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Anthelminthic drug safety and drug administration in the control of soil-transmitted helminthiasis in community campaigns
Acta Tropica 86 (2003) 215 /221 www.parasitology-online.com
Review article
Anthelminthic drug safety and drug administration in the control of soil-transmitted helminthiasis in community campaigns Carlo Urbani a, Marco Albonico b,* a Vectorborne and other Parasitic Diseases, World Health Organisation, P.O. Box 52, Hanoi, Viet Nam b Ivo de Carneri Foundation, Via IV Marzo 14, 10122 Turin, Italy
Abstract Helminth infections are now recognised as being a major health priority worldwide. Morbidity due to these infections can be controlled at a reasonable cost by means of periodic chemotherapy using effective drugs. Deworming campaigns targeted at high risk groups, such as school-age children, pre-school children and women of child-bearing age, are the mainstay of the control strategy launched by WHO. Anthelminthic drugs can be delivered effectively through the school system, women’s associations or other community-based interventions, each of which often lack health personnel supervision. The safety of anthelminthic drugs is, therefore, of paramount importance and side effects have to be recognised and monitored, especially when generic drugs are widespread. Four anthelminthic drugs are considered to provide appropriate single dose treatment against soil-transmitted helminthiasis: albendazole, levamisole, mebendazole and pyrantel. Side effects, at the dosage recommended for deworming, have been described as negligible and selflimiting. However, a limited number of reports have associated more severe adverse reactions to the distribution of anthelminthic medicines. Even if the available information cannot confirm a cause /effect relationship, it is essential that these effects are known. Ministries of Health can then set up efficient and safe delivery, monitoring and referral systems, in order to minimise the risk and maximise the benefit of periodic anthelminthic chemotherapy in communities where soil-transmitted helminthiasis is endemic. # 2003 Elsevier Science B.V. All rights reserved. Keywords: Anthelminthic drugs; Drug safety; Side effects; Periodic chemotherapy
1. Introduction There is overwhelming evidence that several helminth infections have a detrimental effect on the health status of large groups of the human
* Corresponding author. Tel./fax: /39-011-436-1474. E-mail address: [email protected] (M. Albonico).
population. Millions of people suffer because of disease caused by soil-transmitted helminths and schistosomes (Crompton, 1999). In recent years, helminth infections have attracted an increasing interest and there is now broad consensus that they should be a priority for the improved health in large parts of the world population. WHO considered the control of schistosomiasis and soil-transmitted helminths as being
0001-706X/03/$ - see front matter # 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0001-706X(03)00036-6
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amongst the top five health priorities within the global Massive Effort Against Poverty. Based on guidelines and technical assistance, WHO has encouraged its member states to set up control programmes. (Savioli et al., 1992; Montresor et al., 1998). Recently, the 54th World Health Assembly adopted a resolution expressing its concern about the global impact of soil-transmitted helminthiasis and schistosomiasis, particularly in the poorest sections of the population (WHO, 2000). There is evidence that three principal strategies serve as effective tools in decreasing the burden of helminth infections on human health. These are periodic universal drug administration, health education and information campaigns and the augmentation of knowledge and skills with regard to the infections in the public health system at central and peripheral levels (Albonico et al., 1999). If family poverty, lack of proper hygiene and sanitation are the main factors causing these diseases to persist, the economic situation in most endemic countries makes the aim of improving the standard of living and sanitation a difficult task. Therefore, current strategies have been developed to target morbidity control by means of regular universal anthelminthic drug distribution (Urbani and Palmer, 2001). The positive experiences from large-scale control programmes, the scientific evidence, and a broad consensus of key partners, have enabled WHO to outline a comprehensive strategy to reduce the impact of these infections. Key elements include the ensured availability of single-dose anthelminthics in primary health care services and the regular treatment of high-risk groups (WHO, 1996a). In particular, periodic chemotherapy with safely-tested, single-dose, affordable drugs at regular intervals ensures that levels of infection can be kept below those associated with morbidity, thereby improving the health and development of individuals, especially of children. WHO now advocates the regular treatment of at least 75% of all school-age children at risk of morbidity by 2010 (WHO, 2000), and also the treatment of children through the Integrated Management of Childhood Illness (IMCI) strategy. The treatment of pregnant women at risk of
iron-deficiency anaemia from hookworm infection is also recommended (WHO, 1996b). The evidence of the efficacy and cost-effectiveness of helminth control through periodic chemotherapy has been demonstrated in many countries (WHO, 1996a). The main target group for intervention is school-age children. Epidemiological studies show this group to be most affected by soil-transmitted helminth infections within the whole population (Bundy et al., 1992). In developing countries, the school network is usually better established than the health system; remote villages without health facilities often have a primary school. This is why, in recent years, the use of the education sector for the delivery of appropriate treatment has been emphasised as a practical means for improving schoolchildren’s health (Bundy et al., 1990). The issue of anthelminthic drug use in women of childbearing age has been recently addressed by a WHO Informal consultation (WHO, 1996b). This recommended that where hookworm infections are endemic and iron deficiency anaemia is a public health problem, women can receive anthelminthic drugs but not normally during the first trimester of pregnancy. There is increasing evidence that pre-school children will benefit from anthelminthic treatment, even though their infection may not be as high compared with other age groups (Stoltzfus et al., 2001). Therefore, there is a need to investigate anthelminthic drug safety in children under two. This group has been excluded from treatment with benzimidazoles from prescribing informationhowever, this is based mainly on the lack of evidence for any beneficial health impact in this age-group, rather than on possible toxicity or side effects. The introduction of drug distribution to target groups or populations raises the issue of drug safety. When treatment is away from health sector supervision, the community needs full assurance that treatment will be safe.
