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Comparison of the effect upon onchocerciasis of five drugs and selection of the one best able to prevent ocular complications
462 TRANSACTIONS OF THE ROYAL SOCIETY OF TROPICAL MEDICINE AND HYGIENE.
Vol. 52. No. 5.
September, 1958.
COMPARISON OF THE EFFECT UPON ONCHOCERCIASIS OF FIVE DRUGS AND SELECTION OF THE ONE BEST ABLE TO PREVENT OCULAR COMPLICATIONS BY
F. C. RODGER*
Research Professor of Ophthalmology, Muslim University, Aligarh, India No drug has been found to date that is entirely effective in the treatment of onchocerciasis. It was decided to conduct a series of tests for comparison of five drugs : cyanine, arsenamide sodium, antimony tartrate, diethylcarbamazine, and suramin sodium. If all should prove equally ineffective in killing the adult filariae, it was hoped that at least there would emerge clear evidence as to which was best able to reduce the infection to a level at which the ocular complications of the disease would not appear. I.
1)
STANDARDS ADOPTED
Index of infectivity
I f the effect of the different drugs is truly to be compared it is obvious that the density of infection in each case should be brought down to a c o m m o n denominator. Such an index had previously been evolved (RoDCER and BROWN, 1957) ; this index is known as the Individual Density Figure, (I.D.F.). 2)
Criterion of cure
On excision and dissection of all the nodules from a patient, it is a frequent finding to observe dead necrotic worms in some of them. On conclusion of a course with a filaricide, therefore, the finding of dead adults or a degenerate worm in only one or some of the nodtiles excised is not necessarily evidence that the drug has caused their death. T h e r e seems no way out of accepting as a criterion immobility of all the worms, both male and female, when examined under the miscroscope, after gentle dissection of the nodule tissue in warm physiological saline at 37°C., as well as complete immobility of the microfilariae contained within the bodies of the female and the nodule fluid. II.
ADMINISTRATION
(a) Cyanine is a compound whose formula is 1-ethyl-3-6-dimethyl-2-phenyl-4pyrimide-2-cyanide chloride. T h e drug was administered by intravenous infusion on five occasions over a period of 18 days. Each infusion lasted about 1½ hours. Owing to * I wish to thank Dr. F. Hawking, Medical Research Council, and Dr. P. K. K. Knudsen, Ghana Ministry of Health for assistance or advice. Messrs. Lederle were most generous with supplies of Hetrazan, and Dr. L. Peters of Tulane University, New Orleans, kindly supplied the sample of cyanine, received initially from Messrs. Parke Davis & Co., Detroit.
F. C. RODGEIt
463
the toxic effects experienced and the difficulties in securing prolonged co-operation of suitable subjects, the courses were interrupted, and the dosages for each varied as the occasion demanded. TABLE I. Subject
Cyanine dosages
Dose mg./kg, body weight.
Total amount in grammes.
0.50 - 0.75
3.0
0.18 - 0.25
1.29
0.25 - 0.44
1.74
0.50 - 0.65
2.55
0.25 - 0.40 (3 doses only)
0.90
The drug was made up freshly before doses 1, 3 and 5, the solution containing 4 mg. of cyanine per c.c. It was administered at room temperature. Dr. F. Hawking, reporting on the toxicity of the sample used, found it to be rather more toxic than a previous sample used against W. bancrofti, and as a result it was decided to restrict the maximum dosage to half that used in the earlier series, i.e., to 1 mg. per kg. body weight ; in addition it was thought wiser to administer it every 2-4 days. (b) Arsenamide sodium or caparsolate (Abbott) is sodium-p-carbamyl-phenyl-arsylenedithio-diacetate. It contains 18 per cent. arsenic, and is readily soluble in a 1 per cent. solution. The course consisted of 460 c.c. of the 1 per cent. solution given intravenously over 37 days. Five c.c. of the 1 per cent. solution were given daily for 12 days, 10 c.c. for 10 days, and 20 c.e. for 15 days. In all, 0. 828 gramme of metallic arsenic was administered. (c) Sodium antimony tartrate B.P. was given intravenously in sterile 5 per cent. dextrose solution at 3-day intervals up to a total of 15½ grains over 31 days, as follows : 3 doses of ½ grain, 3 doses of 1 grain, 3 doses of 2 grains, and 2 doses of 21 grains. (d) Hetrazan (Lederle), 1-diethyl-carbamyl-4-methyl-piperazine citrate, was administered in tablet form under supervision as follows : 3 tablets on the 1st day, 8 tablets on the 2nd day and 9 tablets daily for 3 weeks. The total course, 200 tablets, amounted to 10 grammes over 23 days. No anti-histamine tablets were given. T h e dose of hetrazan refers to the salt.
