- Email: [email protected]
Topical application of DEET for schistosomiasis
Update
TRENDS in Parasitology
women and special occupation groups) will help to avoid the worst effects of infection, even if there is no improvement in safe water supply or sanitation [6]. Treatment with any of the anthelminthic drugs on the WHO essential drugs list (albendazole, levamisole, mebendazole or pyrantel) is safe, even when given to uninfected people, and thus there is no need for individual screening. The WHO recommendations on how frequently to deliver targeted treatment to high-risk groups in different endemic situations have recently been revised [17]. As a complementary approach to hookworm control, work is under way to develop a recombinant hookworm vaccine. The vaccine relies on a cocktail of recombinant larval and adult hookworm antigens, which reproduce some of the effects of live attenuated larval vaccines, in addition to vaccines that target parasite digestion and blood feeding [18]. Phase I trials to test the first recombinant larval antigen in humans are planned for 2004–2005 (http://www.sabin.org). The update presented here clearly indicates that STH infections must still be considered as the most prevalent infections of humankind. Although, in some regions, there has been a precipitous decline in STH prevalence primarily because of economic development and specific control, in many cases the prevalence rates are equivalent to those first estimated by Norman Stoll more than 50 years ago. The extraordinary numbers of STH infections, which approach two billion, are a reflection of a remarkably successful adaptation to parasitism by Ascaris, Trichuris, Necator and Ancylostoma nematodes. Short of dramatic improvements in the global economy, it appears unlikely that the prevalence of infection will decrease any time soon. However, despite this situation, the application on a large-scale of available simple and low-cost interventions can significantly control the morbidity due to these infections in the vulnerable groups. Acknowledgements Financial support for this work was provided by WHO, the Wellcome Trust, and the Disease Control Priorities Project of the Bill and Melinda Gates Foundation. We thank E.A. Padmasiri (WHO Southeast Asia regional office) and Dimbeswar Bora (National Institute of Communicable Diseases, Delhi) for their assistance in gathering prevalence data with regard to India.
References 1 Stoll, N.R. (1999) This Wormy World, 1947. J. Parasitol. 85, 392– 396
Vol.19 No.12 December 2003
551
2 Peters, W. (1978) In The Relevance of Parasitology to Human Welfare Today (Taylor, A.E.R. and Muller, R., eds), Blackwell Scientific 3 Bundy, D.A.P. and Cooper, E.S. (1989) Trichuris and trichuriasis in humans. Adv. Parasitol. 28, 107 – 173 4 Crompton, D.W.T. and Tulley, J.J. (1987) How much ascariasis is there in Africa. Parasitol. Today 3, 123 – 127 5 Chan, M-S. et al. (1994) The evaluation of potential global morbidity attributable to intestinal nematode infections. Parasitology 109, 373 – 387 6 Savioli, L. et al. (2002) Schistosomiasis and soil-transmitted helminth infections: forging control efforts. Trans. R. Soc. Trop. Med. Hyg. 96, 577 – 579 7 Brooker, S. et al. (2000) Towards an atlas of human helminth infection in sub-Saharan Africa: the use of geographical information systems (GIS). Parasitol. Today 16, 303 – 307 8 Brooker, S. et al. (2003) Mapping soil-transmitted helminth infection and implications for parasite control in Southeast Asia. Southeast Asian J. Trop. Med. Public Health 34, 24 – 36 9 Xu, L.O. et al. (1995) Soil-transmitted helminthiases: nationwide survey in China. Bull World Health Organ. 73, 507 – 513 10 de Silva, N.R. et al. (1997) Morbidity and mortality due to ascariasis: re-estimation and sensitivity analysis of global numbers at risk. Trop. Med. Int. Health 2, 519 – 528 11 Fenghua, S. et al. (1998) Epidemiology of human intestinal nematode infections in Wujiang and Pizhou counties, Jiangsu province, China. Southeast Asian J. Trop. Med. Public Health 29, 605– 610 12 Sachs, J.D., Steele, H. eds (2001) Macroeconomics and Health: Investing in Health for Economic Development: Report of the Commission on Macroeconomics and Health WHO 13 Gwatkin, D.R. and Guillot, M. (2000) The Burden of Disease Among the Global Poor: Current Situation, Future Trends, and Implications for Strategy, World Bank 14 Chai, J.Y. and Lee, S.H. (2001) The successful implementation of the nationwide control programme of ascariasis in Korea. In Collected Papers on the Control of Soil-Transmitted Helminthiases (Vol. 7) (Hayashi, S., ed.), pp. 284 – 293, Asian Parasite Control Organization 15 Hara, T. (2001) Large-scale control against intestinal helminthic infections in Japan, with special reference to the activities of Japan Association of Parasite Control. In Collected Papers on the Control of SoilTransmitted Helminthiases (Vol. 7) (Hayashi, S., ed.), pp. 267–271 16 Guyatt, H. (2000) Do intestinal nematodes affect productivity in adulthood? Parasitol. Today 16, 153 – 158 17 WHO Expert Committee, (2002) The prevention and control of schistosomiasis and soil-transmitted helminthiasis. World Health Organ. Tech. Rep. Ser. 912, 1 – 57 18 Hotez, P.J. et al. (2003) Progress in the development of a recombinant vaccine for human hookworm disease: the human hookworm vaccine initiative. Int. J. Parasitol. 33, 1245– 1258 19 United Nations Population Division, (2003) World Population Prospects: The 2002 Revision, United Nations Population Division, New York 1471-4922/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2003.10.002
Topical application of DEET for schistosomiasis Kalyanasundaram Ramaswamy, Yi-Xun He, Buz Salafsky and Takeshi Shibuya Department of Biomedical Sciences, College of Medicine, University of Illinois, 1601 Parkview Avenue, Rockford, IL 61107, USA
N, N-diethyl-m-toluamide (also known as DEET) is a broad-spectrum insect repellent that is used extensively against both human and animal pests, worldwide. Recent studies show that topical lipid formulations of Corresponding author: Kalyanasundaram Ramaswamy ([email protected]). http://parasites.trends.com
DEET, such as LipoDEET, are highly effective in killing schistosome cercariae in the skin. Minimal systemic absorption, low manufacturing cost, and a wide range of activity against insects and schistosomes potentially makes compounds such as LipoDEET an excellent prophylactic agent against human and animal
552
Update
TRENDS in Parasitology
schistosomiasis in endemic areas, especially for travelers, until an effective vaccine is available. An effective vaccine for human or animal schistosomiasis remains elusive, despite the high incidence of these infections in several parts of the world [1]. Schistosomiasis is a water-borne infection. The infective stages of the parasite, called cercariae, are released into fresh water by infected snails from several species such as Biomphalaria spp., Oncomelania spp. and Bulinus spp. Therefore, minimizing water contact and/or destruction of schistosome-bearing snails in endemic areas are probably the best ways to prevent this infection. Indeed, the St Lucia Island project, which involved a 15-year intense schistosomiasis control programme in St Lucia, is probably one of the greatest success stories of schistosomiasis control, indicating that it is possible to control and eradicate schistosomiasis in a well-contained region such as an island [2]. However, restricting people and animals from coming in to close contact with infected water sources in endemic areas in the mainland is an impracticable and daunting task [3]. Snail control in the mainland is probably a much more complicated preposition than that performed in an Island because of the vast