Ultra-long-acting recombinant insulin for the treatment of diabetes mellitus in dogs.

BACKGROUND: For the treatment of diabetes mellitus (DM) in dogs, novel insulins with decreased injection frequency while maintaining safety and efficacy are desirable. Insulin fused with immunoglobulin-fragment-crystallizable (Fc) has an ultra-long plasma half-life because it recycles through cells, protected from proteolysis. HYPOTHESIS: Glycemic control can be achieved in diabetic dogs with a recombinant fusion protein of a synthetic insulin and canine Fc (AKS-218d) administered subcutaneously once-weekly. ANIMALS: Five client-owned dogs with naturally occurring DM. METHODS: Prospective clinical trial in dogs with DM that were recruited from the UC Davis Veterinary Teaching Hospital and local veterinary clinics. Dogs previously controlled using intermediate-acting insulin q12h were transitioned to once-weekly injections of a preliminary construct identified as AKS-218d. The dose of AKS-218d was titrated weekly for 8 weeks based on clinical response and continuous interstitial glucose monitoring. Clinical signs, body weight, serum fructosamine concentrations, and mean interstitial glucose concentrations (IG) over the preceding week were compared between baseline (before AKS-218d) and during the last week of treatment. Data were compared using nonparametric paired tests. RESULTS: Once-weekly AKS-218d, compared to baseline twice-daily insulin therapy, resulted in no significant changes in clinical signs, median (range) body weight (+0.4 kg [-0.5-1.1]; P = .6), fructosamine concentration (-75 mmol/L [-215 to +126]; P = .4), or mean IG (+81 mg/dL [-282 to +144]; P = .8). No adverse reactions were reported. CONCLUSION: Control of clinical signs, body weight, and maintenance of glycemia was achieved with this once-weekly novel insulin construct in 4 of 5 dogs.

An ultra-long-acting recombinant insulin for the treatment of diabetes mellitus in cats.

BACKGROUND: Treatment of diabetes mellitus (DM) in cats typically requires insulin injections q12h-q24h, posing a major compliance barrier for caregivers. Novel treatments enabling decreased injection frequency while maintaining safety are highly desirable. Insulin fused with feline immunoglobulin fragment crystallizable (Fc) has an ultra-long plasma half-life because it recycles through cells where it is protected from proteolysis. HYPOTHESIS: Glycemic control can be achieved in diabetic cats with a recombinant fusion protein of a synthetic insulin and feline Fc (AKS-267c) administered SC weekly. ANIMALS: Five cats with spontaneous DM. METHODS: Cats previously controlled using insulin glargine q12h were transitioned to once-weekly injection of AKS-267c. The dose of AKS-267c was titrated weekly for 7 weeks based on continuous glucose monitoring. Clinical signs, body weight, fructosamine concentrations, and mean interstitial glucose concentrations (IG) were compared between baseline (week 0, on insulin glargine) and the last week of treatment. Data were assessed for normality and compared using parametric or nonparametric paired tests (as appropriate). RESULTS: After 7 weeks of once-weekly injections, compared to baseline, there were no significant changes in clinical signs, body weight (median [range] gain, 0.1 kg [-0.1 to +0.7]; P = .5), fructosamine (-60 mmol/L [-338 to +206]; P = .6), and mean IG concentrations (change = -153 mmol/L [-179 to +29]; P = .3), and no adverse reactions were reported. CONCLUSION: Successful control of clinical signs and maintenance of glycemia was achieved with this once-weekly novel insulin treatment. The efficacy and safety of this novel formulation should be further assessed in a large clinical trial.

Serum levels of innate immunity cytokines are elevated in dogs with metaphyseal osteopathy (hypertrophic osteodytrophy) during active disease and remission.

Metaphyseal osteopathy (MO) (hypertrophic osteodystrophy) is a developmental disorder of unexplained etiology affecting dogs during rapid growth. Affected dogs experience relapsing episodes of lytic/sclerotic metaphyseal lesions and systemic inflammation. MO is rare in the general dog population; however, some breeds (Weimaraner, Great Dane and Irish Setter) have a much higher incidence, supporting a hereditary etiology. Autoinflammatory childhood disorders of parallel presentation such as chronic recurrent multifocal osteomyelitis (CRMO), and deficiency of interleukin-1 receptor antagonist (DIRA), involve impaired innate immunity pathways and aberrant cytokine production. Given the similarities between these diseases, we hypothesize that MO is an autoinflammatory disease mediated by cytokines involved in innate immunity. To characterize immune dysregulation in MO dogs we measured serum levels of inflammatory markers in 26 MO and 102 control dogs. MO dogs had significantly higher levels (pg/ml) of serum Interleukin-1beta (IL-1ß), IL-18, IL-6, Granulocyte-macrophage colony stimulating factor (GM-CSF), C-X-C motif chemokine 10 (CXCL10), tumor necrosis factor (TNF), and IL-10. Notably, recovered MO dogs were not different from dogs during active MO disease, providing a suggestive mechanism for disease predisposition. This is the first documentation of elevated immune markers in MO dogs, uncovering an immune profile similar to comparable autoinflammatory disorders in children.