(e) Suramin or antrypol has a cumbersome formula: urea of acid dimeta-aminobenzoylmeta-aminoethyl-benzoyl-l-napthylamino-4-6-8 trisulphonate. Doses of the solution (1 gramme in 8 c.c.) were given intravenously at 5-day intervals, up to a total of 12 grammes over 41 days. The following course was employed : 1 dose of 0.50 gramme, 2 doses of 0.75 gramme, 2 doses of 1 gramme, and 4 doses of 2 grammes. III.
RESULTS
One week after conclusion of the courses given above, all the existing nodules present in the patients were excised at the same time. Unfortunately, some of the subjects refused
464
TEST
OF
FIVE
DRUGS
IN
ONCHOCERCIASIS
in whole or in part. On the same day the biopsy technique used for assessing the I.D.F. was carried out. Assessment of the relative efficacy of the drugs may be achieved by comparing the results of the nodule dissections and the changes (if any) in the I.D.Fs. in subjects whose initial figures had been the same. The results are summarized in Table II below. Effect of the five drugs on the L D . F . (mf.) and adult worms.
TABLE II. No.
Age.
I D F at onset, (rrff.)
I D F after treatment (inf.)
Finding on nodule dissection (adults and Inf.)
Cyanine 1
48
15
15
2 3 4
45 32 32
23 15 15
23 11 15
5
50
3
19"
M o v e m e n t of adults and mr. in 4 nodules ; none in 3 ; 1 cystic. Refused excision. Refused excision. M o v e m e n t of adults and inf. in 1 nodule ; refused excision of 3 nodules. 1 nodule cystic and degenerate.
Arsenamide 6 7
15 31 31
: i
8
36 34 36
9
30
31
i!
15 31 31 31
10
30
31
]
31
M o v e m e n t of adults and inf. in 2 nodules. N o nodules ; 1 lipoma. M o v e m e n t of adults and inf. in all 3 nodules. M o v e m e n t of adults and inf. in 4 nodules ; 2 cystic and degenerate. M o v e m e n t of adults and inf. in 1 nodule ; 1 soft and cystic.
23 31 15 7 7
Nil. Refused excision. M o v e m e n t of adults and mf. in all 3 nodules. All 3 nodules cystic and soft. Refused excision.
Sodium antimony tartrate 11 12 13 14 15
41 25 29 50 38
23 31 15
i
7
i
7
i
31
M o v e m e n t of adults and mf. in 1 nodule ; 4 others cystic and degenerate. M o v e m e n t s of adults in 1 nodule ; in 2 m o v e m e n t of mr. only ; 2 others cystic. M o v e m e n t of adults and mr. in 1 nodule ; 3 necrotic. Nil. M o v e m e n t of adults and inf. in 6 nodules ; m o v e m e n t of adults in 1, the mr. being dead.
Hetrazan 16
i
46
i
!
!
17
40
31
18 19 20
39 I 60 48
31 31 15
Suramin 21 22
32 50
15 15
0 7
23
40
31
3
24
19
31
0
25
60
31
8
M o v e m e n t of adults, no inf. present in 1 nodule. M o v e m e n t of adults and mf. in 2 nodules ; no m o v e m e n t in 1. N o m o v e m e n t of adults in 2 nodules, b u t mf. very active in these 2 and in another 2. D o u b t f u l m o v e m e n t of adults in single n o d u l e ; no mf. present. M o v e m e n t of adults and mf. in 2 nodules.
* Conjunctiva invaded in middle of course, a unique observation.
It can be seen from Table II that cyanine, arsenamide and antimony tartrate were unsuccessful in killing either the adults or the microfilariae at the levels administered. None
F. e. RODOER
465
of the five drugs, in fact, had any action against the adult worms (see " Criterion of cure", p. 462). Hetrazan and suramin, on the other hand, killed m i c r o f i l a r i a e - in the case of the former drug completely - - so it seems that 10 grammes of hetrazan is an adequate dosage to achieve sterilization of the skin and eye. IV.
