bluuebunny/crossref_metadata_2025 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.
Delayed Gastric Emptying with Dothiepin
Authors: Woodhouse K.W. , Bateman D.N.
Published: December 2008

Dothiepin induced symptoms of delayed gastric emptying in an elderly lady. Rechallenge studies were undertaken and demonstrated a delay in gastric emptying of liquid after re-administration of dothiepin at a time when plasma concentrations were 93 μg/l. Elderly patients may be more susceptible to the anticholinergic effects of tricyclic antidepressants on the gut.
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.
Arsenic Speciation in Urine from Humans Intoxicated by Inorganic Arsenic Compounds
Authors: Lovell M.A. , Farmer J.G.
Published: December 2008

Trends in the urinary concentrations of the four arsenic species, pentavalent [As (V)] and trivalent [As (III)] inorganic arsenic, monomethylarsonic acid (MMAA) and dimethylarsinic acid (DMAA), were followed for several days subsequent to the acute intoxication of two human subjects by arsenic trioxide [As (III)2O3] and sodium orthoarsenate [Na2HAs(V)O4.7H2O], respectively, in unsuccessful suicide attempts. Total arsenic concentrations ranged from 1.6 to 18.7 mg/l. The increasing predominance of the less toxic methylated species, especially DMAA, after 3 or 4 days supports the concept of methylation as a natural detoxification mechanism as part of an overall reduction/methylation sequence involved in the biotransformation of inorganic arsenic by the human body. However, the additional possibility of oxidation of As(III) to As(V) in vivo under extreme immediate postingestion conditions is suggested by initial high urinary As(V) after arsenic trioxide intoxication. Relative proportions of As(V), As(III), MMAA and DMAA in both cases probably reflect species-dependent differences in rates of direct elimination and reactivity with tissues as well as the efficiency of methylation.
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.
Placenta and Milk as Excretory Routes of Lipophilic Pesticides in Women
Authors: Siddiqui M.K.J. , Saxena M.C.
Published: December 2008

Age, diet and ethnic-dependent excretion of chlorinated pesticides through placenta and milk was studied in women from the general population around Lucknow in India by using gas-liquid chromatography equipped with an electron-capture detector (3H+). Pesticidal contaminants in both placenta and milk were 1,1,1-trichloro-2,2-bis( p -chlorophenyl)et'hane (p,p'-DDT ) , its metabolites 1,1-dichloro-2,2-bis( p-chlorophenyl)ethylene (p,p'-DDE) and 1,1-dichloro-2,2-bis( p-chlorophenyl)ethane ( p,p'-DDD), α, β, γ - isomers of benzene hexachloride (BHC) and aldrin. The study revealed higher excretion of pesticides through the placentas of older and non-vegetarian women than younger and vegetarian women. There was higher excretion of total DDT in rural than in urban women while a reverse trend was found in the case of total BHC in two ethnic groups. Similarly, age and dietary habits influenced the excretion of these pesticides in milk. Women undergoing premature delivery and stillbirths were found to excrete more DDT in their milk than those undergoing full-term normal delivery.
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.
Acute Lead Intoxication due to Intravenous Injection
Authors: Sixel-Dietrich F. , Doss M. , Pfeil C.H. , Solcher H.
Published: December 2008

A case of acute lead poisoning due to intravenous injection of lead acetate is reported. The patient developed clinical and biochemical symptoms characteristic for acute hepatic porphyrias. Elevated urinary 5-aminolaevulinic acid and low porphobilinogen correlated to a lead-induced inhibition of 5-aminolaevulinic acid dehydrase with diagnostically indicative reactivation rates by zinc and dithiothreitol. Urinary coproporphyrin excretion was also increased. Additional findings included anaemia and toxic hepatitis. Under the influence of elimination therapy with D-penicillamine pathologic parameters normalized. Except for transient neuralgic pains the patient did not experience any neurologic dysfunctions, thus contrasting the findings in chronic lead intoxication.
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.
Correlation between Alimentary Mycotoxin Contamination and Specific Diseases
Authors: Hadidane R. , Roger-Regnault C. , Bouattour H. , Ellouze F. , Bacha H. , Creppy E.E. , Dirheimer G.
Published: December 2008

Several pathological cases including primitive hepatomas, Reye's syndrome, alimentary toxic aleukaemia, were encountered in two different Tunisian Sahel hospitals. Contamination of some nutriments of the patients by mycotoxins (aflatoxins, trichothecenes, ochratoxin A, citrinin) are most likely involved in the origin of these diseases.
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.
An Accident and Emergency Department's View of Self-poisoning: a Retrospective Study from the United Norwich Hospitals 1978-1982
Authors: Adams R.H.M.
Published: December 2008

