Pharmacokinetics and relative bioavailability of D-penicillamine in fasted and nonfasted dogs.

BACKGROUND: D-Penicillamine is the most commonly used copper-chelating agent in the treatment of copper-associated hepatitis in dogs. Response to therapy can be variable, and there is a lack of pharmacokinetic information available for dogs. Coadministering the drug with food to alleviate vomiting has been recommended for dogs, which contradicts recommendations for drug administration to humans. HYPOTHESIS: Coadministration of d-penicillamine with food decreases relative bioavailability and maximum plasma drug concentrations (C(max)) in dogs. ANIMALS: Nine purpose-bred dogs with a median body weight of 17.0 kg. METHODS: Dogs received D-penicillamine (12.5 mg/kg PO) fasted and with food in a randomized, crossover design. Blood samples were collected before and 0.25, 0.5, 1, 2, 3, 4, 8, 12, and 24 hours after dosing. Total d-penicillamine concentrations were measured using liquid chromatography coupled with tandem quadrupole mass spectrometry. Pharmacokinetic parameters were calculated for each dog. RESULTS: Two fasted dogs (22%) vomited after receiving d-penicillamine. Mean C(max) ± standard deviation (SD) was 8.7 ± 3.1 µg/mL (fasted) and 1.9 ± 1.6 µg/mL (fed). Mean area under the plasma concentration curve ± SD was 16.9 ± 5.9 µg/mL·h (fasted) and 4.9 ± 3.4 µg/mL·h (fed). There were significant reductions in relative bioavailability and C(max) in fed dogs (P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Coadministration of d-penicillamine with food significantly decreases plasma drug concentrations in dogs. Decreased drug exposure could result in decreased copper chelation efficacy, prolonged therapy, additional cost, and greater disease morbidity. Administration of d-penicillamine with food cannot be categorically recommended without additional studies.

Acquired proximal renal tubular dysfunction in 9 Labrador Retrievers with copper-associated hepatitis (2006-2012).

BACKGROUND: Copper-associated hepatitis (CAH) has been well described in Labrador Retrievers. However, the association of CAH with proximal renal tubular dysfunction in this breed has not been characterized. OBJECTIVES: To report clinical features, hepatic and renal histopathologic findings, tissue copper concentrations, and outcome of Labradors with CAH and proximal renal tubular disease. ANIMALS: Nine Labrador Retrievers with renal glucosuria and biopsy-confirmed CAH. METHODS: Clinical, clinicopathologic, and light microscopic findings were retrospectively reviewed. Rhodanine staining or atomic emission spectroscopy was performed on all hepatic samples and available renal tissue (4 dogs) to assess copper concentrations. RESULTS: Eight dogs had a history of polyuria and polydipsia, and all dogs had increased serum bilirubin concentrations. Five dogs had hyperchloremic metabolic acidosis. Three dogs with acidemia had paradoxical alkalinuria. All renal specimens had increased copper concentrations. Renal tubular vacuolization, degeneration, and regeneration were observed on light microscopy. Four dogs died within 10 days of diagnosis. One dog survived 2 months; 4 dogs survived more than 1 year. In long-term survivors, including 2 that did not undergo immediate copper chelation, resolution of renal tubular dysfunction occurred within weeks to months. CONCLUSIONS AND CLINICAL IMPORTANCE: Labrador Retrievers with CAH can develop clinical and laboratory evidence of renal tubular dysfunction in association with increased renal copper concentrations. Given the rarity of renal tubular disorders, detection of renal glucosuria and increased ALT activity in a Labrador Retriever is suggestive of CAH. Although renal tubular dysfunction may indicate advanced disease, successful long-term outcome is possible with a variety of therapies.

Lower initial dose desoxycorticosterone pivalate for treatment of canine primary hypoadrenocorticism.