(a)
COMPLICATIONS
Cyanine
The complications experienced are given in detail in view of the fact that this drug has never before been used against onchocerciasis. Case Case Case Case Case
1 2 3 4 5
: : : : :
Nausea after dose 1. Headache after all 5 doses. Shivering after dose 4. Shivering and rise of temperature (101.2°F.) during dose 3. Headache and shivering after dose 3. Shivering and rise of temperature (99.4°F.) during dose 3. Shivering and rise of temperature (100°F.) during dose 3. Thrombosis of both the superficial brachial veins used for the infusion after dose 3.
During the shivering and fevers in Cases 2, 4 and 5 thick blood films were taken from each and malarial crescents found in vast numbers in Cases 2 and 5. The urine in all five cases showed albumin, which lasted for several days after each dose. In three cases after dose 3 there were casts. Blood pressure was only slightly lowered during treatment and soon recovered. The haemoglobin content fell in four out of the five cases from 75 - 90 per cent. to 65 - 70 per cent. on the Sahli scale. The WBC count was unchanged. The combination in Case 5 of albuminuria, casts, malaria and thrombosis of the only veins with good egress, forced us to abandon the course after dose 3. In general, it can be said that such were the signs of toxicity that it would seem unsafe to administer this drug except in the youngest and fittest of subjects, and even then at not less than 3-day intervals, nor with dosages greater than 1.0 mg./kg, body weight. We believe there is in fact little evidence in our own experiments to encourage further trials with cyanine. (b) Arsenamide. Dermatitis of the axillae, palms and soles of the feet was seen in all the cases after dose 10. Vomiting and abdominal cramps occurred in Case 7 after dose 13 ; the same patient had albuminuria for 2 days during this period. One patient, Case 10, complained of headache and a warm feeling in the stomach after dose 13, and from then on exhibited albuminuria. The blood pictures remained unchanged throughout. The drug, in fact, was well tolerated. (c) Sodium antimony tartrate. In Case 11 only was there any vomiting, perhaps due to the fact that the intravenous injection had been too rapid. (d) Hetrazan. The previous treatment of a large number of cases had convinced us that, where no existing lesion in the eye is present, even although live mL may have invaded the conjunctiva or been seen in the aqueous humour, there will be only a very slight or no reaction to the drug, and not the remotest chance of blindness ensuing. Some danger exists in administering this microfilaricide during an acute ocular attack, although this is nullified by previous protein shock therapy (RODGER, 1957). It is not necessary to give full details of the complications in the present series as they are well known. Cases 16 and 17 were the worst sufferers in the group, having short but high rises in temperature, severe pruritis, arthralgia and myalgia. The knees became badly
466
WEST O~" FIVE DRUGS I N ONCHOCERCIASIS
swollen and stiff and painful in Case 17. occurred in Case 16 only.
Photophobia and lacrimation, moderate in degree,
(e) Suramin. Suramin was administered in this group at shorter intervals than those recommended (WHO Expert Committee, 1953), and the total given was 2.5 grammes greater than the maximum suggested in that report. Despite this, signs of toxicity were less than in earlier cases treated w i t h another sample when we employed lesser doses at greater intervals. For this reason there remains some doubt whether every batch is equally potent and pure. As in both series the results were most disappointing, we cannot very well recommend its use. The patients, moreover, do not enjoy receiving intravenous injections. Complications, although of a minor nature, were experienced by every patient, consisting of headaches, diarrhoea and albuminuria. V.