2. Anthelminthic drugs Listed in the WHO (1997) Model List of Essential Drugs, are four drugs (albendazole,
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levamisole, mebendazole and pyrantel pamoate) that are recommended for programmes using widespread drug distribution for the control of soil-transmitted helminthiasis. Albendazole is available in pharmaceutical form as chewable tablets (200 and 400 mg) and as an oral suspension (100 mg/5 ml). A single dose of 400 mg is highly effective against ascariasis, enterobiasis and hookworm infections. In comparison with mebendazole, albendazole has shown better results in the treatment of hookworm infections (Bennet and Guyatt, 2000). Strongyloidiasis and heavy Trichuris trichiura infection may require a 3-day course of treatment (WHO, 1995). Albendazole, like other benzimidazoles, exerts its action by selectively binding to nematode tubulin, inhibiting the tubulin polymerase, which prevents the formation of microtubules and so impeding cell division. The drug also impairs the uptake of glucose, thereby increasing glycogen depletion, and hampering the formation of ATP which is used as the energy source by the worms (Lacey, 1990). The drug is poorly absorbed by the host and most of its anthelminthic action operates directly in the gastrointestinal tract. It is metabolised by the liver and its active metabolite (albendazole sulphoxide) is found in plasma at a peak concentration (0.04 /0.55 mg/l) after 1/4 h, when given at a higher dosage above 400 mg. When the drug is taken with a fatty meal, a 2/4 fold increase in plasma concentrations are observed. The plasma concentration of albendazole is found to be 15/49 times higher than that of mebendazole. The active sulphoxide metabolite has a half-life of 9 h in plasma. The absorbed fraction is largely excreted through the kidneys (the sulphoxide) and to some extent in the bile (Marriner et al., 1986; Gottschall et al., 1990). Albendazole sulphoxide crosses the blood /brain barrier and reaches a CSF concentration one third of the level in plasma (Jung et al., 1990). The bioavailability of the active sulphoxide metabolite is enhanced by cimetidine, an inhibitor of cytochrome P-450, that may suppress the metabolism of the drug (Wen et al., 1994). Mebendazole is available in pharmaceutical form as chewable tablets (100 and 500 mg), and as an oral suspension (100 mg/5 ml). A 500 mg single dose is effective against ascariasis, hook-
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worm disease and trichuriasis in universal and targeted chemotherapy-based control programmes. The ideal dosage for the hookworm and T. trichiura infections is 100 mg twice daily for 3 consecutive days (WHO, 1995). The drug is almost insoluble in water and is poorly absorbed from the gastrointestinal tract with an oral bioavailability of less than 20% (Dawson et al., 1985). Its absorption can be increased several times if taken with a fatty meal. Peak plasma levels are reached within 4 h (Munst et al., 1980). The concentration of mebendazole in plasma is detectable only with high dosages (1.5 g) (Dawson et al., 1985). The portion which is absorbed is rapidly metabolised by the liver and is excreted in the bile (Gottschall et al., 1990). Levamisole, the laevorotatory isomer of tetramisole, is commonly available in pharmaceutical form as chewable tablets (40 mg) and given at a dose of 2.5 mg/kg in a single administration. It has good efficacy against ascariasis and ancylostomiasis. Necator americanus infection may require a second dose after 1 week (WHO, 1995). Levamisole binds to the acetylcholine receptors of the autonomic ganglia causing a spastic contraction followed by a tonic paralysis of the nematode: the worms are then passively eliminated (Martin, 1993). The drug is highly soluble in water and is almost completely absorbed, rapidly, by the gastrointestinal tract. Peak plasma levels are reached within 2 h of administration. The drug is metabolised in the liver and the metabolites are eliminated in the urine within 2 days (Kouassi et al., 1986). Pyrantel pamoate, a pyrimidine derivative, is available in pharmaceutical form as chewable tablets (250 mg) as embonate and is given at a dose of 10 mg/kg in a single administration. It is effective against ascariasis and hookworm infections (WHO, 1995). Pyrantel has a similar mode of action to levamisole and causes spastic paralysis followed by passive elimination of the worms (Aubry et al., 1970). The drug is insoluble in water and is poorly absorbed by the gastrointestinal tract. Partially metabolised in the liver, a small percentage is excreted with the urine and a large amount is eliminated unchanged in faeces (Webster, 1991).