This 5-year review of deliberate self-poisoning cases seen in an accident and emergency department revealed that about 700 patients were seen per year. Three-quarters of these needed admission (forming some 15% of all hospital admissions). Of these 65% were referred to the psychiatrist. The remaining quarter were dealt with in the accident and emergency department. Analysis of the data identifies problems where further research is needed. In particular the question is raised as to whether these patients would not be better dealt with in an acute medical unit now that accident departments are turning their attention increasingly to the management of trauma.
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.
Cadmium Metabolism in Man
Authors: Kelman G.R.
Published: December 2008

The time course of the fall in blood cadmium concentrations after cessation of exposure has been measured in nine workmen exposed to cadmium. When the initial blood cadmium concentration was below 180 nmol/1 (six subjects) it declined smoothly and roughly exponentially, with a mean half-life of 20.4 months and a final asymptote of 70 nmol/l; in the remaining three subjects (initial blood cadmium concentration above 180 nmol/1) the decay was less regular and more prolonged (mean half-life 31.4 months, final asymptote 92 nmol/l). The significance of these results in relation to occupational cadmium exposure is discussed.
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.
Assessment of Polymorphonucleate Leucocyte Functions in Adult Epileptic Patients Undergoing Long-term Phenytoin Treatment
Authors: Ricevuti G. , Marcoli M. , Gatti G. , Mazzone A. , Lecchini S. , Frigo G.M.
Published: December 2008

Twelve patients given more than 1 year phenytoin monotherapy and 12 healthy control subjects taking no drugs and matched for sex and age were examined for polymorphonucleate (PMN) functions. To assess PMN activity, cell locomotion and directed migration, phagocytosing ability and bactericidal activity were investigated. No change either in the absolute or relative counts of PMN leucocytes was found in the patients. However, a significant impairment of both PMN chemotaxis and stimulated Nitro Blue Tetrazolium reduction or superoxide anion generation was observed in the patients as compared with the control group of subjects.
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.
Acute Toxicity Studies with Jatropha curcas L
Authors: Abdu-Aguye I. , Sannusi A. , Alafiya-Tayo R.A. , Bhusnurmath S.R.
Published: December 2008

The seeds of Jatropha curcas L. ingested accidentally by two children aged 3 and 5 years led to a clinical syndrome of restlessness, severe vomiting and dehydration. A systematic study of the seeds indicated that they produced toxic effects in mice. Macroscopic anal haemorrhage and death occurred when the seeds were administered with the feed. Post-mortem examination revealed infarction of various parts of the gatrointestinal tract with congested vessels. Sodium chloride solution (150 mmol/l: saline) extract of the dried seed administered intraperitoneally into mice caused death in doses as low as 1 mg/kg. Post-mortem studies in this case showed widespread haemorrhages involving the colon, lungs as well as infarction of the liver. Larger intraperitoneal doses (> 30 mg/kg) were lethal rapidly but not associated with gross gastrointestinal haemorrhage.
Massive Glibenclamide Overdose without Hypoglycaemia in a Man with Diabetes after Partial Pancreatectomy
Authors: Ferner R.E. , Alberti K.G.M.M. , Rawlins M.D.
Published: December 2008

A 49-year-old man with non-insulin-dependent diabetes mellitus (NIDDM) from alcoholic pancreatitis took 100 mg of glibenclamide without symptoms of hypoglycaemia even when glibenclamide concentrations were high (191 μg/l). There was no increase in serum C-peptide concentration. The observed half-life of glibenclamide was 6 h. It is concluded that (1) high doses of glibenclamide will not provoke pancreatic insulin secretion in NIDDM caused by pancreatic destruction, (2) there was no evidence for an acute extra-pancreatic effect of glibenclamide and (3) the elimination of glibenclamide may be slower than supposed previously.
Acute Poisoning by Intentional Ingestion of Thallous Malonate
Authors: Aoyama H. , Yoshida M. , Yamamura Y.
Published: December 2008

1 A 26-year-old man who ingested 10 g of thallous malonate was treated by gastric lavage and combined haemodialysis and haemoperfusion.

2 At a blood flow of 100 ml/min, the average of thallium clearance values obtained by combined haemoperfusion and haemodialysis at two different times were 50.2 and 60.4 ml/min.