area involved, cost of chemical or biological application, changing climatic conditions and several ecological problems [4]. Despite these hurdles, there are a few promising reports of partial success in the control of Schistosoma japonicum infection in mainland China and Philippines as a result of improved hygiene measures [5]. Another alternative to control schistosomiasis in endemic areas is mass chemotherapy with praziquantel, the only effective drug against schistosomiasis. Unfortunately, there are indications of potential drug resistance against praziquantel [6]. Added to this is the declining trend of reduced investment of pharmaceutical industries in drug research for tropical diseases mainly because of the high cost of drug development and registration [7]. Despite our enormous efforts directed towards schistosomiasis control during the past 50 years, schistosomiasis continues to be a global problem and there appears to be no decline in the incidence [8]. Infections with schistosomes occur when cercariae penetrate and enter into the body through intact skin. Therefore, blocking entry of cercariae into the skin could potentially control the infection. Over the years, several topical agents have been evaluated for their ability to block cercarial penetration into the skin [9– 17]. Some of these compounds are highly effective, but none have been further developed for clinical application possibly because of potential toxicity, difficulty in manufacturing and/or difficulty in applying under field conditions. Discovery of the cercaricidal property of DEET During a routine drug screening experiment, we made an accidental, but interesting observation that N, N-diethylm-toluamide (also known as DEET) is a potent cercaricidal agent [18]. When cercariae were placed in cavity slides coated with 7.5% DEET, there was a dramatic reduction in the motility of cercariae and they shed their tails. Within five mins after exposure to DEET, degenerative changes were evident in their tegument and deeper parenchyma of http://parasites.trends.com
Vol.19 No.12 December 2003
the cercariae. Ten mins exposure to DEET resulted in 100% death of cercariae. This observation led us to investigate the potential of DEET as a topical agent to prevent cercarial penetration into the skin [18]. Application of 20% DEET in isopropanol to the abdominal skin or tail of mice one hour before exposure to 100– 150 cercariae conferred 100% protection against infection. This confirmed the in vitro observations and the potential of developing DEET as a prophylactic agent against schistosomiasis. Subsequent studies by Secor et al. [19] and Twfeek [20] confirmed these findings. Further optimization studies showed that an application of 10% DEET in isopropanol to the skin 30 mins before infection confers 100% protection against S. mansoni infection in mice [18]. A preliminary study by Jackson et al.p on human subjects who visited Lake Malawi, a reservoir in Africa known for schistosomiasis, showed that application of 50% DEET over the whole body except scalp and genitalia prevented infection in 13 out of 15 individuals. The two infected individuals apparently had schistosomiasis before DEET application. It is not clear from their published report whether the two individuals were actually exposed to the infection or not in Lake Malawi. Nevertheless, this study suggests a potential for developing DEET as a prophylactic agent against schistosomiasis. Lipid formulation of DEET that resists water Schistosomiasis is acquired mainly through water contact. Therefore, a primary requisite for any topical antipenetration agent is that it should be water-resistant. Unfortunately, repeated studies using 10– 40% DEET in isopropanol failed to confer protection in mice when the skin was washed for 5 –60 mins after application [21]. This indicated that DEET preparations in alcohol wash off easily, and therefore might not be suitable as a topical agent for the prevention of schistosomiasis. This finding prompted the screening of several lipid-based hydrophobic chemicals to identify a suitable vehicle that will retain DEET on the skin. Among the various preparations tested, a liposome-based formulation called LipoDEET [22] gave excellent anti-schistosomiasis properties [21]. Studies using a mouse model showed that a single skin application of 20% LipoDEET conferred 100% protection against all three species of human schistosomes, Schistosoma mansoni, S. japonicum and Schistosoma haematobium (Table 1). The livers of LipoDEET-treated animals were apparently normal with no granulomas or other lesions (Figure 1). Pharmacokinetic studies suggested that LipoDEET is retained to the superficial layers of the skin and is not easily washed off with water. The loss of DEET activity was , 10% after washing the skin for 60 mins (applied with 20% LipoDEET) in water at 378C [21]. Washing the skin for 60 mins with water after a single application of 20% LipoDEET still conferred .75% protection against S. mansoni infection and .80% protection against S. japonicum infection (Figure 2). This suggested that, * Jackson, F., et al. (2002) Schistosomiasis prophylaxis using DEET. Abstract no. 263. 51st Annual Meeting of the American Society of Tropical Medicine and Hygiene held 10 –14th November 2002, in Denver, CO, USA.
Update
TRENDS in Parasitology
553
Vol.19 No.12 December 2003
Table 1. Effect of DEET preparations on worm establishmenta Agent (in 100 ml)
Isopropanol control 20% DEET Liposome control 20% LipoDEET Ref.
Schistosoma mansoni (in mice)b
Schistosoma japonicum (in mice)c
Schistosoma haematobium (in hamsters)d
Sample size#
Percentage establishment
Sample size#
Percentage establishment
Sample size#
Percentage establishment
10 10 10 10 [21]
78.47 ^ 7.48 0^0 82.60 ^ 4.67 0^0
10 10 ND 10 –e
70.30 ^ 11.06 0^0 ND 0^0
5 10 5 10 –f
46.00 ^ 16.83 0^0 38.00 ^ 17.27 0^0
a
Worm establishment was determined by perfusion on Day 39– 42 for Schistosoma mansoni, on Day 28– 32 for Schistosoma japonicum and on Day 80–95 for Schistosoma haematobium. ND, no data available. Mice were infected with 100 cercariae via the abdominal skin. c Mice were infected with 100 cercariae via the abdominal skin. d Hamsters were infected with 40 cercariae via the abdominal skin. e Data obtained from B. Salafsky et al. (2000) Topical application of a long-acting, safe, formulation of N-N-diethyl-m-toluamide (DEET) confers protection against Schistosoma japonicum. Abstract no. 507. 49th Annual meeting of the American Society of Tropical Medicine and Hygiene held 29th October to 2nd November 2000, in Houston, TX, USA. f Ramaswamy, K. and He, Y-X., unpublished data. b
in an endemic area, application of 20% LipoDEET to the skin before entering the water could substantially reduce the risk of infection. The anti-schistosomal activity is retained in the skin for up to 48 h if not washed with a detergent. Another interesting observation was that LipoDEET is minimally absorbed through the skin. Both high-performance liquid chromatography (HPLC) and tracer studies confirmed that only , 7% of LipoDEET applied to the skin was systemically absorbed compared with 80% for DEET preparations in an alcohol vehicle [21]. Despite the fact that DEET has been used safely for the past 50 years by millions of people, worldwide, there are a few reports and experimental evidence of toxicity associated with systemic absorption of DEET in humans and animals, especially, if the chemical is misused [23– 25]. The danger is more acute when DEET preparations containing alcohol were used [26,27]. Therefore, LipoDEET or a similar lipid-containing preparation of DEET that minimizes systemic absorption through the skin could be a safer formulation to reduce any possible DEETassociated toxicity [21,28]. When applied post-infection, LipoDEET was only partially effective in preventing worm establishment. Topical application of 20% LipoDEET to the abdominal skin 60 – 90 mins after exposure to infection with S. mansoni in
