bluuebunny/crossref_metadata_2025_split huggingface dataset:
Toxicology of Cimetidine
Authors: Brimblecombe R.W. , Leslie G.B. , Walker T.F. 
Published: December 2008

1 Cimetidine has been shown to have low acute toxicity in dogs and rodents. Repeated-dose studies of up to 24 months' duration in rodents at doses up to 950 mg day kg-1showed few adverse effects. Liver weight was consistently increased at the highest dose and testis, prostate and seminal vesicle weights were reduced in a dose- and time-related fashion. Cimetidine was not carcinogenic in the rat.2 In tests of up to 1 year's duration in dogs two animals receiving 504 mg day kg-1had to be killed before the end of the study. They had degenerative changes in the liver and renal tubular nephrosis. These and other dogs at 504 mg day-1kg-1had elevated serum transaminases. No such changes were seen at 366 mg day-1kg-1or less. Prostate weights were reduced in a dose-and time-related fashion. In a 7-year study in dogs, specifically designed for the purpose, no changes of the stomach mucosa were seen during regular biopsy.3 Although shown to be a mild anti-androgen, cimetidine produced no significant adverse effects in reproductive studies.4 The large body of evidence that cimetidine is not a risk for gastric cancer is reviewed.5 Over 30 million patients have so far been treated with cimetidine and the prediction from the animal studies that it would be an extremely safe therapeutic agent has been borne out in practice.
Enzootic and Epizootic Adrenal Medullary Proliferative Disease of Rats: Influence of Dietary Factors which Affect Calcium Absorption
Authors: Roe F.J.C. , Bär A. 
Published: December 2008

Adrenal medullary hyperplasia and neoplasia occur both enzootically and epizootically in untreated laboratory rats. The lesions are typically chromaffin-negative and are found incidentally in animals that have died from unrelated causes or have been killed at the end of long-term toxicity/ carcinogenicity tests. Urinary excretion of catecholamines is not usually increased. Environmental, particularly dietary, factors are seemingly much more important than genetic ones as determinants of the incidence of proliferative lesions. Recent observations of enhancement of adrenal medullary proliferative disease in rats by the feeding, in high dietary concentration, of certain polyols (sorbitol, mannitol, xylitol, lactitol), or of lactose, suggested that increased absorption of calcium from the gastrointestinal tract may be a risk factor. This evidence is reported and discussed in the light of other evidence linking disturbed calcium homeostasis with adrenal medullary function in the rat. In man, adrenal medullary proliferative disease is relatively rare and there is no evidence of any relation between the hypercalcaemia associated with hyperparathyroidism and increased risk of phaeochromocytoma. Adrenal medullary proliferative disease in rats is usually seen against a background of multiple endocrine neoplasia, with the pituitary gland, the pancreatic islets and the thyroid C-cells being most commonly affected in addition to the adrenal medulla. A parallel between this situation and Sipple's disease in humans has previously been suggested. We now stress the possible importance of three factors as determinants of enzootic and epizootic adrenal medullary proliferative disease in rats: excessive food intake, excessive dietary levels of calcium and phosphate and excessive intake of other food components, such as vitamin D and poorly absorbable carbohydrates, which predispose to increased calcium absorption.
Metabolism of some Industrial Uranium Tetrafluorides after Deposition in the Rat Lung
Authors: Stradling G.N. , Stather J.W. , Strong J.C. , Sumner S.A. , Towndrow C.G. , Moody J.C. , Lennox A. , Sedgwick D. , Cooke N. 
Published: December 2008

Two commercially produced natural uranium tetrafluorides were administered to rats either by inhalation or direct injection into the lungs. The results: 1 show that, for both materials uranium is cleared rapidly from the lungs, much of it to the blood 2 show that the distribution of uranium amongst body tissues, and the fraction of the systemic content excreted in urine, is similar to that obtained after the administration of U(VI) bicarbonate 3 show that the transportability of uranium is much greater than in previously reported studies with other preparations of uranium tetrafluoride 4 suggest that lung radioactivity counting measurements would be of limited value for interpreting human exposures 5 indicate that for setting exposure limits these tetrafluorides should be considered moderately transportable compounds (ICRP inhalation class W).
Solanidine is Present in Sera of Healthy Individuals and in Amounts Dependent on their Dietary Potato Consumption
Authors: Harvey M.H. , McMillan M. , Morgan M.R.A. , Chan H. W. S. 
Published: December 2008

