Efficacy and safety of arachidonic acid for treatment of school-age children in Schistosoma mansoni high-endemicity regions

Rashida Barakat, Nadia E Abou El-Ela, Soraya Sharaf, Ola El Sagheer, Sahar Selim, Hatem Tallima, Maaike J Bruins, Kevin B Hadley, Rashika El Ridi, Rashida Barakat, Nadia E Abou El-Ela, Soraya Sharaf, Ola El Sagheer, Sahar Selim, Hatem Tallima, Maaike J Bruins, Kevin B Hadley, Rashika El Ridi

Abstract

Arachidonic acid (ARA), an omega-6 fatty acid, is a potent schistosomicide that displayed significant and safe therapeutic effects in Schistosoma mansoni-infected schoolchildren in S. mansoni low-prevalence regions. We here report on ARA efficacy and safety in treatment of schoolchildren in S. mansoni high-endemicity areas of Kafr El Sheikh, Egypt. The study was registered with ClinicalTrials.gov (NCT02144389). In total, 268 schoolchildren with light, moderate, or heavy S. mansoni infection were assigned to three study arms of 87, 91, and 90 children and received a single dose of 40 mg/kg praziquantel (PZQ), ARA (10 mg/kg per day for 15 days), or PZQ combined with ARA, respectively. The children were examined before and after treatment for stool parasite egg counts and blood biochemical, hematological, and immunological parameters. ARA, like PZQ, induced moderate cure rates (50% and 60%, respectively) in schoolchildren with light infection and modest cure rates (21% and 20%, respectively) in schoolchildren with high infection. PZQ and ARA combined elicited 83% and 78% cure rates in children with light and heavy infection, respectively. Biochemical and immunological profiles were either unchanged or ameliorated after ARA therapy. Combination of PZQ and ARA might be useful for treatment of children with schistosomiasis in high-endemicity regions.

© The American Society of Tropical Medicine and Hygiene.

Figures

Figure 1.
Figure 1.
Study flow chart. Only 268 of 353 positive children were included in the study based on the availability of ARA capsules shipped from DSM in Columbia, MD to Egypt.
Figure 2.
Figure 2.
Effect of ARA treatment on levels of IL-10 and IFN-γ in plasma of schoolchildren infected with S. mansoni and treated with PZQ, ARA, or PZQ + ARA. Columns represent mean plasma (A) IL-10 and (B) IFN-γ levels, and horizontal bars denote the SEM. Percentage reduction = mean cytokine level before treatment – mean cytokine level after treatment/mean cytokine level before treatment × 100 evaluated for each child 3 days after the end of ARA treatment corresponding to 24 days after PZQ. ***P < 0.0001 as calculated using paired and unpaired two-tailed Student's t test versus baseline.
Figure 3.
Figure 3.
Effect of ARA treatment on whole-blood culture cytokine responses of schoolchildren infected with S. mansoni. Columns represent the percentage of schoolchildren with whole-blood cultures responding to in vitro SAWA stimulation by release of type 2 (IL-4/IL-5) or type 1 (IFN-γ) cytokine before (baseline; 262 children) or after treatment with PZQ (84 children), ARA (90 children), or PZQ + ARA (87 children).

