Strategies for senolytic drug discovery.

Senolytics are a category of drugs that reduce the impact of cellular senescence, an effect associated with a range of chronic and age-related diseases. Since the discovery of the first senolytics in 2015, the number of known senolytic agents has grown dramatically. This review discusses the broad categories of known senolytics-kinase inhibitors, Bcl-2 family protein inhibitors, naturally occurring polyphenols, heat shock protein inhibitors, BET family protein inhibitors, P53 stabilizers, repurposed anti-cancer drugs, cardiac steroids, PPAR-alpha agonists, and antibiotics. The approaches used to screen for new senolytics are articulated including a range of methods to induce senescence, different target cell types, various senolytic assays, and markers. The choice of methods can greatly influence the outcomes of a screen, with high-quality screens featuring robust systems, adequate controls, and extensive validation in alternate assays. Recent advances in single-cell analysis and computational methods for senolytic identification are also discussed. There is significant potential for further drug discovery, but this will require additional research into drug targets and mechanisms of actions and their subsequent rigorous evaluation in pre-clinical models and human trials.

Abnormal sebaceous gland differentiation in 10 kittens ('sebaceous gland dysplasia') associated with generalized hypotrichosis and scaling.

A rare congenital dermatosis, characterized by progressive hypotrichosis with variable scaling and crusting, occurred in 10 short-haired kittens in North America and Europe. Lesions appeared at between 4 and 12 weeks of age, commencing on the head and becoming generalized. The tail was spared in two kittens. Generalized scaling was mild to moderate, often with prominent follicular casts. Periocular, perioral, pinnal and ear canal crusting was occasionally severe. The skin was thick and wrinkled in two kittens. Histologically, the main lesion was abnormal sebaceous gland morphology. Instead of regular differentiation from basal cells to mature sebocytes, the glands were composed of a haphazard collection of undifferentiated basaloid cells, some partly vacuolated and a few containing eosinophilic globules. Mitotic figures and apoptotic cells were present in an irregularly thickened follicular isthmus. Lymphocytic mural folliculitis and mild sebaceous adenitis were rare. Orthokeratotic hyperkeratosis and follicular casts were present. Hair follicles were of normal density and were mostly in anagen, but some contained malacic hair shafts. Perforating folliculitis, leading to dermal trichogranuloma formation, occurred occasionally. Further biopsy samples taken at 2 years and at 3 and 4 years, respectively, from two kittens revealed similar but often more severe sebaceous gland lesions. Hair follicles were smaller, with many in telogen. The young age of onset suggests a genetic defect interfering with sebaceous and, possibly, follicular development. These lesions are discussed with reference to studies of mouse mutants in which genetic defects in sebaceous differentiation cause a similar phenotype of hyperkeratosis and progressive alopecia.

Treatment of feline herpesvirus-1 associated disease in cats with famciclovir and related drugs.

BACKGROUND: Feline herpesvirus 1 (FHV-1) is a common cause of ocular and upper respiratory disease in cats and kittens, and a potential cause of eosinophilic dermatitis. HYPOTHESIS: The systemic anti-herpes drug, famciclovir (Famvir; Novartis), would be effective in the clinical management of disease attributable to FHV-1, including conjunctivitis, keratitis, corneal sequestra, rhinosinusitis and FHV-1 associated dermatitis. CLINICAL OUTCOME: Oral famciclovir was used to treat signs considered referable to FHV-1 in 10 cats: four had primary ocular disease, two had rhinosinusitis and four had FHV-1 associated dermatitis. Patients treated in Australia (five cats) and Europe (one cat) were given 62.5 mg of famciclovir once or twice daily. Four cats treated in the USA were given 125 mg three times daily. Famciclovir was uniformly well tolerated and, in all cases, had a positive impact on the patient's condition. The apparent improvement in lesions was superior to what had been achieved previously using other therapeutic strategies. One cat with severe destructive rhinosinusitis was significantly improved by a 4-month course of famciclovir in combination with antibacterials. Corneal sequestra detached in two out of three cats treated; cats with ocular signs were qualitatively more comfortable, with reduced clinical signs and an improved appearance of the eyes. Critically, oral famciclovir therapy was considered more convenient than topical ocular therapy. All four cats with FHV-1 associated dermatitis improved substantially, although relapse occurred subsequently in three patients. A further cat with presumptive FHV-1 associated dermatitis responded to topical aciclovir cream before famciclovir could be sourced. CONCLUSIONS: Famciclovir appears to be a promising systemic drug for treating diseases associated with FHV-1 infection. More rigorous clinical trials are required to optimise the dosing regimen for safe and effective specific anti-herpes treatment in feline clinical medicine.

CCNU in the treatment of canine epitheliotropic lymphoma.

This retrospective study examined the use of CCNU (1-[2-chloroethyl]3-cyclohexyl-1-nitrosurea) in 36 dogs with epitheliotropic lymphoma. Thirty-one (86%) dogs had the cutaneous form of disease, and 5 (14%) dogs had the oral form of disease. Nineteen (51%) dogs were treated with other chemotherapeutic agents before receiving CCNU. All dogs had detectable disease at the time CCNU therapy was initiated. Dogs received a median starting CCNU dosage of 70 mg/m2 (range, 50-100 mg/m2). The median number of treatments administered was 3 (range, 1-12 treatments). After the initial treatment, the CCNU dosage was adjusted in 9 of 26 (35%) dogs in which CCNU was continued: 7 had dosage reductions, and 2 had dosage escalations. Twenty-eight of 36 (78%) dogs had a measurable response to CCNU for a median duration of 106 days (95% confidence interval [CI], 75-182). Six dogs (17%) had a complete response, including 5 dogs with the cutaneous form and 1 dog with the oral form. Twenty-two dogs (61%) had a partial response, including 20 dogs with the cutaneous form and 2 dogs with the oral form, for a median duration of 88 days (95% CI, 62-170). Toxicoses after CCNU chemotherapy included myelosuppression in up to 29% of the dogs, gastrointestinal signs in up to 22% of the dogs, and liver enzyme activity increases in up to 86% of the dogs. This study demonstrates that CCNU chemotherapy can be considered a reasonable option for the treatment of canine epitheliotropic lymphoma in dogs.