1 Solanidine, a steroidal alkaloid, and its glycosides have been reported to have caused poisoning in man and animals. These alkaloids are normally present in small amounts in potatoes. Measurement of solanidine in body fluid would be expected to establish the real incidence of acute toxicity and help to resolve the question of any chronic toxicity including teratogenicity. 2 We report the detection of solanidine in the serum of 57 normal healthy volunteer subjects in whom it measured 4.0-56.3 nmol/l (1.6-22.5 ng/ml) before the midday meal. There was a significant correlation between serum solanidine concentration and normal dietary intake of potato by the individual concerned. 3 When two subjects abstained from potato and its products serum solanidine fell markedly and became minimal after the second week onwards.
Chronic Pancreatitis Possibly Caused by Occupational Exposure to Organic Solvents
Authors: Dossing M. , Jacobsen O. , Rasmussen S.N. 
Published: December 2008

1 Acute pancreatic injury has been attributed to occupational exposure to chemical agents in workers, but there have been no previous reports of occupationally induced chronic pancreatitis. 2 Severe chronic exocrine pancreatic insufficiency was found in a 29-year-old house painter, where other known causes of chronic pancreatitis could be ruled out. The patient had previously experienced abdominal pain and diarrhoea associated with exposure to spray paints followed by remission of the symptoms during vacations. 3 Although the association between exposure and pancreatic insufficiency may be a random one, a possible causal relation should be further evaluated.
Plasma Protein Changes in Rats Treated with Hypolipidaemic Drugs and with Phthalate Esters
Authors: Hinton R.H. , Price S.C. , Mitchell F.E. , Mann A. , Hall D.E. , Bridges J.W. 
Published: December 2008

1 Treatment of rats with hypolipidaemic drugs or with the plasticizer di-2-ethyl hexyl phthalate caused significant alterations in the concentration of certain plasma proteins. 2 Certain proteins showed dose-dependent increases, in other cases the plasma concentrations fell in treated animals. 3 The changes were quite distinct from the changes in plasma proteins which occur during the acute-phase response to inflammatory agents. 4 Some changes appeared specific to agents which produce peroxisome proliferation in liver, other alterations appeared associated with mild, but sustained, liver injury.
Ferguson's Principle and the Prediction of Fatal Drug Levels in Blood
Authors: King L.A. 
Published: December 2008

1 The median fatal concentrations (EC50) of various types of drugs are shown to be determined solely by their aqueous solubilities (S). Among the test substances, EC50 values show a range of 2000-fold, whereas the ratio EC 50/S is essentially constant. This behaviour is typical of 'Ferguson substances', and enables the fatal toxicity of other (depressant) drugs and related compounds to be calculated. 2 The mean relative saturation (EC50/S) is 0.006, a value which shows that humans are more sensitive to narcotic agents than are the lower animals. 3 The Ferguson principle provides a broad framework for quantitative structure-activity relations in fatal drug toxicity. The empirical Hansch equation can be derived from the same thermodynamic concept of free energy which underlies the Ferguson principle.
Dazoxiben, a Prototype Inhibitor of Thromboxane Synthesis, has Little Toxicity in Laboratory Animals
Authors: Irisarri E. , Kessedjian M.J. , Charuel C. , Faccini J.M. , Greaves P. , Monro A.M. , Nachbaur J. , Rabémampianina Y. 
Published: December 2008

1 Dazoxiben, an orally active specific inhibitor of thromboxane synthetase, was administered by mouth daily to dogs and rats for 6 months.2 Dogs showed no evidence of toxicity up to 300 mg day-1kg-1, the highest dose level used.3 Rats showed no evidence of toxicity after 100 mg day-1kg-1, but at 300 mg day-1kg-1there were slight increases in plasma calcium and urea concentrations and a moderate incidence of focal nephrosis; males showed a slightly increased platelet count.4 Studies in rats and rabbits at dose levels up to 400 mg day-1kg-1, by mouth, revealed no adverse effects on male or female fertility, embryogenesis, parturition or postnatal development.5 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.
Antipyrine Metabolism in African Villagers
Authors: Sommers K. , van Staden D.A. , Moncrieff J. , Schoeman H.S. 
Published: December 2008

