TRANSACTIONS OF THE ROYALSOCIETY OPTROPICAL. MED~CINH AND HYGIENE
(1990) 84, 644447
Evaluation of the clinical efficacy and safety of halofantrine malaria in Ibadan, Nigeria L. A. Salako, A. Sowunmi and 0. Walker Ibadan,
Department of Pharmacology
in falciparum
and Therapeutics,
University of
Zbadan, Nigeria
Abstract Fifty subjects with acute symptomatic uncomplicated falciparum malaria were treated orally with halofantrine hydrochloride 500 mg 6 hourly for 3 doses if their body weight was 40 kg and above, or 8 mg/kg body weight 6 hourly for 3 doses if their weight was below 40 kg. Parasitaemia cleared in all subjects within 72 h. There was recurrence of parasitaemia in 9 subjects after day 14, and retreatment with halofantrine resulted in prompt clearance of parasitaemia in all but one of these patients. The mean clearance times of parasitaemia, fever and other svmntoms were 33*6+13.0 h. 20*7+15*3 h. and 33*6+ 10.7 h respectively. Minor gastrointestinal side effects occurred in 2 subjects and pruritus in 7 subjects. The pruritus was mild in all but one subject. Haematological and biochemical indices were not adversely affected by treatment except in one subject in whom liver enzymes were elevated before treatment and more than doubled following treatment.
Introduction The spread of falciparum malaria resistant to chloroquine all over the African continent has led to increasing use of alternative antimalarial drugs. One of these, halofantrine, a nhenanthrene methanol, is a product-of the antimalarial programme of the Walter Reed Armv Institute of Research (Wasbineton. DC. USA), which has now been developed for marketing by Smith Kline and French. It has been shown in initial studies to be effective against multi-drug resistant Plasmodium falciparum (REINHERT et al,: 1976: COSGRIFFet al., 1982: BOUDREAU et al.. 1988). and is now in phase II and phase III studies in different parts of the world. Although in Nigeria chloroquine remains the drug of choice in the treatment of uncomplicated falciparurn malaria, there are recent reports of decreased sensitivity of P. falciparum to the drug in vivo and in vitro (SALAKO & ADEROUNMU, 1987; EKANEM et al., 1990). There is therefore a possibility that the use of alternatives to chloroquine may become an accepted practice in Nigeria, and halofantrine is a potential candidate. Previous studies of this drug in other countries indicate that the simde dosage regimen with few side effects and relatively short-half %fe of l-2 d (BROOM, 1989) may be an advantage, particularly concerning resistance development. However, there are no published data on the efficacy and safety of halofantrine in subjects with falciparum malaria in Nigeria. These factors prompted us to undertake a Correspondence to Professor L. A. Salako, Department of Pharmacology and Therapeutics, University of Ibadan, Ibadsn, Nigeria.
phase II clinical trial of halofantrine in an area in south-western Nigeria where there is approximately 10% resistance to chloroquine (EKANEM et al., 1990). The objectives of our study were (i) to evaluate the efficacy of halofantrine using the WHO extended in vivo test (WHO, 1973) and (ii) to evaluate the safety of multiple doses of halofantrine in Nigerian subjects.
Methods Fifty-four subjects of both sexes aged 12 to 45 years with acute symptomatic falciparum malaria were studied between February and July 1989. All gave informed consent for participation in the study-and were admitted to the Universitv College Hosoital. Ibadan for at least 8 d. Approval for the study was given by the ethics committee of the College of Medicine, University of Ibadan. The diagnosis of malaria was based on clinical symptoms and signs and confirmed by Giemsa-stained thick and thin blood films. Additional selection criteria were a negative history of antimalaria drug administration in the 2 weeks preceding presentation and negative DillGlazko and lignin tests for 4aminoquinolines and sulphonamides respectively. Pregnant and lactating women were excluded. A thorough history was taken and physical examination performed on each patient at the time of admission and regularly during the period in hospital and at follow-up. The findings were recorded on standard forms. Twice daily parasite counts with examination of thick and thin films were done for 8 d following treatment (days O-7), and then weekly for 3 weeks. Haematocrit and white blood cell, differential, and olatelet counts were done before admission (dav 0), and then on days 1,3,6, 14,21 and 28. Blood urea nitrogen (BUN) and creatinine determinations. liver funcGon tests and urinalysis for albumin, sugar and bile pigments were done on the same days. The pulse rate, blood oressure, resniration and temuerature were measured 12 hourly from days 0 to 7 and thereafter weeklv for the next 3 weeks. The uatients were questionedand examined for the presence and severity of adverse drug reactions daily during the period in hospital and at every subsequent clinic attendance. Halofantrine was given orally as the hydrochloride in the form of 250 mg white tablets manufactured by Smith Kline and French (UK). The natients were treated with either 500 mg orally 6 hourly for 3 doses if their body weight was 40 kg or above, or with 8 mg/kg body weight 6 hourly for 3 doses if their weight was less than 40 ka. The drua was aiven bv a phy:ician and the mouth was inspected after each dose to ensure that it had been swallowed. There was no case of vomiting.