References

    1. Migliardo F, Tallima H, El Ridi R. Is there a sphingomyelin-based hydrogen bond barrier at the mammalian host-schistosome parasite interface? Cell Biochem Biophys. 2014;68:359–367.
    1. Migliardo F, Tallima H, El Ridi R. Rigidity and resistance of larval- and adult schistosomes-medium interface. Biochem Biophys Res Commun. 2014;446:255–260.
    1. Barsoum RS, Esmat G, El-Baz T. Human schistosomiasis: clinical perspective: review. J Adv Res. 2013;4:433–444.
    1. Gray DJ, McManus DP, Li Y, Williams GM, Bergquist R, Ross AG. Schistosomiasis elimination: lessons from the past guide the future. Lancet Infect Dis. 2010;10:733–736.
    1. Murray CJ, Ezzati M, Flaxman AD, Lim S, Lozano R, Michaud C, Naghavi M, Salomon JA, Shibuya K, Vos T, Wikler D, Lopez AD. GBD 2010: design, definitions, and metrics. Lancet. 2012;380:2063–2066.
    1. World Health Organization Schistosomiasis: population requiring preventive chemotherapy and number of people treated in 2010. Wkly Epidemiol Rec. 2012;87:37–44.
    1. Olliaro PL, Vaillant MT, Belizario VJ, Lwambo NJ, Ouldabdallahi M, Pieri OS, Amarillo ML, Kaatano GM, Diaw M, Domingues AC, Favre TC, Lapujade O, Alves F, Chitsulo L. A multicentre randomized controlled trial of the efficacy and safety of single-dose praziquantel at 40 mg/kg vs. 60 mg/kg for treating intestinal schistosomiasis in the Philippines, Mauritania, Tanzania and Brazil. PLoS Negl Trop Dis. 2011;5:e1165.
    1. Zwang J, Olliaro PL. Clinical efficacy and tolerability of praziquantel for intestinal and urinary schistosomiasis-A meta-analysis of comparative and non-comparative clinical trials. PLoS Negl Trop Dis. 2014;8:e3286.
    1. Erko B, Degarege A, Tadesse K, Mathiwos A, Legesse M. Efficacy and side effects of praziquantel in the treatment of Schistosomiasis mansoni in schoolchildren in Shesha Kekele Elementary School, Wondo Genet, southern Ethiopia. Asian Pac J Trop Biomed. 2012;2:235–239.
    1. Black CL, Steinauer ML, Mwinzi PN, Evan Secor W, Karanja DM, Colley DG. Impact of intense, longitudinal retreatment with praziquantel on cure rates of Schistosomiasis mansoni in a cohort of occupationally exposed adults in western Kenya. Trop Med Int Health. 2009;14:450–457.
    1. Webster BL, Diaw OT, Seye MM, Faye DS, Stothard JR, Sousa-Figueiredo JC, Rollinson D. Praziquantel treatment of school children from single and mixed infection foci of intestinal and urogenital schistosomiasis along the Senegal River Basin: monitoring treatment success and re-infection patterns. Acta Trop. 2013;128:292–302.
    1. Huyse T, Van den Broeck F, Jombart T, Webster BL, Diaw O, Volckaert FA, Balloux F, Rollinson D, Polman K. Regular treatments of praziquantel do not impact on the genetic make-up of Schistosoma mansoni in northern Senegal. Infect Genet Evol. 2013;18:100–105.
    1. Utzinger J, N'Goran EK, N'Dri A, Lengeler C, Tanner M. Efficacy of praziquantel against Schistosoma mansoni with particular consideration for intensity of infection. Trop Med Int Health. 2000;5:771–778.
    1. García N, Isturiz G, Aular S, Incani RN. The efficacy of human schistosomicide treatment may depend on the rate of transmission. Parasitol Res. 2006;98:545–549.
    1. Barakat R, El Morshedy H. Efficacy of two praziquantel treatments among primary school children in an area of high Schistosoma mansoni endemicity, Nile Delta, Egypt. Parasitology. 2011;138:440–446.
    1. King CH, Olbrych SK, Soon M, Singer ME, Carter J, Colley DG. Utility of repeated praziquantel dosing in the treatment of schistosomiasis in high-risk communities in Africa: a systematic review. PLoS Negl Trop Dis. 2011;5:e1321.
    1. Wang W, Wang L, Liang YS. Susceptibility or resistance of praziquantel in human schistosomiasis: a review. Parasitol Res. 2012;111:1871–1877.