1 Antipyrine clearance has been measured from serial serum samples in 49 healthy black Africans from a village in Southern Africa. 2 The subjects follow a lifestyle which minimally exposes them to environmental inducing or inhibiting agents. Food is mainly maize cereal, with a protein content of only about 8.8%, together with greens. 3 Antipyrine clearance, half-life and apparent volume of distribution (mean ± SD) were, respectively, 0.538 ± 0.163 ml min-1 kg-1, 14.81 ± 6.5 h and 0.626 ± 0.075 litre/kg. These results do not differ significantly from the mean values found in a group of lactovegetarian Indo-Pakistani immigrants to Britain. 4 This would suggest that the major environmental determinant influencing hepatic mixed-function oxidase activity is the presence or absence of meat in the diet. However, the relative contributions of environment and heredity will be difficult to determine.
Effects of Meals and Meal Times on Uptake of Lead from the Gastrointestinal Tract in Humans
Authors: James H.M. , Hilburn M.E. , Blair J.A. 
Published: December 2008

1 Twenty three adults ingested 203Pb as lead acetate on the 12th hour of a 19 h fast. Retention measured 7 days later in a whole-body counter was 61% and whole-body turnover rates suggested that initial uptake had been considerably greater. 2 Balanced meals eaten with 203Pb reduced lead uptake to 4% and the influence of the food lasted for up to 3 h. The effects of phytate, ethylenediaminetetra acetate (EDTA), caffeine, alcohol, glucose, a liquid meal and a light snack were tested separately with intermediate results. 3 The effect of a meal was probably largely due to its content of calcium and phosphate salts but lead uptake was probably further reduced by phytate which is plentiful in whole cereals and it was probably increased by a factor in milk. Uptake with skimmed milk was the same as with whole milk and we suggested that the factor was not fat. Comestibles with low mineral and phytate contents reduced lead uptake by intermediate amounts, possibly by stimulation of digestive secretions. 4 The avid uptake of lead during a fast, the large reduction of lead uptake with meals and the likelihood of variations in gastric-emptying rates and dietary habits may be major causes of variation in body burdens of lead in the population.
A Toxicology Databank Based on Animal Safety Evaluation Studies of Pharmaceutical Compounds
Authors: Lumley C.E. , Walker S.R. 
Published: December 2008

1 Thirteen UK pharmaceutical companies have provided comprehensive toxicological data from repeated-dose animal safety evaluation studies of 74 pharmaceutical compounds. 2 These data comprise a unique toxicology database and this paper describes its establishment including the problems encountered, its current size with over 35 000 data fields, its content and potential value for retrospective analyses. 3 Increasing reliance on animal studies for predicting the safety of medicines in man necessitates a reappraisal of conventional animal testing procedures and better use of the considerable volume of data in the archives of regulatory authorities and pharmaceutical companies. This reappraisal may be achieved by the use of computer-based toxicology databanks.
Measurement of Potato Steroidal Alkaloids in Human Serum and Saliva by Radioimmunoassay
Authors: Harvey M.H. , Morris B.A. , McMillan M. , Marks V. 
Published: December 2008

1 Radioimmunoassay methods are described for measuring potentially toxic potato glycoalkaloids and the aglycone solanidine in human serum and saliva. 2 Solanidine and total alkaloid concentrations in serum and saliva during the summer are given for a group of subjects from the UK and a group from Sweden. Serum concentrations ranged from 3.2 to > 125 nmol/l for total alkaloid and 2.5 to 92.5 nmol/l for solanidine and were comparable in the two populations. Salivary total alkaloid concentrations were only about 10% of serum values. Salivary solanidine concentrations did not exceed 20% of the serum levels. Good correlation was found between serum and salivary alkaloid concentrations ( r = 0.734, for solanidine; r = 0.892 for total alkaloid). 3 Serum and salivary alkaloid concentrations were significantly raised in a group of Swedish subjects eating potatoes containing unusually high concentrations of alkaloids when compared with those in a group of subjects eating their normal diets.
Metabolism of an Industrial Uranium Trioxide Dust after Deposition in the Rat Lung
Authors: Stradling G.N. , Stather J.W. , Ellender M. , Sumner S.A. , Moody J.C. , Towndrow C.G. , Hodgson A. , Sedgwick D. , Cooke N. 
Published: December 2008

Uranium trioxide, produced industrially, was administered to rats either by inhalation or direct injection of an aqueous suspension into the lungs. The results: 1 show that uranium was cleared rapidly from the lungs, mainly to the blood; 2 show that distribution of uranium among body tissues, and the fraction of the systemic content excreted in urine, was similar to that obtained for other transportable hexavalent uranium compounds; 3 suggest that urine monitoring data would be of more value than lung radioactivity counting measurements for assessing occupational human exposure; 4 indicate that for setting exposure limits by inhalation the uranium trioxide should be considered a highly transportable compound. Thus intakes by workers should be restricted to those recommended for short-term exposures and not those based on an annual limit.
Cardiac Arrhythmias during Cytotoxic Chemotherapy: Role of Domperidone
Authors: Osborne R.J. , Slevin M.L. , Hunter R.W. , Hamer J. 
Published: December 2008

