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1815. Don't lick too much liquorice
NATURAL PRODUCTS
549
during chronic exposure to Et4Pb. The practical importance of this is underlined by the identification of Et3Pb in the tissues of several people who died up to 20 days after acute poisoning with Et4Pb (Bolanowska et al. Arch. Tox. 1967, 22, 278).
1814. TOCP caught napping Buttar, H. S., Tyrrell, D. L. & Taylor, J. D. (1968). Effect of tri-o-cresyl phosphate, tri-ocresyl thiophosphate and 2-(o-cresyl)-4H : l :3 :2 benzodioxaphosphoran-2-one on pentobarbital induced sleeping time in mice. Archs int. Pharmacodyn. Thdr. 172, 373. Tri-o-cresyl phosphate (TOCP), a potent neurotoxin (Cited in F.C.T. 1968, 6, 547) has been found to prolong the sleeping time of mice anaesthetized with pentobarbitone. Intraperitoneal injection of 5.0 mg TOCP or 1-0 mg of its metabolite, 2-(o-cresyl)-4H-1,3,2benzodioxaphosphoran-2-one (CBDP), together with 48 mg pentobarbitone/kg body weight significantly prolonged sleeping time in mice kept at 25°C. When the experiment was repeated at 33°C there was a decrease in the duration of pentobarbitone-induced hypnosis in TOCP-treated mice, but in the controls the sleeping times did not differ significantly between the groups maintained at the two different temperatures. The sleeping time of mice injected intraperitoneally at 33°C with 5.2 mg tri-o-cresyl thiophosphate (TOCSP), a close structural analogue of TOCP, and pentobarbitone did not differ from that of the controls. CBDP, like TOCP, is capable of inducing ataxia and demyelination in hens and cats, and the results of this study suggest that the effect of TOCP on pentobarbitone sleeping time was not due solely to a depression in body temperature but was probably attributable to the effects of a metabolite like CBDP. TOCSP on the other hand has been found relatively ineffective in causing paralysis and ataxia in chickens and it has been postulated that TOCSP has to be metabolized to TOCP before it can become an effective paralytic agent. On the basis of the findings in this study, however, the possibility that TOCSP is metabolized to a toxic substance like CBDP has been discounted, since CBDP is believed to be at least partly responsible for the prolongation of sleeping time caused by TOCP. The most probable mechanism by which CBDP prolongs the hypnosis induced by pentobarbitone involves inhibition of pentobarbitone oxidation.
NATURAL PRODUCTS
1815~Don't lick too much liquorice X Koster, M. & David, G. K. (1968). Reversible severe hypertension due to licorice ingestion. New Engl. J. Med. 278, 1381. Conn, J. W., Rovner, D. R. & Cohen, E. L. (1968). Licorice-induced pseudoaldosteronism. Hypertension, hypokalemia, aldosteronopenia, and suppressed plasma renin activity. J. Am. reed. Ass. 205, 492. ?(Large doses of liquorice (I) used medicinally have been known to cause hypertension accompanied by marked sodium and water retention, oedema and potassium depletion. Similar effects have now been reported in two subjects with a predilection for sweets containing I)~ The first paper cited above concerns a 20-yr-old woman who had consumed about 100 g l/day for 2 yr. She complained of headaches, fatigue and nervousness and was severely hypertensive. Bilateral retinopathy and a slight enlargement of the heart were evident. When
550
COSMETICS, TOILETRIES AND HOUSEHOLD PRODUCTS
100 g I was administered daily for 16 days, her blood pressure remained at about 200/140 mm Hg and marked water and sodium retention and hypokalaemia were demonstrated. Thirteen days after discontinuation of I the blood pressure had returned to normal and there was a weight loss of about 4 kg, with concomitant salt and water diuresis. After a further week the retinopathy had disappeared. After a period of normality, repetition of the treatment with I again caused hypertension and sodium retention. Conn et al. (cited above) describe the case of a 58-yr-old man who had ingested two or three 36-g liquorice candy bars daily for 6-7 yr, an intake equivalent to about 0.5 g/day of the active ingredient, ammonium glycyrrhizate (II). In this case blood pressure rose to 190/120 mm Hg in spite of antihypertensive therapy, which itself aggravated the hypokalaemic alkosis caused by I to such an extent that flaccid paralysis of the extremities resulted. Discontinuation of the antihypertensive treatment, institution of potassium therapy and abstinence from I led to the disappearance of symptoms within 14 days. Subsequently, administration of II for 10 days in daily doses rising from 1 to 4 g increased the patient's weight, blood pressure and serum sodium, decreased serum potassium and markedly suppressed plasma renin activity and aldosterone secretion. After eating no liquorice for 10 months, the patient was asymptomatic, with blood pressure averaging 135/90 Hg, although his response to a low sodium diet was still somewhat suppressed. 