Urinary tract toxicity in rats following administration of beta 3-adrenoceptor agonists.

ZD7114, [(S)-4-[2-(2-hydroxy-3 phenoxypropylamine)ethoxy]-N-(2-methoxyethyl) phenoxyacetamide], and ZD2079, [(R)-N-(2-[4- (carboxymethyl)phenoxy]ethyl)-N-(beta-hydroxyphenethyl)ammonium chloride], are beta 3-adrenoceptor stimulants with selectivity for brown adipose tissue. ZD7144 is the hydrochloride salt of the S-enantiomer of the racemic amide ZD2079. They were developed as potential novel treatments for obesity and non-insulin-dependent diabetes mellitus. Male and female rats were dosed separately by gavage for a minimum of 28 days with 0, 10, 50, and 500 mg/kg/day of ZD7114 or with 0, 10, 30, and 150 mg/kg/day of ZD2079. Two further groups of male and female rats were dosed with 0 and 500 mg/kg/day of ZD7114 for 28 days and were then allowed a 6-wk, undosed withdrawal period. At high doses, both compounds caused urinary tract toxicity, which primarily affected the distal tubules and collecting ducts of the kidney via tubular necrosis. They also caused ureteric inflammation, cystitis, and accumulation of crystalline inclusions throughout the urinary tract. As a result of urinary tract toxicity, affected animals from one or both studies showed reduced red blood cell indices, lower platelet counts, and higher white cell counts. Blood chemistry revealed lower plasma concentrations of glucose (7.28 +/- 1.37 compared to 8.11 +/- 0.65 for the control) and total protein (63.42 +/- 3.65 compared to 69.17 +/- 3.24 for the control) and increased plasma urea (37.15 +/- 19.96 compared to 8.09 +/- 0.87 for the control). Urinalysis showed an increase in the number of crystals, blood, and protein. In the urinary tract, the severe crystalluria with accumulation of crystalline material indicated that this may have a role in the etiology of the target organ toxicity. Poor solubility of the compounds at normal urinary pH was considered a possible mechanism for the crystalluria.

An immunohistochemical study of spontaneous histiocytic tumours in the rat.

Immunocytochemistry was used to examine 18 cases of rat fibrous histiocytic tumours (11 malignant; seven benign). The diagnosis was made by light microscopic criteria and all cases were categorized as pleomorphic-storiform. A selection of polyclonal antibodies to histiocytic, muscle, neural and mesenchymal antigens was used. Fifteen tumours were positive with alpha 1-antitrypsin, four with alpha 1-chymotrypsin, ten with muramidase, five with desmin, 15 with neuron-specific enolase, 14 with S100, one with glial fibrillary acid protein and 12 with vimentin. Many tumours expressed several antigens, highlighting the confusion which has arisen with regard to the histiogenesis of fibrous histiocytic tumours in man, and supporting the concept of differentiation from a primitive mesenchymal common precursor able to differentiate in several directions.

Comparison of a human granular cell tumour (myoblastoma) with granular cell tumours (meningiomas) of the rat meninges--an immunohistological and ultrastructural study.

A single human granular cell tumour (myoblastoma) was compared with seven rat granular cell tumours (meningiomas) of the meninges. The comparison was made histologically, ultrastructurally and using immunocytochemical markers. A selection of antibodies to histiocytic, muscle, neural, neural crest and mesenchymal antigens was used. Histogenesis of both the human and rat tumours from neural crest-derived cells was evident and it is suggested that the term 'meningioma' for these rat tumours is a misnomer.

Isolation and characterization of endothelial cells from rat and cow brain white matter.

A procedure is described for obtaining pure cultures of endothelial cells from rat and cow brain white matter. The morphology of the tissue-cultured cells was studied by both light and transmission electron microscopy. Weibel-Palade bodies, described in the literature as specific for endothelial cells, appeared in small numbers in our cultured cells. Autoradiographic, scintillation counting, immunological and histochemical studies were performed. The usefulness of pure endothelial cell cultures is discussed.

Studies of hydrolytic enzymes and isoenzymes of normal and neoplastic childhood renal tissues and their tissue cultured cells.

The hydrolases of acid and alkaline phosphatase and non-specific esterases were investigated by histochemical and electrophoretic techniques in normal and neoplastic renal tissues and their cultured cells. A distinct tumour specific pattern of non-specific esterases was demonstrated in Wilms' tumour. The reasons for the quantitative differences found in the distribution of alkaline phosphatase in Wilms' tumour and their cultured cells are discussed.

Tumour-specific antibodies reactive with cell-surface antigens in children with Wilms' tumour.

Tumour-specific antibodies directed against membrane antigens were demonstrated by immunofluorescence in three of 45 patients with Wilms' tomour. Antibody capable of collaborating with K cells to kill Wilms' tumour was present in two additional patients. No patient exhibited both membrane immunofluorescence and K-cell collaborating antibody. Of 27 patients with non-renal solid tumours and 52 age-matched controls, none possessed tumour-specific antibody.

Experimental immune retinitis: induction by isolated photoreceptors.

An antigen prepared from the outer limbs of the photoreceptors failed to produce retinal lesions within 3 months by systemic immunisation alone in the rabbit. Intra-vitreal injection of the antigen in a pre-immunised rabbit resulted in an Arthus type response. Repeated systemic immunisation for over 1 year after an intravitreal injection produced retinal degeneration in the uninjected eyes of two rabbits. Anti-visual cell antibodies were not shown to be cytotoxic to organ cultures of retina. Possible reasons are discussed in relation to in vitro studies of thyroid, kidney and spinal cord.