645 Drug treatment was considered curative if there was clearance of P. falcipurum parasitaemia within 4 d and no recrudescence during the 28 d follow-up. If parasitaemia occurred during follow-up the patient was given halofantrine again and then followed up for another 28 d. Patients not responding to the second treatment were regarded as treatment failures and given mefloquine, 15 mg/kg single dose. Parasitaemia was estimated by counting the number of P. falciparurn asexual forms against 1000 leucocytes and multiplying by 5, assuming a white blood cell count of 5000 per ul (WHO, 1985). The fever clearance time was defined as the time from drug administration until the oral temperature fell to 37°C or less and remained so for at least 48 h. The parasite clearance time was the time from drug administration until there was no patent parasitaemia. Results Parasitaemia Only 4 subjects failed to complete the study. One dropped out on day 0 after the &t dose because he changed his mind about snending 8 d in host&al. He was subsequently treated as ai outpatieni. Three dropped out after day 7; their parasitaemia had cleared within 60 h with no recurrence during the 8 days of follow-up; they failed to attend on days34 and 21 but were still well when seen aaain on dav 28. The clinical and parasitological data Tar the Sd subjects who completed the follow-up are summarized in Table 1. Parasitaemia cleared rapidly, so that no patient had patent parasitaemia at 72 h (Figure). There was no recrudescence of parasitaemia in any patient during the first 14 d of follow-up. However, parasitaemia was seen in 9 subjects after day 14, 1 each on days 16,17,18 and 25 and 5 on day 28. When treated again with halofantrine, parasitaemia cleared completely within 48 h in 7 of the 9 subjects, with no recrudescence during another 28 d follow-up. In one of the remaining 2 subjects, parasitaemia cleared in 60 h but recrudescence occurred at 96 h. This subject was regarded as a halofantrine treatment failure and was treated successfully with mefloouine. The other subject treated herself with amodiaqmne on dav 2 because of what she described as ‘non-relief of symptoms’, and so could not be further evaluated. In one subject associated viral infection prolonged the fever and symptom clearance times to 96 h and 72 h respectively; this patient was excluded from the calculation of fever and symptom clearance times. Parasitaemia cleared in this patient in 36 h. Clinical and laboratory data As would be expected in an endemic area, 70% of the subjects gave a history of one or more attacks of malaria in the 6 months preceding presentation. The mean number of orevious attacks was 2*1+2-O (ranee t&6). The commonest presenting symptom was fever (47 subjects& followed by headache (41 subjects), chills (39 subjects), vomiting (21 subjects), nausea (19 subiects). dizziness (18 subiects). abdominal oain (18 sub&tsj; palpitations (7 subject&), diarrhoea’(6 subjects), and pruritus (6 subjects). The last was confined to the trunk, and was neither fleeting nor soothed by patting or rubbing the affected part. Pallor was present in 4, hepatomegaly in 5, splenomegaly in 3, and both organs were enlarged in 3 subjects. Pre-
Table 1. Summary of clinical data of patients with falciparum malaria treated with halofantrine Number of subjects Total, male/female Age (ye4 Rawice Mean+SD” Initial temperature (“C) Range Mea&SD Initial narasite densitv- (per ._ ul) ., Range Geometric mean Temperature clearance time (h) Range Mean+SD Parasite clearance time (h) Range Mean+SD Symptom clearance time (h) Range Mean&SD Cure rate (%)
50, 27123 12-45 16.9k7.9 36.2-40.5 37.9k1.3 560-701196 46411 12-72 20.7k15.3 12-72 33.6zk13.0 12-60 35*0+10*7 98
“SD = standard deviation.
12
26
L0
60
72
Tize (h) Figure. Reduction of Plasmodium falcipanrmparasitaemia in 50 patients treated with halofantrine.
