Purchase on Springer.com
$49.95 / €39.95 / £34.95*
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.
Atovaquone/proguanil is a fixed-dose combination tablet of two antimalarial agents and is highly effective for the prevention of Plasmodium falciparum malaria. In combination with proguanil, the ability of atovaquone to inhibit parasitic mitochondrial electron transport is markedly enhanced. Both atovaquone and proguanil are active against hepatic (pre-erythrocytic) stages of P. falciparum, thereby providing causal prophylaxis and eliminating the need to continue post-travel treatment beyond 7 days. Both agents are also active against erythrocytic stages of P. falciparum, thereby providing suppressive prophylaxis. Atovaquone/proguanil is highly effective against drug-resistant strains of P. falciparum, and cross-resistance has not been observed between atovaquone and other anti-malarial agents.
In comparative, randomised clinical trials, there were no cases of P. falciparum malaria in nonimmune adults, adolescents and children (≥11kg) visiting malaria-endemic regions for ≤28 days and receiving atovaquone/proguanil (250/100mg in adults and dosage based on body weight in children <40kg) once daily. The efficacy for the prevention of P. falciparum malaria was estimated at 100% for atovaquone/proguanil and for mefloquine, and 70% for chloroquine plus proguanil. In individuals (≥11kg) from endemic regions who may carry some immunity to malaria (semi-immune), the prophylactic efficacy rating for atovaquone/proguanil based on placebo-controlled trials was 95–100%.
Atovaquone/proguanil is generally well tolerated by both adults and children. The most common treatment-related adverse events in placebo-controlled trials were headache and abdominal pain, which occurred at a rate similar to that observed with placebo. Atovaquone/proguanil therapy was associated with significantly fewer gastrointestinal adverse events than chloroquine plus proguanil, and significantly fewer neuropsychiatric adverse events than mefloquine in nonimmune individuals. Significantly fewer recipients of atovaquone/proguanil discontinued treatment because of adverse events than individuals receiving chloroquine plus proguanil or mefloquine (p < 0.05).
Conclusion: Atovaquone/proguanil is a fixed-dose combination antimalarial tablet that provides effective prophylaxis of P. falciparum malaria, including drug-resistant strains. Both atovaquone and proguanil are effective against hepatic stages of P. falciparum, which means that treatment need only continue for 7 days after leaving a malaria-endemic region. Atovaquone/proguanil was generally well tolerated and was associated with fewer gastrointestinal adverse events than chloroquine plus proguanil, and fewer neuropsychiatric adverse events than mefloquine. Thus, atovaquone/proguanil provides effective prophylaxis of P. falciparum malaria and compared with other commonly used antimalarial agents has an improved tolerability profile, and, overall, a more convenient dosage regimen, particularly in the post-travel period.
Atovaquone, a hydroxynaphthoquinone, selectively inhibits parasitic mitochondrial electron transport. Although resistance rapidly develops when atovaquone is used as a single agent against Plasmodium falciparum malaria, in combination with proguanil (a biguanide), its activity is enhanced, thereby reducing the likelihood of the emergence of resistance. Cycloguanil, the primary metabolite of proguanil, acts as a parasite dihydrofolate reductase inhibitor. The enhancement of the atovaquone effect, however, is a result of synergy with proguanil, and although this mechanism is not well understood, it is not thought to involve dihydrofolate reductase inhibition.
Both atovaquone and proguanil are active against pre-erythrocytic (hepatic) stages of P. falciparum, thereby providing causal prophylaxis. Both compounds are also active against the erythrocytic parasite stage (suppressive prophylaxis). Atovaquone was more active against various clones and isolates of P. falciparum in the erythrocytic stage than other antimalarial drugs in in vitro studies. The mean 50% inhibitory plasma concentrations (IC50) of atovaquone (0.7–4.3 nmol/L) were lower than those of chloroquine, quinine, mefloquine and artemether against various isolates of P. falciparum. Atovaquone showed similar activity against both chloroquine-sensitive and -resistant isolates of P. falciparum.
Atovaquone/proguanil 250/100mg once daily demonstrated effective causal prophylaxis of P. falciparum malaria in a double-blind, placebo-controlled study in healthy volunteers (n = 16). Parasitaemia was eliminated in all volunteers who received 8 days’ prophylaxis with atovaquone/proguanil and, on day 2, were challenged with bites from mosquitoes infected with P. falciparum malaria; i.e. parasitaemia was eliminated before erythrocytic-stage infection developed. All placebo recipients (n = 4) developed parasitaemia.
