Effects of dietary cholesterol restriction in a feline model of Niemann-Pick type C disease.

A feline model of Niemann-Pick disease type C (NPC) was employed to evaluate the effect of dietary cholesterol restriction on progression of disease. Two NPC-affected treated cats were fed a cholesterol-restricted diet beginning at 8 weeks of age; the cats remained on the diet for 150 and 270 days respectively. The study goal was to lower the amount of low density lipoprotein (LDL) available to cells, hypothetically reducing subsequent lysosomal accumulation of unesterified cholesterol and other lipids. Neurological progression of disease was not altered and dietary cholesterol restriction did not significantly decrease storage in NPC-affected treated cats. One NPC-affected treated cat had decreased serum alkaline phosphatase activity (ALP) and decreased serum cholesterol concentration. Liver lipid concentrations of unesterified cholesterol, cholesterol ester and phospholipids in NPC-affected treated cats were similar to those seen in NPC-affected untreated cats. Ganglioside concentrations in the NPC-affected treated cats and NPC-affected untreated cats were similar. Histological findings in liver sections from NPC-affected treated cats showed a diffuse uniform microvacuolar pattern within hepatocytes and Kupffer cells, in contrast to a heterogeneous macro/microvacuolar pattern and prominent nodular fibrosis in NPC-affected untreated cats. Similar differences in vacuolar patterns were seen in splenic macrophages. Although some hepatic parameters were modified, dietary cholesterol restriction did not appear to alter disease progression in NPC-affected kittens.

Inhibition of canine and feline alcohol dehydrogenase activity by fomepizole.

OBJECTIVE: To determine and compare substrate specificity and kinetic rate constants of feline and canine alcohol dehydrogenase (ADH) with ethanol (EtOH) and ethylene glycol (EG) as substrates in vitro, with and without fomepizole. SAMPLE POPULATION: Livers from 3 dogs and 3 cats. PROCEDURE: Canine and feline ADH activity, in cytosolic fractions of homogenized liver, was determined by use of various concentrations of nicotinamide adenine dinucleotide (NAD), EtOH, or EG as substrates. Initial reaction velocities were calculated, and kinetic inhibition rate constants (Ki) for fomepizole were determined. RESULTS: Substrate specificity of canine and feline ADH for EtOH or EG was not significantly different. A 2-fold difference was detected in the maximal velocity of canine, compared with feline, ADH, using either substrate. Fomepizole Ki in feline hepatic homogenates was significantly greater than Ki in canine hepatic homogenates when either EtOH or EG was used as substrate (10- and 30-fold, respectively). A 6-fold increase in the concentration of fomepizole was required to achieve ADH inhibition, with feline homogenates equivalent to those of canine homogenates. CONCLUSIONS AND CLINICAL RELEVANCE: Feline ADH has lower enzymatic capacity for turnover or is less concentrated in liver than canine ADH with regard to EtOH and EG catalysis. Canine ADH was more effectively inhibited by fomepizole than feline ADH. Results suggest that higher dosages of fomepizole may be more effective to treat cats with EG intoxication than dosages reported to treat dogs.

Complementation studies in human and feline Niemann-Pick type C disease.

Complementation studies were performed to determine if the gene responsible for the major form of human Niemann-Pick type C disease (NPC) and a feline model of NPC are orthologous. Cell fusions between human NPC and feline NPC fibroblasts were conducted to assess whether the multinucleated heterokaryons that were formed showed a reversal of the NPC phenotype. Cultured fibroblasts from NPC-affected humans and NPC-affected cats were hybridized and then analyzed for complementation by challenging the cells with low-density lipoprotein (LDL) and subsequently staining with the fluorescent antibiotic filipin to visualize any abnormal accumulation of unesterified cholesterol. All of the multinucleated cells formed from these fusions retained the NPC staining phenotype, indicating an absence of complementation and suggesting that the underlying defect in the major form of human NPC and this feline model of NPC involve orthologous genes.

Safety and efficacy of 4-methylpyrazole for treatment of suspected or confirmed ethylene glycol intoxication in dogs: 107 cases (1983-1995).

OBJECTIVE: To evaluate safety and efficacy of 4-methylpyrazole (4-MP) treatment in dogs and to determine clinical signs and outcome of, and clinicopathologic abnormalities in, dogs treated in early or late stages of ethylene glycol (EG) intoxication. DESIGN: Retrospective study. ANIMALS: 107 dogs. PROCEDURE: For dogs treated with 4-MP, 1 of 2 dosage regimens was usually used: 20 mg/kg of body weight, IV, initially, 15 mg/kg 17 hours later, and 5 mg/kg 25 and 36 hours after the initial dose, or 20 mg/kg, IV, initially, 15 mg/kg 12 and 24 hours later, and 5 mg/kg 36 hours after the initial dose. RESULTS: Neither adverse clinical signs nor clinicopathologic abnormalities were associated with the administration of 4-MP except in 1 dog, which developed tachypnea, gagging, excess salivation, and trembling after the second dose of 4-MP was given. Ethylene glycol intoxication was confirmed in 37 dogs. Of these, 21 were azotemic or became azotemic within 18 hours after admission, and only 1 of the 21 survived. All 16 dogs that did not become azotemic survived. Median time from EG ingestion to treatment with 4-MP was 5 hours (range, 2 to 8.5 hours) for dogs that were not azotemic at admission and 14.5 hours (range, 8.5 to 38 hours) for dogs that were azotemic at admission. CLINICAL IMPLICATIONS: 4-MP was a safe and effective treatment for EG intoxication when it was given before sufficient quantities of EG had been metabolized to induce renal failure. Dogs treated within 8 hours of EG ingestion had a good prognosis.

Bone mineral density in feline mucopolysaccharidosis VI measured using dual-energy X-ray absorptiometry.

Dual-energy X-ray absorptiometry (DXA) was used to determine the in vivo bone mineral density (BMD) and bone mineral content (BMC) of lumbar vertebrae in six cats affected with the inherited lysosomal storage disease mucopolysaccharidosis VI (MPS VI). DXA was also performed on MPS cats that had a bone marrow transplant (BMT) and total body irradiation (TBI) (MPS + BMT; n = 7), normal cats that had a bone marrow transplant, and TBI (control + BMT; n = 8) and normal cats (control; n = 14). Following euthanasia, one of the lumbar vertebrae that had been scanned (L5) was harvested and bone volume (BV/TV%) was determined by histomorphometry. The in vivo BMD and BMD measurements were compared with the BV/TV%. There was a greater BMD and BMC in the MPS + BMT cats compared with the MPS cats but the difference was not statistically significant. However, there was a greater BV/TV% in the MPS + BMT cats compared with the MPS cats and the difference was significant (P = 0.0152). Correlation between the noninvasive in vivo DXA measurements of BMD and BMC and the BV/TV% was significant (r2 = 0.767, P < 0.0001; r2 = 0.504, P < 0.0001). Noninvasive in vivo DXA was a rapid and precise method for measuring the lumbar BMD and BMC in cats and it correlated well with histomorphometric determination of bone mass. Further, the response of inherited storage diseases such as MPS VI to therapy, such as BMT, could be monitored in a longitudinal fashion using DXA.