Evaluation of d,l-ethionine as a mechanism for pancreatic islet regeneration in dogs.

OBJECTIVE: To determine whether induction of pancreatic necrosis and islet proliferation by d,l-ethionine has potential for treating dogs with beta-cell insufficiency. DESIGN: Eighteen mixed breed dogs of both sexes were given d,l-ethionine at 100 mg/kg three times weekly for 2 weeks; 6 dogs were euthanased at 2, 14 and 28 d after the last dose. METHODS: Clinical signs during administration and recovery were assessed. Routine biochemical analyses were performed before each ethionine dose and then once weekly. Faecal samples were examined weekly for malassimilated nutrients and blood. Blood coagulation screening tests (OSPT and APTT) were determined on four dogs after ethionine administration. Intravenous glucose tolerance tests were conducted before the first and after the last ethionine dose and then fortnightly. All dogs were necropsied and pancreas, liver, kidney and jejunum were examined microscopically. RESULTS: During ethionine administration all animals displayed vomiting, inappetence, diarrhoea (often with blood), weight loss and depression. Three dogs were euthanased prematurely due to severe illness, but those allowed to recover were eating and brighter 7 d after cessation of ethionine administration. Serum concentrations of TLI, amylase and lipase increased initially, then decreased, during administration but retumed to normal during recovery. Concentrations of ALT, ALP, unconjugated and conjugated bilirubin increased during administration then decreased slowly. Histological examination revealed hepatic lipidosis and necrosis, but no renal or jejunal lesions. In most dogs, faecal examination demonstrated increased undigested starch and muscle, as well as increased digested and undigested fat, during ethionine administration or early during the recovery period, suggesting transient malassimilation. APTT was unchanged but OSPT was prolonged in all dogs. There was no impairment of insulin secretion or glucose intolerance and C-peptide concentrations were unaffected. Immediately after ethionine administration there was delayed insulin degradation and by day 43 there was evidence of increased insulin sensitivity. CONCLUSION: d,l-ethionine administration in dogs appeared not to interfere with insulin secretion, but caused clinical signs and laboratory changes indicative of pancreatic exocrine necrosis, severe hepatobiliary disease and transient malassimilation. Pancreatic and hepatic dysfunction was severe but clinical recovery occurred after ethionine administration ceased. The severe side-effects observed with d,l-ethionine should preclude its potential use for treating diabetes mellitus in dogs.

Plasma cortisol concentrations following cortisone infusion in dogs before and after treatment with cortisone acetate.

OBJECTIVE: To evaluate effects of iatrogenic hyperadrenocorticism on plasma cortisol concentrations produced by an infusion of hydrocortisone in dogs. PROCEDURE: Plasma cortisol concentrations were measured regularly during a 6 h infusion of hydrocortisone sodium succinate at two dose rates. The infusions were performed before and after treatment for 30 d with oral cortisone acetate at 10 mg/kg/24 h, divided thrice daily. Adrenal activity during the experimental period was assessed by weekly ACTH stimulation tests. RESULTS: Both infusion rates produced lower plasma cortisol concentrations after treatment for 30 d with cortisone. CONCLUSION: Prior exposure to high concentrations of glucocorticoids may result in accelerated metabolism of glucocorticoids administered subsequently. This may necessitate increased dosages when using glucocorticoids to support inadequate adrenal function.

Plasma cortisol concentrations in normal dogs given hydrocortisone sodium succinate.

OBJECTIVE: To evaluate the effects on plasma cortisol concentration of a continuous infusion of a readily available steroid with equipotent glucocorticoid and mineralocorticoid effects. PROCEDURE: Plasma cortisol concentrations were measured before and regularly after hydrocortisone sodium succinate was administered as a continuous intravenous infusion over 6 h at 0.32 and 0.65 mg kg-1 h-1 to 12 healthy dogs weighing 12 to 22 kg. RESULTS: The infusion at both does rates produced significant and stable increases in plasma cortisol concentrations. The plateau concentrations produced by the large and small doeses were respectively above and below plasma cortisol concentrations likely to provide adequate glucocorticoid and mineralocorticoid activity in stressed dogs with significantly decreased adrenal function. CONCLUSION: This paper presents information regarding the changes in plasma cortisol concentrations in 12 normal dogs given an hydrocortisone sodium succinate infusion at two dose rates. The marked and continuous increase in plasma cortisol concentrations suggests a continuous HSS infusion may be a possible alternative to desoxycorticosterone acetate and dexamethasone in the treatment of acute adrenal dysfunction.

Effects of delmadinone acetate on pituitary-adrenal function, glucose tolerance and growth hormone in male dogs.