(a)
(b)
TRENDS in Parasitology
Figure 1. Effect of LipoDEET on liver pathology caused by Schistosoma japonicum. (a) Gross pathology of liver from a mouse 42 days post-infection with S. japonicum, showing several granulomatous foci. (b) Liver from a similarly infected mouse that had 20% LipoDEET applied topically to the skin 60 mins before infection. http://parasites.trends.com
mice resulted in a reduction in the number of worms established per mouse from 87.2 ^ 5.7 to 68.6 ^ 2.1. This post-exposure effect was slightly improved to 64.4 ^ 4.8% worm recovery when 20% LipoDEETwas applied 30–60 min after exposure to infection with S. mansoni. Because LipoDEET is minimally absorbed through the skin, it is possible that a higher concentration of DEET in the lipid formulation could enhance the therapeutic effect of LipoDEET. LipoDEET or other lipid-containing formulations of DEET are highly effective as prophylactic agents; however, their ability to limit the infection post-exposure seems to be only partial. The major factors that influence the use of an antiinfective compound under field conditions include its cost of manufacture and the ease of bringing it to the end user. In this respect, DEET appears to be highly cost-effective. Manufacture of LipoDEET requires only minimal facilities and can be easily produced in large quantities in an endemic area. The estimated cost for manufacturing 450 g of LipoDEET is , US$1 and 450 g of LipoDEET can be applied to ,12 5000 mm2 surface area. The laboratory investigations to date clearly demonstrate that lipid formulation of DEET is highly effective as a prophylactic agent. However, under field conditions, DEET by itself might not be sufficient to control schistosomiasis in an endemic area, rather lipid formulations of DEET could be used synergistically along with other control measures such as restricted water contact, snail control and prophylactic chemotherapy. DEET as a prophylactic agent for travelers Although chemical research has produced several DEET analogs and other related compounds, none has been consistently used or is as widespread as DEET. Since its first commercial application in 1956, DEET has become one of the most broadly used insect repellents for human and veterinary indications [29]. Repeated studies show that DEET is highly efficient in repelling various biting insects including mosquitoes, sandflies, tsetse, lice, fleas and ticks, which transmit deadly diseases such as malaria, filariasis, leishmaniasis, trypanosomiasis, west Nile fever, spirochetosis, lime disease, yellow fever and dengue fever. A recent study showed that topical application of LipoDEET is highly effective against ticks [30]. In
Update
554
Worms established (%)
(a)
TRENDS in Parasitology
100 80 60 40 * 20
* *
*
0 NW
5
60
C
LipoDEET
NW
5
60
C
Worms established (%)
100 80 60 40 * 20 *
*
0 NW
60
C
LipoDEET
NW
60
C
DEET
Effect of washing on Schistosoma japonicum worm establishment TRENDS in Parasitology
Figure 2. Effect of washing (for 5 mins and 60 mins) with water on the prophylactic activity of DEET and LipoDEET. Percentage of worm establishment in mice (10– 15 mice were used per group) was determined by perfusion on Day 39– 42 for Schistosoma mansoni (a) and on Day 28 –32 for Schistosoma japonicum (b). The asterisks indicate significant p , 0.01 when compared with control mice that were not washed. Data in Figure 2a were obtained from Ref. [21]. Data in Figure 2b were obtained from B. Salafsky et al. (2000) Topical application of a long-acting, safe, formulation of N-N-diethyl-m-toluamide (DEET) confers protection against Schistosoma japonicum. Abstract no. 507. 49th Annual meeting of the American Society of Tropical Medicine and Hygiene held 29th October to 2nd November 2000, in Houston, TX, USA. Abbreviations: 5, 5 mins of washing with water; 60, 60 mins of washing with water; C, control; NW, not washed.
schistosomiasis-endemic regions, people are also exposed to many of these insect-borne diseases. Thus, given its broad insect repellency and anti-schistosomal activity, LipoDEET or a similar lipid-containing preparation of DEET could be of benefit for travelers visiting an endemic area where schistosomiasis and other insect-borne infections are highly prevalent, especially if minimal water contact is expected. However, travelers should be made aware that, unlike insects that create a constant menace reminding the user to apply DEET, the cercarial penetration is an ‘invisible’ danger, requiring application of lipid-containing DEET to all the parts of the body exposed to the water. This is probably one of the major limitations of using DEET against schistosomiasis. Given the cercaricidal effect, a topical application of LipoDEET could also be used against cercarial dermatitis, an allergic skin reaction caused by the cutaneous migration of schistosomula of zoonotic schistosomes in the human skin. Previous studies using ethyl butylacetylaminopropionate (IR3535), http://parasites.trends.com
an insect repellent, formulated as an ointment was unsuccessful in preventing cercarial dermatitis in a group of individuals participating in an annual crosslake race in Annecy, France [31]. Therefore, it is important to develop a DEET preparation that does not wash off easily with water. Hence, the liposome preparation could have an advantage because the liposome can be formulated to stay in the skin for a longer duration of time by manipulating the size and charge of the liposome. However, minimizing water contact is the best way of protecting individuals and animals from schistosomiasis.
DEET
Effect of washing on Schistosoma mansoni worm establishment (b)
Vol.19 No.12 December 2003
Perspective DEET probably has one of the broadest spectrums of insect repellent activity. Despite the routine use of DEET by millions of people, only few adverse conditions have been reported over the past 50 years. New topical formulations of DEET, such as LipoDEET, are potentially safe and are probably ideal for travelers to endemic areas. In addition to protection against schistosomiasis, LipoDEET is also effective against a variety of biting insects that transmit deadly diseases. These unique advantages of lipid formulations of DEET, combined with the possibility of low-cost manufacturing in endemic areas, make them an attractive agent for the field control of schistosomiasis. The conclusions stated here are based largely on laboratory studies. Therefore, further field studies are warranted, in particular studies that evaluate the potential of lipid formulations of DEET in reducing the morbidity due to schistosomiasis in animals living in an endemic area. Similarly, the effects of DEET on post exposure to the infection have been tested only at lower concentrations of DEET. Given that the lipid formulations of DEET are minimally absorbed through the skin, it is possible that a higher concentration of DEET could be used with potentially greater success. Thus, it is becoming more apparent that LipoDEET or other lipid-containing preparations of DEET could be potentially developed into an excellent prophylactic agent against all major species of human and animal schistosomes. Acknowledgements Schistosoma mansoni and Schistosoma haematobium life cycle stages for this work were supplied through National Institute of Health – National Institutes of Allergy and Infectious Diseases contract NO1 – 55270. Schistosoma japonicum infected snails were obtained from Somei Kojima at the University of Tokyo, Japan.
