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1642. Natural antifertility agents
NATURAL PRODUCTS
673
clusion that I interferes with the synthesis of nuclear ribonucleic acid, probably as a result of the binding of the toxin to DNA and the inhibition of DNA-dependent RNA-polymerase. 1640. Second thoughts on rubratoxin B Moss, M. O., Robinson, F. V. & Wood, A. B. (1968). Rubratoxin B, a toxic metabolite of Penicilliurn rubrum. Chemy Ind. p. 587. The structural formula previously assigned to rubratoxin B, one of the two toxic components ofPenicillium rubrum (Moss et al. Chemy lnd, 1967, 755) has now been revised. Chemists at the Tropical Products Institute have shown that a free carboxyl group is not present as was previously thought. Instead, the acidic character is attributed to the presence of a disubstituted maleic anhydride function with an ct,~-unsaturated 8-1actone taking the place of the carboxyl group. The ketone group formerly postulated in the aliphatic side chain of the molecule now gives way to a - C H O H grouping. Despite this reshuffle, the complete picture of the rubratoxin B molecule is still lacking but elucidation of the full structure should soon be accomplished. 1641. A toxic abortifaeient Lipton, A. (1967). Abortifacient and toxic actions of the glycoside 'albitocin' extracted from some Albizia species. J. Pharm. Pharrnac. 19, 792. Albitocin is a glycoside isolated from some species of the Albizia plant. East African witch-doctors have found it useful in accelerating labour and as an abortifacient. Its acute toxicity and abortifacient activity have now been studied. The acute oral LDso in guinea-pigs was found to be 19 mg/kg and the parenteral LDsos in mice, rats, guinea-pigs, rabbits and monkeys ranged from 1 to 6 mg/kg. These doses are quite close to those required to produce abortion, the EDso being in all cases more than half as great as the LDso. It seems likely, however, that the human uterus is more sensitive than that of lower animals to albltocin and that oral doses well below the toxic level are effective in accelerating labour. Animals given lethal doses survived 12-170 hr, exhibiting increasing apathy and anorexia and resulting loss of weight. Necrosis of the renal tubules was found in rabbits at autopsy, and previous workers have reported liver necrosis in rats and mice. (3uinea-pig foetuses that were aborted near term, even from females given lethal doses, survived and developed normally, indicating that the drug either has a low foetal toxicity or does not cross the placenta. 1642. Natural antifertility agents Newton, J. E. & Betts, J. E. (1968). Seasonal oestrogenic activity of various legumes. J. agric. Sci., Camb. 70, 77. Lightfoot, R. J., Croker, K. P. & Nell, H. (3. (1967). Failure of sperm transport in relation to ewe infertility following prolonged grazing on oestrogenic pastures. Aust. J. agric. Res. 18, 755. Matsui, Adelina S., Rogers, Joan, Woo, Y.-K, & Cutting, W. C. (1967). Effects of some natural products on fertility in mice. Medna Pharmac. exp. 16, 414. Doubts have been raised over the possibility that plant oestrogens may be responsible for reduced fertility in grazing cattle (Cited in F.C.T. 1968, 6, 108). Using the teat-length bioassay in wether lambs, Newton & Betts (cited above) demonstrated oestrogenic activity in grazing areas of red and white clover, lucerne and sainfoin. Whereas red clover was active throughout its growing period, white clover and lucerne were v.c.'r.
615--1
674
NATURAL PRODUCTS
active only during June-October and sainfoin to a very limited extent only in May and August. Mouse bioassay confirmed oestrogenic activity in red clover and in one sample only of white clover, but not in any samples of lucerne. This study clearly shows that seasonal variation in oestrogen content and the type of hormone assay used may explain the conflicting results that have been obtained m the past. Evidence is provided by Lightfoot et al. (cited above) that reduced fertility in ewes grazing on clover may be due to impaired sperm penetration into the female genital tract, a condition possibly brought about by the creation of a hostile cervical mucus, although uterine inertia resulting from the effect of oestrogens on the hypothalamo-neurohypophyseal system may be directly involved. Matsui et al. (cited above) screened 122 natural products used in Chinese and Hawaiian medicine for the presence of antifertility agents. Extracts of each product were administered subcutaneously to female mice and the effect on fertility was determined. Reduced fertility (i.e. a decrease in litters of at least 50 %) unaccompanied by general systemic toxicity was recorded for 16 of the products, and the effect appeared to be mediated by interference with tubal transport of the ova or with implantation rather than with ovulation.
