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Oral dosing of antimonials against Schistosoma mansoni
CORRESPONDENCE
291
ORAL DOSING OF ANTIMONIALS AGAINST SCHISTOSOMA MANSONI SIR,--Potassium antimony tartrate (KSb tartrate), tartar emetic, the simplest of the antimonials used for treating schistosomiasis, is given by intravenous injection because oral doses or intramuscular injection produce unacceptable side effects. Using coated preparations MAO et al. (1959) claimed that oral tartar emetic was effective against Schistosoma juponicum in man, but FOR~YTH and SIMPSON (1961) were unable to cure infections of S. haematobium using a similar regime. FRIEDHEIM (1953) used oral MSbB against Trypanosoma gambiense in man with some success, although he has stated (FRIEDHEIM, 1973) that tartar emetic is poorly absorbed from the human intestinal tract, but well absorbed by mice and therefore effective against S. mansoni in this species. Our own observations demonstrate that orally administered KSb tartrate is much safer and therefore more effective in mice than that given by intraperitoneal injection. White mice (Alderley Park strain) infected 7 weeks previously by paddling in water containing S. mansoni cercariae (Wellcome strain, 140 cercariae/mouse) were dosed on 5 successive days with KSb tartrate (B.D.H. Ltd.) and postmortemed 10 days after the last dose. The mean numbers of worms recovered from ten mice receiving 5 daily intraperitoneal injections of KSb tartrate at 25 mg./kg. was 16.9 ( & S.E. 3.0) compared with 24.9 ( I-t S.E. 3.4) in controls, giving a 32% reduction in worm load. At double this dose KSb tartrate killed all the mice. By contrast a regimen of 5 daily doses of KSb tartrate administered orally was tolerated up to 300 mg./kg. but was toxic at 400 mg./kg. Numbers of worms found were 24.2 (& S.E. 2.9) at 25 mg./kg., 11.5 (f S.E. 2.2) at 50 mg./kg., 3.9 (+ S.E. 1.5) at 100 mg./kg., 1.8 (+ S.E. 0.9) at 200 mg./kg. and 0.5 ( f S.E. 0.2) at 300 mg./kg., giving cure rates of 3, 54, 84, 93 and 98% respectively. STANDEN (1955) found 7 out of 10 mice survived intraperitoneal KSb tartrate injections (35 mg./kg. x 5) and there was a 64% reduction in worm load. Using oral KSb tartrate STOHLER and FREY (1963) found a 42% removal of worms with 80 mg./kg. x 5 and reported an LD,, of 180 mg./kg. x 5 in mice, a value considerably below our present findings. In view of the relative cheapness of antimonials it is surprising that more work has not been performed, using suitably coated preparations, on the oral treatment of Schistosoma sp. in primates to see if there is any antimony derivative that would be both adequately tolerated and active. I wish to thank Miss J. J. Selby for technical assistance. I am, etc., G.C.COLES, Imperial Chemical Industries Ltd., Pharmaceuticals Division, Alderley Park, Macclesfield, 30 December, 1974. Cheshire, SK10 4TG. REFERENCES FORSYTH, D. M. & SIMPSON, W. T. (1961). Ann. trop. Med. Parasit., 55, 410. FRIEDHEIM, E. A. (1953). Ibid., 47, 350. (1973). In Chemotherapy of Helminthiasis, Vol. 1, p. 29. Ed. Cavier, R. & Hawking, F. Oxford: Pergamon Press. MAO,Y. C., SHJIN, S. C., Tu, C. K., FANG, K. Y., SHEN, K. S., CHOU, S. N. & HUANG, C. Y.(1959). Chin. med. J., 79, 532. STANDEN, 0. D. (1955). Ann. trop. Med. Parasit., 49, 183. STOHLER, H. R. & FREY, J. R. (1963). Ibid., 57, 466.
MULTIPLE THICK FILMS ON THE SAME SLIDE SIR,-At times when slides and stains are in short supply conservation becomes necessary. The following simnle technique moved of value on two such occasions in Ethionia. first in 1941 in Soddu (in 4th (Gold Coast) Field Ambulance), during the 2nd World War, and recently, from December 1973, ‘to February, 1974, in Wollo Province (under the Ethiopian Medical Action for famine relief). A drop of a patient’s blood is transferred, by apposition of the pricked finger, to a slide as near one end as possible, and spread by the needle to a diameter of about 5 mm. Further individuals’ samples are similarly applied in close sequence, the films being numerically recorded on the slide by grease pencil and in the patients’ notes. A total of 10 to 14 films can be assembled in this manner. The slide containing the dried films is covered with buffered water, which is allowed to stand until haemolysis is complete, any loss being reconstituted. About 5 drops of Giemsa stain are then added and the slide oscillated to ensure uniform distribution. After a further 20 minutes the stain is gently washed away and the slide placed at an angle to dry. It is then a simple matter to examine successive films without the necessity for removing the slide or inserting fresh oil, with enormous saving of slides, stain, buffered water and labour; it takes only a few seconds to switch from one film to the next, and only about half an hour to examine the whole slide. It was common to find several positive films (10 out of 14 on one occasion) on one slide. These included heavy infections of Plasmodium falcibarum rings. P. vivax tronhozoites and. narticularlv in Soddu HURTERS. 1942), Borrelia recurrentis. One-film showed &-unusual preponderance oi k. falcipa&m gametocytes (6 per high power field).