References 1 Bergquist, R. et al. (2002) Blueprint for schistosomiasis vaccine development. Acta Trop. 82, 183– 192 2 Jordan, P. (1985) Schistosomiasis – the St Lucia project, Cambridge University Press, New York 3 Chen, X.Y. (2002) The challenges and strategies in schistosomiasis control program in China. Acta Trop. 82, 279 – 282 4 Morgan, J.A. et al. (2001) Schistosoma mansoni and Biomphalaria: past history and future trends. Parasitology 123(Suppl.), S211 – S228 5 Leonardo, L.R. et al. (2002) Difficulties and strategies in the control of schistosomiasis in the Philippines. Acta Trop. 82, 295 – 299 6 Doenhoff, M.J. et al. (2002) Resistance of Schistosoma mansoni to praziquantel: is there a problem? Trans. R. Soc. Trop. Med. Hyg. 96, 465 – 469 7 Bergquist, N.R. (2002) Schistosomiasis: from risk assessment to control. Trends Parasitol. 18, 309 – 314
Update
TRENDS in Parasitology
8 Engels, D. et al. (2002) The global epidemiological situation of schistosomiasis and new approaches to control and research. Acta Trop. 82, 139 – 146 9 Frischkorn, C.G. et al. (1978) Cercaricidal activity of some essential oils of plants from Brazil. Naturwissenschaften 65, 480– 483 10 Greene, L.K. et al. (1983) Amoscanate as a topically applied chemical for prophylaxis against Schistosoma mansoni infections in mice. Am. J. Trop. Med. Hyg. 32, 1356– 1363 11 Haas, W. (1984) Schistosoma mansoni: cercaricidal effect of 2-tetradecenoic acid, a penetration stimulant. Exp. Parasitol. 58, 215 – 222 12 Grenan, M.M. et al. (1985) Hexachlorophene as a topically applied chemical for prophylaxis against Schistosoma mansoni infections in mice. Rev. Inst. Med. Trop. Sao Paulo 27, 190 – 196 13 Miller, R.E. et al. (1986) Schistosoma mansoni: Salicylanilides as topical prophylactic against ceracarial penetration of mice. Exp. Parasitol. 61, 359 – 368 14 Naples, J.M. et al. (1992) Schistosoma mansoni: cercaricidal effects of cedarwood oil and various of its components. J. Trop. Med. Hyg. 95, 390 – 396 15 Abu-Elyazeed, R.R. et al. (1993) Field trial of 1% niclosamide as a topical antipenetrant to Schistosoma mansoni cercariae. Am. J. Trop. Med. Hyg. 49, 403 – 409 16 Perrett, S. et al. (1995) The plant molluscicide Millettia thonningii (Leguminosae) as a topical antischistosomal agent. J. Ethnopharmacol. 47, 49–54 17 Ingram, R.J. et al. (2002) Dimethicone barrier cream prevents infection of human skin by schistosome cercariae: evidence from Franz cell studies. J. Parasitol. 88, 399– 402 18 Salafsky, B. et al. (1998) Evaluation of N,N-diethyl-m-toluamide (DEET) as a topical agent for preventing skin penetration by cercariae of Schistosoma mansoni. Am. J. Trop. Med. Hyg. 58, 828 – 834 19 Secor, W.E. et al. (1999) Short report: prevention of Schistosoma mansoni infections in mice by the insect repellents AI3-37220 and N,N-diethyl-3-methylbenzamide. Am. J. Trop. Med. Hyg. 60, 1061–1062 20 Twfeek, G.M. (1999) The potential use of N, N-diethyl-m-toluamide
Vol.19 No.12 December 2003
21
22 23
24 25 26
27
28
29 30
31
555
(DEET) as a prophylactic agent in the control of schistosomiasis. J. Egypt. Soc. Parasitol. 29, 763 – 776 Salafsky, B. et al. (1999) Development and evaluation of LIPODEET, a new long-acting formulation of N, N-diethyl-m-toluamide (DEET) for the prevention of schistosomiasis. Am. J. Trop. Med. Hyg. 61, 743 – 750 Lipodeet is a patented product (U.S. Patent No. 6,447,801) Schoenig, G.P. et al. (1999) Evaluation of the chronic toxicity and oncogenicity of N,N-diethyl-m-toluamide (DEET). Toxicol. Sci. 47, 99 – 109 Goodyer, L. and Behrens, R.H. (1998) Short report: the safety and toxicity of insect repellents. Am. J. Trop. Med. Hyg. 59, 323 – 324 Dorman, D.C. et al. (1990) Fenvalerate/N,N-diethyl-m-toluamide (Deet) toxicosis in two cats. J. Am. Vet. Med. Assoc. 196, 100 – 102 Abdel-Rahman, A. et al. (2001) Subchronic dermal application of N,N-diethyl m-toluamide (DEET) and permethrin to adult rats, alone or in combination, causes diffuse neuronal cell death and cytoskeletal abnormalities in the cerebral cortex and the hippocampus, and Purkinje neuron loss in the cerebellum. Exp. Neurol. 172, 153 – 171 Briassoulis, G. et al. (2001) Toxic encephalopathy associated with use of DEET insect repellents: a case analysis of its toxicity in children. Hum. Exp. Toxicol. 20, 8 – 14 Ross, J.S. and Shah, J.C. (2000) Reduction in skin permeation of N,N-diethyl-m-toluamide (DEET) by altering the skin/vehicle partition coefficient. J. Control. Release 67, 211 – 221 Brown, M. and Hebert, A.A. (1997) Insect repellents: an overview. J. Am. Acad. Dermatol. 36, 243 – 249 Salafsky, B. et al. (2000) Short report: study on the efficacy of a new long-acting formulation of N, N-diethyl-m-toluamide (DEET) for the prevention of tick attachment. Am. J. Trop. Med. Hyg. 62, 169– 172 Caumes, E. et al. (2003) Failure of an ointment based on IR3535 (ethyl butylacetylaminopropionate) to prevent an outbreak of cercarial dermatitis during swimming races across Lake Annecy, France. Ann. Trop. Med. Parasitol. 97, 157– 163
1471-4922/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2003.10.001
| Letters
Did Herodotus describe the first airborne use of mosquito repellents? Derek Charlwood Danish Bilharziasis Laboratory, 1-D Jaergersborg Alle´, Charlottenlund, DK 2920, Denmark
Herodotus (2490 – 2428 BP ) is widely known in malariology for describing the use of mosquito nets (impregnated with fish odour) and towers to avoid mosquito bites [1]. I proposed that Herodotus also, inadvertently, described the first known use of a repellent lamp against mosquitoes. After describing fishing practices in the Nile, Herodotus states [2] ‘The Egyptians who live in the marsh-country use an oil extracted from the castor-oil plant. This plant, which grows wild in Greece, they call Kiki, and the Egyptian variety is very prolific and has a disagreeable smell. Their practice is to sow it along the banks of rivers and lakes, and when the fruit is gathered it is either bruised and pressed, or else boiled down, and the liquid thus obtained is of an oily nature and quite as good as oliveoil for burning in lamps, although the smell is unpleasant…The country is infested by swarms of gnats [mosquitoes], and the people have invented various Corresponding author: Derek Charlwood ([email protected]). http://parasites.trends.com
methods of dealing with them; south of the marshes they sleep at night on raised structures, which is a great benefit to them because the gnats are prevented by the wind from flying high; in the marsh-country itself they do not have these towers, but everyone, instead, provides himself with a net, which during the day he uses for fishing, and at night fixes up round his bed, and creeps in under it before he goes to sleep. For anyone to sleep wrapped in a cloak or in linen would be useless, for the gnats would bite through them; but they do not even attempt to get through the net’. If the people in the marsh-country used lamps, it must mean that, despite the mosquitoes, they stayed up some time before crawling under their nets. The mosquitoes in the marsh-country probably included a great number of Mansonia spp. that bite throughout the night. It could be argued that, given the high densities of mosquitoes reported, people would not have stayed up at all without a mosquito repellent.
