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Biomedical subjects

P Greaves

Publications and source records attributed to P Greaves.

At least 37 records · Page 2Linked to original sources
PubMed1990

Pathologic changes in blood vessels following administration of an inotropic vasodilator (ICI 153,110) to the rat.

ICI 153,110 is an inotropic vasodilator compound intended for the treatment of congestive heart failure. It was administered to rats at dose levels of 5, 10, and 250 mg/kg/day for up to 6 months as part of its preclinical development program. Detailed clinical investigations were conducted during the course of the study and histopathological examination took place after 28 days and 182 days of treatment as well as 42 days following cessation of dosing. Changes were identified in blood vessels in the greater proportion of animals from the high dose group, although some of the changes were also observed at lower dose levels. Vascular tissues from a variety of sites were affected, particularly those of the mesentery, splanchnum, heart, testis, and the pampiniform plexus. Early changes characteristic of acute injury such as arterial medial necrosis and inflammation occurred, which were distinguishable from those following chronic administration of the compound where there was a pronounced arterial and venous wall thickening and accompanying plexiform vasculopathy. The essential components contributing to the thickening were a smooth muscle hypertrophy and hyperplasia of the media. At the end of the period following withdrawal of dosing, vascular thickening was still present and arteritis showed an increased incidence relative to that seen at termination of the main test. Systemic hypertension was not detected during these studies. Vasodilation occurring at or near normal blood pressure, resulting in breakdown of vascular autoregulation and excessive critical wall tension, may have been the cause of the pathological changes. Our findings indicate that medial necrosis is an early component in a sequence of adaptive, destructive, and reparative changes not only following a chemically induced perturbation of the hemodynamic status in arteries and veins but also following a shift back to the "normal state" on withdrawal of compound.

Animals↗
PubMed1989

Polyarteritis in a beagle.

A 13-month-old Beagle became anorectic and had fever, stiff gait, and tenderness in the inguinal region. Clinical signs of disease were associated with neutrophilia and a decrease in the albumin-to-globulin ratio. The dog became clinically normal for 5 days after 3 days of treatment with penicillin G and dihydrostreptomycin. Clinical signs of disease recurred, and the dog was euthanatized after failing to respond to administration of a trimethoprim-sulfamethoxazole combination for 9 days. Disseminated arteritis was seen in the testes, epididymides, mesentery, coronary arteries, aorta, and thyroid gland. Lesions were seen in large and medium-sized arteries and varied from acute necrotizing arteries to a chronic lesion with organization and recanalization of thrombi. The clinical signs of disease resembled those of Beagle pain syndrome, described in laboratory Beagles.

Animals↗
PubMed1989

Renal and hepatic toxicity of a benzopyran-4-one in the Cynomolgus monkey.

The administration of PD 119819, a novel benzopyran-4-one brain dopamine autoreceptor agonist, to Cynomolgus monkeys was followed by deposition of needle-like drug crystals in the bile canaliculi, hepatocytes, proximal renal tubules and renal parenchyma. The crystals were associated with a granulomatous inflammation, and histological and biochemical evidence of hepatic and renal cell damage. Although metabolism differences may be the reason why primates, but not rodents, developed these changes, this form of crystallization appeared to be primarily a result of the insolubility of PD 119189 at alkaline pH.

5'-Nucleotidase↗
PubMed1987

A cytochemical study of the livers of rats treated with diethylnitrosamine/phenobarbital, with benzidine/phenobarbital, with phenobarbital, or with clofibrate.

