Further studies on the use of allopurinol to reduce plasma uric acid concentrations in the Red-tailed Hawk (Buteo jamaicensis) hyperuricaemic model.

The present paper reports the effects of allopurinol in a raptor hyperuricaemic model. The study was performed as a follow-up to previous experiments wherein allopurinol was used in doses of 100 and 50 mg/kg, and was proved to be toxic at these higher dose rates. To investigate whether 25 mg/kg (semel in die) s.i.d. allopurinol is a safe and effective dose in Red-tailed Hawks (Buteo jamaicensis) to reduce plasma uric acid concentrations, experimental studies were performed using the physiologically occurring postprandial hyperuricaemia. Preprandial and postprandial plasma concentrations of xanthine, hypoxanthine, allopurinol, oxypurinol and uric acid were established by high-performance liquid chromatography at various time intervals after receiving allopurinol (25 mg/kg SID) or placebo. No significant differences were observed between the experimental and the control group. These results indicate that this dose is safe to administer; however, this dose failed to cause a significant effect on plasma uric acid concentrations. Because of the low therapeutic ratio of allopurinol in Red-tailed Hawks, follow-up studies have concentrated on an alternative for the treatment of hyperuricaemia, namely urate oxidase.

Disturbed vasopressin release in 4 dogs with so-called primary polydipsia.

Primary polydipsia is characterized by a marked increase in water intake and secondary polyuria, and in dogs often is described as a behavioral problem or a psychological disorder. We describe 4 dogs with primary polydipsia, diagnosed on the basis of a modified water deprivation test, in which further examination included serial measurements of urine osmolality (UOsm) and plasma vasopressin (VP) measurements during water deprivation and hypertonic saline infusion. The dogs, ranging in age from 4 months to 4 years, all were presented for evaluation of polyuria and polydipsia. Physical examination, routine blood chemistry, and urinalysis disclosed no specific cause for the polyuria and polydipsia. During serial measurements UOsm spontaneously reached high concentrations in 2 dogs, whereas in the other 2 dogs UOsm also fluctuated but on no occasion exceeded 1,000 mosm/kg. Primary polydipsia was diagnosed when UOsm exceeded 1,000 mosm/kg at the end of the modified water deprivation test and plasma osmolality did not exceed the upper limit of the reference range during testing. During water deprivation, plasma VP concentrations remained relatively low. The VP response to hypertonic saline infusion was abnormal, with an increased threshold value in 3 dogs, an increased sensitivity in 2 dogs, and an exaggerated response in 1 dog. It is concluded that some dogs fulfilling current criteria for primary polydipsia produce concentrated urine spontaneously throughout the day in a pattern similar to what has been observed in healthy pet dogs. This finding can be regarded as diagnostic and precludes the need for a water deprivation test. During water deprivation testing, all 4 dogs produced highly concentrated urine in the face of low basal plasma VP concentrations. The observed abnormal VP release in response to hypertonic stimulation may be interpreted as a primary disturbance in the regulation of VP secretion, although it might also be the result of overhydration caused by a primary abnormality in drinking behavior.

Further studies on allopurinol-induced hyperuricaemia and visceral gout in red-tailed hawks (Buteo jamaicensis).

To investigate the usefulness of allopurinol for the treatment of hyperuricemia in birds, experimental studies were performed using the physiologically occurring post-prandial hyperuricaemia in birds of prey as a model. Pre-and post-prandial plasma concentrations of allopurinol, oxypurinol, xanthine, hypoxan-thine and uric acid were established by high performance liquid chromatography in red-tailed hawks (RTH, Buteo jamaicensis) at various time intervals after receiving allopurinol (50 mg/kg SID) or placebo. The dosage used caused slight, but significantly elevated plasma uric acid concentrations compared to controls, as well as vomiting in the majority of treated birds. Markedly elevated plasma concentrations of oxypurinol, xanthine and hypoxanthine were seen in experimental birds. Toxic signs were attributed to oxypurinol, the active (and toxic) metabolite of allopurinol. Xanthinuria was considered to be the cause of the observed renal function disorder. Extrapolation of data from studies in humans and combining these with those of the present study suggest that the maximum dose of allopurinol that can be safely administered to RTH is about half the dose given in the present study, but this needs verification.

The role of progestins, insulin-like growth factor (IGF) and IGF-binding proteins in the normal and neoplastic mammary gland of the bitch: a review.

The growth hormone (GH) and insulin-like growth factor (IGF) system is an important regulatory system of mammalian epithelial cell proliferation and differentiation. The biological effects of the IGFs are modulated by six different binding proteins (IGFBPs). Progestins play an important role in the regulation of the dynamics of mammary gland development and involution through the modulation of these growth regulating factors. In dogs and cats, progestins stimulate the local production of GH in the mammary gland. In dogs, this results in high plasma concentrations of GH and a concomitant increase in plasma IGF-I and IGFBP-3 concentrations. The administration of progestins also induces high plasma concentrations of IGF-II, even before GH concentrations start to increase. In the mammary gland of the normal bitch, IGFBP-5 and IGFBP-2 are the main IGFBPs expressed. Progestin administration results in a decrease of mRNA encoding IGFBP-5, but does not alter the concentration of mRNA encoding IGFBP-2. This local mammary system of GH, IGFs and IGFBPs plays an important role in the regulation of mammogenesis, lactation and involution. However, the presence of a high proliferative environment may also enhance the risk of malignant transformation and promotion of tumour growth with an associated inhibition of programmed cell death.