    1. El Ridi R, Aboueldahab M, Tallima H, Salah M, Mahana N, Fawzi S, Mohamed SH, Fahmy OM. In vitro and in vivo activities of arachidonic acid against Schistosoma mansoni and Schistosoma haematobium. Antimicrob Agents Chemother. 2010;54:3383–3389.
    1. El Ridi R, Tallima H, Salah M, Aboueldahab M, Fahmy OM, Al-Halbosiy MF, Mahmoud SS. Arachidonic acid efficacy and mechanism of action in treatment of hamsters infected with Schistosoma mansoni or S. haematobium. Int J Antimicrob Agents. 2012;39:232–239.
    1. El Ridi RAF, Tallima HA-M. Novel therapeutic and prevention approaches for schistosomiasis: review. J Adv Res. 2013;4:467–478.
    1. El Ridi R, Tallima H. Solving the riddle of the lung-stage schistosomula paved the way to a novel remedy and an efficacious vaccine for schistosomiasis. In: El Ridi R, editor. Parasitic Diseases—Schistosomiasis. Rijeka, Croatia: InTech; 2013. pp. 179–202.
    1. Selim S, El Sagheer O, El Amir A, Barakat R, Hadley K, Bruins MJ, El Ridi R. Efficacy and safety of arachidonic acid for treatment of Schistosoma mansoni-infected children in Menoufiya, Egypt. Am J Trop Med Hyg. 2014;91:973–981.
    1. Kato K, Miura M. Comparative examinations of faecal thick smear techniques with cellophane paper covers. Kisechugaku Zasshi. 1954;3:35–37.
    1. Katz N, Chaves A, Pellegrino J. A simple device for quantitative stool thick-smear technique in Schistosomiasis mansoni. Rev Inst Med Trop Sao Paulo. 1972;14:397–400.
    1. El Ridi R, Farouk F, Sherif M, Al-Sherbiny M, Osman A, El Gengehi N, Shoemaker CB. T and B cell reactivity to a 42-kDa protein is associated with human resistance to both Schistosomiasis mansoni and haematobium. J Infect Dis. 1998;177:1364–1372.
    1. Barakat R, Farghaly A, el Masry AG, elSayed MK, Husein MH, Miller FD. Schistosoma mansoni in the Nile Delta, Egypt. A large scale epidemiological study in Kafr El Sheikh Governorate. Trop Geogr Med. 1995;47:259–265.
    1. Barakat R, el Masry AG, Farghaly A, el Morshidy HN, elSayed MK, Husein MH, Miller FD. Impact of population-based selective chemotherapy on prevalence and intensity of Schistosoma mansoni infections in the Nile Delta: Kafr El Sheikh. Trop Geogr Med. 1995;47:266–270.
    1. Barakat R, Farghaly A, Morshidy HN, el Sayed MK, Masry AG, Husein MH, Miller FD. Patterns of infection, incidence and reinfection with Schistosoma mansoni in Nile Delta Governorate: Kafr El Sheikh. Trop Geogr Med. 1995;47:270–277.
    1. Garba A, Lamine MS, Barkiré N, Djibo A, Sofo B, Gouvras AN, Labbo R, Sebangou H, Webster JP, Fenwick A, Utzinger J. Efficacy and safety of two closely spaced doses of praziquantel against Schistosoma haematobium and S. mansoni and re-infection patterns in school-aged children in Niger. Acta Trop. 2013;128:334–344.
    1. Barakat R, Farghaly A, El Morshedy H, Hassan M, Miller de W. Impact of National Schistosomiasis Control Program in Kafr El-Sheikh governorate, Nile Delta, Egypt: an independent evaluation. J Egypt Public Health Assoc. 1998;73:737–753.
    1. Greenberg RM. New approaches for understanding mechanisms of drug resistance in schistosomes. Parasitology. 2013;140:1534–1546.
    1. El Ridi R, Tallima H. Equilibrium in lung schistosomula sphingomyelin breakdown and biosynthesis allows very small molecules, but not antibody, to access proteins at the host-parasite interface. J Parasitol. 2006;92:730–737.
    1. Tallima H, Al-Halbosiy MF, El Ridi R. Enzymatic activity and immunolocalization of Schistosoma mansoni and Schistosoma haematobium neutral sphingomyelinase. Mol Biochem Parasitol. 2011;178:23–28.
    1. De Clercq D, Vercruysse J, Verle P, Kongs A, Diop M. What is the effect of combining artesunate and praziquantel in the treatment of Schistosoma mansoni infections? Trop Med Int Health. 2000;5:744–746.