Cross-resistance between atovaquone and other antimalarial agents has not been observed in vitro or in malaria rodent models, possibly due to different target sites.
There were no clinically relevant effects on the pharmacokinetic profiles of atovaquone, proguanil or cycloguanil after oral administration of single or multiple doses of a fixed combination tablet of atovaquone/proguanil 250/100mg once daily for 13 days.
Atovaquone is highly lipophilic with low aqueous solubility and shows linear pharmacokinetics, when administered with food, over a dose range of 100–750mg. The drug is poorly absorbed unless taken with fatty food, which increases maximum plasma concentrations (Cmax) by approximately 5-fold. Following a single dose of atovaquone/proguanil 250/100mg, there is a high degree of inter-individual variability in Cmax, although this variability decreased at steady-state. The mean absolute bioavailability of atovaquone when taken with food is 23%. Atovaquone is highly protein bound (>99%) but does not appear to displace other highly protein-bound compounds. There is no apparent accumulation of atovaquone following multiple doses.
The metabolism of atovaquone in humans appears to be negligible. The main route of elimination is hepatic and negligible amounts are excreted in the urine (<1%). The elimination half-life (t1/2) of atovaquone was similar after single or multiple doses (87.2 and 55.9 hours, respectively). Atovaquone clearance increases by almost 2-fold in children compared with adults.
Proguanil shows linear pharmacokinetics and is rapidly and extensively absorbed regardless of food intake. The absolute bioavailability of proguanil is thought to be as high as 60%, and 75% of the drug is bound to plasma protein. Proguanil primarily localises in erythrocytes with concentrations in whole blood approximately 5-fold higher than those in plasma.
Proguanil is metabolised to cycloguanil and to a lesser extent to 4-chlorophenyl biguanide. Metabolism to cycloguanil is mediated primarily via the cytochrome P450 (CYP)2C19 pathway but differences in absorption parameters and t1/2 for proguanil and cycloguanil between extensive and poor CYP2C19 metabolisers were not clinically relevant (13.1 vs 14.5 hours at steady-state). The main route of elimination of proguanil is via renal excretion.
In children, the pharmacokinetic parameters of proguanil and cycloguanil are similar to adults. In patients with severe renal impairment (creatinine clearance <1.8 L/h [<30 ml/min]) there is an increased risk of accumulation of proguanil and more markedly of cycloguanil. The systemic availability of cycloguanil was raised in the elderly compared with younger individuals but this did not appear to be clinically relevant.
Plasma concentrations of atovaquone are decreased when coadministered with rifampicin (rifampin), rifabutin, metoclopramide or tetracycline. Drug interactions between proguanil or cycloguanil and other agents metabolised by the CYP2C19 pathway have not been demonstrated.
In three, large (n > 185) randomised trials in nonimmune adults and children (weighing 11–40kg) visiting malaria-endemic regions for up to 28 days, there were no cases of P. falciparum malaria in individuals receiving oral atovaquone/proguanil (250/100mg in adults and dosage based on bodyweight in children <40kg) once daily. In nonimmune travellers, the efficacy rating for the prevention of P. falciparum malaria was estimated at 100% for atovaquone/proguanil and for mefloquine, and 70% for chloroquine plus proguanil. In a placebo-controlled trial in nonimmune migrants receiving atovaquone/proguanil for the prevention of P. falciparum malaria for 20 weeks, the prophylactic efficacy was 96%.
In three randomised, double-blind, placebo-controlled trials in semi-immune adults and children (i.e. those living in malaria-endemic regions), atovaquone/proguanil was significantly more effective in the prevention of P. falciparum malaria than placebo (p < 0.001), and the overall prophylactic efficacy rating was 95–100%.
The prophylactic regimen of atovaquone/proguanil once daily, for periods of up to 5 months in nonimmune and up to 3 months in semi-immune individuals, was generally well tolerated in clinical trials including more than 3000 adults and children. Overall, the most common adverse events in recipients of atovaquone/proguanil were headache (approximately 4% of adults) and abdominal pain (approximately 4% of adults), which occurred at a rate similar to that observed with placebo.
