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Biomedical subjects

N Havu

Publications and source records attributed to N Havu.

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

Enterochromaffin-like cell carcinoids in the rat gastric mucosa following long-term administration of ranitidine.

Long-term administration of some long-acting inhibitors of gastric acid secretion has been associated with the development of gastric enterochromaffin-like (ECL)-cell carcinoids in the rat. It has been argued that short-acting, surmountable histamine H2-receptor blockers such as ranitidine do not cause carcinoids. In this study, female rats (n = 100) were treated for 2 years with the histamine H2-receptor blocker ranitidine, 2 g/kg/day in the diet. Specimens from the stomachs of all rats, including 50 controls, were stained for argyrophil cells. Plasma gastrin and ranitidine levels were measured in separate groups of rats at different times during the study. The mean plasma level of ranitidine was 37.5 mumol/l, measured at midnight when the maximal level after food intake was expected. The resulting acid inhibition was associated with an approximately 3-fold increase in plasma gastrin which persisted throughout the whole period of the study. The ranitidine treatment resulted in a pronounced hyperplasia of gastric ECL cells. In 19 rats carcinoids were found, 4 of which were micro-invasive. No carcinoids were found in the control animals. The results provide further support for the gastrin mechanism, i.e. that the development of ECL-cell carcinoids in the rat gastric mucosa is a consequence of prolonged hypergastrinaemia and is not a unique effect of any individual acid-inhibiting drug.

Animals↗
PubMed1990

Gastrin and gastric enterochromaffin-like cell carcinoids in the rat.

Life-long administration (greater than or equal to 2 years) of a number of long-acting gastric acid inhibitors (including H2-receptor antagonists, omeprazole and ciprofibrate) has been associated with the development of gastric enterochromaffin-like cell (ECL cell) carcinoids in rats. It has been postulated that they are a consequence of some unique property of the longer-acting acid inhibitors. There is, however, a great deal of evidence to support the hypothesis that these gastric ECL cell carcinoids develop as a result of life-long hypergastrinaemia in rats. Several lines of investigation reported here show that gastric ECL cell hyperplasia occurs when gastrin levels are increased without the use of acid-inhibiting drugs. In rats, hypergastrinaemia developed after 4 weeks' administration of exogenous gastrin (4 micrograms/kg/h). The number of gastric ECL cells per visual field had increased to 250 compared with 180 in the controls. Long-term hypergastrinaemia, induced by partial gastric corpectomy, increased plasma gastrin levels from 200 to 800 pg/ml and the density of gastric ECL cells increased from 190 to 310 cells/visual field 10 weeks after the operation. Importantly, gastric ECL cell hyperplasia, which was produced in rats by administration of omeprazole, 14 mg/kg/day for 1 year, was fully reversible following normalization of gastrin levels. Until now, gastric ECL cell carcinoids have not been reported in studies of shorter-acting, reversible H2-receptor antagonists such as ranitidine, perhaps because the correct staining techniques (i.e. Grimelius and Sevier-Munger silver stains) have not been used.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

The effect of cobalt on mitochondrial ATP-production in the rat myocardium and skeletal muscle.

Cobalt has been shown to accumulate in the myocardium of uraemic patients and has been suggested as a myocardial toxin inhibiting mitochondrial respiration. In order to study the cellular effects of cobalt exposure three groups of rats (n = 12 per group) were fed a diet containing 12% protein without supplementation or with 20 mg and 40 mg CoSO4 7 H2O/kg body weight/day respectively. After 8 weeks the hearts and soleus muscles were removed. Cobalt in tissues and in four cell fractions were analysed with neutron-activation analysis (ng/g wet weight and ng/mg protein respectively). Mitochondrial respiration was analysed as ATP-production rate using pyruvate + malate and palmitoyl-carnitine + malate as substrate. The ATP-production from pyruvate + malate was unchanged in both heart and skeletal muscle in the exposed animals. With palmitate as substrate, the heart muscle showed a slightly lower ATP-production rate (p less than 0.05) after the 20 mg cobalt dose, but the rate was unchanged in the group with higher cobalt intake. No changes in ATP-production rate from palmitate was observed in soleus muscle. The microsomal (100,000 g) fraction in the myocardial cells contained significantly higher cobalt concentrations compared to the mitochondrial fraction in both the unexposed (1.4 ng/mg protein vs 0.19, p less than 0.05) and exposed rats (53.4 ng/mg protein vs 13.2, p less than 0.005). In conclusion, cobalt showed a large accumulation in myocardial cells, without significant effects on mitochondrial ATP-formation rate from oxidation of pyruvate or palmitate and with the highest cobalt content contained in the microsomal (100,000 g) fraction.

Adenosine Triphosphate↗
PubMed1990

The intracellular distribution of cobalt in exposed and unexposed rat myocardium.

