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Albendazole Dans La Loase Humaine Résultats D'un Essai en Double Aveugle Contre Placebo
Albendazole Dans La Loase Humaine Résultats D'un Essai en Double Aveugle Contre Placebo
To assess the filaricidal activity and clinical safety of albendazole in human loiasis, a double-
blind, placebo-controlled study was conducted in an endemic area in Benin, Africa. Twenty-three
men with microfilaremia (100-30,OOOjmL) were randomly assigned to receive albendazole (200
mg; n = 11) or placebo (n = 12) twice daily for 21 days; 1 patient from each group withdrew from
the study. There were no clinical adverse effects and no observed hepatotoxicity, renal toxicity, or
hematologic abnormalities attributable to the drug. In the albendazole group, microfilarial levels
Loiasis, infection with the filarial parasite Loa loa, affects sis to decrease the parasite burden has been used in combina-
between 3 and 13 million people in Central and West Africa tion with steroids and antihistamines to prevent these com-
[1]. As is true of the other filarial diseases of humans, the plications [9]; however, this approach is impractical in the
clinical spectrum of loiasis is quite broad and includes rare developing world. Finally, diethylcarbamazine treatment of
but severe complications, such as encephalopathy [2], ne- patients with loiasis who have concomitant Onchocerca vol-
phropathy [3, 4], and cardiomyopathy [5]. While the charac- vulus infection may lead inadvertently to a worsening of ocu-
teristic manifestations of loiasis are Calabar swellings (tran- lar pathology [10].
sient localized angioedema) and eyeworm (subconjunctival Other pharmacologic agents have been tried in L. loa in-
migration of the adult worm). a majority of infected individ- fection, including ivermectin, the microfilaricidal drug of
uals from endemic areas have no symptoms despite very high choice in onchocerciasis. and mebendazole, an anthelmintic
numbers of microfilariae (rnf) in the blood [6]. used primarily in the treatment of intestinal nematode infec-
The current drug of choice for the treatment of loiasis is tions [11-14]. Although single-dose ivermectin has been
the piperazine derivative. diethylcarbamazine (DEC). Al- shown to reduce the numbers of L. loa mf in the blood [11,
though the drug is active against both mf and adult worms, 12], in a recent study of ivermectin treatment of 49 patients
multiple courses of therapy may be necessary to eradicate the with high levels of L. loa mf in the blood (>2500 mf/ml.),
infection [4]. Complications of therapy. which include fatal 30% of patients had mild to moderate side effects, including
posttherapeutic encephalitis [7. 8], are thought to be due to urticaria, arthralgias, and fever [15]. This may be particularly
the rapid release of antigens by dying mf and are thus more important as the Widespread use of ivermectin to treat on-
common in patients with high microfilarial loads. Cytaphere- chocerciasis expands into areas of Africa endemic for loiasis.
Several studies with mebendazole have shown efficacy in de-
creasing the mf levels in loiasis and, in high doses, mebenda-
Received 23 December 1992; revised 26 February 1993.
zole may also kill the adult parasites [13, 14]. However, its
Presented in part: annual meeting of the American Society for Tropical poor and variable absorption and the high incidence of side
Medicine and Hygiene, Boston, November 1991 (abstract 414). effects when high doses are used has limited its usefulness in
Written informed consent (in French) was obtained from subjects; if the
loiasis.
individual was unable to read or spoke only a tribal language, the study
protocol, risks, and benefits, were explained verbally. Guidelines for human Albendazole is a benzimidazole derivative related to me-
experimentation of the US Department of Health and Human Services were bendazole but has the advantages of greater absorption after
followed. The project was approved by the Institutional Review Boards of
the Universite Nationale du Benin, Cotonou, and the National Institutes of
oral administration and a wider spectrum of activity [16].
Health, Bethesda. Effective in eradicating experimental filarial infections in sev-
Reprints or correspondence: Dr. Amy Klion, University of Iowa Hospi- eral animal models [17, 18], albendazole has recently been
tals and Clinics, SW 54 GH, Iowa City, IA 52242.
shown to decrease blood mflevels in human filarial infection
The Journal of Infectious Diseases 1993;168:202-6
© 1993 by The University of Chicago. All rights reserved.
[19-21]. To define the kinetics and filaricidal activity of al-
0022-1899/93/6801-0030$01.00 bendazole in loiasis and to assess the clinical safety and toler-
JID 1993; 168 (July) Albendazole in Human Loiasis 203
Table 1. Baseline characteristics of the study population of men those who had received placebo were offered a 2 l-day course of
with microfilaremia. albendazole (200 mg, orally, twice a day).