OBJECTIVE: To evaluate the efficacy of initial doses of desoxycorticosterone pivalate (DOCP) that are lower and less expensive than the presently recommended initial dose of 2.2 mg/kg for treating dogs with primary hypoadrenocorticism. METHODS: A retrospective study was performed on 49 dogs with primary hypoadrenocorticism, including 36 with initial DOCP doses less than 2.2 mg/kg. Medical records were reviewed for clinical data. All study dogs were followed up with telephone calls to owners or veterinarians to determine the date of death or last follow-up. Data were analysed to investigate relationships between initial DOCP dose and survival and serum Na, K and their ratio. RESULTS: Regardless of their initial DOCP dose, none of the dogs developed uncontrolled hypoadrenocorticism or severe electrolyte abnormalities or clinical problems that would have made an increase in the DOCP dose necessary. Over time, most dogs had a decrease in their DOCP dose in mg/kg, because of weight gain during treatment. No statistically significant relationships were found between initial DOCP dose and survival or post-treatment serum Na, K or Na : K, with the exception of one statistically significant result that suggested lower efficacy for higher doses. CONCLUSION: Initial DOCP doses less than 2.2 mg/kg may be effective in controlling serum electrolyte concentrations in dogs with primary hypoadrenocorticism without adversely affecting survival. If confirmed by additional research, these findings would enable practitioners to reduce the cost of DOCP treatment by using lower initial doses, potentially saving the lives of dogs that would otherwise be euthanased because of treatment expense.

A von Willebrand's factor genomic nucleotide variant and polymerase chain reaction diagnostic test associated with inheritable type-2 von Willebrand's disease in a line of german shorthaired pointer dogs.

Heritable, type-2 von Willebrand's disease (vWD) was studied in a line of German Shorthaired Pointers (GSPs) in which some members had a nucleotide variant in exon 28 of the von Willebrand factor (VWF) gene. A polymerase chain reaction (PCR) diagnostic test for the nucleotide variant was developed to establish the disorder's mode of inheritance and to eliminate it from the line. Thirty-six of the 49 GSPs in the line, 14 unrelated GSP controls, and 71 unrelated dogs of various breeds were tested for the presence of the variant nucleotide. All the dogs with a vWF antigen deficiency (<70% of normal) were either homozygous or heterozygous for the nucleotide variant. The variant was not located in any tested dog in the line or outside of the line with a vWF antigen value greater than 68%. Of the GSPs in the line tested, two were homozygous for the variant, 15 were heterozygous, and 19 were variant free. The collective evidence of this and other studies is consistent with the variant nucleotide being the cause of the type-2 vWD in this line of GSPs and German Wirehaired Pointers. The PCR diagnostic test for the variant nucleotide was successfully used to select and produce progeny that were variant free and vWD free. This test should be effective in the subsequent elimination of this same variant from other lines of dogs.

Mutation causing von Willebrand's disease in Scottish Terriers.

Von Willebrand's Disease (vWD) in the Scottish Terrier breed is a serious, often fatal, hereditary bleeding disorder. Elimination of the mutated gene by selective breeding is an important goal for the health of this breed. Although the standard protein-based tests are accurate for identification of affected Scottish Terriers, they are not reliable for the identification of carriers of the mutant gene unless multiple replicate assays are performed. A simple, highly accurate test for carriers of the disease is needed so that veterinarians can counsel clients on which animals to use in their breeding programs. The complete coding region of von Willebrand factor (vWF) complementary DNA (cDNA) was sequenced from an affected animal, and a single base deletion in the codon for amino acid 85 of the prepro-vWF cDNA that leads to Scottish Terrier vWD was identified. A highly accurate polymerase chain reaction assay was developed that can distinguish homozygous normal animals from those that are homozygous affected or heterozygous. In a voluntary survey of 87 animals provided by Scottish Terrier owners, 15 were carriers and 4 were affected with vWD, 2 of which had previously been shown to have undetectable vWF. The determination of the complete canine vWF cDNA sequence should facilitate the identification of additional vWD alleles in other breeds and other species.

Perineurial abnormalities in the spontaneously diabetic dog.