treatment hepatic and splenic enlargement became non-palpable in all subjects by day 14 except one in whom splenomegaly persisted till day 28. Following treatment, pruritus was the most commonly recorded side effect, occurring in 7 subjects in whom it had been absent before treatment. The pruritus was characterized by a fleeting or ‘biting’ sensation, was generalized but more pronounced in the soles, palms, scalp and perineal region, and was easily soothed. The onset of pruritus after commencement of therapy varied from 7 to 30 h (mean 14 h). The duration of itching was 12-48 h (mean 20 h). The itching was severe in 1 subject. Headache,
646 Table 2. Laboratory
findings
in patients
with falciparmn
malaria
before and after halofantrine”
Day 0 Day 1 Day 6 Day 3 Day 14 Day 21 37.5k4.9 Haematocrit (%) 38.325.7 35.2k5.6 37.Ok5.5 37.7k3.6 37.9f7.9 White blood cell count 5070+2060 4921f1562 5131k1582 5308+1941 5542+1671 443821421 (per Pl) Serum urea (mg/lOO ml) 27.6L6.5 21.5f4.5 20.0f5.0 17.324.3 20.2f2.4 26.3f3.1 Srum creatinine (mgi100 ml) 0.9kO.05 0.9fO.l 0.9fO.l 0.8kO.l 0.8kO.l 0.8kO.l Total serum bilirubin (mgi100 ml) 0.750.2 0.5f0.2 0.8kO.l 0.8zkO.3 0.6kO.2 0.9fO.l SGOTb (Cabaud units) 32.5k17.3 39.9k32.6 32.Ok10.5 33.4k14.5 27.4k12.2 26.428.3 SGPTb (Cabaud units) 32.6k17.3 33.6k10.7 40.2zk32.6 19.8f7.4 35.3f19.7 37.6f16.2 “Means+standard deviations. bSGOT=serum glutatnic oxalacetic transaminase; SGPT=serum glutamic pyruvate transaminase. nresent at the commencement of therapy in 41 subjects, was noted to persist beyond 3- d after theranv in 3 subjects. These 3 subiects were free of other- symptoms.’ Absence of taste ‘and nausea were noted in 2 subjects each 24 h after starting therapy, and 1 subject each had weakness and insomnia 48 h after treatment. These symptoms were mild in all cases. Haematological and biochemical data are summarized in Table 2. Haematological results were available for 48 subjects before treatment and for 37 subjects after treatment. Haematocrit values were below 30% in 3 subiects before treatment and above 32% in all subjects by day 14. The pre-treatment white blood cell count was 2OOO/ld or below in one subject and above 11 OOO/ulin 2 subjects. Bv dav 6 no subject had a white cell count below 2OOO/il, but one subiect had a count above 12 OOOiul. The white blood cell’count had fallen to below 10 dOO/ul in this patient by day 14. Biochemical results were available for 40 subjects before treatment and 33 subjects after treatment. Serum urea, creatinine and bihrubin values remained within normal limits throughout the study. In one subject, elevated pre-treatment levels of serum glutamic oxalacetic and pyruvic transaminases, of 76 and 81 Cabaud units respectively, rose to 154 and 167 Cabaud units respectively on day 1 (upper limits of normal range are 40 and 30 Cabaud units respectively). These values returned to normal by day 14. Otherwise there was no clinically significant change in these enzymes. Analysis of variance of the mean values for the different haematological and biochemical variables showed no significant difference for the different days. Urinalysis, performed regularly throughout the study, showed no abnormality. Discussion Increasing resistance of P. falciparum to chloroauine is now freauentlv encountered in areas which were previously fully sensitive to the drug for, in a recent unpublished study, 6 of 50 children showed RI and RI1 responses to chloroquine in such an area in south-western Nigeria (Salako. Walker and Sowumni, unpublished obs&vations). The present study has shown that halofantrine is an effective drug for,the treatment of acute falciparum malaria in an area of gradually emerging chloroquine resistance. The parasite and fever clearance times of 33.6&13-O h and
Day 28 39.3f4.6
5070f1638 26.4f 1.6 0.9kO.l 0.520.6 32.5f13.4 43.4k18.2
20.7f 15.3 h respectively compared favourably with the nublished fiaures of 3Ok17.2 h and 12.222.0 h for &rine, andY33.2f16.3 h and 15.6f8.7 h for a fixed ratio -combination of quinine, quiriidine and cinchonine (SOWUNMI et al., 1990). Our study further confirms previous findings from Africa and elsewhere (WATKINS et aE.. 1988: WIRIMA et al., 1988) that halofantrine is an effective antimalarial drug. However, the relatively short parasite clearance time obtained in this study, compared with 45.4 h and 54.8 h obtained in Kenya, suggests that some P. falciparum strains in Nigeria may be more sensitive to halofantrine than those from Kenya. Comparative in vitro and in viva studies are needed to substantiate this. Previous in vitro testing has shown that P. falciparum from Nigeria is fully-sensitive to halofantrine (50% inhibitorv concentration 0*92-4 rig/ml.; O&OLA et al., 1987). The recrudescences observed m our patients can, therefore, probably be attributed to poor bioavailability of the formulation used. The elevated liver enzyme levels in one patient before treatment, which were more than doubled following treatment, might suggest some effect of halofantrine on the liver. However. malaria itself mav cause increases in serum levels ‘of liver enzyme-s (HALL, 1977). Itching occurred in about 14% of our subiects: it was not accompanied bv a rash and was similar -to the characteristic chloroquine-induced oruritus in Africans (EKPECHI & OKORO, 1964; ‘OLATUNDE 1969; SAL~KO, 1984; SOWUNMI et al.; 1989). The &ing was clearly attributable to halofantrine, because chloroquine ingestion had been excluded by appropriate history and urine testing. Also, the patients were under close observation in the hospital and were given only halofantrine. Of note was the fact that all the 7 subjects who experienced itching when on halofantrine gave a personal or family history of similar itching following chloroquine administration. However, not all subjects with such histories subsequently suffered itching when given halofantrine. In conclusion, halofantrine is a safe and effective drug for the treatment of falcioarum malaria in an area’ of increasing drug resistance in south-western Nigeria. There is need to study further the clinical efficacy of this drug, to compare it with existing antimalarial drugs in controlled clinical trials, and to study its pharmacokinetics in African subjects with and without falciparum malaria.
