Clinicopathological findings, treatment, and outcome in 60 cats with gastrointestinal eosinophilic sclerosing fibroplasia.

BACKGROUND: Gastrointestinal eosinophilic sclerosing fibroplasia (GESF) in cats presents as mass(es) associated with the gastrointestinal tract, mesentery, and abdominal lymph nodes. HYPOTHESIS/OBJECTIVES: To report the clinicopathological findings, treatment, and outcome of cats with GESF. ANIMALS: Sixty client-owned cats diagnosed with GESF. METHODS: Retrospective review of medical records of cats with histopathologically confirmed GESF. RESULTS: The median age was 5.4 years (interquartile range [IQR], 3.3-8.9.); 30% were Domestic Shorthairs and 12% were Domestic Longhair cats, with the most prevalent pedigree breeds being Ragdolls (25%), Exotic Shorthair (10%) and Persian (8%) cats. The median duration of clinical signs was 90 days (IQR, 17.5-247.0); the most common clinical signs were weight loss (60%), hyporexia/anorexia (55%), chronic vomiting (37%), lethargy (35%) and chronic diarrhea (27%). Masses were located in the small intestine (32%), stomach (27%), ileocolic junction (15%), colon (10%), lymph node (8%) and mesentery (8%) and 15% of cats had >1 mass. Eosinophilia was present in 50% and hypoalbuminemia in 28% of cats. The mass was removed surgically in 37% of cases. Most cats (98%) were treated with corticosteroids. Survival was not statistically different between cats treated with surgical resection and cats treated with medical therapy alone, 88% of the cats were still alive at the time of writing. CONCLUSIONS AND CLINICAL IMPORTANCE: GESF is an important differential diagnosis for abdominal masses in cats, and has a much better prognosis than previously reported.

The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile-Part†1.

Nonstructural protein 5A (NS5A) represents a novel target for the treatment of hepatitis C virus (HCV). Daclatasvir, recently reported by Bristol-Myers-Squibb, is a potent NS5A inhibitor currently under investigation in phase 3 clinical trials. While the performance of daclatasvir has been impressive, the emergence of resistance could prove problematic and as such, improved analogues are being sought. By varying the biphenyl-imidazole unit of daclatasvir, novel inhibitors of HCV NS5A were identified with an improved resistance profile against mutant strains of the virus while retaining the picomolar potency of daclatasvir. One compound in particular, methyl ((S)-1-((S)-2-(4-(4-(6-(2-((S)-1-((methoxycarbonyl)-L-valyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)quinoxalin-2-yl)phenyl)-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate (17), exhibited very promising activity and showed good absorption and a long predicted human pharmacokinetic half-life. This compound represents a promising lead that warrants further evaluation.

The discovery of potent nonstructural protein 5A (NS5A) inhibitors with a unique resistance profile-Part†2.

In ongoing studies towards novel hepatitis C virus (HCV) therapeutics, inhibitors of nonstructural protein 5A (NS5A) were evaluated. Specifically, starting from previously reported lead compounds, peripheral substitution patterns of a series of biaryl-linked pyrrolidine NS5A replication complex inhibitors were probed and structure-activity relationships were elucidated. Using molecular modelling and a supercritical fluid chromatographic (SFC) technique, intramolecular H-bonding and peripheral functional group topology were evaluated as key determinants of activity and membrane permeability. The novel compounds exhibited retained potency as compared with the lead compounds, and also showed promising results against a panel of resistance viruses. Together, the results of the study take us a step closer towards understanding the potency of daclatasvir, a clinical candidate upon which the compounds were based, and to designing improved analogues as second-generation antiviral agents targeting NS5A.

Clinical and clinicopathologic abnormalities in young dogs with acquired and congenital portosystemic shunts: 93 cases (2003-2008).

