- Email: [email protected]
673. The effect of high fat
BIOCHEMICAL PHARMACOLOGY
515
solution) which corresponds more closely to conditions of use and to the levels of maximum surface activity, and only 0.05 ml, instead of 0.1 ml of solution is introduced into the eye. Furthermore, eye reaction is assessed at frequent intervals from 1 hr after instillation, and not for the first time after 24 hr, and the washing out procedure of Draize is eliminated, being replaced by the use of known dilutions. The Draize numerical grading was used to evaluate results. The products tested were: A--sodium lauryl diglycol ether sulphate (pure); B--sodium coconut oil acid sarcoside (technical); C--sodium coconut oil acid methyl tauride (technical); D--alkyl dimethyl benzyl ammonium chloride (technical). All 4 samples caused redness and swelling. In the cases of A, B and C, the intensity of symptoms faded with time and concentration. With the cationic material D, however, symptoms increased in severity during the observation period, and did not decrease markedly with concentration. Graphical portrayal of reaction against concentration, at 24 hr after application, shows negligible symptoms for 2--4 % A, sharply declining symptoms for B, reaching 0 at 2 %, and a more gradual decline with C. With D, however, symptoms are still marked even at the 0.5 7O level. In assessing materials for use, preference should be given to those with a steeply falling reaction/concentration curve, as in these, any irritant action will be significantly reduced by dilution resulting from reflex lachrymation. Particularly important, too, is the occurrence of swelling, since this indicates penetration into the deeper tissues. The Draize test is suitable for eliminating materials which cause corneal or ciliary lesions. A, B and C were acceptable in this respect, but D caused corneal opacity, occasionally at 8 % and consistently at higher concentrations. It is suggested that the weak local-anaesthetic effect sometimes attributed to surfactants may be due to the disturbance of nerve endings by the inflammation, and this point is to be investigated.
BIOCHEMICAL PHARMACOLOGY 673. The effect of high fat
Kekwick, A. & Pawan, G. L. S. (1964). The effect of high fat and high carbohydrate diets on rates of weight loss in mice. Metabolism 13, 87. Some years ago, Kekwick & Pawan (Lancet 1956, ii, 155) reported a clinical study which suggested that when groups of obese patients were placed on restricted calorie diets, those whose diet contained a high proportion of fat lost weight more quickly than those whose diet was high in carbohydrate. This result has now been confirmed in mice, and carbon balance studies used in an attempt to clarify the mechanism. Various workers had hinted that the weight loss could be accounted for by reductions in the total body water, but the experiments described in this paper suggest that the losses are due to differences in the rate of body fat metabolism. Mice on a normal diet excreted about one half of their carbon as CO2 and the remainder in the form of half-metabolised organic compounds in the urine and faeces. When the mice were placed on a restricted (50 %) calorie diet with 80 7o fat content, the proportion of carbon excreted as CO2 remained the same, but the urinary excretion of organic carbon rose to a value of 20 7o. On the other hand, when an isocaloric diet containing 80 7oocarbohydrate was fed, a more efficient use of body fats was seen, reflected by an increase of 30 % in the carbon excreted as CO2 with a corresponding reduction in the carbon excretion via the faeces and urine. The extent to which foodstuffs are totally metabolized to CO2 represents a measure of the efficiency of the animal in utilizing the food available for energy purposes. The fact that the CO2 output of the mice placed on a calorie-deficient high fat diet remained essentially the
516
TOXICOLOGY
same as that of animals on a normal diet, indicated that the deficiency was supplemented from endogenous fat stores. The increased CO2 output of the mice given a low calorie high carbohydrate diet indicated an increased efficiency in the utilization of the available food, leaving the animal's own fat deposits largely untouched.
674. Drug--polyphosphate complex Hele, Priscilla (1963). The interaction of phenothiazine derivatives and imipramine with polyphosphates of biological interest. Biochim. biophys. Acta 76, 647. It has been shown that when drugs related to phenothJazine or imipramine are mixed with polyphosphates, an insoluble complex develops rapidly. In this paper, the effect of drug concentration and structure on the rate of formation was examined. Rate of formation altered with varying structure of the ring or side-chain of the drug with the polyphosphate used. The presence of magnesium ions suppressed complex formation, but the action of sod/urn, potassium and lithium ions varied according to the system. The author suggests the possibility that the in vitro complexes studied here may help to explain the mode of action of these drugs in the body.