647 References Boudreau, E. F., Pang, L. W., Dixon, K. E., Webster, H. K., Pavanand, K., Tosingha, L., Somatsakorn, P. & Canfield, C. J. (1988). Malaria treatment efficacy of halofantrine (WR 171,669) in initial field trials in Thailand. Bulletin of the World Health Organization, 66, 227-235. Broom, C. (1989). Human pharmacokinetics of halofantrine hydrochloride. In: Halofantrine in rhe Treatment of Multidrug Resistant Malaria, Warhurst, D. C. & Schofield C. J. (editors). Cambridge, UK: Elsevier Publications, pp. 15-20. Cosgriff, T. M., Boudreau, E. F., Pamplin, C. L., Doberstyn, E. B., Desjardins, R. E. & Canfield, C. J. (1982). Evaluation of the antimalarial activity of the phenanthrene methanol halofantrine (WR 171669). American 3oumal of Tropical Medicine and Hygiene, 31, 1075-1079. Ekanem, 0. J., Weisfeld, J. S., Salako, L. A., Nahlen, B. L., Ezedinachi, E. N. U., Walker, O., Breman, J. G., Laoye, 0. J. & Hedberg K. (19%). In uiwo sensitivity of Plasmodium falciparum to chloroquine and sulfadoxinel pyrimethamine in Nigerian children and in virro testing of chloroquine, quinine and mefloquine. Bulletin of the World Health Organization, in press. Ekapechi, 0. I. & Okoro, A. N. (1964). A pattern of pruritus to chloroquine. Archives of Dermatology, 89, 631-632. Hall, A. P. (1977). The treatment of severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 71, 367-379. Oduola, A. M. J., Milhous, W. K., Salako, L. A., Walker, 0. & Desjardins, R. E. (1987). Reduced in vizro susceptibility to mefloquine in West African isolates of Plasmodium falciparum. Lancer, ii, 13041305. Olatunde, I. A. (1969). Chloroquine-induced pruritus in Lagos, Nigeria. 3oumal of the Nigerian Medical Associa-
rion, 6, 23-33. Reinhert, J., Arnold, J. & Canfield, C. J. (1976). Evaluation of two phenanthrene methanols for antimalarial activity in man. American Townal of Tronical Medicine and Hygiene, 25, 769-774. * Salako, L. A. (1984). Toxicity and side effects of antimalarials in Africa: a critical review. Bulletin of the World Health Organization, 62, supplement, 63-68. Salako, L. A. & Aderounmu, A. F. (1987). In vitro chloroquine and mefloquine resistant P. falciparum in Nigeria. Lancer, i, 572-573. Sowunmi, A., Walker, 0. & Salako, L. A. (1989). Pruritus and antimalarial drugs in Africans. Lancet, ii, 213. Sowumni, A., Salako, L. A., Laoye, 0. J. & Aderounmu, A. F. (1990). Evaluation of a fixed ratio combination of quinine, quinidine and cinchonine in acute falciparum malaria: correlation with the susceptibility of Plasmodium falcipasum to the cinchona alkaloids in vitro. Transactions of the Royal Society of Tropical Medicine and Hygiene, in press. Watkins, W. M., 0100, J. A., Lury, J. D., Mosaba, M., Kariuki, D., Mjomba, M., Koech, D. K. & Gilles, H. M. (1988). Efficacy of multiule-dose halofantrine in the treatment of chloroquine re&ant falciparum malaria in children in Kenya. Lancer, ii, 247-249. Wirima, J., Khoromana, C., Molyneux, M. E. & Gilles, H. M. (1988). Clinical trials with halofantrine hydrochloride in Malawi. Lancer, ii, 250-252. WHO, (1973). Chemotherapy of Malaria and Resistance to Antimalarials. Geneva: World Health Organization, Technical Report Series, no. 529. WHO (1985). Bench aids for the diagnosis of mabia: method of counting malaria parasites in thick blood film. Geneva: World Health Organization, Set no. 2, Plate 8. Received I November 1989; revised 31 January accepted for publication 22 March 1990
1990;
(1990) 84, 644447
Evaluation of the clinical efficacy and safety of halofantrine malaria in Ibadan, Nigeria L. A. Salako, A. Sowunmi and 0. Walker Ibadan,
Department of Pharmacology
in falciparum
and Therapeutics,
University of
Zbadan, Nigeria
Abstract Fifty subjects with acute symptomatic uncomplicated falciparum malaria were treated orally with halofantrine hydrochloride 500 mg 6 hourly for 3 doses if their body weight was 40 kg and above, or 8 mg/kg body weight 6 hourly for 3 doses if their weight was below 40 kg. Parasitaemia cleared in all subjects within 72 h. There was recurrence of parasitaemia in 9 subjects after day 14, and retreatment with halofantrine resulted in prompt clearance of parasitaemia in all but one of these patients. The mean clearance times of parasitaemia, fever and other svmntoms were 33*6+13.0 h. 20*7+15*3 h. and 33*6+ 10.7 h respectively. Minor gastrointestinal side effects occurred in 2 subjects and pruritus in 7 subjects. The pruritus was mild in all but one subject. Haematological and biochemical indices were not adversely affected by treatment except in one subject in whom liver enzymes were elevated before treatment and more than doubled following treatment.