Molecular screening for somatic mutations in corticotropic adenomas of dogs with pituitary-dependent hyperadrenocorticism.

Pituitary tumorigenesis is now generally regarded as a multistep process of genomic damage leading to uncoupling of interdependent systems that control cell proliferation and differentiation. The alterations include mutations in genes encoding for proteins involved in signal transduction pathways, such as G-proteins and the p21 protein encoded for by the ras genes. Apart from their excessive secretion of ACTH, corticotropic adenomas are characterized by decreased sensitivity to inhibition by glucocorticoids. Therefore, mutations in the glucocorticoid receptor leading to decreased sensitivity to glucocorticoids may contribute to corticotropic tumor formation. In this study, 16 corticotropic adenomas of dogs with pituitary-dependent hyperadrenocorticism were screened for mutations in the Gs alpha, H-, K-, N-ras genes and the coding region of the DNA-binding domain of the glucocorticoid receptor. The cDNA fragment of the Gs alpha gene encompassed codons 159-240. The K-, and N-ras fragments spanned codons 1-71. The H-ras gene was only screened for mutations in codons 12/13 by direct sequencing of the PCR product. The cDNA fragment of the DNA-binding domain of the glucocorticoid receptor encompassed codons 410-500. The Gs alpha, K-ras, N-ras genes and the DNA-binding domain of the glucocorticoid receptor were screened by single-strand conformation polymorphism analysis. No mutations were found in the Gs alpha gene, the ras genes and the DNA-binding domain of the glucocorticoid receptor. It is concluded that mutations in the Gs alpha gene (codons 159-240), the K- and N-ras genes (codons 1-71), the H-ras gene (codons 12/13) and mutations in the DNA-binding domain of the glucocorticoid receptor do not play a role in the tumorigenesis of canine corticotropic adenomas.

Urinary excretion of glucocorticoids in the diagnosis of hyperadrenocorticism in cats.

In dogs and humans, the measurement of urinary corticoid excretion has become a standard screening test for the diagnosis of hyperadrenocorticism. Mainly because the urinary excretion of cortisol was considered to be very low in cats, its measurement was not used in the diagnosis of hyperadrenocorticism in this species. We therefore studied the urinary excretion of [3H]cortisol and measured the corticoid/creatinine (C/C) ratio in healthy cats and in cats with hyperadrenocorticism in order to evaluate the applicability of this measurement in the diagnosis of feline hyperadrenocorticism. The median urinary excretion of intravenously administered [3H]cortisol was 1.85% (measured as excreted 3H; range, 1.56 to 1.99; n = 4). High-performance liquid chromatography analysis showed a small peak of cortisol and a large peak consisting primarily of conjugates of cortisol and/or its metabolites. The 2.5 and 97.5 percentiles of the urinary C/C ratio in healthy cats were 2 x 10(-6) to 36 x 10(-6) (n = 42). The C/C ratio was significantly higher in six cats with pituitary-dependent hyperadrenocorticism (median, 122 x 10(-6); range 51 x 10(-6) to 272 x 10(-6)). The administration of a high dose of dexamethasone (0.1 mg/kg thrice daily per os) led to marked suppression of the C/C ratio in healthy cats (median suppression of the average of the C/C ratio of the first two consecutive days was 92%; range, 74 to 96%; n = 12), as well as in five cats with pituitary-dependent hyperadrenocorticism.(ABSTRACT TRUNCATED AT 250 WORDS)

Corticotropin-releasing hormone and adrenocorticotropic hormone concentrations in cerebrospinal fluid of dogs with pituitary-dependent hyperadrenocorticism.

There is still some controversy concerning the question of whether Cushing's disease in man is caused by a primary dysfunction of the pituitary or a hypothalamic disorder. In the latter option, excessive hypothalamic stimulation of pituitary corticotropes would cause or contribute to the genesis of POMC-secreting adenomas. In the present study cerebrospinal fluid (CSF) CRH levels and levels of ACTH and cortisol in CSF and plasma were measured in clinically healthy dogs, in dogs with pituitary-dependent hyperadrenocorticism (PDH), and in dogs with hyperadrenocorticism due to an adrenocortical tumor (ATH). In CSF from dogs with PDH, CRH concentrations (226.6 +/- 14.4 ng/liter) were significantly (P < 0.05) lower than those in control dogs (309.5 +/- 20.3 ng/liter). In the dogs with ATH, CSF CRH concentrations (211.0 +/- 40.3 ng/liter) were in the range of those in PDH dogs. In dogs with ATH, CSF ACTH levels (13.0 +/- 3.0 ng/liter) were significantly (P < 0.05) lower than those in control dogs (63.4 +/- 3.5 ng/liter), whereas in dogs with PDH, the levels (116.8 +/- 47.5 ng/liter) were not different from those in the control group. In control dogs, the concentrations of CSF CRH and plasma ACTH were significantly correlated (r = 0.635; P < 0.01). This functional dependency appeared to be disturbed in dogs with PDH, as in these dogs CSF CRH concentrations did not correlate with plasma ACTH concentrations. It is concluded that continuous hyperstimulation of pituitary corticotropes with hypothalamic CRH is probably not the cause of excessive ACTH secretion in dogs with pituitary-dependent hyperadrenocorticism.