Human & Experimental Toxicology

SK&F 95018, a potential antihypertensive agent with the combined properties of vasodilation and β-adrenoceptor antagonism, induced red urine when given intravenously to a dog. Further studies revealed that in the dog, SK&F 95018 treatment led to haemoglobinaemia, haemoglobinuria and a fall in the red blood cell count. The compound was therefore suspected of causing red cell haemolysis and this was confirmed using dog blood in an in vitro haemolysis test system. Oral administration of the compound to dogs gave no indication of haemolysis, but the animals lost large portions of their dose through vomiting and the lack of effect is therefore questionable. Rats, which have no vomit reflex, were treated orally and although no direct evidence of haemolysis was obtained (e.g. haemoglobinaemia), the presence of polychromasia suggested some loss of mature red blood cells had occurred. Rat blood was haemolysed in vitro by SK&F 95018. Human red cells were also used in the in vitro haemolysis test system and these, too, were lysed by the compound. The haemolysis was shown to be related to the structure of the compound itself rather than to its pharmacological effects and development of SK&F 95018 as an antihypertensive agent was abandoned. Electron microscopy indicated that SK&F 95018 induced alterations in the red cell membrane which led to shape change, characterized by discocyte to spherocyte transformation, and finally haemolysis. The mechanism of this effect remains under investigation.

Thirty healthy volunteers were treated with beta-adrenoceptor blocking doses of long-acting propranolol for at least 28 days before being randomized to continue propranolol treatment, receive identical placebo under double-blind conditions, or discontinue all treatment. No evidence of a central nervous withdrawal syndrome occurred during the next 28 days as assessed by changes in psychomotor tests, rating scales, visual analogue scales, tremor recordings and melatonin excretion. Three subjects in the placebo withdrawal group but none in the propranolol group complained of insomnia for up to 14 days of the withdrawal period.

1 Adult hospital admissions following acute exposures to pesticides are very uncommon and are more often due to parasuicide than to accidents.

2 Most accidental pesticide incidents are work-related.

3 Males are more likely to be involved than females (2.9:1).

4 Life-threatening and fatal consequences developed in 24% of 54 incidents.

5 Of the 10 fatalities, eight were caused by paraquat, eight were due to parasuicide and two to non-work related accidents.

The relative efficacy of citric, malic, malonic, oxalic and succinic acids, and deferoxamine mesylate (DFOA) on the toxicity, distribution and excretion in mice exposed to aluminium were compared. Chelating agents were administered intraperitoneally at a dose equal to one-fourth of their respective LD₅₀. To determine the effect of the various chelators on the toxicity of aluminium, various doses of aluminium nitrate (938-3188 mg/kg) were administered intraperitoneally, followed by one of the chelators. Survival was recorded at the end of 14 days. Malic and succinic acids were the most effective.

Malic acid and DFOA were the most effective in increasing the urinary excretion of aluminium. Citric acid was the most effective in increasing the faecal excretion of aluminium. Malonic, oxalic and succinic acids had no overall beneficial effects. Citric acid would appear to be the most effective agent of those tested in the prevention of acute aluminium intoxication. However, before the use of these compounds in human aluminium intoxication is possible, further investigations including the effects of these chelators after chronic aluminium intoxication are required.

1 Oxytetracycline and pyridostigmine were given alone and in combination for 4 days to 12 normal male volunteers in a double-blind, randomised cross-over study. On the fifth day, the pharmacokinetic profiles of the two drugs were examined, and blood and plasma cholinesterase activity was measured.

2 No significant interaction on absorption or pharmacokinetics of either drugs was detected when they were given in combination.

3 There was a small but statistically significant increase in erythrocyte cholinesterase when oxytetracycline was given in combination with pyridostigmine, the pharmacological significance of which is not clear.

1 Indole, p-cresol and phenol are microbial amino acid metabolites which show co-carcinogenic or promoting activity in animal studies. Their involvement in the development of human bladder cancer has been determined by measuring the urinary excretion of indican (indoxyl sulphate) and conjugated phenols.

