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520. Guinea-pig sensitization by milk proteins
284
NATURAL PRODUCTS
Another approach was the formation of art addition complex of aescin with the flavone derivative hesperidin, as demonstrated by physical measurements of the compressibility of a surface film in a Langmuir trough. Judging by the pharmacological action of aescin in rats it was concluded that an absorption of 5-10 70 of orally administered material had been achieved.
518. A well-known toxicant Langg~rd, H. & Smith, W. O. (1962). Self-induced water intoxication without predisposing illness, Report of two cases. New Engl. J. Med. 266, 378. Two cases of so-called "pure water intoxication" are described. " P u r e " refers here to the intoxication, not the water (H20); in other words there was no predisposing or contributory illness to bring about a metabolic disturbance. The patients simply drank themselves into the intoxicated state, at the rate of 10-20 1 and 5-12 1 H20 daily. The outstanding features of the condition were neurological disturbances, including convulsions and coma. It need hardly be added that both instances occurred in inmates of mental hospitals. Nevertheless one cannot but view with alarm the widespread use of a chemical that appears to have practically no margin of safety at all.]
519. Toxicity of sweat Lac0ur, J. R. & Cier, J. F. (1963). La toxicit~ de la sueur humaine. C.R. Soc. Biol., Paris 157, 1017. In 1897 Arloing (C.R. Acad. Sci., Paris !897, 125, 218, 283) reported on the lethal effect of human sweat administered intravenously in dogs. At a dose of 15 ml/kg, one certainly needed much sweat to achieve a positive result. The belief in the toxicity of sweat grew and it was also asserted that sweat resulting from severe muscular effort and fatigue was particularly toxic. The present authors pursued their studies in mice. In the first experiment one of the authors provided all the sweat. Sweat produced at rest did not prove lethal in volumes of 0.3-1-0 ml, care being taken to render the sweat isotonic by adding 4 g NaCl/l. Sweat produced in a fatigued state was concentrated up to 5 times in a desiccator and 1 ml injected into each mouse was without apparent effect. Experiments followed with sweat from other subjects, both rested and fatigued" one sample killed 4 out of 5 mice and another 5 out of 5. But these were isolated incidents. The authors suggest that early work had involved the injection of large volumes of hypotonic saline with attendant massive haemolyses that had caused the deaths of the animals. [It now only remains for someone to carry out repeated subcutaneous injections in rats to prove that sweat is carcinogenic.] 520. Guinea-pig sensitization by milk proteins Cole, W. Q. & Dees, Susan C. (1963). Allergenic properties of milk and milk proteins. A study of anaphylaxis in guinea pigs. J. Pediat. 63, 256. Advantage was taken of the opportunity afforded by the introduction of a new milk preparation S-26, containing demineralized whey, to study cross reactions between S-26, two standard forms of milk (skimmed milk and evaporated milk); the proteins of demineralized whey and protein fractions in unheated milk (casein, c~-lactalbumin,/3-1actoglobulin arid bovine immune globulin). Separate groups of~guinea-pigs were sensitized either with one or other milk preparation or with one of the protein fractions. Three weeks later, a number of animals in each group were challenged with a small intravenous dose of another milk product or protein fraction.