3 Forty hours after ingestion, he died of cardiac failure. A higher concentration of thallium was found in the heart than in other organs, suggesting that the heart is the main target of thallium in the early stage of acute poisoning.
The Epidemiology and Prevention of Paraquat Poisoning
Authors: Onyon Lesley J. , Volans Glyn N.
Published: December 2008

1 In the UK there was an increase in the annual number of deaths associated with paraquat poisoning between 1966 and 1975. Since that time there has been little change in numbers.

2 High mortality is associated commonly with suicidal intent. Serious accidental poisoning from paraquat has never been frequent in the UK and there have been no deaths reported in children since 1977.

3 The National Poisons Information Service has monitored in detail all reports of paraquat poisoning since 1980. Of the 1074 cases recorded there were 209 deaths. In recent years serious poisoning has been more commonly associated with ingestion of concentrated products by males. Local exposure to paraquat has not resulted in systemic poisoning.

4 International data for paraquat poisoning is incomplete and difficult to compare. There is a scarcity of morbidity data at both international and national levels. Information obtained from Poison Control Centres indicates that paraquat poisoning occurs in many countries but detailed comparisons are hindered by lack of standardised methods of recording.

5 Various measures to prevent paraquat poisoning have been introduced. Their effectiveness has not been studied in detail. Some support is provided by the low incidence of serious accidental paraquat poisoning in the UK, but because of the suicidal nature of paraquat poisoning it is unlikely that current preventative measures will influence the number of deaths occurring each year.

6 Preventative measures against paraquat poisoning should be tailored to national needs, based on and assessed by epidemiological studies.
Pharmacological Treatments of Paraquat Poisoning
Authors: Bateman D.N.
Published: December 2008

1 A large number of pharmacological techniques aimed at modifying paraquat toxicity have been investigated. There is no convincing controlled evidence that any are unequivocally useful.

2 Studies with an ascorbic acid and riboflavin combination appear effective in rats, and there is a suggestion that cyclophosphamide and dexamethasone may in some way alter paraquat toxicity in man and by pretreatment, but not concurrent treatment, also in the rat.

3 Further controlled studies are required of these treatments in patients who are potentially salvageable. There is a need for a rapid paraquat assay for clinical use in order that patients in this category can be identified quickly and included in appropriate controlled studies.
Haemodialysis for Paraquat Poisoning
Authors: Proudfoot A.T. , Prescott L.F. , Jarvie D.R.
Published: December 2008

1 Paraquat can be removed by haemodialysis and haemoperfusion but, although clearance values are high, the quantities recovered are insignificant. Prevention of death is most unlikely except perhaps in patients with plasma paraquat concentrations very close to the previously proposed line separating concentrations in fatal cases and survivors at different time intervals.

2 Even if delays incurred in measuring plasma paraquat concentrations and in setting up haemodialysis or haemoperfusion could be reduced to a minimum, elimination by these procedures would achieve little because paraquat disappears rapidly from the plasma in the first few hours after ingestion as it is taken up by the tissues and excreted into the urine.

3 Further studies on patients at borderline risk are required and the value of 'continuous' haemoperfusion requires further assessment.
Paraquat lung: is there a role for radiotherapy?
Authors: Williams M.V. , Webb D.B.
Published: December 2008

1 We have previously reported the clinical course of a patient poisoned with paraquat who was treated with whole lung irradiation and who survived severe pulmonary damage.

2 Four further cases are reported who were much more severely poisoned and who died despite early pulmonary irradiation.

3 There is no definite evidence that this or any other form of cytotoxic therapy can influence the course of paraquat lung. As there is no adequate laboratory model, further investigation of such therapy should be in the context of a prospective clinical trial. Treatment of only one lung would allow rapid identification of a therapeutic effect of irradiation.
Emergency Analysis of Paraquat in Biological Fluids
Authors: Braithwaite R.A.
Published: December 2008

1 A variety of spectrophotometric, gas and liquid chromatographic and radioimmunoassay techniques have been applied to the measurement of paraquat in biological fluids. A brief review of these techniques is presented.

2 The majority of described methods are far from suitable in the provision of an accurate and reliable quantitative result in an emergency situation and the further development of suitable 'rapid' techniques is desirable.