OBJECTIVE: To characterise the effects of delmadinone acetate on the pituitary-adrenal axis, glucose tolerance and growth hormone concentration in normal male dogs and dogs with benign prostatic hyperplasia. DESIGN: A prospective study involving nine normal male dogs and seven with prostatic hyperplasia. PROCEDURE: Delmadinone acetate was administered to six normal male dogs and seven dogs with benign prostatic hyperplasia at recommended dose rates (1.5 mg/kg subcutaneously at 0, 1 and 4 weeks). Three normal controls received saline at the same intervals. Blood concentrations of ACTH, cortisol, glucose, insulin and growth hormone were measured over 50 days. Intravenous glucose tolerance and ACTH response tests were performed before and after treatment in the nine normal animals. RESULTS: A substantial suppression of basal and 2 h post-ACTH plasma cortisol secretion was demonstrated after one dose in all dogs given delmadinone acetate. Individual responses after the second and third administration varied between recovery in adrenal responsiveness to continued suppression. Plasma ACTH concentration was also diminished after one treatment. No effects were evident on glucose tolerance or serum growth hormone concentrations. CONCLUSION: Delmadinone acetate causes adrenal suppression from inhibition of release of ACTH from the pituitary gland. Treated dogs may be at risk of developing signs of glucocorticoid insufficiency if subjected to stressful events during or after therapy. Neither glucose intolerance nor hypersomatotropism seems likely in male dogs given delmadinone acetate at the recommended dose rate, but the potential for excessive growth hormone secretion in treated bitches remains undetermined.

Plasma cortisol responses to three corticotrophic preparations in normal dogs.

OBJECTIVE: To compare cortisol responses to three corticotrophic preparations in normal dogs. ANIMALS: Eight clinically normal dogs (four intact males, four intact females) of medium size. PROCEDURES: Each dog received four treatments on four separate occasions in a duplicated Latin square pattern. Treatments were two adrenocorticotrophin (ACTH) preparations given intramuscularly at 2.2 U/kg, one of the ACTH preparations given intramuscularly at 1 U/kg and a synthetic polypeptide with ACTH-like activity (tetracosactrin, cosyntropin) given intravenously at 5 micrograms/kg. Plasma samples were taken for cortisol assay before and at 0.5, 1, 2 and 4 h after treatment. RESULTS: Plasma cortisol concentrations were similar with the two ACTH preparations and at both dose rates. Tetracosactrin produced smaller mean peak cortisol concentrations, which tended to occur earlier than with ACTH, and smaller values for the area under the curve of plasma cortisol concentration from zero time to 4 h. CONCLUSION: The findings suggest that canine adrenal function can be tested adequately by giving ACTH intramuscularly at 1 U/kg and measuring plasma cortisol in samples taken at 0 and 2 h, or by giving tetracosactrin intravenously at 5 micrograms/kg and determining cortisol concentration at 0 and 1 h.

Effect of ingesta and of tablets of different strengths on the systemic availability of digoxin in normal dogs.

The plasma concentrations of digoxin were measured in eight normal dogs given digoxin on four occasions, using three different feeding regimens and tablets of two strengths. Although ingesta tended to slow the absorption of digoxin, the systemic availability of the drug, based on measurements of Cmax, tmax and AUC did not differ when digoxin tablets were given with canned food, with dry food, or without food. However, some of the pharmacokinetic characteristics and smaller individual variations with the dry food regimen would be considered advantageous for maintenance therapy. Tablets containing 62.5 micrograms or 250 micrograms of digoxin had a similar relative bioavailability. The peak plasma digoxin concentrations were higher in female dogs, and the trends in other data also suggested that the systemic availability of digoxin was better in female dogs.

Effect of chronic hypocortisolaemia on plasma cortisol concentrations during intravenous infusions of hydrocortisone sodium succinate in dogs.

Intravenous infusions of hydrocortisone sodium succinate (HSS) were given at 0.625 mg kg-1 hour-1 and 0.312 mg kg-1 hour-1 to six dogs. Plasma cortisol concentrations were measured by radioimmunoassay at 0, 15, 30, 45 and 60 minutes and then every 30 minutes for a further five hours. Chronic hypocortisolaemia was induced and maintained with mitotane and the HSS infusions were repeated after 31 and 50 days. No statistically significant difference was observed in the plasma cortisol concentrations after either period of hypocortisolaemia, but the plasma cortisol concentrations tended to be higher in most of the dogs.

Effects of proligestone and megestrol on plasma adrenocorticotrophic hormone, insulin and insulin-like growth factor-1 concentrations in cats.

This paper reports changes in adrenocorticotrophic hormone (ACTH), insulin and insulin-like growth factor-1 (IGF-1) concentrations in cats from a previously published study. The cats were given oral megestrol acetate (MA, 5 mg once daily for 14 days), subcutaneous proligestone (PRG, 100 mg on two occasions one week apart) or subcutaneous saline (1 ml as for PRG). In the cats given saline (n = 6), basal ACTH, insulin and IGF-1 did not change significantly throughout the following seven weeks. The cats given MA (n = 7) developed significant suppression of plasma ACTH concentrations and hyperinsulinaemia during treatment and for two to four weeks after MA dosage ceased. In the cats given PRG (n = 7), plasma ACTH concentrations were not significantly altered although three cats had markedly suppressed values for some time after PRG treatment had ceased. Serum insulin concentrations were not significantly altered in the PRG-treated cats. The results suggest PRG may be a preferable alternative to MA in some situations.