Structural abnormalities of the perineurium from six spontaneously diabetic dogs (diabetes duration 4-8 years and six control animals were quantified using detailed electron microscopic morphometric methods on superficial peroneal nerve biopsy specimens. Total perineurial sheath thickness (microm) was significantly increased in diabetic (8.8+/-0.6) compared to control animals (6.2+/-0.3) (P < 0.02). This was attributed to a significant increase in the mean perineurial lamellar width in diabetic (0.49+/-0.03) compared to control (0.40+/-0.01) (P < 0.04) animals. The number of lamellae also showed a non-significant increase in diabetic animals (7.8+/-0.4) compared to controls (6.9+/-0.13) (P < 0.06). There was no change in the mean interlamellar space in diabetic (0.7+/-0.05) compared to control (0.6+/-0.06) (P = 0.15) animals. The total interlamellar space was increased in diabetic (5.7+/-0.5) compared to control (4.1+/-0.36) (P < 0.04) animals. The perineurial cell basement membrane thickness (nm) was significantly increased in diabetic (126.9+/-9.8) compared to control (62.8+/-6.1) (P < 0.005) animals. The current study has demonstrated significant abnormalities of the perineurium in the spontaneously diabetic dog, which may have relevance to the pathogenesis of diabetic neuropathy.

Surgical correction of late-onset Budd-Chiari-like syndrome in a dog.

An 18-month-old dog was examined because of ascites of 1 month's duration. Typical causes of ascites, including hepatic failure, heart failure, and protein-losing enteropathy, were ruled out. The dog's history included being hit by a car 6 months earlier, and the caudal vena cava had an S shape on thoracic radiographs. In addition, the abdominal fluid had a high protein concentration and low cellular content. These findings were all consistent with a diagnosis of postsinusoidal hypertension secondary to obstruction of hepatic venous outflow (Budd-Chiari-like syndrome). During exploratory thoracotomy, the pericardium appeared to have been torn from the heart and was partially wrapped around the caudal vena cava, causing a constriction. The pericardium was removed and the dog recovered without any further complications. Blunt trauma has been previously reported to cause kinking of the caudal vena cava and Budd-Chiari-like syndrome in dogs; but in these dogs, clinical signs of ascites developed a few days to several weeks after the traumatic incident. It appears that, depending on the cause of the hepatic venous outflow obstruction, onset of Budd-Chiari-like syndrome may be delayed for months.

Basal and ACTH-stimulated plasma aldosterone concentrations are normal or increased in dogs with trichuriasis-associated pseudohypoadrenocorticism.

We measured plasma concentrations of cortisol and aldosterone before and after administration of adrenocorticotropin (ACTH) in dogs with trichuriasis. These dogs had physical examination, historical, and serum electrolyte findings suggestive of hypoadrenocorticism; trichuriasis-associated pseudohypoadrenocorticism has been reported previously. We found normal basal and ACTH-stimulated plasma cortisol concentrations. Basal and ACTH-stimulated plasma aldosterone concentrations were normal in 2 dogs and increased in 3 dogs, suggesting that the electrolyte abnormalities seen in this clinical syndrome are not due to aldosterone deficiency.

Adrenal function in 15 dogs with insulin-dependent diabetes mellitus.

Pituitary-adrenal function was assessed by a combined dexamethasone suppression-ACTH stimulation test in 15 diabetic and 9 healthy dogs. In both groups, plasma cortisol concentrations decreased (P less than 0.001) after dexamethasone administration and increased (P less than 0.001) after ACTH administration. Differences between groups (P greater than 0.05) and group-by-time interactions were not significant (P greater than 0.05). Seemingly, adrenal function was not altered in well-regulated diabetic dogs.

Severe hypophosphatemia associated with diabetes mellitus in six dogs and one cat.

Severe hypophosphatemia was found in 6 diabetic dogs and in one diabetic cat. The cat suffered from hemolysis, and one dog had seizures, both apparently as a result of the severe hypophosphatemia. Clinical signs were not determined solely by the serum concentration of phosphorus, as seen in 5 other patients that did not have signs of disease despite similar serum phosphorus concentrations.

Effect of nonadrenal illness on adrenal function in the cat.