Introduction The spread of falciparum malaria resistant to chloroquine all over the African continent has led to increasing use of alternative antimalarial drugs. One of these, halofantrine, a nhenanthrene methanol, is a product-of the antimalarial programme of the Walter Reed Armv Institute of Research (Wasbineton. DC. USA), which has now been developed for marketing by Smith Kline and French. It has been shown in initial studies to be effective against multi-drug resistant Plasmodium falciparum (REINHERT et al,: 1976: COSGRIFFet al., 1982: BOUDREAU et al.. 1988). and is now in phase II and phase III studies in different parts of the world. Although in Nigeria chloroquine remains the drug of choice in the treatment of uncomplicated falciparurn malaria, there are recent reports of decreased sensitivity of P. falciparum to the drug in vivo and in vitro (SALAKO & ADEROUNMU, 1987; EKANEM et al., 1990). There is therefore a possibility that the use of alternatives to chloroquine may become an accepted practice in Nigeria, and halofantrine is a potential candidate. Previous studies of this drug in other countries indicate that the simde dosage regimen with few side effects and relatively short-half %fe of l-2 d (BROOM, 1989) may be an advantage, particularly concerning resistance development. However, there are no published data on the efficacy and safety of halofantrine in subjects with falciparum malaria in Nigeria. These factors prompted us to undertake a Correspondence to Professor L. A. Salako, Department of Pharmacology and Therapeutics, University of Ibadan, Ibadsn, Nigeria.
phase II clinical trial of halofantrine in an area in south-western Nigeria where there is approximately 10% resistance to chloroquine (EKANEM et al., 1990). The objectives of our study were (i) to evaluate the efficacy of halofantrine using the WHO extended in vivo test (WHO, 1973) and (ii) to evaluate the safety of multiple doses of halofantrine in Nigerian subjects.
Methods Fifty-four subjects of both sexes aged 12 to 45 years with acute symptomatic falciparum malaria were studied between February and July 1989. All gave informed consent for participation in the study-and were admitted to the Universitv College Hosoital. Ibadan for at least 8 d. Approval for the study was given by the ethics committee of the College of Medicine, University of Ibadan. The diagnosis of malaria was based on clinical symptoms and signs and confirmed by Giemsa-stained thick and thin blood films. Additional selection criteria were a negative history of antimalaria drug administration in the 2 weeks preceding presentation and negative DillGlazko and lignin tests for 4aminoquinolines and sulphonamides respectively. Pregnant and lactating women were excluded. A thorough history was taken and physical examination performed on each patient at the time of admission and regularly during the period in hospital and at follow-up. The findings were recorded on standard forms. Twice daily parasite counts with examination of thick and thin films were done for 8 d following treatment (days O-7), and then weekly for 3 weeks. Haematocrit and white blood cell, differential, and olatelet counts were done before admission (dav 0), and then on days 1,3,6, 14,21 and 28. Blood urea nitrogen (BUN) and creatinine determinations. liver funcGon tests and urinalysis for albumin, sugar and bile pigments were done on the same days. The pulse rate, blood oressure, resniration and temuerature were measured 12 hourly from days 0 to 7 and thereafter weeklv for the next 3 weeks. The uatients were questionedand examined for the presence and severity of adverse drug reactions daily during the period in hospital and at every subsequent clinic attendance. Halofantrine was given orally as the hydrochloride in the form of 250 mg white tablets manufactured by Smith Kline and French (UK). The natients were treated with either 500 mg orally 6 hourly for 3 doses if their body weight was 40 kg or above, or with 8 mg/kg body weight 6 hourly for 3 doses if their weight was less than 40 ka. The drua was aiven bv a phy:ician and the mouth was inspected after each dose to ensure that it had been swallowed. There was no case of vomiting.