    1. Utzinger J, Keiser J, Shuhua X, Tanner M, Singer BH. Combination chemotherapy of schistosomiasis in laboratory studies and clinical trials. Antimicrob Agents Chemother. 2003;47:1487–1495.
    1. Mohamed AA, Mahgoub HM, Magzoub M, Gasim GI, Eldein WN, Ahmed Ael A, Adam I. Artesunate plus sulfadoxine/pyrimethamine versus praziquantel in the treatment of Schistosoma mansoni in eastern Sudan. Trans R Soc Trop Med Hyg. 2009;103:1062–1064.
    1. Belton O, Fitzgerald DJ. The three major pathways involved in arachidonic acid metabolism. Expert Rev Mol Med. 2003;5:7.
    1. Seyberth HW, Oelz O, Kennedy T, Sweetman BJ, Danon A, Frölich JC, Heimberg M, Oates JA. Increased arachidonate in lipids after administration to man: effects on prostaglandin biosynthesis. Clin Pharmacol Ther. 1975;18:521–529.
    1. Nelson GJ, Schmidt PC, Bartolini G, Kelley DS, Kyle D. The effect of dietary arachidonic acid on platelet function, platelet fatty acid composition, and blood coagulation in humans. Lipids. 1997;32:421–425.
    1. Roberts MD, Iosia M, Kerksick CM, Taylor LW, Campbell B, Wilborn CD, Harvey T, Cooke M, Rasmussen C, Greenwood M, Wilson R, Jitomir J, Willoughby D, Kreider RB. Effects of arachidonic acid supplementation on training adaptations in resistance-trained males. J Int Soc Sports Nutr. 2007;4:21.
    1. Innis SM, Hansen JW. Plasma fatty acid responses, metabolic effects, and safety of microalgal and fungal oils rich in arachidonic and docosahexaenoic acids in healthy adults. Am J Clin Nutr. 1996;64:159–167.
    1. Turner JD, Meurs L, Dool P, Bourke CD, Mbow M, Dièye TN, Mboup S, Polman K, Mountford AP. Schistosome infection is associated with enhanced whole-blood IL-10 secretion in response to cercarial excretory/secretory products. Parasite Immunol. 2013;35:147–156.
    1. Joseph S, Jones FM, Walter K, Fulford AJ, Kimani G, Mwatha JK, Kamau T, Kariuki HC, Kazibwe F, Tukahebwa E, Kabatereine NB, Ouma JH, Vennervald BJ, Dunne DW. Increases in human T helper 2 cytokine responses to Schistosoma mansoni worm and worm-tegument antigens are induced by treatment with praziquantel. J Infect Dis. 2004;190:835–842.
    1. Leenstra T, Acosta LP, Wu HW, Langdon GC, Solomon JS, Manalo DL, Su L, Jiz M, Jarilla B, Pablo AO, McGarvey ST, Olveda RM, Friedman JF, Kurtis JD. T-helper-2 cytokine responses to Sj97 predict resistance to reinfection with Schistosoma japonicum. Infect Immun. 2006;74:370–381.
    1. Black CL, Muok EM, Mwinzi PN, Carter JM, Karanja DM, Secor WE, Colley DG. Increases in levels of schistosome-specific immunoglobulin E and CD23(+) B cells in a cohort of Kenyan children undergoing repeated treatment and reinfection with Schistosoma mansoni. J Infect Dis. 2010;202:399–405.
    1. Wilson S, Jones FM, Kenty LC, Mwatha JK, Kimani G, Kariuki HC, Dunne DW. Posttreatment changes in cytokines induced by Schistosoma mansoni egg and worm antigens: dissociation of immunity- and morbidity-associated type 2 responses. J Infect Dis. 2014;209:1792–1800.
    1. Betz M, Fox BS. Prostaglandin E2 inhibits production of Th1 lymphokines but not of Th2 lymphokines. J Immunol. 1991;146:108–113.
    1. Kelley DS, Taylor PC, Nelson GJ, Schmidt PC, Mackey BE, Kyle D. Effects of dietary arachidonic acid on human immune response. Lipids. 1997;32:449–456.
    1. Kelley DS, Taylor PC, Nelson GJ, Mackey BE. Arachidonic acid supplementation enhances synthesis of eicosanoids without suppressing immune functions in young healthy men. Lipids. 1998;33:125–130.
    1. Harbige LS. Fatty acids, the immune response, and autoimmunity: a question of n-6 essentiality and the balance between n-6 and n-3. Lipids. 2003;38:323–341.

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