Y chromosome haplotype analysis in purebred dogs.

In order to evaluate the genetic structure of purebred dogs, six Y chromosome microsatellite markers were used to analyze DNA samples from 824 unrelated dogs from 50 recognized breeds. A relatively small number of haplotypes (67) were identified in this large sample set due to extensive sharing of haplotypes between breeds and low haplotype diversity within breeds. Fifteen breeds were characterized by a single Y chromosome haplotype. Breed-specific haplotypes were identified for 26 of the 50 breeds, and haplotype sharing between some breeds indicated a common history. A molecular variance analysis (AMOVA) demonstrated significant genetic variation across breeds (63.7%) and with geographic origin of the breeds (11.5%). A network analysis of the haplotypes revealed further relationships between the breeds as well as deep rooting of many of the breed-specific haplotypes, particularly among breeds of African origin.

Epidemiologic evaluation of multiple respiratory pathogens in cats in animal shelters.

Upper respiratory tract infection (URI) propagates readily within cats in shelters and often results in euthanasia of affected cats. In a case-control evaluation of 573 cats in eight shelters in California in 2001 and 2002, the prevalence of feline calicivirus (FCV) was from 13 to 36%, feline herpesvirus (FHV) was from 3 to 38%, and prevalence of Bordetella bronchiseptica, Chlamydophila felis, and Mycoplasma species was from 2 to 14%. Cats with URI tended to be housed in isolation, dehydrated, and younger than cats without URI, and infected with FHV, Mycoplasma species, FCV, or C felis. Shelters differed in the prevalence of pathogens and many cats appeared positive for infection after about 1 week of sheltering. It is helpful for shelters to understand the risk factors associated with URI in order to evaluate the costs and benefits of treatment and improve their procedures to decrease the incidence of URI within their facilities. Antiherpetics and antimycoplasmal drugs may be beneficial for individual animal care. Results document the utility of comprehensive URI surveillance and herd management for specific pathogens typical in that shelter.

Correlation of rhinoscopic signs of inflammation with histologic findings in nasal biopsy specimens of cats with or without upper respiratory tract disease.

OBJECTIVE: To investigate the correlation of cumulative rhinoscopic findings of hyperemia, mucus accumulation, and turbinate destruction with the type and severity of inflammatory infiltrates in nasal biopsy specimens of cats with or without upper respiratory tract disease. DESIGN: Prospective study. ANIMALS: Cats with (n = 11) and without (6) upper respiratory tract disease and cats with unknown medical histories (27). PROCEDURES; Lesions of hyperemia, mucus accumulation, and turbinate destruction detected rhinoscopically were each scored (scale, 0 [absent] to 3 [severe]), and a cumulative rhinoscopic score for each nasal cavity was calculated. Fifty biopsy specimens were examined histologically, and inflammatory infiltrates (lymphoplasmacytic or neutrophilic) were graded as absent, mild, moderate, or severe. Cumulative rhinoscopic scores and inflammation grades were compared for each specimen-cavity combination. RESULTS: In cats of known disease status, there was a positive but weak correlation between cumulative rhinoscopic scores and inflammation grades in biopsy specimens. In cats of unknown disease status, there was no similar correlation. Biopsy specimens with minimal inflammation were commonly obtained from nasal cavities with low rhinoscopic scores; specimens with moderate or severe inflammatory changes were frequently obtained from cavities that appeared normal rhinoscopically. Type of inflammatory infiltrates was not correlated with rhinoscopic signs of inflammation. CONCLUSIONS AND CLINICAL RELEVANCE: The correlation of rhinoscopic findings with inflammation severity in nasal biopsy specimens (determined histologically) was weak or lacking in cats of known and unknown disease status, respectively. Results indicated that rhinoscopy with biopsy provides more complete evaluation of nasal disease than rhinoscopy alone in cats.