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3. Anthelminthic drugs and safety issues To date, millions of individuals have been routinely treated with these four anthelminthic drugs. The most widely used drugs are the benzimidazoles (albendazole and mebendazole) which are currently employed for large-scale distribution campaigns in school-age children. A recent overview of albendazole efficacy and safety has been published by Horton (2000). According to Horton, the incidence of side effects reported in the literature on the use of albendazole for intestinal helminthiasis is very low, with only transient mild gastrointestinal symptoms occurring in around 1% of treated individuals. The finding that albendazole is extremely well tolerated and easy to administer, both in the treatment of individuals and of whole communities, has led to its use by paramedical and non-medical personnel to improve general community health. Albendazole and mebendazole are also used in long term treatment regimens for echinococcosis. This long term treatment is also reported to be well tolerated (Reuter et al., 2000). However, after treatment with a single dose of albendazole (400 mg), minor and transient side effects can be seen. In a very small number of cases, migration of A. lumbricoides through the mouth, occasional gastrointestinal symptoms (epigastric pain 0.3%, diarrhoea 0.3%, nausea 0.2%, vomiting 0.1%), CNS symptoms (headache 0.2%, dizziness 0.1%), and rare allergic phenomena (oedema 0.7/1000, rashes 0.2/ 1000, urticaria 0.1/1000) have been reported. All these reactions are transient and disappear after 48 h (Rossignol and Maissonneuve, 1983; Coulaud and Rossignol, 1984; Albonico et al., 1994b). Liver function abnormalities and leucopenia have been occasionally reported, but only at higher dosages and after prolonged treatment (Morris and Smith, 1987; Davis et al., 1989). Albendazole can be given to children between 12 and 24 months at a dosage of 200 mg, and when administered to children 9/ 23 months of age, there was no evidence of any side effects or abnormalities in liver enzymes or in other haematological laboratory tests (Mbendi et al., 1988). In the case of mebendazole, a few instances are reported of erratic migration of A. lumbricoides ,
mild gastrointestinal disturbances, transient abdominal pain and diarrhoea (Chavarria et al., 1973; Muttalib et al., 1981; Albonico et al., 1994b). Only high doses (50 mg/kg for 3/4 weeks) such as those used for the treatment of hydatid disease, can give rise to severe abdominal pain, raised transaminase levels, allergic conditions, vertigo, headache, neutropenia and bone marrow depression (Miskovitz and Javitt, 1980; Kammerer and Schantz, 1984; Fernandez Banares et al., 1986; Issaragrisil et al., 1997). More recently, an outbreak of Stevens/Johnson syndrome among Filipino overseas contract workers who used mebendazole for helminthiasis prophylaxis was reported (Ajonuma and Chika, 2000). Moreover, Wilmshurst and Robb (1998) suggested a possible association between treatment with mebendazole and increased incidence of occipital seizures. Although mebendazole is not recommended in children below 2 years, studies have shown that the drug can be administered to younger children without any observable side effects (Albonico et al., 1994a; Montresor et al., 2002). Mebendazole and albendazole have been shown experimentally to have teratogenic potential in rats and rabbits at high dosages (van den Bossche et al., 1982; WHO, 1996b). The risk of congenital abnormalities when benzimidazoles are administered during pregnancy has been analysed by Bradley and Horton, (2001) and De Silva et al. (1999). These authors conclude that benzimidazole therapy during pregnancy is not associated with a significant increase in major congenital defects, but that treatment should be avoided during the first trimester. This therapy could offer beneficial effects to pregnant women in developing countries where intestinal helminthiasis is endemic by reducing iron-deficiency anaemia (WHO, 1996b). There is no evidence to suggest that maternal albendazole therapy presents a risk to breast-fed babies. Levamisole has been used for mass administration in China, Iran, Vietnam, Brazil, Kenya, and Nigeria. Reported side effects were occasional vomiting (5%), dizziness (3%), headache (3%), and weakness (2%); all were mild and transient (Lionel et al., 1969; Farid et al., 1977). No abnormalities in haematological laboratory tests