645 Drug treatment was considered curative if there was clearance of P. falcipurum parasitaemia within 4 d and no recrudescence during the 28 d follow-up. If parasitaemia occurred during follow-up the patient was given halofantrine again and then followed up for another 28 d. Patients not responding to the second treatment were regarded as treatment failures and given mefloquine, 15 mg/kg single dose. Parasitaemia was estimated by counting the number of P. falciparurn asexual forms against 1000 leucocytes and multiplying by 5, assuming a white blood cell count of 5000 per ul (WHO, 1985). The fever clearance time was defined as the time from drug administration until the oral temperature fell to 37°C or less and remained so for at least 48 h. The parasite clearance time was the time from drug administration until there was no patent parasitaemia. Results Parasitaemia Only 4 subjects failed to complete the study. One dropped out on day 0 after the &t dose because he changed his mind about snending 8 d in host&al. He was subsequently treated as ai outpatieni. Three dropped out after day 7; their parasitaemia had cleared within 60 h with no recurrence during the 8 days of follow-up; they failed to attend on days34 and 21 but were still well when seen aaain on dav 28. The clinical and parasitological data Tar the Sd subjects who completed the follow-up are summarized in Table 1. Parasitaemia cleared rapidly, so that no patient had patent parasitaemia at 72 h (Figure). There was no recrudescence of parasitaemia in any patient during the first 14 d of follow-up. However, parasitaemia was seen in 9 subjects after day 14, 1 each on days 16,17,18 and 25 and 5 on day 28. When treated again with halofantrine, parasitaemia cleared completely within 48 h in 7 of the 9 subjects, with no recrudescence during another 28 d follow-up. In one of the remaining 2 subjects, parasitaemia cleared in 60 h but recrudescence occurred at 96 h. This subject was regarded as a halofantrine treatment failure and was treated successfully with mefloouine. The other subject treated herself with amodiaqmne on dav 2 because of what she described as ‘non-relief of symptoms’, and so could not be further evaluated. In one subject associated viral infection prolonged the fever and symptom clearance times to 96 h and 72 h respectively; this patient was excluded from the calculation of fever and symptom clearance times. Parasitaemia cleared in this patient in 36 h. Clinical and laboratory data As would be expected in an endemic area, 70% of the subjects gave a history of one or more attacks of malaria in the 6 months preceding presentation. The mean number of orevious attacks was 2*1+2-O (ranee t&6). The commonest presenting symptom was fever (47 subjects& followed by headache (41 subjects), chills (39 subjects), vomiting (21 subjects), nausea (19 subiects). dizziness (18 subiects). abdominal oain (18 sub&tsj; palpitations (7 subject&), diarrhoea’(6 subjects), and pruritus (6 subjects). The last was confined to the trunk, and was neither fleeting nor soothed by patting or rubbing the affected part. Pallor was present in 4, hepatomegaly in 5, splenomegaly in 3, and both organs were enlarged in 3 subjects. Pre-
Table 1. Summary of clinical data of patients with falciparum malaria treated with halofantrine Number of subjects Total, male/female Age (ye4 Rawice Mean+SD” Initial temperature (“C) Range Mea&SD Initial narasite densitv- (per ._ ul) ., Range Geometric mean Temperature clearance time (h) Range Mean+SD Parasite clearance time (h) Range Mean+SD Symptom clearance time (h) Range Mean&SD Cure rate (%)
50, 27123 12-45 16.9k7.9 36.2-40.5 37.9k1.3 560-701196 46411 12-72 20.7k15.3 12-72 33.6zk13.0 12-60 35*0+10*7 98
“SD = standard deviation.
12
26
L0
60
72
Tize (h) Figure. Reduction of Plasmodium falcipanrmparasitaemia in 50 patients treated with halofantrine.
