (CLE) that is not well characterized. HYPOTHESIS/OBJECTIVES: We report herein the signalment, clinical signs, treatment outcome, histopathology and immunological findings of 10 dogs with GDLE. METHODS: Inclusion criteria were: (i) a >3 month history of generalized skin lesions indicating a chronic or recurrent nature; (ii) skin lesions resembling those of human GDLE; (iii) histopathology of CLE (lymphocyte-rich interface dermatitis). Direct immunofluorescence (IF) and antinuclear antibody serology were investigated whenever possible. RESULTS: Various breeds were affected in their mid- to late adulthood. Selection criteria of generalized multifocal, annular ("discoid") to polycyclic plaques with pigment changes, erythematous margin, adherent scaling, follicular plugging and central alopecia were shown in all dogs. In nine dogs, plaques contained mild to moderate central scarring with depigmentation and/or hyperpigmentation. There were no dogs in which the disease progressed to systemic lupus erythematosus within a median follow-up of 2.5 years. Per inclusion criteria, interface dermatitis occurred with basement membrane zone (BMZ) thickening, suprabasal apoptosis and/or dermal fibrosis in some dogs. Infundibular interface folliculitis was common; it sometimes transitioned to mural folliculitis in lower follicle segments, and occurred with follicular and sebaceous gland atrophy. The direct IF revealed patchy deposition of immunoglobulin IgG and IgM at the BMZ. Lesions responded to a variety of treatments, including ciclosporin, hydroxychloroquine, topical tacrolimus and tetracycline/niacinamide. Relapses were common after medications were tapered. CONCLUSIONS AND CLINICAL IMPORTANCE: These observations support the existence of a canine homologue of human GDLE.

Optimization of Novel Aza-benzimidazolone mGluR2 PAMs with Respect to LLE and PK Properties and Mitigation of CYP TDI.

Investigation of a novel amino-aza-benzimidazolone structural class of positive allosteric modulators (PAMs) of metabotropic glutamate receptor 2 (mGluR2) identified [2.2.2]-bicyclic amine 12 as an intriguing lead structure due to its promising physicochemical properties and lipophilic ligand efficiency (LLE). Further optimization led to chiral amide 18, which exhibited strong in vitro activity and attractive pharmacokinetic (PK) properties. Hypothesis-driven target design identified compound 21 as a potent, highly selective, orally bioavailable mGluR2 PAM, which addressed a CYP time-dependent inhibition (TDI) liability of 18, while maintaining excellent drug-like properties with robust in vivo activity in a clinically validated model of antipsychotic potential.

Mucocutaneous lupus erythematosus in dogs (21 cases).

BACKGROUND: The diagnosis of dogs with chronic juxtamucosal erosive lesions and histopathology typical of cutaneous lupus erythematosus (CLE) is unclear. HYPOTHESIS/OBJECTIVES: We report herein 21 dogs with mucocutaneous erosive lesions and lupus-specific histopathology that we propose to be affected with mucocutaneous lupus erythematosus (MCLE), another variant of chronic CLE. METHODS: Inclusion criteria were the presence of the following: (i) a >2 month history of chronic or recurrent skin lesions; (ii) erosions or ulcers predominating at mucosae or mucocutaneous junctions; (iii) microscopic lesions of CLE (i.e. a lymphocyte-rich interface dermatitis with basal keratinocyte damage); and (iv) a lack of complete remission following antimicrobials. Clinical questionnaires and skin biopsies were reviewed. Direct immunofluorescence and antinuclear antibody serology were performed whenever possible. RESULTS: More than half of the 21 dogs were German shepherds or their crosses. The disease affected mostly dogs in their mid-adulthood and there was an over-representation of females. Erosions and ulcers predominated at genital/perigenital and anal/perianal areas, with a lower frequency of involvement of periocular, perioral and perinasal regions. In these dogs, there were no clinical signs suggestive of an associated systemic lupus erythematosus. Microscopic lesions were specific for CLE, but they were patchy and often infected with bacteria. The most common immunological finding was focal IgG deposition at the basement membrane zone. Lesions responded to varying interventions, but oral glucocorticoids led to a shorter time to complete remission. Relapses were common upon treatment tapering. CONCLUSIONS AND CLINICAL IMPORTANCE: These observations support MCLE being another variant of canine CLE.

Generalized canine discoid lupus erythematosus responsive to tetracycline and niacinamide therapy.

Discoid lupus erythematosus (DLE) is a commonly reported canine autoimmune disease that normally presents with a phenotype consisting of erythema, depigmentation, scaling, erosions/ulcers, and scarring over the nasal planum and the proximal dorsal muzzle. Recently, two cases of a generalized variant of this disease have been reported, whose lesions responded to either systemic glucocorticoids or a combination of topical corticosteroids, topical tacrolimus, and the oral antimalarial hydroxychloroquine. The purpose of this report is to describe an 11 yr old shih tzu that presented with skin lesions consisting of multiple annular, erythematous papules and plaques, hyperpigmentation, adherent scaling, and atrophic scars over the caudal dorsum, flanks, craniodorsal thorax, and lateroproximal extremities. A diagnosis of generalized DLE was made based on the clinical presentation, histopathology, laboratory values, and direct immunofluorescence findings. Treatment consisted of oral tetracycline and oral niacinamide, which resulted in complete remission of clinical signs. This is the first documented report of generalized canine DLE responding to the described immunomodulating regimen. Such a combination might therefore be considered as a glucocorticoid and/or antimalarial alternative for the management of generalized DLE.

Concurrent Bartonella henselae infection in a dog with panniculitis and owner with ulcerated nodular skin lesions.