Adrenal function was assessed by a combined dexamethasone suppression-ACTH stimulation test in 18 healthy cats, 17 diabetic cats, and 19 sick nondiabetic cats. In all groups, plasma cortisol concentrations decreased after dexamethasone was administered and increased after ACTH was administered. There were no significant (P greater than 0.05) differences among groups in time trend changes in cortisol concentration. There was considerable variation in adrenal response between cats in each group. Diabetic cats had more variation in base-line and postdexamethasone plasma cortisol concentrations (P less than 0.05) than did other groups. In sick, nondiabetic cats, cortisol concentrations tended to be higher in cats with hyperthyroidism (P = 0.06) than in cats with other diseases.

Cyclosporine pharmacokinetics in normal and pancreatectomized dogs.

Oral and i.v. cyclosporine (Cs) pharmacokinetics determined from radioimmunoassay (RIA) data were compared in normal and pancreatectomized dogs. An altered pharmacokinetics of Cs was observed in the pancreatectomized dogs that include: a 170% larger central compartment volume; a 34% greater total-body clearance; and lower steady-state average serum concentrations relative to the normals. Even though there were marked intersubject variations, both groups displayed a triexponential decline in Cs serum concentrations and disposition kinetics. Following 7 daily oral doses of commercial cyclosporine (CsA) (20 mg/kg) the Cs serum trough concentrations of the pancreatectomized dogs were consistently below 100 ng/ml, while those of the normal dogs were above 400 ng/ml. No alteration of CsA oral absorption was noted following pancreatectomy. This study suggests that frequent serum Cs concentration monitoring, with appropriate dosage adjustments, even in normals, is necessary to assure adequate drug levels. More significantly, the CsA dosage for pancreatectomized dogs should be several times greater to maintain serum concentrations comparable to normal dogs.

Transplantation of pancreatic islets in dogs.

Dispersed pancreatic islet tissue, prepared by collagenase digestion without separation of exocrine and endocrine components, was transplanted into the splenic pulp of 12 dogs made diabetic by total pancreatectomy. Four dogs (group 1) were given autotransplants, and all became euglycemic 4.5 +/- 1.5 days (mean +/- SE) after the transplantation was done. Three of these dogs remained euglycemic until splenectomized 60 days after transplantation was done. Four dogs (group 2) given allogeneic transplants from histocompatible littermates within the same group were administered cyclosporine (40 mg/kg of body weight/day; starting 2 days before transplantation was done until dogs were splenectomized), and 3 of these dogs became euglycemic 8.0 +/- 2.0 days after the transplant was done. Two of the 3 dogs that became euglycemic remained so until splenectomized 60 days after transplantation was done, and the 3rd was euglycemic until 31 days after transplantation. Four dogs (group 3) given allogeneic islet transplants from nonrelated histocompatible donors within the same group were given cyclosporine (40 mg/kg/day; as described for group 2), and none became euglycemic.

Adherence of neutrophils from dogs with diabetes mellitus.

Adherence of neutrophils from dogs with type I (insulin-dependent) diabetes mellitus controlled by insulin administration was compared with that from control dogs. Neutrophil adherence in whole blood decreased with increased serum glucose concentration, but was not different from normal cell adherence when isolated cells were examined. The decreased adherence in whole blood was considered to be the result of media factors and not dependent on altered neutrophil function.

Chronic active hepatitis in 26 Doberman pinschers.

Chronic active hepatitis with increased hepatic copper concentration was diagnosed in 25 female and 1 male Doberman Pinscher dogs. Common clinical signs included polyuria/polydipsia, weight loss, anorexia, icterus, and ascites. Increased liver enzyme activities and abnormal liver function test results were the most consistent clinicopathologic changes. The dogs were assigned to 3 groups on the basis of clinical course of the disease. Group 1 dogs (n = 12) had clinical signs of advanced liver failure and died within one week. Group 2 dogs (n = 7) had less severe clinical signs of liver disease and died within one month. Group 3 dogs (n = 5) did not have clinical signs of illness or had mild clinical signs of liver disease and died 1 to 42 months after initial evaluation. One dog could not be reevaluated and another dog was alive 3 months after initial examination. Treatments consisted of supportive care for dogs in group 1, and dietary manipulations and corticosteroids for dogs in groups 2 and 3. The association of increased liver copper concentration and chronic active hepatitis is not known.