DISCUSSION
The excellent review of the chemotherapy of filarial infection by HAWKING (1955) makes it unnecessary to repeat the various arguments in connection with hetrazan, suramin and antimony tartrate, except perhaps to stress that in the case of suramin we found it less satisfactory than other workers have claimed. As for cyanine and arsenamide it can be said at once that they do not appear likely to prove of any real value in the treatment of onchocerciasis ; cyanine is clearly a dangerous drug. When WELCH, PETERS and their colleagues (1947) used it, unsuccessfully, against W. bancrofti the subjects experienced dyspnoea, persistent vomiting, severe headache, bradycardia and marked hypertension. Experimental animals treated with the same sample exhibited permanent injury to the kidneys. Dr. Hawking's assays suggested that the sample of cyanine used in the present experiment was twice as toxic as that used by Welch. In the circumstances the doses administered, although low, were the greatest that could be reasonably given without jeopardizing the future health of the patients. ASI-IBURN and his colleagues (1949) found some evidence of damage to the adult worms after a course of arsenamide in three subjects of onchocerciasis. Here we believe the criterion of efficacy was at fault. OTTO and MAREN (1948) who tested a large number of phenyl arsenoxide derivatives, concluded that arsenamide was the one most likely to prove successful. The dosages we used were higher than those recommended, so one is forced to conclude that arsenamide has little effect on O. volvulus. Thus the state of affairs envisaged when framing the experiment at the start unforttunately came about. No drug capable of killing the adults was found. As a result it is clear the only way to tackle the problem at the moment is to reduce the microfilarial population in the body to a level at which ocular complications will be unlikely to occur. This level we believe stands at an I.D.F. of under 6. It is obvious from the results obtained that the drug best able to do this is diethylcarbamazine (hetrazan). It is easy to administer. The course recommended is one of 200 tablets (10.0 grammes) of the dihydrogen citrate twice yearly. It is our belief that with such treatment a patient can be confidently reassured that no ocular complication of onchocerciasis will arise. If the I.D.F. is found at the outset to be under 6, then treatment is unnecessary, although twice yearly reassessment of the I.D.F. would be a wise precaution. The only type of patient whom one would classify as an exception to this general ruling is one with a head nodule. The close proximity of the eye to a nodule (the source of the
F. C. RODGER
467
blinding mf.) leads to an earlier invasion of the ocular tissues with a corresponding increase in the likelihood of blindness supervening. Here radical excision of the head nodule and three microfilaricidal courses a year for the first year is advised ; subsequently the n u m b e r of courses annually can be reduced to two. SUMMARY
1) Trials were carried out with five drugs to test their therapeutic action in human onchocerciasis: cyanine, arsenamide sodium, sodium antimony tartrate, diethylcarbamazine (hetrazan) and suramin sodium (antrypol). 2) None of these drugs was found to kill the adult worms. As dead adults are found in the normal course of events in untreated cases in some of the nodules, it is felt that the true criterion of cure must be the death of every adult worm in every nodule. 3) Hetrazan was successflll in destroying the entire microfilarial population of the skin and eye. Six months later the microfilarial population was still greatly reduced. Suramin was only partly successful in destroying the microfilariae. T h e other drugs had no effect on the microfilariae. 4) Cyanine was used for the first time in onchocerciasis. T h e toxic complications experienced were headache, shivering, albuminuria and renal casts, thrombosis of the superficial brachial veins, and a fall in the haemoglobin content. 5) Where the I.D.F. is under 6 it is believed that the only risk of ocular complications is when a head nodule exists. Hetrazan is the drug best able to keep the I.D.F. down to this safe level, and it is recommended that a course of 10 grammes is given twice a year where the I.D.F. is over 5. Head nodules should be excised immediately, and three courses a year given to such patients. REFERENCES ASHBURN,L. L., PERRIN, T. L., BRADY, F. J. • LAWTON, A. H. (1945). Arch. Path., 40, 334. , BURCH,W. A. & BRADY,F. J. (1949). Bol. Ofic., Sanit Panamer, 28, 1107. BURCH, T. A. (1949). Ibid., 28, 233. CULBERTSON,J. T. (1947). Trans. R. Soc. trop. Med. Hyg., 41, 18. HAWKING, F. (1955). Pharmacol. Rev., 7, 279. OTTO, G. F. & MAaeN, T. H. (1948). Ann. N . Y . Acad. Sci., 50, 92. PETERS, L., WELCH, A. D. & HmASHt, A. (1949). J. Pharmacol., 96, 460. PUYUELO, R. (1950). Bull. Soc. Path. exot., 43, 462. RODGER, F.C. (1957). Brit. ~. Ophthalmol., 41, 544. - & BROWN,J. A. C. (1957). Trans. R. Soc. trop. Med. Hyg., 51, 271. WANSON, M. (1950). Ann. Soc. belge. Med. trop., 30, 671. WELCH, A. D., PETERS,L., BUEDING,E., VALK,A. Jr. & HIGASHI, A. (1947). Science, 105, 485.
