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STREPTOCOCCAL SAGA
1163
questioned, the physician may regard them as " refractory " cases and resort to intramuscular or intravenous iron preparations. There are various ways of minimising these side-effects. The most usual is to insist that the iron tablets are taken with meals, but FRANKLIN et al. point out that this reduces the effectiveness of the iron preparation. Another way has been to use organic instead of inorganic iron salts-e.g., ferrous gluconate O’SULLIVAN or succinate instead of ferrous sulphate. et al.7 showed that the relative freedom from side-effects of the organic salts was due to the fact that they contain less iron. Where equal iron doses were given under comparable conditions, all these ferrous salts were about equally effective; and the troublesome side-effects affected about 13% of their patients, whichever iron preparation was used. The ferric salts are better tolerated so long as the dose is kept down, but they are definitely less effective and treatment takes longer. FRANKLIN et al. have lately described their results with an oral chelated-iron compound. Chelation has been used before, but mainly to try to prepare safe and effective parenteral iron drugs. WILL and VILTERused sodium iron edetate, a chelated compound, as an oral substitute for ferrous sulphate; they found that it released iron satisfactorily and was notably free from unpleasant side-effects; but interchange between iron and calcium occurs with this compound, and, though the effect is small, it is probably best avoided. The complex used by FRANKLIN et al. was an iron choline citrate containing 12-5% of elemental iron-about the same as in ferrous gluconate (11-5% Fe). This compound was put up in tablets containing 40 mg. of iron, and three to six tablets a day were given between meals. In 18 patients receiving 160 mg. Fe daily as iron choline citrate, the average
haemoglobin gain per day
0- 14 g. per 100 ml. the figure obtained by
Franklin, M., Rohse, W. G.,
tablets of 0-2 g. ferrous sulphate or four tablets of 0-3 g. ferrous gluconate daily. The 10% or so of patients who get gastrointestinal upsets with these drugs can be given ferrous fumarate or succinate or larger doses of a ferric hydroxide preparation, though they may still get symptoms with these alternatives. These difficult patients and those who do not respond to oral iron can be treated with the intramuscular iron-dextran compounds, which have gained deserved popularity. GRIMES and HUTT9 have shown that almost all the absorbed iron given in this way is utilised for haemoglobin formation; but only 60% of an injected dose is absorbed quickly, the remainder being absorbed slowly over a period of perhaps four weeks. EVANS and RAMSAY,1° studying absorption of iron-dextran in pregnancy, found evidence of maximum absorption from the injection site in ten to twenty days, 80% absorption within three weeks, and residual absorption for as long as six months. These results indicate that intramuscular iron-dextran is an efficient way of giving iron; but, to allow for the relatively slow absorption of 40% of the injected dose, it is customary to allow 40 mg. of iron for every haemoglobin deficit. With such a scheme every patient with irondeficiency anaemia should respond to treatment; if they do not the diagnosis may not be correct, and the patient should be referred to the nearest suitable clinic without
delay.
a
Annotations
was
-which is of the same order as O’SULLIVAN et al. for ferrous gluconate or sulphate. None of these 18 patients complained of gastrointestinal upsets. A larger group of 88 patients in hospital were given two tablets three times daily (240 mg. Fe) and 6 complained of mild nausea, diarrhoea, or constipation; the therapy was continued despite these symptoms, and they soon disappeared. Animal experiments indicate that the choline citrate complex was less toxic than ferrous sulphate or gluconate. This chelated-iron complex may well have therapeutic possibilities, and enable us to reduce still further the number of patients who have to be given parenteral iron. How widely iron choline citrate is used may depend on its cost. Ferrous sulphate is very cheap; ferrous gluconate costs about five times as much as sulphate; ferrous succinate and fumarate still more. Parenteral treatment is still considerably more expensive than oral treatment. It would clearly be uneconomic to substitute an expensive iron compound just to eliminate the side-effects that involve 13% of patients, but chelated iron may reasonably be kept in reserve for intolerant patients. Every doctor sees patients with iron-deficiency 6.
anaemia; and, nowadays, every doctor can have a scheme for treating them satisfactorily. Most of the patients will respond to oral iron, and, as O’SULLIVAN et al. showed, relatively small doses yielding about 210 mg. elemental iron a day are sufficient; this means three
de la Huerga, J., Kemp, C. R. J. Amer. med. Ass. 1958, 166, 1685. 7. O’Sullivan, D. J., Higgins, P. G., Wilkinson, J. F. Lancet, 1955, ii, 482. 8. Will, J. J., Vilter, R. R. J. Lab. clin. Med. 1954, 44, 499.