TRENDS in Parasitology
women and special occupation groups) will help to avoid the worst effects of infection, even if there is no improvement in safe water supply or sanitation [6]. Treatment with any of the anthelminthic drugs on the WHO essential drugs list (albendazole, levamisole, mebendazole or pyrantel) is safe, even when given to uninfected people, and thus there is no need for individual screening. The WHO recommendations on how frequently to deliver targeted treatment to high-risk groups in different endemic situations have recently been revised [17]. As a complementary approach to hookworm control, work is under way to develop a recombinant hookworm vaccine. The vaccine relies on a cocktail of recombinant larval and adult hookworm antigens, which reproduce some of the effects of live attenuated larval vaccines, in addition to vaccines that target parasite digestion and blood feeding [18]. Phase I trials to test the first recombinant larval antigen in humans are planned for 2004–2005 (http://www.sabin.org). The update presented here clearly indicates that STH infections must still be considered as the most prevalent infections of humankind. Although, in some regions, there has been a precipitous decline in STH prevalence primarily because of economic development and specific control, in many cases the prevalence rates are equivalent to those first estimated by Norman Stoll more than 50 years ago. The extraordinary numbers of STH infections, which approach two billion, are a reflection of a remarkably successful adaptation to parasitism by Ascaris, Trichuris, Necator and Ancylostoma nematodes. Short of dramatic improvements in the global economy, it appears unlikely that the prevalence of infection will decrease any time soon. However, despite this situation, the application on a large-scale of available simple and low-cost interventions can significantly control the morbidity due to these infections in the vulnerable groups. Acknowledgements Financial support for this work was provided by WHO, the Wellcome Trust, and the Disease Control Priorities Project of the Bill and Melinda Gates Foundation. We thank E.A. Padmasiri (WHO Southeast Asia regional office) and Dimbeswar Bora (National Institute of Communicable Diseases, Delhi) for their assistance in gathering prevalence data with regard to India.
References 1 Stoll, N.R. (1999) This Wormy World, 1947. J. Parasitol. 85, 392– 396
Vol.19 No.12 December 2003
551
2 Peters, W. (1978) In The Relevance of Parasitology to Human Welfare Today (Taylor, A.E.R. and Muller, R., eds), Blackwell Scientific 3 Bundy, D.A.P. and Cooper, E.S. (1989) Trichuris and trichuriasis in humans. Adv. Parasitol. 28, 107 – 173 4 Crompton, D.W.T. and Tulley, J.J. (1987) How much ascariasis is there in Africa. Parasitol. Today 3, 123 – 127 5 Chan, M-S. et al. (1994) The evaluation of potential global morbidity attributable to intestinal nematode infections. Parasitology 109, 373 – 387 6 Savioli, L. et al. (2002) Schistosomiasis and soil-transmitted helminth infections: forging control efforts. Trans. R. Soc. Trop. Med. Hyg. 96, 577 – 579 7 Brooker, S. et al. (2000) Towards an atlas of human helminth infection in sub-Saharan Africa: the use of geographical information systems (GIS). Parasitol. Today 16, 303 – 307 8 Brooker, S. et al. (2003) Mapping soil-transmitted helminth infection and implications for parasite control in Southeast Asia. Southeast Asian J. Trop. Med. Public Health 34, 24 – 36 9 Xu, L.O. et al. (1995) Soil-transmitted helminthiases: nationwide survey in China. Bull World Health Organ. 73, 507 – 513 10 de Silva, N.R. et al. (1997) Morbidity and mortality due to ascariasis: re-estimation and sensitivity analysis of global numbers at risk. Trop. Med. Int. Health 2, 519 – 528 11 Fenghua, S. et al. (1998) Epidemiology of human intestinal nematode infections in Wujiang and Pizhou counties, Jiangsu province, China. Southeast Asian J. Trop. Med. Public Health 29, 605– 610 12 Sachs, J.D., Steele, H. eds (2001) Macroeconomics and Health: Investing in Health for Economic Development: Report of the Commission on Macroeconomics and Health WHO 13 Gwatkin, D.R. and Guillot, M. (2000) The Burden of Disease Among the Global Poor: Current Situation, Future Trends, and Implications for Strategy, World Bank 14 Chai, J.Y. and Lee, S.H. (2001) The successful implementation of the nationwide control programme of ascariasis in Korea. In Collected Papers on the Control of Soil-Transmitted Helminthiases (Vol. 7) (Hayashi, S., ed.), pp. 284 – 293, Asian Parasite Control Organization 15 Hara, T. (2001) Large-scale control against intestinal helminthic infections in Japan, with special reference to the activities of Japan Association of Parasite Control. In Collected Papers on the Control of SoilTransmitted Helminthiases (Vol. 7) (Hayashi, S., ed.), pp. 267–271 16 Guyatt, H. (2000) Do intestinal nematodes affect productivity in adulthood? Parasitol. Today 16, 153 – 158 17 WHO Expert Committee, (2002) The prevention and control of schistosomiasis and soil-transmitted helminthiasis. World Health Organ. Tech. Rep. Ser. 912, 1 – 57 18 Hotez, P.J. et al. (2003) Progress in the development of a recombinant vaccine for human hookworm disease: the human hookworm vaccine initiative. Int. J. Parasitol. 33, 1245– 1258 19 United Nations Population Division, (2003) World Population Prospects: The 2002 Revision, United Nations Population Division, New York 1471-4922/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2003.10.002
Topical application of DEET for schistosomiasis Kalyanasundaram Ramaswamy, Yi-Xun He, Buz Salafsky and Takeshi Shibuya Department of Biomedical Sciences, College of Medicine, University of Illinois, 1601 Parkview Avenue, Rockford, IL 61107, USA
N, N-diethyl-m-toluamide (also known as DEET) is a broad-spectrum insect repellent that is used extensively against both human and animal pests, worldwide. Recent studies show that topical lipid formulations of Corresponding author: Kalyanasundaram Ramaswamy ([email protected]). http://parasites.trends.com
DEET, such as LipoDEET, are highly effective in killing schistosome cercariae in the skin. Minimal systemic absorption, low manufacturing cost, and a wide range of activity against insects and schistosomes potentially makes compounds such as LipoDEET an excellent prophylactic agent against human and animal
552
Update
TRENDS in Parasitology
schistosomiasis in endemic areas, especially for travelers, until an effective vaccine is available. An effective vaccine for human or animal schistosomiasis remains elusive, despite the high incidence of these infections in several parts of the world [1]. Schistosomiasis is a water-borne infection. The infective stages of the parasite, called cercariae, are released into fresh water by infected snails from several species such as Biomphalaria spp., Oncomelania spp. and Bulinus spp. Therefore, minimizing water contact and/or destruction of schistosome-bearing snails in endemic areas are probably the best ways to prevent this infection. Indeed, the St Lucia Island project, which involved a 15-year intense schistosomiasis control programme in St Lucia, is probably one of the greatest success stories of schistosomiasis control, indicating that it is possible to control and eradicate schistosomiasis in a well-contained region such as an island [2]. However, restricting people and animals from coming in to close contact with infected water sources in endemic areas in the mainland is an impracticable and daunting task [3]. Snail control in the mainland is probably a much more complicated preposition than that performed in an Island because of the vast area involved, cost of chemical or biological