Effect of non-adrenal illness, anaesthesia and surgery on plasma cortisol concentrations in dogs.

Basal plasma cortisol concentrations in 25 dogs with non-adrenal illness were two to three times higher than in 25 normal dogs (158 +/- 25 nmol litre-1 compared with 65 +/- 22; mean +/- SD). In addition, plasma cortisol concentrations were measured in 12 animals undergoing major abdominal, thoracic or orthopaedic surgery and compared to a group of six anaesthetised dogs. Anaesthesia alone failed to significantly alter plasma cortisol levels, however, all forms of surgery produced a significant increase in plasma cortisol concentration which returned to normal 24 hours after completion of surgery.

Plasma cortisol concentrations in dogs given cortisone or placebo by mouth.

Fasted normal dogs (n = 8) were given fixed doses of cortisone acetate orally as 5 mg and 25 mg tablets; plasma cortisol concentrations were determined, and Cmax, tmax and area under the curve of plasma cortisol concentration plotted against time from zero to 12 hours were compared for the two preparations. In addition, these variables were compared when 25 mg tablets were administered with and without food. No significant difference in cortisol availability was noted for the two preparations and feeding did not apparently affect cortisone absorption. The findings in two hypoadrenocorticoid dogs were similar. Plasma cortisol concentrations in placebo-treated dogs similarly sampled showed minor fluctuations and were generally within accepted reference limits for normal dogs.

Comparative effects of proligestone and megestrol acetate on basal plasma glucose concentrations and cortisol responses to exogenous adrenocorticotrophic hormone in cats.

Cats were given megestrol acetate (MA, 5 mg once daily for 14 days), subcutaneous proligestone (PRG, 100 mg on two occasions one week apart) or subcutaneous saline (1 ml as for PRG). In cats given saline (n = 6) basal cortical concentrations, cortisol concentrations after adrenocorticotrophic hormone (ACTH) administration and fasting blood glucose concentrations did not change significantly during the following seven weeks. Cats given MA (n = 7) developed suppression of basal and ACTH-stimulated cortisol concentrations and fasting hyperglycaemia during treatment. Effects on cortisol persisted for two weeks after MA dosage ceased. In cats given PRG (n = 7), basal cortisol concentrations were reduced overall, but only three cats had persistently suppressed post-ACTH cortisol concentrations. Adrenal suppression continued for 14 weeks in one of these and for at least 22 weeks in two cats. Fasting blood glucose concentrations were unchanged in PRG-treated cats.

Effect of ingesta on systemic availability of penicillins administered orally in dogs.

Six penicillin preparations were administered to six dogs of various types, both when the dogs were fasted and when fed a standard meal immediately before dosing. The preparations used were: amoxycillin tablets and drops, ampicillin tablets, penicillin V tablets, phenethicillin tablets and cloxacillin capsules. A Latin square design was employed with ampicillin and the two amoxycillin preparations, while three separate cross-over studies were done with penicillin V, phenethicillin and cloxacillin. Dose rates used were 50 mg/kg for cloxacillin, and 10 mg/kg for the others. A microbiological method was used to assay penicillin in blood samples taken at intervals after dosing. Values for peak plasma drug concentration (Cmax), the time at which it occurred (Tmax), and area under the curve (AUC) were obtained for each curve of drug concentration plotted against time. In fasted dogs, ampicillin showed poorer systemic availability than did amoxycillin, with Cmax and AUC values of less than half those of amoxycillin. The solid and liquid preparations of amoxycillin had similar bioavailability. Ingesta adversely affected the systemic availability of antibiotic from all preparations tested. With ampicillin and both amoxycillin preparations, there were reduced Cmax and AUC and prolonged Tmax, indicating slowed and diminished absorption. Feeding did not alter Tmax with the other drugs, but reduced the Cmax of penicillin V, phenethicillin and cloxacillin and the AUC of cloxacillin. It is suggested that, if minimal impairment of bioavailability by ingesta is desired, then the penicillins commonly administered by mouth (amoxycillin, ampicillin, penicillin V, phenethicillin, cloxacillin) should be given to dogs that are fasting.

Sporozoa in dogs and cats.

Faecal samples from 110 dogs and 71 cats were examined for sporozoan parasites by flotation. Isospora spp were present in 5.5% dogs and 4.2% cats; Sarcocystis spp in 20.9% dogs and 1.4% cats. 74.5% dogs and 77.5% cats were fed raw meat from various sources; beef was fed most often. Animals fed raw meat were more frequently infected with protozoa. No Toxoplasma oocysts were found. The results are compared with those from other surveys in Australia and New Zealand.