2 Thirty-two patients (22 males, 10 females) with histologically confirmed carcinoma of the urinary bladder and a similar number of age and sex matched controls took part in the study. The excretion of indican, p-cresol and phenol showed wide interindividual variability, but did not differ significantly between the two groups.

3 The findings indicate that these endogenous metabolites do not contribute significantly to the development of human bladder cancer.

1 The metabolic oxidation of debrisoquine has been studied in a group of 96 San Bushmen.

2 The amounts of debrisoquine and 4-hydroxy-debrisoquine excreted in 0-8 h urine were measured and the metabolic ratio (% dose as debrisoquine/% dose as 4-hydroxy-debrisoquine) calculated.

3 On the basis of Caucasian criteria, that metabolic ratios > 12.6 represent poor metabolizers, 19% of the Bushmen were poor metabolizers in contrast to the 8-10% found in Caucasian studies.

4 Probit plots showed four modes may be present in the data, which may represent at least three isozymes of the relevant enzyme which may also differ from the Caucasian isozymes.

1 Antipyrine clearance and average daily consumption of tobacco, alcohol and coffee/tea were determined in 303 healthy men.

2 The antipyrine clearance was positively correlated with the consumption of tobacco (r = 0.24; P < 0.0001) and coffee/tea (r = 0.18; P < 0.001), and negatively with age (r = -0.14; P < 0.05) and the alcohol consumption (r = —0.13; P < 0.05).

3 The multiple regression coefficients suggested an increase in antipyrine clearance of 0.8% per daily cigarette or cup of tea and 1.4% per daily cup of coffee; the decrease per daily drink or year of age was 2.8% or 0.4%, respectively.

Shock is a well-known complication of iron poisoning. Its aetiology is multifactorial with hypovolaemia due to gastrointestinal blood loss and myocardial depression due to systemic acidosis contributing to its genesis. Primary myocardial dysfunction has not been considered to play a role. Our clinical experiences and autopsy findings in three fatal cases of iron poisoning support myocardial dysfunction and damage as contributing factors to their cardiovascular collapse.

The three patients, all female, were 3½, 16 and 28-years-old. Onset of shock occurred at 1, 2 and 5 days post-ingestion. There was no response to vigorous fluid replacement therapy and aggressive catecholamine infusions. Central venous pressures were elevated. Microscopic examination of postmortem tissue showed myocardial damage and the presence of stainable iron. It is speculated that the myocardial depression is mediated by lipid peroxidation of myocyte organelle membranes due to iron catalysed free radical generation.

The presence of myocardial dysfunction has therapeutic implications. Patients with severe iron poisoning require early and serial measurements of arterial blood pressure, central venous pressure and cardiac output. If primary myocardial dysfunction is documented then fluid replacement, inotropic support and afterload reduction should be considered.

1 Alpha-chloralose, formed by the condensation of glucose with chloral, is used as a rodenticide and in the control of bird pests.

2 In two cases of poisoning with alpha-chloralose the clinical features included coma and generalized convulsions resembling the effects of strychnine more than those of chloral hydrate.

3 The principles of management are the support of vital functions in the unconscious patient and removal of unabsorbed poison by gastric lavage. Diazepam may be used to control convulsions.

1 Two cases of serious intoxication with phenoxy herbicides (MCPP) are reported.

2 Both patients had central nervous system involvement, became unconscious and had an inadequate respiration. Muscle cramps and rhabdomyolysis with renal failure were noted in both. Shortly after admission both patients developed a serious decrease in arterial blood pressure (160/ 80 mmHg to 80/45 mmHg). In one patient this was demonstrated to be caused by a reduction in peripheral vascular resistance.

3 Plasma concentration of MCPP in patient 2 was 298 mg/l (3-4 h after ingestion). The plasma t _½ was about 17 h. MCPP plasma elimination probably follows first-order kinetics.

A 15-year-old girl with normal renal function took 75 tablets of allopurinol 300 mg. She did not suffer any ill-effects. Samples obtained over 84 h showed prolonged elimination of allopurinol, with a half-life of 3.6 h, and oxipurinol, with a half-life of 26 h.