treatment hepatic and splenic enlargement became non-palpable in all subjects by day 14 except one in whom splenomegaly persisted till day 28. Following treatment, pruritus was the most commonly recorded side effect, occurring in 7 subjects in whom it had been absent before treatment. The pruritus was characterized by a fleeting or ‘biting’ sensation, was generalized but more pronounced in the soles, palms, scalp and perineal region, and was easily soothed. The onset of pruritus after commencement of therapy varied from 7 to 30 h (mean 14 h). The duration of itching was 12-48 h (mean 20 h). The itching was severe in 1 subject. Headache,
646 Table 2. Laboratory
findings
in patients
with falciparmn
malaria
before and after halofantrine”
Day 0 Day 1 Day 6 Day 3 Day 14 Day 21 37.5k4.9 Haematocrit (%) 38.325.7 35.2k5.6 37.Ok5.5 37.7k3.6 37.9f7.9 White blood cell count 5070+2060 4921f1562 5131k1582 5308+1941 5542+1671 443821421 (per Pl) Serum urea (mg/lOO ml) 27.6L6.5 21.5f4.5 20.0f5.0 17.324.3 20.2f2.4 26.3f3.1 Srum creatinine (mgi100 ml) 0.9kO.05 0.9fO.l 0.9fO.l 0.8kO.l 0.8kO.l 0.8kO.l Total serum bilirubin (mgi100 ml) 0.750.2 0.5f0.2 0.8kO.l 0.8zkO.3 0.6kO.2 0.9fO.l SGOTb (Cabaud units) 32.5k17.3 39.9k32.6 32.Ok10.5 33.4k14.5 27.4k12.2 26.428.3 SGPTb (Cabaud units) 32.6k17.3 33.6k10.7 40.2zk32.6 19.8f7.4 35.3f19.7 37.6f16.2 “Means+standard deviations. bSGOT=serum glutatnic oxalacetic transaminase; SGPT=serum glutamic pyruvate transaminase. nresent at the commencement of therapy in 41 subjects, was noted to persist beyond 3- d after theranv in 3 subjects. These 3 subiects were free of other- symptoms.’ Absence of taste ‘and nausea were noted in 2 subjects each 24 h after starting therapy, and 1 subject each had weakness and insomnia 48 h after treatment. These symptoms were mild in all cases. Haematological and biochemical data are summarized in Table 2. Haematological results were available for 48 subjects before treatment and for 37 subjects after treatment. Haematocrit values were below 30% in 3 subiects before treatment and above 32% in all subjects by day 14. The pre-treatment white blood cell count was 2OOO/ld or below in one subject and above 11 OOO/ulin 2 subjects. Bv dav 6 no subject had a white cell count below 2OOO/il, but one subiect had a count above 12 OOOiul. The white blood cell’count had fallen to below 10 dOO/ul in this patient by day 14. Biochemical results were available for 40 subjects before treatment and 33 subjects after treatment. Serum urea, creatinine and bihrubin values remained within normal limits throughout the study. In one subject, elevated pre-treatment levels of serum glutamic oxalacetic and pyruvic transaminases, of 76 and 81 Cabaud units respectively, rose to 154 and 167 Cabaud units respectively on day 1 (upper limits of normal range are 40 and 30 Cabaud units respectively). These values returned to normal by day 14. Otherwise there was no clinically significant change in these enzymes. Analysis of variance of the mean values for the different haematological and biochemical variables showed no significant difference for the different days. Urinalysis, performed regularly throughout the study, showed no abnormality. Discussion Increasing resistance of P. falciparum to chloroauine is now freauentlv encountered in areas which were previously fully sensitive to the drug for, in a recent unpublished study, 6 of 50 children showed RI and RI1 responses to chloroquine in such an area in south-western Nigeria (Salako. Walker and Sowumni, unpublished obs&vations). The present study has shown that halofantrine is an effective drug for,the treatment of acute falciparum malaria in an area of gradually emerging chloroquine resistance. The parasite and fever clearance times of 33.6&13-O h and
Day 28 39.3f4.6
5070f1638 26.4f 1.6 0.9kO.l 0.520.6 32.5f13.4 43.4k18.2
20.7f 15.3 h respectively compared favourably with the nublished fiaures of 3Ok17.2 h and 12.222.0 h for &rine, andY33.2f16.3 h and 15.6f8.7 h for a fixed ratio -combination of quinine, quiriidine and cinchonine (SOWUNMI et al., 1990). Our study further confirms previous findings from Africa and elsewhere (WATKINS et aE.. 1988: WIRIMA et al., 1988) that halofantrine is an effective antimalarial drug. However, the relatively short parasite clearance time obtained in this study, compared with 45.4 h and 54.8 h obtained in Kenya, suggests that some P. falciparum strains in Nigeria may be more sensitive to halofantrine than those from Kenya. Comparative in vitro and in viva studies are needed to substantiate this. Previous in vitro testing has shown that P. falciparum from Nigeria is fully-sensitive to halofantrine (50% inhibitorv concentration 0*92-4 rig/ml.; O&OLA et al., 1987). The recrudescences observed m our patients can, therefore, probably be attributed to poor bioavailability of the formulation used. The elevated liver enzyme levels in one patient before treatment, which were more than doubled following treatment, might suggest some effect of halofantrine on the liver. However. malaria itself mav cause increases in serum levels ‘of liver enzyme-s (HALL, 1977). Itching occurred in about 14% of our subiects: it was not accompanied bv a rash and was similar -to the characteristic chloroquine-induced oruritus in Africans (EKPECHI & OKORO, 1964; ‘OLATUNDE 1969; SAL~KO, 1984; SOWUNMI et al.; 1989). The &ing was clearly attributable to halofantrine, because chloroquine ingestion had been excluded by appropriate history and urine testing. Also, the patients were under close observation in the hospital and were given only halofantrine. Of note was the fact that all the 7 subjects who experienced itching when on halofantrine gave a personal or family history of similar itching following chloroquine administration. However, not all subjects with such histories subsequently suffered itching when given halofantrine. In conclusion, halofantrine is a safe and effective drug for the treatment of falcioarum malaria in an area’ of increasing drug resistance in south-western Nigeria. There is need to study further the clinical efficacy of this drug, to compare it with existing antimalarial drugs in controlled clinical trials, and to study its pharmacokinetics in African subjects with and without falciparum malaria.