Male Sprague-Dawley rats were treated with clofibrate (CLOF) in the diet for 2 years or with 4 i.p. injections of either diethylnitrosamine (DEN) or benzidine (BZ) followed by phenobarbital (PB) in the diet for 67 weeks, or just with PB for 41 weeks. Animals were killed at frequent intervals, some while still on treatment and others after 3 or 6 months withdrawal of treatment. The livers were subjected to cytochemical measurements of the parenchyma, foci, nodules and carcinomas. The parenchyma of the CLOF groups showed, in general, increases in glucose-6-phosphate dehydrogenase (G-6PD), alpha-glycerophosphate dehydrogenase (alpha-GPD), 5'-nucleotidase (5'-Nu), acid phosphatase (AP) and catalase and decreases in uricase and glutathione (GSH). CLOF induced a low incidence of GSH positive foci; nodules showed universally lower levels of catalase and GSH. In the DEN/PB and BZ/PB groups the parenchyma showed increases (even before PB treatment started) in G-6PD and in gamma-glutamyl transpeptidase (gamma-GT) and decreases in GSH. DEN raised and BZ lowered 5'-Nu. Neither initiator affected alpha-GPD. Both initiators caused a high incidence of foci positive for G-6PD and for gamma-GT; nodules induced by DEN/PB were mainly positive for gamma-GT and showed an erratic response to the other parameters. Carcinomas, found only after DEN/PB, were all positive for G-6PD and, with one exception, all were negative for alpha-GPD, 5'-Nu, AP and GSH. All changes regressed within 3 months of withdrawal of CLOF but not after withdrawal of PB from DEN-initiated animals. In conclusion G-6PD, alpha-GPD and 5'-Nu may be useful histocytochemical parameters for studying the precarcinogenic hepatic changes and nodules induced by peroxisome proliferators and by genotoxic hepatocarcinogens.

Administration, Oral↗
PubMed1987

Periarteritis in a beagle colony.

Primary periarteritis, an uncommon necrotizing vasculitis in the dog, was found to affect, almost exclusively, the major branches of the coronary arteries in a number of young beagle dogs. The arteritis was mainly distributed in the proximal segment of the right coronary artery. Immunocytochemical studies failed to identify immunoglobulin deposits in the lesions and the cause of the arteritis remains unknown. It is important to be aware of this spontaneous condition and its regional distribution since certain cardiovascular drugs may also produce necrotizing arteritis at similar sites.

Animals↗
PubMed1986

Neoplasia and hyperplasia of pancreatic endocrine tissue in the rat: an immunocytochemical study.

Spontaneously occurring neoplasms and non-neoplastic proliferative changes of the pancreatic cells in aging Sprague-Dawley and Long-Evans rats were examined for the presence and distribution of pancreatic hormones using immunocytochemical techniques. Islet cell tumors were indistinguishable in the two rat strains. They were composed principally of insulin-containing beta cells, but had additional and variable small proportions of cells that stained for somatostatin, glucagon, or rarely, pancreatic polypeptide. The heterogeneity in these spontaneous islet cell neoplasms was similar to that reported in humans as well as those induced in rats by streptozotocin. Hyperplasia of the islet cells also mainly affected the beta cells, but the overall pattern of immunocytochemical staining usually remained similar to that of normal islets, a point of distinction from islet cell neoplasms. In addition, rats with exocrine atrophy and fibrosis were found to have considerable disruption and focal proliferation of the islets.

Adenoma, Islet Cell↗
PubMed1986

Hepatic foci of cellular and enzymatic alteration and nodules in rats treated with clofibrate or diethylnitrosamine followed by phenobarbital: their rate of onset and their reversibility.

The histologic appearance and cytochemical characteristics of foci of hepatic cellular alteration, hepatic nodules, and hepatocellular carcinomas occurring in male Sprague-Dawley rats treated with the hypolipidemic agent clofibrate (CAS: 637-07-0), with phenobarbital (CAS: 50-06-6), or with diethylnitrosamine [(DENA) CAS: 55-18-5] followed by phenobarbital were studied after treatment periods from 1 month to 2 years. Rats treated with clofibrate revealed foci of cellular alteration that were more often basophilic and occurred slightly sooner (wk 42) than those in untreated controls (wk 60). Of 36 rats that had received 68 or more weeks of continuous clofibrate, 19 had hepatic nodules. Of the 11 nodules examined cytochemically, none was gamma-glutamyltransferase (gamma-GT) positive and 2 were positive to glucose-6-phosphate dehydrogenase (G-6-PD) under oxygen. In rats withdrawn from clofibrate for 16-18 weeks after 68-95 weeks of clofibrate, 0 of 14 had nodules. In several of these rats zones of hepatic scarring were observed, suggesting the reversibility of the nodules. Phenobarbital alone had little effect on the incidence of foci of cellular alteration, although the number of gamma-GT-positive foci was increased. DENA followed by phenobarbital led to the early appearance of foci of cellular alteration (from wk 4), of nodules (from wk 13), and of hepatocellular carcinomas (from wk 26). gamma-GT activity was raised in most of these nodules and carcinomas, while G-6-PD activity was raised in only 3 of 9 nodules but in all 9 carcinomas examined. DENA-phenobarbital given for 13 or 26 weeks followed by withdrawal of phenobarbital for 28 and 26 weeks, respectively, produced an essentially similar pattern of lesions. In view of the growing recognition of the nonspecificity gamma-GT as a marker of carcinogen-initiated foci, the value of G-6-PD (under oxygen) as a marker merits further investigation.