3 The preparation and characterisation of internal accuracy control materials and the introduction of an external quality assessment scheme would be valuable in the improvement of laboratory investigations of paraquat poisoning.
Evidence for Lipid Peroxidation in Man Following Paraquat Ingestion
Authors: Situnayake R.D. , Crump B.J. , Thurnham D.I. , Davies J.A. , Davis M.
Published: December 2008

1 Four patients were investigated for evidence of lipid peroxidation between 4.5 and 36 h (mean 22 h) after ingestion of paraquat by measuring plasma phospholipid-2-esterified, diene-conjugated 18:2Δ9,11-linoleic acid (9,11-LA) and expressing it also as a ratio R (9,11-LA/9,12-LA x 100) of the 'parent' linoleic acid.

2 The mean value for R was 4.73 (range 3.7-7.1) at presentation and 6.91 at peak values (range 3.8-13.4) which occurred at a mean of 34 h after ingestion. Both values were significantly higher (P < 0.001) than that of 107 healthy controls (1.94, range 0.67-3.8).

3 Parallel changes in plasma vitamin E and 9,11-LA occurred in the 2 patients in whom serial measurements were made suggesting an involvement of vitamin E in the formation of this isomer.

4 These findings support the hypothesis that lipid peroxidation occurs during paraquat poisoning in man and the early appearance of 9,11-LA suggests that it may be a primary event.
Nomifensine and Convulsive Seizures
Authors: Guy Edwards J. , Glen-Bott M.
Published: December 2008

Four cases of convulsive seizures occurring during treatment with nomifensine have been notified to the Committee on the Safety of Medicines of the United Kingdom, and 22 cases have been reported from other countries. The occurrence of convulsions is not in keeping with the results of animal experiments, studies of epileptic patients treated with nomifensine or observations made following overdoses of this drug. Nomifensine may thus not be entirely free from epileptogenic properties as previously presumed.
A Study of the Effect of Decimal and Centesimal Dilutions of Arsenic on the Retention and Mobilization of Arsenic in the Rat
Authors: Cazin J.C. , Cazin M. , Gaborit J.L. , Chaoui A. , Boiron J. , Belon P. , Cherruault Y. , Papapanayotou C.
Published: December 2008

Having developed a pharmacokinetic method for studying the fate of orally administered arsenious anhydride by a radioactive tracer method, the influence of Hahnemannian dilutions of arsenicum album on the elimination and retention of this toxin in the rat was then investigated. The effects of centesimal (cH) and decimal (dH) dilutions were studied.

All the dilutions studied were found to be active. The strongest effects were observed after the administration of dilutions corresponding to a concentration of 10-14 (14dH and 7cH). Overall, the decimal dilutions augmented the elimination of arsenic more than the centesimals.

The observed results were submitted to mathematical analysis. A mathematical model, which confirms that Hahnemannian dilutions have biological effects which are a direct function of the degree of dilution, was developed.
The Influence of the Homoeopathic Remedy Plumbum Metallicum on the Excretion Kinetics of Lead in Rats
Authors: Fisher P. , House I. , Belon P. , Turner P.
Published: December 2008

There are a number of reports that certain metals, when prepared by the homoeopathic method of serial dilution with succussion, stimulate excretion of the same metal from previously loaded animals. We report an experiment on the effect of homoeopathically diluted lead on urinary lead excretion in the rat, controlled against distilled water and the chelating agent DMPS.

The homoeopathic preparations were made specially, with precautions against contamination. Homoeopathic treatment did not cause a significant change in urinary lead excretion compared to distilled water, although there were significant differences between different homoeopathic dilutions. DMPS produced a large increase in urinary lead excretion.
Self-poisoning and Therapeutic Intoxication with Lithium
Authors: Dyson E.H. , Simpson D. , Prescott L.F. , Proudfoot A.T.
Published: December 2008

1 Of 68 admissions for lithium overdose over 16 years, 25 were due to therapeutic intoxication and 43 to deliberate self-poisoning.

2 Three patients with therapeutic intoxication had acute diabetes insipidus with hypernatraemia. One of them had acute renal failure requiring dialysis, prolonged Parkinsonism and generalised myopathy.

3 Twenty-two patients with therapeutic intoxication had peak serum lithium concentrations above the therapeutic range. In contrast, of 22 self-poisoned patients with peak serum lithium concentrations above the therapeutic range only 3 developed toxicity.

4 The mean admission plasma urea concentration in patients with therapeutic intoxication was higher than in self-poisoned patients and the mean admission plasma bicarbonate concentration was lower.

5 The mean serum lithium half-life in 8 patients with therapeutic intoxication was considerably longer than in 5 self-poisoned patients.