STREPTOCOCCAL SAGA
THE severity and frequency of streptococcal respiratory infections seem to be slowly declining, at any rate in Great Britain; and the decrease is especially noticeable in regard to rheumatic fever. Much useful epidemiological information has been derived from American studies on the prevention and treatment of streptococcal pharyngitis, and in particular on the transmission of group-A streptococci 11; and some of the difficulties which may hinder attempts to eradicate epidemic strains of streptococci by the use of penicillin prophylaxis have recently been discussed by Frank.12 In the American army extensive bacteriological studies have been carried out in a streptococcaldisease-control programme, prompted chiefly by the high incidence in this population of rheumatic fever, following upper respiratory infections with group-A streptococci. This incidence-about 3 per 100 streptococcal infections 13 is considerably higher than would be expected in, say, British schoolchildren similarly convalescent. Holmes and Williams 14 at the Streptococcal Reference Laboratory, Colindale, have made a valuable long-term investigation of streptococcal disease in a large residential home for children. 9. Grimes, A. J., Hutt, M. S. R. Brit. med. J. 1957, ii, 1074. 10. Evans, L. A. J., Ramsay, N. W. Lancet, 1957, ii, 1192. 11. Perry, W. D., Siegel, A. C., Rammelkamp, C. H., Wannamaker, L. W., Marple, E. C. Amer. J. Hyg. 1957, 66, 85, 96. 12. Frank, P. F. U.S. Forces med. J. 1958, 9, 543. 13. Rammelkamp, C. H., Wannamaker, L. W., Denny, F. W. Bull. N.Y. Acad. Med. 1952, 28, 321. 14. Holmes, M. C., Williams, R. E. G. J. Hyg., Camb. 1958, 56, 43.
1164 These workers studied 300-500 children living in a large Dr. Barnardo’s Home for thirty months, giving a total of about 12,500 child-months. During this period 473 sore throats were observed, of which 60% were streptococcal (group A). The overall attack-rate (1-9 streptococcal throat infections per 100 children per month) was very similar to that reported by Dingle et al.15 in a study of American families living at home (1-2 per 100 person-months), but the incidence of a streptococcal sore throat in the children increased with age; of the illnesses diagnosed as ’sore throat ’ the proportion yielding streptococci increased from about 34% in the 1-2-year-old group to about 74% in the children over 10 years old ". The influence of tonsillectomy on severity of streptococcal infections was found to be negligible. Most previous workers found a lower throat carriage-rate in tonsillectomised convalescent children than in others, and in previous work Holmes and Williams 16 found that this applied to both the throat and the nose carrier state; but in this latest survey they found that, while throat carrier-rates in convalescence decreased more rapidly when tonsils were out than when tonsils were in, the nasal carriage-rate was much higher in the tonsillectomised children both on admission and during convalescence. This is a puzzling point, which is related to the second part of the "
survey. an attempt was made to define the potential of infection among the incubating, the convalescent, and healthy carriers, classified as nasal or throat type. No similar study has been reported, and Holmes and Williams have devised a simple objective way of relating cases of sore throat to their recognised infected contacts. They were able to relate 94 out of 205 sore throats to their probable or possible contacts; of these two-thirds were heavy nasal carriers of streptococci, and the remainder about equally light nasal or throat-only carriers. This confirms the importance attached by Hamburger et al. 17 to nasal carriers as sources of infection. Holmes and Williams point out, however, that the importance of health carriers may have been overstressed, since both persons incubating streptococcal disease and convalescent carriers could also reasonably be incriminated as sources of infection, the numbers in each category equalling those of healthy carriers responsible for spread. No cases of rheumatic fever were observed among several hundred cases of streptococcal illness; nor was acute glomerulonephritis found despite 49 cases of infection with type-12 streptococcus. It looks as if the nature of streptococcal disease is undergoing a slow change, or at any rate is showing widening variation, which studies like this one help to define. We look forward to the concluding chapters of Holmes and Williams’ saga.