647 References Boudreau, E. F., Pang, L. W., Dixon, K. E., Webster, H. K., Pavanand, K., Tosingha, L., Somatsakorn, P. & Canfield, C. J. (1988). Malaria treatment efficacy of halofantrine (WR 171,669) in initial field trials in Thailand. Bulletin of the World Health Organization, 66, 227-235. Broom, C. (1989). Human pharmacokinetics of halofantrine hydrochloride. In: Halofantrine in rhe Treatment of Multidrug Resistant Malaria, Warhurst, D. C. & Schofield C. J. (editors). Cambridge, UK: Elsevier Publications, pp. 15-20. Cosgriff, T. M., Boudreau, E. F., Pamplin, C. L., Doberstyn, E. B., Desjardins, R. E. & Canfield, C. J. (1982). Evaluation of the antimalarial activity of the phenanthrene methanol halofantrine (WR 171669). American 3oumal of Tropical Medicine and Hygiene, 31, 1075-1079. Ekanem, 0. J., Weisfeld, J. S., Salako, L. A., Nahlen, B. L., Ezedinachi, E. N. U., Walker, O., Breman, J. G., Laoye, 0. J. & Hedberg K. (19%). In uiwo sensitivity of Plasmodium falciparum to chloroquine and sulfadoxinel pyrimethamine in Nigerian children and in virro testing of chloroquine, quinine and mefloquine. Bulletin of the World Health Organization, in press. Ekapechi, 0. I. & Okoro, A. N. (1964). A pattern of pruritus to chloroquine. Archives of Dermatology, 89, 631-632. Hall, A. P. (1977). The treatment of severe falciparum malaria. Transactions of the Royal Society of Tropical Medicine and Hygiene, 71, 367-379. Oduola, A. M. J., Milhous, W. K., Salako, L. A., Walker, 0. & Desjardins, R. E. (1987). Reduced in vizro susceptibility to mefloquine in West African isolates of Plasmodium falciparum. Lancer, ii, 13041305. Olatunde, I. A. (1969). Chloroquine-induced pruritus in Lagos, Nigeria. 3oumal of the Nigerian Medical Associa-
rion, 6, 23-33. Reinhert, J., Arnold, J. & Canfield, C. J. (1976). Evaluation of two phenanthrene methanols for antimalarial activity in man. American Townal of Tronical Medicine and Hygiene, 25, 769-774. * Salako, L. A. (1984). Toxicity and side effects of antimalarials in Africa: a critical review. Bulletin of the World Health Organization, 62, supplement, 63-68. Salako, L. A. & Aderounmu, A. F. (1987). In vitro chloroquine and mefloquine resistant P. falciparum in Nigeria. Lancer, i, 572-573. Sowunmi, A., Walker, 0. & Salako, L. A. (1989). Pruritus and antimalarial drugs in Africans. Lancet, ii, 213. Sowumni, A., Salako, L. A., Laoye, 0. J. & Aderounmu, A. F. (1990). Evaluation of a fixed ratio combination of quinine, quinidine and cinchonine in acute falciparum malaria: correlation with the susceptibility of Plasmodium falcipasum to the cinchona alkaloids in vitro. Transactions of the Royal Society of Tropical Medicine and Hygiene, in press. Watkins, W. M., 0100, J. A., Lury, J. D., Mosaba, M., Kariuki, D., Mjomba, M., Koech, D. K. & Gilles, H. M. (1988). Efficacy of multiule-dose halofantrine in the treatment of chloroquine re&ant falciparum malaria in children in Kenya. Lancer, ii, 247-249. Wirima, J., Khoromana, C., Molyneux, M. E. & Gilles, H. M. (1988). Clinical trials with halofantrine hydrochloride in Malawi. Lancer, ii, 250-252. WHO, (1973). Chemotherapy of Malaria and Resistance to Antimalarials. Geneva: World Health Organization, Technical Report Series, no. 529. WHO (1985). Bench aids for the diagnosis of mabia: method of counting malaria parasites in thick blood film. Geneva: World Health Organization, Set no. 2, Plate 8. Received I November 1989; revised 31 January accepted for publication 22 March 1990
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