OBJECTIVE: To determine whether clinical and clinicopathologic data could assist differentiation of congenital portosystemic shunts (CPSSs) from acquired portosystemic shunts (APSSs) in young dogs. DESIGN: Retrospective case series. ANIMALS: Dogs < 30 months of age with CPSSs (n = 62) or APSSs (31). PROCEDURES: Medical records from 3 referral centers identified 31 dogs with APSSs and 62 dogs with CPSSs diagnosed from July 2003 to July 2008. Signalment, clinical signs, physical examination, and clinicopathological data were recorded, and statistical analyses were performed to determine differences between groups. RESULTS: Univariable analysis showed APSS patients were older, heavier, and in poorer body condition, compared with CPSS patients. In CPSS patients, diarrhea was less prevalent, and neurologic signs were more prevalent. Ascites was more prevalent in APSS (Fisher exact test; OR, 50.2; 95% confidence interval [CI], 6.2 to 409.7), with no significant difference in albumin concentration between groups. The logistic regression model used to assess clinicopathological parameters showed lower Hct (OR, 1.42 × 10(-12); 95% CI, 1.42 × 10(-17) to 4.0 × 10(-6)), higher mean corpuscular volume (OR, 1.27; 95% CI, 1.08 to 1.50), and higher alanine aminotransferase concentrations (OR, 1.005; 95% CI, 1.001 to 1.009) were more likely in APSS patients. CONCLUSIONS AND CLINICAL RELEVANCE: Several clinicopathologic differences between dogs with congenital and acquired shunts were identified; however, assessed alone, these would be unlikely to enable differentiation between the 2 conditions. Awareness of the rarity of ascites in CPSS cases should prompt recognition of a likely diagnosis of APSS, allowing the veterinarian to target further diagnostics and counsel the owner appropriately.

Discovery of a highly potent series of TLR7 agonists.

The discovery of a series of highly potent and novel TLR7 agonist interferon inducers is described. Structure-activity relationships are presented, along with pharmacokinetic studies of a lead molecule from this series of N9-pyridylmethyl-8-oxo-3-deazapurine analogues. A rationale for the very high potency observed is offered. An investigation of the clearance mechanism of this class of compounds in rat was carried out, resulting in aldehyde oxidase mediated oxidation being identified as a key component of the high clearance observed. A possible solution to this problem is discussed.

Design and optimisation of orally active TLR7 agonists for the treatment of hepatitis C virus infection.

The synthesis and structure-activity relationships of a series of novel interferon inducers are described. Pharmacokinetic studies and efficacy assessment of a series of 8-oxo-3-deazapurine analogues led to the identification of compound 33, a potent and selective agonist of the TLR7 receptor with an excellent in vivo efficacy profile in a mouse model.

Barium toxicosis in a dog.

CASE DESCRIPTION: A 2-year-old 14.9-kg (32.8-lb) neutered female Shetland Sheepdog was admitted to the University of Liverpool Small Animal Teaching Hospital for evaluation of acute collapse. CLINICAL FINDINGS: At admission, the dog was tachypneic and had reduced limb reflexes and muscle tone in all limbs consistent with diffuse lower motor neuron dysfunction. The dog was severely hypokalemic (1.7 mEq/L; reference range, 3.5 to 5.8 mEq/L). Clinical status of the dog deteriorated; there was muscle twitching, flaccid paralysis, and respiratory failure, which was considered a result of respiratory muscle weakness. Ventricular arrhythmias and severe acidemia (pH, 7.18; reference range, 7.35 to 7.45) developed. Intoxication was suspected, and plasma and urine samples submitted for barium analysis had barium concentrations comparable with those reported in humans with barium toxicosis. Analysis of barium concentrations in 5 control dogs supported the diagnosis of barium toxicosis in the dog. TREATMENT AND OUTCOME: Fluids and potassium supplementation were administered IV. The dog recovered rapidly. Electrolyte concentrations measured after recovery were consistently unremarkable. Quantification of plasma barium concentration 56 days after the presumed episode of intoxication revealed a large decrease; however, the plasma barium concentration remained elevated, compared with that in control dogs. CLINICAL RELEVANCE: To our knowledge, this case represented the first description of barium toxicosis in the veterinary literature. Barium toxicosis can cause life-threatening hypokalemia; however, prompt supportive treatment can yield excellent outcomes. Barium toxicosis is a rare but important differential diagnosis in animals with hypokalemia and appropriate clinical signs.

Design and optimisation of potent gp120-CD4 inhibitors.

The synthesis and structure-activity relationship of a series of novel gp120-CD4 inhibitors are described. Pharmacokinetic studies and antiviral spectrum assessment of lead compounds led to the identification of compound 36, a potent gp120-CD4 inhibitor which exhibited antiviral potency across a spectrum of 25 clade B isolates.

Discovery of a small molecule inhibitor through interference with the gp120-CD4 interaction.

A series of piperazine derivatives were designed and synthesised as gp120-CD4 inhibitors. SAR studies led to the discovery of potent inhibitors in a cell based anti viral assay represented by compounds 9 and 28. The rat pharmacokinetic and antiviral profiles of selected compounds are also presented.