application, changing climatic conditions and several ecological problems [4]. Despite these hurdles, there are a few promising reports of partial success in the control of Schistosoma japonicum infection in mainland China and Philippines as a result of improved hygiene measures [5]. Another alternative to control schistosomiasis in endemic areas is mass chemotherapy with praziquantel, the only effective drug against schistosomiasis. Unfortunately, there are indications of potential drug resistance against praziquantel [6]. Added to this is the declining trend of reduced investment of pharmaceutical industries in drug research for tropical diseases mainly because of the high cost of drug development and registration [7]. Despite our enormous efforts directed towards schistosomiasis control during the past 50 years, schistosomiasis continues to be a global problem and there appears to be no decline in the incidence [8]. Infections with schistosomes occur when cercariae penetrate and enter into the body through intact skin. Therefore, blocking entry of cercariae into the skin could potentially control the infection. Over the years, several topical agents have been evaluated for their ability to block cercarial penetration into the skin [9– 17]. Some of these compounds are highly effective, but none have been further developed for clinical application possibly because of potential toxicity, difficulty in manufacturing and/or difficulty in applying under field conditions. Discovery of the cercaricidal property of DEET During a routine drug screening experiment, we made an accidental, but interesting observation that N, N-diethylm-toluamide (also known as DEET) is a potent cercaricidal agent [18]. When cercariae were placed in cavity slides coated with 7.5% DEET, there was a dramatic reduction in the motility of cercariae and they shed their tails. Within five mins after exposure to DEET, degenerative changes were evident in their tegument and deeper parenchyma of http://parasites.trends.com
Vol.19 No.12 December 2003
the cercariae. Ten mins exposure to DEET resulted in 100% death of cercariae. This observation led us to investigate the potential of DEET as a topical agent to prevent cercarial penetration into the skin [18]. Application of 20% DEET in isopropanol to the abdominal skin or tail of mice one hour before exposure to 100– 150 cercariae conferred 100% protection against infection. This confirmed the in vitro observations and the potential of developing DEET as a prophylactic agent against schistosomiasis. Subsequent studies by Secor et al. [19] and Twfeek [20] confirmed these findings. Further optimization studies showed that an application of 10% DEET in isopropanol to the skin 30 mins before infection confers 100% protection against S. mansoni infection in mice [18]. A preliminary study by Jackson et al.p on human subjects who visited Lake Malawi, a reservoir in Africa known for schistosomiasis, showed that application of 50% DEET over the whole body except scalp and genitalia prevented infection in 13 out of 15 individuals. The two infected individuals apparently had schistosomiasis before DEET application. It is not clear from their published report whether the two individuals were actually exposed to the infection or not in Lake Malawi. Nevertheless, this study suggests a potential for developing DEET as a prophylactic agent against schistosomiasis. Lipid formulation of DEET that resists water Schistosomiasis is acquired mainly through water contact. Therefore, a primary requisite for any topical antipenetration agent is that it should be water-resistant. Unfortunately, repeated studies using 10– 40% DEET in isopropanol failed to confer protection in mice when the skin was washed for 5 –60 mins after application [21]. This indicated that DEET preparations in alcohol wash off easily, and therefore might not be suitable as a topical agent for the prevention of schistosomiasis. This finding prompted the screening of several lipid-based hydrophobic chemicals to identify a suitable vehicle that will retain DEET on the skin. Among the various preparations tested, a liposome-based formulation called LipoDEET [22] gave excellent anti-schistosomiasis properties [21]. Studies using a mouse model showed that a single skin application of 20% LipoDEET conferred 100% protection against all three species of human schistosomes, Schistosoma mansoni, S. japonicum and Schistosoma haematobium (Table 1). The livers of LipoDEET-treated animals were apparently normal with no granulomas or other lesions (Figure 1). Pharmacokinetic studies suggested that LipoDEET is retained to the superficial layers of the skin and is not easily washed off with water. The loss of DEET activity was , 10% after washing the skin for 60 mins (applied with 20% LipoDEET) in water at 378C [21]. Washing the skin for 60 mins with water after a single application of 20% LipoDEET still conferred .75% protection against S. mansoni infection and .80% protection against S. japonicum infection (Figure 2). This suggested that, * Jackson, F., et al. (2002) Schistosomiasis prophylaxis using DEET. Abstract no. 263. 51st Annual Meeting of the American Society of Tropical Medicine and Hygiene held 10 –14th November 2002, in Denver, CO, USA.
Update
TRENDS in Parasitology
553
Vol.19 No.12 December 2003
Table 1. Effect of DEET preparations on worm establishmenta Agent (in 100 ml)
Isopropanol control 20% DEET Liposome control 20% LipoDEET Ref.
Schistosoma mansoni (in mice)b
Schistosoma japonicum (in mice)c
Schistosoma haematobium (in hamsters)d
Sample size#
Percentage establishment
Sample size#
Percentage establishment
Sample size#
Percentage establishment
10 10 10 10 [21]
78.47 ^ 7.48 0^0 82.60 ^ 4.67 0^0
10 10 ND 10 –e
70.30 ^ 11.06 0^0 ND 0^0
5 10 5 10 –f
46.00 ^ 16.83 0^0 38.00 ^ 17.27 0^0
a
Worm establishment was determined by perfusion on Day 39– 42 for Schistosoma mansoni, on Day 28– 32 for Schistosoma japonicum and on Day 80–95 for Schistosoma haematobium. ND, no data available. Mice were infected with 100 cercariae via the abdominal skin. c Mice were infected with 100 cercariae via the abdominal skin. d Hamsters were infected with 40 cercariae via the abdominal skin. e Data obtained from B. Salafsky et al. (2000) Topical application of a long-acting, safe, formulation of N-N-diethyl-m-toluamide (DEET) confers protection against Schistosoma japonicum. Abstract no. 507. 49th Annual meeting of the American Society of Tropical Medicine and Hygiene held 29th October to 2nd November 2000, in Houston, TX, USA. f Ramaswamy, K. and He, Y-X., unpublished data. b
in an endemic area, application of 20% LipoDEET to the skin before entering the water could substantially reduce the risk of infection. The anti-schistosomal activity is retained in the skin for up to 48 h if not washed with a detergent. Another interesting observation was that LipoDEET is minimally absorbed through the skin. Both high-performance liquid chromatography (HPLC) and tracer studies confirmed that only , 7% of LipoDEET applied to the skin was systemically absorbed compared with 80% for DEET preparations in an alcohol vehicle [21]. Despite the fact that DEET has been used safely for the past 50 years by millions of people, worldwide, there are a few reports and experimental evidence of toxicity associated with systemic absorption of DEET in humans and animals, especially, if the chemical is misused [23– 25]. The danger is more acute when DEET preparations containing alcohol were used [26,27]. Therefore, LipoDEET or a similar lipid-containing preparation of DEET that minimizes systemic absorption through the skin could be a safer formulation to reduce any possible DEETassociated toxicity [21,28]. When applied post-infection, LipoDEET was only partially effective in preventing worm establishment. Topical application of 20% LipoDEET to the abdominal skin 60 – 90 mins after exposure to infection with S. mansoni in
