PHENOTHIAZINE AS AN ANTHELMINTHIC IN THREADWORM AND ROUNDWORM INFECTIONS

808

PHENOTHIAZINE AS AN ANTHELMINTHIC IN THREADWORM AND ROUNDWORM

INFECTIONS

BY PHILIP MANSON-BAHR, C.M.G., D.S.O., M.D. Camb., F.R.C.P. SENIOR PHYSICIAN TO THE HOSPITAL FOR TROPICAL

DISEASES, LONDON

(thiodiphenyl-amine) is a thiazine dye a large number of these substances, including thionol, Lauth’s violet and methylene blue. It is a fine, smooth, pale lemon-yellow powder, almost insoluble in water and almost tasteless, and melting sharply at 180° C. It was first prepared by Bernthsen in 1885, but no evidence of its parasiticidal properties was obtained until 1934, when Campbell and his colleagues reported on its toxicity for culicine larvx. As the result of a report of Knipling (1938) on the efficiency of the dye in preventing the development of horn-fly larvae in the fseces of cattle a trial was carried out by Taylor and Sanderson on pigs infected with ascaris at the veterinary laboratory of the Ministry of Agriculture, but In 1939 the dye no definite conclusions were arrived at. was found in Australia and Canada to be effective against strongyloid worms in sheep, and this was afterwards confirmed by Taylor and Sanderson (1940) for the Agricul* PHENOTHIAZINE

and the

parent

of

tural Research Council.*

,

Phenothiazine is highly effective against the strongyloids in the large intestines of animals, and is also toxic to stomach worms associated with parasitic gastritis, but it is less efficient in the small intestine. Domestic animals in general are remarkably tolerant to the drug, and there is a great difference between the therapeutic and toxic dose. Two sheep and a goat, as reported by Taylor and Sanderson, were dosed with eighty times the effective anthelminthic dose without any signs of intoxication. Repeated small doses are, however, considerably more toxic than occasional large ones. In animals a total dosage of 0-5 gramme per pound body-weight is safe, and on this basis a man of 12 st. could safely be given up to 84 g., but dosage of this magnitude is unnecessary. The dye is mostly excreted in the urine, which is tinged red 20-30 minutes after its administration ; it has been shown to act as a urinary antiseptic (Thomas et al. 1938, de Eds et al. 1939). HOOKWORMS, ROUNDWORMS, AND WHIPWOBMS I first began to use phenothiazine in the treatment of helminthic diseases in man a year ago when I had under my care Indian lascars infested with various species of nematodes in the Dreadnought Hospital, Greenwich, and the Albert Dock Hospital. Lately this clinical material has no longer been available, but I have been greatly assisted by general practitioners in finding suitable cases. Ancylostoma duodenale.-The largest single dose given was to a native Indian weighing 8 st., who received 40 g. Some difficulty was experienced in getting him to swallow the powder, which was made into a paste with’ syrup. Apart from the fact that he passed pink urine the dye had no apparent effect. Subsequently two other Indians heavily infested with Ancylostoma duodenale One were each given 30 g. on two successive days. EFFECT ON

-

*

In veterinary medicine phenothiazine is known under the trade name

of Phenovis.

DR. CHALMERS:

REFERENCES

Baker, H. M. (1927) J. Amer. med. Ass. 88, 1137. Dobriner, K. (1937) J. biol. Chem. 120, 115. and Rhoads, C. P. (1938) J. clin. Invest. 17, 95. Grotepass, W. (1937) Ned. Tijdschr. Geneesk. 81, 362. Kegel, A. H., McNally, W. D. and Pope, A. S. (1929) J. Amer. med. Ass. 93, 353. Lemberg, R. (1935) Biochem. J. 29, 1322. Rimington, C. (1938) C. R. Lab. Carlsberg, 22, 454. and Hemmings, A. W. (1939) Biochem. J. 33, 960. (1938) Lancet, 1, 710. and Goldblatt, M. W. (1940) Lancet. 1, 73. Roth, O. (1923) Rev. Suisse Accid. Trav. 17, 169. van den Bergh, A. A. H., Grotepass, W. and Revers, F. E. (1932) Klin. Wschr. 11, 1534. Watson, C. J. (1937) J. clin, Invest. 16, 383. and Clarke, W. O. (1937) Proc. Soc. exp. Biol., N.Y. 36, 65. —

