Metrifonate in Urinary Schistosomiasis*
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Bull. Org. mond. Santeh 1969, 41, Bull. Wld Hlth Org. 209-224 Metrifonate in Urinary Schistosomiasis* A. DAVIS & D. R. BAILEY This paper describes the effect oforal metrifonate, an organophosphorus cholinesterase inhibitor, on Schistosoma haematobium infections. The methodology ofinitial studies in hospitalpatients and 3field trials in schoolchildren, using spaced doses ranging from S mg to 15 mg per kg of body-weight is detailed. The expected fall in plasma cholinesterase was confirmed. No major side-effects were encountered and minor symptoms were associated with high doses only. The optimum dose was 7.5 mg per kg, given once every 14 days or once monthly to a maximum of 3 doses if necessary. About two-thirds of patients were cured after 1 or 2 doses, but some 10 % of these relapsed within 6 months of treatment. In 2 trials of this dose, cure rates of 71 % and 79 % were obtained. The authors conclude that metrifonate is a useful addition to oral schistosomicides for the treatment of S. haematobium infections in children, but suggest that more trials with spaced dose regimes are indicated and that further experimental studies are needed to define its mode of action. The organophosphorous cholinesterase inhibitor, sidered the extension of this property to other O,O-dimethylhydroxy-2,2,2-trichlorethyl-phospho- invertebrates including the helminths. After in vitro nate, has been used sporadically in the treatment of experiments, Dipterex was selected for human trials human schistosomiasis for a decade. This compound, and preliminary results showed evidence of thera- the structural formula of which is shown as follows, peutic activity in schistosomiasis, hookworm, ascariasis, trichuriasis and creeping eruption. Recent CH3O\ tO work suggests activity in onchocerciasis (Salazar- Mallen, Gonzalez-Barranco & Mitrani-Levy, 1969). CH30 \ Extensive bioc,hemical monitoring during the initial H-C-OH clinical trials revealed the expected fall in plasma and red cell cholinesterase but no abnormal findings Cd3 referable to the haemopoietic tissues, liver, spleen, kidneys, pancreas or cardiovascular system (Beheyt has insecticidal properties and was originally used et al., 1961). Tolerance was good, although sub- for plant protection in technical grade purity as jective gastrointestinal disturbance occurred. The Dipterex (Bayer). It was issued in pure form for enzyme reactivator, pralidoximine iodide, also known human trials as Vermicide Bayer 2349; the accepted as 2-pyridinium aldoxime methiodide or 2-PAM, was generic name became trichlorphone which was an effective antidote and atropine could be used for changed later to metrifonate (International Non- symptomatic relief. proprietary Name). Later clinical trials were characterized by pro- The insecticidal action of organophosphorous nounced variation in dosage and in length of esters depends on enzymic inhibition of specific treatment, which ranged from 2 to 20 days. Thera- esterases in ganglionar synapses and neuromuscular peutic results in schistosomiasis were predictably junctions. Cerf, Lebrun & Dierickx (1962) con- variable but Schistosoma mansoni infections re- sponded much less favourably than those due to * From the Bilharziasis Chemotherapy Centre (World S. haematobium. It that the Health Organization/Medical Research Council of Great appeared optimum dose Britain/Tanzania), Tanga, Tanzania. compatible with maximum cure and minimum side- 2362 - 209 - 3 210 A. DAVIS & D. R. BAILEY effects lay between 5 mg and 15 mg per kg of body- with metrifonate in doses ranging from 5 mg per kg, weight but the preferred length of treatment was not given fortnightly, to 10 mg per kg given monthly. clear. Varying numbers of doses were given until all In an investigation involving 4 schistosomicides patients were cured, and remained so after prolonged given at spaced intervals of one month to children follow-up, although it was noted that the pre- with S. haematobium infections, Forsyth & Rashid treatment egg output of these patients was low (1967a) treated 10 Zanzibari schoolboys with metri- (Forsyth & Rashid, 1967b). fonate at a dose of 10 mg per kg, for 1-6 doses. These results encouraged us to undertake trials of One patient was cured after 1 dose, another after metrifonate 1 in urinary schistosomiasis. We de- 2 doses, and the others showed a fall in urinary egg scribe three investigations into different doses and output. Later the same authors treated 76 patients times of administration. MATERIAL In preliminary studies male and female African and Arab children, of 5-15 years of age, who adults and children, aged from 5 to 65 years, attended local authority schools in the areas of were treated. In field trials the patients were endemic S. haematobium infection surrounding male and female African children, and a few Asian Tanga, Tanzania. METHODS The methods used have been described in detail described