Vol. 52. No. 5.
September, 1958.
COMPARISON OF THE EFFECT UPON ONCHOCERCIASIS OF FIVE DRUGS AND SELECTION OF THE ONE BEST ABLE TO PREVENT OCULAR COMPLICATIONS BY
F. C. RODGER*
Research Professor of Ophthalmology, Muslim University, Aligarh, India No drug has been found to date that is entirely effective in the treatment of onchocerciasis. It was decided to conduct a series of tests for comparison of five drugs : cyanine, arsenamide sodium, antimony tartrate, diethylcarbamazine, and suramin sodium. If all should prove equally ineffective in killing the adult filariae, it was hoped that at least there would emerge clear evidence as to which was best able to reduce the infection to a level at which the ocular complications of the disease would not appear. I.
1)
STANDARDS ADOPTED
Index of infectivity
I f the effect of the different drugs is truly to be compared it is obvious that the density of infection in each case should be brought down to a c o m m o n denominator. Such an index had previously been evolved (RoDCER and BROWN, 1957) ; this index is known as the Individual Density Figure, (I.D.F.). 2)
Criterion of cure
On excision and dissection of all the nodules from a patient, it is a frequent finding to observe dead necrotic worms in some of them. On conclusion of a course with a filaricide, therefore, the finding of dead adults or a degenerate worm in only one or some of the nodtiles excised is not necessarily evidence that the drug has caused their death. T h e r e seems no way out of accepting as a criterion immobility of all the worms, both male and female, when examined under the miscroscope, after gentle dissection of the nodule tissue in warm physiological saline at 37°C., as well as complete immobility of the microfilariae contained within the bodies of the female and the nodule fluid. II.
ADMINISTRATION
(a) Cyanine is a compound whose formula is 1-ethyl-3-6-dimethyl-2-phenyl-4pyrimide-2-cyanide chloride. T h e drug was administered by intravenous infusion on five occasions over a period of 18 days. Each infusion lasted about 1½ hours. Owing to * I wish to thank Dr. F. Hawking, Medical Research Council, and Dr. P. K. K. Knudsen, Ghana Ministry of Health for assistance or advice. Messrs. Lederle were most generous with supplies of Hetrazan, and Dr. L. Peters of Tulane University, New Orleans, kindly supplied the sample of cyanine, received initially from Messrs. Parke Davis & Co., Detroit.
F. C. RODGEIt
463
the toxic effects experienced and the difficulties in securing prolonged co-operation of suitable subjects, the courses were interrupted, and the dosages for each varied as the occasion demanded. TABLE I. Subject
Cyanine dosages
Dose mg./kg, body weight.
Total amount in grammes.
0.50 - 0.75
3.0
0.18 - 0.25
1.29
0.25 - 0.44
1.74
0.50 - 0.65
2.55
0.25 - 0.40 (3 doses only)
0.90
The drug was made up freshly before doses 1, 3 and 5, the solution containing 4 mg. of cyanine per c.c. It was administered at room temperature. Dr. F. Hawking, reporting on the toxicity of the sample used, found it to be rather more toxic than a previous sample used against W. bancrofti, and as a result it was decided to restrict the maximum dosage to half that used in the earlier series, i.e., to 1 mg. per kg. body weight ; in addition it was thought wiser to administer it every 2-4 days. (b) Arsenamide sodium or caparsolate (Abbott) is sodium-p-carbamyl-phenyl-arsylenedithio-diacetate. It contains 18 per cent. arsenic, and is readily soluble in a 1 per cent. solution. The course consisted of 460 c.c. of the 1 per cent. solution given intravenously over 37 days. Five c.c. of the 1 per cent. solution were given daily for 12 days, 10 c.c. for 10 days, and 20 c.e. for 15 days. In all, 0. 828 gramme of metallic arsenic was administered. (c) Sodium antimony tartrate B.P. was given intravenously in sterile 5 per cent. dextrose solution at 3-day intervals up to a total of 15½ grains over 31 days, as follows : 3 doses of ½ grain, 3 doses of 1 grain, 3 doses of 2 grains, and 2 doses of 21 grains. (d) Hetrazan (Lederle), 1-diethyl-carbamyl-4-methyl-piperazine citrate, was administered in tablet form under supervision as follows : 3 tablets on the 1st day, 8 tablets on the 2nd day and 9 tablets daily for 3 weeks. The total course, 200 tablets, amounted to 10 grammes over 23 days. No anti-histamine tablets were given. T h e dose of hetrazan refers to the salt.