TOXICOLOGY
675. Toxic effects of a lonely life Hatch, Anita, Balazs, T., Wiberg, G. S. & Grice, H. C. (1963). Long-term isolation stress in rats. Science 142, 507. The individual caging of rats and mice for long-term nutritional studies facilitates accurate measurement of food consumption and other pai'ameters. It has been shown however that animals isolated for long periods become different physiological entities, with alterations in several relative organ weights (mice and rats), increased plasma 17-hydroxy-ketosteroids (rats) and an increase in the cardiotoxicity of isoproterenol in rats. The authors used over 350 weanling Wistar rats of both sexes bred from their laboratory stock. Half of them were housed individually and the remainder in groups of ten, the study being carried out over 13 weeks. Signs of 'isolation stress' became apparent after 4-6 weeks and by 3 months the isolated rats were nervous, aggressive and intractable, with a tendency to bite which necessitated handling with gloves. There was 100 ~o incidence of ascending caudal dermatitis compared to a zero incidence in communally caged animals. Ratios of adrenal and thyroid weights to body weight increased, whilst that of spleen and thymus (absolute weight) became significantly less in the isolated rats. It was observed that the most significant increases in adrenal and thyroid weights relative to body weight were in females. The evidence suggests that isolation stress is characterized by an endocrinopathy which involves the adrenal cortex. Daily handling of isolated rats was insufficient to overcome the stress syndrome but housing in pairs resulted in normal behaviour. The reaction to isoproterenol provided a criterion for assessing the development of isolation stress. The LDso of this material was 850 mg/kg in rats in the community cages. By week 8 the LDso was 118 mg/kg in isolated rats decreasing to less than 50 mg/kg after 3 months. This effect was reversible but required a period of 19 days of community life following maximum isolation, after which the sensitivity to isoproterenol was normal. Behaviour also reverted to normal after a return to community life, with no sign of their previous intractability after 19 days. The authors suggest that pairing or routine handling of animals could become a standard procedure in chronic toxicity or nutritional studies.
515
solution) which corresponds more closely to conditions of use and to the levels of maximum surface activity, and only 0.05 ml, instead of 0.1 ml of solution is introduced into the eye. Furthermore, eye reaction is assessed at frequent intervals from 1 hr after instillation, and not for the first time after 24 hr, and the washing out procedure of Draize is eliminated, being replaced by the use of known dilutions. The Draize numerical grading was used to evaluate results. The products tested were: A--sodium lauryl diglycol ether sulphate (pure); B--sodium coconut oil acid sarcoside (technical); C--sodium coconut oil acid methyl tauride (technical); D--alkyl dimethyl benzyl ammonium chloride (technical). All 4 samples caused redness and swelling. In the cases of A, B and C, the intensity of symptoms faded with time and concentration. With the cationic material D, however, symptoms increased in severity during the observation period, and did not decrease markedly with concentration. Graphical portrayal of reaction against concentration, at 24 hr after application, shows negligible symptoms for 2--4 % A, sharply declining symptoms for B, reaching 0 at 2 %, and a more gradual decline with C. With D, however, symptoms are still marked even at the 0.5 7O level. In assessing materials for use, preference should be given to those with a steeply falling reaction/concentration curve, as in these, any irritant action will be significantly reduced by dilution resulting from reflex lachrymation. Particularly important, too, is the occurrence of swelling, since this indicates penetration into the deeper tissues. The Draize test is suitable for eliminating materials which cause corneal or ciliary lesions. A, B and C were acceptable in this respect, but D caused corneal opacity, occasionally at 8 % and consistently at higher concentrations. It is suggested that the weak local-anaesthetic effect sometimes attributed to surfactants may be due to the disturbance of nerve endings by the inflammation, and this point is to be investigated.