1643. Factors affecting caffeine toxicity Peters, J. M. & Boyd, E. M. (1967). The influence of a cachexigenic diet on caffeine toxicity. Toxic. appl. Pharmac. 11, 121. Colton, T., Gosselin, R. E. & Smith, R. P. (1968). The tolerance of coffee drinkers to caffeine. Clin. Pharmac. Ther. 9, 3 I. It is common to find an enhancement in the toxicity of a compound in animals subjected to stress. In the case of caffeine, a 50 % reduction in food intake was necessary to achieve this effect (Cited in F.C.T. 1967, 5, 424). Peters & Boyd (cited above) studied the effect on caffeine toxicity of a biotin-deficient raw egg-white diet that became rancid on prolonged standing. This diet was capable in its own right of producing severe cachexia, with loss in body weight, reduced food intake, diarrhoea and diuresis in rats. Caffeine-treated rats succumbed more easily to the rancid diet than to standard Purina Laboratory Chow diet. This was to be expected, but rather surprisingly, the biotin-deficient diet was more toxic to caffeine-treated rats when presented in a fresh state than when it was rancid. In other words, rancidity appeared to confer a protective effect. The authors conclude that malnutrition does not necessarily accentuate toxicity. Do regular coffee drinkers develop a tolerance towards caffeine ? This question has been investigated by Colton et al. (cited above) in over 130 medical students who were divided into two groups: those who drank more than one cup of coffee or tea or one bottle of cola a day and those who did not. After a 150-mg oral dose of caffeine, the response of these two groups in respect of pulse rate, sleeping pattern, 'morning-after' and other symptoms was determined. The habitual drinker of caffeinated beverages was significantly less sensitive than the occasional drinker to the pulse rate-reducing action and sleep-disturbing effects of caffeine. Nevertheless the tolerance of the habitual drinker towards caffeine was considered to be of a low order.
1644. Biochemical effects of caffeine Mitoma, C., Sorich, T. J., II & Neubauer, Susanna E. (1968). The effect of caffeine on drug metabolism. Life Sci. 7, 145.
673
clusion that I interferes with the synthesis of nuclear ribonucleic acid, probably as a result of the binding of the toxin to DNA and the inhibition of DNA-dependent RNA-polymerase. 1640. Second thoughts on rubratoxin B Moss, M. O., Robinson, F. V. & Wood, A. B. (1968). Rubratoxin B, a toxic metabolite of Penicilliurn rubrum. Chemy Ind. p. 587. The structural formula previously assigned to rubratoxin B, one of the two toxic components ofPenicillium rubrum (Moss et al. Chemy lnd, 1967, 755) has now been revised. Chemists at the Tropical Products Institute have shown that a free carboxyl group is not present as was previously thought. Instead, the acidic character is attributed to the presence of a disubstituted maleic anhydride function with an ct,~-unsaturated 8-1actone taking the place of the carboxyl group. The ketone group formerly postulated in the aliphatic side chain of the molecule now gives way to a - C H O H grouping. Despite this reshuffle, the complete picture of the rubratoxin B molecule is still lacking but elucidation of the full structure should soon be accomplished. 1641. A toxic abortifaeient Lipton, A. (1967). Abortifacient and toxic actions of the glycoside 'albitocin' extracted from some Albizia species. J. Pharm. Pharrnac. 19, 792. Albitocin is a glycoside isolated from some species of the Albizia plant. East African witch-doctors have found it useful in accelerating labour and as an abortifacient. Its acute toxicity and abortifacient activity have now been studied. The acute oral LDso in guinea-pigs was found to be 19 mg/kg and the parenteral LDsos in mice, rats, guinea-pigs, rabbits and monkeys ranged from 1 to 6 mg/kg. These doses are quite close to those required to produce abortion, the EDso being in all cases more than half as great as the LDso. It seems likely, however, that the human uterus is more sensitive than that of lower animals to albltocin and that oral doses well below the toxic level are effective in accelerating labour. Animals given lethal doses survived 12-170 hr, exhibiting increasing apathy and anorexia and resulting loss of weight. Necrosis of the renal tubules was found in rabbits at autopsy, and previous workers have reported liver necrosis in rats and mice. (3uinea-pig foetuses that were aborted near term, even from females given lethal doses, survived and developed normally, indicating that the drug either has a low foetal toxicity or does not cross the placenta. 1642. Natural antifertility agents Newton, J. E. & Betts, J. E. (1968). Seasonal oestrogenic activity of various legumes. J. agric. Sci., Camb. 70, 77. Lightfoot, R. J., Croker, K. P. & Nell, H. (3. (1967). Failure of sperm transport in relation to ewe infertility following prolonged grazing on oestrogenic pastures. Aust. J. agric. Res. 18, 755. Matsui, Adelina S., Rogers, Joan, Woo, Y.-K, & Cutting, W. C. (1967). Effects of some natural products on fertility in mice. Medna Pharmac. exp. 16, 414. Doubts have been raised over the possibility that plant oestrogens may be responsible for reduced fertility in grazing cattle (Cited in F.C.T. 1968, 6, 108). Using the teat-length bioassay in wether lambs, Newton & Betts (cited above) demonstrated oestrogenic activity in grazing areas of red and white clover, lucerne and sainfoin. Whereas red clover was active throughout its growing period, white clover and lucerne were v.c.'r.