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8 dead worms, but in the second there was no result. In both patients no hookworm eggs could be found in the faeces for three days after the last dose of phenothiazine, but they then reappeared ; subsequent treatment with oil of chenopodium and carbon tetrachloride removed the worms. It therefore seems clear that phenothiazine is ineffective for hookworms in the small intestine, and it should be noted that in animals also it has proved useless for worms in that part of the gut. Ascaris lumbricoides.-An attempt was next made to find the optimum dosage for roundworm infection in seven native patients (six Indians and one Egyptian) ; five had a double infection of roundworm and hookworm, and the other two a double infection of roundworm and the whipworm (Trichuri$trichiura). They received a total dosage ranging from 16 to 48 g., as follows : 4 g. daily for four days ; 6 g. daily for five days ; or 4 g. daily for four days followed by 8 g. daily for four days. Only one dead roundworm was recovered, and the drug had no effect on the whipworms. Soon an opportunity presented itself for treating 2 further Indians heavily infected with roundworms. In these 8 g. of phenothiazine in powder was exhibited on three consecutive mornings (24 g. in all), followed by 3 3 of sodium sulphate. The results were much more

passed

_

e

satisfactory. infection with roundworms, hookworms, and threadworms (egg-count : roundworm 314, hookworm 63, whipworm 20 eggs per 1 c.cm. offseces). After the second dose 9 dead roundworms (8 females and 1 male) and 21 dead threadworms were passed. The first 4 roundworms which appeared were stained bright red. Another female roundworm was passed after the third dose. On subsequent fsecal examination roundworm ova were absent, but hookworm and whipworm eggs were undiminished in number ; treatment with oil of chenopodium and carbon tetrachloride produced 53 dead hookworms. CASE 2.-Heavy infection with roundworms (egg-count 350 eggs per 1 c.cm. of faeces). After the second dose 10 males and 2 females were passed dead, of which the first 5 were stained red. On subsequent examinations ova were absent from the faeces. In neither of these cases were any toxic symptoms noted. The urine was stained pink 20 mins. after the first dose, and remained so until two days after cessation CASE

I.-Multiple

whipworms,

of treatment. EFFECT ON THREADWORMS

Therapeutic trials have been carried out on Oxyuris vermicularis infections, and, especially in children, phenothiazine has given consistently satisfactory results. Smaller doses are required than in roundworm infections. For children under 8 years a dose of 2 g. daily for seven days appears to be sufficient, and half this for children under 4 (about 0-17 g. per pound body-weight). For adults of both sexes, in whom threadworms are as a rule difficult to eradicate, the dose is 4-8 g. daily for seven to ten days. To facilitate administration, the drug has been prepared by Imperial Chemical Industries Ltd. in tablet form in two strengths, containing 0-5 g. and 1 g., made up with ox bile. More recently a granular preparation sweetened with limejuice and suitable for children has been perfected. No dietetic restrictions are required, and it does not seem necessary to give aperients. There is no need for the traditional cotton gloves and mercurial ointment, and the treatment does away with the unpleasantness of enemata. The drug is almost tasteless, and either the tablets or the granular preparation can easily be concealed in sweets or chocolate. No disagreeable after-effects have been noted; one child had a slight rise of temperature. During August, 1940, phenothiazine was given to four children infected with threadworms. A boy aged 4 years received 0 5 g. daily for seven days, and three girls aged 7 or 8 years received 1 g. daily for seven days. During the first two days of treatment numerous active threadworms were On the third day many were seen to be seen in the stools. sluggish and the remainder dead ; some were stained red. In three cases no more worms have since been seen during three months’ observation. In the fourth case, a boy who received the smaller dose, there was a relapse, but a course of 1 g. daily for seven days produced a permanent cure. In a family infected with threadworms the father and mother had been infected for at least six years. Quassia

..

809 and hexylresorcinol had been tried without avail. The father (aged 44) and mother (aged 39) received 2 g. of phenothiazine daily for five days ; the daughter (aged 7) received 1 g. daily for five days ; and the son (aged 4) received 0 5 g. daily for five days. A drachm of sodium sltlpliate was given after each dose of phenothiazine. A cure was effected in all except the father, who relapsed, but he was subsequently cured by a course of 4 g. daily, It seems clear that a daily dose of 2 g. is sometimes too small for adults. A man of 47, complaining of loss of weight, mental irritability and anal itching, was found to have a heavy infection with oxyuris in September, 1940. He was given 4 g. of phenothiazine daily for four days. After the third dose dead worms were found in the faeces, and he continued to pass them for the next two days ; at the same time the anal itching ceased. After a week some more live worms were seen and the course was repeated, with an apparently permanent result.

irrigations, santonin, beta-naphthol

From this brief experience in adults it appears that doses of 4 g. are inadequate, and that in future 8 g. daily should be given for not less than five days, as in ascaris

infections. More reliable information about the effects of phenoon threadworms has been obtained by Dr. G. 1‘I. Vevers from the treatment of a young gorilla at the Zoo. This animal was heavily infested with ancylostomes,

thiazine

and threadworms. It was given 0 3 g. of phenothiazine on the three successive days, March 13-15, 1940. As a result 18 cesophagostomum worms were passed in a dead or dying condition with an unspecified number of threadworms. The gorilla died on May 14, and at the autopsy, done by Col. A. E. Hamerton, no cesophagostomums or threadworms were found in the intestinal canal, though large numbers of ancylostomes were present and had undoubtedly caused the animal’s death.

cesophagostomum

VOLVULUS OF THE INTESTINE WITH INTERTWINING LOOPS BY MILROY

PAUL, M.S. Lond., F.R.C.S., M.R.C.P.