(a)
(b)
TRENDS in Parasitology
Figure 1. Effect of LipoDEET on liver pathology caused by Schistosoma japonicum. (a) Gross pathology of liver from a mouse 42 days post-infection with S. japonicum, showing several granulomatous foci. (b) Liver from a similarly infected mouse that had 20% LipoDEET applied topically to the skin 60 mins before infection. http://parasites.trends.com
mice resulted in a reduction in the number of worms established per mouse from 87.2 ^ 5.7 to 68.6 ^ 2.1. This post-exposure effect was slightly improved to 64.4 ^ 4.8% worm recovery when 20% LipoDEETwas applied 30–60 min after exposure to infection with S. mansoni. Because LipoDEET is minimally absorbed through the skin, it is possible that a higher concentration of DEET in the lipid formulation could enhance the therapeutic effect of LipoDEET. LipoDEET or other lipid-containing formulations of DEET are highly effective as prophylactic agents; however, their ability to limit the infection post-exposure seems to be only partial. The major factors that influence the use of an antiinfective compound under field conditions include its cost of manufacture and the ease of bringing it to the end user. In this respect, DEET appears to be highly cost-effective. Manufacture of LipoDEET requires only minimal facilities and can be easily produced in large quantities in an endemic area. The estimated cost for manufacturing 450 g of LipoDEET is , US$1 and 450 g of LipoDEET can be applied to ,12 5000 mm2 surface area. The laboratory investigations to date clearly demonstrate that lipid formulation of DEET is highly effective as a prophylactic agent. However, under field conditions, DEET by itself might not be sufficient to control schistosomiasis in an endemic area, rather lipid formulations of DEET could be used synergistically along with other control measures such as restricted water contact, snail control and prophylactic chemotherapy. DEET as a prophylactic agent for travelers Although chemical research has produced several DEET analogs and other related compounds, none has been consistently used or is as widespread as DEET. Since its first commercial application in 1956, DEET has become one of the most broadly used insect repellents for human and veterinary indications [29]. Repeated studies show that DEET is highly efficient in repelling various biting insects including mosquitoes, sandflies, tsetse, lice, fleas and ticks, which transmit deadly diseases such as malaria, filariasis, leishmaniasis, trypanosomiasis, west Nile fever, spirochetosis, lime disease, yellow fever and dengue fever. A recent study showed that topical application of LipoDEET is highly effective against ticks [30]. In
Update
554
Worms established (%)
(a)
TRENDS in Parasitology
100 80 60 40 * 20
* *
*
0 NW
5
60
C
LipoDEET
NW
5
60
C
Worms established (%)
100 80 60 40 * 20 *
*
0 NW
60
C
LipoDEET
NW
60
C
DEET
Effect of washing on Schistosoma japonicum worm establishment TRENDS in Parasitology
Figure 2. Effect of washing (for 5 mins and 60 mins) with water on the prophylactic activity of DEET and LipoDEET. Percentage of worm establishment in mice (10– 15 mice were used per group) was determined by perfusion on Day 39– 42 for Schistosoma mansoni (a) and on Day 28 –32 for Schistosoma japonicum (b). The asterisks indicate significant p , 0.01 when compared with control mice that were not washed. Data in Figure 2a were obtained from Ref. [21]. Data in Figure 2b were obtained from B. Salafsky et al. (2000) Topical application of a long-acting, safe, formulation of N-N-diethyl-m-toluamide (DEET) confers protection against Schistosoma japonicum. Abstract no. 507. 49th Annual meeting of the American Society of Tropical Medicine and Hygiene held 29th October to 2nd November 2000, in Houston, TX, USA. Abbreviations: 5, 5 mins of washing with water; 60, 60 mins of washing with water; C, control; NW, not washed.
schistosomiasis-endemic regions, people are also exposed to many of these insect-borne diseases. Thus, given its broad insect repellency and anti-schistosomal activity, LipoDEET or a similar lipid-containing preparation of DEET could be of benefit for travelers visiting an endemic area where schistosomiasis and other insect-borne infections are highly prevalent, especially if minimal water contact is expected. However, travelers should be made aware that, unlike insects that create a constant menace reminding the user to apply DEET, the cercarial penetration is an ‘invisible’ danger, requiring application of lipid-containing DEET to all the parts of the body exposed to the water. This is probably one of the major limitations of using DEET against schistosomiasis. Given the cercaricidal effect, a topical application of LipoDEET could also be used against cercarial dermatitis, an allergic skin reaction caused by the cutaneous migration of schistosomula of zoonotic schistosomes in the human skin. Previous studies using ethyl butylacetylaminopropionate (IR3535), http://parasites.trends.com
an insect repellent, formulated as an ointment was unsuccessful in preventing cercarial dermatitis in a group of individuals participating in an annual crosslake race in Annecy, France [31]. Therefore, it is important to develop a DEET preparation that does not wash off easily with water. Hence, the liposome preparation could have an advantage because the liposome can be formulated to stay in the skin for a longer duration of time by manipulating the size and charge of the liposome. However, minimizing water contact is the best way of protecting individuals and animals from schistosomiasis.
DEET
Effect of washing on Schistosoma mansoni worm establishment (b)
Vol.19 No.12 December 2003
Perspective DEET probably has one of the broadest spectrums of insect repellent activity. Despite the routine use of DEET by millions of people, only few adverse conditions have been reported over the past 50 years. New topical formulations of DEET, such as LipoDEET, are potentially safe and are probably ideal for travelers to endemic areas. In addition to protection against schistosomiasis, LipoDEET is also effective against a variety of biting insects that transmit deadly diseases. These unique advantages of lipid formulations of DEET, combined with the possibility of low-cost manufacturing in endemic areas, make them an attractive agent for the field control of schistosomiasis. The conclusions stated here are based largely on laboratory studies. Therefore, further field studies are warranted, in particular studies that evaluate the potential of lipid formulations of DEET in reducing the morbidity due to schistosomiasis in animals living in an endemic area. Similarly, the effects of DEET on post exposure to the infection have been tested only at lower concentrations of DEET. Given that the lipid formulations of DEET are minimally absorbed through the skin, it is possible that a higher concentration of DEET could be used with potentially greater success. Thus, it is becoming more apparent that LipoDEET or other lipid-containing preparations of DEET could be potentially developed into an excellent prophylactic agent against all major species of human and animal schistosomes. Acknowledgements Schistosoma mansoni and Schistosoma haematobium life cycle stages for this work were supplied through National Institute of Health – National Institutes of Allergy and Infectious Diseases contract NO1 – 55270. Schistosoma japonicum infected snails were obtained from Somei Kojima at the University of Tokyo, Japan.