615--1
674
NATURAL PRODUCTS
active only during June-October and sainfoin to a very limited extent only in May and August. Mouse bioassay confirmed oestrogenic activity in red clover and in one sample only of white clover, but not in any samples of lucerne. This study clearly shows that seasonal variation in oestrogen content and the type of hormone assay used may explain the conflicting results that have been obtained m the past. Evidence is provided by Lightfoot et al. (cited above) that reduced fertility in ewes grazing on clover may be due to impaired sperm penetration into the female genital tract, a condition possibly brought about by the creation of a hostile cervical mucus, although uterine inertia resulting from the effect of oestrogens on the hypothalamo-neurohypophyseal system may be directly involved. Matsui et al. (cited above) screened 122 natural products used in Chinese and Hawaiian medicine for the presence of antifertility agents. Extracts of each product were administered subcutaneously to female mice and the effect on fertility was determined. Reduced fertility (i.e. a decrease in litters of at least 50 %) unaccompanied by general systemic toxicity was recorded for 16 of the products, and the effect appeared to be mediated by interference with tubal transport of the ova or with implantation rather than with ovulation.
1643. Factors affecting caffeine toxicity Peters, J. M. & Boyd, E. M. (1967). The influence of a cachexigenic diet on caffeine toxicity. Toxic. appl. Pharmac. 11, 121. Colton, T., Gosselin, R. E. & Smith, R. P. (1968). The tolerance of coffee drinkers to caffeine. Clin. Pharmac. Ther. 9, 3 I. It is common to find an enhancement in the toxicity of a compound in animals subjected to stress. In the case of caffeine, a 50 % reduction in food intake was necessary to achieve this effect (Cited in F.C.T. 1967, 5, 424). Peters & Boyd (cited above) studied the effect on caffeine toxicity of a biotin-deficient raw egg-white diet that became rancid on prolonged standing. This diet was capable in its own right of producing severe cachexia, with loss in body weight, reduced food intake, diarrhoea and diuresis in rats. Caffeine-treated rats succumbed more easily to the rancid diet than to standard Purina Laboratory Chow diet. This was to be expected, but rather surprisingly, the biotin-deficient diet was more toxic to caffeine-treated rats when presented in a fresh state than when it was rancid. In other words, rancidity appeared to confer a protective effect. The authors conclude that malnutrition does not necessarily accentuate toxicity. Do regular coffee drinkers develop a tolerance towards caffeine ? This question has been investigated by Colton et al. (cited above) in over 130 medical students who were divided into two groups: those who drank more than one cup of coffee or tea or one bottle of cola a day and those who did not. After a 150-mg oral dose of caffeine, the response of these two groups in respect of pulse rate, sleeping pattern, 'morning-after' and other symptoms was determined. The habitual drinker of caffeinated beverages was significantly less sensitive than the occasional drinker to the pulse rate-reducing action and sleep-disturbing effects of caffeine. Nevertheless the tolerance of the habitual drinker towards caffeine was considered to be of a low order.
1644. Biochemical effects of caffeine Mitoma, C., Sorich, T. J., II & Neubauer, Susanna E. (1968). The effect of caffeine on drug metabolism. Life Sci. 7, 145.