Animals↗
PubMed1985

Dazoxiben, a prototype inhibitor of thromboxane synthesis, has little toxicity in laboratory animals.

Dazoxiben, an orally active specific inhibitor of thromboxane synthetase, was administered by mouth daily to dogs and rats for 6 months. Dogs showed no evidence of toxicity up to 300 mg day-1 kg-1, the highest dose level used. Rats showed no evidence of toxicity after 100 mg day-1 kg-1, but at 300 mg day-1 kg-1 there were slight increases in plasma calcium and urea concentrations and a moderate incidence of focal nephrosis; males showed a slightly increased platelet count. Studies in rats and rabbits at dose levels up to 400 mg day-1 kg-1, by mouth, revealed no adverse effects on male or female fertility, embryogenesis, parturition or postnatal development. As dazoxiben is well absorbed after oral administration, the generally negative outcome to these toxicity studies suggests that selective inhibitors of thromboxane synthesis may be largely free of adverse effects which might impede their therapeutic or prophylactic use in clinical medicine.

Animals↗
PubMed1985

Malignant fibrous histiocytoma in rats at sites of implanted millipore filters.

Soft-tissue tumors developing in rats at the site of implanted Millipore filters showed the structural, cytochemical, and biologic characteristics of the malignant fibrous histiocytomas occurring in man. Evidence from this tumor model suggests that malignant fibrous histiocytomas can arise from pluripotential mesenchymal stem cells which are not derived from the mononuclear/phagocytic system and that chronic inflammation and scarring may predispose to their development.

Animals↗
PubMed1985

Coronary hyperemia and cardiac hypertrophy following inhibition of fatty acid oxidation. Evidence of a regulatory role for cytosolic phosphorylation potential.

Oxfenicine (S-4-hydroxyphenylglycine) is a cardioselective inhibitor of long-chain fatty acid oxidation. In anesthetized dogs, oxfenicine (3.3 mg/kg, i.v.) increased myocardial blood flow by 33% under normal conditions and by 71% during isoprenaline infusion, but produced no other hemodynamic changes. Similar results were obtained with two other inhibitors of fatty acid oxidation, 2-bromopalmitate and 2-tetradecylglycidate. Chronic administration of oxfenicine to dogs for 1 year produced dose-related, nonpathological increases in relative heart weight (up to 85% at 750 mg/kg per day). Smaller effects (up to 30% at 900 mg/kg per day) were observed in a similar study in rats. Cardiac hypertrophy has previously been reported in rodents treated with 2-tetradecylglycidate. Moreover, cardiomegaly is frequently observed in cases of carnitine deficiency. We therefore suggest that coronary hyperemia and cardiac hypertrophy following either inhibition of fatty acid oxidation or an increase in cardiac work load may be adaptive changes triggered by a common mechanism-namely, a fall in cytosolic phosphorylation potential. In support of this, oxfenicine decreased the phosphocreatine/creatine ratio in rat hearts perfused in the presence of oleate. These findings suggest the possibility that metabolic abnormalities may provide the key to many idiopathic cardiomyopathies of uncertain origin.

Adenosine Diphosphate↗
PubMed1984

Cardiac hypertrophy in the dog and rat induced by oxfenicine, an agent which modifies muscle metabolism.

Oxfenicine (S-4-hydroxyphenyl glycine) has been shown to protect the rat and dog heart from experimentally induced myocardial ischaemia probably as a result of its ability to divert myocardial metabolism from fatty acid to carbohydrate utilization with a consequent reduction in oxygen consumption. When various dose levels of oxfenicine were administered to dogs for periods of up to 1 year and rats for periods of up to 2 years, dose-related increases in cardiac weight were observed. No increases in cardiac weight were observed in the rat after only 3 months of treatment but increases were observed in the dogs after a similar treatment period. Macroscopic, light, histochemical and electron microscopic examination of the myocardium revealed that the increase in heart weight was due to uniform myocardial fibre hypertrophy involving all cardiac chambers. Individual muscle fibres were increased in size but there was no clear disproportion of mitochondria and myofibrils. Although intracellular lipid was increased, vacuolated lysosomal structures were only occasionally observed. No histochemical differences in lysosomal enzyme activity were observed between the treated and the control rats. The structural changes were fully compatible with myocardial hypertrophy due to the decreased energy forming capacity of heart muscle resulting from inhibition of fatty acid oxidation by oxfenicine.

