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Biomedical subjects

A Poole

Publications and source records attributed to A Poole.

At least 19 recordsLinked to original sources
PubMed1992

Does Graves' disease or thyrotoxicosis affect the prognosis of thyroid cancer.

Twenty-one patients who underwent surgical treatment for thyrotoxicosis and who were found at operation to have thyroid cancer are presented. Sixteen had Graves' disease and 5 had toxic nodular goiter. The group with Graves' is compared with 110 euthyroid patients with thyroid cancer who underwent their initial surgery in the same time period and who were of the same age (+/- 1 yr) and sex as the patients with Graves' disease. None of the thyrotoxic patients died during follow-up of 2-24 yr or developed subsequent metastases. The 1 patient with a local lymph node metastasis has not shown evidence of recurrence. Hypoparathyroidism appeared as a complication in only 1 patient. The size of tumors in the patients with Graves' disease was significantly smaller than in the euthyroid group. The course of the disease in both the patients with Graves' disease and the thyrotoxic group as a whole was relatively benign. This series does not support the recent suggestions that thyroid cancer in patients with Graves' disease is more aggressive than in either patients with toxic nodular goiter or euthyroid subjects. Patients with Graves' disease and thyroid cancer should be treated identically to other patients with thyroid cancer. Therapy should consist of total thyroidectomy followed by a postoperative 131I scan. Residual tissue or metastases found on the scan should be ablated with 6 GBq 131I. The patient should receive a suppressive dose of T4.

Adult↗
PubMed1990

In vivo biliary excretion and in vitro cellular accumulation of thyroxine by rats or cultured rat hepatocytes treated with a novel histamine H1-receptor antagonist.

Rats treated with temelastine (SK&F 93,944), a novel histamine H1-receptor antagonist, develop thyroid lesions characterized by hypertrophy and colloid depletion. To investigate the mechanism underlying the lesion the biliary clearance and hepatocellular accumulation of radio-labelled iodothyronines was measured in rats or cultured rat hepatocytes. Treatment with temelastine increased both the biliary clearance (approximately 300% of control) and hepatocellular accumulation (approximately 200%) of thyroxine (T4) but had little or no effect on tri-iodothyronine (T3). Chromatographic analysis of bile samples from temelastine-treated rats showed that the majority (approximately 78%) of T4 was present in the unconjugated form. This contrasted with data from phenobarbitone-treated rats which showed that approximately 80% of T4 in the bile was present as the glucuronide conjugate. Studies with cultured hepatocytes showed that the hepatocellular accumulation of T4 was energy dependent. At 4 degrees C the treatment-related increases in accumulation of T4 were abolished, suggesting that temelastine is specifically affecting the high affinity, energy dependent system which preferentially transports thyroxine into hepatocytes. Because temelastine is metabolized extensively, investigations were undertaken to discover if the hepatic effects were caused by the parent compound or an oxidative metabolite. The results showed that the hepatocellular accumulation of T4 remained increased in hepatocytes co-incubated with temelastine and 1-aminobenzotriazole (a suicide inhibitor of cytochrome P450), even though no measurable P450 could be found in the cells. Also, in studies with two major "rat" metabolites of temelastine, i.e. 93,944-Met I or 93,944-Met VIII, treatments failed to reproduce the responses seen with the parent compound.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Comparative toxicology of temelastine. A novel H1 antagonist in dog, rat, and monkey.

The toxicity of temelastine 2-[4-(5-bromo-3-methylpyrid-2-yl)butylamino]-5-[(6-methylpyrid+ ++-3-yl) methyl]-4-pyrimidone a potent, selective, competitive histamine H1-receptor antagonist was examined in dogs and rats. The major toxicological response seen in the dog was marked, but intermittent and reversible, increases in the plasma activity of a number of liver-associated enzymes, viz alanine aminotransferase (ALT), glutamate dehydrogenase (GLDH), and alkaline phosphatase (ALP). The increases first seen in two male dogs treated for 30 consecutive days at a dose of 300 mg/kg became apparent at lower doses, i.e., 100 and 33.3 mg/kg/day, in 6- and 12-month studies. Although the increases were suggestive of hepatotoxicity, the only histological changes were increases in hepatocellular lipofuscin pigment and foci of macrophages seen in dogs treated at 300 mg/kg for 12 months. Rats treated for up to 12 months at doses as high as 300 mg/kg/day showed no treatment-related increases in plasma enzymes although increases in liver weights and hepatocellular lipofuscin pigment together with centrilobular hypertrophy were seen in the 300 mg/kg/day treatment group. To investigate differences in hepatic responsiveness between species dogs, rats, and monkeys were exposed to high concentrations of temelastine by continuous 24-hr intravenous infusion. The results of the study showed the dog to be most sensitive to the hepatic effects of temelastine. The major toxicological effect of temelastine in the rat was a histopathological lesion of the thyroid gland characterized by agglomeration and depletion of colloid, follicular epithelial hypertrophy and reduced follicular size. The no-effect dose for this lesion was between 10 and 33.3 mg/kg/day. These histopathological changes, characteristic of a "TSH-driven" thyroid gland, were not seen in the thyroid glands of dogs.