Atovaquone/proguanil 250/100mg (dosage reduced in children) once daily was at least as well tolerated as comparator agents. In nonimmune travellers atovaquone/proguanil was associated with significantly fewer gastrointestinal adverse events (p = 0.001) than chloroquine plus proguanil (participants aged ≥14 years), and significantly fewer neuropsychiatric adverse events (p = 0.001) and less nausea (p = 0.001) than mefloquine (participants aged ≥3 years). Compared with chloroquine plus proguanil, or mefloquine, atovaquone/proguanil was associated with a significantly lower incidence of treatment-related adverse events (i.e. events that started while the individual was taking the study drug) that lead to withdrawal of prophylaxis (p < 0.05). Eight weeks’ treatment with atovaquone/proguanil 250/100mg daily appeared to be better tolerated than doxycycline in nonimmune adult volunteers.
In nonimmune children (11–40kg), atovaquone/proguanil (dosage based on bodyweight) once daily was associated with fewer treatment-related gastrointestinal adverse events than chloroquine plus proguanil. In a study of semi-immune children, atovaquone/proguanil and placebo were associated with a higher incidence of abdominal pain, vomiting and headache than that reported by adults, but all events were considered mild. Atovaquone/proguanil was at least as well tolerated in the elderly (>65 years) [n = 47] as it was in the entire study population (≥3 years) [n = 1998].
Dosage and Administration
For prophylaxis of P. falciparum malaria in adults, the fixed-dose combination tablet of atovaquone/proguanil 250/100mg should be administered once daily. Dosage in children is based on bodyweight, with a paediatric tablet containing atovaquone/proguanil 62.5/25mg available for children weighing 11–40kg.
Atovaquone/proguanil should be taken at the same time each day with food or a milky drink to maximise absorption. Treatment should be started 1 or 2 days before entering a malaria-endemic area, continued during the stay and for 7 days after leaving the region. If vomiting occurs within 1 hour of administration, a repeat dose should be taken.
Atovaquone/proguanil is contraindicated in patients with severe renal impairment (creatinine clearance 1.8 L/h [<30 ml/min]). Dosage adjustment is not required in the elderly. Concomitant administration of atovaquone/proguanil is not recommended with rifampicin or rifabutin. P. falciparum malaria carries an increased risk in pregnancy both to the mother and the fetus and, if possible, pregnant women should not travel to malaria-endemic regions. Breast feeding is not recommended while receiving atovaquone/proguanil therapy.
- Kain KC. Prophylactic drugs for malaria: why do we need another one? J Travel Med 1999; 6 Suppl. 1: S2–7
- Bradley DJ, Bannister B. Guidelines for malaria prevention in travellers from the United Kingdom for 2001. Advisory Committee on Malaria Prevention for UK Travellers. Commun Dis Public Health 2001; 4(2): 84–101
- Goodyear L. Malaria. Pharm J 2000; 264: 405–10
- Kain KC, Shanks GD, Keystone JS. Malaria chemoprophylaxis in the age of drug resistance. I. Currently recommended drug regimens. Clin Infect Dis 2001; 33(2): 226–34 CrossRef
- Palmer KJ, Holliday SM, Brogden RN. Mefloquine: a review of its antimalarial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 1993; 45(3): 430–75 CrossRef
- Baird JK, Hoffman L. Prevention of malaria in travelers. Travel Medicine 1999; 83(4): 923–44
- Fry M, Pudney M. Site of action of the antimalarial hydroxynaphthoquinone, 2-[trans-4-(4′-chlorophenyl) cyclohexyl]-3-hydroxy-l, 4-naphthoquinone (566C80). Biochem Pharmacol 1992; 43(7): 1545–53 CrossRef
- Spencer CM, Goa KL. Atavaquone: a review of its pharmacological properties and therapeutic efficacy in opportunistic infections. Drugs 1995; 50(1): 176–96 CrossRef