Animals↗
PubMed1984

Sialomucins and carcinoembryonic antigen in the evolution of colorectal cancer.

We have explored the merit of a simultaneous study of sialomucin content and carcinoembryonic antigen (CEA) expression in the identification of early malignancy in adenomas. One hundred and thirteen colorectal adenomas were investigated by histochemical and immunocytochemical techniques. We compared adenomas from 'high risk' patients having synchronous carcinoma and 'low risk' groups with incidental polyps only. Twenty-three metaplastic and eight inflammatory polyps were also included. Our data suggest that size and dysplasia are not always closely related and that synchronous adenomas seem to carry a higher malignant potential than incidental polyps irrespective of size. The degree of O-acylation of sialic acids appears to be a sensitive indicator of early malignant change: loss of O-acylation was seen in all II adenomas with highly atypical foci ('focal carcinoma') but noted in only four of the remaining polyps with lower grade dysplasia (P less than 0.005). By contrast the intensity of staining for CEA was a gradual phenomenon and showed no statistically significant increase with the onset of malignancy. Inflammatory polyps showed staining characteristics similar to normal mucosa. Metaplastic polyps, however, revealed increased expression of CEA and reduced O-acylation with increased size which may reflect a disorder of growth and differentiation. Finally, by comparing these profiles of staining with those of normal mucosa, 'transitional' mucosa adjacent to carcinoma and carcinoma, we further illustrate a progression of changes occurring in colonic mucosa in carcinogenesis.

Adenocarcinoma↗
PubMed1984

Altered patterns of mucin secretion in gastric hyperplasia in mice.

Gastric hyperplasia occurred more frequently among densely housed mice than mice housed singly, and crowding stress may have been implicated in this increased prevalence. Affected stomachs had striking increases in sulfomucin secretion when compared with unaffected gastric mucosa. The mucin changes suggested incomplete maturation of mucous cells in this condition and were similar to those reported in association with early neoplastic or pre-neoplastic lesions in the stomach of both man and rodents.

Animals↗
PubMed1984

Spontaneous eye lesions in laboratory animals: incidence in relation to age.

Examination of the eye in experiments designed to test the toxicity of drugs or chemicals is of considerable importance and the investigator must have a clear idea of the spontaneous eye changes he can expect in the test species. We have attempted to review the literature relating to commonly used laboratory animals--the rat, mouse, and dog as well as the hamster--but as there is still only a handful of workers that publish their findings, the literature is not fully comprehensive. Our own unpublished data have been used to try and provide a more complete account. There is, therefore, a considerable need for further work in this area and, in the future, newer techniques such as electron microscopy and histochemistry can help us in the understanding of the pathogenesis of age-related changes in laboratory animals.

Aging↗
PubMed1982

Choice of rat strain: a comparison of the general pathology and the tumour incidence in 2-year old Sprague-Dawley and Long-Evans rats.

As the choice of species and strain of laboratory animal is of considerable importance in carcinogenicity studies, a two-year, spontaneous carcinogenicity study was performed to compare Sprague-Dawley (Crl: Cobs CD(SD)BR) and Long-Evans rats (CRL: Cobs (LE)BR) under the laboratory conditions at Amboise. Of the 108 animals per strain (54 per sex), no overall differences were noted in survival. Nearly half of the premature deaths in both strains appeared to be due to large pituitary adenomas compressing brain parenchyma. Although the incidence of benign mammary fibroadenomas was similar for both female groups, the incidence of invasive mammary carcinoma was higher in Sprague-Dawley females. Other differences were related to the higher incidence of pancreatic atrophy and nephrosis among Long-Evans rats. Studies of this type can help in the understanding of the pathology of laboratory rodents which may aid in the choice of strain in carcinogenicity studies.

Animals↗