References 1 Bergquist, R. et al. (2002) Blueprint for schistosomiasis vaccine development. Acta Trop. 82, 183– 192 2 Jordan, P. (1985) Schistosomiasis – the St Lucia project, Cambridge University Press, New York 3 Chen, X.Y. (2002) The challenges and strategies in schistosomiasis control program in China. Acta Trop. 82, 279 – 282 4 Morgan, J.A. et al. (2001) Schistosoma mansoni and Biomphalaria: past history and future trends. Parasitology 123(Suppl.), S211 – S228 5 Leonardo, L.R. et al. (2002) Difficulties and strategies in the control of schistosomiasis in the Philippines. Acta Trop. 82, 295 – 299 6 Doenhoff, M.J. et al. (2002) Resistance of Schistosoma mansoni to praziquantel: is there a problem? Trans. R. Soc. Trop. Med. Hyg. 96, 465 – 469 7 Bergquist, N.R. (2002) Schistosomiasis: from risk assessment to control. Trends Parasitol. 18, 309 – 314
Update
TRENDS in Parasitology
8 Engels, D. et al. (2002) The global epidemiological situation of schistosomiasis and new approaches to control and research. Acta Trop. 82, 139 – 146 9 Frischkorn, C.G. et al. (1978) Cercaricidal activity of some essential oils of plants from Brazil. Naturwissenschaften 65, 480– 483 10 Greene, L.K. et al. (1983) Amoscanate as a topically applied chemical for prophylaxis against Schistosoma mansoni infections in mice. Am. J. Trop. Med. Hyg. 32, 1356– 1363 11 Haas, W. (1984) Schistosoma mansoni: cercaricidal effect of 2-tetradecenoic acid, a penetration stimulant. Exp. Parasitol. 58, 215 – 222 12 Grenan, M.M. et al. (1985) Hexachlorophene as a topically applied chemical for prophylaxis against Schistosoma mansoni infections in mice. Rev. Inst. Med. Trop. Sao Paulo 27, 190 – 196 13 Miller, R.E. et al. (1986) Schistosoma mansoni: Salicylanilides as topical prophylactic against ceracarial penetration of mice. Exp. Parasitol. 61, 359 – 368 14 Naples, J.M. et al. (1992) Schistosoma mansoni: cercaricidal effects of cedarwood oil and various of its components. J. Trop. Med. Hyg. 95, 390 – 396 15 Abu-Elyazeed, R.R. et al. (1993) Field trial of 1% niclosamide as a topical antipenetrant to Schistosoma mansoni cercariae. Am. J. Trop. Med. Hyg. 49, 403 – 409 16 Perrett, S. et al. (1995) The plant molluscicide Millettia thonningii (Leguminosae) as a topical antischistosomal agent. J. Ethnopharmacol. 47, 49–54 17 Ingram, R.J. et al. (2002) Dimethicone barrier cream prevents infection of human skin by schistosome cercariae: evidence from Franz cell studies. J. Parasitol. 88, 399– 402 18 Salafsky, B. et al. (1998) Evaluation of N,N-diethyl-m-toluamide (DEET) as a topical agent for preventing skin penetration by cercariae of Schistosoma mansoni. Am. J. Trop. Med. Hyg. 58, 828 – 834 19 Secor, W.E. et al. (1999) Short report: prevention of Schistosoma mansoni infections in mice by the insect repellents AI3-37220 and N,N-diethyl-3-methylbenzamide. Am. J. Trop. Med. Hyg. 60, 1061–1062 20 Twfeek, G.M. (1999) The potential use of N, N-diethyl-m-toluamide
Vol.19 No.12 December 2003
21
22 23
24 25 26
27
28
29 30
31
555
(DEET) as a prophylactic agent in the control of schistosomiasis. J. Egypt. Soc. Parasitol. 29, 763 – 776 Salafsky, B. et al. (1999) Development and evaluation of LIPODEET, a new long-acting formulation of N, N-diethyl-m-toluamide (DEET) for the prevention of schistosomiasis. Am. J. Trop. Med. Hyg. 61, 743 – 750 Lipodeet is a patented product (U.S. Patent No. 6,447,801) Schoenig, G.P. et al. (1999) Evaluation of the chronic toxicity and oncogenicity of N,N-diethyl-m-toluamide (DEET). Toxicol. Sci. 47, 99 – 109 Goodyer, L. and Behrens, R.H. (1998) Short report: the safety and toxicity of insect repellents. Am. J. Trop. Med. Hyg. 59, 323 – 324 Dorman, D.C. et al. (1990) Fenvalerate/N,N-diethyl-m-toluamide (Deet) toxicosis in two cats. J. Am. Vet. Med. Assoc. 196, 100 – 102 Abdel-Rahman, A. et al. (2001) Subchronic dermal application of N,N-diethyl m-toluamide (DEET) and permethrin to adult rats, alone or in combination, causes diffuse neuronal cell death and cytoskeletal abnormalities in the cerebral cortex and the hippocampus, and Purkinje neuron loss in the cerebellum. Exp. Neurol. 172, 153 – 171 Briassoulis, G. et al. (2001) Toxic encephalopathy associated with use of DEET insect repellents: a case analysis of its toxicity in children. Hum. Exp. Toxicol. 20, 8 – 14 Ross, J.S. and Shah, J.C. (2000) Reduction in skin permeation of N,N-diethyl-m-toluamide (DEET) by altering the skin/vehicle partition coefficient. J. Control. Release 67, 211 – 221 Brown, M. and Hebert, A.A. (1997) Insect repellents: an overview. J. Am. Acad. Dermatol. 36, 243 – 249 Salafsky, B. et al. (2000) Short report: study on the efficacy of a new long-acting formulation of N, N-diethyl-m-toluamide (DEET) for the prevention of tick attachment. Am. J. Trop. Med. Hyg. 62, 169– 172 Caumes, E. et al. (2003) Failure of an ointment based on IR3535 (ethyl butylacetylaminopropionate) to prevent an outbreak of cercarial dermatitis during swimming races across Lake Annecy, France. Ann. Trop. Med. Parasitol. 97, 157– 163
1471-4922/$ - see front matter q 2003 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2003.10.001
| Letters
Did Herodotus describe the first airborne use of mosquito repellents? Derek Charlwood Danish Bilharziasis Laboratory, 1-D Jaergersborg Alle´, Charlottenlund, DK 2920, Denmark
Herodotus (2490 – 2428 BP ) is widely known in malariology for describing the use of mosquito nets (impregnated with fish odour) and towers to avoid mosquito bites [1]. I proposed that Herodotus also, inadvertently, described the first known use of a repellent lamp against mosquitoes. After describing fishing practices in the Nile, Herodotus states [2] ‘The Egyptians who live in the marsh-country use an oil extracted from the castor-oil plant. This plant, which grows wild in Greece, they call Kiki, and the Egyptian variety is very prolific and has a disagreeable smell. Their practice is to sow it along the banks of rivers and lakes, and when the fruit is gathered it is either bruised and pressed, or else boiled down, and the liquid thus obtained is of an oily nature and quite as good as oliveoil for burning in lamps, although the smell is unpleasant…The country is infested by swarms of gnats [mosquitoes], and the people have invented various Corresponding author: Derek Charlwood ([email protected]). http://parasites.trends.com
methods of dealing with them; south of the marshes they sleep at night on raised structures, which is a great benefit to them because the gnats are prevented by the wind from flying high; in the marsh-country itself they do not have these towers, but everyone, instead, provides himself with a net, which during the day he uses for fishing, and at night fixes up round his bed, and creeps in under it before he goes to sleep. For anyone to sleep wrapped in a cloak or in linen would be useless, for the gnats would bite through them; but they do not even attempt to get through the net’. If the people in the marsh-country used lamps, it must mean that, despite the mosquitoes, they stayed up some time before crawling under their nets. The mosquitoes in the marsh-country probably included a great number of Mansonia spp. that bite throughout the night. It could be argued that, given the high densities of mosquitoes reported, people would not have stayed up at all without a mosquito repellent.