BACKGROUND: Bartonella henselae, a Gram-negative, zoonotic Alphaproteobacteria that infects erythrocytes, endothelial cells and dendritic cells, has previously been implicated as a cause of panniculitis in dogs and a human. ANIMAL AND OWNER: An 8-year-old, spayed female Labrador retriever and its 78-year-old male owner living in the same household. METHODS AND RESULTS: When preliminary and advanced testing failed to identify the cause of near-simultaneous-onset dermatological lesions, Bartonella serology, Bartonella Alphaproteobacteria growth medium (BAPGM) enrichment blood culture/PCR and immunohistochemistry were used to test specimens from the dog and owner. Bartonella henselae, genotype San Antonio 2 DNA was amplified and sequenced from the man's BAPGM enrichment blood culture and the dog's panniculitis lesion. The bacterium was visualized by immunohistochemistry in the dog's panniculitis lesion; however, neither the dog nor the owner was B. henselae seroreactive. Antibiotic therapy elicited dermatological improvement in both dog and owner. CONCLUSIONS AND CLINICAL IMPORTANCE: Bartonella henselae is an emerging zoonotic pathogen that induces granulomatous inflammatory lesions in various tissues of animals, including humans. We conclude that this bacterium had a contributory or causative role in the development of the dermatological lesions in the dog and owner.

Breast artery calcium noted on screening mammography is predictive of high risk coronary calcium in asymptomatic women: a case control study.

BACKGROUND: The relationship between breast artery calcification (BAC) noted on mammography and both coronary artery disease and cardiovascular risk remains controversial. Few studies have examined the clinical significance of BAC in asymptomatic women. In the present study we evaluated the relationship between BAC and coronary artery calcium (CAC) as identified by multi-slice CT scanning (MSCT). PATIENTS AND METHODS: Consecutive women (n = 98) with BAC noted on routine mammography but without known coronary artery disease (CAD) were assessed for CAD risk factors and had assessment of coronary calcium by MSCT. A control cohort of consecutive women who were BAC(-) (n = 104) underwent an identical assessment. RESULTS: Women who were BAC(+) were older than those who were BAC(-); otherwise, there were no differences between the 2 groups with regard to traditional cardiac risk factors. Significantly more BAC(+) vs. BAC(-) women were found to have “high risk” CAC scores, defined as CAC > 400 (11.2 % vs. 1.0 %, p = 0.006). However, the rates of CAC scores of 0 were not different between the two groups (50.0 % vs. 54.8 % for BAC(+) and BAC(-) , respectively, p = 0.586). When examined in a multivariate model including the traditional risk factors of diabetes, increasing age, smoking, hyperlipidemia, and family history of CAD, the presence of BAC remained significantly associated with CAC > 400 (OR = 22.6, 95 % CI = 2.1 - 237.1). CONCLUSIONS: The presence of breast artery calcium on screening mammography was a strong independent predictor (odds ratio > 22) of high risk coronary artery calcium scores (defined as CAC > 400). The presence of BAC in those with significant CAD risk factors may warrant further evaluation.

A pilot study of the validation of percutaneous testing in cats.

BACKGROUND: Intradermal testing is useful for the identification of environmental allergens to which cats could be hypersensitive; intradermal test reactions are often subtle and difficult to interpret in cats. Percutaneous testing is the standard technique for the detection of significant environmental allergens in people, but it has not yet been evaluated in cats with hypersensitivity dermatitis. HYPOTHESIS/OBJECTIVES: The purpose of this study was to evaluate and compare the skin test responses of healthy cats to percutaneous application and intradermal injections of control solutions. METHODS: Ten clinically healthy cats were studied. Percutaneous applications of 0.0275 and 0.1 mg/mL aqueous histamine, 6 mg/mL glycerinated histamine, 0.9% buffered saline and 50% glycerosaline solution were performed using Greer Pick (Greer Laboratories, Lenoir, NC, USA) and Duotip-Test II (Lincoln Diagnostics, Decatur, IL, USA) percutaneous applicators. Reactions were compared with intradermal injections of 0.0275 mg/mL aqueous histamine and 0.9% buffered saline as controls. RESULTS: Positive responses to histamine solutions were significantly greater with the Greer Pick than with the Duotip-Test II. There were no significant differences between the histamine reactions using the Greer Pick applicator and the intradermal injections. Percutaneous reactions to histamine were more well demarcated and easier to read than intradermal injection reactions. Reactions to the saline controls were not noted. CONCLUSIONS AND CLINICAL IMPORTANCE: Percutaneous application of 6 mg/mL glycerinated histamine solution, 50% glycerosaline solution and 0.9% buffered saline produced similar positive and negative control wheals. These observations warrant further studies of percutaneous allergen testing in cats with hypersensitivity dermatitis.

Allosteric inhibitors of Akt1 and Akt2: discovery of [1,2,4]triazolo[3,4-f][1,6]naphthyridines with potent and balanced activity.

A series of [1,2,4]triazolo[3,4-f][1,6]naphthyridine allosteric dual inhibitors of Akt1 and 2 have been developed. These compounds have been shown to have potent dual Akt1 and 2 cell potency. The representative compound 13 provided potent inhibitory activity against Akt1 and 2 in vivo in a mouse model.

Stereoselective synthesis of tetrahydrofurans via the palladium-catalyzed reaction of aryl bromides with gamma-hydroxy alkenes: evidence for an unusual intramolecular olefin insertion into a Pd(Ar)(OR) intermediate.

A new, stereoselective method for the synthesis of substituted tetrahydrofurans from gamma-hydroxy alkenes that forms both a C-C and a C-O bond with diastereoselectivities of up to >20:1 is described. Initial mechanistic studies that suggest the reactions proceed via the intramolecular insertion of an olefin into a Pd(Ar)(OR) intermediate are discussed.