Alanine Transaminase↗
PubMed1989

Activities of enzymes of collagen biosynthesis and levels of type III procollagen peptide in the serum of patients with sarcoidosis.

Serum immunoreactive prolylhydroxylase (IRPH), galactosylhydroxylsyl glucosyltransferase activity (GGT) and amino-terminal propeptides of type III procollagen (Pro(III) peptide) were measured in fifty three patients with sarcoidosis (all having some degrees of pulmonary fibrosis). The levels of IRPH and Pro(III) peptide showed no relationships to the clinical assessment of the disease and while GGT activity was raised in approximately 80% of the patients there was no correlation between the size of the increases and the clinical activity of the disease. The results of this study would suggest that measurement of the above parameters offer no specificity in either diagnosing or assessing the clinical activity of sarcoidosis. The observed increases in serum GGT activity in affected patients would however suggest that measurement of this enzyme may be useful perhaps in more severe pulmonary fibrotic reactions.

Biomarkers↗
PubMed1989

Mechanistic investigation of species-specific thyroid lesions induced by treatment with the histamine H1 antagonist temelastine (SK&F 93944) in rats.

Temelastine (SK&F 93944), an H1 histamine receptor antagonist, induces thyroid histopathological lesions in the rat, indicative of thyroid follicular cell stimulation, at oral doses of 10-33 mg/kg body weight/day. These changes do not occur in the dog or mouse. Endocrinological short-term studies support an increased thyroid follicular activity (increased radioiodide accumulation) with decreased circulating thyroxine (T4) at oral doses at or above 300 mg/kg body weight/day and increased circulating thyroid stimulating hormone (TSH). This is thought to be responsible for the thyroid follicular stimulation following Temelastine treatment. No direct inhibition of thyroid function occurs. Temelastine produces these species-specific changes by enhancing thyroxine clearance from the circulation in the rat, but not in the dog or mouse. In vitro studies with cultured rat hepatocytes suggest that the mechanism behind these changes is a drug-induced increase of hepatocellular T4 binding and uptake which leads to an enhanced metabolic clearance of the hormone.

Animals↗
PubMed1989

1-Naphthol--single and repeated dose (30-day) oral toxicity studies in the mouse.

The oral toxicity of 1-naphthol in Charles River CD1 mice was investigated in single (2, 1 and 0.5 g/kg body weight) and 30-day repeat dosing (200, 100 and 50 mg/kg body weight) studies. In the single-dose study, animals dosed by oral gavage at 2 g/kg body weight either died or were killed in extremis between 15 and 90 min after dosing, and although the animals treated at 1 g/kg body weight survived to the end of the study (14 days post-dosing), one male in the 0.5 g/kg body weight dose group was killed in extremis approximately 2 hr after treatment. Acute dosing was associated with histopathological lesions seen in the kidneys and stomachs of mice from all treatment groups. The kidney lesions consisted of degeneration of the distal tubule epithelium, papillary necrosis and tubular dilatation. Gastric changes characterized by splitting of the epithelium of the forestomach and sloughing of the superficial epithelium of the glandular mucosa were generally accompanied by vascular congestion and acute inflammatory cell infiltration. In the 30-day study, mice dosed by oral gavage at 50 and 100 mg/kg body weight tolerated the treatment well, as did the female mice treated at 200 mg/kg body weight. Three male mice in the 200 mg/kg body weight group did, however, show gastric histopathological effects. Two of the mice (one killed in extremis on the fourth day of the study with the other surviving treatment) showed focal mucosal erosion, and a third (killed in extremis on the twentieth day of the study) exhibited peeling of the mucosa of the forestomach. Both of these gastric lesions were considered to be related to treatment at 200 mg/kg body weight. None of the mice in the 30-day study showed any kidney lesions or changes in haematology or clinical chemistry parameters.