(e) Suramin or antrypol has a cumbersome formula: urea of acid dimeta-aminobenzoylmeta-aminoethyl-benzoyl-l-napthylamino-4-6-8 trisulphonate. Doses of the solution (1 gramme in 8 c.c.) were given intravenously at 5-day intervals, up to a total of 12 grammes over 41 days. The following course was employed : 1 dose of 0.50 gramme, 2 doses of 0.75 gramme, 2 doses of 1 gramme, and 4 doses of 2 grammes. III.
RESULTS
One week after conclusion of the courses given above, all the existing nodules present in the patients were excised at the same time. Unfortunately, some of the subjects refused
464
TEST
OF
FIVE
DRUGS
IN
ONCHOCERCIASIS
in whole or in part. On the same day the biopsy technique used for assessing the I.D.F. was carried out. Assessment of the relative efficacy of the drugs may be achieved by comparing the results of the nodule dissections and the changes (if any) in the I.D.Fs. in subjects whose initial figures had been the same. The results are summarized in Table II below. Effect of the five drugs on the L D . F . (mf.) and adult worms.
TABLE II. No.
Age.
I D F at onset, (rrff.)
I D F after treatment (inf.)
Finding on nodule dissection (adults and Inf.)
Cyanine 1
48
15
15
2 3 4
45 32 32
23 15 15
23 11 15
5
50
3
19"
M o v e m e n t of adults and mr. in 4 nodules ; none in 3 ; 1 cystic. Refused excision. Refused excision. M o v e m e n t of adults and inf. in 1 nodule ; refused excision of 3 nodules. 1 nodule cystic and degenerate.
Arsenamide 6 7
15 31 31
: i
8
36 34 36
9
30
31
i!
15 31 31 31
10
30
31
]
31
M o v e m e n t of adults and inf. in 2 nodules. N o nodules ; 1 lipoma. M o v e m e n t of adults and inf. in all 3 nodules. M o v e m e n t of adults and inf. in 4 nodules ; 2 cystic and degenerate. M o v e m e n t of adults and inf. in 1 nodule ; 1 soft and cystic.
23 31 15 7 7
Nil. Refused excision. M o v e m e n t of adults and mf. in all 3 nodules. All 3 nodules cystic and soft. Refused excision.
Sodium antimony tartrate 11 12 13 14 15
41 25 29 50 38
23 31 15
i
7
i
7
i
31
M o v e m e n t of adults and mf. in 1 nodule ; 4 others cystic and degenerate. M o v e m e n t s of adults in 1 nodule ; in 2 m o v e m e n t of mr. only ; 2 others cystic. M o v e m e n t of adults and mr. in 1 nodule ; 3 necrotic. Nil. M o v e m e n t of adults and inf. in 6 nodules ; m o v e m e n t of adults in 1, the mr. being dead.
Hetrazan 16
i
46
i
!
!
17
40
31
18 19 20
39 I 60 48
31 31 15
Suramin 21 22
32 50
15 15
0 7
23
40
31
3
24
19
31
0
25
60
31
8
M o v e m e n t of adults, no inf. present in 1 nodule. M o v e m e n t of adults and mf. in 2 nodules ; no m o v e m e n t in 1. N o m o v e m e n t of adults in 2 nodules, b u t mf. very active in these 2 and in another 2. D o u b t f u l m o v e m e n t of adults in single n o d u l e ; no mf. present. M o v e m e n t of adults and mf. in 2 nodules.
* Conjunctiva invaded in middle of course, a unique observation.
It can be seen from Table II that cyanine, arsenamide and antimony tartrate were unsuccessful in killing either the adults or the microfilariae at the levels administered. None
F. e. RODOER
465
of the five drugs, in fact, had any action against the adult worms (see " Criterion of cure", p. 462). Hetrazan and suramin, on the other hand, killed m i c r o f i l a r i a e - in the case of the former drug completely - - so it seems that 10 grammes of hetrazan is an adequate dosage to achieve sterilization of the skin and eye. IV.
