No abstract

Impromidine is a specific, potent histamine H2-receptor agonist. The present paper describes the results of acute and short-term repeated-dose toxicity studies with impromidine in rodents and dogs. The intravenous LD50 was 9.6 mg kg-1 in male mice, 12.7 mg kg-1 in female mice and 25.5 mg kg-1 in rats. The minimum lethal dose in dogs after 30 min intravenous infusion was 27.7 mg kg-1 during the infusion and 4 mg kg-1 within 14 days. In 12- or 14-day tests in rats by the intravenous (maximum dose 3.24 mg per kg per day) and subcutaneous (maximum dose 20 mg per kg per day) routes, impromidine had no serious toxicological effects. In 12- or 14-day studies in dogs by the i.v. (maximum dose 0.259 mg per kg per day) and intramuscular (maximum dose 0.5 mg per kg per day) routes, impromidine caused vasodilation, tachycardia and vomiting. In a few dogs, at the highest dose levels, there was erosion and irritation of the gastrointestinal tract and myocardial damage. Other minor pathological changes were seen in the liver, kidneys and pancreas. No changes were seen other than those to be expected from the pharmacological actions of impromidine as an H2-receptor agonist. Studies in anaesthetized rats, either spontaneously respiring or sustained by artificial respiration, indicate that, at acute doses, impromidine causes death by respiratory failure.

Prizidilol (SK&F 92657-A2), an anti-hypertensive agent, has undergone a range of prescribed toxicity studies required for the investigation of possible adverse drug effects. During the second year of the 2-year rat oral study, a variety of symptoms were exhibited by males receiving 1600 mg of the compound day–1kg–1 by gavage. These animals became lethargic, slouched and developed dyspnoea which became progressively more severe during the course of the study. Necropsy of the affected rats revealed severely haemorrhagic lungs, cardiac hypertrophy and lordosis of the spine into the thoracic cavity. At the 2-year terminal kill, a proportion of the male rats receiving 100 and 400 mg of prizidilol day–1kg–1 were identified with similar but less severe spinal deformation. No female was found with spinal changes but all the rats receiving prizidilol showed haemorrhagic lungs and enlarged hearts. The lordosis of the affected males was always confined to the thoracic spine and this, along with the cardiac hypertrophy, presumably led to marked reduction in the volume of the thoracic cavity, inducing the dyspnoea. Thoracic vertebral body damage, possibly a precursor to the spinal deformities, was found in male rats from both drug-treated and control groups. The nature of the spinal lesion is at present under investigation.

1 In anaesthetized cats and dogs treated with mecamylamine, the pressor response to was increased when the animals were changed from a supine to a head-up, tilted position. This potentiation was not seen in rats. 2 The potentiation of the McN-A-343 pressor response was not affected by propranolol, destruction of the brain, or removal of the intestines, spleen or adrenal glands. It was promptly abolished by applying pressure to the lower half of the tilted animal. No increase in the pressor response to McN-A-343 occurred when cats were tilted head down. The potentiated response in tilted cats was abolished by atropine. 3 The pressor effects of adrenaline, noradrenaline, tryamine and angiotensin in cats treated with mecamylamine were either reduced or unchanged when the animal was changed from the supine to the tilted position. In one cat not treated with mecamylamine in which orthostatic hypotension occurred, tilting potentiated the pressor responses to dimethyl phenylpiperazinium iodide. 4 In cats anaesthetized with chloralose, the reflex pressor response to bilateral carotid occlusion was reduced by tilting. After mecamylamine treatment the residual atropine-sensitive response to carotid occlusion was potentiated when the animal was placed in the tilted position. 5 These results suggest that muscarinic stimulation of sympathetic ganglia by McN-A-343 raises blood pressure by predominantly reducing venous capacity, in contrast to noradrenaline and angiotension which increase blood pressure mainly by arterial vasoconstriction. 6 It is not clear whether this is a general property of sympathetic ganglionic stimulation or is restricted to stimulation of muscarinic sites.

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.