Here
sources
LONG-ACTING COUGH SUPPRESSANT
IT is often desirable to ensure the slow and steady release of an active drug from the gut. The simplest way of doing this is to take the drug after food. A recent valuable innovation is the use of capsules each containing the drug in the form of a large number of microspheres coated with a digestible wax in varying thicknesses.l8 A new principle has now been employed-the integration of the active drug in an ion-exchanging-resin complex. It 15. Dingle, J. H., Badger, G. F., Feller, A. E., Hodges, R. E., Jordan, W. S., Rammelkamp, C. H. Amer. J. Hyg., 1953, 58, 16. 16. Holmes, M. C., Williams, R. E. O. J. Hyg., Camb. 1954, 52, 165. 17. Hamburger, M., Green, M. J., Hamburger, V. G. J. infect. Dis. 1945,
77, 68, 96. 18. Thomson, T. J. Glasg. med. J. 1955, 48, 423.
is claimed that a drug given in this way is released from the resin at a slow and steady rate which is independent of the environmental pH and of enzyme activity.19 A preliminary report of a long-acting cough suppressant, in which dihydrocodeinone and the anti-histamine phenyltoloxamine are combined in a sulphonic resin complex, has been published. 20 The evaluation of cough suppressants is not always easy, and perhaps greater objectivity in the conduct of the trial might have strengthened the author’s case. But the preliminary results do suggest that this is a useful new approach. ZIRCONIUM GRANULOMAS
recorded 21 the appearance of a new and unique dermatological entity, first described by Rubin et al. in Chicago.22 23 This consisted of dusky reddishbrown discrete papules, 1-4 mm. in diameter, which were closely set in the domes of the axilla and more sparsely placed at the periphery. Histologically there were granulomas in the corium, composed of epithelioid cells and Langhans giant cells surrounded by lymphoThere was no cytes in typical tuberculoid pattern. of of the sort seen in sarcoidosis, tubercles delineation and no evidence of necrosis. Foreign bodies could not be detected by polaroscopic examination. The infiltrate lay along the course of blood-vessels. It was noted that these novel lesions appeared after the use of deodorant sticks which contained sodium zirconium lactate in addition to the commonly used ingredients. Rubin et al. were uncertain of the cause of this granulomatous eruptions but thought that the linear distribution of the lesions suggested razor abrasions. Further cases were soon described, always arising after the use of a deodorant containing zirconium salts. But zirconium seemed non-toxic,2! and there were no recorded instances of its having proved harmful in industry. In biopsy specimens from the axillary lesions no zirconium was found, even by such refined means as X-ray fluorescence and emission spectrometry.25 Many alternative causes were suggested, such as foreign-body reactions to the lipid vehicle of the deodorant stick 26 and inflammation as the result of extravasation of apocrine sweat.2’ Shelley and Hurley 28 have contributed a well-integrated review of 64 cases previously reported and 6 of their own. They find the clinical signs as well as the histological changes in the dermis to be strictly uniform and diagnostic. Most cases were in women, and most of them shaved their axillx. No one brand of deodorant stick was responsible. The eruption might follow a solitary use of the " zirconium stick " or appear only after it had been used daily for months. LAST year
we
Shelley and Hurley then conducted experiments to elucidate the role of zirconium. They instructed 30 healthy male volunteers to rub a standard commercial stick deodorant, containing 5% zirconium, vigorously into their left axilla every morning for five minutes. A zirconium-free but otherwise identical stick was rubbed daily into the right axilla for the same period. Both axillx were closely shaved every other day. None of the men had previously used zirconium stick 19. 20. 21. 22. 23. 24. 25.
26. 27. 28.
Abrahams, A., Linnell, W. H. Lancet, 1957, ii, 1317. Townsend, E. H. New Engl. J. Med. 1958, 258, 63. Lancet, 1957, i, 519. Weber, L. F., Neuhauser, I., Rubin, L., Slepyan, A. H., Shellow, H. J. Amer. med. Ass. 1956, 162, 65. Rubin, L., Slepyan, A. H., Weber, L. F., Neuhauser, I. ibid. p. 953. Harrison, J., Trabin, B., Martin, E. J. Pharmacol. 1951, 102, 179. Sheard, C., Cornia, F. E., Atkinson, S. C., Worthington, E. L. J. Amer. med. Ass. 1957, 164, 1085. Zimmermann, M. Arch. Derm., Chicago, 1957, 75, 766. Saunders, T. S. ibid. 1957, 76, 619. Shelley, W. B., Hurley, H. J. Brit. J. Derm. 1958, 70, 75.