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have been detected at a single dose of 2.5 mg/kg. Although levamisole is regarded as a well-tolerated treatment, it has been associated with a low risk of developing encephalitis syndromes involving the CNS in a large cohort study in China. The incidence of the syndrome in the levamisole treated group was 5/10 000, significantly different from matched untreated controls (Zheng et al., 1992). Recently, the use of levamisole in soil-transmitted helminthiasis control has been associated with several severe CNS disorders in Vietnam. A total of 116 cases were observed in North Vietnam during the period 1994 /2000 following assumption of locally produced levamisole (Centre for Adverse Drug Reaction, Ministry of Health, Vietnam, unpublished report). This report of severe adverse reactions from a generic levamisole raises the issue of quality assurance. If quality is not properly assessed, there is a risk that substandard or counterfeit drugs may affect therapeutic efficacy as well as increase the risk of toxicity and side effects. This could be potentially damaging to compliance of communities in chemotherapy based helminth control programmes. Levamisole has shown no teratogenic effect at doses up to 40 mg/kg in rats and in farm animals and it can be used in pregnancy, although it should not normally be administered during the first trimester (WHO, 1996b). Pyrantel has been extensively used in numerous helminth control programmes, particularly in South /East Asia and Latin America. In a study with 1506 individuals, side effects were mild and transient including occasional diarrhoea (4.3%), abdominal pain (4%), nausea (3.5%), vomiting (2%) and headache (3%) (Pitts and Migliardi, 1974). Transient raised serum transaminase was detected in 2% of patients. Tests in rats, sheep and rabbits have shown no teratogenic effects, but pyrantel should not normally be administered during the first trimester of pregnancy (WHO, 1996b). Anthelminthic drugs may be administered in combination. Albendazole treatment alone or in combination with praziquantel produced no appreciable side effects (Olds et al., 1999). The side effects of both medications together were no worse than those observed with praziquantel alone and
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co-administration is both safe and potentially more cost-effective (Olds et al., 1999). Mebendazole can be given in association with levamisole and this regimen has been shown to be more effective than either drug alone against the hookworms, without reported side effects (Albonico et al., 2003). Pyrantel in combination with oxantel has proved to be more effective against soiltransmitted nematodes than either drug alone (Lim, 1978; Cabrera et al., 1980), particularly against T. trichiura infection (Albonico et al., 2002) and no major adverse events were reported in large-scale helminth control programmes (Sasongko et al., 2003). In conclusion, although a range of minor side effects are associated with drugs used in the treatment of soil-transmitted helminthiasis, they are reported to be of mild intensity, transient and self-clearing. This general finding allows their distribution to be made by non-health staff, for instance teachers in school-based programmes. According to the data published so far, there is no evidence for side effects that would require immediate treatment and clinical care from expert staff following drug distribution. The few severe side effects described, including the encephalitis syndrome among subjects treated with levamisole, occurred either with higher dosages than those recommended in community deworming campaigns or with a delay of days after the treatment. Nevertheless, it is important that Ministries of Health are aware of this risk, however, remote. The quality of generic drugs is another parameter of paramount importance and should be carefully monitored as drugs of substandard quality may generate unexpected side effects even when taken at lower doses. The use of generic drugs represents an important source of budgetary ‘saving of money’ in the field of helminth control and raises concerns that drug efficacy or patient safety might be affected or compromised as generics could escape the strict quality control to which the original products are subjected. Considering the widespread use of generic anthelminthics for population-oriented interventions, programme managers must consider the issue of quality (quality control, distribution system, correct utilisation) and effectiveness. For this purpose, sur-
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veillance of pilot sites should be part of the overall strategy. The report, with extremely low frequency, of severe reactions indicates a need to set up effective reporting systems in community treatment campaigns. Data on side effects should be collected at central level, and made accessible without delays to the international scientific community.