1816. An excellent 'refresher' on pyrrolizidine alkaloids Schoental, R. (1968). Toxicology and carcinogenic action of pyrrolizidine alkaloids. Cancer Res. 28, 2237. The biological effects of pyrrolizidine alkaloids always make fascinating reading and it is appropriate that this important subject should be reviewed by one of the world's leading authorities. Although pushed out of the limelight by the onslaught of the fungal toxins, these alkaloids, derived from a variety of plants, still present a major hazard to livestock and people in the developing countries. Their biological effects range widely and have been shown to include pulmonary and veno-occlusive lesions, hepatotoxicity, hepatocarcinogenicity, teratogenicity and anticholinergic effects in animals and mutagenicity in Drosophila. Age, sex, species and diet are important factors in the degree of toxicity in animals, and man's susceptibility to the hepatotoxic pyrrolizidine alkaloids has been demonstrated epidemiologically. Understandably no direct relationship has been established between the incidence of kwashiorkor, marasmus, veno-occlusive disease and primary liver cancer, but the author raises some interesting questions in connexion with the aetiology of kwashiorkor, which is still regarded as a purely nutritional deficiency syndrome. It is regrettable that use is still being made of the pyrrolizidine alkaloids as herbal medicines for various conditions, including those occurring in pregnancy and parturition, since these practices may place the foetus and newborn at special risk.
COSMETICS, TOILETRIES AND HOUSEHOLD PRODUCTS 1817. Enzymes inhaled
Flindt, M. L. H. (1969). Pulmonary disease due to inhalation of derivatives of Bacillus subtilis containing proteolytic enzyme. Lancet i, 1177. Pepys, J., Hargreave, F. E., Longbottom, J. L. & Faux, J. (1969). Allergic reactions of the lungs to enzymes of Bacillus subtilis. Lancet i, 1181.
549
during chronic exposure to Et4Pb. The practical importance of this is underlined by the identification of Et3Pb in the tissues of several people who died up to 20 days after acute poisoning with Et4Pb (Bolanowska et al. Arch. Tox. 1967, 22, 278).
1814. TOCP caught napping Buttar, H. S., Tyrrell, D. L. & Taylor, J. D. (1968). Effect of tri-o-cresyl phosphate, tri-ocresyl thiophosphate and 2-(o-cresyl)-4H : l :3 :2 benzodioxaphosphoran-2-one on pentobarbital induced sleeping time in mice. Archs int. Pharmacodyn. Thdr. 172, 373. Tri-o-cresyl phosphate (TOCP), a potent neurotoxin (Cited in F.C.T. 1968, 6, 547) has been found to prolong the sleeping time of mice anaesthetized with pentobarbitone. Intraperitoneal injection of 5.0 mg TOCP or 1-0 mg of its metabolite, 2-(o-cresyl)-4H-1,3,2benzodioxaphosphoran-2-one (CBDP), together with 48 mg pentobarbitone/kg body weight significantly prolonged sleeping time in mice kept at 25°C. When the experiment was repeated at 33°C there was a decrease in the duration of pentobarbitone-induced hypnosis in TOCP-treated mice, but in the controls the sleeping times did not differ significantly between the groups maintained at the two different temperatures. The sleeping time of mice injected intraperitoneally at 33°C with 5.2 mg tri-o-cresyl thiophosphate (TOCSP), a close structural analogue of TOCP, and pentobarbitone did not differ from that of the controls. CBDP, like TOCP, is capable of inducing ataxia and demyelination in hens and cats, and the results of this study suggest that the effect of TOCP on pentobarbitone sleeping time was not due solely to a depression in body temperature but was probably attributable to the effects of a metabolite like CBDP. TOCSP on the other hand has been found relatively ineffective in causing paralysis and ataxia in chickens and it has been postulated that TOCSP has to be metabolized to TOCP before it can become an effective paralytic agent. On the basis of the findings in this study, however, the possibility that TOCSP is metabolized to a toxic substance like CBDP has been discounted, since CBDP is believed to be at least partly responsible for the prolongation of sleeping time caused by TOCP. The most probable mechanism by which CBDP prolongs the hypnosis induced by pentobarbitone involves inhibition of pentobarbitone oxidation.