PROFESSOR OF SURGERY AT THE CEYLON MEDICAL COLLEGE, AND SURGEON TO THE GENERAL HOSPITAL, COLOMBO

VOLVULUS leading to the intertwining of two loops of bowel is much rarer than volvulus due to twisting of the bowel about its mesenteric axis. Entanglements of the kind are most often found between the sigmoid colon and a loop of terminal ileum ; they are more rare between two loops of small intestine, and rarest between the caecum and a loop of small bowel. UA8E tGL’YUtG’1

A

woman

aged

50

was

admitted to

hospital

with excrucia-

ting colicky abdominal pain which had started suddenly at 4 A.M., and was felt diffusely in the abdomen and in the back. She felt a desire to relieve it by passing a stool, but could not even expel flatus. She had vomited once that morning. She had had a somewhat similar attack three years before, which had ceased

spontaneously. The abdomen was distended centrally

by the outline of an omega-shaped loop, showing waves of peristalsis, and rising from the pelvis (fig. 1). The

abdomen was soft and not tender. The rectum was empty. The patient had a good pulse (66), and a subnormal FiG. 1 -Omega loop, showing wavess of temperature (97-6° F.). The condition The larger apes, besides harbouring many of the peristalsis through was diagnosed as volvulus of the sigabdominal wall. intestinal parasites common in man, react in the same moid and colon, operation was perway to anthelminthics, so that the effectiveness of these under spinal anaesthesia. The peritoneal cavity comparatively small doses of phenothiazine in the formed contained bloodstained exudate and what looked at first sight gorilla are significant. ° like a volvulus of the sigmoid colon: The sigmoid loop, about SUMMARY 2 feet long, was plum-covered owing to strangulation, and its Phenothiazine, a thiazine dye, has been shown to be mesentery was thick with extravasated blood and serum. effective against culicine larvae, against strongyloid worms Rotation of the loop did not relieve the strangulation, and a in sheep, and against stomach worms in animals. It is . closer inspection showed that the sigmoid colon (fig. 2A) was excreted in the urine and acts as a urinary antiseptic. strangulated by a loop of small bowel (fig. 2o) wound tightly Three Indian lascars infested with Ancylostoma duoround its base. Coils of small intestine, about 2 ft. long, and denale were given phenothiazine in doses ranging from also plum-coloured from strangulation, were seen to the leftt 30-40 g. but the results suggest that the drug is ineffecof the sigmoid (fig. 2B). The two loops of strangulated bowel tive for worms in the small intestine ; similar results were separated by the rest of the small intestine with its mesenhave been found. in animals. tery (fig. 2c) ; this part of the small intestine was not stranguNine patients with ascaris lumbricoides were treated ; lated. Immediately to the left of the coil of ileum encircling five had a double infection with roundworms and hookthe sigmoid loop there was an arch (fig. 2s) formed by the worms and two a double infection with roundworms and mesentery of the unaffected portion of the small intestine, and whipworms. These seven patients were given total this arch was also tightly compressing both the strangulated doses ranging from 16 to 48 g. Only one roundworm loops of bowel. When a finger had been placed under this Of was recovered and the whipworms were unaffected. arch the loop of ileum encircling the sigmoid was seen to be the remaining two patients, one had a multiple infection continuous with the loop of strangulated ileum. By lifting the with roundworms, hookworms, whipworms, and threadarch of mesentery it was possible to reduce the strangulated worms, the other had roundworms only. They were given 8 g. daily for three days, followed by a dose of sodium sulphate, and results were more satisfactory, all

the roundworms being removed. Phenothiazine has given good and permanent results in the treatment of threadworm infections, especially in children. Effects on six children and three adults are recorded; all were cured, though three (one child and two adults) required a second course. The following doses are advised : 2 grammes daily for seven days for children under 8, and half the dose for children under 4 ; 8 grammes daily for at least five days for adults. I am indebted to Dr. Geoffrey Lapage of the Institute of Animal Pathology, Cambridge, and to Dr. E. L. Taylor of the Veterinary Laboratory, Cambridge, for their help ; to Dr. A. Winder of We sterham, and Dr. C. A. Lupton of Farnborough" for records of private cases; to my house-physicians Dr. B. Freedman and Dr. S. W. Hinds; and to Mr. A. H. Walters, technical assistant. The Agricultural Research Council and Dr. C. M. Scott of Imperial Chemical Industries, Ltd. kindly supplied me with phenothiazine. REFERENCES de Eds, F., Stockton, A. B., Thomas, J. O.(1939) J. Pharmacol. 65, 353. Knipling, E. P. (1938) J. econ. Ent. 31, 315. Taylor, E. L. and Sanderson, K. M. (1940) Vet. Rec. 52, 635. Thomas. de Eds and Eddy, C. W. (1938) J. Pharmacol. 64, 280.

FIG. 2-Condition formd at time of operation. A, sigmoid loop. B, strangulated loop of ileum. 0, loop of ileum encircling base of sigmoid. D, normal portion of small intestine. E, arch of mesentery strangulating bowel. 4-,, (,

2

FIG. 3-Condition found when the strangulated loop of ileum had been reduced from under the strangulating arch of the mesentery. Arrow shows path taken by ileal

loon.