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soil-transmitted helminth control program in Jakarta 1987 / 1999. In: Crompton, D.W.T., Montresor, A., Nesheim, M.C., Savioli, L. (Eds.). Controlling Disease due to SoilTransmitted Helminths 1987, World Health Organization, Geneva, in press. Savioli, L., Bundy, D.A.P., Tomkins, A., 1992. Intestinal parasitic infections: a soluble public health problem. Trans. R. Soc. Trop. Med. Hyg. 86, 353 /354. Stoltzfus, R.J., Kvalsvig, J.D., Chwaya, H.M., Montresor, A., Albonico, M., Tielsch, J.M., Savioli, L., Pollitt, E., 2001. Effects of iron supplementation and anthelmintic treatment on motor and language development of preschool children in Zanzibar: double blind, placebo controlled study. Br. Med. J. 323 (7326), 1389. Urbani, C., Palmer, K., 2001. Drug-based helminth control in Western Pacific countries: a general perspective. Trop. Med. Int. Health 6 (11), 935 /944. van den Bossche, H., Rochette, F., Horig, C., 1982. Mebendazole and related anthelminthics. Adv. Pharmacol. Chemother. 19, 67 /128. Webster, L.T., 1991. Drugs used in the chemotherapy of helminthiasis. In: Goodman Gilman, A., Rall, T.W., Nies, A.S., Taylor, P. (Eds.), The Pharmacological Basis of Therapeutics, eighth ed. Pergamon Press, pp. 959 /977. Wen, H., Zhang, H.W., Muhmut, M., Zou, P.F., New, R.R., Craig, P.S., 1994. Initial observation on albendazole in combination with cimetidine for the treatment of human cystic echinococcosis. Ann. Trop. Med. Parasitol. 88 (1), 49 /52. Wilmshurst, J.M., Robb, S.A., 1998. Can mebendazole cause lateralized occipital seizures. Eur. J. Paediatr. Neurol. 2 (6), 323 /324. World Health Organization (WHO), 1995. WHO Model Prescribing Information. Drugs used in parasitic diseases, second ed., Geneva. World Health Organization (WHO), 1996a. Report of the WHO informal consultation on the use of chemotherapy for the control of morbidity due to soil-transmitted nematodes in humans. Geneva 29 April to 1 May 1996. Division of Control of Tropical Diseases. WHO/CTD/SIP.96.2. Geneva. World Health Organization (WHO), 1996b. Report of the WHO Informal Consultation on hookworm infection and anaemia in girls and women. Division of Control of Tropical Diseases, WHO/CTD/SIP.96.1. Geneva. World Health Organization (WHO), 1997. The use of essential drugs. WHO Technical Report Series no. 867. Geneva. World Health Organization (WHO), 2000. Control of schistosomiasis and soil-transmitted helminth infections. Report by secretariat. 27 October 2000. Division of Communicable Diseases, EB107/31. Zheng, R.Y., Jiang, Z.C., Zhang, X., 1992. Relationship between levamisole and encephalitis syndrome. Chung Hua Nei Ko Tsa Chih 31(9), 530-2, 585.
Review article
Anthelminthic drug safety and drug administration in the control of soil-transmitted helminthiasis in community campaigns Carlo Urbani a, Marco Albonico b,* a Vectorborne and other Parasitic Diseases, World Health Organisation, P.O. Box 52, Hanoi, Viet Nam b Ivo de Carneri Foundation, Via IV Marzo 14, 10122 Turin, Italy
Abstract Helminth infections are now recognised as being a major health priority worldwide. Morbidity due to these infections can be controlled at a reasonable cost by means of periodic chemotherapy using effective drugs. Deworming campaigns targeted at high risk groups, such as school-age children, pre-school children and women of child-bearing age, are the mainstay of the control strategy launched by WHO. Anthelminthic drugs can be delivered effectively through the school system, women’s associations or other community-based interventions, each of which often lack health personnel supervision. The safety of anthelminthic drugs is, therefore, of paramount importance and side effects have to be recognised and monitored, especially when generic drugs are widespread. Four anthelminthic drugs are considered to provide appropriate single dose treatment against soil-transmitted helminthiasis: albendazole, levamisole, mebendazole and pyrantel. Side effects, at the dosage recommended for deworming, have been described as negligible and selflimiting. However, a limited number of reports have associated more severe adverse reactions to the distribution of anthelminthic medicines. Even if the available information cannot confirm a cause /effect relationship, it is essential that these effects are known. Ministries of Health can then set up efficient and safe delivery, monitoring and referral systems, in order to minimise the risk and maximise the benefit of periodic anthelminthic chemotherapy in communities where soil-transmitted helminthiasis is endemic. # 2003 Elsevier Science B.V. All rights reserved. Keywords: Anthelminthic drugs; Drug safety; Side effects; Periodic chemotherapy
1. Introduction There is overwhelming evidence that several helminth infections have a detrimental effect on the health status of large groups of the human
* Corresponding author. Tel./fax: /39-011-436-1474. E-mail address: [email protected] (M. Albonico).