Administration, Oral↗
PubMed1989

In vitro accumulation of thyroid hormones by cultured rat hepatocytes and the biliary excretion of iodothyronines in rats treated with a novel histamine H2-receptor antagonist.

The administration of SK&F 93479, a novel histamine H2 antagonist, to Wistar rats has been shown to produce thyroid lesions associated with an increased clearance of plasma thyroxine (T4) and elevated plasma TSH concentrations. To determine if these changes were mediated via an increase in the hepatic clearance of thyroid hormones, the biliary clearance and hepatic accumulation of iodothyronines were measured in rats and cultured hepatocytes treated with SK&F 93479. Both the in vitro and in vivo results showed that treatment with SK&F 93479 caused an increased hepatic accumulation (approx. 200% of control) and biliary excretion (2-3-fold control values) of T4 but had little or no effect on T3 uptake. The in vitro studies showed that the treatment related increase in hepatic thyroxine accumulation was temperature and therefore probably energy dependent, while inhibition of cytochrome P-450 dependent enzyme activity did not alter the accumulation of T4 suggesting that the parent compound and not some oxidative metabolite was responsible for the hepatic effects. Chromatographic analysis of bile from SK&F 93479 and phenobarbitone-treated rats showed that in the latter animals 81% of the T4 was present as the glucuronide conjugate (consistent with enzyme induction) whereas in the SK&F 93479-treated rats only 25% was present as the conjugate with 75% being in the unconjugated form. These studies show that SK&F 93479 increases the hepatic accumulation and biliary clearance of T4 by a novel mechanism not associated with liver microsomal enzyme induction.

Animals↗
PubMed1989

Characterization of excessive collagen production during development of pulmonary fibrosis induced by chronic silica inhalation in rats.

The activation of collagen synthesis during development of silicotic fibrosis was studied in rats exposed, in dusting chambers, to respirable SiO2 for periods of 2, 4, 6 or 12 months. Control animals were exposed similarly to clean air or TiO2. Development of fibrosis was followed by histological examination, measurement of lung weight and determination of lung collagen content (as hydroxyproline). A steady increase in lung weight and collagen content together with changes in cellularity and metabolic activity of the lungs, as ascertained by chemical determination of DNA and RNA, were measured in the lungs of the SiO2-exposed animals. Hybridization of total lung RNA, extracted at each time point, with cDNA probes specific for type I and type III procollagen mRNA levels showed that the development of fibrosis was associated with increased levels, as compared to age matched controls, of pulmonary procollagen mRNAs. Interestingly, the highest levels of procollagen mRNAs were observed in young (pretreatment control) animals, suggesting that during pulmonary development collagen metabolism in lungs is even greater than during development of fibrosis. In rats exposed to SiO2 the increase in type III procollagen mRNA occurred earlier than the increase in type I procollagen mRNAs. These observations demonstrate both age-dependent and silicosis-related changes in pulmonary procollagen mRNA levels. The results suggest that development of silicosis is associated with an altered capacity of the lungs to regulate collagen accumulation.

Administration, Inhalation↗
PubMed1978

Productivity of ospreys in Connecticut--Long Island increases as DDE residues decline.

Nesting success of ospreys (Pandion haliaetus) breeding in the Connecticut--Long Island area has increased since 1973 and is now approaching the levels recorded prior to the 1950's. Simultaneously, DDE and dieldrin residues have declined in unhatched eggs. Levels of polychorinated biphenyls have shown no changes over the period 1969 to 1976. The increase in productivity is attributed primarily to lower levels of DDE contamination. Detrimental effects in the past on ospreys in the Connecticut River estuary are attributed to local contamination with dieldrin.

Animals↗
PubMed1978

Uniform data recording for head and neck cancer.

A uniform method of recording data on head and neck cancer patients is presented. This has been shown to work well in the clinical field. The records are always completely up to date and immediately available at any time for data analysis.

Data Collection↗