questioned, the physician may regard them as " refractory " cases and resort to intramuscular or intravenous iron preparations. There are various ways of minimising these side-effects. The most usual is to insist that the iron tablets are taken with meals, but FRANKLIN et al. point out that this reduces the effectiveness of the iron preparation. Another way has been to use organic instead of inorganic iron salts-e.g., ferrous gluconate O’SULLIVAN or succinate instead of ferrous sulphate. et al.7 showed that the relative freedom from side-effects of the organic salts was due to the fact that they contain less iron. Where equal iron doses were given under comparable conditions, all these ferrous salts were about equally effective; and the troublesome side-effects affected about 13% of their patients, whichever iron preparation was used. The ferric salts are better tolerated so long as the dose is kept down, but they are definitely less effective and treatment takes longer. FRANKLIN et al. have lately described their results with an oral chelated-iron compound. Chelation has been used before, but mainly to try to prepare safe and effective parenteral iron drugs. WILL and VILTERused sodium iron edetate, a chelated compound, as an oral substitute for ferrous sulphate; they found that it released iron satisfactorily and was notably free from unpleasant side-effects; but interchange between iron and calcium occurs with this compound, and, though the effect is small, it is probably best avoided. The complex used by FRANKLIN et al. was an iron choline citrate containing 12-5% of elemental iron-about the same as in ferrous gluconate (11-5% Fe). This compound was put up in tablets containing 40 mg. of iron, and three to six tablets a day were given between meals. In 18 patients receiving 160 mg. Fe daily as iron choline citrate, the average
haemoglobin gain per day
0- 14 g. per 100 ml. the figure obtained by
Franklin, M., Rohse, W. G.,
tablets of 0-2 g. ferrous sulphate or four tablets of 0-3 g. ferrous gluconate daily. The 10% or so of patients who get gastrointestinal upsets with these drugs can be given ferrous fumarate or succinate or larger doses of a ferric hydroxide preparation, though they may still get symptoms with these alternatives. These difficult patients and those who do not respond to oral iron can be treated with the intramuscular iron-dextran compounds, which have gained deserved popularity. GRIMES and HUTT9 have shown that almost all the absorbed iron given in this way is utilised for haemoglobin formation; but only 60% of an injected dose is absorbed quickly, the remainder being absorbed slowly over a period of perhaps four weeks. EVANS and RAMSAY,1° studying absorption of iron-dextran in pregnancy, found evidence of maximum absorption from the injection site in ten to twenty days, 80% absorption within three weeks, and residual absorption for as long as six months. These results indicate that intramuscular iron-dextran is an efficient way of giving iron; but, to allow for the relatively slow absorption of 40% of the injected dose, it is customary to allow 40 mg. of iron for every haemoglobin deficit. With such a scheme every patient with irondeficiency anaemia should respond to treatment; if they do not the diagnosis may not be correct, and the patient should be referred to the nearest suitable clinic without
delay.
a
Annotations
was
-which is of the same order as O’SULLIVAN et al. for ferrous gluconate or sulphate. None of these 18 patients complained of gastrointestinal upsets. A larger group of 88 patients in hospital were given two tablets three times daily (240 mg. Fe) and 6 complained of mild nausea, diarrhoea, or constipation; the therapy was continued despite these symptoms, and they soon disappeared. Animal experiments indicate that the choline citrate complex was less toxic than ferrous sulphate or gluconate. This chelated-iron complex may well have therapeutic possibilities, and enable us to reduce still further the number of patients who have to be given parenteral iron. How widely iron choline citrate is used may depend on its cost. Ferrous sulphate is very cheap; ferrous gluconate costs about five times as much as sulphate; ferrous succinate and fumarate still more. Parenteral treatment is still considerably more expensive than oral treatment. It would clearly be uneconomic to substitute an expensive iron compound just to eliminate the side-effects that involve 13% of patients, but chelated iron may reasonably be kept in reserve for intolerant patients. Every doctor sees patients with iron-deficiency 6.
anaemia; and, nowadays, every doctor can have a scheme for treating them satisfactorily. Most of the patients will respond to oral iron, and, as O’SULLIVAN et al. showed, relatively small doses yielding about 210 mg. elemental iron a day are sufficient; this means three
de la Huerga, J., Kemp, C. R. J. Amer. med. Ass. 1958, 166, 1685. 7. O’Sullivan, D. J., Higgins, P. G., Wilkinson, J. F. Lancet, 1955, ii, 482. 8. Will, J. J., Vilter, R. R. J. Lab. clin. Med. 1954, 44, 499.