BIOCHEMICAL PHARMACOLOGY 673. The effect of high fat
Kekwick, A. & Pawan, G. L. S. (1964). The effect of high fat and high carbohydrate diets on rates of weight loss in mice. Metabolism 13, 87. Some years ago, Kekwick & Pawan (Lancet 1956, ii, 155) reported a clinical study which suggested that when groups of obese patients were placed on restricted calorie diets, those whose diet contained a high proportion of fat lost weight more quickly than those whose diet was high in carbohydrate. This result has now been confirmed in mice, and carbon balance studies used in an attempt to clarify the mechanism. Various workers had hinted that the weight loss could be accounted for by reductions in the total body water, but the experiments described in this paper suggest that the losses are due to differences in the rate of body fat metabolism. Mice on a normal diet excreted about one half of their carbon as CO2 and the remainder in the form of half-metabolised organic compounds in the urine and faeces. When the mice were placed on a restricted (50 %) calorie diet with 80 7o fat content, the proportion of carbon excreted as CO2 remained the same, but the urinary excretion of organic carbon rose to a value of 20 7o. On the other hand, when an isocaloric diet containing 80 7oocarbohydrate was fed, a more efficient use of body fats was seen, reflected by an increase of 30 % in the carbon excreted as CO2 with a corresponding reduction in the carbon excretion via the faeces and urine. The extent to which foodstuffs are totally metabolized to CO2 represents a measure of the efficiency of the animal in utilizing the food available for energy purposes. The fact that the CO2 output of the mice placed on a calorie-deficient high fat diet remained essentially the
516
TOXICOLOGY
same as that of animals on a normal diet, indicated that the deficiency was supplemented from endogenous fat stores. The increased CO2 output of the mice given a low calorie high carbohydrate diet indicated an increased efficiency in the utilization of the available food, leaving the animal's own fat deposits largely untouched.
674. Drug--polyphosphate complex Hele, Priscilla (1963). The interaction of phenothiazine derivatives and imipramine with polyphosphates of biological interest. Biochim. biophys. Acta 76, 647. It has been shown that when drugs related to phenothJazine or imipramine are mixed with polyphosphates, an insoluble complex develops rapidly. In this paper, the effect of drug concentration and structure on the rate of formation was examined. Rate of formation altered with varying structure of the ring or side-chain of the drug with the polyphosphate used. The presence of magnesium ions suppressed complex formation, but the action of sod/urn, potassium and lithium ions varied according to the system. The author suggests the possibility that the in vitro complexes studied here may help to explain the mode of action of these drugs in the body.
TOXICOLOGY
675. Toxic effects of a lonely life Hatch, Anita, Balazs, T., Wiberg, G. S. & Grice, H. C. (1963). Long-term isolation stress in rats. Science 142, 507. The individual caging of rats and mice for long-term nutritional studies facilitates accurate measurement of food consumption and other pai'ameters. It has been shown however that animals isolated for long periods become different physiological entities, with alterations in several relative organ weights (mice and rats), increased plasma 17-hydroxy-ketosteroids (rats) and an increase in the cardiotoxicity of isoproterenol in rats. The authors used over 350 weanling Wistar rats of both sexes bred from their laboratory stock. Half of them were housed individually and the remainder in groups of ten, the study being carried out over 13 weeks. Signs of 'isolation stress' became apparent after 4-6 weeks and by 3 months the isolated rats were nervous, aggressive and intractable, with a tendency to bite which necessitated handling with gloves. There was 100 ~o incidence of ascending caudal dermatitis compared to a zero incidence in communally caged animals. Ratios of adrenal and thyroid weights to body weight increased, whilst that of spleen and thymus (absolute weight) became significantly less in the isolated rats. It was observed that the most significant increases in adrenal and thyroid weights relative to body weight were in females. The evidence suggests that isolation stress is characterized by an endocrinopathy which involves the adrenal cortex. Daily handling of isolated rats was insufficient to overcome the stress syndrome but housing in pairs resulted in normal behaviour. The reaction to isoproterenol provided a criterion for assessing the development of isolation stress. The LDso of this material was 850 mg/kg in rats in the community cages. By week 8 the LDso was 118 mg/kg in isolated rats decreasing to less than 50 mg/kg after 3 months. This effect was reversible but required a period of 19 days of community life following maximum isolation, after which the sensitivity to isoproterenol was normal. Behaviour also reverted to normal after a return to community life, with no sign of their previous intractability after 19 days. The authors suggest that pairing or routine handling of animals could become a standard procedure in chronic toxicity or nutritional studies.