- Hudson AT, Dickins M, Ginger CD, et al. 566C80: a potent broad spectrum anti-infective agent with activity against malaria and opportunistic infections in AIDS patients. Drugs Exptl Clin Res 1991; 17(9): 427–35
- Basco LK, Ramiliarisoa O, Le Bras J. In vitro activity of atovaquone against the African isolates and clones of Plasmodium falciparum. Am J Trop Med Hyg 1995; 53(4): 388–91
- Gay F, Bustos D, Traore B, et al. In vitro response of Plasmodium falciparum to atovaquone and correlation with other antimalarials: comparison between African and Asian strains. Am J Trop Med Hyg 1997; 56(3): 315–7
- Davies CS, Suhrbier AS, Winger L.A., et al. Improved techniques for the culture of the liver stages of Plasmodium berghei and their relevance to the study of causal prophylactic drugs. Acta Leiden 1989; 58(2): 97–113
- Davies CS, Pudney M, Matthews PJ, et al. The causal prophylactic activity of the novel hydroxynaphthoquinone 566C80 against Plasmodium berghei infections in rats. Acta Leiden 1989; 58(2): 115–28
- Shapiro TA, Ranasinha CD, Kumar N, et al. Prophylactic activity of atovaquone against Plasmodium falciparum in humans. Am J Trop Med Hyg 1999; 60(5): 831–6
- Watkins WM, Sixsmith DG, Chulay JD. The activity of proguanil and its metabolites, cycloguanil and p-chlorophenylbiguanide, against Plasmodium falciparum in vitro. Ann Trop Med Parasitol 1984; 78(3): 273–8
- Srivastava IK, Vaidya AB. A mechanism for the synergistic antimalarial action of atovaquone and proguanil. Antimicrob Agents Chemother 1999 Jun; 43(6): 1334–9
- Canfield CJ, Pudney M, Gutteridge WE. Interactions of atovaquone with other antimalarial drugs against Plasmodium falciparum in vitro. Exp Parasitol 1995 May; 80: 373–81 CrossRef
- Enosse S, Butcher GA, Margos G, et al. The mosquito transmission of malaria: the effects of atovaquone-proguanil (Malarone) and chloroquine. Trans R Soc Trop Med Hyg 2000 Jan; 94(1): 77–82 CrossRef
- Berman JD, Nielsen R, Chulay JD, et al. Causal prophylactic efficacy of atovaquone-proguanil (Malarone) in a human challenge model. Trans R Soc Trop Med Hyg 2001 Jul; 95(4): 429–32 CrossRef
- GlaxoSmithKline. Malarone: US Prescribing Information [online]. Available from URL: http://www.gsk.com [Accessed 2002 Oct 10]
- Winstanley PA, Ward SA, Snow RW. Clinical status and implications of antimalarial drug resistance. Microbes Infect 2002 Feb; 4(2): 157–64 CrossRef
- White NJ. Drug resistance in malaria. Br Med Bull 1998; 54(3): 703–15 CrossRef
- Vaidya AB, Mather MW. Atovaquone resistance in malaria parasites. Drug Resist Update 2000; 3(5): 283–7 CrossRef
- Korsinczky M, Chen N, Kotecka B, et al. Mutations in Plasmodium falciparum cytochrome b that are associated with atovaquone resistance are located at a putative drug-binding site. Antimicrob Agents Chemother 2000 Aug; 44(8): 2100–8 CrossRef
- Looareesuwan S, Viravan C, Webster HK, et al. Clinical studies of atovaquone, alone or in combination with other antimalarial drugs, for treatment of acute uncomplicated malaria in Thailand. Am J Trop Med Hyg 1996; 54(1): 62–6
- Foote SJ, Galatis D, Cowman AF. Amino acids in the dihydrofolate reductase-thymidylate synthase gene of Plasmodium falciparum involved in cycloguanil resistance differ from those involved in pyrimethamine resistance. Proc Natl Acad Sci USA 1990; 87: 3014–7 CrossRef
- Khan B, Omar S, Kanyara JN, et al. Antifolate drug resistance and point mutations in Plasmodium falciparum in Kenya. Trans R Soc Trop Med Hyg 1997; 91: 456–60 CrossRef
- Peterson DS, Walliker D, Wellems TE. Evidence that a point mutation in dihydrofolate reductase-thymidylate synthase confers resistance to pyrimethamine in falciparum malaria. Proc Natl Acad Sci USA 1988; 85: 9114–8 CrossRef
- Fidock DA, Wellems TE. Transformation with human dihydrofolate reductase renders malaria parasites insensitive to WR99210 but does not affect the intrinsic activity of proguanil. Proc Natl Acad Sci USA 1997; 94: 10931–6 CrossRef