1 Four patients receiving platinum-containing chemotherapy were treated with domperidone (20 mg) by slow intravenous injection followed by a continuous infusion for 24 h at a dose of 10 mg 24 h-1 kg-1. Cardiac monitoring and plasma potassium and domperidone concentration measurements were performed. Severe cardiac arrhythmias occurred in two patients. 2 A control group of 14 patients treated with similar chemotherapy, without domperidone, also underwent cardiac and plasma potassium monitoring. No significant arrhythmias were seen. 3 The electrophysiologic effects of domperidone are discussed. 4 It is concluded that treatment with intravenous domperidone is associated with the occurrence of cardiac arrhythmias.
An Association of Mercury with Selenium in Inorganic Mercury Intoxication
Authors: Aoi T. , Higuchi T. , Kidokoro R. , Fukumura R. , Yagi A. , Ohguchi S. , Sasa A. , Hayashi H. , Sakamoto N. , Hanaichi T. 
Published: December 2008

1 Energy dispersive X-ray analysis was performed on the renal tubular cells of two patients with inorganic mercury intoxication. 2 Some lysosomes of these cells consisted of unusual matrices of aggregated electron-dense grains which were positive for mercury, selenium and sulphur. 3 Though maps of the specific X-rays of both mercury and selenium coincided exactly with these lysosomes, the molecular ratio of selenium to mercury ranged between zero and 2.9. 4 It is unlikely that the trace element of selenium and exogenous inorganic mercury are deposited in the lysosomes independent of each other, but rather their coexistence in the characteristic lysosomes strongly suggests a compound formed by binding mercury to the SeH residues of selenoprotein.
Distribution of Aluminium between Plasma and Erythrocytes
Authors: van der Voet G.B. , de Wolff F.A. 
Published: December 2008

1 It is common use to monitor body burdens of toxic trace metals by measuring concentrations in whole blood. To monitor aluminium (Al) body burden in renal patients on haemodialysis, which is a high-risk group for Al poisoning, the concentrations of Al in plasma (AIP) or serum (AlS) are determined rather than Al in whole blood (AlB). 2 To evaluate this custom, which exists in clinical laboratories, an investigation was made into the distribution of Al between the plasma and the blood-cell compartment and on the extent of binding of Al to the blood cells both in rats and in dialysed patients. 3 The results show that Al is distributed between plasma and blood cells with only very small quantitative differences, that binding of Al to blood cells is very weak and that AlP and AIB have similar prognostic value for toxicity.
Metauothionein and Cadmium in Human Kidney Cortex: Influence of Smoking
Authors: Summer K.H. , Drasch G.A. , Heilmaier H.E. 
Published: December 2008

1 Post-mortem specimens of human kidney cortex of 47 individuals classified according to their imoking habits were analysed for tissue cadmium and cadmium bound to metallothionein. 2 The cadmium content in the kidney cortex of all individuals was 5-99 μg/g wet wt. In smokers consuming more than 20 cigarettes/day the mean content of renal cortex cadmium was twice that of ion-smokers and amounted to 33.3 ± 12.5 μg/g wet wt. 3 The amount of cadmium bound to metallothionein of all individuals was 0.3-66 μg/g wet wt. iirectly correlating with the cadmium content of the kidney cortex (r = 0.932). 4 More than 50% of renal cortex cadmium was associated with the metallothionein fractions. Due to constant values of zinc and copper in metallothionein the relative amount of zinc and copper to cadmium in metallothionein decreased with increasing tissue cadmium. 5 Together with the elevated binding of cadmium to renal cortex metallothionein, cadmium ncreasingly was bound to non-metallothionein ligands. 6 These results suggest that, in the renal cortex of smokers with elevated cadmium, a major portion of cadmium is bound to metallothionein. However, it is unclear yet whether (a) the binding of cadmium to metallothionein with subsequent liberation of the metal during degradation of the protein, (b) the impairment of metallothionein functions by the binding of cadmium or (c) the increased binding to non-metallothionein ligands contribute to the toxicity of cadmium in highly exposed individuals.
Laxative Phosphate Poisoning: Pharmacokinetics of Serum Phosphorus
Authors: Larson J.E. , Swigart S.A. , Angle C.R. 
Published: December 2008