population. Millions of people suffer because of disease caused by soil-transmitted helminths and schistosomes (Crompton, 1999). In recent years, helminth infections have attracted an increasing interest and there is now broad consensus that they should be a priority for the improved health in large parts of the world population. WHO considered the control of schistosomiasis and soil-transmitted helminths as being
0001-706X/03/$ - see front matter # 2003 Elsevier Science B.V. All rights reserved. doi:10.1016/S0001-706X(03)00036-6
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amongst the top five health priorities within the global Massive Effort Against Poverty. Based on guidelines and technical assistance, WHO has encouraged its member states to set up control programmes. (Savioli et al., 1992; Montresor et al., 1998). Recently, the 54th World Health Assembly adopted a resolution expressing its concern about the global impact of soil-transmitted helminthiasis and schistosomiasis, particularly in the poorest sections of the population (WHO, 2000). There is evidence that three principal strategies serve as effective tools in decreasing the burden of helminth infections on human health. These are periodic universal drug administration, health education and information campaigns and the augmentation of knowledge and skills with regard to the infections in the public health system at central and peripheral levels (Albonico et al., 1999). If family poverty, lack of proper hygiene and sanitation are the main factors causing these diseases to persist, the economic situation in most endemic countries makes the aim of improving the standard of living and sanitation a difficult task. Therefore, current strategies have been developed to target morbidity control by means of regular universal anthelminthic drug distribution (Urbani and Palmer, 2001). The positive experiences from large-scale control programmes, the scientific evidence, and a broad consensus of key partners, have enabled WHO to outline a comprehensive strategy to reduce the impact of these infections. Key elements include the ensured availability of single-dose anthelminthics in primary health care services and the regular treatment of high-risk groups (WHO, 1996a). In particular, periodic chemotherapy with safely-tested, single-dose, affordable drugs at regular intervals ensures that levels of infection can be kept below those associated with morbidity, thereby improving the health and development of individuals, especially of children. WHO now advocates the regular treatment of at least 75% of all school-age children at risk of morbidity by 2010 (WHO, 2000), and also the treatment of children through the Integrated Management of Childhood Illness (IMCI) strategy. The treatment of pregnant women at risk of
iron-deficiency anaemia from hookworm infection is also recommended (WHO, 1996b). The evidence of the efficacy and cost-effectiveness of helminth control through periodic chemotherapy has been demonstrated in many countries (WHO, 1996a). The main target group for intervention is school-age children. Epidemiological studies show this group to be most affected by soil-transmitted helminth infections within the whole population (Bundy et al., 1992). In developing countries, the school network is usually better established than the health system; remote villages without health facilities often have a primary school. This is why, in recent years, the use of the education sector for the delivery of appropriate treatment has been emphasised as a practical means for improving schoolchildren’s health (Bundy et al., 1990). The issue of anthelminthic drug use in women of childbearing age has been recently addressed by a WHO Informal consultation (WHO, 1996b). This recommended that where hookworm infections are endemic and iron deficiency anaemia is a public health problem, women can receive anthelminthic drugs but not normally during the first trimester of pregnancy. There is increasing evidence that pre-school children will benefit from anthelminthic treatment, even though their infection may not be as high compared with other age groups (Stoltzfus et al., 2001). Therefore, there is a need to investigate anthelminthic drug safety in children under two. This group has been excluded from treatment with benzimidazoles from prescribing informationhowever, this is based mainly on the lack of evidence for any beneficial health impact in this age-group, rather than on possible toxicity or side effects. The introduction of drug distribution to target groups or populations raises the issue of drug safety. When treatment is away from health sector supervision, the community needs full assurance that treatment will be safe.
2. Anthelminthic drugs Listed in the WHO (1997) Model List of Essential Drugs, are four drugs (albendazole,
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levamisole, mebendazole and pyrantel pamoate) that are recommended for programmes using widespread drug distribution for the control of soil-transmitted helminthiasis. Albendazole is available in pharmaceutical form as chewable tablets (200 and 400 mg) and as an oral suspension (100 mg/5 ml). A single dose of 400 mg is highly effective against ascariasis, enterobiasis and hookworm infections. In comparison with mebendazole, albendazole has shown better results in the treatment of hookworm infections (Bennet and Guyatt, 2000). Strongyloidiasis and heavy Trichuris trichiura infection may require a 3-day course of treatment (WHO, 1995). Albendazole, like other benzimidazoles, exerts its action by selectively binding to nematode tubulin, inhibiting the tubulin polymerase, which prevents the formation of microtubules and so impeding cell division. The drug also impairs the uptake of glucose, thereby increasing glycogen depletion, and hampering the formation of ATP which is used as the energy source by the worms (Lacey, 1990). The drug is poorly absorbed by the host and most of its anthelminthic action operates directly in the gastrointestinal tract. It is metabolised by the liver and its active metabolite (albendazole sulphoxide) is found in plasma at a peak concentration (0.04 /0.55 mg/l) after 1/4 h, when given at a higher dosage above 400 mg. When the drug is taken with a fatty meal, a 2/4 fold increase in plasma concentrations are observed. The plasma concentration of albendazole is found to be 15/49 times higher than that of mebendazole. The active sulphoxide metabolite has a half-life of 9 h in plasma. The absorbed fraction is largely excreted through the kidneys (the sulphoxide) and to some extent in the bile (Marriner et al., 1986; Gottschall et al., 1990). Albendazole sulphoxide crosses the blood /brain barrier and reaches a CSF concentration one third of the level in plasma (Jung et al., 1990). The bioavailability of the active sulphoxide metabolite is enhanced by cimetidine, an inhibitor of cytochrome P-450, that may suppress the metabolism of the drug (Wen et al., 1994). Mebendazole is available in pharmaceutical form as chewable tablets (100 and 500 mg), and as an oral suspension (100 mg/5 ml). A 500 mg single dose is effective against ascariasis, hook-