6 Renal lithium clearance is enhanced by increased sodium excretion and we recommend that lithium toxicity be treated with saline diuresis and frusemide if fluid retention occurs. Haemodialysis is mandatory when renal failure is present, and may be indicated when serum lithium concentrations are very high or rising rapidly.
Paracetamol Conjugation: An Interethnic and Dietary Study
Authors: Sommers De K. , Moncrieff J. , Avenant J.C.
Published: December 2008

To test whether dietary or hereditary factors affect paracetamol metabolism, two groups of Venda and a group of Caucasian medical students were investigated. The Venda groups were selected as traditionally living villagers and those who followed a Western life-style.

Salivary concentrations of paracetamol and urinary amounts of the glucuronide and sulphate metabolites eliminated over 22 h were determined by HPLC. The metabolite formation rate constants and the percentage of the dose eliminated as each metabolite were calculated.

No significant differences were found between the data for total Venda, rural Venda, westernized Venda and Caucasian students for the calculated metabolite parameters.

Thus environmental effects showed no apparent influence on the sulphide and glucuronide conjugation of paracetamol, and no hereditary effect was evident between the Venda and Caucasians.
Influence of Several Chelating Agents on the Distribution and Binding of Cadmium in Rats
Authors: Rau W. , Planas-Bohne F. , Taylor D.M.
Published: December 2008

1 Male Sprague-Dawley rats were injected with109CdCl2(3 μmol Cd/kg) and killed between 1 h and 200 d afterwards. Metal concentration in the critical organs, i.e. liver and kidneys decreased very slowly. Within the cells Cd is found mainly in the cytosol and — at very early times — in the nuclei. Within the cytosol of the liver most of the metal is initially bound to proteins with high molecular weight but as early as 3 h after incorporation more than 90% is bound to metallothionein which is always the main binding site in the kidneys.

2 Of the chelating agents tested only BAL and Puchel were able to reduce the body burden significantly. Both are lipophilic substances. Puchel cannot reduce the kidney Cd burden but removes Cd from the liver only while BAL is effective in both organs. Both chelating agents exert their effects at doses which are too near to the LDso to be considered as safe enough for human use.
Detoxification of Styrene Oxide by Human Liver Glutathione Transferase
Authors: Pacifici G.M. , Warholm M. , Guthenberg C. , Mannervik B. , Rane A.
Published: December 2008

Cytosolic glutathione transferase (GST) was investigated in four human livers. The profile of GST activity was determined by isoelectric focusing using 1-chloro-2,4-dinitrobenzene as the electrophilic substrate. Three livers contained at least one basic and a near-neutral isoenzyme (GST μ). GSTμ was not detectable in the fourth liver. The kinetics of GST with styrene oxide as the electrophilic substrate were studied in the cytosolic fraction, with the pooled fractions from isoelectric focusing containing high activity of GSTμ transferase, and with GSTμ purified to homogeneity. The cytosol obeyed Michaelis-Menten kinetics when styrene oxide was used as the variable substrate. The average (± s.e.m.) of the Vmax and Kmwere 21.9 ± 7.9 nmol min-1mg-1and 4.9 ± 0.4 mM, respectively. At varying concentrations of glutathione, the enzyme did not obey Michaelis-Menten kinetics. Such kinetics were also observed with the fractions from isoelectric focusing and with the homogeneous GSTμ fraction. The Eadie-Hofstee plot showed two phases: one with a low and another with a high Kmvalue.

The apparent Kmvalues for the cytosol were 0.035 ± 0.022 and 0.88 ± 0.36 mM. The kinetic pattern of purified GSTμ is consistent with that found in the cytosol.
Bone Marrow Hypoplasia During Intensive Care: Bone Marrow Culture Studies Implicating Ranitidine in the Suppression of Haemopoiesis
Authors: Amos R.J. , Kirk B. , Amess J.A.L. , Jones A.L. , Hinds C.J.
Published: December 2008

Two seriously ill patients with renal failure developed bone marrow hypoplasia and peripheral blood cytopenias during admission to an Intensive Care Unit (ICU). Both patients were being treated with ranitidine and, in both, there was evidence of drug accumulation. Serum from the patient with the highest concentration of ranitidine inhibited granulocyte-macrophage colony growth from normal bone marrow. The addition of ranitidine to cultures of normal bone marrow also produced a concentration-dependent inhibition of colony growth. Ranitidine should be used with caution in patients with renal failure where drug accumulation may seriously impair bone marrow function.