Despite the frequency of acute poisoning in normal children by oral or rectal phosphosoda laxatives, the rate of clearance of the resultant high level of phosphorus and the rationale for therapy are defined incompletely. 1 Pharmacokinetic analysis has been made of plasma inorganic phosphate ( Pi) in an infant after ingestion of phosphosoda laxative and of data reported for four comparable poisonings in healthy infants to provide a nomogram which predicts the decline in Pi in paediatric phosphate poisoning. 2 Clearance of Pi is exponential; it directly correlates with and approaches the glomerular filtration rate. 3 After single oral or rectal overdoses, plasma Pi at diagnosis is 4-20 mmoul and has a half-life of 5-11 h that appears independent of therapy. The time for plasma Pi to return to normal can be calculated from the initial Pi as t = (In 5/ Pi )/0.1292. 4 Neuromuscular and cardiac abnormalities relate to the low serum calcium; the increase of total serum calcium during recovery from phosphate poisoning is linear but is accelerated by intravenous (i.v.) calcium salt. Continued i.v. calcium therapy may be required since restoration of plasma calcium is often delayed.
Urinary Excretion of Benzidine in Relation to the Acetylator Status of Occupationally Exposed Subjects
Authors: Dewan A. , Jani J.P. , Shah K.S. , Kashyap S.K. 
Published: December 2008

1 Twenty-four male workers engaged in the manufacture of benzidine dihydrochloride for 1-4 years were included in this study. 2 Urinary levels of free benzidine were estimated by high-pressure liquid chromatography in all the workers. 3 Acetylator status of the workers was determined with sulphamethazine. 4 There was substantial absorption of benzidine over an 8-h work shift. 5 A significant correlation was observed between the rate of sulphamethazine acetylation and urinarv excretion of free benzidine.
Arterial-Venous Plasma Concentration Differences of Meprobamate in Acute Human Poisonings
Authors: Sato S. , Baud F.J. , Bismuth C. , Galliot M. , Vicaut E. , Buisine A. 
Published: December 2008

1 Arterial-venous plasma concentration differences of meprobamate were studied on admission of acute overdose in man. 2 The patients were divided in two groups. In the control group ( n= 25) two successive blood samples were collected from the same vessel. In the study group ( n = 35) femoral arterial and venous blood samples were collected simultaneously. 3 In the control group the differences were not significant. In the study group the differences were statistically significant (P < 0.01). 4 The present study suggests that the origin of blood samples should be stated for toxicological studies and that the toxicokinetics may be more complex than those recognized previously.
Effect of Purgatives on Antidotal Efficacy of Oral Activated Charcoal
Authors: Neuvonen P.J. , Olkkola K.T. 
Published: December 2008

1 The effects of purgatives on the antidotal efficacy of oral activated charcoal were studied in seven volunteer subjects.2 The volunteer subjects were given 1000 mg of aspirin, 100 mg of atenolol and 50 mg of phenylpropanolamine with 100 ml of water on an empty stomach and were assigned randomly to the following treatment groups: (A) after 5 min 150 ml of water, (B) after 5 min 25 g of charcoal, (C) after 5 min charcoal orally with 20 mg of metoclopramide rectally, followed by 10 mg of bisacodyl rectally 3 h afterwards, (D) after 5 min charcoal with 250 ml of magnesium citrate USP and (E) after 60 min charcoal with metoclopramide followed by bisacodyl 3 h thereafter.3 The plasma concentrations (0-24 h) and the cumulative urinary excretion (0-72 h) of salicylates, atenolol and phenylpropanolamine were measured.4 Both magnesium citrate and metoclopramide combined with bisacodyl hastened the gastrointestinal transit but magnesium citrate was more effective.5 Charcoal alone reduced the absorption of aspirin and phenylpropanolamine by about 50% and that of atenolol by about 95%. The purgatives did not modify significantly the efficacy of charcoal.6 When the antidotal treatment was delayed by 60 min its efficacy was reduced to some extent, possibly depending on the pharmaceutical formulation of the test drugs.7 The present results do not support the routine use of purgatives in combination with activated charcoal. In some instances, however, their use may promote the evacuation of, for example, depot formulations from the gastrointestinal tract and thus have a beneficial effect together with activated charcoal in reducing absorption.