NATURAL PRODUCTS
1815~Don't lick too much liquorice X Koster, M. & David, G. K. (1968). Reversible severe hypertension due to licorice ingestion. New Engl. J. Med. 278, 1381. Conn, J. W., Rovner, D. R. & Cohen, E. L. (1968). Licorice-induced pseudoaldosteronism. Hypertension, hypokalemia, aldosteronopenia, and suppressed plasma renin activity. J. Am. reed. Ass. 205, 492. ?(Large doses of liquorice (I) used medicinally have been known to cause hypertension accompanied by marked sodium and water retention, oedema and potassium depletion. Similar effects have now been reported in two subjects with a predilection for sweets containing I)~ The first paper cited above concerns a 20-yr-old woman who had consumed about 100 g l/day for 2 yr. She complained of headaches, fatigue and nervousness and was severely hypertensive. Bilateral retinopathy and a slight enlargement of the heart were evident. When
550
COSMETICS, TOILETRIES AND HOUSEHOLD PRODUCTS
100 g I was administered daily for 16 days, her blood pressure remained at about 200/140 mm Hg and marked water and sodium retention and hypokalaemia were demonstrated. Thirteen days after discontinuation of I the blood pressure had returned to normal and there was a weight loss of about 4 kg, with concomitant salt and water diuresis. After a further week the retinopathy had disappeared. After a period of normality, repetition of the treatment with I again caused hypertension and sodium retention. Conn et al. (cited above) describe the case of a 58-yr-old man who had ingested two or three 36-g liquorice candy bars daily for 6-7 yr, an intake equivalent to about 0.5 g/day of the active ingredient, ammonium glycyrrhizate (II). In this case blood pressure rose to 190/120 mm Hg in spite of antihypertensive therapy, which itself aggravated the hypokalaemic alkosis caused by I to such an extent that flaccid paralysis of the extremities resulted. Discontinuation of the antihypertensive treatment, institution of potassium therapy and abstinence from I led to the disappearance of symptoms within 14 days. Subsequently, administration of II for 10 days in daily doses rising from 1 to 4 g increased the patient's weight, blood pressure and serum sodium, decreased serum potassium and markedly suppressed plasma renin activity and aldosterone secretion. After eating no liquorice for 10 months, the patient was asymptomatic, with blood pressure averaging 135/90 Hg, although his response to a low sodium diet was still somewhat suppressed. 1816. An excellent 'refresher' on pyrrolizidine alkaloids Schoental, R. (1968). Toxicology and carcinogenic action of pyrrolizidine alkaloids. Cancer Res. 28, 2237. The biological effects of pyrrolizidine alkaloids always make fascinating reading and it is appropriate that this important subject should be reviewed by one of the world's leading authorities. Although pushed out of the limelight by the onslaught of the fungal toxins, these alkaloids, derived from a variety of plants, still present a major hazard to livestock and people in the developing countries. Their biological effects range widely and have been shown to include pulmonary and veno-occlusive lesions, hepatotoxicity, hepatocarcinogenicity, teratogenicity and anticholinergic effects in animals and mutagenicity in Drosophila. Age, sex, species and diet are important factors in the degree of toxicity in animals, and man's susceptibility to the hepatotoxic pyrrolizidine alkaloids has been demonstrated epidemiologically. Understandably no direct relationship has been established between the incidence of kwashiorkor, marasmus, veno-occlusive disease and primary liver cancer, but the author raises some interesting questions in connexion with the aetiology of kwashiorkor, which is still regarded as a purely nutritional deficiency syndrome. It is regrettable that use is still being made of the pyrrolizidine alkaloids as herbal medicines for various conditions, including those occurring in pregnancy and parturition, since these practices may place the foetus and newborn at special risk.
COSMETICS, TOILETRIES AND HOUSEHOLD PRODUCTS 1817. Enzymes inhaled
Flindt, M. L. H. (1969). Pulmonary disease due to inhalation of derivatives of Bacillus subtilis containing proteolytic enzyme. Lancet i, 1177. Pepys, J., Hargreave, F. E., Longbottom, J. L. & Faux, J. (1969). Allergic reactions of the lungs to enzymes of Bacillus subtilis. Lancet i, 1181.