Study design. Study drug was administered and signs and
Treatment group
symptoms were recorded twice daily for 21 days. Acetamino-
Albendazole Placebo
phen for pain or fever and antihistamines for pruritus or urti-
Characteristic (n = 10) (n = II) caria were administered when clinically indicated. Blood and
urine were collected on days 0 (before treatment), I, 3, 6, 10,
Median age, years 42 (25-54) 44 (25-55) 14, 21, and 28 and at 3 and 6 months after the beginning of
Geometric mean treatment. Mf counts, white blood cell counts with differentials,
microfilariae/rnl, 2369 (385-20,200) 3119 (236-27,500) and urinalyses were done on the day of collection at each time
Geometric mean point, and serum was frozen in liquid nitrogen for drug and
eosinophils/rnm' 1681 (320-3465) 1426 (750-3312) anti-filarial antibody levels. Liver function tests (alanine amino-
Geometric mean transferase [AL T] and aspartate aminotransferase [AST]), he-
antifilarial IgG,
matocrit determinations, and stool examinations were done on
units/rnl. 358 (84-2271) 308 ( I 19-1321)
days 0 and 21 by the laboratories at the Centre National Hospi-
Geometric mean
antifilarial IgG4, talier et Universitaire, Cotonou.
200
200
~
~ 150
l@
en 150
~ f-<
Z *
~100 ~
f-<
100
PLACEBO
~
-<
~
~ 50 50
~
~~
ALBENDAZOLE
0 0
10 100 10 1{)(}
DAYS DAYS
Figure 1. Kinetics of microfilarial clearance. Geometric mean Figure 2. Kinetics of eosinophilia. Geometric mean eosinophil
verity of posttreatment reactions, therapy must be safe, well tively more susceptible to chemotherapeutic agents than are
tolerated, and effective. While diethylcarbamazine fulfills adult O. volvulus, as evidenced by the macrofilaricidal activ-
these criteria in the treatment of individuals with undetect- ity of diethylcarbamazine in loiasis but not in onchocerci-
able levels of bloodborne mf, serious side effects, including asis [32].
fatal encephalitis and hypotension, limit its use in microfilar- Determination of drug efficacy in loiasis ideally would in-
ernie subjects (especially in those with high levels of microfi- clude direct measures of both microfilaricidal and macrofi-
laremia). Although precise estimates of the incidence of such laricidal activity. Direct quantification of adult parasites,
complications in endemic populations are unavailable, in which reside in the subcutaneous tissues, is impossible; thus,
one study of 60 patients, 14 of whom were microfilarernic, persistently decreased mf levels as well as eosinophil and
Mazzotti-like posttreatment reactions occurred in 17 pa- anti-filarial antibody levels at 6 months after treatment were
tients after a single dose of diethylcarbamazine [27]. Milder used as an indicator of adult parasite death. Reinfections
adverse effects of the drug, including pruritus, urticaria, and with significant production ofmfare unlikely to occur within
nausea are nearly universal in this population [28]. this period and residual microfilaricidal effects of albenda-
Albendazole, initially developed as an intestinal anthel- zole would be expected to have ceased. Although total elimi-
mintic, is effective against a variety of systemic helminth in- nation of detectable mf at 6 months was achieved in only 1
an embryotoxic effect on the developing mf, as observed in 15. Carme B, Ebikili B, Mbitsi A, Copin N. Essai therapeutique de l'iver-
onchocerciasis [21], must also be considered. A larger trial mectine au cours de la loase a moyenne et forte microfilaremie. Ann
Soc Beige Med Trop 1991;71:47-50.
and longer follow-up will be necessary to more completely
16. Edwards G, Breckenridge AM. Clinical pharmacokinetics of anthel-
assess the efficacy of albendazole in eradicating L. loa infec- mintic drugs. Clin Pharmacokinet 1988; 15:67-93.
tion and its potential use in mass treatment of infected indi- 17. Denham DA, Liron DA. Brandt E. The anthelmintic effects ofalb enda-
viduals in endemic areas. Should albendazole prove to have zole on Brugia pahangi. J Helminthol 1980;54: 199-200.
an embryotoxic rather than macrofilaricidal effect on L. loa, 18. Reddy AB, Rao UR, Chandrashekar R, Shrivastava R, Subrahmanyam
the utility of eliminating microfilaremia (and presumably ad- D. Comparative efficacy of some benzimidazoles and amoscanate
(Go. 9333) against experimental filarial infections. Tropenmed Para-
verse effects) with a short course ofalbendazole before dieth-
sitol 1983;34:259-62.
ylcarbamazine therapy will merit investigation. 19. Sanguigni S, Bianchini C, Marangi M, et al. The treatment of filariasis
with a new drug: albendazole. Ther Infect Dis 1986; 1:77-81.
Acknowledgments 20. Cline BL, Hernandez JL, Mather FJ, et al. Albendazole in the treat-
ment of onchocerciasis: double-blind clinical trial in Venezuela. Am
We thank the administrative staff of the Center for Palm Oil J Trop Med Hyg 1992;47:512-20.
Research, Pobe, for access to the study population, and Robert 21. Awadzi K, Hero M, Opoku 0, Buttner OW, Gilles HM. The chemother-