291
ORAL DOSING OF ANTIMONIALS AGAINST SCHISTOSOMA MANSONI SIR,--Potassium antimony tartrate (KSb tartrate), tartar emetic, the simplest of the antimonials used for treating schistosomiasis, is given by intravenous injection because oral doses or intramuscular injection produce unacceptable side effects. Using coated preparations MAO et al. (1959) claimed that oral tartar emetic was effective against Schistosoma juponicum in man, but FOR~YTH and SIMPSON (1961) were unable to cure infections of S. haematobium using a similar regime. FRIEDHEIM (1953) used oral MSbB against Trypanosoma gambiense in man with some success, although he has stated (FRIEDHEIM, 1973) that tartar emetic is poorly absorbed from the human intestinal tract, but well absorbed by mice and therefore effective against S. mansoni in this species. Our own observations demonstrate that orally administered KSb tartrate is much safer and therefore more effective in mice than that given by intraperitoneal injection. White mice (Alderley Park strain) infected 7 weeks previously by paddling in water containing S. mansoni cercariae (Wellcome strain, 140 cercariae/mouse) were dosed on 5 successive days with KSb tartrate (B.D.H. Ltd.) and postmortemed 10 days after the last dose. The mean numbers of worms recovered from ten mice receiving 5 daily intraperitoneal injections of KSb tartrate at 25 mg./kg. was 16.9 ( & S.E. 3.0) compared with 24.9 ( I-t S.E. 3.4) in controls, giving a 32% reduction in worm load. At double this dose KSb tartrate killed all the mice. By contrast a regimen of 5 daily doses of KSb tartrate administered orally was tolerated up to 300 mg./kg. but was toxic at 400 mg./kg. Numbers of worms found were 24.2 (& S.E. 2.9) at 25 mg./kg., 11.5 (f S.E. 2.2) at 50 mg./kg., 3.9 (+ S.E. 1.5) at 100 mg./kg., 1.8 (+ S.E. 0.9) at 200 mg./kg. and 0.5 ( f S.E. 0.2) at 300 mg./kg., giving cure rates of 3, 54, 84, 93 and 98% respectively. STANDEN (1955) found 7 out of 10 mice survived intraperitoneal KSb tartrate injections (35 mg./kg. x 5) and there was a 64% reduction in worm load. Using oral KSb tartrate STOHLER and FREY (1963) found a 42% removal of worms with 80 mg./kg. x 5 and reported an LD,, of 180 mg./kg. x 5 in mice, a value considerably below our present findings. In view of the relative cheapness of antimonials it is surprising that more work has not been performed, using suitably coated preparations, on the oral treatment of Schistosoma sp. in primates to see if there is any antimony derivative that would be both adequately tolerated and active. I wish to thank Miss J. J. Selby for technical assistance. I am, etc., G.C.COLES, Imperial Chemical Industries Ltd., Pharmaceuticals Division, Alderley Park, Macclesfield, 30 December, 1974. Cheshire, SK10 4TG. REFERENCES FORSYTH, D. M. & SIMPSON, W. T. (1961). Ann. trop. Med. Parasit., 55, 410. FRIEDHEIM, E. A. (1953). Ibid., 47, 350. (1973). In Chemotherapy of Helminthiasis, Vol. 1, p. 29. Ed. Cavier, R. & Hawking, F. Oxford: Pergamon Press. MAO,Y. C., SHJIN, S. C., Tu, C. K., FANG, K. Y., SHEN, K. S., CHOU, S. N. & HUANG, C. Y.(1959). Chin. med. J., 79, 532. STANDEN, 0. D. (1955). Ann. trop. Med. Parasit., 49, 183. STOHLER, H. R. & FREY, J. R. (1963). Ibid., 57, 466.
MULTIPLE THICK FILMS ON THE SAME SLIDE SIR,-At times when slides and stains are in short supply conservation becomes necessary. The following simnle technique moved of value on two such occasions in Ethionia. first in 1941 in Soddu (in 4th (Gold Coast) Field Ambulance), during the 2nd World War, and recently, from December 1973, ‘to February, 1974, in Wollo Province (under the Ethiopian Medical Action for famine relief). A drop of a patient’s blood is transferred, by apposition of the pricked finger, to a slide as near one end as possible, and spread by the needle to a diameter of about 5 mm. Further individuals’ samples are similarly applied in close sequence, the films being numerically recorded on the slide by grease pencil and in the patients’ notes. A total of 10 to 14 films can be assembled in this manner. The slide containing the dried films is covered with buffered water, which is allowed to stand until haemolysis is complete, any loss being reconstituted. About 5 drops of Giemsa stain are then added and the slide oscillated to ensure uniform distribution. After a further 20 minutes the stain is gently washed away and the slide placed at an angle to dry. It is then a simple matter to examine successive films without the necessity for removing the slide or inserting fresh oil, with enormous saving of slides, stain, buffered water and labour; it takes only a few seconds to switch from one film to the next, and only about half an hour to examine the whole slide. It was common to find several positive films (10 out of 14 on one occasion) on one slide. These included heavy infections of Plasmodium falcibarum rings. P. vivax tronhozoites and. narticularlv in Soddu HURTERS. 1942), Borrelia recurrentis. One-film showed &-unusual preponderance oi k. falcipa&m gametocytes (6 per high power field).