- Shanks GD, Gordon DM, Klotz FW, et al. Efficacy and safety of atovaquone/proguanil as suppressive prophylaxis for Plasmodium falciparum malaria. Clin Infect Dis 1998 Sep; 27(3): 494–9 CrossRef
- Fivelman QL, Butcher GA, Adagu IS, et al. Malarone treatment failure and in vitro confirmation of resistance of Plasmodium falciparum isolate from Lagos, Nigeria. Malaria J 2002; 1(1): 1–3 CrossRef
- Thapar MM, Ashton M, Lindegardh N, et al. Time-dependent pharmacokinetics and drug metabolism of atovaquone plus proguanil (Malarone) when taken as chemoprophylaxis. Eur J Clin Pharmacol 2002 Apr; 58(1): 19–27 CrossRef
- Beerahee M, Clarke P, Overbosch D, et al. Prophylaxis with Malarone (atovaquone and proguanil hydrochloride) in non-immune subjects 65 years of age and older [poster]. Proceedings of Third European Conference on Travel Medicine; 2002 May 15–18; Florence
- Sabchareon A, Attanath P, Phanuaksook P, et al. Efficacy and pharmacokinetics of atovaquone and proguanil in children with multidrug-resistant Plasmodium falciparum malaria. Trans R Soc Trop Med Hyg 1998; 92: 201–6 CrossRef
- Hussein Z, Eaves J, Hutchinson DB, et al. Population pharmacokinetics of atovaquone in patients with acute malaria caused by Plasmodium falciparum. Clin Pharmacol Ther 1997: 61(5): 518–30 CrossRef
- Rolan PE, Mercer AJ, Weatherley BC, et al. Examination of some factors responsible for a food-induced increase in absorption of atovaquone. Br J Clin Pharmac 1994; 37: 13–20 CrossRef
- Beerahee M. Clinical pharmacology of atovaquone and proguanil hydrochloride. J Travel Med 1999; 6 Suppl. 1: S13–7
- GlaxoSmithKline. Malarone: atovaquone/proguanil hydrochloride [product monograph]. United Kingdom: GlaxoSmithKline, 2001 Jul
- Hughes WT, Kennedy W, Shenep JL, et al. Safety and pharmacokinetics of 566C80, a hydroxynaphthoquinone with anti-Pneumocystis carinii activity: a phase I study in human immunodeficieny virus (HlV)-infected men. J Infect Dis 1991; 163(4): 843–8 CrossRef
- Hussein Z, Eaves CJ, Hutchinson DB, et al. Population pharmacokinetics of proguanil in patients with acute P. falciparum malaria after combined therapy with atovaquone. Br J Clin Pharmacol 1996 Nov; 42: 589–97
- Wattanagoon Y, Taylor RB, Moody RR, et al. Single dose pharmacokinetics of proguanil and its metabolites in healthy subjects. Br J Clin Pharmacol 1987; 24: 775–80 CrossRef
- Gillotin C, Mamet JP, Veronese L. Lack of a pharmacokinetic interaction between atovaquone and proguanil. Eur J Clin Pharmacol 1999 Jun; 55(4): 311–5 CrossRef
- Helsby NA, Edwards G, Breckenridge A.M., etal. The multiple dose pharmacokinetics of proguanil. Br J Clin Pharmacol 1993; 35: 653–6 CrossRef
- Funck-Brentano C, Becquemont L, Leneveu A, et al. Inhibition by omeprazole of proguanil metabolism: mechanism of the interaction in vitro and prediction of in vivo results from the in vitro experiments. J Pharmacol Exp Ther 1997; 280(2): 730–8
- Birkett DJ, Rees D, Andersson T, et al. In vitro proguanil activation to cycloguanil by human liver microsomes is mediated by CYP3A isoforms as well as by S-mephenytoin hydroxylase. Br J Clin Pharmac 1994; 37: 413–20 CrossRef
- Helsby NA, Ward SA, Edwards G, et al. The pharmacokinetics and activation of proguanil in man: consequences of variability in drug metabolism. Br J Clin Pharmacol 1990; 30(4): 593–8 CrossRef
- Edstein MD, Yeo AET, Kyle DE, et al. Proguanil polymorphism does not affect the antimalarial activity of proguanil combined with atovaquone in vitro. Trans R Soc Trop Med Hyg 1996 Jul; 90: 418–21 CrossRef
- Looareesuwan S, Chulay JD, Canfield CJ, et al. Malarone (atovaquone and proguanil hydrochloride): a review of its clinical development for treatment of malaria. Am J Trop Med Hyg 1999; 60(4): 533–41
- van Vugt M, Edstein MD, Proux S, et al. Absence of an interaction between artesunate and atovaquone—proguanil. Eur J Clin Pharmacol 1999 Aug; 55(6): 469–74 CrossRef