STREPTOCOCCAL SAGA
THE severity and frequency of streptococcal respiratory infections seem to be slowly declining, at any rate in Great Britain; and the decrease is especially noticeable in regard to rheumatic fever. Much useful epidemiological information has been derived from American studies on the prevention and treatment of streptococcal pharyngitis, and in particular on the transmission of group-A streptococci 11; and some of the difficulties which may hinder attempts to eradicate epidemic strains of streptococci by the use of penicillin prophylaxis have recently been discussed by Frank.12 In the American army extensive bacteriological studies have been carried out in a streptococcaldisease-control programme, prompted chiefly by the high incidence in this population of rheumatic fever, following upper respiratory infections with group-A streptococci. This incidence-about 3 per 100 streptococcal infections 13 is considerably higher than would be expected in, say, British schoolchildren similarly convalescent. Holmes and Williams 14 at the Streptococcal Reference Laboratory, Colindale, have made a valuable long-term investigation of streptococcal disease in a large residential home for children. 9. Grimes, A. J., Hutt, M. S. R. Brit. med. J. 1957, ii, 1074. 10. Evans, L. A. J., Ramsay, N. W. Lancet, 1957, ii, 1192. 11. Perry, W. D., Siegel, A. C., Rammelkamp, C. H., Wannamaker, L. W., Marple, E. C. Amer. J. Hyg. 1957, 66, 85, 96. 12. Frank, P. F. U.S. Forces med. J. 1958, 9, 543. 13. Rammelkamp, C. H., Wannamaker, L. W., Denny, F. W. Bull. N.Y. Acad. Med. 1952, 28, 321. 14. Holmes, M. C., Williams, R. E. G. J. Hyg., Camb. 1958, 56, 43.
1164 These workers studied 300-500 children living in a large Dr. Barnardo’s Home for thirty months, giving a total of about 12,500 child-months. During this period 473 sore throats were observed, of which 60% were streptococcal (group A). The overall attack-rate (1-9 streptococcal throat infections per 100 children per month) was very similar to that reported by Dingle et al.15 in a study of American families living at home (1-2 per 100 person-months), but the incidence of a streptococcal sore throat in the children increased with age; of the illnesses diagnosed as ’sore throat ’ the proportion yielding streptococci increased from about 34% in the 1-2-year-old group to about 74% in the children over 10 years old ". The influence of tonsillectomy on severity of streptococcal infections was found to be negligible. Most previous workers found a lower throat carriage-rate in tonsillectomised convalescent children than in others, and in previous work Holmes and Williams 16 found that this applied to both the throat and the nose carrier state; but in this latest survey they found that, while throat carrier-rates in convalescence decreased more rapidly when tonsils were out than when tonsils were in, the nasal carriage-rate was much higher in the tonsillectomised children both on admission and during convalescence. This is a puzzling point, which is related to the second part of the "
survey. an attempt was made to define the potential of infection among the incubating, the convalescent, and healthy carriers, classified as nasal or throat type. No similar study has been reported, and Holmes and Williams have devised a simple objective way of relating cases of sore throat to their recognised infected contacts. They were able to relate 94 out of 205 sore throats to their probable or possible contacts; of these two-thirds were heavy nasal carriers of streptococci, and the remainder about equally light nasal or throat-only carriers. This confirms the importance attached by Hamburger et al. 17 to nasal carriers as sources of infection. Holmes and Williams point out, however, that the importance of health carriers may have been overstressed, since both persons incubating streptococcal disease and convalescent carriers could also reasonably be incriminated as sources of infection, the numbers in each category equalling those of healthy carriers responsible for spread. No cases of rheumatic fever were observed among several hundred cases of streptococcal illness; nor was acute glomerulonephritis found despite 49 cases of infection with type-12 streptococcus. It looks as if the nature of streptococcal disease is undergoing a slow change, or at any rate is showing widening variation, which studies like this one help to define. We look forward to the concluding chapters of Holmes and Williams’ saga.