(a)
COMPLICATIONS
Cyanine
The complications experienced are given in detail in view of the fact that this drug has never before been used against onchocerciasis. Case Case Case Case Case
1 2 3 4 5
: : : : :
Nausea after dose 1. Headache after all 5 doses. Shivering after dose 4. Shivering and rise of temperature (101.2°F.) during dose 3. Headache and shivering after dose 3. Shivering and rise of temperature (99.4°F.) during dose 3. Shivering and rise of temperature (100°F.) during dose 3. Thrombosis of both the superficial brachial veins used for the infusion after dose 3.
During the shivering and fevers in Cases 2, 4 and 5 thick blood films were taken from each and malarial crescents found in vast numbers in Cases 2 and 5. The urine in all five cases showed albumin, which lasted for several days after each dose. In three cases after dose 3 there were casts. Blood pressure was only slightly lowered during treatment and soon recovered. The haemoglobin content fell in four out of the five cases from 75 - 90 per cent. to 65 - 70 per cent. on the Sahli scale. The WBC count was unchanged. The combination in Case 5 of albuminuria, casts, malaria and thrombosis of the only veins with good egress, forced us to abandon the course after dose 3. In general, it can be said that such were the signs of toxicity that it would seem unsafe to administer this drug except in the youngest and fittest of subjects, and even then at not less than 3-day intervals, nor with dosages greater than 1.0 mg./kg, body weight. We believe there is in fact little evidence in our own experiments to encourage further trials with cyanine. (b) Arsenamide. Dermatitis of the axillae, palms and soles of the feet was seen in all the cases after dose 10. Vomiting and abdominal cramps occurred in Case 7 after dose 13 ; the same patient had albuminuria for 2 days during this period. One patient, Case 10, complained of headache and a warm feeling in the stomach after dose 13, and from then on exhibited albuminuria. The blood pictures remained unchanged throughout. The drug, in fact, was well tolerated. (c) Sodium antimony tartrate. In Case 11 only was there any vomiting, perhaps due to the fact that the intravenous injection had been too rapid. (d) Hetrazan. The previous treatment of a large number of cases had convinced us that, where no existing lesion in the eye is present, even although live mL may have invaded the conjunctiva or been seen in the aqueous humour, there will be only a very slight or no reaction to the drug, and not the remotest chance of blindness ensuing. Some danger exists in administering this microfilaricide during an acute ocular attack, although this is nullified by previous protein shock therapy (RODGER, 1957). It is not necessary to give full details of the complications in the present series as they are well known. Cases 16 and 17 were the worst sufferers in the group, having short but high rises in temperature, severe pruritis, arthralgia and myalgia. The knees became badly
466
WEST O~" FIVE DRUGS I N ONCHOCERCIASIS
swollen and stiff and painful in Case 17. occurred in Case 16 only.
Photophobia and lacrimation, moderate in degree,
(e) Suramin. Suramin was administered in this group at shorter intervals than those recommended (WHO Expert Committee, 1953), and the total given was 2.5 grammes greater than the maximum suggested in that report. Despite this, signs of toxicity were less than in earlier cases treated w i t h another sample when we employed lesser doses at greater intervals. For this reason there remains some doubt whether every batch is equally potent and pure. As in both series the results were most disappointing, we cannot very well recommend its use. The patients, moreover, do not enjoy receiving intravenous injections. Complications, although of a minor nature, were experienced by every patient, consisting of headaches, diarrhoea and albuminuria. V.