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worm disease and trichuriasis in universal and targeted chemotherapy-based control programmes. The ideal dosage for the hookworm and T. trichiura infections is 100 mg twice daily for 3 consecutive days (WHO, 1995). The drug is almost insoluble in water and is poorly absorbed from the gastrointestinal tract with an oral bioavailability of less than 20% (Dawson et al., 1985). Its absorption can be increased several times if taken with a fatty meal. Peak plasma levels are reached within 4 h (Munst et al., 1980). The concentration of mebendazole in plasma is detectable only with high dosages (1.5 g) (Dawson et al., 1985). The portion which is absorbed is rapidly metabolised by the liver and is excreted in the bile (Gottschall et al., 1990). Levamisole, the laevorotatory isomer of tetramisole, is commonly available in pharmaceutical form as chewable tablets (40 mg) and given at a dose of 2.5 mg/kg in a single administration. It has good efficacy against ascariasis and ancylostomiasis. Necator americanus infection may require a second dose after 1 week (WHO, 1995). Levamisole binds to the acetylcholine receptors of the autonomic ganglia causing a spastic contraction followed by a tonic paralysis of the nematode: the worms are then passively eliminated (Martin, 1993). The drug is highly soluble in water and is almost completely absorbed, rapidly, by the gastrointestinal tract. Peak plasma levels are reached within 2 h of administration. The drug is metabolised in the liver and the metabolites are eliminated in the urine within 2 days (Kouassi et al., 1986). Pyrantel pamoate, a pyrimidine derivative, is available in pharmaceutical form as chewable tablets (250 mg) as embonate and is given at a dose of 10 mg/kg in a single administration. It is effective against ascariasis and hookworm infections (WHO, 1995). Pyrantel has a similar mode of action to levamisole and causes spastic paralysis followed by passive elimination of the worms (Aubry et al., 1970). The drug is insoluble in water and is poorly absorbed by the gastrointestinal tract. Partially metabolised in the liver, a small percentage is excreted with the urine and a large amount is eliminated unchanged in faeces (Webster, 1991).
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3. Anthelminthic drugs and safety issues To date, millions of individuals have been routinely treated with these four anthelminthic drugs. The most widely used drugs are the benzimidazoles (albendazole and mebendazole) which are currently employed for large-scale distribution campaigns in school-age children. A recent overview of albendazole efficacy and safety has been published by Horton (2000). According to Horton, the incidence of side effects reported in the literature on the use of albendazole for intestinal helminthiasis is very low, with only transient mild gastrointestinal symptoms occurring in around 1% of treated individuals. The finding that albendazole is extremely well tolerated and easy to administer, both in the treatment of individuals and of whole communities, has led to its use by paramedical and non-medical personnel to improve general community health. Albendazole and mebendazole are also used in long term treatment regimens for echinococcosis. This long term treatment is also reported to be well tolerated (Reuter et al., 2000). However, after treatment with a single dose of albendazole (400 mg), minor and transient side effects can be seen. In a very small number of cases, migration of A. lumbricoides through the mouth, occasional gastrointestinal symptoms (epigastric pain 0.3%, diarrhoea 0.3%, nausea 0.2%, vomiting 0.1%), CNS symptoms (headache 0.2%, dizziness 0.1%), and rare allergic phenomena (oedema 0.7/1000, rashes 0.2/ 1000, urticaria 0.1/1000) have been reported. All these reactions are transient and disappear after 48 h (Rossignol and Maissonneuve, 1983; Coulaud and Rossignol, 1984; Albonico et al., 1994b). Liver function abnormalities and leucopenia have been occasionally reported, but only at higher dosages and after prolonged treatment (Morris and Smith, 1987; Davis et al., 1989). Albendazole can be given to children between 12 and 24 months at a dosage of 200 mg, and when administered to children 9/ 23 months of age, there was no evidence of any side effects or abnormalities in liver enzymes or in other haematological laboratory tests (Mbendi et al., 1988). In the case of mebendazole, a few instances are reported of erratic migration of A. lumbricoides ,