NATURAL PRODUCTS
285
The largest number of reactions occurred in animals sensitized with one milk product when challenged by a dose of another form of milk. In this group were also the largest number of deaths from anaphylactic shock. Next in order was the group of animals sensitized with casein and challenged with one of the milk preparations. The group of animals sensitized with ~-lactalbumin had twice as many reactions as the group sensitized with/~lactoglobulin. Casein and ,-lactalbumin have a high heat resistance. It is probable that the heating processes involved in the preparation of these milk products are insufficient to affect appreciably the stability of these proteins and it is likely that these two protein fractions are chiefly responsible for the allergic potentialities of cow's milk./~-Lactoglobulin is much less resistant to heat but it is considered that sufficient remains after processing to contribute to this undesirable effect. It is emphasized that these results are not directly applicable to human reactions to these proteins and that they need to be confirmed in larger groups of animals, using varied dosage schedules and additional immunological techniques. [This field abounds in old wives' tales and many of the old wives were scientists whose methods were not sensitive enough to establish the true facts. Advances in immunology have made it imperative to retrace all the steps by which our present-day ideas on milk have been arrived at.] 521. Penicillin in milk Eberhart, R. J., Watrous, Jr., G. H., Hokanson, J. F. & Butch, (3. E. (1963). Persistence of antibacterial agents in milk after intramammary treatment of clinical mastitis. J. Amer. vet. reed. Ass. 143, 390. Hokanson, J. F., Watrous, Jr., (3. H., Butch, G. & Eberhart, R. J. (1963). Persistence of antibacterial agents in milk after intravenous treatment of acute bovine mastitis, ibid 143, 395. Contamination of milk for human consumption by antibacterial agents has been of concern to public health authorities and to the dairy industry. These drugs, especially penicillin, are known to be capable of provoking an allergic reaction in susceptible individuals while their presence in milk interferes with the manufacture of cultured dairy products. Administration of these agents to affected cows by most routes contaminates milk but perhaps the most common means of contamination is through intramammary infusion for the treatment of clinical mastitis. It is usually held that by 72 hr after the last administration, the level of antibacterial agent in milk is negligible. Previous reports, however, have shown that these drugs may persist much longer than this guideline (Albright et al. J. Amer. vet. med. Ass. 1961, 138, 70; Blobel, ibid 1960, 137, I10; Fincher et al. ibid 1962, 141, 223). In the first part of the present study the persistence of antibacterial agents in milk was investigated after intramammary infusion for clinical mastitis. Groups of 5-6 cows were treated by methods and at dose levels commonly employed by veterinary practitioners. The presence of the antibacterial agent was determined by the FDA rapid disc assay method, using whey agar as the medium. It was found that the maximum time after the last treatment that bacterial inhibition was detected in bucket samples was: 24-36 hr after potassium penicillin (3, 48-72 hr after potassium penicillin (3 in oily suspension, 24-132 hr after 100,000 U. penicillin and 250 mg dihydrostreptomycin in water, 60-120 hr after commercial antibiotic combination. No bacterial inhibition was detected in bucket samples after treatment with 60 mg of nitrofurazone, and in view of the fact that within 12 hr this drug disappears from milk taken from the treated quarter, doubts arise about its therapeutic efficacy. These results indicate the existence of a striking variation among individual cows. Drugs
NATURAL PRODUCTS
Another approach was the formation of art addition complex of aescin with the flavone derivative hesperidin, as demonstrated by physical measurements of the compressibility of a surface film in a Langmuir trough. Judging by the pharmacological action of aescin in rats it was concluded that an absorption of 5-10 70 of orally administered material had been achieved.
518. A well-known toxicant Langg~rd, H. & Smith, W. O. (1962). Self-induced water intoxication without predisposing illness, Report of two cases. New Engl. J. Med. 266, 378. Two cases of so-called "pure water intoxication" are described. " P u r e " refers here to the intoxication, not the water (H20); in other words there was no predisposing or contributory illness to bring about a metabolic disturbance. The patients simply drank themselves into the intoxicated state, at the rate of 10-20 1 and 5-12 1 H20 daily. The outstanding features of the condition were neurological disturbances, including convulsions and coma. It need hardly be added that both instances occurred in inmates of mental hospitals. Nevertheless one cannot but view with alarm the widespread use of a chemical that appears to have practically no margin of safety at all.]
519. Toxicity of sweat Lac0ur, J. R. & Cier, J. F. (1963). La toxicit~ de la sueur humaine. C.R. Soc. Biol., Paris 157, 1017. In 1897 Arloing (C.R. Acad. Sci., Paris !897, 125, 218, 283) reported on the lethal effect of human sweat administered intravenously in dogs. At a dose of 15 ml/kg, one certainly needed much sweat to achieve a positive result. The belief in the toxicity of sweat grew and it was also asserted that sweat resulting from severe muscular effort and fatigue was particularly toxic. The present authors pursued their studies in mice. In the first experiment one of the authors provided all the sweat. Sweat produced at rest did not prove lethal in volumes of 0.3-1-0 ml, care being taken to render the sweat isotonic by adding 4 g NaCl/l. Sweat produced in a fatigued state was concentrated up to 5 times in a desiccator and 1 ml injected into each mouse was without apparent effect. Experiments followed with sweat from other subjects, both rested and fatigued" one sample killed 4 out of 5 mice and another 5 out of 5. But these were isolated incidents. The authors suggest that early work had involved the injection of large volumes of hypotonic saline with attendant massive haemolyses that had caused the deaths of the animals. [It now only remains for someone to carry out repeated subcutaneous injections in rats to prove that sweat is carcinogenic.] 520. Guinea-pig sensitization by milk proteins Cole, W. Q. & Dees, Susan C. (1963). Allergenic properties of milk and milk proteins. A study of anaphylaxis in guinea pigs. J. Pediat. 63, 256. Advantage was taken of the opportunity afforded by the introduction of a new milk preparation S-26, containing demineralized whey, to study cross reactions between S-26, two standard forms of milk (skimmed milk and evaporated milk); the proteins of demineralized whey and protein fractions in unheated milk (casein, c~-lactalbumin,/3-1actoglobulin arid bovine immune globulin). Separate groups of~guinea-pigs were sensitized either with one or other milk preparation or with one of the protein fractions. Three weeks later, a number of animals in each group were challenged with a small intravenous dose of another milk product or protein fraction.
