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Acta Tropica, 56(1994)213-231
213
© 1994 Elsevier Science B.V. All rights reserved 0001-706X/94/$06.00 ACTROP 00352
Drug resistance to schistosomicides and other anthelmintics of medical significance P a u l J. B r i n d l e y * Tropical Health Program, Queensland lnstitute of Medical Research, The Bancroft Centre, 300 Herston Road, Brisbane, QLD 4029, Australia It is usual for people to be infected for some period in life with parasitic worms, which may cause morbidity or even kill. Anthelmintics are used for the treatment and control of the human helminthiases, since no vaccines are yet available. Despite the widespread use of these compounds, drug resistance has become apparent only with antischistosomal chemotherapy, in contrast to the situation with other anti-infective agents in human medicine and with veterinary anthelmintics, where resistance is widespread. This paper reviews research on drug resistance in human helminthiasis with emphasis on schistosomicidal drugs. Key words: Drug resistance; Praziquantel
Human
helminthiasis;
Chemotherapy; Schistosome; Oxamniquine;
Introduction
Chemotherapy is used widely for treatment of human helminthiasis. Despite this and in spite of the prevalence of worm infections in people (see Warren and Mahmoud, 1990), resistance to antiparasitic drugs is uncommon in the human helminths, in marked contrast to the situation with veterinary anthelmintics and indeed, to the situation with antiparasitics employed against human malaria and other microbes. However, resistance to medical anthelmintics has occurred in schistosomes and can be expected to increase concomitant with continued use of chemotherapeutic agents. It is pertinent to note that more than 500 000 doses of praziquantel have been administered in China to treat human Schistosomajaponicum since 1980 (Yue et al., 1990). Schistosomiasis is considered the most important of the human helminthiases in terms of morbidity and infection: 200 to 300 million people are infected, a further 600 million people are at risk situations in endemic regions and an estimate of 200000 deaths annually was reported recently (Gibbons, 1992). Chemotherapy is the major method of control, and mass chemotherapy or targeted mass chemotherapy programs are in place in some endemic regions. Since chemotherapy is used to control schistosomiasis and because drug resistance has appeared in field isolates and in laboratory strains of schistosomes but apparently not yet in other human hehninths, this review emphasizes research on drug resistance to schistosomicidal compounds. *Corresponding author. Fax: +61 7 3620104. SSDI 0 0 0 1 - 7 0 6 4 ( 9 3 ) E 0 0 8 5 - Z
214 The introduction of schistosomicides Historically, antimonials and emetine were introduced during the first World War as the first effective anthelmintics for schistosomiasis. These were superseded after the 1939-45 war by the miracil series including lucanthone and about 30 years ago by niridazole, a nitrothiozole derivative and the organophosphorus compound metrifonate. Nowadays, metrifonate is widely used to treat Schistosoma haematobium in Africa and oxamniquine is employed to treat S. mansoni-infected patients in Brazil, while praziquantel is the drug of choice for all human schistosome infections including the Asian schistosomes. It is not understood why oxamniquine and metrifonate are species-specific in their efficacy against schistosomes, in contrast to the antimonials, niridazole and praziquantel, which are broad-spectrum schistosomicides (Marshall, 1987; Grove, 1990)(Table 1).
Drug resistance to miracils and analogs In 1948, German workers described the development and testing of a series of xanthenone compounds known as the miracil series, including Miracil D, or lucanthone (Kilkuth and Gonnert, 1948). Later, Rosi et al. (1965) obtained hycanthone from microbial fermentation of Miracil D by Aspergillus, which was found to be many times more effective than lucanthone against S. mansoni in rodents. It was reported in the 1970s that drug resistance to hycanthone and related compounds could be induced by exposing schistosomes in vivo to the drug (Rogers and Bueding, 1971; Jansma et al., 1977). These were important findings, and together with reports of adverse side effects and the mutagenic potential of hycanthone (Hartman et al., 1971; Hulbert, Bueding and Hartman, 1974) contributed to its discontinuation in the treatment of S. mansoni. Notwithstanding and because more than 20 years later, the mechanism(s) that led to the appearance of drug resistance in these reports has not been explained and because other workers continue to pursue these methods (Brindley et al., 1989a; Yue et al., 1990; Pica-Mattoccia, Archer and Cioli, 1992), it is timely to reiterate the results here. In an earlier report (Rogers and Bueding, 1971), rodents infected with a Puerto Rican strain of S. mansoni were exposed to hycanthone (furoate or methane sulfonate salts) by intramuscular (i.m.) administration of 30 mg kg -~ or 60 mg kg 1 in mice or 16 mg kg-1 in hamsters. Hycanthone damaged the worms in all cases as determined by a complete shift of the worms from the mesenteric veins to the liver, alterations in the female reproductive system, stunting and reduction in wet weight of both sexes and/or reduction in the glycogen stores of the male. Eight months later, however, approximately 10-20% of the number of worms before treatment were alive, had again established themselves in the mesenteric veins and resumed laying eggs. Miracidia hatched from these eggs gave rise to schistosomes that were resistant to hycanthone at 80 mg kg-1 i.m. and indeed to that dose administered four times over several days. The second and third generation of progeny of the drug-treated worms remained resistant to 80 mg kg- 1 hycanthone. Bueding and coworkers expanded the investigation of experimentally induced drug resistance in a subsequent paper, again with enigmatic results (Jansma et al., 1977). Further to the above study, the effect of age of infection with regard to drug
~ 1917 1917 1946
1962
1964 1967
1973
1975
Antimonials Emetine Lucanthone
Metrifonate
Niridazole Hycanthone
Oxamniquine
Praziquantel
aReferences dealing with drug resistance.
Introduction
Compound
+
-
+ +
+
+ + ÷
S. haematobium
Activity against
+
-
+ -
-
+ + -
S. japonicum
+
+
+ +
_
+ + ÷
S. mansoni
_
+
_ +
?
_ _ ÷
Drug resistance
Brief history of compounds employed in the treatment of human schistosomiasis and the appearance of drug resistance
TABLE 1
Christopherson ( 1918), Grove (1990) Grove (1990) Kilkuth and Gonnert (1948) Rogers and Bueding ( 1971 )a Cerf et al. (1962) Feldmeier et al. (1982) Coles and Bruce (1987) a Lambert (1964) Rosi et al. (1965) Rogers and Bueding (1971)a Archer (1985) Jansma et al. (1977) a Dias et al. (1982) a Andrews (1985) Yue et al. (1990) a
References
216
administration and the geographical origin of laboratory strains of S. mansoni

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