previously in the same papers, but, in previously (Davis, 1966, 1968). Urines were ex- brief, for 3 consecutive days urines were subjected to amined after the hatching of a 10-ml random sample hatching tests and examined for miracidia and eggs of the total bladder content of each patient, collected following sedimentation for 30 minutes, after which between 10.00 hours and 14.00 hours. Miracidia 10 ml from the bottom of the container were with- were killed and fixed with alcohol, then stained with drawn and processed. Each urine jar and each piece eosin. Following centrifugation and withdrawal of of apparatus for the processing of urine was labelled the supernatant the miracidial and dead egg content with the patient's name and trial number and were of the final 0.1 ml was counted in a cover-slip used throughout the follow-up period. The total preparation under the 16-mm objective lens. bladder content from each patient was collected The details of follow-up procedures have also been between 10.00 hours and 14.00 hours. INITIAL STUDIES Patients attending a schistosomiasis reference Six patients were given 1 dose, 4 patients were clinic were selected. All had S. haematobium infec- given 2 doses and 2 patients were given 3 doses. tion; none had any other serious condition, and, in Their pretreatment plasma cholinesterase values, particular, none had a previous history of asthma. estimated with the Tintometer Ltd field kit, based After urinary miracidial counts, parasitological and on a modification of Edson's method (1955), ranged haematological screening, chest X-ray and electro- from 87.5 % to 100 %, which fell to 25 % in 1-24 hours cardiography, 12 patients were given metrifonate as after 1 dose of drug. The levels gradually regained a single dose of 7.5 mg per kg of body-weight. If their pretreatment values over 14-21 days but were hatched miracidia were detected in the urine after depressed again if further doses were given. There 14 days this dose was repeated and urines were were no significant changes in serial estimations of re-examined after a further 2 weeks. If necessary, a third dose was given. 'Supplied by courtesy of Farbenfabriken Bayer A.G. METRIPONATE IN URINARY SCHISTOSOMIASIS 211 haemoglobin, blood urea, total and differential white passing viable ova after 2 doses. Mild abdominal cell counts, and repeated electrocardiograms showed pain, vomiting, diarrhoea, or weakness on the day of no alterations of note. Four patients complained of dosage were noted by the majority of patients but in abdominal pain, 3 patients had diarrhoea and all cases except one these symptoms were not marked, 2 patients were nauseated. These symptoms were had disappeared on the day following treatment, and mild and no medication was needed. required no medication. One boy aged 11 years was Three patients were lost to follow-up and 8 were said to have collapsed 11/2 hours after his first dose. cured 6 weeks after treatment. One was a failure. Examination soon afterwards revealed no evidence Five of7 patients with pretreatment hookworm infec- of severe intoxication and his plasma cholinesterase tion were negative at post-treatment examinations. was 25 %. He was given intramuscular atropine and The drug was considered promising and a further was symptom-free the following day. 11 patients were given 10 mg metrifonate per kg, With the exception of the fall in plasma cholin- 12 patients were given 12.5 mg per kg and 14 patients esterase, clinicopathological investigations again were given 15 mg per kg of body-weight. These revealed no significant changes after treatment. It doses were repeated after 14 days ifhatched miracidia was concluded that the drug was safe, given in spaced were isolated at that time. The maximum number of dosage, and that 15 mg per kg should be the maxi- doses was fixed at 3. Most patients were no longer mum single dose. FIELD TRIALS TRIAL 1 per standardized volume of randomly sampled urine, body-weights and sex-are shown in Table 1. In Trial 1, doses of 5.0 mg or 7.5 mg metrifonate The urinary miracidial output was dealt with by a per kg of body-weight were given at monthly transformation of the 2 pretreatment counts to the intervals for a maximum of 3 doses if necessary. logarithm of the geometric mean (log MG) which Following primary screening and 2 consecutive stabilized the variance and corrected the skewed daily pretreatment urinary miracidial and egg counts, frequency distribution of the original units to a 85 schoolchildren were available, 56 boys and normal distribution (Table 2). Body-weights were 29 girls, aged 5-12 years. Allwere examined clinically treated in the original kilogram units. and all were fit to receive metrifonate. Using a The variances of the transformed miracidial counts table of random numbers, patients were simply in each treatment group were similar (F= 1.064; randomized into one of two groups, A or B, and 42 and 41 degrees offreedom; non-significant at Fo.05 doses were randomized to group.