The intracellular distribution of cobalt was analysed in the myocardium of exposed and unexposed rats. The exposed rats were given a dietary cobalt supplementation of 40 mg CoSO4.7 H2O/kg body weight for 8 weeks. The mitochondrial fraction showed the greatest relative increase in cobalt: 0.09 ng/mg protein in the unexposed rats to 8.43 ng/mg protein in the exposed rats. In the exposed rats the submitochondrial particles had the highest levels of cobalt: 19.43 ng/mg protein, followed by the sarcoplasmatic reticulum: 12.3 ng/mg protein. The microsomal 44,000 g supernatant also showed an increase, although the levels remained low (0.51 ng/mg protein in the exposed animals). Apparently the calcium-storing organelles had the highest levels of cobalt. This could affect calcium flux in myocardial cells and, secondarily, tension development in cardiac muscle.

Animals↗
PubMed1989

Qualitative studies of gastric endocrine cells in patients treated long-term with omeprazole.

A total of 543 endoscopic biopsies (a mean of three tissue samples each) were taken from the gastric oxyntic mucosa of 122 patients suffering from reflux oesophagitis or peptic ulcer resistant to H2-receptor antagonist therapy. All were treated with omeprazole, 40 mg/day, until healing and then assigned to 20 mg/day for a mean of 13 months. Proliferative changes of endocrine cells were evaluated according to an internationally agreed classification and the paraffin sections were stained with haematoxylin-eosin and Sevier-Munger silver. Only hyperplastic (no dysplastic or neoplastic) lesions of endocrine cells were observed in 11-19% of patients examined, the incidence and severity of these lesions being unaffected by treatment. A relationship between linear and/or micronodular hyperplasia and chronic gastritis was observed.

Biopsy↗
PubMed1988

Histopathological classification of nonantral gastric endocrine growths in man.

Recently, the gastric endocrine system has been recognized as the origin of benign and malignant tumors in pernicious anemia. It has also been found that the gastric endocrine cells respond to permanent elevation of serum gastrin levels induced by changes in acid secretion in response to surgical procedures, drug therapy and age. Therefore, a definition of nonantral gastric endocrine hyperplasia (simple or diffuse, linear or chain-forming, micronodular, adenomatoid), dysplasia (enlarging or fusing micronodules, microinvasion, nodular growth) and neoplasia (intramucosal carcinoid, invasive carcinoid) is presented. The individual entities are illustrated, together with the literature discussed and the techniques for their identification presented.

Endocrine System Diseases↗
PubMed1986

Oesophageal ulcerations and plasma levels of different alprenolol salts: potential implications for the clinic.

The ulcerogenic effect of five different salts of alprenolol were tested against placebo in a porcine oesophageal test model. The salts with high water solubility, such as the hydrochloride and the fumarate, gave rise to the highest plasma concentrations of alprenolol and evoked serious oesophageal lesions, while the salts with low solubility-the benzoate, maleate and sebacate-had no irritative effect on the oesophagus. The plasma levels of alprenolol were much higher following administration of alprenolol hydrochloride in the oesophagus than after an identical intraduodenal dose of the same salt possibly because of the avoidance of the first-pass degradation during oesophageal absorption.

Absorption↗
PubMed1986

Enterochromaffin-like cell carcinoids of gastric mucosa in rats after life-long inhibition of gastric secretion.

Small intramucosal tumours in the oxyntic area of the rat stomach were observed in an oncogenicity study with omeprazole. The tumours could be defined as carcinoids of enterochromaffin-like (ECL) cell origin. ECL cells occur exclusively in oxyntic mucosa and respond to the trophic hormone gastrin with a proliferation that becomes exaggerated in old rats. Inhibition of gastric acid secretion is known to induce hypergastrinaemia in rats. According to the common concept of endocrine cells, a sustained hormonal stimulation with gastrin may induce a continuous gradient between hyperplasia and neoplasia of the ECL cells. The tumours found are thus to be regarded as hormone-induced endocrine tumours of the ECL cells in the stomach. The ECL-cell tumours of the rats in the oncogenicity study appeared to belong to the low-malignancy type of carcinoids and did not make their appearance until the end-life period of the study. The sex and species differences observed may be explained by inherent differences in gastrin response, spontaneous ECL cell density or in responsiveness to gastrin-stimulated ECL cell proliferation between sexes and species.

Animals↗
PubMed1985

Toxicological studies on omeprazole.

As part of the safety evaluation of the gastric antisecretory drug, omeprazole, toxicological studies have been performed in several species of animals. The acute toxicity after oral administration to rodents was low. The oral LD50 value was above 4 g/kg. The general toxicity after repeated administration has been studied in rats and dogs. No clinical signs of adverse reactions were seen. Some minor changes in hematology parameters were observed. In rats and mice decreases in the erythrocyte count, hematocrit and hemoglobin have occasionally been found at doses of 125 mumol/kg/day and more. Hyperplasia of oxyntic mucosal cells, concomitant with increases in stomach weight, oxyntic mucosal thickness and folding, has been observed in the species investigated, the dog, rat and mouse. In addition, slight chief cell atrophy and eosinophilia of the chief cell granules were observed in rats. The oxyntic mucosal effects were reversible upon treatment being discontinued. In the oncogenicity studies, gastric carcinoids occurred in the rat but not in the mouse. Investigations of the carcinoids showed that the vast majority of the endocrine cells could be characterised as ECL-cells. The hyperplasia of oxyntic mucosal cells, including hyperplasia of endocrine ECL-cells and development of gastric carcinoids in rats, is attributable to the pronounced hypergastrinemia produced as a secondary effect of almost complete inhibition of acid secretion by the large doses of omeprazole used in the toxicity studies. In agreement with this hypothesis, the hyperplasia of the oxyntic cells was prevented by antrectomy. The reproduction studies performed in rats and rabbits showed no sign of fetal toxicity or teratogenic effect. The results of the short-term mutagenicity tests, Ames test, the micronucleus test in mice and the mouse lymphoma test were all negative.