DISCUSSION
The excellent review of the chemotherapy of filarial infection by HAWKING (1955) makes it unnecessary to repeat the various arguments in connection with hetrazan, suramin and antimony tartrate, except perhaps to stress that in the case of suramin we found it less satisfactory than other workers have claimed. As for cyanine and arsenamide it can be said at once that they do not appear likely to prove of any real value in the treatment of onchocerciasis ; cyanine is clearly a dangerous drug. When WELCH, PETERS and their colleagues (1947) used it, unsuccessfully, against W. bancrofti the subjects experienced dyspnoea, persistent vomiting, severe headache, bradycardia and marked hypertension. Experimental animals treated with the same sample exhibited permanent injury to the kidneys. Dr. Hawking's assays suggested that the sample of cyanine used in the present experiment was twice as toxic as that used by Welch. In the circumstances the doses administered, although low, were the greatest that could be reasonably given without jeopardizing the future health of the patients. ASI-IBURN and his colleagues (1949) found some evidence of damage to the adult worms after a course of arsenamide in three subjects of onchocerciasis. Here we believe the criterion of efficacy was at fault. OTTO and MAREN (1948) who tested a large number of phenyl arsenoxide derivatives, concluded that arsenamide was the one most likely to prove successful. The dosages we used were higher than those recommended, so one is forced to conclude that arsenamide has little effect on O. volvulus. Thus the state of affairs envisaged when framing the experiment at the start unforttunately came about. No drug capable of killing the adults was found. As a result it is clear the only way to tackle the problem at the moment is to reduce the microfilarial population in the body to a level at which ocular complications will be unlikely to occur. This level we believe stands at an I.D.F. of under 6. It is obvious from the results obtained that the drug best able to do this is diethylcarbamazine (hetrazan). It is easy to administer. The course recommended is one of 200 tablets (10.0 grammes) of the dihydrogen citrate twice yearly. It is our belief that with such treatment a patient can be confidently reassured that no ocular complication of onchocerciasis will arise. If the I.D.F. is found at the outset to be under 6, then treatment is unnecessary, although twice yearly reassessment of the I.D.F. would be a wise precaution. The only type of patient whom one would classify as an exception to this general ruling is one with a head nodule. The close proximity of the eye to a nodule (the source of the
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blinding mf.) leads to an earlier invasion of the ocular tissues with a corresponding increase in the likelihood of blindness supervening. Here radical excision of the head nodule and three microfilaricidal courses a year for the first year is advised ; subsequently the n u m b e r of courses annually can be reduced to two. SUMMARY
1) Trials were carried out with five drugs to test their therapeutic action in human onchocerciasis: cyanine, arsenamide sodium, sodium antimony tartrate, diethylcarbamazine (hetrazan) and suramin sodium (antrypol). 2) None of these drugs was found to kill the adult worms. As dead adults are found in the normal course of events in untreated cases in some of the nodules, it is felt that the true criterion of cure must be the death of every adult worm in every nodule. 3) Hetrazan was successflll in destroying the entire microfilarial population of the skin and eye. Six months later the microfilarial population was still greatly reduced. Suramin was only partly successful in destroying the microfilariae. T h e other drugs had no effect on the microfilariae. 4) Cyanine was used for the first time in onchocerciasis. T h e toxic complications experienced were headache, shivering, albuminuria and renal casts, thrombosis of the superficial brachial veins, and a fall in the haemoglobin content. 5) Where the I.D.F. is under 6 it is believed that the only risk of ocular complications is when a head nodule exists. Hetrazan is the drug best able to keep the I.D.F. down to this safe level, and it is recommended that a course of 10 grammes is given twice a year where the I.D.F. is over 5. Head nodules should be excised immediately, and three courses a year given to such patients. REFERENCES ASHBURN,L. L., PERRIN, T. L., BRADY, F. J. • LAWTON, A. H. (1945). Arch. Path., 40, 334. , BURCH,W. A. & BRADY,F. J. (1949). Bol. Ofic., Sanit Panamer, 28, 1107. BURCH, T. A. (1949). Ibid., 28, 233. CULBERTSON,J. T. (1947). Trans. R. Soc. trop. Med. Hyg., 41, 18. HAWKING, F. (1955). Pharmacol. Rev., 7, 279. OTTO, G. F. & MAaeN, T. H. (1948). Ann. N . Y . Acad. Sci., 50, 92. PETERS, L., WELCH, A. D. & HmASHt, A. (1949). J. Pharmacol., 96, 460. PUYUELO, R. (1950). Bull. Soc. Path. exot., 43, 462. RODGER, F.C. (1957). Brit. ~. Ophthalmol., 41, 544. - & BROWN,J. A. C. (1957). Trans. R. Soc. trop. Med. Hyg., 51, 271. WANSON, M. (1950). Ann. Soc. belge. Med. trop., 30, 671. WELCH, A. D., PETERS,L., BUEDING,E., VALK,A. Jr. & HIGASHI, A. (1947). Science, 105, 485.