mild gastrointestinal disturbances, transient abdominal pain and diarrhoea (Chavarria et al., 1973; Muttalib et al., 1981; Albonico et al., 1994b). Only high doses (50 mg/kg for 3/4 weeks) such as those used for the treatment of hydatid disease, can give rise to severe abdominal pain, raised transaminase levels, allergic conditions, vertigo, headache, neutropenia and bone marrow depression (Miskovitz and Javitt, 1980; Kammerer and Schantz, 1984; Fernandez Banares et al., 1986; Issaragrisil et al., 1997). More recently, an outbreak of Stevens/Johnson syndrome among Filipino overseas contract workers who used mebendazole for helminthiasis prophylaxis was reported (Ajonuma and Chika, 2000). Moreover, Wilmshurst and Robb (1998) suggested a possible association between treatment with mebendazole and increased incidence of occipital seizures. Although mebendazole is not recommended in children below 2 years, studies have shown that the drug can be administered to younger children without any observable side effects (Albonico et al., 1994a; Montresor et al., 2002). Mebendazole and albendazole have been shown experimentally to have teratogenic potential in rats and rabbits at high dosages (van den Bossche et al., 1982; WHO, 1996b). The risk of congenital abnormalities when benzimidazoles are administered during pregnancy has been analysed by Bradley and Horton, (2001) and De Silva et al. (1999). These authors conclude that benzimidazole therapy during pregnancy is not associated with a significant increase in major congenital defects, but that treatment should be avoided during the first trimester. This therapy could offer beneficial effects to pregnant women in developing countries where intestinal helminthiasis is endemic by reducing iron-deficiency anaemia (WHO, 1996b). There is no evidence to suggest that maternal albendazole therapy presents a risk to breast-fed babies. Levamisole has been used for mass administration in China, Iran, Vietnam, Brazil, Kenya, and Nigeria. Reported side effects were occasional vomiting (5%), dizziness (3%), headache (3%), and weakness (2%); all were mild and transient (Lionel et al., 1969; Farid et al., 1977). No abnormalities in haematological laboratory tests
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have been detected at a single dose of 2.5 mg/kg. Although levamisole is regarded as a well-tolerated treatment, it has been associated with a low risk of developing encephalitis syndromes involving the CNS in a large cohort study in China. The incidence of the syndrome in the levamisole treated group was 5/10 000, significantly different from matched untreated controls (Zheng et al., 1992). Recently, the use of levamisole in soil-transmitted helminthiasis control has been associated with several severe CNS disorders in Vietnam. A total of 116 cases were observed in North Vietnam during the period 1994 /2000 following assumption of locally produced levamisole (Centre for Adverse Drug Reaction, Ministry of Health, Vietnam, unpublished report). This report of severe adverse reactions from a generic levamisole raises the issue of quality assurance. If quality is not properly assessed, there is a risk that substandard or counterfeit drugs may affect therapeutic efficacy as well as increase the risk of toxicity and side effects. This could be potentially damaging to compliance of communities in chemotherapy based helminth control programmes. Levamisole has shown no teratogenic effect at doses up to 40 mg/kg in rats and in farm animals and it can be used in pregnancy, although it should not normally be administered during the first trimester (WHO, 1996b). Pyrantel has been extensively used in numerous helminth control programmes, particularly in South /East Asia and Latin America. In a study with 1506 individuals, side effects were mild and transient including occasional diarrhoea (4.3%), abdominal pain (4%), nausea (3.5%), vomiting (2%) and headache (3%) (Pitts and Migliardi, 1974). Transient raised serum transaminase was detected in 2% of patients. Tests in rats, sheep and rabbits have shown no teratogenic effects, but pyrantel should not normally be administered during the first trimester of pregnancy (WHO, 1996b). Anthelminthic drugs may be administered in combination. Albendazole treatment alone or in combination with praziquantel produced no appreciable side effects (Olds et al., 1999). The side effects of both medications together were no worse than those observed with praziquantel alone and
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co-administration is both safe and potentially more cost-effective (Olds et al., 1999). Mebendazole can be given in association with levamisole and this regimen has been shown to be more effective than either drug alone against the hookworms, without reported side effects (Albonico et al., 2003). Pyrantel in combination with oxantel has proved to be more effective against soiltransmitted nematodes than either drug alone (Lim, 1978; Cabrera et al., 1980), particularly against T. trichiura infection (Albonico et al., 2002) and no major adverse events were reported in large-scale helminth control programmes (Sasongko et al., 2003). In conclusion, although a range of minor side effects are associated with drugs used in the treatment of soil-transmitted helminthiasis, they are reported to be of mild intensity, transient and self-clearing. This general finding allows their distribution to be made by non-health staff, for instance teachers in school-based programmes. According to the data published so far, there is no evidence for side effects that would require immediate treatment and clinical care from expert staff following drug distribution. The few severe side effects described, including the encephalitis syndrome among subjects treated with levamisole, occurred either with higher dosages than those recommended in community deworming campaigns or with a delay of days after the treatment. Nevertheless, it is important that Ministries of Health are aware of this risk, however, remote. The quality of generic drugs is another parameter of paramount importance and should be carefully monitored as drugs of substandard quality may generate unexpected side effects even when taken at lower doses. The use of generic drugs represents an important source of budgetary ‘saving of money’ in the field of helminth control and raises concerns that drug efficacy or patient safety might be affected or compromised as generics could escape the strict quality control to which the original products are subjected. Considering the widespread use of generic anthelminthics for population-oriented interventions, programme managers must consider the issue of quality (quality control, distribution system, correct utilisation) and effectiveness. For this purpose, sur-
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veillance of pilot sites should be part of the overall strategy. The report, with extremely low frequency, of severe reactions indicates a need to set up effective reporting systems in community treatment campaigns. Data on side effects should be collected at central level, and made accessible without delays to the international scientific community.
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