Administration, Oral↗
PubMed1983

The ulcerogenic effect on the oesophagus of three beta-adrenoceptor antagonists, investigated in a new porcine oesophagus test model.

Drug-induced oesophageal lesions have attracted increasing attention during the past few years. A test model is presented for assessing irritative or ulcerogenic effects of potential drugs on the oesophagus. In this model the pig oesophagus is used, as it is more similar to the human oesophagus than models used in other techniques that have been suggested. The beta-blockers, alprenolol and propranolol, displayed the same ulcerogenic properties with this test model as reported with other test models in the literature. The beta 1-selective blocker metoprolol, did not have such ulcerogenic effects. The pig model is suggested as the method of choice in evaluating the potential irritative or ulcerogenic effects of pharmaceutical formulations intended for human use.

Adrenergic beta-Antagonists↗
PubMed1979

The iron content of split skin grafts after general infiltration and percutaneous anaesthesia.

The iron content of split skin grafts from guinea pigs has been studied by flameless atomic absorption spectrophotometry from the time the grafts were cut until the transplants had been in contact with a standardized recipient area for 7 days. The iron content was taken as a measure of the blood content of the grafts. In order to relieve pain, general anaesthesia with ether, local anaesthesia by infiltration and local percutaneous anaesthesia with a solution of ketocaine. A2358, were used. At the time of cutting the grafts the iron content was highest when percutaneous anaesthesia had been used. After a decrease in the iron content in all grafts during the two first postoperative days there was an increasing level from the third day as a sign of revascularization. A stabilization of the values when general and percutaneous anaesthesia had preceded the operation was noted from the fifth postoperative day. The level was highest in the grafts cut after percutaneous anaesthesia.

Anesthesia, Inhalation↗
PubMed1977

Microchemical assays of glutathione, zinc, cobalt and manganese in micro-dissected areas of the endocrine pancreas in the hagfish, Myxine glutinosa.

In hagfish islet parenchyma, consisting practically only of insulin-producing B-cells and agranular B-cell precursors, the contents of glutathione (GSH) and total protein-free thiols (NPSH) were determined on micro-dissected islet lobules. GSH was found to be of the same order of magnitude (22-25 mg/100 g wet weight) as in the islet parenchyma of a previously studied teleost fish and of some mammals, including man. However, the NPSH was found to be considerably higher in the islet lobules of the hagfish than in the teleostean islet parachyma. As in both teleost fish and mammals, GSH made up most of the NPSH in the hagfish erythrocytes, myocardium, and skeletal musculature. This discrepancy between hagfish islet parenchyma and other tissues indicates that the non-GSH portion of NPSH may be of particular significance for the insulin-producing B-cells. By means of flameless atomic absorption spectrophotometry the contents of zinc, cobalt, and manganese were determined in micro-dissected hagfish islet lobules. Neither zinc, nor cobalt, occurred in significantly higher concentrations in the islet parenchyma than in the liver or the skeletal musculature. Only manganese was found in somewhat higher amounts in the islet lobules than in the other tissues, but the contents were still low. The results indicate that none of the three heavy metals play any important role in the synthesis, storage, or release of insulin in the hagfish. The significance of this in relation to the prevailing hypotheses regarding the pathogenesis of alloxan diabetes is discussed.

Animals↗
PubMed1977

Zinc and manganese contents of micro-dissected pancreatic islets of some rodents. A microchemical study in adult and newborn guinea pigs, rats, Chinese hamsters and spiny mice.

By a flameless atomic absorption spectrophotometry procedure, using a graphite furnace, it was possible to assay the contents of zinc and managanese in micro-dissected pancreatic islets of several rodents. Interest was focused upon the islets of guinea-pigs, due to the fact that guinea-pig insulin lacks a histidine residue in the B10 position of the molecule which normally binds zinc (or other heavy metals) in the hexamer formation, probably involved in the storage of insulin. Both the zinc and manganese contents were too low in the guinea-pig islet parenchyma to be reasonably involved in the storage of insulin in the beta-granules. Instead, it was suggested that guinea-pig insulin, like hagfish insulin, might crystallize without access to zinc or other heavy metals. Low zinc and manganese contents were also observed in newborn and diabetic guinea-pigs. The islet zinc content was high in the Wistar rat, the Chinese hamster, and the spiny mouse. No significant amounts of manganese were found in any of these kinds of islet parenchyma.

Animals↗