Here
sources
LONG-ACTING COUGH SUPPRESSANT
IT is often desirable to ensure the slow and steady release of an active drug from the gut. The simplest way of doing this is to take the drug after food. A recent valuable innovation is the use of capsules each containing the drug in the form of a large number of microspheres coated with a digestible wax in varying thicknesses.l8 A new principle has now been employed-the integration of the active drug in an ion-exchanging-resin complex. It 15. Dingle, J. H., Badger, G. F., Feller, A. E., Hodges, R. E., Jordan, W. S., Rammelkamp, C. H. Amer. J. Hyg., 1953, 58, 16. 16. Holmes, M. C., Williams, R. E. O. J. Hyg., Camb. 1954, 52, 165. 17. Hamburger, M., Green, M. J., Hamburger, V. G. J. infect. Dis. 1945,
77, 68, 96. 18. Thomson, T. J. Glasg. med. J. 1955, 48, 423.
is claimed that a drug given in this way is released from the resin at a slow and steady rate which is independent of the environmental pH and of enzyme activity.19 A preliminary report of a long-acting cough suppressant, in which dihydrocodeinone and the anti-histamine phenyltoloxamine are combined in a sulphonic resin complex, has been published. 20 The evaluation of cough suppressants is not always easy, and perhaps greater objectivity in the conduct of the trial might have strengthened the author’s case. But the preliminary results do suggest that this is a useful new approach. ZIRCONIUM GRANULOMAS
recorded 21 the appearance of a new and unique dermatological entity, first described by Rubin et al. in Chicago.22 23 This consisted of dusky reddishbrown discrete papules, 1-4 mm. in diameter, which were closely set in the domes of the axilla and more sparsely placed at the periphery. Histologically there were granulomas in the corium, composed of epithelioid cells and Langhans giant cells surrounded by lymphoThere was no cytes in typical tuberculoid pattern. of of the sort seen in sarcoidosis, tubercles delineation and no evidence of necrosis. Foreign bodies could not be detected by polaroscopic examination. The infiltrate lay along the course of blood-vessels. It was noted that these novel lesions appeared after the use of deodorant sticks which contained sodium zirconium lactate in addition to the commonly used ingredients. Rubin et al. were uncertain of the cause of this granulomatous eruptions but thought that the linear distribution of the lesions suggested razor abrasions. Further cases were soon described, always arising after the use of a deodorant containing zirconium salts. But zirconium seemed non-toxic,2! and there were no recorded instances of its having proved harmful in industry. In biopsy specimens from the axillary lesions no zirconium was found, even by such refined means as X-ray fluorescence and emission spectrometry.25 Many alternative causes were suggested, such as foreign-body reactions to the lipid vehicle of the deodorant stick 26 and inflammation as the result of extravasation of apocrine sweat.2’ Shelley and Hurley 28 have contributed a well-integrated review of 64 cases previously reported and 6 of their own. They find the clinical signs as well as the histological changes in the dermis to be strictly uniform and diagnostic. Most cases were in women, and most of them shaved their axillx. No one brand of deodorant stick was responsible. The eruption might follow a solitary use of the " zirconium stick " or appear only after it had been used daily for months. LAST year
we
Shelley and Hurley then conducted experiments to elucidate the role of zirconium. They instructed 30 healthy male volunteers to rub a standard commercial stick deodorant, containing 5% zirconium, vigorously into their left axilla every morning for five minutes. A zirconium-free but otherwise identical stick was rubbed daily into the right axilla for the same period. Both axillx were closely shaved every other day. None of the men had previously used zirconium stick 19. 20. 21. 22. 23. 24. 25.
26. 27. 28.
Abrahams, A., Linnell, W. H. Lancet, 1957, ii, 1317. Townsend, E. H. New Engl. J. Med. 1958, 258, 63. Lancet, 1957, i, 519. Weber, L. F., Neuhauser, I., Rubin, L., Slepyan, A. H., Shellow, H. J. Amer. med. Ass. 1956, 162, 65. Rubin, L., Slepyan, A. H., Weber, L. F., Neuhauser, I. ibid. p. 953. Harrison, J., Trabin, B., Martin, E. J. Pharmacol. 1951, 102, 179. Sheard, C., Cornia, F. E., Atkinson, S. C., Worthington, E. L. J. Amer. med. Ass. 1957, 164, 1085. Zimmermann, M. Arch. Derm., Chicago, 1957, 75, 766. Saunders, T. S. ibid. 1957, 76, 619. Shelley, W. B., Hurley, H. J. Brit. J. Derm. 1958, 70, 75.