NATURAL PRODUCTS
285
The largest number of reactions occurred in animals sensitized with one milk product when challenged by a dose of another form of milk. In this group were also the largest number of deaths from anaphylactic shock. Next in order was the group of animals sensitized with casein and challenged with one of the milk preparations. The group of animals sensitized with ~-lactalbumin had twice as many reactions as the group sensitized with/~lactoglobulin. Casein and ,-lactalbumin have a high heat resistance. It is probable that the heating processes involved in the preparation of these milk products are insufficient to affect appreciably the stability of these proteins and it is likely that these two protein fractions are chiefly responsible for the allergic potentialities of cow's milk./~-Lactoglobulin is much less resistant to heat but it is considered that sufficient remains after processing to contribute to this undesirable effect. It is emphasized that these results are not directly applicable to human reactions to these proteins and that they need to be confirmed in larger groups of animals, using varied dosage schedules and additional immunological techniques. [This field abounds in old wives' tales and many of the old wives were scientists whose methods were not sensitive enough to establish the true facts. Advances in immunology have made it imperative to retrace all the steps by which our present-day ideas on milk have been arrived at.] 521. Penicillin in milk Eberhart, R. J., Watrous, Jr., G. H., Hokanson, J. F. & Butch, (3. E. (1963). Persistence of antibacterial agents in milk after intramammary treatment of clinical mastitis. J. Amer. vet. reed. Ass. 143, 390. Hokanson, J. F., Watrous, Jr., (3. H., Butch, G. & Eberhart, R. J. (1963). Persistence of antibacterial agents in milk after intravenous treatment of acute bovine mastitis, ibid 143, 395. Contamination of milk for human consumption by antibacterial agents has been of concern to public health authorities and to the dairy industry. These drugs, especially penicillin, are known to be capable of provoking an allergic reaction in susceptible individuals while their presence in milk interferes with the manufacture of cultured dairy products. Administration of these agents to affected cows by most routes contaminates milk but perhaps the most common means of contamination is through intramammary infusion for the treatment of clinical mastitis. It is usually held that by 72 hr after the last administration, the level of antibacterial agent in milk is negligible. Previous reports, however, have shown that these drugs may persist much longer than this guideline (Albright et al. J. Amer. vet. med. Ass. 1961, 138, 70; Blobel, ibid 1960, 137, I10; Fincher et al. ibid 1962, 141, 223). In the first part of the present study the persistence of antibacterial agents in milk was investigated after intramammary infusion for clinical mastitis. Groups of 5-6 cows were treated by methods and at dose levels commonly employed by veterinary practitioners. The presence of the antibacterial agent was determined by the FDA rapid disc assay method, using whey agar as the medium. It was found that the maximum time after the last treatment that bacterial inhibition was detected in bucket samples was: 24-36 hr after potassium penicillin (3, 48-72 hr after potassium penicillin (3 in oily suspension, 24-132 hr after 100,000 U. penicillin and 250 mg dihydrostreptomycin in water, 60-120 hr after commercial antibiotic combination. No bacterial inhibition was detected in bucket samples after treatment with 60 mg of nitrofurazone, and in view of the fact that within 12 hr this drug disappears from milk taken from the treated quarter, doubts arise about its therapeutic efficacy. These results indicate the existence of a striking variation among individual cows. Drugs