- High B, Clarke PD, Camus D, et al. Atovaquone-proguanil versus chloroquine-proguanil for malaria prophylaxis in non-immune travellers: a randomised, double-blind study. Malarone International Study Team. Lancet 2000 Dec 2; 356(9245): 1888–94
- Overbosch D, Schilthuis H, Bienzle U, et al. Atovaquone-proguanil versus mefloquine for malaria prophylaxis in nonimmune travelers: results from a randomized, double-blind study. Clin Infect Dis 2001 Oct 1; 33(7): 1015–21 CrossRef
- Camus D, Malvy D, Schilthuis H, et al. Atovaquone/proguanil versus chloroquine/proguanil or mefloquine in clinical trials of non-immune paediatric travellers ll-40kg [poster]. Proceedings of Third European Conference on Travel Medicine; 2002 May 15–18; Florence
- Nasveld PE, Edstein MD, Kitchener SJ, et al. Comparison of the effectiveness of atovaquone/proguanil combination and doxycycline in the chemoprophylaxis of malaria in Australian Defence Force personnel [abstract no. 16]. Am J Trop Med Hyg 2000; 62(3): 139
- van der Berg JD, Duvenage CSJ, Roskeil NS, et al. Safety and efficacy of atovaquone and proguanil hydrochloride for the prophylaxis of Plasmodium falciparum malaria in South Africa. Clin Ther 1999; 21(4): 741–9 CrossRef
- Ling J, Baird JK, Fryauff DJ, et al. Randomized, placebocontrolled trial of atovaquone/proguanil for the prevention of Plasmodium falciparum or Plasmodium vivax malaria among migrants to Papua, Indonesia. Clin Infect Dis 2002 Oct 1; 35(7): 825–33 CrossRef
- Sukwa TY, Mulenga M, Chisdaka N, et al. A randomized, double-blind, placebo-controlled field trial to determine the efficacy and safety of Malarone (atovaquone/proguanil) for the prophylaxis of malaria in Zambia. Am J Trop Med Hyg 1999 Apr; 60(4): 521–5
- Lell B, Luckner D, Ndjave M, et al. Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children. Lancet 1998; 351(9104): 709–13 CrossRef
- White NJ. The development of immunity to malaria (a clinical view). Asian Pac J Allergy Immunol 1993; 11: 1–3
- Nosten F. Prophylactic effect of Malarone against malaria: all good news? Lancet 2000 Dec 2; 356(9245): 1864–5 CrossRef
- Boots M, Phillips M, Curtis JR. Megaloblastic anemia and pancytopenia due to proguanil in patients with chronic renal failure. Clin Nephrol 1982; 18(2): 106–8
- Sirsat RA, Dasgupta A. Haematological complications of proguanil in a patient with chronic renal failure. Nephron 1997; 75: 108 CrossRef
- van Riemsdijk MM, Sturkenboom MCJM, Ditters JM, et al. Atovaquone plus chloroguanide versus mefloquine for malaria prophylaxis: a focus on neuropsychiatric adverse events. Clin Pharmacol Ther 2002; 72(3): 294–301 CrossRef
- GlaxoSmithKline. Malarone: UK Prescribing Information [online]. Available from URL: http://www.gsk.com [Accessed 2002 Apr 5]
- Vidal. Malarone [online]. Available from URL: http://www.vidalpro.net [Accessed 2003 Feb 20]
- World Health Organization. International travel and health [online]. Available from URL: http://www.who/ith [Accessed 2002 Jun 19]
- Olukayode Oyediran ABO, Heisler MH. Malarone™ donation program. J Travel Med 1999; 6 Suppl. 1: S28–30
- Nosten F, Brasseur P. Combination therapy for malaria: the way forward? Drugs 2002; 62(9): 1315–29 CrossRef
- Ryan ET, Kain KC. Primary care: health advice and immunizations for travelers. N Engl J Med 2000; 342(23): 1716–25 CrossRef
- Luxemburger C, Nosten F, Ter Kuiile F, et al. Mefloquine for multidrug-resistant malaria [letter]. Lancet 1991; 338: 1268 CrossRef
- he Cheshire Medical Center. Doxycycline (Vibramycin) [online]. Available from URL: http://www.cheshire-med.com/services/pharm [Accessed 2002 Sep 2]
- enters for Disease Control and Prevention. Travellers Health[online]. Available from URL: http://www.cdc.gov [Accessed 2002 Sep 2]
Volume 63, Issue 6 , pp 597-623
- Cover Date
- Print ISSN
- Online ISSN
- Springer International Publishing
- Additional Links